Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med 2013;368: DOI: /NEJMoa

2 RE: Randomized Phase 3 Trial of Abiraterone Acetate in Men with Metastatic Castration Resistant Prostate Cancer and No Prior Chemotherapy This supplement contains the following items: 1. Original protocol, final protocol, summary of changes. 2. Original statistical analysis plan, final statistical analysis plan, summary of changes

3 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Clinical Study Protocol: COU-AA-302 Study Title: A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer Study Number: COU-AA-302 Study Phase: 3 Product Name: Abiraterone acetate IND Number: EudraCT No: 71, Indication: Treatment of Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer Investigators: Multicenter Sponsor: Cougar Biotechnology, Inc. Sponsor Clinical Contact: Sponsor Medical Monitor: Haneefa Wawda, MPH Associate Clinical Trial Manager Cougar Biotechnology Wilshire Blvd, Los Angeles, CA Phone: (310) Ext. 162 Fax: hwawda@cougarbiotechnology.com Thomas Griffin, MD Vice-President, Clinical Research and Development Cougar Biotechnology Wilshire Blvd, Los Angeles, CA Phone: (310) Ext. 177 Fax: tgriffin@cougarbiotechnology.com Arturo Molina, MD, MS Chief Medical Officer Cougar Biotechnology Wilshire Blvd., Los Angeles, CA Phone: (310) Ext. 124 Fax: amolina@cougarbiotechnology.com Date Version Original Protocol: Feb. 11, Confidentiality Statement This document contains confidential information of Cougar Biotechnology, Inc. This document must not be disclosed to anyone other than the study staff and members of the Independent Ethics Committee/Institutional Review Board. The information in this document cannot be used for any purpose other than the evaluation or conduct of the clinical investigation without the prior written consent of Cougar Biotechnology, Inc Confidential Page 1 of 96

4 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 SYNOPSIS Sponsor: Cougar Biotechnology, Inc. Name of Finished Product: Abiraterone acetate tablets Name of Active Ingredient: Abiraterone acetate Study Title: A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer Study Number: COU-AA-302 Study Phase: 3 Primary Objective: To compare the clinical benefit of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with chemotherapy-naïve castration-resistant prostate cancer (CRPC) who are asymptomatic or mildly symptomatic Secondary Objectives: To establish additional clinically relevant improvements in prostate cancer patients treated with abiraterone acetate in comparison to placebo To characterize the safety profile of abiraterone acetate in this patient population To characterize the pharmacokinetics of abiraterone acetate when administered concurrently with prednisone Study Design: This study is a multinational, multicenter, randomized, double-blind placebo-controlled study with a randomization allocation ratio of 1:1 between the abiraterone acetate group and the placebo group. Abiraterone acetate and placebo tablets will be referred to as study drug in a blinded fashion. Patients randomized to the abiraterone acetate group will receive a dose of 1000 mg daily (QD). Study drug will be administered as 4 x 250-mg abiraterone acetate tablets or 4 placebo tablets. Prednisone will be administered as 5 mg orally twice a day (BID) for both groups. Randomization will be stratified according to the following: ECOG performance status: 0 versus 1 Study Population: Approximately 1,000 medically or surgically castrated male patients with metastatic CRPC who have shown tumor progression and are non- or mildly-symptomatic will be enrolled from approximately 150 global study sites. Confidential Page 2 of 96

5 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Test Product, Dose, and Mode of Administration: Abiraterone acetate (CB7630), 1000 mg/day (4 x 250-mg tablets), or matching placebo given orally Duration of Treatment: Patients will have a screening period of up to 14 days prior to randomization on Cycle 1 Day 1. Each cycle consists of 28 days. Patients will be treated until disease progression as defined in the protocol. After discontinuing study treatment, patients will be contacted once every three months up to 60 months (5 years) for survival follow-up. In addition to overall survival, opiate use, ECOG performance status, and next therapy for prostate cancer (including dose and treatment duration of cytotoxic chemotherapy) will also be collected. Efficacy Assessment: The primary efficacy endpoints are Overall Survival (OS) and Radiographic Progression- Free Survival (rpfs) (co-primary). Efficacy assessment in rpfs will utilize sequential imaging studies as defined by PCWG2 and modified RECIST criteria. Survival data will be collected throughout the study treatment phase and during follow-up. Secondary efficacy assessments: Time to opiate use for cancer-related pain and time to administration of cytotoxic chemotherapy for metastatic prostate cancer will be prospectively assessed. ECOG performance status will be evaluated throughout the study to assess time to first deterioration. PSA values will be collected throughout the study to assess time to PSA progression. Safety Assessments: Medical history, vital sign measurements, physical examination, and body weight Concomitant therapy and procedures Adverse events (AEs) and serious adverse events (SAEs), including laboratory test AEs will be graded and summarized according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 Blood chemistry, hematology, coagulation studies, serum lipids, and urinalysis Electrocardiograms (ECGs) Other Assessments: Quality of Life (QoL) using FACT-P Quality of Life questionnaire Medical resource utilization (MRU) information PK measurements at selected sites TMPRSS2-ERG in primary tumor or in circulating tumor cells (CTC s) at selected sites Confidential Page 3 of 96

6 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 TABLE OF CONTENTS CLINICAL STUDY PROTOCOL: COU-AA SYNOPSIS...2 TABLE OF CONTENTS...4 LIST OF IN-TEXT TABLES...8 LIST OF IN-TEXT FIGURES...8 LIST OF APPENDICES...8 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS INTRODUCTION Metastatic Castrate Resistant Prostate Cancer Asymptomatic or Mildly Symptomatic Patients with Castrate Resistant Prostate Cancer Second line hormonal therapies for CRPC Adrenal Androgen Inhibitor Glucocorticoids Estrogens Chemotherapy and Bisphosphonates for CRPC Abiraterone Acetate (CB7630) and the Active Metabolite Abiraterone (CB7598) Dosing Rationale Concurrent Prednisone Status of Current Clinical Trials of Abiraterone Acetate Chemotherapy-Naïve Castration-Resistant Prostate Cancer (CRPC) Castration-Resistant Prostate Cancer (CRPC) Post-Docetaxel Clinical Benefits of Current Treatment Quality of Life Assessments Rationale for Study Design and Control Group Radiographic PFS as an Efficacy Endpoint STUDY OBJECTIVES Primary Objective(s) Secondary Objective(s) INVESTIGATIONAL PLAN Overall Study Design and Plan Primary Efficacy Endpoints Secondary Efficacy Endpoints Other Study Endpoints Safety Assessments Other Assessments...27 Confidential Page 4 of 96

7 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Study Duration and Dates Study Activities Screening Period Randomization Treatment Period Follow-up Period STUDY POPULATION SELECTION Study Population Inclusion Criteria Exclusion Criteria STUDY TREATMENT(S) Description of Treatment(s) Treatments Administered Abiraterone Acetate/Placebo Prednisone Selection and Timing of Dose for Each Patient Randomization Procedures Stratification Blinding Randomization Codes Laboratory Tests Results Accidental Unblinding Concomitant Therapy Prohibited Concomitant Medication Restrictions Potential for Drug-Drug Interactions Treatment Compliance Packaging and Labeling Storage Pharmacy Storage Requirements Storage Requirements For The Patient Investigational Product Retention and Accountability at Study Site STUDY PROCEDURES Informed Consent Medical History Physical Examination Clinical Laboratory Tests Laboratory Parameters Pharmacokinetics (PK) Assessments and Additional ECG Monitoring...40 Confidential Page 5 of 96

8 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, TMPRSS Sample Collection, Storage, and Shipping SAFETY DATA COLLECTION, RECORDING, AND REPORTING Definitions Adverse Events Serious Adverse Events Suspected Unexpected Serious Adverse Reactions (SUSARS) Reporting Procedures for All Adverse Events Severity of Adverse Events Serious Adverse Event Reporting Procedures Long-Term Follow-Up Abnormal Laboratory Results Management of Study Drug-Related Events Management of Hypokalemia Management of Hypertension Side Effects Management of Edema, Fluid Retention Management of Abnormal Liver Function Tests Management of Non-Mineralocorticoid Based Side Effects Dose-Reduction Procedure for Adverse Event Management Criteria for Discontinuation of Study Treatment Withdrawal from Study Treatment Phase STUDY ACTIVITIES Screening Period (Days 14 to Day 1) Treatment Period (Cycle 1 Day 1 to End of Study Treatment) Cycle 1 Day Cycle 1 Day 15 Visit Cycles 2, 4, 6, 8, 9, 11, and 12 Day 1 (Continue every 1 st and 2 nd cycle Beyond Cycle 10, e.g. Cycles 11, 12, 14, 15, 17, 18, 20, 21 ) Day 15 of Cycles 2 and Cycles 3, 5, 7, and 10 (continue every 3 rd cycle beyond Cycle 10, e.g. Cycles 13, 16, 19, 22 ) and Treatment Discontinuation Visit End of Study Treatment Visit Unscheduled Visits Post-Treatment Follow-up Period (Survival or Long-Term Follow-Up) QUALITY CONTROL AND ASSURANCE PLANNED STATISTICAL METHODS General Considerations Determination of Sample Size Sample Size Determination...59 Confidential Page 6 of 96

9 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Hypothesized OS Hazard Ratio of Hypothesized rpfs Hazard Ratio of Interim and Final Analyses Analysis Populations Demographics and Baseline Characteristics Study Endpoint(s) Efficacy Endpoint(s) Efficacy Analysis Population and Methods Safety Evaluations Safety Analysis Population and Methods: Pharmacokinetics Analysis Other Assessments or Analyses ADMINISTRATIVE CONSIDERATIONS Investigators and Study Administrative Structure Investigator Responsibilities Protocol Adherence and Investigator Agreement Institutional Review Board (IRB) or Independent Ethics Committee (IEC) Approval Ethical Conduct of the Study Patient Information and Consent Patient Confidentiality Study Monitoring Case Report Forms Laboratory Assessments Independent Data Monitoring Committee (IDMC) Central Radiologic Review Protocol Violations/Deviations Access to Source Documentation Retention of Data Financial Disclosure Study Publication Guidelines and Disclosure Policy First Publication Subsequent Publications REFERENCE LIST...70 Confidential Page 7 of 96

10 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 LIST OF IN-TEXT TABLES Table 1. Inhibition of Cytochrome P450 Enzymes by abiraterone acetate and abiraterone...36 Table 2. List of Laboratory Tests...39 Table 3. Hypokalemia Management...46 LIST OF IN-TEXT FIGURES Figure 1. The Enzyme Complexes Inhibited by Abiraterone...19 Figure 2. Prodrug Abiraterone Acetate is Converted to Abiraterone after Absorption...19 LIST OF APPENDICES Appendix 1: Schedule of Events...77 Appendix 2: Study Treatment Preparation and Dispensing Instructions...80 Appendix 3: Protocol-Specific PCWG2 Criteria...81 Appendix 4: Modified Response Evaluation Criteria in Solid Tumors (RECIST) 82 Appendix 5: National Cancer Institute Common Terminology Criteria for AEs...86 Appendix 6: ECOG Performance Status...87 Appendix 7: Creatinine Clearance...88 Appendix 8: Brief Pain Inventory (Short Form)...89 Appendix 9: Quality of Life...91 Appendix 10: Protocol Definition of Chronic Administration of Opiate Analgesia 94 Appendix 11: Sponsor Signatures...95 Appendix 12: Investigator s Signature...96 Confidential Page 8 of 96

11 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS AAWD ACTH AD AE AIPC ALT ALK-P AR ASCO AR AST BID BPI-SF BUN C CALGB CaPSURE CBC CrCl CFR CIOMS CR CMH CRF CRPC CRO CT CTC Antiandrogen withdrawal Adrenocorticotropic hormone Androgen deprivation Adverse event Androgen independent prostate cancer Alanine aminotransferase (SGPT) Alkaline phosphatase Androgen receptor American Society of Clinical Oncology Adverse reaction Aspartate aminotransferase (SGOT) Twice daily Brief Pain Inventory Short Form Blood urea nitrogen Celsius Cancer and Leukemia Group B Cancer of the Prostate Strategic Urologic Research Endeavor Complete blood count Creatinine clearance Code of Federal Regulations Council For International Organizations of Medical Sciences Complete Response Cochran-Mantel-Haenszel Case Report Form Castration resistant prostate cancer Contract Research Organization Computed tomography Circulating tumor cells Confidential Page 9 of 96

12 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 CTCAE DES DHEA DHEA-S DRE EAU EC ECG ECOG ECHO EORTC-QLQ EP ESMO EU F FACT-P FDA FISH GCP GGT HEENT Hct Hgb HIPAA HRPC HTN ICH IDMC IEC Common Terminology Criteria for Adverse Events Diethylstilbestrol Dehydroepiandrosterone Dehydroepiandrosterone sulphate Digital Rectal Exam European Association of Urology Ethics committee Electrocardiogram Eastern Cooperative Oncology Group Echocardiogram European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire European Pharmacopoeia European Society for Medical Oncology European Union Fahrenheit Functional Assessment of Cancer Therapy-Prostate Food and Drug Administration Fluorescence in situ Hybridization Good Clinical Practice Gamma-glutamyl transferase Head, Eyes, Ears, Nose, Throat Hematocrit Hemoglobin Health Information Portability and Accountability Act Hormone refractory prostate cancer Hypertension International Conference on Harmonization Independent Data Monitoring Committee Independent Ethics Committee Confidential Page 10 of 96

13 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 IND INR IRB ITT IWRS LD LDH LH LHRH MedDRA mg MRI MRU MUGA NCI NF NF-kβ NYHA OS PCS PCWG PD PFS PO PPI PR PROSQOLI PT PTT Investigational New Drug International normalized ratio Institutional Review Board Intent-to-treat Interactive web response system Longest diameter Lactate dehydrogenase Luteinizing hormone Luteinizing hormone releasing hormone Medical Dictionary for Regulatory Activities Milligrams Magnetic resonance imaging Medical resource utilization Multiple Gated Acquisition Scan National Cancer Institute National Formulary Nuclear Factor kappa beta (Transcription Factor) New York Heart Association Overall survival Pain Catastrophizing Scale Prostate Cancer Working Group Progressive disease Progression Free Survival Per Os (by mouth) Present pain index Partial Response Prostate Cancer Specific Quality of Life Instrument Prothrombin time Partial thromboplastin time Confidential Page 11 of 96

14 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 PK PSA PSAWG QoL RBC RECIST RH rpfs SAE SAR SD SGOT SGPT SSRI(s) SUSAR SWOG TTP ULN USP WBC WHO Pharmacokinetics Prostate Specific Antigen Prostate Specific Antigen Working Group Quality of life Red blood cell (count) Response evaluation criteria in solid tumors Relative humidity Radiographic Progression Free Survival Serious adverse event Serious adverse reaction Stable disease Serum glutamic oxaloacetic transaminase (AST) Serum glutamic pyruvic transaminase (ALT) Selective serotonin uptake inhibitor(s) Suspected unexpected serious adverse reaction Southwest Oncology Group Time to progression Upper limit of normal United States Pharmacopeia White blood cell (count) World Health Organization Confidential Page 12 of 96

15 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, INTRODUCTION 1.1 Metastatic Castrate Resistant Prostate Cancer Prostate cancer has become an increasingly important health issue globally. With 679,060 men diagnosed each year, prostate cancers are the fifth most common tumor type worldwide [1]. It is estimated by the American Cancer Society that in 2008, prostate cancer will be diagnosed in 186,320 men in the United States alone and that 28,660 will die [2]. The most significant morbidity of prostate cancer is bone metastasis. It develops initially in the axial skeleton and later in the appendicular skeleton [3] in advanced prostate cancer and metastasis to bone is present in > 90% of patients [4]. These lesions can cause pain, skeletal fractures, spinal cord compression, anemia and thrombocytopenia. Clinical sequelae can include pain, paralysis, diminished mobility, fatigue and increased risk of infections. Side effects such as constipation and delirium from analgesics required to palliate pain are also significant. They further compromise patient quality of life. In addition, soft tissue metastasis occurs in about 40% of advanced patients. Pelvic lymphadenopathy may lead to anatomic obstruction of the ureters, or fistula formation [4]. When tumor recurs in the prostate gland or bed, urethral obstruction may also ensue. Prostate cancer is hormone sensitive at the time of initial diagnosis. Although most patients with advanced metastatic disease initially respond to conventional androgen deprivation with medical [5] or surgical [6] castration, the median duration of disease control has been 13 to 22 months and overall survival months [7]. The clinical status of patients after failure of castration is commonly referred to as hormone-refractory prostate cancer (HRPC), or androgen-independent prostate cancer (AIPC). However, recent investigations have established that tumor progression often remains androgen-dependent albeit at much reduced systemic androgen levels after castration. Although used widely in clinical settings, the terms HRPC and AIPC do not reflect the biology of advanced prostate cancer where androgen receptor and its ligand remain pivotal in tumor growth. Prostate cancer progression after conventional medical or surgical castration should, therefore, be considered castrationresistant prostate cancer (CRPC). Patients with metastatic CRPC have a very limited life expectancy and most often die of their prostate cancer. In the castrate state, ligands to the androgen receptor have been thought to be derived primarily from the adrenal glands. Conventional androgen deprivation therapy removes 90% of circulating androgens produced in the gonads. As much as 10% of circulating testosterone remains, in part due to the peripheral conversion of adrenal steroids to testosterone. In addition, several recent studies suggest that androgen levels in the microenvironment of prostate cancer may be maintained in spite of reduced systemic levels [8,9]. In patients with castrate levels of testosterone, the tissue levels of dehydroepiandrosterone, dihydrotestosterone, and androstenedione all remain sufficient to activate the androgen receptor (AR). Furthermore, the ARs are predominately located in the nucleus in biopsy tissue, indicating ligand-binding and the activation of androgen-dependent gene expression. Increased expression of the AR is common in advanced prostate cancer, and allows lower ligand levels to more strongly activate the AR [10]. A recent investigation made the Confidential Page 13 of 96

16 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 observation that in high risk primary prostate tumors and in metastatic biopsies, CYP17A1 gene expression is highly upregulated [11], suggesting the possibility of in situ production of androgens as autocrine or paracrine growth factors despite castration [12]. Similarly, investigators at MD Anderson Cancer Center also detected CYP17 expression by immunohistochemistry in bone marrow metastasis in CRPC [13]. Although these preliminary findings require further corroborating evidence, the need to suppress androgen production in adrenal glands and possibly at tissue levels persists in CRPC. Complete androgen independence in CRPC is thought to be rare. A few patients (9%) have mutations in the androgen receptor [14]; these changes could allow the androgen receptor to be activated by non-androgen ligands, or might allow ligand-independent AR association with coactivator molecules. Although gene fusions are well known to drive the development of blood cancers and sarcomas, only rarely have they been detected in the common solid cancers. Recent evidence indicates that a gene fusion may be important in the pathogenesis of prostate carcinoma [15,16,17,18,19]. Chromosomal translocations involving the androgen-responsive gene transmembrane protease serine 2 (TMPRSS2) and erythroblast transformation specific (ETS)-related transcription factors ETV1, ETV4, and ETV5, have been identified in 50% to 70% of prostate cancer cases [15,16]. Translocation of TMPRSS2 to the ERG gene, found in a high proportion of human prostate cancer, results in overexpression of the 3'-ERG sequences joined to the 5'-TMPRSS2 promoter. ERG and other ETS family members are transcription factors that are implicated in the control of cell growth and differentiation and the chimeric protein product of the gene translocation appears to retain hormoneresponsiveness [17]. Specific translocations in primary tumors have been associated with more aggressive natural clinical history, more advanced disease at diagnosis and greater lethality [18,19,20,21]. These gene rearrangements may be associated with tumor response to androgen deprivation therapy, including abiraterone [22]. 1.2 Asymptomatic or Mildly Symptomatic Patients with Castrate Resistant Prostate Cancer Approximately 50% of patients with metastatic prostate cancer will have no noticeable symptoms related to the tumor [23]. The optimal management of these patients with asymptomatic or mildly symptomatic metastatic prostate cancer refractory to medical or surgical castration remains undefined [24]. There are no approved second-line hormonal therapies for this population, and cytotoxic chemotherapy (docetaxel or mitoxantrone) is ordinarily reserved for patients with symptomatic or rapidly progressive cancer [25]. The American Society of Clinical Oncology / Cancer Care of Ontario and EAU guidelines for the cytotoxic treatment of CRPC [26,27] emphasize the need to individualize the timing of nonhormonal therapy for prostate cancer and consider routine docetaxel questionable in men who have metastatic disease but lack symptoms. Similarly, the current ESMO guidelines [28] for metastatic prostate cancer recommend that patients with castrate-resistant disease should receive second and possibly third line hormonal therapies, while chemotherapy with docetaxel given every three weeks should be considered for patients with CRPC who are symptomatic [28]. Thus the non-cytotoxic treatment of patients with CRPC who are asymptomatic or mildly symptomatic remains a significant unmet medical need. Confidential Page 14 of 96

17 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Patients with metastatic CRPC who are not good candidates for immediate chemotherapy may still benefit from alternate therapies since they develop symptomatic disease progression in a short period of time. This adverse natural history of patients with asymptomatic or mildly symptomatic CRPC was documented in two recent Phase III trials of novel agents in this population. A multinational, double-blind, placebo-controlled trial [29] of the endothelin antagonist atrasentan in patients with metastatic CRPC who had not received chemotherapy and did not require opiates for cancer related pain enrolled 809 men. Patients were randomized 1:1 to receive either atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed. Greater than 50% of patients on both the experimental and control arms developed protocol defined progression in less than 100 days, with 87% of the progressions by radiographic criteria. In addition more than half of patients on the control arm had a 50% worsening of the PCS pain score within 12 months of study entry, primarily due to increasingly painful bone metastases [30]. The median survival was 20.5 months for atrasentan treated patients and 20.3 months for the control patients. A second smaller Phase III study [31] compared the investigational immunotherapy product Sipuleucel-T with placebo in patients with CRPC who had not received chemotherapy. Patients with cancerrelated bone pain, those requiring opioid analgesics for cancer pain, and those with visceral metastases were not eligible. Disease progression events included radiographic progression, cancer pain, and clinical events, with the great majority radiographic. The median for time to disease progression (TTP) for Sipuleucel-T was 11.7 weeks compared with 10.0 weeks for placebo. Median survival was 25.9 months for Sipuleucel-T and 21.4 months for placebo. These results demonstrate that patients with asymptomatic or mildly symptomatic CRPC have short times to disease progression and to the rapid appearance of painful metastases, with an approximate overall survival of two years or less. Therefore the development of an alternate non-cytotoxic therapy with an improved safety and toxicity profile, capable of delaying tumor progression, blocking onset or worsening of pain, and improving survival would be of significant clinical benefit to patients with CRPC. The current study is focused on patients with progressive CRPC who are not in immediate need of docetaxel or mitoxantrone due to their lack of moderate to severe bone pain or rapid tumor progression. Patients will be required to have a score of 3 or less on components of the Brief Pain Intensity Short Form. Additionally, opiate use for cancer related pain is prohibited at study entry. Outside of a clinical trial, these mildly symptomatic patients with CRPC would commonly be treated with unapproved second-line hormonal therapies (see Section 1.3). 1.3 Second line hormonal therapies for CRPC Second line hormonal therapies in prostate cancer have limited efficacy, and none have received regulatory approval for this use. Historically, bilateral adrenalectomy was the first second line hormonal therapy to be evaluated [32]. Several of the adrenalectomized patients with widespread bone metastases had decreases in the bulkiness of their prostate tumor, reductions in prostatic acid phosphatase levels, increases in hemoglobin and red blood cell levels, and strikingly, 5 of 7 patients had complete relief of their cancer pain within 48 hours Confidential Page 15 of 96

18 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 of the surgery. However, patient and physician acceptance of adrenalectomy was low, due to the morbidity of major surgery in an advanced stage cancer patient population Adrenal Androgen Inhibitor Historical attempts to obtain the benefits of total adrenalectomy medically without the side effects of surgery have met with limited success. Aminoglutethimide and ketoconazole both inhibit several adrenal enzymes involved with adrenal androgen synthesis. Modest therapeutic activities on prostate cancer were observed. However, the side effects were significant. For example, in combination with hydrocortisone, aminoglutethimide resulted in a PSA response proportion of 37% with the median duration for responders of nine months in a Phase 2 study [33] at the expense of lethargy, skin rash, hypothyroidism, nausea and vomiting. Its use has been limited [33,34]. Ketoconazole inhibits several adrenal enzymes required for steroid biosynthesis. Its efficacy in prostate cancer in terms of PSA response is comparable to that of aminoglutethimide. Pilot studies in patients after failure of combined androgen blockade where ketoconazole was given simultaneously with anti-androgen withdrawal (AAWD) showed that 55% of patients achieved a 50% PSA decline [35]. When administered after AAWD, 36%-62.5% of patients had a 50% PSA decline [36,37]. In a Phase 3 study conducted by Cancer and Leukemia Group B, PSA response rate was 27% with a median duration of response of 9 months in the group of patients randomized to the combination arm of AAWD and ketoconazole plus hydrocortisone versus the AAWD alone arm [38]. However, ketoconazole inhibits CYP3A4 with substantial risk of drug-drug interactions, such as warfarin and statins [39]. It is often poorly tolerated by patients, with commonly occurring side effects including diarrhea, nausea, vomiting, and depression [36,37,38]. Ketoconazole is not approved for the treatment of CRPC Glucocorticoids Glucocorticoids appear to possess both hormonal and direct anti-tumor effects in prostate cancer. Patients with CRPC may still have hormone-sensitive disease that is stimulated by weak androgens of adrenal origin, and these androgens are suppressed by prednisone through its negative feedback on secretion of adrenocorticotrophic hormone (ACTH). Tannock et al [40] have demonstrated that low-dose prednisone treatment (7.5 to 10 mg daily) led to a decrease in the concentration of serum testosterone in seven of nine patients where it was not initially suppressed below 2.0 nmol/ml, and caused a decrease in serum levels of androstenedione and dehydroepiandrosterone sulfate in more than 50% of patients. These changes were associated with symptomatic and clinical improvement. Glucocorticoids may also have direct inhibitory effects on prostate cancer cells through enhanced growthinhibitory TGF-ß1 signaling and suppression of the transcriptional activities of NF κb. [41,42]. Prednisone, dexamethasone, and hydrocortisone have been frequently administered as standard of care in advanced prostate cancer because of their modest antitumor activity and palliative effects on disease. Two prospective Phase 3 studies have documented the adverse event profile and palliative benefit of prednisone. Prednisone mg daily was examined Confidential Page 16 of 96

19 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 among 81 patients in one arm of a Phase 3 trial, with 22% of patients achieving a 50% PSA decline and a median time to progression of 4.0 months [43]. Likewise, in a randomized study control arm where 201 patients were treated with prednisone 5 mg twice daily, PSA decline of 50% was observed in 21% of patients [44]. Significant improvements in pain, quality of life and fatigue were also reported. Other glucocorticoids have similar activity in advanced prostate cancer. Hydrocortisone has been evaluated as a control arm in prospective Phase 3 studies. In one study, 231 patients treated with hydrocortisone alone (control arm) showed that 16% of patients achieved a PSA decline of 50% with a median duration of response of 2.5 months [45]. Similarly, 14% of patients given hydrocortisone 40 mg daily achieved a PSA decline 50% lasting a median of 2.3 months in a Cancer and Leukemia Group B (CALGB) study [46]. The antitumor activity of hydrocortisone was slightly lower than prednisone in these Phase 3 studies (14%-16% PSA response rate for hydrocortisone versus 21%-22% PSA response rate for prednisone; median duration of response also favored prednisone). Likewise, dexamethasone has antitumor activity in prostate cancer [47,48,49]. No prostate cancer trials have directly compared 2 glucocorticoids Estrogens Prostate cancer normally expresses estrogen receptors, and estrogenic compounds have been used for the treatment of CRPC. The most commonly used estrogen is diethylstilbestrol (DES), although DES-diphosphate, and the herbal phytoestrogenic supplement, PC-SPES, have also been investigated in clinical trials. Recently, DES has been evaluated in two studies [50,51] including 21 and 32 patients. A positive PSA response was achieved in 43% and 80%, respectively; the estimated survival at 2 years was 63%. However, even at low doses, 31% of the patients developed deep venous thrombosis and 7% experienced myocardial infarction. In another prospective randomized phase II trial, the clinical efficacy of the herbal supplement PC-SPES and DES were tested in a cohort of 90 patients, with PSA progression following initial androgen deprivation [52]. A PSA decline > 50% was noted in 40% with PC-SPES and in 24% with DES. Median time to progression was 5.5 months with PC-SPES and 2.9 months with DES; the differences were statistically not significant. Although estrogens remain an option for the secondary hormonal treatment of CRPC, their use is limited by concerns regarding cardiovascular toxicity [27]. 1.4 Chemotherapy and Bisphosphonates for CRPC Several agents have been approved as palliative therapy for prostate cancer. Estramustine was approved in the 1970s. However, in a randomized study where overall survival was compared, diethystilbesterol was found to be superior to estramustine [53]. In 1996, mitoxantrone and prednisone were approved in the United States for palliation of pain and improvement in quality of life in a randomized study with prednisone as control [43]. However, there was no survival benefit. Recently, zoledronic acid was approved for Confidential Page 17 of 96

20 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 reduction in skeletal morbidity in solid tumors, including prostate cancer [54]. None of these agents improved the overall or prostate cancer-specific survival of patients with CRPC. Docetaxel is the only agent to date that has demonstrated a survival benefit in CRPC. A 3- weekly docetaxel regimen had a median overall survival of 18.9 months (95% confidence interval ), compared with the mitoxantrone control arm of 16.5 months (95% confidence interval months). The hazard ratio for death was 0.76 (95% confidence interval , p =0.009) in the docetaxel regimen as compared with control [55]. Results from the SWOG Study trial of 770 men (3-weekly docetaxel + estramustine + dexamethasone vs mitoxantrone + prednisone [56]), median overall survival 17.5 months vs 15.6 months, respectively, p=0.02 were consistent with the TAX-327 data. Results from TAX-327 were updated at ASCO Overall survival results were maintained after the additional 2 years of follow-up and an additional 276 deaths [57]. The median survival in the docetaxel 3-weekly arm and mitoxantrone arms were the same as previously reported in 2004, 18.9 months (95% confidence interval ) for docetaxel every 3 weeks plus prednisone, and 16.5 months (95% confidence interval ) for mitoxantrone plus prednisone. In an exploratory subset analysis, benefit was seen in patients who were free of pain at the time therapy was initiated. However, this analysis confirmed only consistency of effect across subpopulations, and the study was not powered to demonstrate survival advantage in asymptomatic patients. Also, the similar benefit produced by docetaxel treatment in patients with or without pain suggests that holding chemotherapy in reserve for asymptomatic patients is a reasonable option. 1.5 Abiraterone Acetate (CB7630) and the Active Metabolite Abiraterone (CB7598) Abiraterone (CB7598) is [17-(3-pyridyl)androsta-5,16-dien-3β-ol] and is a steroidal inhibitor of CYP17 (17α hydroxylase/c17,20-lyase) that blocks two important enzymatic activities in the synthesis of testosterone (Figure 1), based on the observation that nonsteroidal 3 pyridyl esters improve selectivity for inhibition of 17α-hydroxylase/C17,20 lyase. Abiraterone is a potent inhibitor with an apparent inhibition constant of 0.5 nm. Pharmacodynamic studies demonstrated that its effects on adrenal steroid synthesis were consistent with its mechanism of action. Antitumor effects were evident with PSA response and durable objective responses using Response evaluation criteria in solid tumors (RECIST) criteria [58] in Phase 1 and Phase 2 studies conducted to date. Abiraterone acetate (CB7630) is the 3-acetylated analog of abiraterone and thus a pro-drug of abiraterone. The chemical nomenclature of abiraterone acetate is 3β acetoxy-17-(3- pyridyl)androsta-5,16-diene; its empirical formula is C 26 H 33 NO 2 and molecular weight is Once absorbed after oral administration, abiraterone acetate is rapidly converted to the active form, abiraterone (Figure 2). In initial research studies, abiraterone was the predominant, if not the only, metabolite of abiraterone acetate detected in blood, both in preclinical studies [59] and in previously conducted clinical studies [60]. Confidential Page 18 of 96

21 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Figure 1. The Enzyme Complexes Inhibited by Abiraterone Figure 2. Prodrug Abiraterone Acetate is Converted to Abiraterone after Absorption Dosing Rationale The dose of abiraterone acetate in this study is 1000 mg daily based on results of two Phase 1 dose-finding studies. In the first Phase 1 study with capsule formulation (COU-AA-001) [61], abiraterone acetate was evaluated for safety, pharmacokinetics, and its effects on adrenal steroid synthesis at dose levels ranging from 250 mg to 2000 mg. Preliminary analysis showed that abiraterone acetate had an acceptable safety profile at all dose levels. Patients have received abiraterone acetate in this study and an extension protocol for up to 30 months. In the second Phase 1 study (COU-AA-002) [62,63] that evaluated the safety and tolerability of abiraterone acetate tablet formulation at doses ranging from 250 to 1000 mg, a daily dose of 1000 mg has also been found to have an acceptable safety profile for further development. Confidential Page 19 of 96

22 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Consistent with abiraterone acetate s mechanism of action, hypertension (HTN), hypokalemia, and lower extremity edema were the most commonly-observed drug-related adverse events, which were all manageable with medication. Pharmacokinetic (PK) studies showed increased systemic drug exposure at higher doses. Adrenal metabolite analysis showed inhibition of CYP17 even at low doses of abiraterone acetate and a compensatory increase of corticosterone and deoxycorticosterone. Data from dose-finding studies indicated that when PK, adrenal CYP17 inhibition, and efficacy signals are taken into consideration, the 1000-mg dose offered consistent pharmacological effects without additional side effects. Therefore, the 1000-mg dose has been chosen for further efficacy and safety evaluation in this Phase 3 study Concurrent Prednisone In ongoing studies, some patients receiving abiraterone acetate have been treated concurrently with glucocorticoids, including prednisone. Data from early studies have contributed to the current understanding of the mechanism of abiraterone action. These suggest that a state of mineralocorticoid excess can occur after pharmacologic inhibition of CYP17, with the resulting reduced cortisol levels leading to a compensatory ACTH surge and accompanying hypertension, hypokalemia, and fluid retention [64]. These side effects were readily managed with potassium supplementation, eplerenone (selective mineralocorticoid antagonist), antihypertensive agents, and low dose corticosteroids. Grade 1-2 fatigue was observed in some patients and was associated with discontinuation of corticosteroids as required per Phase 2 protocol entry criteria and extended duration of treatment with abiraterone acetate. Although there was no evidence of an abiraterone dose-response relationship, administration of low dose cortiscosteroids as specified in the study improved symptoms of fatigue and tolerability of abiraterone acetate, including symptoms of mineralocorticosteroid excess. The improved tolerability of abiraterone acetate after concomitant administration of low-dose corticosteroids was associated with suppression of ACTH and upstream adrenal steroids, suggesting that this combination may be a better tolerated and safer regimen in this older and frail patient population. Prednisone was selected over other corticosteroids because it is commonly used as standard of care [27] in combination with approved chemotherapy agents or as a monotherapy for palliation of symptoms. The safety and efficacy evaluation of abiraterone acetate with concurrently administered prednisone is continuing in ongoing Phase 2 and 3 studies. The regimen of abiraterone acetate 1000 mg daily and low dose prednisone 5-mg twice daily has been chosen as the experimental intervention arm in this study Status of Current Clinical Trials of Abiraterone Acetate Over two hundred seventy (270) patients have been treated to date with abiraterone acetate in Phase I and II studies, with approximately 240 patients at the 1000-mg dose level Chemotherapy-Naïve Castration-Resistant Prostate Cancer (CRPC) Following selection of the 1000-mg dosing regimen, the COU-AA-001 study enrolled additional patients to further evaluate antitumor activity in chemotherapy-naïve CRPC Confidential Page 20 of 96

23 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 patients. Chemotherapy-naïve men (n = 54) with CRPC resistant to multiple hormonal therapies were treated in this two-stage phase I/II study. Declines in PSA 30%, 50% and 90% were observed in 43 (80%), 38 (70%) and 14 (24%) of patients respectively. Radiological evaluation reported disease regression by RECIST (CR or PR) in 52% of patients. Falls in circulating tumor cell counts [65], normalization of lactate dehydrogenase and improving symptoms with a reduction in analgesic use were commonly documented. Twenty-three patients have received abiraterone acetate capsules for more than 12 months as part of an extension protocol [58,66]. Similar responses rates have been seen in COU-AA- 002, a parallel Phase I/II study investigating a tablet formulation [67] Castration-Resistant Prostate Cancer (CRPC) Post-Docetaxel Two Phase 2 studies (COU-AA-003 and COU-AA-004) in post-docetaxel CRPC patients are also being conducted. Preliminary results are available from the COU-AA-003 study. Fortyseven evaluable patients have been recruited. In an analysis of 28 patients, 14 have achieved PSA declines 50% and the median time to PSA progression is 167 days (24 weeks). Eighteen patients had measurable lesions at baseline and 4 (22%) of these had a confirmed radiologic PR. Eleven patients have been on treatment for more than a year. To date, no relationship has been found between true progression on prior docetaxel chemotherapy or stopping docetaxel for another reason such as toxicity, and response to abiraterone. (Refer to the current version of the abiraterone acetate Investigator s Brochure for additional or updated information). 1.6 Clinical Benefits of Current Treatment Quality of Life Assessments Observational studies have documented a rapid decline in health status in CRPC. A population-based sample of 1,243 patients was followed in Sweden during the year prior to their death from prostate cancer using the brief pain inventory short form (BPI-SF) and the Euro EQ-5D quality of life survey instruments. Declines across scales were highest in the 8 months preceding death [68]. Similarly, Litwin et al [69] and Melmed et al [70] assessed qualify of life (QOL) in metastatic prostate cancer patients in CaPSURE database from the United States. Declines across all 8 domains measured by the SF-36 were found during the 12 months prior to death. In contrast to observational studies, the TAX-327 interventional study found that global QOL measured by the FACT-P was improved for both docetaxel regimens [55], although only the 3-weekly docetaxel arm had improved survival over mitoxantrone in this study. In the SWOG study, a significant survival advantage was found for docetaxel plus estramustine compared with mitoxantrone and prednisone; QOL was assessed with the EORTC-QLQ-C30 instrument and the prostate subscale PR25 QOL [71] and pain palliation did not favor either study arm. In the Canadian study comparing mitoxantrone and prednisone with prednisone alone in advanced prostate cancer, the PROSQOLI and EORTC QLQ-C30 and prostate specific subscale QOLM-P14 were used, demonstrating that patients in the mitoxantrone arm had greater and longer lasting improvements in QOL [72]. Confidential Page 21 of 96

24 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Though there is no consensus on the best QOL instrument to use in interventional trials, the FACT-P has been selected for use in this trial based on several factors: 1) its content and psychometric properties have been well validated [73], and 2), clinically meaningful changes in the FACT-P have been determined by validation comparisons with clinical measures of disease burden [74]. 1.7 Rationale for Study Design and Control Group There is no standard therapy for asymptomatic or mildly symptomatic patients with CRPC. Abiraterone acetate has shown significant antitumor activity in a Phase II trial in symptomatic and asymptomatic chemo naive patients with CRPC. Its safety profile and tolerability appears reasonable in this population when given in combination with prednisone. Phase 2 studies were also conducted to evaluate the safety and efficacy of abiraterone acetate in CRPC patients receiving low dose prednisone [13,75]. Adverse events known to be associated with abiraterone acetate monotherapy, namely, hypokalemia, hypertension, and fluid retention appear to be less frequent when abiraterone acetate is used in combination with low-dose prednisone. The high degree of antitumor activity, as shown by PSA response, demonstrated by abiraterone in combination with prednisone in patients with CRPC together with a favorable toxicity profile supports the study of this regimen in a Phase III trial. Although this trial is blinded, randomized and placebo controlled for abiraterone acetate, patients on the control arm will receive active treatment in the form of prednisone. Prednisone 5 mg bid has been selected for use in both study treatment groups. Prednisone therapy of patients with CRPC is not simply a palliative intervention, but is associated with direct hormonal antitumor effects. The current EAU Guidelines for secondary hormonal therapy of patients with CRPC recommend treatment with adrenal testosterone inhibitors, low-dose DES, or glucocorticoids such as prednisone/prednisolone as standard approaches [27]. Therefore patients will receive either abiraterone acetate or placebo in a double-blinded manner, but also receive an active control in the form of prednisone rather than no treatment. The primary hypothesis of this randomized, double-blind, placebo-controlled study is that patients receiving abiraterone acetate and prednisone will have improved overall survival (OS) and/or radiographic progression-free survival (rpfs) compared with patients receiving placebo and prednisone. Radiographic progression requires visceral or soft-tissue progression on CT or MRI scans using modified RECIST criteria (Appendix 4), or, more commonly, appearance of new bone metastases on radionuclide scans [76]. Assessment of bone scan worsening of individual lesions can be problematic; this study will utilize bone scan standards for disease progression recommended by the PCWG2 criteria [76], Appendix 3], and the rpfs endpoint will be based on independent radiologic review by blinded assessors. This endpoint is more rigorous than the composite endpoints used in previous Phase III trials in CRPC in that it is objective, prospectively defined, and capable of thorough review and confirmation by an independent referee. Confidential Page 22 of 96

25 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 In addition, secondary endpoints will allow a direct estimation of the clinical benefit of delay in radiographic progression. Data on time to opiate administration for cancer pain, time to chemotherapy for metastatic prostate cancer, and time to deterioration in performance status will be collected prospectively using clear definitions of events. This should allow a comprehensible clinical context for improvements in time to radiographic progression. Standard secondary endpoints of efficacy in CRPC (time-to-psa progression based on PCWG2 criteria) will also be measured. 1.8 Radiographic PFS as an Efficacy Endpoint Clinical research in prostate cancer has been hindered by the difficulty in objectively defining cancer progression. Previous studies have used composite endpoints that included a mixture of patient reported, radiographic, and skeletal-related events. These composite endpoints attempted to address the complexity of clinical prostate cancer but suffered from subjectivity, difficulties in prospective definition, and were not amenable to independent review. Radiographic PFS as defined in this protocol is not a composite endpoint; each measurement is objective and associated with clinical significance. The issues from using RECIST criteria alone to define radiographic progression in prostate cancer are well documented. Fewer than 50% of men with CRPC have measurable lesions greater than 2cm in size, and most of these lesions are in lymph nodes which impact survival less than visceral metastases [4]. Conventional RECIST also lacks provisions to differentiate true progression of bone metastasis from the flare phenomenon on bone scan due to healing of previous bone metastasis [76,77]. Although radiographic PFS has not been established as a strong predictor for overall survival in a small study of patients receiving docetaxel therapy, it was found to outperform PSA based progression [77]. Previous development programs (atrasentan [29] and docetaxel-treated patients [78]) have shown that two factors can limit the correlation of radiographic PFS with survival in CRPC. These will be mitigated in this study. First, analyses of PFS have highlighted the difficulty in determining treatment effects based on PFS when the interval between assessments (12 weeks) was similar to the length of PFS. For this reason, the interval between radiographic assessments is 8 weeks over the first 24 weeks of the study, then every 12 weeks thereafter. Second, because early progression events could be confounded by tumor flare phenomenon, in this study new consensus guidelines will be applied to define progression requiring confirmatory bone scans at least six weeks after the original scan. This will reduce the number of false positive determinations of CRPC progression. rpfs in the study will be determined by an independent central reader blinded to PSA and other clinical data. Progression of metastatic bone disease is of paramount importance to CRPC patients since it is responsible for the severe morbidity of the skeletal related events such as fracture, pain, spinal cord compression, pre-emptive surgery or radiation for impeding fracture or spinal cord compression. In addition, painful bone metastasis often requires radiation, chemotherapy or radionuclide therapy [78]. Similarly, progression of soft tissue metastasis Confidential Page 23 of 96

26 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 may be associated with clinically significant morbidity. Prevention of disease progression in pelvic and para-aortic lymph nodes reduces the risk for urinary outlet tract obstruction requiring invasive stent placement that is frequently complicated by infection. Development of liver metastasis could lead to organ failure and death. Thus, delay in cancer progression should result in clear clinical benefit to the patient. In conclusion, rpfs as defined above is an objective and verifiable measurement likely to predict clinical benefit in the proposed study populations. Confidential Page 24 of 96

27 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, STUDY OBJECTIVES 2.1 Primary Objective(s) To compare the clinical benefit of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with chemotherapy-naïve castration-resistant prostate cancer (CRPC) who are asymptomatic or mildly symptomatic. 2.2 Secondary Objective(s) The secondary objectives of this study are: To establish additional clinically relevant improvements in prostate cancer patients treated with abiraterone acetate in comparison to placebo To characterize the safety profile of abiraterone acetate in this patient population To characterize the pharmacokinetics of abiraterone acetate when administered concurrently with prednisone 3 INVESTIGATIONAL PLAN 3.1 Overall Study Design and Plan This is a Phase 3 multinational, multicenter, randomized, double-blind, placebo-controlled study with a randomization allocation ratio of 1:1 (abiraterone acetate + prednisone: placebo + prednisone). This study will be conducted at approximately 150 investigative sites and approximately 1000 patients will be enrolled Primary Efficacy Endpoints Overall survival (OS) and radiographic progression-free survival (rpfs) are co-primary endpoints. Overall survival is defined as the time from randomization to date of death from any cause. Radiographic progression-free survival is based on parameters suggested by PCWG2 [76] and modified RECIST as the time from randomization to the occurrence of one of the following: 1. A patient is considered to have progressed by bone scan if: a. The first bone scan with 2 new lesions compared to baseline is observed <12 weeks from randomization and is confirmed by a second bone scan taken 6 weeks later showing 2 additional new lesions (a total of 4 new lesions compared to baseline); b. The first bone scan with 2 new lesions compared to baseline is observed 12 weeks from randomization and the new lesions are verified on the next bone scan 6 weeks later (a total of 2 new lesions compared to baseline). Confidential Page 25 of 96

28 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Progression of soft tissue lesions measured by CT or MRI as defined in modified RECIST criteria. 3. Death from any cause Secondary Efficacy Endpoints The secondary endpoints for this study include: Time to opiate use for cancer pain Time to initiation of cytotoxic chemotherapy Time to deterioration in ECOG performance score by 1 point Time-to-PSA progression based on PCWG2 criteria Other Study Endpoints PSA response rate [Proportion of patients achieving a PSA decline 50% according to Prostate Cancer Working Group (PCWG2) criteria] Objective response rate in patients with measurable disease (RECIST) Duration of response in patients with measurable disease QoL total score and each subscale score as assessed by FACT-P Time to pain progression Time to analgesic progression Safety Assessments Medical history, vital sign measurements, physical examination, and body weight Concomitant therapy and procedures Adverse events (AEs) and serious adverse events (SAEs) including laboratory test AEs will be graded and summarized according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 (Appendix 5) Blood chemistry, hematology, coagulation studies, serum lipids, and urinalysis Electrocardiograms (ECGs) Confidential Page 26 of 96

29 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Other Assessments Quality of Life (QOL) using FACT-P Quality of Life questionnaire Medical resource utilization (MRU) information PK measurements at selected sites TMPRSS2-ERG in primary tumor or circulating tumor cells (CTC s) at selected sites Study Duration and Dates The study period will consist of screening, treatment, and follow-up phases. In this study, patients will receive study treatment (abiraterone acetate or placebo) plus prednisone until radiographic progression of disease and/or unequivocal clinical progression as defined in Section 6.6. Follow-up will continue for 60 months (5 years) or until patient dies, is lost to follow-up, or withdraws informed consent. 3.2 Study Activities Screening Period All patients must sign a written informed consent form before study specific screening procedures are performed. Screening procedures to evaluate patient eligibility for the study will be conducted within 14 days prior to Cycle 1 Day 1. If the patient meets eligibility and screening requirements he will be randomized and will return to the site for the Cycle 1 Day 1 visit and dosing Randomization Once eligibility is confirmed, patients will be randomized to a treatment group according to the randomization schedule. All patients must commence treatment within 72 hours (3 calendar days) of randomization Treatment Period Randomized patients will have Cycle 1 Day 1 procedures and receive study treatment (abiraterone acetate or placebo) that will subsequently be administered orally once daily. Patients who participate in the pharmacokinetics testing will take their Day 1 dose of Cycles 1, 2 and 5 in the clinic. All patients will also take 5 mg of prednisone or prednisolone orally twice daily. In regions where prednisone is not marketed or available, prednisolone will be provided. If a patient has been receiving glucocorticoids other than prednisone or prednisolone, it will be necessary to switch the glucocorticoid to prednisone or prednisolone 5 mg bid prior to Cycle 1 Day 1. No crossover will be permitted between the 2 treatment groups. Each cycle of treatment will be 28 days. Patients will return for a Cycle 1 Day 15 visit ± 2 days to evaluate safety and dosing adherence (a count of study drug tablets), with additional safety visits at Cycle 2 Day Confidential Page 27 of 96

30 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, and Cycle 3 Day 15. From Cycle 2 to End of Study Treatment, Day 1 visits will occur every 28 days with a ± 2 day window. Study windows are to be calculated from Cycle 1 Day 1 date, and if utilized, every effort will be made for the patient to return to schedule. Patients may have additional imaging visits up to 8 days before Cycles requiring images (Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 10 Day 1 and every 3 rd cycle beyond Cycle 10) or at Treatment Discontinuation Visit Follow-up Period During the Follow-up Period, overall survival, opiate use, ECOG performance status, and next therapy for prostate cancer should be assessed every 3 months for up to 60 months (5 years) and may be collected by telephone interview or chart review. During the Follow-up Period, deaths regardless of causality and serious adverse events thought to be related to study treatment (abiraterone acetate or placebo) will be collected and reported within 24 hours of discovery or notification of the event. See Appendix 1, Schedule of Events. Confidential Page 28 of 96

31 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, STUDY POPULATION SELECTION 4.1 Study Population Approximately 1000 medically or surgically castrated male patients with metastatic CRPC who have shown tumor progression and are non- or mildly-symptomatic by prospectively defined criteria (Section 4.2) will be enrolled from approximately 150 global study sites. 4.2 Inclusion Criteria Each patient must meet the following criteria to be enrolled in this study. 1. Willing and able to provide written informed consent 2. Written Authorization for Use and Release of Health and Research Study Information (US sites only) or Data Protection Consent (European sites only) has been obtained 3. Male aged 18 years and above 4. Histologically or cytologically confirmed adenocarcinoma of the prostate 5. Metastatic disease documented by positive bone scan or metastatic lesions other than liver or visceral metastasis on CT, MRI. If lymph node metastasis is the only evidence of metastasis, it must be 2 cm in diameter 6. Prostate cancer progression documented by PSA according to PCWG2 or radiographic progression according to modified RECIST criteria 7. Asymptomatic or mildly symptomatic from prostate cancer. A score of 0-1 on BPI-SF Question #3 (worst pain in last 24 hours) will be considered asymptomatic, and a score of 2-3 will be considered mildly symptomatic. 8. Surgically or medically castrated, with testosterone levels of < 50 ng/dl (< 2.0 nm). If the patient is being treated with LHRH agonists (patient who have not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to Cycle 1 Day 1 and must be continued throughout the study. 9. Previous anti-androgen therapy and progression after withdrawal. Patients who received combined androgen blockade with an anti-androgen must have shown PSA progression after discontinuing the anti-androgen prior to enrollment ( 4 weeks since last flutamide, 6 weeks since last bicalutamide or nilutamide). 10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or Hemoglobin 10.0 g/dl independent of transfusion 12. Platelet count 100,000/µL 13. Serum albumin 3.5 g/dl 14. Serum creatinine < 1.5 x ULN or a calculated creatinine clearance 60 ml/min (see Appendix 7) 15. Serum potassium 3.5 mmol/l Confidential Page 29 of 96

32 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Liver function: i. Serum bilirubin < 1.5 x ULN (except for patients with documented Gilbert s disease) ii. AST or ALT < 2.5 x ULN 17. Able to swallow the study drug whole as a tablet 18. Life expectancy of at least 6 months 19. Patients who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 13 weeks after last study drug administration. 4.3 Exclusion Criteria Patients who meet any of the following criteria will be excluded from the study: 1. Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated 2. Any chronic medical condition requiring a higher dose of corticosteroid than 5mg prednisone/prednisolone bid. 3. Pathological finding consistent with small cell carcinoma of the prostate 4. Liver or visceral organ metastasis 5. Known brain metastasis 6. Use of opiate analgesics for cancer-related pain, including codeine and dextropropoxyphene, currently or anytime within 4 weeks of Cycle 1 Day 1 7. Prior cytotoxic chemotherapy or biologic therapy for the treatment of CRPC 8. Radiation therapy for treatment of the primary tumor within 6 weeks of Cycle 1, Day 1 9. Radiation or radionuclide therapy for treatment of metastatic CRPC 10. Previously treated with ketoconazole for prostate cancer for greater than 7 days 11. Prior systemic treatment with an azole drug (e.g. fluconazole, itraconazole) within 4 weeks of Cycle 1, Day Prior flutamide (Eulexin) treatment within 4 weeks of Cycle 1, Day 1 (patients whose PSA did not decline for three or more months in response to antiandrogen given as a second line or later intervention will require only a two week washout prior to Cycle 1, Day 1) 13. Bicalutamide (Casodex), nilutamide (Nilandron) within 6 weeks of Cycle 1 Day 1 (patients whose PSA did not decline for three or more months in response to antiandrogen given as a second line or later intervention will require only a two week washout prior to Cycle 1, Day 1) Confidential Page 30 of 96

33 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Uncontrolled hypertension (systolic BP 160 mmhg or diastolic BP 95 mmhg). Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment 15. Active or symptomatic viral hepatitis or chronic liver disease 16. History of pituitary or adrenal dysfunction 17. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of < 50% at baseline 18. Atrial Fibrillation, or other cardiac arrhythmia requiring therapy 19. Other malignancy, except non-melanoma skin cancer, with a 30% probability of recurrence within 24 months 20. Administration of an investigational therapeutic within 30 days of Cycle 1, Day Any condition which, in the opinion of the investigator, would preclude participation in this trial. Confidential Page 31 of 96

34 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, STUDY TREATMENT(S) 5.1 Description of Treatment(s) Study Drug Abiraterone acetate 250-mg tablets are oval, white to off-white and contain abiraterone acetate and compendial (USP/NF/EP) grade lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, colloidal silicon dioxide, and purified water, in descending order of concentration (the water is removed during tabletting). Placebo Placebo will be provided as a tablet formulation and will be matched in size, color (white to off-white), and shape (oval) to abiraterone acetate tablets to maintain the study blind. Prednisone Prednisone (5-mg tablets) will be prescribed or provided. Where prednisone is not commercially available, prednisolone will be substituted. Prednisone tablets are open label. 5.2 Treatments Administered Abiraterone Acetate/Placebo Patients will be instructed to take 4 tablets (abiraterone acetate or placebo) orally (PO) at least 1 hour before a meal or 2 hours after a meal Prednisone Patients will be instructed to take 5-mg prednisone, twice daily. 5.3 Selection and Timing of Dose for Each Patient Each treatment cycle consists of 28 consecutive days. Patients may take study treatment (abiraterone acetate plus prednisone or placebo plus prednisone) until radiographic disease progression and/or unequivocal clinical progression (as defined in Section 6.6), at which time study treatment will be discontinued. If the patient had radiographic progression but no unequivocal clinical progression, and alternate treatment is not initiated, the patient may continue on study treatment at the Investigator s discretion (see Section 6.6). The dose of prednisone will be gradually reduced if clinically indicated. Confidential Page 32 of 96

35 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 It is not required for the prednisone to be taken at the same time as study treatment (abiraterone acetate or placebo). The dose of prednisone will remain unchanged in the event that the study drug dose is changed. If a prednisone dose is missed, it should be omitted and will not be made up. 5.4 Randomization Procedures Patients will be randomized after the investigator has verified that all eligibility criteria have been met. Patients will be randomized to receive abiraterone acetate plus prednisone or placebo plus prednisone in a 1:1 ratio. Randomization will take place across all study sites using a centralized Interactive Web/Voice Response System (IWRS/IVRS). At randomization, the IWRS/IVRS will assign a unique patient identification number to each patient. The patient s identification number will be used on all study-related documents including case report forms (CRFs). A treatment number will also be assigned to each patient. This treatment number is the link between a patient s CRF and blinded treatment group assignment. Patient identification numbers will not be reused. Patients withdrawn from the study will not be replaced. All patients must commence treatment within 72 hours (3 calendar days) of randomization. 5.5 Stratification In this study, patients will be stratified according to baseline ECOG performance status (0 versus 1). Patients withdrawn/discontinued from the study will not be replaced. 5.6 Blinding This is a randomized, double-blind study. Patients will receive abiraterone acetate plus prednisone or placebo plus prednisone. At the time of disease progression, patient treatment assignments will remain blinded. The following precautions are to be taken to ensure that blinding is adequately maintained throughout the study Randomization Codes The treatment to which a patient is assigned will be determined by IWRS/IVRS (Section 5.4). A randomization schedule will be generated and maintained within the IWRS/IVRS. All study personnel will be blinded to the patient treatment assignments Laboratory Tests Results In order to maintain the blind, the Central Laboratory will not send PK and TMPRSS2-ERG results to the sites and will not transfer results to the clinical database until the blind is broken. Investigators must not obtain local laboratory serum testosterone after Cycle 1 Day 1, as this measurement may unblind the patient. Similarly, investigators must not obtain postbaseline circulating tumor cell measurements, as these may bias the investigator s decisionmaking on the study. Confidential Page 33 of 96

36 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Accidental Unblinding If a patient s treatment assignment is accidentally unblinded, that patient should remain in the study and continue treatment with the assigned treatment and all protocol tests and assessments. Unblinding information will be captured in the CRF. 5.7 Concomitant Therapy The use of any concurrent medication from screening and while on study, prescription or over-the-counter, is to be recorded on the patient's CRF along with the reason the medication was taken. In addition, tobacco and alcohol use will be collected. Concurrent enrollment in another clinical investigational drug or device study is prohibited. Supportive care medications are permitted with their use following institutional guidelines. For patients who did not undergo orchiectomy, concurrent treatment with LHRH analogue is mandatory and must be recorded. The following supportive care medications are considered permissible during the study: Luteinizing hormone-releasing hormone (LHRH) agonists to maintain testosterone <50ng/dL (< 2.0 nm) Conventional multivitamins, selenium and soy supplements Additional systemic glucocorticoid administration such as stress dose glucocorticoid is permitted if clinically indicated for a life threatening medical condition, and in such cases, the use of steroids will be documented as concomitant drug Bisphosphonate usage is allowed only if patients are on the medication prior to Study Day 1 Transfusions and hematopoietic growth factors per institutional practice guidelines If the permissibility of a specific drug/treatment is in question, please contact the study sponsor. 5.8 Prohibited Concomitant Medication Restrictions The concurrent administration of other anticancer therapy, including cytotoxic, hormonal (except LHRH agonists), or immunotherapy is prohibited during study treatment phase. Use of other investigational drug therapy for any reason is prohibited. Bisphosphonate usage is allowed only if patients are on the medication prior to randomization. New bisphosphonate therapy can not be initiated after randomization. Confidential Page 34 of 96

37 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Concomitant therapy during the treatment phase of the study with any of the following listed is prohibited: 5 α-reductase inhibitor Chemotherapy Immunotherapy Bicalutamide, nilutamide, flutamide Systemic ketoconazole (or other azole drugs such as fluconazole and itraconazole) Diethylstilbestrol, PC-SPES, and other preparations such as saw palmetto thought to have endocrine effects on prostate cancer Radiopharmaceuticals such as strontium (89Sr) or samarium (153Sm) Aldactone, Spironol (spironolactone) Digoxin, digitoxin, and other digitalis drugs Cyproterone acetate Fludrocortisone acetate (Florinef) 5.9 Potential for Drug-Drug Interactions Investigators should keep in mind the possibility that abiraterone may interact with concomitant medications, particularly those that are metabolized or activated by P450 CYPs 2D6 and 1A2 (see Table 1). Please refer to the current IB for a listing of drugs metabolized by P450 CYPs inhibited by abiraterone or abiraterone acetate and for other additional information. If at any time an investigator suspects a drug-drug interaction due to abiraterone acetate therapy, an adverse event report should be completed and Cougar notified. Confidential Page 35 of 96

38 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Table 1. Inhibition of Cytochrome P450 Enzymes by abiraterone acetate and abiraterone CYP450 ENZYMES ABIRATERONE ACETATE (CB7630) ABIRATERONE (CB7598) Type of Inhibition Ki µm Type of Inhibition Ki µm CYP2A6 Not Not CYP2E1 Moderate 31.8 Not CYP2C9 Moderate 17.6 Moderate 29.8 CYP2C19 Potent 0.12 Moderate 46.3 CYP3A4/5 Moderate 11.4 Moderate 8.01 CYP1A2 Potent 0.32 Potent 0.44 CYP2D6 Potent 0.16 Potent Treatment Compliance A current and accurate account of the number of study treatment tablets the investigator received from Cougar, dispensed to the patients, the number of units returned to the investigator by the patient, and the number of units returned to Cougar or its representative or destroyed on site during and at the completion of the study must be maintained. A detailed inventory must be completed for the study treatment Packaging and Labeling Abiraterone acetate or placebo tablets will be provided to each site packaged for patient assignment at the time of randomization. Patients will be provided with a 30-day supply to allow for visits to occur every 28 days with a ± 2 day window. Information presented on the labels for investigational product will comply with applicable local regulations. Site pharmacist or medically qualified staff will dispense the blinded study treatment to each patient in accordance with this protocol. Confidential Page 36 of 96

39 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Storage Pharmacy Storage Requirements The study treatment must be stored in a secure area and administered only to patients entered into the clinical study in accordance with the conditions specified in this protocol. Bottles of blinded study treatment should be stored at room temperature [15º-30º C; 59º-86º F] in the original container/closure with the cap on tightly; it should never be refrigerated. Additional information is provided in the abiraterone acetate Investigator s Brochure Storage Requirements For The Patient Bottles of blinded study treatment should be stored at room temperature [15º-30º C; 59º-86º F] in the original container/closure with the cap on tightly and should not be refrigerated. Patients should be advised to keep all medications out of the reach and out of sight of children Investigational Product Retention and Accountability at Study Site At the time of delivery of study treatment to the site, the investigator, designee, or Pharmacist (where appropriate) will sign a drug receipt form to confirm that the supplies for the study have been received. This form will specify supply, lot numbers, quantities shipped/delivered, and date of receipt. The form will also contain statements confirming that the study treatment has been received in good condition. Study treatment must be stored in a secure location between 15ºC-30º C, 59º-86º F. Accountability for study treatment is the responsibility of the investigator. More details concerning this responsibility are included in Appendix 2. Study treatment must only be dispensed by a pharmacist or medically qualified staff. Study treatment is to be dispensed only to patients enrolled in this study. Once the study treatment is prepared for a patient, it can only be administered to that patient. The study site must maintain accurate records demonstrating dates and amount of study treatment (abiraterone acetate, placebo, prednisone) received, to whom dispensed (patient by patient accounting), and accounts of any study treatment accidentally or deliberately destroyed. At the end of the study, reconciliation must be made between the amount of study treatment supplied, dispensed, and subsequently destroyed or returned to Cougar or its representative. Study site staff should refer to Appendix 2, information located in the Pharmacy Manual, and the Investigator s Brochure for specific instructions on the handling, storage, and administration of the study treatment. All study treatment will be returned to Cougar or its representative or destroyed at the site as specified in writing by Cougar. Confidential Page 37 of 96

40 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, STUDY PROCEDURES 6.1 Informed Consent A signed, Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved, written informed consent form must be obtained from patients before any study specific procedures or randomization can occur. Confirmation of the patient s informed consent and the informed consent process must also be documented in the patient s medical record. A copy of the signed informed consent form will be given to the patient. 6.2 Medical History Medical history, such as previous treatments, procedures, and conditions will be collected during the screening period. 6.3 Physical Examination Evaluations should be performed by the same evaluator throughout the study whenever possible. If it is not possible to use the same evaluator to follow the patient, then evaluations should overlap (i.e., examine the patient together and discuss findings) for at least one visit. Physical examination includes HEENT (head, eyes, ears, nose, and throat), chest, cardiac, abdominal, extremities, neurologic, and lymph node examinations. Weight will be recorded at every visit. Height will be recorded at screening visit only. Vital signs include upright blood pressure, heart rate, respiratory rate, and oral or aural body temperature. 6.4 Clinical Laboratory Tests Laboratory Parameters Clinical laboratory tests will include the following: Confidential Page 38 of 96

41 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Table 2. List of Laboratory Tests. Hematology: - Hematocrit (Hct) - Hemoglobin (Hgb) - Platelet count with differential - Red blood cell (RBC) count - White blood cell (WBC) count with differential Coagulation Factors: - Prothrombin Time (PT) - Partial Thromboplastin Time (PTT) - International Normalized Ratio (INR) Urinalysis dipstick for: - Blood - Protein - Glucose (Microscopic examination if abnormal) Serum Chemistry: Albumin (ALB) Alkaline phosphatase (ALK-P) Alanine aminotransferase (ALT; SGPT) Amylase Aspartate aminotransferase (AST; SGOT) Blood urea nitrogen (BUN) Calcium (Ca) Carbon dioxide (CO2) Chloride (Cl) Creatinine Direct bilirubin Gamma-glutamyl transferase (GGT) (at Screening only) Glucose - Lactate dehydrogenase (LDH) - Magnesium - Phosphorus - Potassium (K) - Sodium (Na) - Total bilirubin - Total protein - Uric acid Serum Lipids (Cholesterol, HDL, LDL, triglycerides) Additional laboratory tests: - Prostate specific antigen (PSA) - Serum testosterone - Pharmacokinetics (PK) * - TMPRSS2-ERG* *Blinding will be maintained by not reporting PK and TMPRSS2-ERG results to the Investigators or patients. Confidential Page 39 of 96

42 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Pharmacokinetics (PK) Assessments and Additional ECG Monitoring Pharmacokinetic samples will be obtained from approximately patients at selected study centers. A total of 6 blood samples will be drawn (2 samples during Cycle 1; 2 samples during Cycle 2, and 2 samples during Cycle 5). These data will be used for an integrated population pharmacokinetic analysis. In addition, 12-lead ECG assessment will be done pre-dose and at approximately two hours post-dose. Samples will be assayed for both abiraterone acetate and its major metabolite, abiraterone TMPRSS2 Tissue block known to contain cancer will be obtained on primary tumors from patients at selected sites, where available. If a tissue block is not available, unstained slides may be used instead. Patients who are known not to have available tissue or unstained slides at study entry may have blood drawn for CTC s. FISH using an ERG break-apart assay will be performed to perform TMPRSS2 status. Detailed sample requirements will be provided in a protocol-specific lab manual Sample Collection, Storage, and Shipping A Central Laboratory will analyze all hematology, blood chemistry, tissue and urine samples collected for the study. Samples will be analyzed at a facility meeting regulatory requirements and/or using methods documented in a methods validation report. All shipping requirements and storage conditions will be provided in a protocol-specific lab manual. 6.5 SAFETY DATA COLLECTION, RECORDING, AND REPORTING All observed or volunteered adverse events regardless of treatment group or causal relationship to study drug will be recorded on the adverse event page(s) of the case report form (CRF) Definitions Adverse Events An adverse event is defined in the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. (ICH E6:1.2) This definition of adverse events is broadened in this study to include any such occurrence (e.g., sign, symptom, or diagnosis) or worsening of a pre-existing medical condition from the time that a subject has signed informed consent to the time of randomization or initiation of investigational drug. Worsening indicates that the pre-existing medical condition (e.g., diabetes, migraine headaches, gout, hypertension, etc.) has increased in severity, frequency, or duration of the condition or an association with significantly worse outcomes. Confidential Page 40 of 96

43 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 For all adverse events, the investigator must pursue and obtain information adequate to both determine the outcome of the adverse event and to assess whether it meets the criteria for classification as a serious adverse event (see Section ) requiring immediate notification to Cougar or its designated representative. For all adverse events, sufficient information should be obtained by the investigator to determine the causality of the adverse event. The investigator is required to assess causality. For adverse events with a causal relationship to the investigational product, follow-up by the investigator is required until the event resolves or stabilizes at a level acceptable to the investigator and Cougar clinical monitor or his/her designated representative. Interventions for pretreatment conditions (e.g., elective cosmetic surgery) or medical procedures that were planned before study enrollment are not considered adverse events Serious Adverse Events A serious adverse event (SAE) is defined as an adverse event that: Results in death; Is life threatening (places the subject at immediate risk of death); Requires in-patient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity; Is a congenital anomaly/birth defect Important medical events that may not result in death, be life threatening, or require hospitalization may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. A hospitalization meeting the definition for serious is any inpatient hospital admission that includes a minimum of an overnight stay in a health care facility. Inpatient admission does not include: rehabilitation facilities, hospice facilities, skilled nursing facilities, nursing homes, routine emergency room admissions, same day surgeries (as outpatient/same day/ambulatory procedures), or social admission (e.g., subject has no place to sleep) Suspected Unexpected Serious Adverse Reactions (SUSARS) Suspected Unexpected Serious Adverse Reactions (SUSARS) are events which are serious as per the above criteria, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator s Brochure) and are judged by the investigator or Cougar to be unlikely, possibly, or related to study treatment. Confidential Page 41 of 96

44 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Reporting Procedures for All Adverse Events The investigator is responsible for ensuring that all adverse events (as defined in Section and as further specified below) observed by the investigator or reported by subjects are collected and recorded in the subjects medical records, in the CRF, and, for serious adverse events, on the serious adverse event report (SAER) form. These adverse events will include the following: All serious adverse events (as defined in Section ) that occur after the subject has signed the informed consent form and up to 30 days after the last dose will be documented. All non-serious adverse events (as defined in Section 6.5.1) that occur after randomization to study treatment up to 30 days after the last dose will be documented. The following adverse event attributes must be assigned by the investigator: adverse event diagnosis or syndrome(s) (if known, signs or symptoms if not known); event description (with detail appropriate to the event); dates of onset and resolution; severity; assessment of relatedness to study treatment (abiraterone acetate or placebo); and action taken. The investigator may be asked to provide follow-up information, discharge summaries, and extracts from medical records or CRFs. For all adverse events, sufficient information should be obtained by the investigator to determine the causality of the adverse event (e.g. study drug or other illness). The relationship of the adverse event to the study treatment (abiraterone acetate or placebo) will be assessed following the definitions below: Unrelated: any event that does not follow a reasonable temporal sequence from administration of study drug AND that is likely to have been produced by the patient s clinical state or other modes of therapy administered to the patient. Unlikely: any event that does not follow a reasonable temporal sequence from administration of study drug OR that is likely to have been produced by the patient s clinical state or other modes of therapy administered to the patient. Possibly: any reaction that follows a reasonable temporal sequence from administration of study drug OR that follows a known response pattern to the suspected drug AND that could not be reasonably explained by the known characteristics of the patient s clinical state or other modes of therapy administered to the patient. Related: any reaction that follows a reasonable temporal sequence from administration of study drug AND that follows a known response pattern to the suspected drug AND that recurs with re-challenge, AND/OR is improved by stopping the drug or reducing the dose. Confidential Page 42 of 96

45 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Severity of Adverse Events Adverse event severity is a clinical determination of the intensity of an AE and SAEs. The severity assessment for an AE/SAE should be completed using the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 3.0, Appendix 5). Any AE/SAE not listed in the CTCAE version 3.0 will be graded as follows: SEVERITY OF EVENT Grade Definition 1 Mild: Symptoms which do not interfere with patient s daily activities 2 Moderate: Symptoms which may interfere with patient s daily activities 3 Severe: Events which interrupt patient s usual daily activities 4 Life-threatening or disabling. 5 Death Medically significant adverse events considered related to the study treatment (abiraterone acetate or placebo) by the investigator or the sponsor will be followed until resolved or considered stable. It will be left to the investigator s clinical judgment to determine whether an adverse event is related and of sufficient severity to require the subject s removal from treatment or from the study. A subject may also voluntarily withdraw from treatment due to what he or she perceives as an intolerable adverse event. If either of these situations arises, the subject should be strongly encouraged to undergo an End of Study Treatment assessment and be under medical supervision until symptoms cease or the condition becomes stable Serious Adverse Event Reporting Procedures Serious adverse events will be collected and recorded at least throughout the study period, beginning with the signing of the informed consent through 30 days after the end of the treatment phase. All serious adverse events that occur after the subject has signed the informed consent form or during the study must be reported within 24 hours of discovery or notification of the event to a Cougar representative or study personnel through the planned adverse event reporting process and recorded on the appropriate case report form (CRF). Relevant medical records should be provided to Cougar as soon as they become available; autopsy reports should be provided for deaths if available. Related serious adverse events are events that are judged by the investigator or Cougar Biotechnology to be unlikely, possibly, or related to study treatment (abiraterone acetate or placebo). See definitions above. Determination of expectedness will be based on the contents of the Investigator s Brochure. Confidential Page 43 of 96

46 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 If the event is serious, unexpected, and related then it will be deemed to be a SUSAR and will be reported as a blinded SUSAR in order to maintain the blind and protect the integrity of the clinical investigation. Since a fatal outcome (death) is the primary efficacy endpoint for this study, deaths events will remain blinded in order to protect the integrity of the clinical investigation. SUSARs will be reported as required by the relevant authorities. All deaths, whether SUSARs or not, will be reported in an expedited manner to the FDA and to Health Canada. If a subject is permanently withdrawn from the study because of a serious adverse event, this information must be included in the initial or follow-up Serious Adverse Event Report Form as well as the End of Study Treatment Case Report Form. The investigator should notify the appropriate IRB or ethics committee of serious adverse events occurring at the site and other adverse event reports received from Cougar, in accordance with local procedures and statutes Long-Term Follow-Up For the long-term follow-up (e.g., to collect outcomes), serious adverse events considered related to investigational drug will be collected and reported on the Serious Adverse Event Report form to Cougar within 24 hours of discovery or notification of the event Abnormal Laboratory Results All clinically important abnormal laboratory tests occurring during the study will be repeated at appropriate intervals until they return either to baseline or to a level deemed acceptable by the investigator and the Cougar medical monitor (or his/her designated representative), or until a diagnosis that explains them is made. The criteria for determining whether an abnormal laboratory test result should be reported as an adverse event are as follows: 1. Test result is associated with accompanying symptoms, and/or 2. Test result requires additional diagnostic testing or medical/surgical intervention (merely repeating an abnormal test, in the absence of any of the above conditions, does not meet criteria for reporting and an AE), and/or 3. Test result leads to a change in study dosing or discontinuation from the study, significant additional concomitant drug treatment or other therapy, and/or 4. Test result leads to any of the outcomes included in the definition of a serious adverse event, and/or 5. Test result is considered to be an adverse event by the investigator or sponsor Any abnormal test result that is determined to be an error does not require reporting as an adverse event, even if it did meet one of the above conditions except for condition #4. Clinically significant laboratory results must be recorded in the patient s CRF. Confidential Page 44 of 96

47 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Management of Study Drug-Related Events Based upon experience from Phase 1 and ongoing Phase 2 studies, abiraterone acetate is generally well tolerated. The most common adverse events related to abiraterone acetate monotherapy include fatigue due to reduced cortisol level as a result of CYP17 inhibition; and hypertension, fluid retention, and hypokalemia due to mineralocorticoid excess caused by compensatory ACTH drive. In this study, the concomitant administration of prednisone is expected to mitigate these side effects by supplementing cortisol and abrogating ACTH drive. It has been documented that following prolonged therapy with corticosteroids, patients may develop Cushings syndrome characterized by central adiposity, thin skin, easy bruising, and proximal myopathy. Withdrawal of the corticosteroid may result in symptoms that include fever, myalgia, fatigue, arthralgia, and malaise. This may occur even without evidence of adrenal insufficiency. For guidance on management of side effects of glucocorticoid usage, symptoms related to castration (androgen deprivation), severe and refractory headaches, fatigue, or other toxicities, please contact the Medical Monitor. Re-initiation of study treatment after resolution of adverse events must be discussed with and approved by the Protocol Medical Monitor Management of Hypokalemia At the initial observation of Grade 1 hypokalemia (serum potassium < 3.5 mm or below lower limit of normal range, but 3.0 mm), oral potassium supplement will be initiated. The dose of potassium supplement must be carefully titrated to maintain serum potassium at 3.5 mm but 5.0 mm. Any patient with low potassium while on study or a history of hypokalemia from a pre-existing or concurrent medical condition will undergo weekly or more frequent laboratory electrolyte evaluation. The investigator should consider maintaining the patient s potassium level at 4.0 mm in these patients. If any patient experiences Grade 3 hypokalemia (serum potassium levels < 3.0 mm 2.5 mm, NCI CTCAE v3.0) or life-threatening hypokalemia with potassium levels < 2.5 mm (NCI CTCAE v3.0 hypokalemia Grade 4), study treatment will be withheld, and the patient hospitalized for intravenous potassium replacement and cardiac monitoring. Re-initiation of study treatment after normalization of potassium levels must be discussed with and approved by the Medical Monitor. Confidential Page 45 of 96

48 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Table 3. Hypokalemia Management Serum K+ Low K+ and/or history of hypokalemia Grade of Hypokalemia < 3.5mM - 3.0mM Grade 1 < 3.0mM 2.5mM Grade 3 < 2.5mM Grade 4 Action Weekly (or more frequent) laboratory electrolyte evaluations Initiate oral K+ supplementation Withhold study treatment and initiate IV K+ and cardiac monitoring Withhold study treatment and initiate IV K+ and cardiac monitoring Further Action and/or Maintenance Titrate patients to maintain a serum K+ 3.5mM 5.0mM (Maintenance of pts at 4.0mM is recommended) Titrate patients to maintain a serum K+ 3.5mM 5.0mM (Maintenance of pts at 4.0mM is recommended) Call Cougar Biotechnology Medical Monitor prior to re-initiating study treatment Call Cougar Biotechnology Medical Monitor prior to re-initiating study treatment Management of Hypertension Side Effects Grade 1-2: Management per Investigator. No study treatment dose reduction. Grade 3-4: Hold study treatment. Adjust or add medications to mitigate the toxicity and/or consider the specific mineralocorticoid receptor blocker, Eplerenone (Inspra). When hypertension resolves to Grade 1, resume study treatment at full dose. If toxicity recurs, hold study treatment, and adjust or add medications to mitigate the toxicity. When resolved to Grade 1, resume study treatment with the first dose level reduction (3 tablets, 750 mg of study treatment). If toxicity recurs, hold study treatment, and adjust or add medications to mitigate the toxicity. When resolved to Grade 1, resume study treatment with the second dose level reduction (2 tablets, 500 mg of study treatment). If toxicity recurs despite optimal medical management and two dose level reductions, discontinue study treatment. Confidential Page 46 of 96

49 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Management of Edema, Fluid Retention Pedal edema: Supportive management per Investigator. No study treatment dose reduction Anasarca and/or pulmonary edema requiring supplemental oxygen: Hold study treatment. Adjust or add medications to mitigate the toxicity and/or consider the specific mineralocorticoid receptor blocker, Eplerenone (Inspra). When toxicity resolves to Grade 1, resume study treatment at full dose. If toxicity recurs, hold study treatment, and adjust or add medications to mitigate the toxicity. When resolved to Grade 1, resume study treatment with the first dose level reduction (3 tablets, 750 mg of study treatment). If toxicity recurs again, hold study treatment, and adjust or add medications to mitigate the toxicity. When resolved to Grade 1, resume study treatment with the second dose level reduction (2 tablets, 500 mg of study treatment). If toxicity recurs despite optimal medical management and two dose level reductions, discontinue study treatment Management of Abnormal Liver Function Tests If Grade 1 increases in AST, ALT or bilirubin occur (e.g. increase in AST or ALT from ULN to 2.5X ULN; increase in total bilirubin from ULN to 1.5X ULN): The frequency of liver function test monitoring should be increased, if the Investigator judges that the laboratory abnormalities are potentially related to study medication. No study treatment dose reduction is required. If Grade 2 increases in AST, ALT or bilirubin occur (e.g. increase in AST or ALT to >2.5-5X ULN; increase in total bilirubin from >1.5-3X ULN): The frequency of liver function test monitoring should be increased to once a week, if the Investigator judges that the laboratory abnormalities are potentially related to study medication. No study treatment dose reduction is required. If Grade 3 or higher increases in AST, ALT, or bilirubin occur (e.g. increase in AST or ALT to >5X ULN; increase in total bilirubin to >3X ULN), hold study medication and all other concomitant medications that are potentially hepatotoxic. Frequent laboratory evaluations (at least once weekly) should be conducted until the liver function tests return to baseline value or Grade 1. Liver enzyme measurements should be made immediately, regardless of when the next study visit or monitoring interval is scheduled. o If study treatment resumption is considered for subjects who have experienced Grade 3 increases in AST, ALT, or bilirubin, and the Medical Monitor agrees, resume study treatment with the first dose level reduction (3 tablets, 750 mg of study treatment) when Grade 3 toxicities resolve to Grade 1 or baseline. Confidential Page 47 of 96

50 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 o If Grade 3 or higher increases in AST, ALT, or bilirubin recur after the first dose reduction hold study medication and all other concomitant medications that are potentially hepatotoxic. Frequent laboratory evaluations should be conducted (at minimum weekly) until the liver function tests return to baseline value or Grade 1. Liver enzyme measurements should be made immediately, regardless of when the next study visit or monitoring interval is scheduled. o If study treatment resumption is considered for patients who have experienced Grade 3 increases in AST, ALT, or bilirubin with the first dose reduction, and the Medical Monitor agrees, resume study treatment with the second dose level reduction (2 tablets, 500 mg of study treatment) when AST, ALT, or bilirubin returns to baseline value or Grade 1. If Grade 4 increases in AST, ALT, or bilirubin occur (e.g. increase in AST or ALT to >20X ULN; increase in total bilirubin to >10X ULN), patients must discontinue study treatment immediately and will not be re-challenged. They should be followed until resolution of abnormal liver function tests Management of Non-Mineralocorticoid Based Side Effects If Grade 1-2 toxicities, give supportive care per institutional guidelines. No study treatment dose reduction. If Grade 3 or higher toxicities including headache (interferes with ADL), nausea (TPN, IVF), vomiting (>6 episodes/24hrs, TPN or IVF), diarrhea (IVF, hospitalization, hemodynamic collapse), or any other toxicity judged to be related to study treatment is observed where the patient s safety is jeopardized, hold study treatment. When toxicity resolves to Grade 1, resume study treatment at full dose. If toxicity recurs, hold study treatment, and adjust or add medications to mitigate the toxicity. When resolved to Grade 1, resume study treatment with the first dose level reduction (3 tablets, 750 mg of study treatment). If toxicity recurs, hold study treatment, and adjust or add medications to mitigate the toxicity. When resolve to Grade 1, resume study treatment with the second dose level reduction (2 tablets, 500 mg of study treatment). If toxicity recurs despite aggressive medical management and two dose level reductions, discontinue study treatment Dose-Reduction Procedure for Adverse Event Management In the event where dose-reduction is used for AE management, 2 dose reductions are allowed. At each dose reduction, one tablet of abiraterone or placebo will be removed, e.g., 4 3 tablets, and 3 2 tablets. Any return to protocol dose level after dose reduction must follow documentation of AE resolution and a discussion with the Medical Monitor. Confidential Page 48 of 96

51 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Criteria for Discontinuation of Study Treatment The co-primary efficacy endpoint is rpfs, as defined in Sections and 9.7. Confirmed radiographic progression may be a reliable indicator of clinical benefit in patients with CRPC [75]. Patients should ordinarily be maintained on study treatment until confirmed radiographic progression. If the patient has radiographic progression but no unequivocal clinical progression and alternate treatment is not initiated, the patient may continue on study treatment, at the investigator s discretion However, if patients have unequivocal clinical progression without radiographic progression, these patients are indicated for the current standard of care. Study treatment should be stopped and patients advised regarding available treatment options. For this study, unequivocal clinical progression will be characterized as: 1) Cancer pain requiring initiation of chronic administration of opiate analgesia (oral opiate use for 3 weeks; parenteral opiate use for 7 days, as listed in Appendix 10). Patients with cancer pain requiring opiate analgesia for relief should also be assessed by the investigator for the need for initiating systemic chemotherapy. Or 2) Immediate need to initiate cytotoxic chemotherapy or the immediate need to have either radiation therapy or surgical intervention for complications due to tumor progression, even in the absence of radiographic evidence of disease progression. Or 3) Deterioration in ECOG performance status to grade 3 or higher. Patients whose ECOG performance status decreases to grade 2 during the study should be assessed carefully for their need for docetaxel therapy. When study treatment is discontinued due to unequivocal clinical progression, the investigator should obtain imaging studies at the End of Study Treatment Visit to assess for radiographic progression, including a confirmatory bone scan, as appropriate. Study treatment will be continued on patients who have increasing PSA values in the absence of radiographic or unequivocal clinical progression. Although serial PSA s will be measured on this study, progression or change in PSA values is not considered a reliable measure of disease progression, and should not be used as an indication to discontinue study therapy. 6.7 Withdrawal from Study Treatment Phase A patient may withdraw from study treatment phase for any reason. In this event, the reason(s) for withdrawal must be documented and clarification requested whether withdrawal of consent applies only to the Treatment Phase (i.e. patient has not withdrawn consent for data collection during the post-treatment Follow-Up Phase) or to both the Treatment and Follow-Up Phases. A patient s Confidential Page 49 of 96

52 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 decision to take part in the study is voluntary, and he may choose not to take part in the study or to stop taking part at anytime. If he chooses not to take part or to stop at anytime, it will not affect his future medical care or medical benefits. An investigator may withdraw a patient from the study Treatment Phase at any time based on clinical judgment or for any of the following reasons listed below. When possible all End of Study Treatment procedures should be conducted and the patient should be followed for survival as specified in Section 7.3. Discontinuation of treatment criteria as defined in Section 6.6 Sustained Side Effects: Patients who have sustained toxicities that do not return to NCI CTCAE (version 3.0) Grade 1 or less with appropriate medical management, should be discontinued from the study treatment. Initiation of new anticancer treatment: Patients will be discontinued from the study treatment when investigator determines new treatment for prostate cancer is warranted. For patients who did not undergo orchiectomy, concurrent treatment with LHRH analogue is mandatory and must be recorded. The concurrent administration of other anticancer therapy, including cytotoxic, hormonal (except LHRH agonists), or immunotherapy is prohibited during study treatment Phase. Use of other investigational drug therapy for any reason is prohibited. Confidential Page 50 of 96

53 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, STUDY ACTIVITIES 7.1 Screening Period (Days 14 to Day 1) The following activities/procedures will be conducted during the screening period which may occur over 14 days: Medical history including prior prostate cancer therapies, PSA, Stage, and Gleason score at diagnosis Previous hormonal, cytotoxic, and experimental treatments with start and stop dates Demographics Pain (BPI-SF, see Appendix 8) and analgesic use For study eligibility, a score of 0-1 on BPI-SF Question #3 (worst pain in last 24 hours) will be considered asymptomatic, and a score of 2-3 will be considered mildly symptomatic. Physical examination, weight, and height with baseline signs and symptoms 12 lead ECG MUGA (Multiple Gated Acquisition scan). Left ventricular ejection fraction (LVEF) must be 50% for study eligibility. An ECHO (Echocardiogram) can be performed if MUGA is not possible. MUGA performed up to 28 days prior to Cycle 1 Day 1 can be used for baseline assessments. Vital signs including upright blood pressure, heart rate, respiratory rate, and oral or aural body temperature Assessment of ECOG Performance Status by investigator (Appendix 6) Laboratory tests: Hematology (Table 2, Section 6.4.1) Coagulation factors (Table 2, Section 6.4.1) Serum chemistry with electrolytes and GGT (Table 2, Section 6.4.1) Fasting glucose (8 hr. fast) Serum Lipids (Table 2, Section 6.4.1) Urine sample for urinalysis (Table 2, Section 6.4.1) Confidential Page 51 of 96

54 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 PSA: If patient undergoes a digital rectal exam (DRE), PSA must be sampled prior to the DRE. Serum testosterone Baseline tumor assessment: CT or MRI of chest, abdomen, and pelvis must be included. Tumor burden must be evaluated by physical examination and image-based evaluation (modified RECIST criteria). Ultrasound should not be used to measure lesions that are not clinically accessible, such as liver lesions. Chest x-ray is not recommended. Bone Scan Scans performed up to 28 days prior to Cycle 1 Day 1 can be used for baseline assessments. Concomitant medications listing Obtain a complete and thorough listing of all prescription and nonprescription (over the counter) medications currently taken including pain medications. This also includes any nutritional supplements and/or herbal preparations. TMPRSS2-ERG: tissue block or unstained slides known to contain cancer should be obtained on primary tumors from patients at selected sites, where available. Patients who are known not to have available tissue at study entry may have blood drawn for CTC s. 7.2 Treatment Period (Cycle 1 Day 1 to End of Study Treatment) Cycle 1 Day 1 Patients who are eligible will be randomized and start study treatment within 14 days after the screening visit. Cycle 1 Day 1 visit may occur on the same day as the Screening visit provided that all screening assessments have been completed and screening results are reviewed prior to the commencement of Cycle 1 Day 1 assessments. The following procedures should be carried out: Quality of Life (FACT-P, see Appendix 9) Pain (BPI-SF) and analgesic use Concomitant Medications listing Vital signs including upright blood pressure, heart rate, respiratory rate, and oral or aural body temperature Assessment of ECOG Performance Status by investigator Confidential Page 52 of 96

55 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Laboratory tests Hematology (Table 2, Section 6.4.1) Serum chemistry with electrolytes (Table 2, Section 6.4.1) PSA: If patient undergoes a DRE, PSA must be sampled prior to the DRE. AE evaluation and recording PK Assessment for Patients at Selected Study Centers Only: PK pre-dose sample (up to 1 hour prior to on-site study dose administration) Dosing of study treatment: Collect date and time of most recent meal patient had prior to providing study treatment. Administer study treatment and collect time The following procedures should be carried out following dosing of study treatment: 12-lead ECG at approximately 2 hours post-dose Collect PK sample between 1 and 5 hours post-dose Cycle 1 Day 15 Visit The following assessments should be carried out: Physical examination and weight Vital signs including upright blood pressure, heart rate, respiratory rate, and oral or aural body temperature Assessment of ECOG Performance Status by investigator Laboratory tests Serum chemistry with electrolytes (Table 2, Section 6.4.1) Coagulation factors (Table 2, Section 6.4.1) Concomitant Medications listing AE evaluation and recording will be monitored throughout the study. At each post baseline visit, the investigator will begin by querying for adverse events by asking each patient a general, nondirected question such as How have you been feeling since the last visit? Directed questioning and examination will then be done as appropriate. Confidential Page 53 of 96

56 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Dosing compliance check, a count of study treatment tablets, will be conducted during this visit and patient dosing compliance will be assessed. If dosing compliance is 75% in the absence of toxicity, patient should be re-instructed regarding proper dosing procedures and may continue in the protocol. Source documentation of the compliance check and any patient verbal re-instruction provided should be documented in patient s chart Cycles 2, 4, 6, 8, 9, 11, and 12 Day 1 (Continue every 1 st and 2 nd cycle Beyond Cycle 10, e.g. Cycles 11, 12, 14, 15, 17, 18, 20, 21 ) The following assessments should be carried out at the indicated time point: Physical examination and weight Vital signs including upright blood pressures, heart rate, respiratory rate, and oral or aural body temperature Assessment of ECOG Performance Status by investigator Concomitant medications listing AE evaluation and recording Pain (BPI-SF) and analgesic use Dosing compliance check, a count of study treatment tablets, will be conducted during this visit and patient dosing compliance will be assessed. If compliance is 75% patient should be re-instructed regarding proper dosing procedures. Source documentation of the compliance check and any patient verbal re-instruction provided should be documented in patient s chart. Laboratory Tests: Hematology (Table 2, Section 6.4.1) Serum chemistry with electrolytes (Table 2, Section 6.4.1) PK Assessment for Selected Study Centers (Cycle 2 only): PK pre-dose sample (up to 1 hour prior to on-site study dose administration) Dosing of study treatment: Collect date and time of most recent study treatment prior to the study visit. Collect date and time of most recent meal patient had prior to providing study treatment in the clinic. Administer study treatment and collect time Confidential Page 54 of 96

57 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 The following procedures should be carried out following dosing of study treatment: 12-lead ECG at approximately 2 hours post-dose Collect PK sample between 1 and 5 hours post-dose Day 15 of Cycles 2 and 3 The following assessments should be carried out: Laboratory tests: Liver function testing: ALK-P, ALT (SGPT), AST (SGOT), LDH, and direct and total bilirubin Cycles 3, 5, 7, and 10 (continue every 3 rd cycle beyond Cycle 10, e.g. Cycles 13, 16, 19, 22 ) and Treatment Discontinuation Visit In preparation for the study visit, the following assessments should be conducted up to 8 days prior to the indicated visit. - CT or MRI of chest, abdomen, and pelvis Bone Scan If progressive disease is observed on bone scan at any timepoint (without RECIST progression on CT/MRI), a confirmatory bone scan is required at least six weeks later. The patient should remain on study treatment in the interim unless there is unequivocal clinical progression as defined in Section 6.6 At the study visit the following assessments should be conducted: Pain (BPI-SF) and analgesic use Quality of Life (FACT-P) Physical examination and weight 12-lead ECG Vital signs including upright blood pressures, heart rate, respiratory rate, and oral or aural body temperature Assessment of ECOG Performance Status by investigator Laboratory Tests Hematology (Table 2, Section 6.4.1) Serum chemistry with electrolytes (Table 2, Section 6.4.1) Confidential Page 55 of 96

58 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Fasting glucose (at least 8 hr. fast) Serum Lipids (Table 2, Section 6.4.1) PSA: If patient undergoes a DRE, then PSA must be sampled prior to the DRE. Concomitant medications listing AE evaluation and recording Disease progression assessment Dosing compliance check. If Treatment Discontinuation Visit, then a count of study drug tablets will be conducted and final patient dosing compliance will be assessed. PK Assessment for Selected Study Centers (Cycle 5 only): PK pre-dose sample (up to 1 hour prior to on-site study dose administration) Dosing of study treatment: Collect date and time of most recent study treatment prior to the study visit. Collect date and time of most recent meal patient had prior to providing study treatment in the clinic. Administer study treatment and collect time The following procedures should be carried out following dosing of study treatment: 12-lead ECG at approximately 2 hours post-dose Collect PK sample between 1 and 5 hours post-dose Treatment Discontinuation The Treatment Discontinuation Visit can occur at any scheduled or unscheduled visit when applicable. At this visit, documentation to confirm progressive disease or unequivocal clinical progression as defined in Section 6.6 is required End of Study Treatment Visit The End of Study Treatment Visit should be scheduled to collect safety assessments between 15 to 28 days after the patient stops treatment. Patients will enter the Follow up Phase at that time. The following safety assessments should be carried out at the End of Study Treatment Visit after patients discontinue study treatment for any reason: Physical examination and weight Vital signs including upright blood pressures, heart rate, respiratory rate, and oral or aural body temperature. Confidential Page 56 of 96

59 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Assessment of ECOG Performance Status by investigator Pain (BPI-SF) and analgesic use Quality of Life (FACT-P) 12-lead ECG Laboratory tests Hematology (Table 2, Section 6.4.1) Serum chemistry with electrolytes (Table 2, Section 6.4.1) Fasting glucose (8 hr. fast) PSA: If patient undergoes a DRE, PSA must be sampled prior to the DRE. Serum Lipids (Table 2, Section 6.4.1) Concomitant medications listing Adverse events AE follow-up (to determine if any new or ongoing drug-related AE or any SAE regardless of relationship to study drug exists) is required for 30 days post last dose or until patient receives anticancer therapy, whichever comes first. Followup could be conducted by site via telephone attempts. The attempts and outcomes should be recorded as part of the patient source documents. Final Dosing compliance check if not performed at the Treatment Discontinuation Visit Unscheduled Visits If an imaging procedure is performed at an unscheduled visit, and progression is observed by bone scan, a confirmatory bone scan should be obtained at least 6 weeks later. 7.3 Post-Treatment Follow-up Period (Survival or Long-Term Follow-Up) Once a patient has completed the treatment period, overall survival follow-up will be performed every 3 months for up to 60 months (5 years). In addition to overall survival, opiate use, ECOG performance status, and next therapy for prostate cancer (including dose and treatment duration of cytotoxic chemotherapy) will also be collected. Follow up may be performed by telephone interview or chart review and will be reported on the case report form. During the Follow-up Period, deaths regardless of causality and serious adverse events thought to be related to study treatment (abiraterone acetate or placebo) will be collected and reported within 24 hours of discovery or notification of the event. Confidential Page 57 of 96

60 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, QUALITY CONTROL AND ASSURANCE Cougar representatives are responsible for contacting and visiting the investigator for the purpose of inspecting the facilities and, upon request, inspecting the various records of the clinical study (e.g., CRFs and other pertinent data) provided that patient confidentiality is respected. The investigator agrees to cooperate with the monitor to ensure resolution of all problems detected in the course of these monitoring visits, including delays in completing CRFs. During and after completion of the study, quality assurance auditor (s) named by Cougar or the regulatory authorities may perform on-site audits/inspections. The investigators will be expected to cooperate with any audit/inspection and to provide assistance and documentation (including source data) as requested. The investigator will immediately inform Cougar Quality Assurance if contacted by a regulatory authority regarding an on-site audit/inspection of this study. In accordance with ICH GCP and the sponsor s audit plans, investigators may be selected for audit by representatives from Cougar s Quality Assurance Department (or designees). Inspection of site facilities (e.g., pharmacy, drug storage areas, laboratories) and review of study-related records will occur to evaluate the study conduct and compliance with applicable regulatory requirements (e.g., US IND regulations (21CFR312), EU Clinical Trials Directive (Directive 2001/20/EC), the protocol and ICH Good Clinical Practice (ICH E6). Confidential Page 58 of 96

61 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, PLANNED STATISTICAL METHODS 9.1 General Considerations All statistical analyses will be performed using SAS. The resulting statistic will be evaluated using East given the precise number of events observed at the time of interim analysis. Unless otherwise specified, all continuous endpoints will be summarized using descriptive statistics, which will include the number of patients (n), mean, standard deviation, median, minimum, and maximum. All categorical endpoints will be summarized using frequencies and percentages. The baseline measurement will be the last value on or before the date of first study treatment. 9.2 Determination of Sample Size Sample Size Determination The overall level of significance for the study will be However, 0.04 will be used in the testing of OS, and 0.01 will be used in the testing of rpfs. The exact timing of the analysis will be carried out according to the pre-specified required number of events for each endpoint. Patients will be randomized in a 1:1 ratio to receive abiraterone acetate or placebo. Recent publications suggest that a similar patient population has an estimated median OS of approximately 20 to 22 months. A median of 22 months is assumed in the sample size calculation accounting for differences in patient populations in comparing these study designs. These publications also suggest the estimated median rpfs of approximately 4 months for these patients Hypothesized OS Hazard Ratio of 0.80 It was assumed that the hazards for the two treatment groups follow a proportional hazards model for OS. The test to detect a difference between a median OS of 22 months in the placebo group and a median OS of 27.5 months in the abiraterone acetate group (HR=0.80) at the 2-tailed significance level of 0.04 with a power of 85% would require 772 events. Assuming an enrollment rate of 50 patients per month over 20 months, a total sample size of approximately 1000 patients is planned for the study. The OS endpoint will incorporate group sequential design by including 2 interim analyses and one final analysis using the O Brien-Fleming boundaries as implemented by Lan-DeMets alpha spending method. This method ensures that the type I error rate is not inflated. The interim analyses are planned at 15% (estimated) and 50% of the required number of events. The cumulative alpha spent will be , , and for each of the 3 analyses respectively. The exact timing of the first interim analysis will be determined according to the rpfs events required. Confidential Page 59 of 96

62 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Hypothesized rpfs Hazard Ratio of Only one analysis will be conducted for rpfs. Assuming that the hazards for the two treatment groups follow a proportional hazard model, it is estimated that 378 rpfs events would be required to provide a 91% power in detecting a median rpfs of 4 months for the placebo group versus 6 months for the abiraterone group (HR=0.667) at a 2-tailed level of significance of 0.01; the same enrollment assumptions as described for OS is assumed. It is anticipated that at the time of observing the required rpfs events, approximately 680 patients will have been enrolled. At the conclusion of the rpfs analysis, including data review by the data monitoring committee, it is expected that nearly 1000 patients will have been enrolled. 9.3 Interim and Final Analyses Interim analysis for rpfs is not planned. The analysis of rpfs will be carried out at the twotailed 0.01 level of significance. The first interim analysis for OS will be timed according to the required number of events for rpfs. The alpha spent for OS will be adjusted accordingly using the alpha spending method as indicated above for all the analyses which should protect from inflating the type I error rate. 9.4 Analysis Populations Patient disposition and efficacy analyses will be performed on data from the intent-to-treat (ITT) population. All patients randomized into the study will be classified according to their assigned treatment group, regardless of the actual treatment received. The primary efficacy analyses will be on the ITT basis. All patients who receive any part of study drug will be included in the analysis of safety (Safety Population). 9.5 Demographics and Baseline Characteristics Demographic variables will include age, race, ethnicity, height, and weight. Baseline disease characteristics will include time from diagnosis, number of prior hormonal therapies, and other clinical characteristics as documented in the CRF. 9.6 Study Endpoint(s) Efficacy Endpoint(s) Co-Primary efficacy endpoints: Overall survival Radiographic progression-free survival Confidential Page 60 of 96

63 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Secondary efficacy endpoints: Time to opiate use for cancer pain Time to initiation of cytotoxic chemotherapy Time to deterioration in ECOG performance score by 1 points Time-to-PSA progression based on PCWG2 criteria Other endpoints : PSA response rate [Proportion of patients achieving a PSA decline 50% according to Prostate Cancer Working Group (PCWG2) criteria] Objective response rate in patients with measurable disease (RECIST) Duration of response in patients with measurable disease QoL total score and each subscale score as assessed by FACT-P Time to pain progression Time to analgesic progression 9.7 Efficacy Analysis Population and Methods All randomized patients will be included in the intent-to-treat (ITT) population who will be classified according to their assigned treatment group, regardless of the actual treatment received. Overall survival is defined as the time from randomization to date of death from any cause. Radiographic progression-free survival is defined as the time from randomization to the occurrence of radiographic progression (Section 3.1.1) or death. The analysis of rpfs endpoint will use the centrally reviewed radiographic assessment of progression. The overall 5% level of significance will be used to compare the treatment effect with respect to both OS and rpfs endpoints. The OS and rpfs endpoints will be tested using 0.04 and 0.01 level of significance, respectively. The analyses of the primary endpoints for OS and rpfs are event driven according to the required number of events for each endpoint. If the rpfs endpoint is significant, the results will be summarized for regulatory review, along with the secondary endpoints. If the OS analysis is not significant, the study will continue and the patients will be followed for survival until the required number of events is observed. Distributions of time-to-event variables will be estimated using the Kaplan-Meier productlimit method. The median times to event with two-sided 95% confidence intervals will be estimated. The stratified logrank test will be used as the primary analysis for treatment Confidential Page 61 of 96

64 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 comparison. The estimate of the hazard ratios and their 95% confidence intervals will also be provided. Response rate will be the proportion of patients fulfilling the respective criteria for response. The relative risk (treatment: control) will be reported along with the associated 95% confidence interval. Statistical inference will be evaluated using Chi-square statistic; the Fisher s exact test may be used if the expected counts in some cells are small. Sensitivity analysis for time to event endpoints using non-stratified logrank test and Cox proportional hazards model will also be performed as supportive analyses. Subgroup analyses will be carried out to assess if treatment effects are consistent within subgroup. 9.8 Safety Evaluations Safety analysis will be summarized using the Safety Population. Extent of exposure to study drug will be summarized and details will be provided. Treatment emergent adverse events (AEs) are those events that occur or worsen on or after first dose of study drug up through 30 days post last dose. Adverse events will be coded using the MedDRA coding system and all AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (NCI- CTCAE). Incidence of AEs will be summarized by system organ class (SOC) and preferred term (PT), and will be presented by treatment groups and overall. Adverse events will be summarized by grade, according to the worst grade experienced. In addition, most frequently observed AEs will be summarized by treatment groups. In the summary of AE, an AE occurs more than once within a SOC and PT will be counted only once using the worst grade experienced. Serious AE and deaths will be provided in a listing. All adverse events resulting in discontinuation, dose modification, dosing interruption, and/or treatment delay of study drug will also be listed and tabulated by preferred term. Clinical laboratory test results will be collected pretreatment and through 30 days post last dose of study treatment. All laboratory test results will be classified according to the NCI CTCAE v3.0 criteria. Standard reference ranges will be used for missing or discrepant normal ranges. Baseline laboratory test values are the results from the last blood samples drawn on or prior to the first day of study treatment. On-study laboratory test values are those results from blood samples drawn after the first study treatment up until 30 days after the last dose of study treatment. Mean change from baseline in laboratory test values at each visit will be provided. On-study clinical laboratory test abnormalities will be summarized. Shifts in laboratory test values will also be summarized. Confidential Page 62 of 96

65 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Safety Analysis Population and Methods: All patients who receive any part of a dose of abiraterone acetate or placebo will be analyzed for safety. Safety endpoints will be summarized descriptively for vital signs, adverse events, clinical laboratory parameters, and ECG. Serious adverse events and deaths, and patients discontinued from study treatment will be listed. 9.9 Pharmacokinetics Analysis Approximately patients are scheduled to be enrolled at selected sites for the PK assessment. Based on the 1:1 randomization, this should yield approximately patients on active treatment (abiraterone acetate). Nonlinear mixed effects modeling will be used to develop a population PK model for abiraterone acetate and abiraterone plasma concentrations in CRPC patients. A covariate analysis will be performed to investigate the influence of patient factors on the apparent clearance of abiraterone. Patient factors will include, but are not limited to, body weight, calculated creatinine clearance, liver function, sex, age, race, and time of meal relative to the time of dose administration. Patient factors on other disposition (e.g., apparent volume of distribution) and absorption parameters will be tested in a secondary fashion. A separate report will be generated summarizing the results from the PK modeling and covariate analysis Other Assessments or Analyses In addition, analysis of pharmacoeconomic data and production of a final pharmacoeconomic report will be handled separately from the final clinical study report. Information obtained from the collection of medical resource utilization data may be combined with other data, such as cost data or other clinical parameters, in the production of final pharmacoeconomic report. Confidential Page 63 of 96

66 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, ADMINISTRATIVE CONSIDERATIONS 10.1 Investigators and Study Administrative Structure Investigator Responsibilities The investigator undertakes to perform the study in accordance with ICH Guidelines per Good Clinical Practice (GCP) and the applicable regulatory requirements. A copy of the guidelines will be available in the Investigator Site File. It is the investigator s responsibility to ensure that adequate time and appropriate resources are available at the investigational site prior to commitment to participate in this study. The investigator should also be able to demonstrate a potential for recruiting the required number of suitable patients within the agreed recruitment period. The investigator will maintain a list of appropriately qualified persons to whom the investigator has delegated significant study-related tasks. An up-to-date copy of the curriculum vitae for the investigator and sub-investigator(s) will be provided to Cougar (or its representative) before starting the study. The investigator will inform Cougar of any updates to the list of sub-investigators after the start of the study. If the patient has a primary physician, the investigator should, with the patient s consent, inform them of the patient s participation in the study. Agreement with the final clinical study report will be documented by the signed and dated signature of the principal or coordinating investigator in compliance with ICH E Protocol Adherence and Investigator Agreement The investigator must adhere to the protocol as detailed in this document. The investigator will be responsible for enrolling only those patients who have met protocol eligibility criteria. The investigators will be required to sign an investigator agreement to confirm acceptance and willingness to comply with the study protocol. It is the investigator s responsibility to communicate with their local IRB/IEC to ensure accurate and timely information is provided at all phases during the study. In particular, the appropriate approvals must be in place prior to recruitment, and the IRB/IEC must be informed of study completion. The investigator should also notify the appropriate IRB or ethics committee of serious adverse events occurring at the site and other adverse event reports received from Cougar Biotechnology, in accordance with local procedures and statutes Institutional Review Board (IRB) or Independent Ethics Committee (IEC) Approval It is the responsibility of the investigator to submit this protocol, the final approved informed consent document (approved by Cougar or its representative), relevant supporting information, and all types of patient recruitment or advertisement information (approved by Confidential Page 64 of 96

67 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Cougar or its representative) to the IRB/IEC for review and it must be approved before the study is initiated. Prior to implementing changes in the study, Cougar will produce a protocol amendment and the IRB/IEC must also approve any amendments to the protocol. On the approval letter, the study (title, protocol number and version), the documents reviewed (protocol, informed consent material, amendments) and the date of review should be clearly stated. Drug supplies will not be released and the patient recruitment will not begin until this written approval has been received by Cougar or its designee. The investigator is responsible for keeping the IRB/IEC apprised of the progress of the study and of any changes made to the protocol as deemed appropriate, but in any case at least once a year. The investigator must also keep the IRB/IEC informed of any serious and significant adverse events Ethical Conduct of the Study This protocol accords with the principles of the Declaration of Helsinki as set forth at the 18th World Medicines Association (Helsinki 1964) and amendments of the 29th (Tokyo 1975), the 35th (Venice 1983), the 41st (Hong Kong 1989), the 48th, and the 52nd (Edinburgh 2000) World Medicines Association. As these accords are reviewed and amended periodically, the most current amended version will be in effect Patient Information and Consent It is the responsibility of the investigator to obtain written informed consent from patients. Each patient is requested to sign the Patient Information and Consent Form after the patient has received written information and an explanation of what the study involves, i.e., the objectives, potential benefits and risk, inconveniences and the patient s rights and responsibilities. A copy of the Patient Information and signed Consent Form must be given to the patient. If applicable, it will be provided in a certified translation of the local language. Signed consent forms must remain in each patient s study file and must be available for verification by study monitors at any time. If the IRB/IEC requires modification of this form, the documentation supporting this requirement must be provided to Cougar along with the new version. Cougar reserves the right to reject these modifications, should they not cover the minimum information required by ICH GCP Patient Confidentiality Data collected during this study may be used to support the development, registration or marketing of abiraterone acetate. All data collected during the study will be controlled by Cougar or designee and Cougar will abide by all relevant data protection laws. After patients have consented to take part in the study, their medical records and the data collected during the study will be reviewed by representatives of Cougar and/or the company organizing the research on Cougar s behalf to confirm that the data collected are accurate and for the Confidential Page 65 of 96

68 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 purpose of analyzing the results. These records and data may additionally be reviewed by auditors or by regulatory authorities. The patient s name, however, will not be disclosed outside the hospital. They will be known by a unique patient number. The results of this study may be used in other countries throughout the world that have ensured an adequate level of protection for personal data. Written Authorization (US sites only) or Data Protection Consent (European sites only) is to be obtained from each patient prior to enrollment into the study, and/or from the patient's legally authorized representative in accordance with the applicable privacy requirements [eg, the Health Insurance Portability and Accountability Act of 1996 Standards for Privacy of Individually Identifiable Health Information ( HIPAA ), European Union Data Protection Directive 95/46/EC ( EU Directive ) and any other state and country privacy requirements] Study Monitoring To ensure compliance with relevant regulations, data generated by this study must be available for inspection upon request by representatives of regulatory authorities, Cougar and its representatives, and the IRB/EC for each study site. As a sponsor of this study, Cougar may delegate some administrative aspects of this study to a duly authorized representative including, but not limited to, study initiation, monitoring, and management of SAE reports. Cougar or representative s monitor is responsible for verifying the ecrfs at regular intervals (approximately every 6-8 weeks) throughout the study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; and adherence to local regulations on the conduct of clinical research. The monitor should have access to the patients medical records and other study-related records needed to verify the entries on the ecrfs Case Report Forms Electronic Case Report Forms (ecrfs) will be provided by Cougar or its representative and should be handled in accordance with instructions from Cougar or its representative. The investigator is responsible for maintaining adequate and accurate ecrfs which have been designed to record all observations and other data pertinent to the clinical investigation. Each ecrf should be filled out completely by the investigator or delegate as stated in the Site Delegation List. All data captured for the study is planned to be electronic. However, if necessary, data capture may be performed using paper CRFs. If paper CRFs are used, then all CRFs should be completed in a neat legible manner to ensure accurate interpretation of the data; a black ball-point pen should be used to ensure the clarity of reproduced copies of all CRFs. Incorrect entries should be crossed out with a single line. Corrections must be made adjacent to the item to be altered, initialed and dated with the reason for the correction if necessary, by an authorized (investigator/co-worker) person. Overwriting of this information or use of liquid correcting fluid is not allowed. The ecrfs should be reviewed, signed and dated by the investigator. Confidential Page 66 of 96

69 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Once the site monitor has verified the contents of the completed ecrf pages against the source data, the EDC system will be locked for those pages. Queries may be raised if the data are unclear or contradictory, which must be addressed by the investigator Laboratory Assessments A Central Laboratory will be used to analyze all lab specimens collected for the study. In the rare instance when it is not possible for the site to send a sample to the central lab, the local laboratory results will be captured on supplemental lab ecrfs Independent Data Monitoring Committee (IDMC) An external Independent Data Monitoring Committee (IDMC) will monitor and advise on interim safety and efficacy aspects of the study and relevance of new external information as specified in the IDMC charter. Key safety and efficacy (e.g. SAEs) data will be provided to the IDMC with treatment groups randomly identified (from meeting to meeting) as either X or Y. Treatment group identification may be obtained from the Independent Biostatistician if the IDMC determines that unblinding is necessary to determine whether the study should be stopped early for either safety or efficacy Central Radiologic Review All CT, MRI, and bone scans will be collected centrally for independent review of radiographic progression (a primary endpoint in this study) Protocol Violations/Deviations Protocol violations and deviations should be reported to Cougar (or designee) as they occur or are discovered and should be captured in ecrfs at the time of monitoring Access to Source Documentation Source data to be reviewed during this study will include, but is not restricted to: original source data such as the patient s medical file, patient s diary cards (if applicable), and laboratory test, histology, and pathology reports. All key data must be recorded in the patient s hospital notes/medical chart. The investigator will permit authorized representatives of Cougar, the respective national or local health authorities, and auditors to inspect facilities and records relevant to this study. The monitor (or auditors or regulatory inspectors) will check the CRF entries against the source documents. The consent form will include a statement by which the patients allow the monitor/auditor/inspector from the IEC/IRB or regulatory authority access to source data (eg, patient s medical file, appointment books, original laboratory test reports, X rays etc) that substantiate information in the CRFs. These personnel, bound by professional secrecy, will not disclose any personal information. Confidential Page 67 of 96

70 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Retention of Data As described in the ICH GCP Guidelines, essential documents, including CRFs, source documents, consent forms, laboratory test results, and drug inventory records, should be retained by the investigator until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirements or by an agreement with Cougar. The investigator should obtain written permission from Cougar prior to the destruction of any study document. These records should be made available at reasonable times for inspection and duplication by a properly authorized representative of the Regulatory Authorities Financial Disclosure The investigator will be required to disclose any financial arrangement whereby the value of the compensation for conducting the study could be influenced by the outcome of the study; any significant payments of other sorts from Cougar, such as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation, or honoraria; any proprietary interest in abiraterone acetate; any significant equity interest in Cougar as defined in the US Code of Federal Regulations [21 CFR 54 2(b)]. In consideration of participation in the study, Cougar will pay the investigator, or nominated payee the sums set out in the payment schedule attached to the Investigator Agreement Study Publication Guidelines and Disclosure Policy Cougar Biotechnology ( Sponsor ) encourages publication of results derived from the clinical research it sponsors. Publication includes publication of a paper in a peer-reviewed medical journal, abstract submission with a poster or oral presentation at a scientific meeting, or making results public by some other means. Sponsor will retain the right to review all material prior to presentation or submission for publication, and neither institution(s) nor Study Co-Chairs/Principal Investigator(s) is/are permitted to publish/present the results of the study, in part or in their entirety, without the written authorization of the Sponsor. The review is aimed at complying with 21CFR312.7 (non promotion of investigational drugs) as well as the intellectual property rights and commercial interests of the Sponsor First Publication The results of the entire multi-center study shall be presented in a first publication upon completion of the entire multi-center study (data lock), with authorship being determined by the Sponsor and Protocol Steering Committee using the criteria defined by the International Committee of Medical Journal Editors. At least 2 Sponsor representatives will also be included as coauthors on the first publication of the results of the entire multi-center study to allow recognition of the Sponsor s involvement in the design and execution of the study. Confidential Page 68 of 96

71 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Subsequent Publications Results from data subsets should not be published in advance of and must make reference to the first publication. Publications must include at least 2 Sponsor authors to allow recognition of the Sponsor s involvement. In all publications, the study is to be identified as COU-AA-302. Confidential Page 69 of 96

72 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, REFERENCE LIST 1. Kamangar F, Dores G.M, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24: Jemal A., Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin 2008;58: Jacobs SC. Spread of Prostatic Cancer to Bone. Urology 1983;21(4): Scher, HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: "RECIST"ing a step backwards. Clin Cancer Res 2005;11: Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989;321: Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998;339: Schmitt B, Wilt TJ, Schellhammer PF, DeMasi V, Sartor O, Crawford ED, et al. Combined androgen blockade with nonsteroidal antiandrogens for advanced prostate cancer: a systematic review. Urology 2001;57: Forti G, Salerno R, Moneti G, Zoppi S, Fiorelli G, Marinoni T, et al. Three-month treatment with a long-acting gonadotropin-releasing hormone agonist of patients with benign prostatic hyperplasia: effects on tissue androgen concentration, 5 alphareductase activity and androgen receptor content. J Clin Endocrinol Metab 1989;68: Mohler JL, Gregory CW, Ford OH 3rd, Kim D, Weaver CM, Petrusz P, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res 2004;10: Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004;10: Stigliano A, Gandini O, Cerquetti L, Gazzaniga P, Misiti S, Monti S, et al. Increased metastatic lymph node 64 and CYP17 expression are associated with high stage prostate cancer. J Endocrinol 2007;194: Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 2008; 68: Confidential Page 70 of 96

73 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Logothetis CJ, Wen S, Molina A, Chieffo N, Smith P, Troncoso E, et al. Identification of an androgen withdrawal responsive phenotype in castrate resistant prostate cancer (CRPC) patients (pts) treated with abiraterone acetate (AA). ASCO 2008; 26:Abstract Taplin, ME, Rajeshkumar B, Halabi S, Werner CP, Woda BA, Picus J, et al. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study J Clin Oncol 2003;21: Tomlin SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005;310: Setlur SR, Mertz KD, Hoshida Y, Demichelis F, Lupien M, Perner S, et al. Estrogendependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J Natl Cancer Institute 2008;100: Hegelson BE, Tomlins SA, Shah N, et al. Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusion in prostate cancer. Cancer Res 2008;68: Perner S, Demichelis F, Beroukhim R, et al. TMPRSS2-ERG fusion associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res 2006; 66: Demichelis F, Fall K, Perner S, et al. TMPRSS2-ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 2007; 26: Mehra R, Han B, Tomlins SA, et al. Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate adenocarcinoma: Molecular evidence for an independent group of diseases. Cancer Res 2007; 67: Attard G, Clark J, Ambroisine L, et al. Duplication of the fusion TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 2008; 27: Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical trial of a selective inhibitor of CYP17, arbiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol (in press). 23. Logothetis C, Provenge, FDA Presentation, Mar 29, 2007, Nabhan C, Is Chemotherapy the standard for asymptomatic androgen-independent prostate cancer? J.Clin.Oncol. 2008; 26: Calabro F, Sternberg CN. Current indications for chemotherapy in prostate cancer patients. Eur Urol 2007; 51:17-26 Confidential Page 71 of 96

74 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Basch EM, Somerfield MR, Beer TM, Carducci MA, Higano CS, Scher HI. American Society of Clinical Oncology Endorsement of the Cancer Care Ontario Practice Guidelines on Nonhormonal Therapy for Men With Metastatic Hormone_Refractory (Castration-Resistant) Prostate Cancer. J Clin Oncol 2007; 25: Heidenreich A, Aus G, Abbou CC, Bolla M, Joniau S, Matveev V, et al. Guidelines on Prostate Cancer. European Association of Urology ESMO Clinical Recommendations. Annals of Oncology: 19:Supplement 2, May, Carducci MA, Saad F, Abrahamsson P-A et al: A phase 3 randomized controlled trial of the efficacy and safety of Atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer 2007; 110: Sleep D. Atrasentin, ODAC Presentation, Sept 13, 2005, Small EJ, Sceilhammer PF, Higano CS et al. Placebo-controlled Phase III trial of immunologic therapy with sipuleucel-t CAPC8015 in patients with metastatic, asymptomatic hormone refractory prostate cancer. J.Clin.Oncol 2006; 24: Huggins C, Bergenstal DM. Inhibition of human mammary and prostatic cancers by adrenalectomy. Cancer Res 1952;12: Kruit WH, Stoter G, Klijn JG. Effect of combination therapy with aminoglutethimide and hydrocortisone on prostate-specific antigen response in metastatic prostate cancer refractory to standard endocrine therapy. Anticancer Drugs 2004;15: Dawson N, Figg WD, Brawley OW, Bergan R, Cooper MR, Senderowicz A, et al. Phase II study of suramin plus aminoglutethimide in two cohorts of patients with androgen-independent prostate cancer: simultaneous antiandrogen withdrawal and prior antiandrogen withdrawal. Clin Cancer Res 1998;4: Small EJ, Baron A, Bok R. Simultaneous antiandrogen withdrawal and treatment with ketoconazole and hydrocortisone in patients with advanced prostate carcinoma. Cancer 1997;80: Millikan R. Baez,L, Banerjee T, Wade J, Edwards K, Winn R, et al. Randomized Phase 2 trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate cancer. Urol Oncol 2001;6: Small EJ, Baron AD, Fippin L, Apodaca D.: Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol 1997;157: Confidential Page 72 of 96

75 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a Phase 3 trial (CALGB 9583). J Clin Oncol 2004;22: Itakura H, Vaughn D, Haller DG, O'Dwyer PJ. Rhabdomyolysis from cytochrome p- 450 interaction of ketoconazole and simvastatin in prostate cancer. J Urol 2003;169: Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response Journal of Clinical Oncology 1989, Vol 7, Nishimura K, Nonomura N, Satoh E, et al. Potential mechanisms for the effects of dexamethasone on growth of androgen-independent prostate cancer. JNCI 2001; 93: Li Z, Chen Y, Cao D et al. Glucocorticoid up-regulates transforming growth factor- {beta} (TGF-{beta}) type II receptor and enhances TGF-{beta} signaling in human prostate cancer PC-3 cells. Endocrinology 2006; 147: Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone resistant prostate cancer: a Canadian randomized trial with palliative endpoints. J Clin Oncol 1996; 14: Fossa SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW, et al. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a Phase 3 study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol 2001;19: Small EJ, Meyer M, Marshall ME, Reyno LM, Meyers FJ, Natale RB, et al. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized Phase 3 trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone. J Clin Oncol 2000;18: Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999;17: Morioka M, Kobayashi T, Furukawa Y, Jo Y, Shinkai M, Matsuki, T, et al. Prostatespecific antigen levels and prognosis in patients with hormone-refractory prostate cancer treated with low-dose dexamethasone. Urol Int 2002;68:10-5. Confidential Page 73 of 96

76 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Saika T, Kusaka N, Tsushima T, Yamato T, Ohashi T, Suyama B, et al. Treatment of androgen-independent prostate cancer with dexamethasone: a prospective study in stage D2 patients. Int J Urol 2001;8: Storlie JA, Buckner JC, Wiseman GA, Burch PA, Hartmann LC, Richardson RL. Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate carcinoma. Cancer 1995;76: Smith DC, Redman BG, Flaherty LE, Li L, Strawderman M, Pienta KJ. A phase II trial of oral diethylbestrol as a second line hormonal agent in advanced prostate cancer. Urology 1998; 52: Klotz L, McNeill I, Fleshner N. A phase 1-2 trial of diethylbestrol plus low dose warfarin in advanced prostate carcinoma. J Urol 1999; 161: Oh WK, Kanthoff PW, Weinberg V, Jones G, Rini BI, Derynck MK, et al. Prospective, multicentre, randomized phase II trial of the herbal supplement PC-SPES and diethylbestrol in patients with androgen-independent prostate cancer. J Clin Oncol 2004; 22: Hedlund PO, Jacobsson H, Vaage S, Hahne B, Sandin T, Kontturi, M, et al. Treatment of high-grade, high-stage prostate cancer with estramustine phosphate or diethylstilbestrol. A double-blind study. The SPCG-1 Study Group. Scandinavian Prostate Cancer Group. Scand J Urol Nephrol 1997;31: Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96: Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351: Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351: Berthold DR, Pond G, DeWit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival of the TAX-327 study. Journal of Clinical Oncology 2007;25:Abstract Attard G, Reid A, Barrett M, Karavasilis V, Molife R, Thompson E, et al. Inhibition of androgen synthesis results in a high response rate in castration refractory prostate cancer. In: American Association for Cancer Research Annual Meeting: Proceedings; 2007 Apr 14-18; Los Angeles, CA. Philadelphia (PA): AACR; 2007, Abstract LB Confidential Page 74 of 96

77 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Barrie, SE, Potter GA, Goddard PM, Haynes BP, Dowsett M, Jarman M, et al. Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alphahydroxylase/c17-20 lyase). J Steroid Biochem Mol Biol 1994;50: O'Donnell A, Judson I, Dowsett M, Raynaud F, Dearnaley D, Mason, M, et al. Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer 2004;90: Attard G, Reid A, Yap TA, Raynaud F, Dowsett M, Settatree1 S, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol2008 Oct 1;26(28): Ryan CJ, Rosenberg J, Lin AM, Huey V, Kim JJ, Martins V, et al. C2 Effect of concomitant food intake on pharmacokinetics of abiraterone acetate, a 17 alphahydroxylase C17,20-lyase inhibitor in castration-resistant prostate cancer (CRPC). AACR-EORTC Meeting Abstract C2, Ryan CJ, Rosenberg J, Lin A, Valiente J, Kim J, and Small, EJ. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings 2007;Part I (25)18S (June 20 Supplement): Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am 2001;30(1): de Bono JS, Attard G, Adjei A, et al. Potential applications for circulating tumor cells expressing the insulin-like growth factor-i receptor. Clin Cancer Res 2007;13: de Bono JS, Attard G, Reid A, Parker C, Dowsett M, Mollife R, et al. Abiraterone acetate (AA), a CYP17 inhibitor of androgen synthesis, has significant and durable anti-tumor activity in both chemotherapy naïve and docetaxel pre-treated castration resistant prostate cancer (CRPC). J Clin Oncol 2008 ASCO Annual Meeting Proceedings; 26:Abstract Ryan CJ, Rosenberg J, Lin A, and Small EJ. Phase I evaluation of abiraterone acetate (CB7630), a 17-alpha hydroxylase C17,20-lyase inhibitor in androgen-independent prostate cancer (AiPCa). J Clin Oncol 2007 ASCO Annual Meeting Proceedings; 25:Abstract Sandblom G, Carlsson P, Sennfalt K, Varenhorst E. A population-based study of pain and quality of life during the year before death in men with prostate cancer. Br J Cancer 2004;90: Litwin MS, Lubeck DP, Stoddard ML, Pasta DJ, Flanders SC, Henning JM. Quality of life before death for men with prostate cancer: results from the CaPSURE database. J Urol 2001;165: Confidential Page 75 of 96

78 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, Melmed GY, Kwan L, Reid K. Litwin MS. Quality of life at the end of life: trends in patients with metastatic prostate cancer. Urology 2002;59: Berry DL, Moinpour CM, Jiang CS, Ankerst DP, Petrylak DP, Vinson L. Quality of life and pain in advanced stage prostate cancer: results of a Southwest Oncology Group randomized trial comparing docetaxel and estramustine to mitoxantrone and prednisone. J Clin Oncol 2006;24: Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol 1999;17: Esper P, Mo F, Chodak G, Sinner M, Cella D, Pienta KJ. Measuring quality of life in men with prostate cancer using the functional assessment of cancer therapy-prostate instrument. Urology 1997;50: Carducci M, Nelson JB, Vogelzang NJ, Mulani P. Determination of Clinically Meaningful Change (CMC) for Functional Assessment of Cancer Therapy-Prostate (FACT-P). Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Abstract 8077;23: Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008; 26: Pollen JJ, Witztum KF, Ashburn WL. The flare phenomenon on radionuclide bone scan in metastatic prostate cancer. AJR Am J Roentgenol 1984; 142: Scher HI, Warren M, Heller G. The association between measures of progression and survival in castrate-metastatic prostate cancer. Clin Cancer Res 2007;13: Brundage MD, Crook JM, Lukka H. Use of strontium-89 in endocrine-refractory prostate cancer metastatic to bone. Provincial Genitourinary Cancer Disease Site Group. Cancer Prev Control 1998; 2: Confidential Page 76 of 96

79 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Appendix 1: Schedule of Events Evaluation Screening Day -14 to 1 1 Day 1 of Cycle 1 Table of Scheduled Events Day 15 of Cycle 1 2 Day 1 of Cycles 2, 4, 6, 8, 9, 11, 12 Treatment Phase Day 15 of Cycles 2 and 3 2 Day 1 of Cycles 3, 5, 7, 10, and at Treatment Discontinuation 3 End of Study Treatment Visit 4 X Procedures Signed consent form X Medical history, X demographics, prior prostate therapies QOL - FACT-P X X X BPI-SF, analgesic X X X X X usage Physical exam and X X X X Weight 5 Vital signs 6 X X X X X X ECOG X X X X X X 12 Lead ECG 7 X X X MUGA Scan or X Cardiac ECHO 8 Dosing compliance X X X X Concomitant X X X X X X medications Adverse events X 9 X X X X X 10 Laboratory Assessments Hematology X X X X X Coagulation Factors- X X PT/PTT (INR) Serum chemistry, X X X X X X electrolytes Fasting Glucose X X X Serum Lipids X X X Liver function tests 16 X 16 PSA 11 X X X X Serum testosterone X Urinalysis (dipstick) X Follow-Up Phase Q3 Months up to Month 60 Confidential Page 77 of 96

80 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Evaluation Screening Day -14 to 1 1 Day 1 of Cycle 1 Day 15 of Cycle 1 2 Day 1 of Cycles 2, 4, 6, 8, 9, 11, 12 Treatment Phase Day 15 of Cycles 2 and 3 2 Day 1 of Cycles 3, 5, 7, 10, and at Treatment Discontinuation 3 Tumor Assessments CT / MRI /other X 12 X imaging procedure Bone Scan X 12 X 13 Disease progression X assessment TMPRSS2-ERG (at selected study centers) X PK 14 Sampling at Select Study Centers Pre-dose PK X 14 X 14 X 14 End of Study Treatment Visit 4 Follow-Up Phase Q3 Months up to Month 60 In Clinic Dosing of X 14 X 14 X 14 Study Treatment for PK Post-dose 12-Lead X 14 X 14 X 14 ECG Post dose PK X 14 X 14 X 14 Follow-Up Period Assessments Follow-Up X 15 Assessments 15 1 The Cycle 1 Day 1 visit may occur on the same day as the Screening Visit provided that all screening assessments have been completed and results reviewed prior to the commencement of Cycle 1 Day1 assessments. 2 If patients continue on study without disease progression or discontinuation of treatment beyond Cycle 12, they should receive visit assessments as follows: - At Cycle 13 and every third cycle thereafter (i.e. Cycles 13, 16, 19, 22 ), patients should receive the same assessments as indicated for Cycles 3, 5, 7, and At all other cycles (i.e. Cycles 14, 15, 17, 18, 20, 21 ) they should receive the same assessments as indicated for Cycles 2, 4, 6, 8, 9, 11, and Treatment Discontinuation Visit can occur at any scheduled or unscheduled visit when applicable. At this visit, documentation to confirm progressive disease is required. 4 End of Study Treatment Visit should be scheduled to collect safety assessments between 15 to 28 days after the patient stops treatment. Patients will enter Follow up Phase at that time. 5 Weight will be recorded at every indicated visit. Height will be measured at Screening visit only. 6 Vitals include upright blood pressure, heart rate, respiratory rate, and oral or aural body temperature. 7 ECGs should not be obtained when serum potassium is < 3.5mg/mL. Hypokalemia should be corrected prior to ECG collection. 8 A MUGA scan should be obtained at baseline (up to 28 days prior to Cycle 1 Day 1). A cardiac ECHO can be used if MUGA is not available or when ECHO is standard of care at the study site. 9 Pre-Treatment SAEs should be reported from time patient signs a consent form up to Cycle 1 Day 1 treatment administration. 10 Adverse event follow-up is required for 30 days following last dose to determine if any new or ongoing drug related AE or any SAE regardless of relationship to drug exists. Follow-up could be conducted by sites via telephone attempts and must be documented in source notes. Confidential Page 78 of 96

81 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Treatment Phase Follow-Up Phase 2 Day 1 of Cycles 3, 5, 7, End of Screening 1 Day 1 Day 15 2 Day 1 of Day 15 of 10, and at Study Q3 Months Day of Cycle of Cycle Cycles 2, 4, 6, Cycles 2 Treatment Treatment up to Evaluation -14 to , 9, 11, 12 and 3 Discontinuation 3 Visit 4 Month If patient undergoes a digital rectal exam (DRE), PSA must be sampled prior to the DRE 12 Scans (CT, MRI, and Bone) performed up to 28 days prior to Cycle 1 Day 1 can be used for baseline assessments. 13 If disease progression is observed on the bone scan, confirmatory bone scan is required at least 6 weeks later. Study treatment should be continued in the interim unless there is unequivocal clinical progression as defined in Section 6.6. If the confirmatory scan is negative (does not confirm PD), then the patient should be seen again at the next scheduled study visit as specified in the protocol. 14 Selected Study Centers Only: PK blood samples collected pre and post dose at the following visits: Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 5 Day 1. Patients will be asked to withhold their daily dose and take study treatment following pre-dose PK collection. 15 Follow-up assessments may be collected by telephone interview or chart review. Information will be collected on overall survival, opiate use, ECOG performance status, next therapy for prostate cancer (including dose and treatment duration of cytotoxic chemotherapy), and study treatment related SAEs. 16 Liver function tests include: ALK-P, ALT (SGPT), AST (SGOT), LDH, and direct and total bilirubin Confidential Page 79 of 96

82 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Appendix 2: Study Treatment Preparation and Dispensing Instructions Labeling/Packaging Study treatment (abiraterone acetate and placebo) will be provided to each site packaged for patient assignment at the time of randomization. Packaging includes a 30-day supply. Site pharmacist will dispense the study treatment to each patient in accordance with this protocol under the guidelines of the site s dispensation standard operating procedure. Storage of Study Treatments The study treatment must be stored in a secure area and administered only to patients who entered into the clinical study, at no cost to the patient, in accordance with the conditions specified in this protocol. Investigational product should be stored at the study site at a room temperature between 15ºC to 30º C 59º-86º F. Bottles of study drug should be stored with the cap on tightly and should not be refrigerated as this is a high relative humidity environment. Clinical Supply Inventory The investigator must keep an accurate accounting of the number of investigational units received from Cougar Biotechnology, Inc., dispensed to the patients, the number of units returned to the investigator by the patient, and the number of units returned to Cougar Biotechnology, Inc. during and at the completion of the study. A detailed inventory must be completed for the study treatment. The study treatment must be dispensed only by an appropriately qualified person to patients in the study. The treatment is to be used in accordance with the protocol by patients who are under the direct supervision of an investigator. Return or Disposal of Study Medications/Treatments All clinical study treatments will be returned to Cougar Biotechnology, Inc. or destroyed at the site as specified in writing by Cougar Biotechnology, Inc. Destruction of study treatments at the site should be done in the presence of a Cougar Biotechnology, Inc. representative. Alternatively, destruction of the treatments may be carried out by a suitably qualified person based on written instructions from Cougar Biotechnology, Inc. Confidential Page 80 of 96

83 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Appendix 3: Protocol-Specific PCWG2 Criteria Progressive Disease after Androgen Deprivation Eligibility Criteria: The reference value (#1) is the last PSA measured before increases are documented, with subsequent values obtained a minimum of 1 week apart. If the PSA at time point 3 (value #3A) is greater than that at point 2, then eligibility has been met. If the PSA is not greater than point 2 (value #3B), but value #4 is, the patient is eligible assuming that other criteria are met, if values 3A or #4 are 2 ng/ml or higher. Figure A3.1. Eligibility Based on PSA Confidential Page 81 of 96

84 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Appendix 4: Modified Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference for the COU-AA-302 study: A Phase 3, Randomized, Double-blind, Placebo Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer Eligibility RECIST criteria will be used on measurable soft tissue and visceral lesions Measurable disease - the presence of at least one measurable lesion. If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology. Measurable lesions Visceral or extranodal lesions need to be at least 10 mm in one dimension using spiral CT; however, lymph nodes need to be 20 mm in at least one dimension to be considered as target or evaluable lesions to assess changes in size. Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm), i.e., leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, and also abdominal masses that are not confirmed and followed by imaging techniques. For this study, bone lesions are not considered non-measurable lesions for RECIST. Bone lesions will be assessed by bone scan only. All measurements should be taken and recorded in metric notation, using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 14 days before the beginning of the treatment; nodal and visceral/extra-nodal disease will be recorded separately. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Confidential Page 82 of 96

85 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Methods of Measurement CT and MRI are the best currently available and reproducible methods to measure target lesions selected for response assessment. Conventional CT and MRI should be performed with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Ultrasound (US), endoscopy and laparoscopy should not be used to measure tumor lesions. Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after treatment to differentiate between residual benign lesions and residual malignant lesions. Baseline Documentation of Target and Non-Target Lesions All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor. All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each should be noted throughout follow-up. Evaluation of Target Lesions * Complete Response (CR): Disappearance of all target lesions * Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD * Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions * Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Confidential Page 83 of 96

86 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Evaluation of Non-Target Lesions * Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level * Incomplete Response/ Stable Disease (SD): Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits * Progressive Disease (PD): Appearance of new lesions and/or unequivocal progression of existing non-target lesions (1) (1) Although a clear progression of non target lesions only is exceptional, in such circumstances, the opinion of the treating physician should prevail. Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In general, the patient's best response assignment will depend on the achievement of both measurement and confirmation criteria Response Criteria Target lesions Non-Target lesions New Lesions Overall Response CR CR No CR CR Incomplete No PR response/sd PR Non-PD No PR SD Non-PD No SD PD Any Yes or No PD Any PD Yes or No PD Any Any Yes PD Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be classified as having symptomatic deterioration. Every effort should be made to document the objective progression even after discontinuation of treatment. In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the evaluation of complete response depends on this determination, it is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. Confidential Page 84 of 96

87 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Duration of Overall Response The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started. Duration of Stable Disease Stable disease is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started. Reporting of Results All patients included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). All of the patients who met the eligibility criteria should be included in the main analysis of the response rate. Patients in response categories 4-9 should be considered as failing to respond to treatment (disease progression). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be protocol specific. All conclusions should be based on all eligible patients. Sub-analyses may then be performed on the basis of a subset of patients, excluding those for whom major protocol deviations have been identified. However, these subanalyses may not serve as the basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis should be clearly reported. The 95% confidence intervals should be provided Confidential Page 85 of 96

88 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Appendix 5: National Cancer Institute Common Terminology Criteria for AEs V3.0 (CTCAE): publish date August 9, 2006: Confidential Page 86 of 96

89 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Appendix 6: ECOG Performance Status ECOG Grade Scale (with Karnofsky conversion) 0 Fully active, able to carry on all pre-disease performance without restriction. (Karnofsky ) 1 Restricted in physically strenuous activity but ambulatory and able to carry out work on a light or sedentary nature, eg., light housework, office work. (Karnofsky 70-80) 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. (Karnofsky 50-60) 3 Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. (Karnofsky 30-40) 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. (Karnofsky 10-20) 5 Dead Confidential Page 87 of 96

90 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Appendix 7: Creatinine Clearance Creatinine clearance (CrCl) is to be estimated by using the following formula: Adult male CrCl = (140 - age) x weight measured in kg (72 x serum creatinine measured in mg/deciliter) Confidential Page 88 of 96

91 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Appendix 8: Brief Pain Inventory (Short Form) Confidential Page 89 of 96

92 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Confidential Page 90 of 96

93 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Appendix 9: Quality of Life Confidential Page 91 of 96

94 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Confidential Page 92 of 96

95 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Confidential Page 93 of 96

96 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Appendix 10: Protocol Definition of Chronic Administration of Opiate Analgesia The chronic administration of opiate analgesia will be defined as parenteral opiate use for 7 days or use of WHO Analgesic Ladder Level 3 oral opiates/opioids for moderate or severe pain for 3 weeks ( This includes: Alfentanil Codeine Phosphate Codeine Sulfate Fentanyl Hydrocodone Bitartrate Hydromorphone Levomethadyl Acetate Levorphanol Tartrate Meperdine Methadone Morphine Sulfate Oxycodone Oxymorphone Propoxyphene Sufentanil Citrate Tramadol Confidential Page 94 of 96

97 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Appendix 11: Sponsor Signatures Study Title: A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer Study Number: COU-AA-302 EudraCT No: Protocol Date: February 11, 2009 Version Number: 1.0 This clinical study protocol was subject to critical review and has been approved by the sponsor. The following personnel contributed to writing and/or approving this protocol: Signed: <enter name and credentials> <enter title> <enter affiliation> Date: Signed: <enter name and credentials> <enter title> <enter affiliation> Date: Signed: <enter name and credentials> <enter title> <enter affiliation> Date: Confidential Page 95 of 96

98 Cougar Biotechnology, Inc Clinical Study Protocol: COU-AA-302 February 11, 2009 Appendix 12: Investigator s Signature Study Title: A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer Study Number: COU-AA-302 EudraCT No: Protocol Date: February 11, 2009 Version Number: 1.0 I have read the protocol described above. I agree to comply with all applicable regulations and to conduct the study as described in the protocol. Signed: <enter name and credentials> <enter title> <enter affiliation> <enter address> <enter phone number> Date: Confidential Page 96 of 96

99 Clinical Study Protocol: COU-AA-302 April 2, 2012 Clinical Study Protocol: COU-AA-302 Study Title: A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer Study Number: COU-AA-302 Study Phase: 3 Product Name: Abiraterone acetate IND Number: 71,023 EudraCT No: Indication: Treatment of Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer Investigators: Multicenter Sponsor: Janssen Research & Development* *Janssen Research & Development is a global organization that operates through different legal entities in various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious Diseases BVBA; Janssen R&D Ireland; or Janssen Research & Development, LLC. The term sponsor is used throughout the protocol to represent these various legal entities. Sponsor Clinical Contact: Sponsor Medical Monitor: Effective 01 April 2012, trial sponsorship transferred from Cougar Biotechnology, Inc. to Janssen Research and Development. All references to Cougar in the protocol should be taken to refer to Janssen from that date forwards. Haneefa Wawda, MPH Global Trial Manager Janssen Research & Development, LLC Wilshire Blvd, Los Angeles, CA Phone: Ext Fax: hwawda@its.jnj.com Thomas Griffin, MD Senior Director, Clinical Research Janssen Research & Development, LLC Wilshire Blvd, Los Angeles, CA Phone: Fax: tgriffi1@its.jnj.com Arturo Molina, MD, MS Vice-President, Clinical Research Janssen Research & Development, LLC Wilshire Blvd., Los Angeles, CA Phone: Fax: amolina7@its.jnj.com Date Version Original Protocol: Feb. 11, Confidential Page 1 of 101

100 Clinical Study Protocol: COU-AA-302 April 2, 2012 Amendment 1: April 14, Amendment 2: June 7, Amendment 3: April 2, Confidentiality Statement The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or confidential. Confidential Page 2 of 101

101 Clinical Study Protocol: COU-AA-302 April 2, 2012 SYNOPSIS Sponsor: Janssen Research and Development *Janssen Research & Development is a global organization that operates through different legal entities in various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Infectious Diseases BVBA; Janssen R&D Ireland; or Janssen Research & Development, LLC. The term sponsor is used throughout the protocol to represent these various legal entities. Effective 01 April 2012, trial sponsorship transferred from Cougar Biotechnology, Inc. to Janssen Research and Development. All references to Cougar in the protocol should be taken to refer to Janssen from that date forwards. Name of Finished Product: Abiraterone acetate tablets Name of Active Ingredient: Abiraterone acetate Study Title: A Phase 3, Randomized, Double-blind, Placebo-Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer Study Number: COU-AA-302 Study Phase: 3 Primary Objective: To compare the clinical benefit of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with chemotherapy-naïve castration-resistant prostate cancer (CRPC) who are asymptomatic or mildly symptomatic Secondary Objectives: To establish additional clinically relevant improvements in prostate cancer patients treated with abiraterone acetate in comparison to placebo To characterize the safety profile of abiraterone acetate in this patient population To characterize the pharmacokinetics of abiraterone acetate when administered concurrently with prednisone Study Design: This study is a multinational, multicenter, randomized, double-blind placebo-controlled study with a randomization allocation ratio of 1:1 between the abiraterone acetate group and the placebo group. Abiraterone acetate and placebo tablets will be referred to as study drug in a blinded fashion. Patients randomized to the abiraterone acetate group will receive a dose of 1000 mg daily (QD). Study drug will be administered as 4 x 250-mg abiraterone acetate tablets or 4 placebo tablets. Prednisone will be administered as 5 mg orally twice a day (bid) for both groups. Randomization will be stratified according to the following: ECOG performance status: 0 versus 1 The independent data monitoring committee (IDMC) reviewed the efficacy and safety data Confidential Page 3 of 101

102 Clinical Study Protocol: COU-AA-302 April 2, 2012 from the interim analysis of OS (43% of death events). The IDMC concluded that all of the data pointed to a significant advantage for patients in one arm of the study compared with the other arm. The IDMC unanimously recommended stopping the study, unblinding, and allowing crossover from the placebo arm to active therapy. A brief summary of the efficacy and safety data is provided in Appendix 11. Patients currently receiving placebo will be offered crossover therapy to abiraterone acetate as outlined in Appendix 11. The Schedule of Events for patients who were originally randomized to the abiraterone acetate treatment group will not change. Study Population: Approximately 1,000 medically or surgically castrated male patients with metastatic CRPC who have shown tumor progression and are non- or mildly-symptomatic will be enrolled from approximately 150 global study sites. Test Product, Dose, and Mode of Administration: Abiraterone acetate (CB7630), 1000 mg/day (4 x 250-mg tablets), or matching placebo given orally Duration of Treatment: Patients will have a screening period of up to 14 days prior to randomization on Cycle 1 Day 1. Each cycle consists of 28 days. Patients will be treated until disease progression as defined in the protocol. After discontinuing study treatment, patients will be contacted once every three months up to 60 months (5 years) for survival follow-up. In addition to overall survival, opiate use, ECOG performance status, and next therapy for prostate cancer (including dose and treatment duration of cytotoxic chemotherapy) will also be collected. Efficacy Assessment: The primary efficacy endpoints are Overall Survival (OS) and Radiographic Progression- Free Survival (rpfs) (co-primary). Efficacy assessment in rpfs will utilize sequential imaging studies as defined by PCWG2 and modified RECIST criteria. Survival data will be collected throughout the study treatment phase and during follow-up. Secondary efficacy assessments: Time to opiate use for cancer-related pain and time to administration of cytotoxic chemotherapy for metastatic prostate cancer will be prospectively assessed. ECOG performance status will be evaluated throughout the study to assess time to first deterioration. PSA values will be collected throughout the study to assess time to PSA progression. Safety Assessments: Medical history, vital sign measurements, physical examination, and body weight Concomitant therapy and procedures Adverse events (AEs) and serious adverse events (SAEs), including laboratory test AEs will be graded and summarized according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 Confidential Page 4 of 101

103 Clinical Study Protocol: COU-AA-302 April 2, 2012 Blood chemistry, hematology, coagulation studies, serum lipids, and urinalysis Electrocardiograms (ECGs) Other Assessments: Quality of Life (QoL) using FACT-P Quality of Life questionnaire Medical resource utilization (MRU) information PK measurements at selected sites TMPRSS2-ERG and other biomarkers in primary tumor or in circulating tumor cells (CTC s) at selected sites Confidential Page 5 of 101

104 Clinical Study Protocol: COU-AA-302 April 2, 2012 TABLE OF CONTENTS CLINICAL STUDY PROTOCOL: COU-AA SYNOPSIS...3 TABLE OF CONTENTS...6 LIST OF IN-TEXT TABLES...10 LIST OF IN-TEXT FIGURES...10 LIST OF APPENDICES...10 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS INTRODUCTION Metastatic Castrate Resistant Prostate Cancer Asymptomatic or Mildly Symptomatic Patients with Castrate Resistant Prostate Cancer Second line hormonal therapies for CRPC Adrenal Androgen Inhibitor Glucocorticoids Estrogens Chemotherapy and Bisphosphonates for CRPC Abiraterone Acetate (CB7630) and the Active Metabolite Abiraterone (CB7598) Dosing Rationale Concurrent Prednisone Status of Current Clinical Trials of Abiraterone Acetate Chemotherapy-Naïve Castration-Resistant Prostate Cancer (CRPC) Castration-Resistant Prostate Cancer (CRPC) Post-Docetaxel Clinical Benefits of Current Treatment Quality of Life Assessments Rationale for Study Design and Control Group Radiographic PFS as an Efficacy Endpoint STUDY OBJECTIVES Primary Objective(s) Secondary Objective(s) INVESTIGATIONAL PLAN Overall Study Design and Plan Primary Efficacy Endpoints Secondary Efficacy Endpoints Other Study Endpoints Safety Assessments Other Assessments...28 Confidential Page 6 of 101

105 Clinical Study Protocol: COU-AA-302 April 2, Study Duration and Dates Study Activities Screening Period Randomization Treatment Period Follow-up Period STUDY POPULATION SELECTION Study Population Inclusion Criteria Exclusion Criteria STUDY TREATMENT(S) Description of Treatment(s) Treatments Administered Abiraterone Acetate/Placebo Prednisone Selection and Timing of Dose for Each Patient Randomization Procedures Stratification Blinding Randomization Codes Laboratory Tests Results Accidental Unblinding Concomitant Therapy Prohibited Concomitant Medication Restrictions Potential for Drug-Drug Interactions Treatment Compliance Packaging and Labeling Storage Pharmacy Storage Requirements Storage Requirements For The Patient Investigational Product Retention and Accountability at Study Site STUDY PROCEDURES Informed Consent Medical History Physical Examination Clinical Laboratory Tests Laboratory Parameters Pharmacokinetics (PK) Assessments and Additional ECG Monitoring...40 Confidential Page 7 of 101

106 Clinical Study Protocol: COU-AA-302 April 2, TMPRSS2-ERG and other biomarkers Sample Collection, Storage, and Shipping SAFETY DATA COLLECTION, RECORDING, AND REPORTING Definitions Adverse Events Serious Adverse Events Suspected Unexpected Serious Adverse Reactions (SUSARS) Reporting Procedures for All Adverse Events Severity of Adverse Events Serious Adverse Event Reporting Procedures Long-Term Follow-Up Abnormal Laboratory Results Management of Study Drug-Related Events Management of Hypokalemia Management of Hypertension Side Effects Management of Edema, Fluid Retention Management of Abnormal Liver Function Tests Management of Non-Mineralocorticoid Based Side Effects Dose-Reduction Procedure for Adverse Event Management Criteria for Discontinuation of Study Treatment Withdrawal from Study Treatment Phase STUDY ACTIVITIES Screening Period (Days 14 to Day 1) Treatment Period (Cycle 1 Day 1 to End of Study Treatment) Cycle 1 Day Cycle 1 Day 15 Visit Cycles 2, 4, 6, 8, 9, 11, and 12 Day 1 (Continue every 1 st and 2 nd cycle Beyond Cycle 10, e.g. Cycles 11, 12, 14, 15, 17, 18, 20, 21 ) Day 15 of Cycles 2 and Cycles 3, 5, 7, and 10 (continue every 3 rd cycle beyond Cycle 10, e.g. Cycles 13, 16, 19, 22 ) and Treatment Discontinuation Visit End of Study Treatment Visit Unscheduled Visits Post-Treatment Follow-up Period (Survival or Long-Term Follow-Up) QUALITY CONTROL AND ASSURANCE PLANNED STATISTICAL METHODS General Considerations Determination of Sample Size Sample Size Determination...58 Confidential Page 8 of 101

107 Clinical Study Protocol: COU-AA-302 April 2, Hypothesized OS Hazard Ratio of Hypothesized rpfs Hazard Ratio of Interim and Final Analyses Analysis Populations Demographics and Baseline Characteristics Study Endpoint(s) Efficacy Endpoint(s) Efficacy Analysis Population and Methods Safety Evaluations Safety Analysis Population and Methods: Pharmacokinetics Analysis Other Assessments or Analyses ADMINISTRATIVE CONSIDERATIONS Investigators and Study Administrative Structure Investigator Responsibilities Protocol Adherence and Investigator Agreement Institutional Review Board (IRB) or Independent Ethics Committee (IEC) Approval Ethical Conduct of the Study Patient Information and Consent Patient Confidentiality Study Monitoring Case Report Forms Laboratory Assessments Independent Data Monitoring Committee (IDMC) Central Radiologic Review Protocol Violations/Deviations Access to Source Documentation Retention of Data Financial Disclosure Study Publication Guidelines and Disclosure Policy First Publication Subsequent Publications REFERENCE LIST...68 Confidential Page 9 of 101

108 Clinical Study Protocol: COU-AA-302 April 2, 2012 LIST OF IN-TEXT TABLES Table 1. Inhibition of Cytochrome P450 Enzymes by abiraterone acetate and abiraterone...36 Table 2. List of Laboratory Tests Table 3. Hypokalemia Management...47 LIST OF IN-TEXT FIGURES Figure 1. The Enzyme Complexes Inhibited by Abiraterone...21 Figure 2. Prodrug Abiraterone Acetate is Converted to Abiraterone after Absorption...21 LIST OF APPENDICES Appendix 1: Schedule of Events...76 Appendix 2: Study Treatment Preparation and Dispensing Instructions...79 Appendix 3: Protocol-Specific PCWG2 Criteria...80 Appendix 4: Modified Response Evaluation Criteria in Solid Tumors (RECIST)...81 Appendix 5: National Cancer Institute Common Terminology Criteria for AEs...85 Appendix 6: ECOG Performance Status...86 Appendix 7: Creatinine Clearance...87 Appendix 8: Brief Pain Inventory (Short Form)...88 Appendix 9: Quality of Life...90 Appendix 10: Protocol Definition of Chronic Administration of Opiate Analgesia...93 Appendix 11: Eligibility Criteria and Modified Schedule of Events for Patients who Crossover from Placebo to Abiraterone Acetate After Study Unblinding...94 Appendix 12: Sponsor Signatures Appendix 13: Investigator s Signature Confidential Page 10 of 101

109 Clinical Study Protocol: COU-AA-302 April 2, 2012 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS AAWD ACTH AE AIPC ALT ALK-P AR ASCO AST bid BPI-SF BUN C CALGB CaPSURE CBC CrCl CFR CR CRF CRPC CT CTC CTCAE DHEA-S DRE EAU EC Antiandrogen withdrawal Adrenocorticotropic hormone Adverse event Androgen independent prostate cancer Alanine aminotransferase (SGPT) Alkaline phosphatase Androgen receptor American Society of Clinical Oncology Aspartate aminotransferase (SGOT) Twice daily Brief Pain Inventory Short Form Blood urea nitrogen Celsius Cancer and Leukemia Group B Cancer of the Prostate Strategic Urologic Research Endeavor Complete blood count Creatinine clearance Code of Federal Regulations Complete Response Case Report Form Castration resistant prostate cancer Computed tomography Circulating tumor cells Common Terminology Criteria for Adverse Events Dehydroepiandrosterone sulphate Digital Rectal Exam European Association of Urology Ethics committee Confidential Page 11 of 101

110 Clinical Study Protocol: COU-AA-302 April 2, 2012 ECG ECOG ECHO EORTC-QLQ ESMO EU F FACT-P FISH GCP GGT HEENT Hct Hgb HIPAA HRPC HTN ICH IDMC IEC IND INR IRB ITT IVRS IWRS LD LDH LHRH Electrocardiogram Eastern Cooperative Oncology Group Echocardiogram European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire European Society for Medical Oncology European Union Fahrenheit Functional Assessment of Cancer Therapy-Prostate Fluorescence in situ Hybridization Good Clinical Practice Gamma-glutamyl transferase Head, Eyes, Ears, Nose, Throat Hematocrit Hemoglobin Health Information Portability and Accountability Act Hormone refractory prostate cancer Hypertension International Conference on Harmonization Independent Data Monitoring Committee Independent Ethics Committee Investigational New Drug International normalized ratio Institutional Review Board Intent-to-treat Interactive voice response system Interactive web response system Longest diameter Lactate dehydrogenase Luteinizing hormone releasing hormone Confidential Page 12 of 101

111 Clinical Study Protocol: COU-AA-302 April 2, 2012 MedDRA mg MRI MRU MUGA NCI NYHA OS PCS PCWG PD PFS PO PR PROSQOLI PT PTT PK PSA PSAWG QoL RBC RECIST rpfs SAE SD SGOT SGPT SUSAR Medical Dictionary for Regulatory Activities Milligrams Magnetic resonance imaging Medical resource utilization Multiple Gated Acquisition Scan National Cancer Institute New York Heart Association Overall survival Pain Catastrophizing Scale Prostate Cancer Working Group Progressive disease Progression Free Survival Per Os (by mouth) Partial Response Prostate Cancer Specific Quality of Life Instrument Prothrombin time Partial thromboplastin time Pharmacokinetics Prostate Specific Antigen Prostate Specific Antigen Working Group Quality of life Red blood cell (count) Response evaluation criteria in solid tumors Radiographic Progression Free Survival Serious adverse event Stable disease Serum glutamic oxaloacetic transaminase (AST) Serum glutamic pyruvic transaminase (ALT) Suspected unexpected serious adverse reaction Confidential Page 13 of 101

112 Clinical Study Protocol: COU-AA-302 April 2, 2012 SWOG TTP ULN USP WBC WHO Southwest Oncology Group Time to progression Upper limit of normal United States Pharmacopeia White blood cell (count) World Health Organization Confidential Page 14 of 101

113 Clinical Study Protocol: COU-AA-302 April 2, INTRODUCTION 1.1 Metastatic Castrate Resistant Prostate Cancer Prostate cancer has become an increasingly important health issue globally. With 679,060 men diagnosed each year, prostate cancers are the fifth most common tumor type worldwide [1]. It is estimated by the American Cancer Society that in 2008, prostate cancer will be diagnosed in 186,320 men in the United States alone and that 28,660 will die [2]. The most significant morbidity of prostate cancer is bone metastasis. It develops initially in the axial skeleton and later in the appendicular skeleton [3] in advanced prostate cancer and metastasis to bone is present in > 90% of patients [4]. These lesions can cause pain, skeletal fractures, spinal cord compression, anemia and thrombocytopenia. Clinical sequelae can include pain, paralysis, diminished mobility, fatigue and increased risk of infections. Side effects such as constipation and delirium from analgesics required to palliate pain are also significant. They further compromise patient quality of life. In addition, soft tissue metastasis occurs in about 40% of advanced patients. Pelvic lymphadenopathy may lead to anatomic obstruction of the ureters, or fistula formation [4]. When tumor recurs in the prostate gland or bed, urethral obstruction may also ensue. Prostate cancer is hormone sensitive at the time of initial diagnosis. Although most patients with advanced metastatic disease initially respond to conventional androgen deprivation with medical [5] or surgical [6] castration, the median duration of disease control has been 13 to 22 months and overall survival months [7]. The clinical status of patients after failure of castration is commonly referred to as hormone-refractory prostate cancer (HRPC), or androgen-independent prostate cancer (AIPC). However, recent investigations have established that tumor progression often remains androgen-dependent albeit at much reduced systemic androgen levels after castration. Although used widely in clinical settings, the terms HRPC and AIPC do not reflect the biology of advanced prostate cancer where androgen receptor (AR) and its ligand remain pivotal in tumor growth. Prostate cancer progression after conventional medical or surgical castration should, therefore, be considered castration-resistant prostate cancer (CRPC). Patients with metastatic CRPC have a very limited life expectancy and most often die of their prostate cancer. In the castrate state, ligands to the AR have been thought to be derived primarily from the adrenal glands. Conventional androgen deprivation therapy removes 90% of circulating androgens produced in the gonads. As much as 10% of circulating testosterone remains, in part due to the peripheral conversion of adrenal steroids to testosterone. In addition, several recent studies suggest that androgen levels in the microenvironment of prostate cancer may be maintained in spite of reduced systemic levels [8,9]. In patients with castrate levels of testosterone, the tissue levels of dehydroepiandrosterone, dihydrotestosterone, and androstenedione all remain sufficient to activate the AR. Furthermore, the ARs are predominately located in the nucleus in biopsy tissue, indicating ligand-binding and the activation of androgen-dependent gene expression. Increased expression of the AR is common in advanced prostate cancer, and allows lower ligand levels to more strongly activate the AR [10]. A recent investigation made the observation that in high risk primary Confidential Page 15 of 101

114 Clinical Study Protocol: COU-AA-302 April 2, 2012 prostate tumors and in metastatic biopsies, CYP17A1 gene expression is highly upregulated [11], suggesting the possibility of in situ production of androgens as autocrine or paracrine growth factors despite castration [12]. Similarly, investigators at MD Anderson Cancer Center also detected CYP17 expression by immunohistochemistry in bone marrow metastasis in CRPC [13]. Although these preliminary findings require further corroborating evidence, the need to suppress androgen production in adrenal glands and possibly at tissue levels persists in CRPC. Complete androgen independence in CRPC is thought to be rare. A few patients (9%) have mutations in the AR [14]; these changes could allow the AR to be activated by non-androgen ligands, or might allow ligand-independent AR association with coactivator molecules. Although gene fusions are well known to drive the development of blood cancers and sarcomas, only rarely have they been detected in the common solid cancers. Recent evidence indicates that a gene fusion may be important in the pathogenesis of prostate carcinoma [15,16,17,18,19]. Chromosomal translocations involving the androgen-responsive gene transmembrane protease serine 2 (TMPRSS2) and erythroblast transformation specific (ETS)-related transcription factors ETV1, ETV4, and ETV5, have been identified in 50% to 70% of prostate cancer cases [15,16]. Translocation of TMPRSS2 to the ERG gene, found in a high proportion of human prostate cancer, results in overexpression of the 3'-ERG sequences joined to the 5'-TMPRSS2 promoter. ERG and other ETS family members are transcription factors that are implicated in the control of cell growth and differentiation and the chimeric protein product of the gene translocation appears to retain hormoneresponsiveness [17]. Specific translocations in primary tumors have been associated with more aggressive natural clinical history, more advanced disease at diagnosis and greater lethality [18,19,20,21]. These gene rearrangements may be associated with tumor response to androgen deprivation therapy, including abiraterone [22]. 1.2 Asymptomatic or Mildly Symptomatic Patients with Castrate Resistant Prostate Cancer Approximately 50% of patients with metastatic prostate cancer will have no noticeable symptoms related to the tumor [23]. The optimal management of these patients with asymptomatic or mildly symptomatic metastatic prostate cancer refractory to medical or surgical castration remains undefined [24]. There are no approved second-line hormonal therapies for this population, and cytotoxic chemotherapy (docetaxel or mitoxantrone) is ordinarily reserved for patients with symptomatic or rapidly progressive cancer [25]. The American Society of Clinical Oncology / Cancer Care of Ontario and EAU guidelines for the cytotoxic treatment of CRPC [26,27] emphasize the need to individualize the timing of nonhormonal therapy for prostate cancer and consider routine docetaxel questionable in men who have metastatic disease but lack symptoms. Similarly, the current ESMO guidelines [28] for metastatic prostate cancer recommend that patients with castrate-resistant disease should receive second and possibly third line hormonal therapies, while chemotherapy with docetaxel given every three weeks should be considered for patients with CRPC who are symptomatic [28]. Thus the non-cytotoxic treatment of patients with CRPC who are asymptomatic or mildly symptomatic remains a significant unmet medical need. Confidential Page 16 of 101

115 Clinical Study Protocol: COU-AA-302 April 2, 2012 Patients with metastatic CRPC who are not good candidates for immediate chemotherapy may still benefit from alternate therapies since they develop symptomatic disease progression in a short period of time. This adverse natural history of patients with asymptomatic or mildly symptomatic CRPC was documented in two recent Phase III trials of novel agents in this population. A multinational, double-blind, placebo-controlled trial [29] of the endothelin antagonist atrasentan in patients with metastatic CRPC who had not received chemotherapy and did not require opiates for cancer related pain enrolled 809 men. Patients were randomized 1:1 to receive either atrasentan 10 mg per day or placebo. The primary endpoint was time to disease progression (TTP), which was determined according to radiographic and clinical measures. Analyses of overall survival and changes in biomarkers also were performed. Greater than 50% of patients on both the experimental and control arms developed protocol defined progression in less than 100 days, with 87% of the progressions by radiographic criteria. In addition more than half of patients on the control arm had a 50% worsening of the Pain Catastrophizing Scale (PCS) pain score within 12 months of study entry, primarily due to increasingly painful bone metastases [30]. The median survival was 20.5 months for atrasentan treated patients and 20.3 months for the control patients. A second smaller Phase III study [31] compared the investigational immunotherapy product Sipuleucel-T with placebo in patients with CRPC who had not received chemotherapy. Patients with cancer-related bone pain, those requiring opioid analgesics for cancer pain, and those with visceral metastases were not eligible. Disease progression events included radiographic progression, cancer pain, and clinical events, with the great majority radiographic. The median for time to disease progression (TTP) for Sipuleucel-T was 11.7 weeks compared with 10.0 weeks for placebo. Median survival was 25.9 months for Sipuleucel-T and 21.4 months for placebo. These results demonstrate that patients with asymptomatic or mildly symptomatic CRPC have short times to disease progression and to the rapid appearance of painful metastases, with an approximate overall survival of two years or less. Therefore the development of an alternate non-cytotoxic therapy with an improved safety and toxicity profile, capable of delaying tumor progression, blocking onset or worsening of pain, and improving survival would be of significant clinical benefit to patients with CRPC. The current study is focused on patients with progressive CRPC who are not in immediate need of docetaxel or mitoxantrone due to their lack of moderate to severe bone pain or rapid tumor progression. Patients will be required to have a score of 3 or less on components of the Brief Pain Intensity Short Form. Additionally, opiate use for cancer related pain is prohibited at study entry. Outside of a clinical trial, these mildly symptomatic patients with CRPC would commonly be treated with unapproved second-line hormonal therapies (see Section 1.3). 1.3 Second line hormonal therapies for CRPC Second line hormonal therapies in prostate cancer have limited efficacy, and none have received regulatory approval for this use. Historically, bilateral adrenalectomy was the first second line hormonal therapy to be evaluated [32]. Several of the adrenalectomized patients with widespread bone metastases had decreases in the bulkiness of their prostate tumor, reductions in prostatic acid phosphatase levels, increases in hemoglobin and red blood cell levels, and strikingly, 5 of 7 patients had complete relief of their cancer pain within 48 hours Confidential Page 17 of 101

116 Clinical Study Protocol: COU-AA-302 April 2, 2012 of the surgery. However, patient and physician acceptance of adrenalectomy was low, due to the morbidity of major surgery in an advanced stage cancer patient population Adrenal Androgen Inhibitor Historical attempts to obtain the benefits of total adrenalectomy medically without the side effects of surgery have met with limited success. Aminoglutethimide and ketoconazole both inhibit several adrenal enzymes involved with adrenal androgen synthesis. Modest therapeutic activities on prostate cancer were observed. However, the side effects were significant. For example, in combination with hydrocortisone, aminoglutethimide resulted in a PSA response proportion of 37% with the median duration for responders of nine months in a Phase 2 study [33] at the expense of lethargy, skin rash, hypothyroidism, nausea and vomiting. Its use has been limited [33,34]. Ketoconazole inhibits several adrenal enzymes required for steroid biosynthesis. Its efficacy in prostate cancer in terms of PSA response is comparable to that of aminoglutethimide. Pilot studies in patients after failure of combined androgen blockade where ketoconazole was given simultaneously with anti-androgen withdrawal (AAWD) showed that 55% of patients achieved a 50% PSA decline [35]. When administered after AAWD, 36%-62.5% of patients had a 50% PSA decline [36,37]. In a Phase 3 study conducted by Cancer and Leukemia Group B, PSA response rate was 27% with a median duration of response of 9 months in the group of patients randomized to the combination arm of AAWD and ketoconazole plus hydrocortisone versus the AAWD alone arm [38]. However, ketoconazole inhibits CYP3A4 with substantial risk of drug-drug interactions, such as warfarin and statins [39]. It is often poorly tolerated by patients, with commonly occurring side effects including diarrhea, nausea, vomiting, and depression [36,37,38]. Ketoconazole is not approved for the treatment of CRPC Glucocorticoids Glucocorticoids appear to possess both hormonal and direct anti-tumor effects in prostate cancer. Patients with CRPC may still have hormone-sensitive disease that is stimulated by weak androgens of adrenal origin, and these androgens are suppressed by prednisone through its negative feedback on secretion of adrenocorticotrophic hormone (ACTH). Tannock et al [40] have demonstrated that low-dose prednisone treatment (7.5 to 10 mg daily) led to a decrease in the concentration of serum testosterone in seven of nine patients where it was not initially suppressed below 2.0 nmol/ml, and caused a decrease in serum levels of androstenedione and dehydroepiandrosterone sulfate in more than 50% of patients. These changes were associated with symptomatic and clinical improvement. Glucocorticoids may also have direct inhibitory effects on prostate cancer cells through enhanced growthinhibitory TGF-ß1 signaling and suppression of the transcriptional activities of NF κb. [41,42]. Prednisone, dexamethasone, and hydrocortisone have been frequently administered as standard of care in advanced prostate cancer because of their modest antitumor activity and palliative effects on disease. Two prospective Phase 3 studies have documented the adverse event profile and palliative benefit of prednisone. Prednisone mg daily was examined Confidential Page 18 of 101

117 Clinical Study Protocol: COU-AA-302 April 2, 2012 among 81 patients in one arm of a Phase 3 trial, with 22% of patients achieving a 50% PSA decline and a median time to progression of 4.0 months [43]. Likewise, in a randomized study control arm where 201 patients were treated with prednisone 5 mg twice daily, PSA decline of 50% was observed in 21% of patients [44]. Significant improvements in pain, quality of life and fatigue were also reported. Other glucocorticoids have similar activity in advanced prostate cancer. Hydrocortisone has been evaluated as a control arm in prospective Phase 3 studies. In one study, 231 patients treated with hydrocortisone alone (control arm) showed that 16% of patients achieved a PSA decline of 50% with a median duration of response of 2.5 months [45]. Similarly, 14% of patients given hydrocortisone 40 mg daily achieved a PSA decline 50% lasting a median of 2.3 months in a Cancer and Leukemia Group B (CALGB) study [46]. The antitumor activity of hydrocortisone was slightly lower than prednisone in these Phase 3 studies (14%-16% PSA response rate for hydrocortisone versus 21%-22% PSA response rate for prednisone; median duration of response also favored prednisone). Likewise, dexamethasone has antitumor activity in prostate cancer [47,48,49]. No prostate cancer trials have directly compared 2 glucocorticoids Estrogens Prostate cancer normally expresses estrogen receptors, and estrogenic compounds have been used for the treatment of CRPC. The most commonly used estrogen is diethylstilbestrol (DES), although DES-diphosphate, and the herbal phytoestrogenic supplement, PC-SPES, have also been investigated in clinical trials. Recently, DES has been evaluated in two studies [50,51] including 21 and 32 patients. A positive PSA response was achieved in 43% and 80%, respectively; the estimated survival at 2 years was 63%. However, even at low doses, 31% of the patients developed deep venous thrombosis and 7% experienced myocardial infarction. In another prospective randomized phase II trial, the clinical efficacy of the herbal supplement PC-SPES and DES were tested in a cohort of 90 patients, with PSA progression following initial androgen deprivation [52]. A PSA decline > 50% was noted in 40% with PC-SPES and in 24% with DES. Median time to progression was 5.5 months with PC-SPES and 2.9 months with DES; the differences were statistically not significant. Although estrogens remain an option for the secondary hormonal treatment of CRPC, their use is limited by concerns regarding cardiovascular toxicity [27]. 1.4 Chemotherapy and Bisphosphonates for CRPC Several agents have been approved as palliative therapy for prostate cancer. Estramustine was approved in the 1970s. However, in a randomized study where overall survival was compared, diethystilbesterol was found to be superior to estramustine [53]. In 1996, mitoxantrone and prednisone were approved in the United States for palliation of pain and improvement in quality of life in a randomized study with prednisone as control [43]. However, there was no survival benefit. Recently, zoledronic acid was approved for Confidential Page 19 of 101

118 Clinical Study Protocol: COU-AA-302 April 2, 2012 reduction in skeletal morbidity in solid tumors, including prostate cancer [54]. None of these agents improved the overall or prostate cancer-specific survival of patients with CRPC. Docetaxel is the only agent to date that has demonstrated a survival benefit in CRPC. A 3-weekly docetaxel regimen had a median overall survival of 18.9 months (95% confidence interval ), compared with the mitoxantrone control arm of 16.5 months (95% confidence interval months). The hazard ratio for death was 0.76 (95% confidence interval , p =0.009) in the docetaxel regimen as compared with control [55]. Results from the SWOG Study trial of 770 men (3-weekly docetaxel + estramustine + dexamethasone vs mitoxantrone + prednisone [56]), median overall survival 17.5 months vs 15.6 months, respectively, p=0.02 were consistent with the TAX-327 data. Results from TAX-327 were updated at ASCO Overall survival results were maintained after the additional 2 years of follow-up and an additional 276 deaths [57]. The median survival in the docetaxel 3-weekly arm and mitoxantrone arms were the same as previously reported in 2004, 18.9 months (95% confidence interval ) for docetaxel every 3 weeks plus prednisone, and 16.5 months (95% confidence interval ) for mitoxantrone plus prednisone. In an exploratory subset analysis, benefit was seen in patients who were free of pain at the time therapy was initiated. However, this analysis confirmed only consistency of effect across subpopulations, and the study was not powered to demonstrate survival advantage in asymptomatic patients. Also, the similar benefit produced by docetaxel treatment in patients with or without pain suggests that holding chemotherapy in reserve for asymptomatic patients is a reasonable option. 1.5 Abiraterone Acetate (CB7630) and the Active Metabolite Abiraterone (CB7598) Abiraterone (CB7598) is [17-(3-pyridyl)androsta-5,16-dien-3β-ol] and is a steroidal inhibitor of CYP17 (17α hydroxylase/c17,20-lyase) that blocks two important enzymatic activities in the synthesis of testosterone (Figure 1), based on the observation that nonsteroidal 3 pyridyl esters improve selectivity for inhibition of 17α-hydroxylase/C17,20 lyase. Abiraterone is a potent inhibitor with an apparent inhibition constant of 0.5 nm. Pharmacodynamic studies demonstrated that its effects on adrenal steroid synthesis were consistent with its mechanism of action. Antitumor effects were evident with PSA response and durable objective responses using Response evaluation criteria in solid tumors (RECIST) criteria [58] in Phase 1 and Phase 2 studies conducted to date. Abiraterone acetate (CB7630) is the 3-acetylated analog of abiraterone and thus a pro-drug of abiraterone. The chemical nomenclature of abiraterone acetate is 3β acetoxy-17-(3- pyridyl)androsta-5,16-diene; its empirical formula is C 26 H 33 NO 2 and molecular weight is Once absorbed after oral administration, abiraterone acetate is rapidly converted to the active form, abiraterone (Figure 2). In initial research studies, abiraterone was the predominant, if not the only, metabolite of abiraterone acetate detected in blood, both in preclinical studies [59] and in previously conducted clinical studies [60]. Confidential Page 20 of 101

119 Clinical Study Protocol: COU-AA-302 April 2, 2012 Figure 1. The Enzyme Complexes Inhibited by Abiraterone Figure 2. Prodrug Abiraterone Acetate is Converted to Abiraterone after Absorption Dosing Rationale The dose of abiraterone acetate in this study is 1000 mg daily based on results of two Phase 1 dose-finding studies. In the first Phase 1 study with capsule formulation (COU-AA-001) [61], abiraterone acetate was evaluated for safety, pharmacokinetics, and its effects on adrenal steroid synthesis at dose levels ranging from 250 mg to 2000 mg. Preliminary analysis showed that abiraterone acetate had an acceptable safety profile at all dose levels. Patients have received abiraterone acetate in this study and an extension protocol for up to 30 months. In the second Phase 1 study (COU-AA-002) [62,63] that evaluated the safety and tolerability of abiraterone acetate tablet formulation at doses ranging from 250 to 1000 mg, a daily dose of 1000 mg has also been found to have an acceptable safety profile for further development. Confidential Page 21 of 101

120 Clinical Study Protocol: COU-AA-302 April 2, 2012 Consistent with abiraterone acetate s mechanism of action, hypertension (HTN), hypokalemia, and lower extremity edema were the most commonly-observed drug-related adverse events, which were all manageable with medication. Pharmacokinetic (PK) studies showed increased systemic drug exposure at higher doses. Adrenal metabolite analysis showed inhibition of CYP17 even at low doses of abiraterone acetate and a compensatory increase of corticosterone and deoxycorticosterone. Data from dose-finding studies indicated that when PK, adrenal CYP17 inhibition, and efficacy signals are taken into consideration, the 1000-mg dose offered consistent pharmacological effects without additional side effects. Therefore, the 1000-mg dose has been chosen for further efficacy and safety evaluation in this Phase 3 study Concurrent Prednisone In ongoing studies, some patients receiving abiraterone acetate have been treated concurrently with glucocorticoids, including prednisone. Data from early studies have contributed to the current understanding of the mechanism of abiraterone action. These suggest that a state of mineralocorticoid excess can occur after pharmacologic inhibition of CYP17, with the resulting reduced cortisol levels leading to a compensatory ACTH surge and accompanying hypertension, hypokalemia, and fluid retention [64]. These side effects were readily managed with potassium supplementation, eplerenone (selective mineralocorticoid antagonist), antihypertensive agents, and low dose corticosteroids. Grade 1-2 fatigue was observed in some patients and was associated with discontinuation of corticosteroids as required per Phase 2 protocol entry criteria and extended duration of treatment with abiraterone acetate. Although there was no evidence of an abiraterone dose-response relationship, administration of low dose cortiscosteroids as specified in the study improved symptoms of fatigue and tolerability of abiraterone acetate, including symptoms of mineralocorticosteroid excess. The improved tolerability of abiraterone acetate after concomitant administration of low-dose corticosteroids was associated with suppression of ACTH and upstream adrenal steroids, suggesting that this combination may be a better tolerated and safer regimen in this older and frail patient population. Prednisone was selected over other corticosteroids because it is commonly used as standard of care [27] in combination with approved chemotherapy agents or as a monotherapy for palliation of symptoms. The safety and efficacy evaluation of abiraterone acetate with concurrently administered prednisone is continuing in ongoing Phase 2 and 3 studies. The regimen of abiraterone acetate 1000 mg daily and low dose prednisone 5-mg twice daily has been chosen as the experimental intervention arm in this study Status of Current Clinical Trials of Abiraterone Acetate Over two hundred seventy (270) patients have been treated to date with abiraterone acetate in Phase I and II studies, with approximately 240 patients at the 1000-mg dose level Chemotherapy-Naïve Castration-Resistant Prostate Cancer (CRPC) Following selection of the 1000-mg dosing regimen, the COU-AA-001 study enrolled additional patients to further evaluate antitumor activity in chemotherapy-naïve CRPC Confidential Page 22 of 101

121 Clinical Study Protocol: COU-AA-302 April 2, 2012 patients. Chemotherapy-naïve men (n = 54) with CRPC resistant to multiple hormonal therapies were treated in this two-stage phase I/II study. Declines in PSA 30%, 50% and 90% were observed in 43 (80%), 38 (70%) and 14 (24%) of patients respectively. Radiological evaluation reported disease regression by RECIST (CR or PR) in 52% of patients. Falls in circulating tumor cell counts [65], normalization of lactate dehydrogenase and improving symptoms with a reduction in analgesic use were commonly documented. Twenty-three patients have received abiraterone acetate capsules for more than 12 months as part of an extension protocol [58,66]. Similar responses rates have been seen in COU-AA-002, a parallel Phase I/II study investigating a tablet formulation [67] Castration-Resistant Prostate Cancer (CRPC) Post-Docetaxel Two Phase 2 studies (COU-AA-003 and COU-AA-004) in post-docetaxel CRPC patients are also being conducted. Preliminary results are available from the COU-AA-003 study. Fortyseven evaluable patients have been recruited. In an analysis of 28 patients, 14 have achieved PSA declines 50% and the median time to PSA progression is 167 days (24 weeks). Eighteen patients had measurable lesions at baseline and 4 (22%) of these had a confirmed radiologic PR. Eleven patients have been on treatment for more than a year. To date, no relationship has been found between true progression on prior docetaxel chemotherapy or stopping docetaxel for another reason such as toxicity, and response to abiraterone. (Refer to the current version of the abiraterone acetate Investigator s Brochure for additional or updated information). 1.6 Clinical Benefits of Current Treatment Quality of Life Assessments Observational studies have documented a rapid decline in health status in CRPC. A population-based sample of 1,243 patients was followed in Sweden during the year prior to their death from prostate cancer using the brief pain inventory short form (BPI-SF) and the Euro EQ-5D quality of life survey instruments. Declines across scales were highest in the 8 months preceding death [68]. Similarly, Litwin et al [69] and Melmed et al [70] assessed qualify of life (QOL) in metastatic prostate cancer patients in Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database from the United States. Declines across all 8 domains measured by the SF-36 were found during the 12 months prior to death. In contrast to observational studies, the TAX-327 interventional study found that global QOL measured by the FACT-P was improved for both docetaxel regimens [55], although only the 3-weekly docetaxel arm had improved survival over mitoxantrone in this study. In the SWOG study, a significant survival advantage was found for docetaxel plus estramustine compared with mitoxantrone and prednisone; QOL was assessed with the EORTC-QLQ-C30 instrument and the prostate subscale PR25 QOL [71] and pain palliation did not favor either study arm. In the Canadian study comparing mitoxantrone and prednisone with prednisone alone in advanced prostate cancer, the PROSQOLI and EORTC QLQ-C30 and prostate specific subscale QOLM-P14 were used, demonstrating that patients in the mitoxantrone arm had greater and longer lasting improvements in QOL [72]. Confidential Page 23 of 101

122 Clinical Study Protocol: COU-AA-302 April 2, 2012 Though there is no consensus on the best QOL instrument to use in interventional trials, the FACT-P has been selected for use in this trial based on several factors: 1) its content and psychometric properties have been well validated [73], and 2), clinically meaningful changes in the FACT-P have been determined by validation comparisons with clinical measures of disease burden [74]. 1.7 Rationale for Study Design and Control Group There is no standard therapy for asymptomatic or mildly symptomatic patients with CRPC. Abiraterone acetate has shown significant antitumor activity in a Phase II trial in symptomatic and asymptomatic chemo naive patients with CRPC. Its safety profile and tolerability appears reasonable in this population when given in combination with prednisone. Phase 2 studies were also conducted to evaluate the safety and efficacy of abiraterone acetate in CRPC patients receiving low dose prednisone [13,75]. Adverse events known to be associated with abiraterone acetate monotherapy, namely, hypokalemia, hypertension, and fluid retention appear to be less frequent when abiraterone acetate is used in combination with low-dose prednisone. The high degree of antitumor activity, as shown by PSA response, demonstrated by abiraterone in combination with prednisone in patients with CRPC together with a favorable toxicity profile supports the study of this regimen in a Phase III trial. Although this trial is blinded, randomized and placebo controlled for abiraterone acetate, patients on the control arm will receive active treatment in the form of prednisone. Prednisone 5 mg bid has been selected for use in both study treatment groups. Prednisone therapy of patients with CRPC is not simply a palliative intervention, but is associated with direct hormonal antitumor effects. The current EAU Guidelines for secondary hormonal therapy of patients with CRPC recommend treatment with adrenal testosterone inhibitors, low-dose DES, or glucocorticoids such as prednisone/prednisolone as standard approaches [27]. Therefore patients will receive either abiraterone acetate or placebo in a double-blinded manner, but also receive an active control in the form of prednisone rather than no treatment. The primary hypothesis of this randomized, double-blind, placebo-controlled study is that patients receiving abiraterone acetate and prednisone will have improved overall survival (OS) and/or radiographic progression-free survival (rpfs) compared with patients receiving placebo and prednisone. Radiographic progression requires visceral or soft-tissue progression on CT or MRI scans using modified RECIST criteria (Appendix 4), or, more commonly, appearance of new bone metastases on radionuclide scans [75]. Assessment of bone scan worsening of individual lesions can be problematic; this study will utilize bone scan standards for disease progression recommended by the PCWG2 criteria [75], and the rpfs endpoint will be based on independent radiologic review by blinded assessors. This endpoint is more rigorous than the composite endpoints used in previous Phase III trials in CRPC in that it is objective, prospectively defined, and capable of thorough review and confirmation by an independent referee. Confidential Page 24 of 101

123 Clinical Study Protocol: COU-AA-302 April 2, 2012 In addition, secondary endpoints will allow a direct estimation of the clinical benefit of delay in radiographic progression. Data on time to opiate administration for cancer pain, time to chemotherapy for metastatic prostate cancer, and time to deterioration in performance status will be collected prospectively using clear definitions of events. This should allow a comprehensible clinical context for improvements in time to radiographic progression. Standard secondary endpoints of efficacy in CRPC (time-to-psa progression based on PCWG2 criteria) will also be measured. 1.8 Radiographic PFS as an Efficacy Endpoint Clinical research in prostate cancer has been hindered by the difficulty in objectively defining cancer progression. Previous studies have used composite endpoints that included a mixture of patient reported, radiographic, and skeletal-related events. These composite endpoints attempted to address the complexity of clinical prostate cancer but suffered from subjectivity, difficulties in prospective definition, and were not amenable to independent review. Radiographic PFS as defined in this protocol is not a composite endpoint; each measurement is objective and associated with clinical significance. The issues from using RECIST criteria alone to define radiographic progression in prostate cancer are well documented. Fewer than 50% of men with CRPC have measurable lesions greater than 2cm in size, and most of these lesions are in lymph nodes which impact survival less than visceral metastases [4]. Conventional RECIST also lacks provisions to differentiate true progression of bone metastasis from the flare phenomenon on bone scan due to healing of previous bone metastasis [76,77]. Although radiographic PFS has not been established as a strong predictor for overall survival in a small study of patients receiving docetaxel therapy, it was found to outperform PSA based progression [77]. Previous development programs (atrasentan [29] and docetaxel-treated patients [55]) have shown that two factors can limit the correlation of radiographic PFS with survival in CRPC. These will be mitigated in this study. First, analyses of PFS have highlighted the difficulty in determining treatment effects based on PFS when the interval between assessments (12 weeks) was similar to the length of PFS. For this reason, the interval between radiographic assessments is 8 weeks over the first 24 weeks of the study, then every 12 weeks thereafter. Second, because early progression events could be confounded by tumor flare phenomenon, in this study new consensus guidelines will be applied to define progression requiring confirmatory bone scans at least six weeks after the original scan. This will reduce the number of false positive determinations of CRPC progression. rpfs in the study will be determined by an independent central reader blinded to PSA and other clinical data. Progression of metastatic bone disease is of paramount importance to CRPC patients since it is responsible for the severe morbidity of the skeletal related events such as fracture, pain, spinal cord compression, pre-emptive surgery or radiation for impeding fracture or spinal cord compression. In addition, painful bone metastasis often requires radiation, chemotherapy or radionuclide therapy [78]. Similarly, progression of soft tissue metastasis Confidential Page 25 of 101

124 Clinical Study Protocol: COU-AA-302 April 2, 2012 may be associated with clinically significant morbidity. Prevention of disease progression in pelvic and para-aortic lymph nodes reduces the risk for urinary outlet tract obstruction requiring invasive stent placement that is frequently complicated by infection. Development of liver metastasis could lead to organ failure and death. Thus, delay in cancer progression should result in clear clinical benefit to the patient. In conclusion, rpfs as defined above is an objective and verifiable measurement likely to predict clinical benefit in the proposed study populations. 2 STUDY OBJECTIVES 2.1 Primary Objective(s) To compare the clinical benefit of abiraterone acetate plus prednisone versus placebo plus prednisone in patients with chemotherapy-naïve castration-resistant prostate cancer (CRPC) who are asymptomatic or mildly symptomatic. 2.2 Secondary Objective(s) The secondary objectives of this study are: To establish additional clinically relevant improvements in prostate cancer patients treated with abiraterone acetate in comparison to placebo To characterize the safety profile of abiraterone acetate in this patient population To characterize the pharmacokinetics of abiraterone acetate when administered concurrently with prednisone 3 INVESTIGATIONAL PLAN The independent data monitoring committee (IDMC) reviewed the efficacy and safety data from the interim analysis of OS (43% of death events). The IDMC concluded that all of the data pointed to a significant advantage for patients in one arm of the study compared with the other arm. A brief summary of the efficacy and safety data is provided in Appendix 11. The IDMC unanimously recommended stopping the study, unblinding, and allowing crossover from the placebo arm to active therapy. Patients currently receiving placebo will be offered crossover therapy to abiraterone acetate as outlined in Appendix 11. The Schedule of Events for patients who were originally randomized to the abiraterone acetate treatment group will not change. 3.1 Overall Study Design and Plan This is a Phase 3 multinational, multicenter, randomized, double-blind, placebo-controlled study with a randomization allocation ratio of 1:1 (abiraterone acetate + prednisone: placebo + prednisone). This study will be conducted at approximately 150 investigative sites and approximately 1000 patients will be enrolled. Confidential Page 26 of 101

125 Clinical Study Protocol: COU-AA-302 April 2, Primary Efficacy Endpoints Overall survival (OS) and radiographic progression-free survival (rpfs) are co-primary endpoints. Overall survival is defined as the time from randomization to date of death from any cause. Radiographic progression-free survival is based on parameters suggested by PCWG2 [75] and modified RECIST as the time from randomization to the occurrence of one of the following: 1. A patient is considered to have progressed by bone scan if: a. The first bone scan with 2 new lesions compared to baseline is observed <12 weeks from randomization and is confirmed by a second bone scan taken 6 weeks later showing 2 additional new lesions (a total of 4 new lesions compared to baseline); b. The first bone scan with 2 new lesions compared to baseline is observed 12 weeks from randomization and the new lesions are verified on the next bone scan 6 weeks later (a total of 2 new lesions compared to baseline). 2. Progression of soft tissue lesions measured by CT or MRI as defined in modified RECIST criteria. 3. Death from any cause Secondary Efficacy Endpoints The secondary endpoints for this study include: Time to opiate use for cancer pain Time to initiation of cytotoxic chemotherapy Time to deterioration in ECOG performance score by 1 point Time-to-PSA progression based on PCWG2 criteria Other Study Endpoints PSA response rate [Proportion of patients achieving a PSA decline 50% according to Prostate Cancer Working Group (PCWG2) criteria] Objective response rate in patients with measurable disease (RECIST) Duration of response in patients with measurable disease QoL total score and each subscale score as assessed by FACT-P Time to pain progression Time to analgesic progression Confidential Page 27 of 101

126 Clinical Study Protocol: COU-AA-302 April 2, Safety Assessments Medical history, vital sign measurements, physical examination, and body weight Concomitant therapy and procedures Adverse events (AEs) and serious adverse events (SAEs) including laboratory test AEs will be graded and summarized according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 (Appendix 5) Blood chemistry, hematology, coagulation studies, serum lipids, and urinalysis Electrocardiograms (ECGs) Other Assessments Quality of Life (QOL) using FACT-P Quality of Life questionnaire Medical resource utilization (MRU) information PK measurements at selected sites TMPRSS2-ERG and other biomarkers in primary tumor or circulating tumor cells (CTC s) at selected sites Study Duration and Dates The study period will consist of screening, treatment, and follow-up phases. In this study, patients will receive study treatment (abiraterone acetate or placebo) plus prednisone until radiographic progression of disease and/or unequivocal clinical progression as defined in Section 6.6. Follow-up will continue for 60 months (5 years) or until patient dies, is lost to follow-up, or withdraws informed consent. 3.2 Study Activities Screening Period All patients must sign a written informed consent form before study specific screening procedures are performed. Screening procedures to evaluate patient eligibility for the study will be conducted within 14 days prior to Cycle 1 Day 1. If the patient meets eligibility and screening requirements he will be randomized and will return to the site for the Cycle 1 Day 1 visit and dosing Randomization Once eligibility is confirmed, patients will be randomized to a treatment group according to the randomization schedule. All patients must commence treatment within 72 hours (3 calendar days) of randomization. Confidential Page 28 of 101

127 Clinical Study Protocol: COU-AA-302 April 2, Treatment Period Randomized patients will have Cycle 1 Day 1 procedures and receive study treatment (abiraterone acetate or placebo) that will subsequently be administered orally once daily. Patients who participate in the pharmacokinetics testing will take their Day 1 dose of Cycles 1, 2 and 5 in the clinic. All patients will also take 5 mg of prednisone or prednisolone orally twice daily. In regions where prednisone is not marketed or available, prednisolone will be provided. If a patient has been receiving glucocorticoids other than prednisone or prednisolone, it will be necessary to switch the glucocorticoid to prednisone or prednisolone 5 mg bid prior to Cycle 1 Day 1. No crossover will be permitted between the 2 treatment groups. Each cycle of treatment will be 28 days. Patients will return for a Cycle 1 Day 15 visit ± 2 days to evaluate safety and dosing adherence (a count of study drug tablets), with additional safety visits at Cycle 2 Day 15 and Cycle 3 Day 15. From Cycle 2 to End of Study Treatment, Day 1 visits will occur every 28 days with a ± 2 day window. Study windows are to be calculated from Cycle 1 Day 1 date, and if utilized, every effort will be made for the patient to return to schedule. Patients may have additional imaging visits up to 8 days before Cycles requiring images (Cycle 3 Day 1, Cycle 5 Day 1, Cycle 7 Day 1, Cycle 10 Day 1 and every 3 rd cycle beyond Cycle 10) or at Treatment Discontinuation Visit Follow-up Period During the Follow-up Period, overall survival, opiate use, ECOG performance status, and next therapy for prostate cancer should be assessed every 3 months for up to 60 months (5 years) and may be collected by telephone interview or chart review. During the Follow-up Period, deaths regardless of causality and serious adverse events thought to be related to study treatment (abiraterone acetate or placebo) will be collected and reported within 24 hours of discovery or notification of the event. See Appendix 1, Schedule of Events. 4 STUDY POPULATION SELECTION 4.1 Study Population Approximately 1000 medically or surgically castrated male patients with metastatic CRPC who have shown tumor progression and are non- or mildly-symptomatic by prospectively defined criteria (Section 4.2) will be enrolled from approximately 150 global study sites. 4.2 Inclusion Criteria Each patient must meet the following criteria to be enrolled in this study. 1. Willing and able to provide written informed consent Confidential Page 29 of 101

128 Clinical Study Protocol: COU-AA-302 April 2, Written Authorization for Use and Release of Health and Research Study Information (US sites only) or Data Protection Consent (European sites only) has been obtained 3. Male aged 18 years and above 4. Histologically or cytologically confirmed adenocarcinoma of the prostate 5. Metastatic disease documented by positive bone scan or metastatic lesions other than liver or visceral metastasis on CT, MRI. If lymph node metastasis is the only evidence of metastasis, it must be 2 cm in diameter 6. Prostate cancer progression documented by PSA according to PCWG2 or radiographic progression according to modified RECIST criteria 7. Asymptomatic or mildly symptomatic from prostate cancer. A score of 0-1 on BPI-SF Question #3 (worst pain in last 24 hours) will be considered asymptomatic, and a score of 2-3 will be considered mildly symptomatic. 8. Surgically or medically castrated, with testosterone levels of < 50 ng/dl (< 2.0 nm). If the patient is being treated with LHRH agonists (patient who have not undergone orchiectomy), this therapy must have been initiated at least 4 weeks prior to Cycle 1 Day 1 and must be continued throughout the study. 9. Previous anti-androgen therapy and progression after withdrawal. Patients who received combined androgen blockade with an anti-androgen must have shown PSA progression after discontinuing the anti-androgen prior to enrollment ( 4 weeks since last flutamide, 6 weeks since last bicalutamide or nilutamide). 10. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or Hemoglobin 10.0 g/dl independent of transfusion 12. Platelet count 100,000/µL 13. Serum albumin 3.5 g/dl 14. Serum creatinine < 1.5 x ULN or a calculated creatinine clearance 60 ml/min (see Appendix 7) 15. Serum potassium 3.5 mmol/l 16. Liver function: i. Serum bilirubin < 1.5 x ULN (except for patients with documented Gilbert s disease) ii. AST or ALT < 2.5 x ULN 17. Able to swallow the study drug whole as a tablet 18. Life expectancy of at least 6 months 19. Patients who have partners of childbearing potential must be willing to use a method of birth control with adequate barrier protection as determined to be acceptable by the principal investigator and sponsor during the study and for 13 weeks after last study drug administration. Confidential Page 30 of 101

129 Clinical Study Protocol: COU-AA-302 April 2, Exclusion Criteria Patients who meet any of the following criteria will be excluded from the study: 1. Active infection or other medical condition that would make prednisone/prednisolone (corticosteroid) use contraindicated 2. Any chronic medical condition requiring a higher dose of corticosteroid than 5mg prednisone/prednisolone bid. 3. Pathological finding consistent with small cell carcinoma of the prostate 4. Liver or visceral organ metastasis 5. Known brain metastasis 6. Use of opiate analgesics for cancer-related pain, including codeine and dextropropoxyphene, currently or anytime within 4 weeks of Cycle 1 Day 1 7. Prior cytotoxic chemotherapy or biologic therapy for the treatment of CRPC 8. Radiation therapy for treatment of the primary tumor within 6 weeks of Cycle 1, Day 1 9. Radiation or radionuclide therapy for treatment of metastatic CRPC 10. Previously treated with ketoconazole for prostate cancer for greater than 7 days 11. Prior systemic treatment with an azole drug (e.g. fluconazole, itraconazole) within 4 weeks of Cycle 1, Day Prior flutamide (Eulexin) treatment within 4 weeks of Cycle 1, Day 1 (patients whose PSA did not decline for three or more months in response to antiandrogen given as a second line or later intervention will require only a two week washout prior to Cycle 1, Day 1) 13. Bicalutamide (Casodex), nilutamide (Nilandron) within 6 weeks of Cycle 1 Day 1 (patients whose PSA did not decline for three or more months in response to antiandrogen given as a second line or later intervention will require only a two week washout prior to Cycle 1, Day 1) 14. Uncontrolled hypertension (systolic BP 160 mmhg or diastolic BP 95 mmhg). Patients with a history of hypertension are allowed provided blood pressure is controlled by anti-hypertensive treatment 15. Active or symptomatic viral hepatitis or chronic liver disease 16. History of pituitary or adrenal dysfunction 17. Clinically significant heart disease as evidenced by myocardial infarction, or arterial thrombotic events in the past 6 months, severe or unstable angina, or New York Heart Association (NYHA) Class II-IV heart disease or cardiac ejection fraction measurement of < 50% at baseline 18. Atrial Fibrillation, or other cardiac arrhythmia requiring therapy 19. Other malignancy, except non-melanoma skin cancer, with a 30% probability of recurrence within 24 months Confidential Page 31 of 101

130 Clinical Study Protocol: COU-AA-302 April 2, Administration of an investigational therapeutic within 30 days of Cycle 1, Day Any condition which, in the opinion of the investigator, would preclude participation in this trial. 5 STUDY TREATMENT(S) 5.1 Description of Treatment(s) Study Drug Abiraterone acetate 250-mg tablets are oval, white to off-white and contain abiraterone acetate and compendial (USP/NF/EP) grade lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, povidone, sodium lauryl sulfate, magnesium stearate, colloidal silicon dioxide, and purified water, in descending order of concentration (the water is removed during tabletting). Placebo Placebo will be provided as a tablet formulation and will be matched in size, color (white to off-white), and shape (oval) to abiraterone acetate tablets to maintain the study blind. Prednisone Prednisone (5-mg tablets) will be prescribed or provided. Where prednisone is not commercially available, prednisolone will be substituted. Prednisone tablets are open label. 5.2 Treatments Administered Abiraterone Acetate/Placebo Patients will be instructed to take 4 tablets (abiraterone acetate or placebo) orally (PO) at least 1 hour before a meal or 2 hours after a meal Prednisone Patients will be instructed to take 5-mg prednisone, twice daily. 5.3 Selection and Timing of Dose for Each Patient Each treatment cycle consists of 28 consecutive days. Patients may take study treatment (abiraterone acetate plus prednisone or placebo plus prednisone) until radiographic disease progression and/or unequivocal clinical progression (as defined in Section 6.6), at which time study treatment will be discontinued. If the patient had radiographic progression but no unequivocal clinical progression, and alternate treatment is not initiated, the patient may continue on study treatment at the Investigator s discretion (see Section 6.6). The dose of prednisone will be gradually reduced if clinically indicated.it is not required for the Confidential Page 32 of 101

131 Clinical Study Protocol: COU-AA-302 April 2, 2012 prednisone to be taken at the same time as study treatment (abiraterone acetate or placebo). The dose of prednisone will remain unchanged in the event that the study drug dose is changed. If a prednisone dose is missed, it should be omitted and will not be made up. 5.4 Randomization Procedures Patients will be randomized after the investigator has verified that all eligibility criteria have been met. Patients will be randomized to receive abiraterone acetate plus prednisone or placebo plus prednisone in a 1:1 ratio. Randomization will take place across all study sites using a centralized Interactive Web/Voice Response System (IWRS/IVRS). At randomization, the IWRS/IVRS will assign a unique patient identification number to each patient. The patient s identification number will be used on all study-related documents including case report forms (CRFs). A treatment number will also be assigned to each patient. This treatment number is the link between a patient s CRF and blinded treatment group assignment. Patient identification numbers will not be reused. Patients withdrawn from the study will not be replaced. All patients must commence treatment within 72 hours (3 calendar days) of randomization. 5.5 Stratification In this study, patients will be stratified according to baseline ECOG performance status (0 versus 1). Patients withdrawn/discontinued from the study will not be replaced. 5.6 Blinding This is a randomized, double-blind study. Patients will receive abiraterone acetate plus prednisone or placebo plus prednisone. At the time of disease progression, patient treatment assignments will remain blinded. The following precautions are to be taken to ensure that blinding is adequately maintained throughout the study Randomization Codes The treatment to which a patient is assigned will be determined by IWRS/IVRS (Section 5.4). A randomization schedule will be generated and maintained within the IWRS/IVRS. All study personnel will be blinded to the patient treatment assignments Laboratory Tests Results In order to maintain the blind, the Central Laboratory will not send PK and TMPRSS2-ERG results to the sites and will not transfer results to the clinical database until the blind is broken. Investigators must not obtain local laboratory serum testosterone after Cycle 1 Day 1, as this measurement may unblind the patient. Similarly, investigators must not obtain post-baseline circulating tumor cell measurements, as these may bias the investigator s decision-making on the study. Confidential Page 33 of 101

132 Clinical Study Protocol: COU-AA-302 April 2, Accidental Unblinding If a patient s treatment assignment is accidentally unblinded, that patient should remain in the study and continue treatment with the assigned treatment and all protocol tests and assessments. Unblinding information will be captured in the CRF. 5.7 Concomitant Therapy The use of any concurrent medication from screening and while on study, prescription or over-the-counter, is to be recorded on the patient's CRF along with the reason the medication was taken. In addition, tobacco and alcohol use will be collected. Concurrent enrollment in another clinical investigational drug or device study is prohibited. Supportive care medications are permitted with their use following institutional guidelines. For patients who did not undergo orchiectomy, concurrent treatment with LHRH analogue is mandatory and must be recorded. The following supportive care medications are considered permissible during the study: Luteinizing hormone-releasing hormone (LHRH) agonists to maintain testosterone <50ng/dL (< 2.0 nm) Conventional multivitamins, selenium and soy supplements Additional systemic glucocorticoid administration such as stress dose glucocorticoid is permitted if clinically indicated for a life threatening medical condition, and in such cases, the use of steroids will be documented as concomitant drug Bisphosphonate usage is allowed only if patients are on the medication prior to Study Day 1 Transfusions and hematopoietic growth factors per institutional practice guidelines If the permissibility of a specific drug/treatment is in question, please contact the study sponsor. 5.8 Prohibited Concomitant Medication Restrictions The concurrent administration of other anticancer therapy, including cytotoxic, hormonal (except LHRH agonists), or immunotherapy is prohibited during study treatment phase. Use of other investigational drug therapy for any reason is prohibited. Bisphosphonate usage is allowed only if patients are on the medication prior to randomization. New bisphosphonate therapy cannot be initiated after randomization. Concomitant therapy during the treatment phase of the study with any of the following listed is prohibited: 5 α-reductase inhibitor Confidential Page 34 of 101

133 Clinical Study Protocol: COU-AA-302 April 2, 2012 Chemotherapy Immunotherapy Bicalutamide, nilutamide, flutamide Systemic ketoconazole (or other azole drugs such as fluconazole and itraconazole) Diethylstilbestrol, PC-SPES, and other preparations such as saw palmetto thought to have endocrine effects on prostate cancer Radiopharmaceuticals such as strontium (89Sr) or samarium (153Sm) Aldactone, Spironol (spironolactone) Digoxin, digitoxin, and other digitalis drugs Cyproterone acetate Fludrocortisone acetate (Florinef) 5.9 Potential for Drug-Drug Interactions Investigators should keep in mind the possibility that abiraterone may interact with concomitant medications, particularly those that are metabolized or activated by P450 CYPs 2D6 and 1A2 (see Table 1). Please refer to the current IB for a listing of drugs metabolized by P450 CYPs inhibited by abiraterone or abiraterone acetate and for other additional information. If at any time an investigator suspects a drug-drug interaction due to abiraterone acetate therapy, an adverse event report should be completed and Cougar notified. Confidential Page 35 of 101

134 Clinical Study Protocol: COU-AA-302 April 2, 2012 Table 1. Inhibition of Cytochrome P450 Enzymes by abiraterone acetate and abiraterone CYP450 ENZYMES ABIRATERONE ACETATE (CB7630) ABIRATERONE (CB7598) Type of Inhibition Ki µm Type of Inhibition Ki µm CYP2A6 Not Not CYP2E1 Moderate 31.8 Not CYP2C9 Moderate 17.6 Moderate 29.8 CYP2C19 Potent 0.12 Moderate 46.3 CYP3A4/5 Moderate 11.4 Moderate 8.01 CYP1A2 Potent 0.32 Potent 0.44 CYP2D6 Potent 0.16 Potent Treatment Compliance A current and accurate account of the number of study treatment tablets the investigator received from Cougar, dispensed to the patients, the number of units returned to the investigator by the patient, and the number of units returned to Cougar or its representative or destroyed on site during and at the completion of the study must be maintained. A detailed inventory must be completed for the study treatment Packaging and Labeling Abiraterone acetate or placebo tablets will be provided to each site packaged for patient assignment at the time of randomization. Patients will be provided with a 30-day supply to allow for visits to occur every 28 days with a ± 2 day window. Information presented on the labels for investigational product will comply with applicable local regulations. Site pharmacist or medically qualified staff will dispense the blinded study treatment to each patient in accordance with this protocol. Confidential Page 36 of 101

135 Clinical Study Protocol: COU-AA-302 April 2, Storage Pharmacy Storage Requirements The study treatment must be stored in a secure area and administered only to patients entered into the clinical study in accordance with the conditions specified in this protocol. Bottles of blinded study treatment should be stored at room temperature [15º-30ºC; 59º-86º F] in the original container/closure with the cap on tightly; it should never be refrigerated. Additional information is provided in the abiraterone acetate Investigator s Brochure Storage Requirements For The Patient Bottles of blinded study treatment should be stored at room temperature [15º-30ºC; 59º-86ºF] in the original container/closure with the cap on tightly and should not be refrigerated. Patients should be advised to keep all medications out of the reach and out of sight of children Investigational Product Retention and Accountability at Study Site At the time of delivery of study treatment to the site, the investigator, designee, or Pharmacist (where appropriate) will sign a drug receipt form to confirm that the supplies for the study have been received. This form will specify supply, lot numbers, quantities shipped/delivered, and date of receipt. The form will also contain statements confirming that the study treatment has been received in good condition. Study treatment must be stored in a secure location between 15º-30ºC; 59º-86ºF. Accountability for study treatment is the responsibility of the investigator. More details concerning this responsibility are included in Appendix 2. Study treatment must only be dispensed by a pharmacist or medically qualified staff. Study treatment is to be dispensed only to patients enrolled in this study. Once the study treatment is prepared for a patient, it can only be administered to that patient. The study site must maintain accurate records demonstrating dates and amount of study treatment (abiraterone acetate, placebo, prednisone) received, to whom dispensed (patient by patient accounting), and accounts of any study treatment accidentally or deliberately destroyed. At the end of the study, reconciliation must be made between the amount of study treatment supplied, dispensed, and subsequently destroyed or returned to Cougar or its representative. Study site staff should refer to Appendix 2, information located in the Pharmacy Manual, and the Investigator s Brochure for specific instructions on the handling, storage, and administration of the study treatment. All study treatment will be returned to Cougar or its representative or destroyed at the site as specified in writing by Cougar. Confidential Page 37 of 101

136 Clinical Study Protocol: COU-AA-302 April 2, STUDY PROCEDURES 6.1 Informed Consent A signed, Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved, written informed consent form must be obtained from patients before any study specific procedures or randomization can occur. Confirmation of the patient s informed consent and the informed consent process must also be documented in the patient s medical record. A copy of the signed informed consent form will be given to the patient. 6.2 Medical History Medical history, such as previous treatments, procedures, and conditions will be collected during the screening period. 6.3 Physical Examination Evaluations should be performed by the same evaluator throughout the study whenever possible. If it is not possible to use the same evaluator to follow the patient, then evaluations should overlap (i.e., examine the patient together and discuss findings) for at least one visit. Physical examination includes HEENT (head, eyes, ears, nose, and throat), chest, cardiac, abdominal, extremities, neurologic, and lymph node examinations. Weight will be recorded at every visit. Height will be recorded at screening visit only. Vital signs include upright blood pressure, heart rate, respiratory rate, and oral or aural body temperature. 6.4 Clinical Laboratory Tests Laboratory Parameters Clinical laboratory tests will include the following: Confidential Page 38 of 101

137 Clinical Study Protocol: COU-AA-302 April 2, 2012 Table 2. List of Laboratory Tests Hematology: - Hematocrit (Hct) - Hemoglobin (Hgb) - Platelet count with differential - Red blood cell (RBC) count - White blood cell (WBC) count with differential Coagulation Factors: - Prothrombin Time (PT) - Partial Thromboplastin Time (PTT) - International Normalized Ratio (INR) Urinalysis dipstick for: - Blood - Protein - Glucose (Microscopic examination if abnormal) Serum Chemistry: Albumin (ALB) Alkaline phosphatase (ALK-P) Alanine aminotransferase (ALT; SGPT) Amylase Aspartate aminotransferase (AST; SGOT) Blood urea nitrogen (BUN) Calcium (Ca) Carbon dioxide (CO2) Chloride (Cl) Creatinine Direct bilirubin Gamma-glutamyl transferase (GGT) (at Screening only) Glucose - Lactate dehydrogenase (LDH) - Magnesium - Phosphorus - Potassium (K) - Sodium (Na) - Total bilirubin - Total protein - Uric acid Serum Lipids (Cholesterol, HDL, LDL, triglycerides) Additional laboratory tests: - Prostate specific antigen (PSA) - Serum testosterone - Pharmacokinetics (PK) * - TMPRSS2-ERG, other biomarkers* *Blinding will be maintained by not reporting PK and biomarker results to the Investigators or patients. Confidential Page 39 of 101

138 Clinical Study Protocol: COU-AA-302 April 2, Pharmacokinetics (PK) Assessments and Additional ECG Monitoring Pharmacokinetic samples will be obtained from approximately patients at selected study centers. A total of 6 blood samples will be drawn (2 samples during Cycle 1; 2 samples during Cycle 2, and 2 samples during Cycle 5). These data will be used for an integrated population pharmacokinetic analysis. In addition, 12-lead ECG assessment will be done pre-dose (at the Screening Visit) and at approximately two hours post-dose (at Cycles 1, 2, and 5). Samples will be assayed for both abiraterone acetate and its major metabolite, abiraterone TMPRSS2-ERG and other biomarkers Variation in response to treatment in advanced prostate cancer studies may be attributable in part to disease heterogeneity and differences in hormone sensitivity [79]. Molecular studies within this trial will seek to define subjects with tumor subtypes that may respond better to therapy with abiraterone acetate. The results of these studies will be used to identify response classifiers and inform the design of other clinical trials involving abiraterone acetate. Previously archived paraffin-embedded, formalin-fixed tumor tissue from the time of the subject s initial tumor diagnosis or from a subsequent procedure conducted as part of the subject s standard care but before abiraterone acetate drug treatment will be utilized. Subjects who do not have tumor blocks or unstained slides may have blood drawn for collection of circulating tumor cells (CTC s). FISH using an ERG break-apart assay will be performed to determine TMPRSS2 status and global micro-rna profiling will be conducted using qprc profiling technology. Purified DNA and RNA from these samples may also be examined to detect abnormalities (mutations, deletions, amplifications) in selected genes by utilizing various technologies (e.g. qrt-pcr, DASL, microarray profiling). Genes implicated in prostate cancer progression or prognosis or genes thought to be related to the mechanism of action of abiraterone acetate may be examined if sufficient sample remains. Biomarker Samples Biomarker sample collections will be applicable only for sites in countries where the health authorities have approved of this testing and where IRB/EC approval has also been obtained. Instructions on sample handling, labeling, and shipment are given in the laboratory manual. Withdrawal From Biomarker Testing If a subject withdraws consent for the additional biomarker testing, any DNA or RNA extracted from the subject s sample will be destroyed. The investigator must notify the sponsor site contact, who will request sample destruction using the withdrawal of consent for biomarker testing form. The investigator will receive written confirmation from the sponsor that the samples have been destroyed. Confidential Page 40 of 101

139 Clinical Study Protocol: COU-AA-302 April 2, Sample Collection, Storage, and Shipping A Central Laboratory will analyze all hematology, blood chemistry, tissue and urine samples collected for the study. Samples will be analyzed at a facility meeting regulatory requirements and/or using methods documented in a methods validation report. All shipping requirements and storage conditions will be provided in a protocol-specific lab manual. 6.5 SAFETY DATA COLLECTION, RECORDING, AND REPORTING All observed or volunteered adverse events regardless of treatment group or causal relationship to study drug will be recorded on the adverse event page(s) of the case report form (CRF) Definitions Adverse Events An adverse event is defined in the International Conference on Harmonisation (ICH) Guideline for Good Clinical Practice as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. (ICH E6:1.2) This definition of adverse events is broadened in this study to include any such occurrence (e.g., sign, symptom, or diagnosis) or worsening of a pre-existing medical condition from the time that a subject has signed informed consent to the time of randomization or initiation of investigational drug. Worsening indicates that the pre-existing medical condition (e.g., diabetes, migraine headaches, gout, hypertension, etc.) has increased in severity, frequency, or duration of the condition or an association with significantly worse outcomes. For all adverse events, the investigator must pursue and obtain information adequate to both determine the outcome of the adverse event and to assess whether it meets the criteria for classification as a serious adverse event (see Section ) requiring immediate notification to Cougar or its designated representative. For all adverse events, sufficient information should be obtained by the investigator to determine the causality of the adverse event. The investigator is required to assess causality. For adverse events with a causal relationship to the investigational product, follow-up by the investigator is required until the event resolves or stabilizes at a level acceptable to the investigator and Cougar clinical monitor or his/her designated representative. Interventions for pretreatment conditions (e.g., elective cosmetic surgery) or medical procedures that were planned before study enrollment are not considered adverse events Serious Adverse Events A serious adverse event (SAE) is defined as an adverse event that: Results in death; Is life threatening (places the subject at immediate risk of death); Confidential Page 41 of 101

140 Clinical Study Protocol: COU-AA-302 April 2, 2012 Requires in-patient hospitalization or prolongation of existing hospitalization; Results in persistent or significant disability/incapacity; Is a congenital anomaly/birth defect Important medical events that may not result in death, be life threatening, or require hospitalization may be considered an SAE when, based upon appropriate medical judgment, they may jeopardize the patient and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of drug dependency or drug abuse. A hospitalization meeting the definition for serious is any inpatient hospital admission that includes a minimum of an overnight stay in a health care facility. Inpatient admission does not include: rehabilitation facilities, hospice facilities, skilled nursing facilities, nursing homes, routine emergency room admissions, same day surgeries (as outpatient/same day/ambulatory procedures), or social admission (e.g., subject has no place to sleep) Suspected Unexpected Serious Adverse Reactions (SUSARS) Suspected Unexpected Serious Adverse Reactions (SUSARS) are events which are serious as per the above criteria, the nature or severity of which is not consistent with the applicable product information (e.g., Investigator s Brochure) and are judged by the investigator or Cougar to be unlikely, possibly, or related to study treatment Reporting Procedures for All Adverse Events The investigator is responsible for ensuring that all adverse events (as defined in Section and as further specified below) observed by the investigator or reported by subjects are collected and recorded in the subjects medical records, in the CRF, and, for serious adverse events, on the serious adverse event report (SAER) form. These adverse events will include the following: All serious adverse events (as defined in Section ) that occur after the subject has signed the informed consent form and up to 30 days after the last dose will be documented. All non-serious adverse events (as defined in Section 6.5.1) that occur after randomization to study treatment up to 30 days after the last dose will be documented. The following adverse event attributes must be assigned by the investigator: adverse event diagnosis or syndrome(s) (if known, signs or symptoms if not known); event description (with detail appropriate to the event); dates of onset and resolution; severity; assessment of relatedness to study treatment (abiraterone acetate or placebo); and action taken. The Confidential Page 42 of 101

141 Clinical Study Protocol: COU-AA-302 April 2, 2012 investigator may be asked to provide follow-up information, discharge summaries, and extracts from medical records or CRFs. For all adverse events, sufficient information should be obtained by the investigator to determine the causality of the adverse event (e.g. study drug or other illness). The relationship of the adverse event to the study treatment (abiraterone acetate or placebo) will be assessed following the definitions below: Unrelated: any event that does not follow a reasonable temporal sequence from administration of study drug AND that is likely to have been produced by the patient s clinical state or other modes of therapy administered to the patient. Unlikely: any event that does not follow a reasonable temporal sequence from administration of study drug OR that is likely to have been produced by the patient s clinical state or other modes of therapy administered to the patient. Possibly: any reaction that follows a reasonable temporal sequence from administration of study drug OR that follows a known response pattern to the suspected drug AND that could not be reasonably explained by the known characteristics of the patient s clinical state or other modes of therapy administered to the patient. Related: any reaction that follows a reasonable temporal sequence from administration of study drug AND that follows a known response pattern to the suspected drug AND that recurs with re-challenge, AND/OR is improved by stopping the drug or reducing the dose Severity of Adverse Events Adverse event severity is a clinical determination of the intensity of an AE and SAEs. The severity assessment for an AE/SAE should be completed using the NCI Common Terminology Criteria for Adverse Events (CTCAE, version 3.0, Appendix 5). Any AE/SAE not listed in the CTCAE version 3.0 will be graded as follows: SEVERITY OF EVENT Grade Definition 1 Mild: Symptoms which do not interfere with patient s daily activities 2 Moderate: Symptoms which may interfere with patient s daily activities 3 Severe: Events which interrupt patient s usual daily activities 4 Life-threatening or disabling. 5 Death Medically significant adverse events considered related to the study treatment (abiraterone acetate or placebo) by the investigator or the sponsor will be followed until resolved or considered stable. Confidential Page 43 of 101

142 Clinical Study Protocol: COU-AA-302 April 2, 2012 It will be left to the investigator s clinical judgment to determine whether an adverse event is related and of sufficient severity to require the subject s removal from treatment or from the study. A subject may also voluntarily withdraw from treatment due to what he or she perceives as an intolerable adverse event. If either of these situations arises, the subject should be strongly encouraged to undergo an End of Study Treatment assessment and be under medical supervision until symptoms cease or the condition becomes stable Serious Adverse Event Reporting Procedures Serious adverse events will be collected and recorded at least throughout the study period, beginning with the signing of the informed consent through 30 days after the end of the treatment phase. All serious adverse events that occur after the subject has signed the informed consent form or during the study must be reported within 24 hours of discovery or notification of the event to a Cougar representative or study personnel through the planned adverse event reporting process and recorded on the appropriate case report form (CRF). Relevant medical records should be provided to Cougar as soon as they become available; autopsy reports should be provided for deaths if available. Related serious adverse events are events that are judged by the investigator or Cougar Biotechnology to be unlikely, possibly, or related to study treatment (abiraterone acetate or placebo). See definitions above. Determination of expectedness will be based on the contents of the Investigator s Brochure. If the event is serious, unexpected, and related then it will be deemed to be a SUSAR and will be reported as a blinded SUSAR in order to maintain the blind and protect the integrity of the clinical investigation. Since a fatal outcome (death) is the primary efficacy endpoint for this study, deaths events will remain blinded in order to protect the integrity of the clinical investigation. SUSARs will be reported as required by relevant authorities. If a subject is permanently withdrawn from the study because of a serious adverse event, this information must be included in the initial or follow-up Serious Adverse Event Report Form as well as the End of Study Treatment Case Report Form. The investigator should notify the appropriate IRB or ethics committee (EC) of serious adverse events occurring at the site and other adverse event reports received from Cougar, in accordance with local procedures and statutes. Confidential Page 44 of 101

143 Clinical Study Protocol: COU-AA-302 April 2, Long-Term Follow-Up For the long-term follow-up (e.g., to collect outcomes), serious adverse events considered related to investigational drug will be collected and reported on the Serious Adverse Event Report form to Cougar within 24 hours of discovery or notification of the event Abnormal Laboratory Results All clinically important abnormal laboratory tests occurring during the study will be repeated at appropriate intervals until they return either to baseline or to a level deemed acceptable by the investigator and the Cougar medical monitor (or his/her designated representative), or until a diagnosis that explains them is made. The criteria for determining whether an abnormal laboratory test result should be reported as an adverse event are as follows: 1. Test result is associated with accompanying symptoms, and/or 2. Test result requires additional diagnostic testing or medical/surgical intervention (merely repeating an abnormal test, in the absence of any of the above conditions, does not meet criteria for reporting and an AE), and/or 3. Test result leads to a change in study dosing or discontinuation from the study, significant additional concomitant drug treatment or other therapy, and/or 4. Test result leads to any of the outcomes included in the definition of a serious adverse event, and/or 5. Test result is considered to be an adverse event by the investigator or sponsor Any abnormal test result that is determined to be an error does not require reporting as an adverse event, even if it did meet one of the above conditions except for condition #4. Clinically significant laboratory results must be recorded in the patient s CRF Management of Study Drug-Related Events Based upon experience from Phase 1 and ongoing Phase 2 studies, abiraterone acetate is generally well tolerated. The most common adverse events related to abiraterone acetate monotherapy include fatigue due to reduced cortisol level as a result of CYP17 inhibition; and hypertension, fluid retention, and hypokalemia due to mineralocorticoid excess caused by compensatory ACTH drive. In this study, the concomitant administration of prednisone is expected to mitigate these side effects by supplementing cortisol and abrogating ACTH drive. It has been documented that following prolonged therapy with corticosteroids, patients may develop Cushings syndrome characterized by central adiposity, thin skin, easy bruising, and proximal myopathy. Withdrawal of the corticosteroid may result in symptoms that include fever, myalgia, fatigue, arthralgia, and malaise. This may occur even without evidence of adrenal insufficiency. Confidential Page 45 of 101

144 Clinical Study Protocol: COU-AA-302 April 2, 2012 For guidance on management of side effects of glucocorticoid usage, symptoms related to castration (androgen deprivation), severe and refractory headaches, fatigue, or other toxicities, please contact the Medical Monitor. Re-initiation of study treatment after resolution of adverse events must be discussed with and approved by the Protocol Medical Monitor Management of Hypokalemia At the initial observation of Grade 1 hypokalemia (serum potassium < 3.5 mm or below lower limit of normal range, but 3.0 mm), oral potassium supplement will be initiated. The dose of potassium supplement must be carefully titrated to maintain serum potassium at 3.5 mm but 5.0 mm. Any patient with low potassium while on study or a history of hypokalemia from a pre-existing or concurrent medical condition will undergo weekly or more frequent laboratory electrolyte evaluation. The investigator should consider maintaining the patient s potassium level at 4.0 mm in these patients. If any patient experiences Grade 3 hypokalemia (serum potassium levels < 3.0 mm 2.5 mm, NCI CTCAE v3.0) or life-threatening hypokalemia with potassium levels < 2.5 mm (NCI CTCAE v3.0 hypokalemia Grade 4), study treatment will be withheld, and the patient hospitalized for intravenous potassium replacement and cardiac monitoring. Re-initiation of study treatment after normalization of potassium levels must be discussed with and approved by the Medical Monitor. Confidential Page 46 of 101

145 Clinical Study Protocol: COU-AA-302 April 2, 2012 Table 3. Hypokalemia Management Serum K+ Low K+ and/or history of hypokalemia Grade of Hypokalemia < 3.5mM - 3.0mM Grade 1 < 3.0mM 2.5mM Grade 3 < 2.5mM Grade 4 Action Weekly (or more frequent) laboratory electrolyte evaluations Initiate oral K+ supplementation Withhold study treatment and initiate IV K+ and cardiac monitoring Withhold study treatment and initiate IV K+ and cardiac monitoring Further Action and/or Maintenance Titrate dose to maintain a serum K+ 3.5mM 5.0mM (Maintenance of pts at 4.0mM is recommended) Titrate dose to maintain a serum K+ 3.5mM 5.0mM (Maintenance of pts at 4.0mM is recommended) Call Cougar Biotechnology Medical Monitor prior to re-initiating study treatment Call Cougar Biotechnology Medical Monitor prior to re-initiating study treatment Management of Hypertension Side Effects Grade 1-2: Management per Investigator. No study treatment dose reduction. Grade 3-4: Hold study treatment. Adjust or add medications to mitigate the toxicity and/or consider the specific mineralocorticoid receptor blocker, Eplerenone (Inspra). When hypertension resolves to Grade 1, resume study treatment at full dose. If toxicity recurs, hold study treatment, and adjust or add medications to mitigate the toxicity. When resolved to Grade 1, resume study treatment with the first dose level reduction (3 tablets, 750 mg of study treatment). If toxicity recurs, hold study treatment, and adjust or add medications to mitigate the toxicity. When resolved to Grade 1, resume study treatment with the second dose level reduction (2 tablets, 500 mg of study treatment). If toxicity recurs despite optimal medical management and two dose level reductions, discontinue study treatment. Confidential Page 47 of 101

146 Clinical Study Protocol: COU-AA-302 April 2, Management of Edema, Fluid Retention Pedal edema: Supportive management per Investigator. No study treatment dose reduction Anasarca and/or pulmonary edema requiring supplemental oxygen: Hold study treatment. Adjust or add medications to mitigate the toxicity and/or consider the specific mineralocorticoid receptor blocker, Eplerenone (Inspra). When toxicity resolves to Grade 1, resume study treatment at full dose. If toxicity recurs, hold study treatment, and adjust or add medications to mitigate the toxicity. When resolved to Grade 1, resume study treatment with the first dose level reduction (3 tablets, 750 mg of study treatment). If toxicity recurs again, hold study treatment, and adjust or add medications to mitigate the toxicity. When resolved to Grade 1, resume study treatment with the second dose level reduction (2 tablets, 500 mg of study treatment). If toxicity recurs despite optimal medical management and two dose level reductions, discontinue study treatment Management of Abnormal Liver Function Tests If Grade 1 increases in AST, ALT or bilirubin occur (e.g. increase in AST or ALT from ULN to 2.5X ULN; increase in total bilirubin from ULN to 1.5X ULN): The frequency of liver function test monitoring should be increased, if the Investigator judges that the laboratory abnormalities are potentially related to study medication. No study treatment dose reduction is required. If Grade 2 increases in AST, ALT or bilirubin occur (e.g. increase in AST or ALT to >2.5-5X ULN; increase in total bilirubin from >1.5-3X ULN): The frequency of liver function test monitoring should be increased to once a week, if the Investigator judges that the laboratory abnormalities are potentially related to study medication. No study treatment dose reduction is required. If Grade 3 or higher increases in AST, ALT, or bilirubin occur (e.g. increase in AST or ALT to >5X ULN; increase in total bilirubin to >3X ULN), hold study medication and all other concomitant medications that are potentially hepatotoxic. Frequent laboratory evaluations (at least once weekly) should be conducted until the liver function tests return to baseline value or Grade 1. Liver enzyme measurements should be made immediately, regardless of when the next study visit or monitoring interval is scheduled. o If study treatment resumption is considered for subjects who have experienced Grade 3 increases in AST, ALT, or bilirubin, and the Medical Monitor agrees, resume study treatment with the first dose level reduction (3 tablets, 750 mg of study treatment) when Grade 3 toxicities resolve to Grade 1 or baseline. o If Grade 3 or higher increases in AST, ALT, or bilirubin recur after the first dose reduction hold study medication and all other concomitant medications that are potentially hepatotoxic. Frequent laboratory evaluations should be Confidential Page 48 of 101

147 Clinical Study Protocol: COU-AA-302 April 2, 2012 conducted (at minimum weekly) until the liver function tests return to baseline value or Grade 1. Liver enzyme measurements should be made immediately, regardless of when the next study visit or monitoring interval is scheduled. o If study treatment resumption is considered for patients who have experienced Grade 3 increases in AST, ALT, or bilirubin with the first dose reduction, and the Medical Monitor agrees, resume study treatment with the second dose level reduction (2 tablets, 500 mg of study treatment) when AST, ALT, or bilirubin returns to baseline value or Grade 1. If Grade 4 increases in AST, ALT, or bilirubin occur (e.g. increase in AST or ALT to >20X ULN; increase in total bilirubin to >10X ULN), patients must discontinue study treatment immediately and will not be re-challenged. They should be followed until resolution of abnormal liver function tests Management of Non-Mineralocorticoid Based Side Effects If Grade 1-2 toxicities, give supportive care per institutional guidelines. No study treatment dose reduction. If Grade 3 or higher toxicities including headache (interferes with ADL), nausea (TPN, IVF), vomiting (>6 episodes/24hrs, TPN or IVF), diarrhea (IVF, hospitalization, hemodynamic collapse), or any other toxicity judged to be related to study treatment is observed where the patient s safety is jeopardized, hold study treatment. When toxicity resolves to Grade 1, resume study treatment at full dose. If toxicity recurs, hold study treatment, and adjust or add medications to mitigate the toxicity. When resolved to Grade 1, resume study treatment with the first dose level reduction (3 tablets, 750 mg of study treatment). If toxicity recurs, hold study treatment, and adjust or add medications to mitigate the toxicity. When resolve to Grade 1, resume study treatment with the second dose level reduction (2 tablets, 500 mg of study treatment). If toxicity recurs despite aggressive medical management and two dose level reductions, discontinue study treatment Dose-Reduction Procedure for Adverse Event Management In the event where dose-reduction is used for AE management, 2 dose reductions are allowed. At each dose reduction, one tablet of abiraterone or placebo will be removed, e.g., 4 3 tablets, and 3 2 tablets. Any return to protocol dose level after dose reduction must follow documentation of AE resolution and a discussion with the Medical Monitor. Confidential Page 49 of 101

148 Clinical Study Protocol: COU-AA-302 April 2, Criteria for Discontinuation of Study Treatment The co-primary efficacy endpoint is rpfs, as defined in Sections and 9.7. Confirmed radiographic progression may be a reliable indicator of clinical benefit in patients with CRPC [75]. Patients should ordinarily be maintained on study treatment until confirmed radiographic progression. If the patient has radiographic progression but no unequivocal clinical progression and alternate treatment is not initiated, the patient may continue on study treatment, at the investigator s discretion However, if patients have unequivocal clinical progression without radiographic progression, these patients are indicated for the current standard of care. Study treatment should be stopped and patients advised regarding available treatment options. For this study, unequivocal clinical progression will be characterized as: 1) Cancer pain requiring initiation of chronic administration of opiate analgesia (oral opiate use for 3 weeks; parenteral opiate use for 7 days, as listed in Appendix 10). Patients with cancer pain requiring opiate analgesia for relief should also be assessed by the investigator for the need for initiating systemic chemotherapy. Or 2) Immediate need to initiate cytotoxic chemotherapy or the immediate need to have either radiation therapy or surgical intervention for complications due to tumor progression, even in the absence of radiographic evidence of disease progression. Or 3) Deterioration in ECOG performance status to grade 3 or higher. Patients whose ECOG performance status decreases to grade 2 during the study should be assessed carefully for their need for docetaxel therapy. When study treatment is discontinued due to unequivocal clinical progression, the investigator should obtain imaging studies at the Treatment Discontinuation Visit to assess for radiographic progression, including a confirmatory bone scan, as appropriate. Study treatment will be continued on patients who have increasing PSA values in the absence of radiographic or unequivocal clinical progression. Although serial PSA s will be measured on this study, progression or change in PSA values is not considered a reliable measure of disease progression, and should not be used as an indication to discontinue study therapy. 6.7 Withdrawal from Study Treatment Phase A patient may withdraw from study treatment phase for any reason. In this event, the reason(s) for withdrawal must be documented and clarification requested whether withdrawal of consent applies only to the Treatment Phase (i.e. patient has not withdrawn consent for data collection during the post-treatment Follow-Up Phase) or to both the Treatment and Follow-Up Phases. A patient s Confidential Page 50 of 101

149 Clinical Study Protocol: COU-AA-302 April 2, 2012 decision to take part in the study is voluntary, and he may choose not to take part in the study or to stop taking part at anytime. If he chooses not to take part or to stop at anytime, it will not affect his future medical care or medical benefits. An investigator may withdraw a patient from the study Treatment Phase at any time based on clinical judgment or for any of the following reasons listed below. When possible all End of Study Treatment procedures should be conducted and the patient should be followed for survival as specified in Section 7.3. Discontinuation of treatment criteria as defined in Section 6.6. Sustained Side Effects: Patients who have sustained toxicities that do not return to NCI CTCAE (version 3.0) Grade 1 or less with appropriate medical management, should be discontinued from the study treatment. Initiation of new anticancer treatment: Patients will be discontinued from the study treatment when investigator determines new treatment for prostate cancer is warranted. For patients who did not undergo orchiectomy, concurrent treatment with LHRH analogue is mandatory and must be recorded. The concurrent administration of other anticancer therapy, including cytotoxic, hormonal (except LHRH agonists), or immunotherapy is prohibited during study treatment Phase. Use of other investigational drug therapy for any reason is prohibited. 7 STUDY ACTIVITIES 7.1 Screening Period (Days 14 to Day 1) The following activities/procedures will be conducted during the screening period which may occur over 14 days: Medical history including prior prostate cancer therapies, PSA, Stage, and Gleason score at diagnosis Previous hormonal, cytotoxic, and experimental treatments with start and stop dates Demographics Pain (BPI-SF, see Appendix 8) and analgesic use For study eligibility, a score of 0-1 on BPI-SF Question #3 (worst pain in last 24 hours) will be considered asymptomatic, and a score of 2-3 will be considered mildly symptomatic. Physical examination, weight, and height with baseline signs and symptoms 12 lead ECG MUGA (Multiple Gated Acquisition scan). Left ventricular ejection fraction (LVEF) must be 50% for study eligibility. An ECHO (Echocardiogram) can be performed if MUGA is not possible. MUGA performed up to 28 days prior to Cycle 1 Day 1 can be used for baseline assessments. Vital signs including upright blood pressure, heart rate, respiratory rate, and oral or aural body temperature Confidential Page 51 of 101

150 Clinical Study Protocol: COU-AA-302 April 2, 2012 Assessment of ECOG Performance Status by investigator (Appendix 6) Laboratory tests: Hematology (Table 2, Section 6.4.1) Coagulation factors (Table 2, Section 6.4.1) Serum chemistry with electrolytes and GGT (Table 2, Section 6.4.1) Fasting glucose (8 hr. fast) Serum Lipids (Table 2, Section 6.4.1) Urine sample for urinalysis (Table 2, Section 6.4.1) PSA: If patient undergoes a digital rectal exam (DRE), PSA must be sampled prior to the DRE. Serum testosterone Baseline tumor assessment: CT or MRI of chest, abdomen, and pelvis must be included. Tumor burden must be evaluated by physical examination and image-based evaluation (modified RECIST criteria). Ultrasound should not be used to measure lesions that are not clinically accessible, such as liver lesions. Chest x-ray is not recommended. Bone Scan Scans performed up to 28 days prior to Cycle 1 Day 1 can be used for baseline assessments. Concomitant medications listing Obtain a complete and thorough listing of all prescription and nonprescription (over the counter) medications currently taken including pain medications. This also includes any nutritional supplements and/or herbal preparations. TMPRSS2-ERG, other biomarkers: tissue block or unstained slides known to contain cancer should be obtained on primary tumors from patients, where available in countries where the health authorities have approved of this testing and where IRB/EC approval has also been obtained. Patients who are known not to have available tissue at study entry may have blood drawn for CTC s. Sample shipment to the central laboratory may occur anytime after Screening. 7.2 Treatment Period (Cycle 1 Day 1 to End of Study Treatment) Cycle 1 Day 1 Patients who are eligible will be randomized and start study treatment within 14 days after the screening visit. Cycle 1 Day 1 visit may occur on the same day as the Screening visit provided that all screening assessments have been completed and screening results are reviewed prior to the commencement of Cycle 1 Day 1 assessments. The following procedures should be carried out: Quality of Life (FACT-P, see Appendix 9) Pain (BPI-SF) and analgesic use Concomitant Medications listing Confidential Page 52 of 101

151 Clinical Study Protocol: COU-AA-302 April 2, 2012 Vital signs including upright blood pressure, heart rate, respiratory rate, and oral or aural body temperature Assessment of ECOG Performance Status by investigator Laboratory tests Hematology (Table 2, Section 6.4.1) Serum chemistry with electrolytes (Table 2, Section 6.4.1) PSA: If patient undergoes a DRE, PSA must be sampled prior to the DRE. AE evaluation and recording PK Assessment for Patients at Selected Study Centers Only: PK pre-dose sample (up to 1 hour prior to on-site study dose administration) Dosing of study treatment: Collect date and time of most recent meal patient had prior to providing study treatment. Administer study treatment and collect time The following procedures should be carried out following dosing of study treatment: 12-lead ECG at approximately 2 hours post-dose Collect PK sample between 1 and 5 hours post-dose Cycle 1 Day 15 Visit The following assessments should be carried out: Physical examination and weight Vital signs including upright blood pressure, heart rate, respiratory rate, and oral or aural body temperature Assessment of ECOG Performance Status by investigator Laboratory tests Serum chemistry with electrolytes (Table 2, Section 6.4.1) Coagulation factors (Table 2, Section 6.4.1) Concomitant Medications listing AE evaluation and recording will be monitored throughout the study. At each post baseline visit, the investigator will begin by querying for adverse events by asking each patient a general, nondirected question such as How have you been feeling since the last visit? Directed questioning and examination will then be done as appropriate. Confidential Page 53 of 101

152 Clinical Study Protocol: COU-AA-302 April 2, 2012 Dosing compliance check, a count of study treatment tablets, will be conducted during this visit and patient dosing compliance will be assessed. If dosing compliance is 75% in the absence of toxicity, patient should be re-instructed regarding proper dosing procedures and may continue in the protocol. Source documentation of the compliance check and any patient verbal re-instruction provided should be documented in patient s chart Cycles 2, 4, 6, 8, 9, 11, and 12 Day 1 (Continue every 1 st and 2 nd cycle Beyond Cycle 10, e.g. Cycles 11, 12, 14, 15, 17, 18, 20, 21 ) The following assessments should be carried out at the indicated time point: Physical examination and weight Vital signs including upright blood pressures, heart rate, respiratory rate, and oral or aural body temperature Assessment of ECOG Performance Status by investigator Concomitant medications listing AE evaluation and recording Pain (BPI-SF) and analgesic use Dosing compliance check, a count of study treatment tablets, will be conducted during this visit and patient dosing compliance will be assessed. If compliance is 75% patient should be re-instructed regarding proper dosing procedures. Source documentation of the compliance check and any patient verbal re-instruction provided should be documented in patient s chart. Laboratory Tests: Hematology (Table 2, Section 6.4.1) Serum chemistry with electrolytes (Table 2, Section 6.4.1) PK Assessment for Selected Study Centers (Cycle 2 only): PK pre-dose sample (up to 1 hour prior to on-site study dose administration) Dosing of study treatment: Collect date and time of most recent study treatment prior to the study visit. Collect date and time of most recent meal patient had prior to providing study treatment in the clinic. Administer study treatment and collect time The following procedures should be carried out following dosing of study treatment: 12-lead ECG at approximately 2 hours post-dose Collect PK sample between 1 and 5 hours post-dose Confidential Page 54 of 101

153 Clinical Study Protocol: COU-AA-302 April 2, Day 15 of Cycles 2 and 3 The following assessments should be carried out: Laboratory tests: Liver function testing: ALK-P, ALT (SGPT), AST (SGOT), LDH, and direct and total bilirubin Cycles 3, 5, 7, and 10 (continue every 3 rd cycle beyond Cycle 10, e.g. Cycles 13, 16, 19, 22 ) and Treatment Discontinuation Visit In preparation for the study visit, the following assessments should be conducted up to 8 days prior to the indicated visit. - CT or MRI of chest, abdomen, and pelvis Bone Scan If progressive disease is observed on bone scan at any timepoint (without RECIST progression on CT/MRI), a confirmatory bone scan is required at least six weeks later. The patient should remain on study treatment in the interim unless there is unequivocal clinical progression as defined in Section 6.6 At the study visit the following assessments should be conducted: Pain (BPI-SF) and analgesic use Quality of Life (FACT-P) Physical examination and weight 12-lead ECG Vital signs including upright blood pressures, heart rate, respiratory rate, and oral or aural body temperature Assessment of ECOG Performance Status by investigator Laboratory Tests Hematology (Table 2, Section 6.4.1) Serum chemistry with electrolytes (Table 2, Section 6.4.1) Fasting glucose (at least 8 hr. fast) Serum Lipids (Table 2, Section 6.4.1) PSA: If patient undergoes a DRE, then PSA must be sampled prior to the DRE. Concomitant medications listing AE evaluation and recording Disease progression assessment Confidential Page 55 of 101

154 Clinical Study Protocol: COU-AA-302 April 2, 2012 Dosing compliance check. If Treatment Discontinuation Visit, then a count of study drug tablets will be conducted and final patient dosing compliance will be assessed. PK Assessment for Selected Study Centers (Cycle 5 only): PK pre-dose sample (up to 1 hour prior to on-site study dose administration) Dosing of study treatment: Collect date and time of most recent study treatment prior to the study visit. Collect date and time of most recent meal patient had prior to providing study treatment in the clinic. Administer study treatment and collect time The following procedures should be carried out following dosing of study treatment: 12-lead ECG at approximately 2 hours post-dose Collect PK sample between 1 and 5 hours post-dose Treatment Discontinuation The Treatment Discontinuation Visit can occur at any scheduled or unscheduled visit when applicable. At this visit, documentation to confirm progressive disease or unequivocal clinical progression as defined in Section 6.6 is required End of Study Treatment Visit The End of Study Treatment Visit should be scheduled to collect safety assessments between 15 to 28 days after the patient stops treatment. Patients will enter the Follow up Phase at that time. The following safety assessments should be carried out at the End of Study Treatment Visit after patients discontinue study treatment for any reason: Physical examination and weight Vital signs including upright blood pressures, heart rate, respiratory rate, and oral or aural body temperature. Assessment of ECOG Performance Status by investigator Pain (BPI-SF) and analgesic use Quality of Life (FACT-P) 12-lead ECG Laboratory tests Hematology (Table 2, Section 6.4.1) Serum chemistry with electrolytes (Table 2, Section 6.4.1) Fasting glucose (8 hr. fast) PSA: If patient undergoes a DRE, PSA must be sampled prior to the DRE. Confidential Page 56 of 101

155 Clinical Study Protocol: COU-AA-302 April 2, 2012 Serum Lipids (Table 2, Section 6.4.1) Concomitant medications listing Adverse events AE follow-up (to determine if any new or ongoing drug-related AE or any SAE regardless of relationship to study drug exists) is required for 30 days post last dose or until patient receives anticancer therapy, whichever comes first. Followup could be conducted by site via telephone attempts. The attempts and outcomes should be recorded as part of the patient source documents. Final Dosing compliance check if not performed at the Treatment Discontinuation Visit Unscheduled Visits If an imaging procedure is performed at an unscheduled visit, and progression is observed by bone scan, a confirmatory bone scan should be obtained at least 6 weeks later. 7.3 Post-Treatment Follow-up Period (Survival or Long-Term Follow-Up) Once a patient has completed the treatment period, overall survival follow-up will be performed every 3 months for up to 60 months (5 years). In addition to overall survival, opiate use, ECOG performance status, and next therapy for prostate cancer (including dose and treatment duration of cytotoxic chemotherapy) will also be collected. Follow up may be performed by telephone interview or chart review and will be reported on the case report form. During the Follow-up Period, deaths regardless of causality and serious adverse events thought to be related to study treatment (abiraterone acetate or placebo) will be collected and reported within 24 hours of discovery or notification of the event. 8 QUALITY CONTROL AND ASSURANCE Cougar representatives are responsible for contacting and visiting the investigator for the purpose of inspecting the facilities and, upon request, inspecting the various records of the clinical study (e.g., CRFs and other pertinent data) provided that patient confidentiality is respected. The investigator agrees to cooperate with the monitor to ensure resolution of all problems detected in the course of these monitoring visits, including delays in completing CRFs. During and after completion of the study, quality assurance auditor (s) named by Cougar or the regulatory authorities may perform on-site audits/inspections. The investigators will be expected to cooperate with any audit/inspection and to provide assistance and documentation (including source data) as requested. The investigator will immediately inform Cougar Confidential Page 57 of 101

156 Clinical Study Protocol: COU-AA-302 April 2, 2012 Quality Assurance if contacted by a regulatory authority regarding an on-site audit/inspection of this study. In accordance with ICH GCP and the sponsor s audit plans, investigators may be selected for audit by representatives from Cougar s Quality Assurance Department (or designees). Inspection of site facilities (e.g., pharmacy, drug storage areas, laboratories) and review of study-related records will occur to evaluate the study conduct and compliance with applicable regulatory requirements (e.g., US IND regulations (21CFR312), EU Clinical Trials Directive (Directive 2001/20/EC), the protocol and ICH Good Clinical Practice (ICH E6). 9 PLANNED STATISTICAL METHODS 9.1 General Considerations All statistical analyses will be performed using SAS. The resulting statistic will be evaluated using East given the precise number of events observed at the time of interim analysis. Unless otherwise specified, all continuous endpoints will be summarized using descriptive statistics, which will include the number of patients (n), mean, standard deviation, median, minimum, and maximum. All categorical endpoints will be summarized using frequencies and percentages. The baseline measurement will be the last value on or before the date of first study treatment. 9.2 Determination of Sample Size Sample Size Determination The overall level of significance for the study will be However, 0.04 will be used in the testing of OS, and 0.01 will be used in the testing of rpfs. The exact timing of the analysis will be carried out according to the pre-specified required number of events for each endpoint. Patients will be randomized in a 1:1 ratio to receive abiraterone acetate or placebo. Recent publications suggest that a similar patient population has an estimated median OS of approximately 20 to 22 months. A median of 22 months is assumed in the sample size calculation accounting for differences in patient populations in comparing these study designs. These publications also suggest the estimated median rpfs of approximately 4 months for these patients Hypothesized OS Hazard Ratio of 0.80 It was assumed that the hazards for the two treatment groups follow a proportional hazards model for OS. The test to detect a difference between a median OS of 22 months in the placebo group and a median OS of 27.5 months in the abiraterone acetate group (HR=0.80) at the 2-tailed significance level of 0.04 with a power of 85% would require 773 events. Confidential Page 58 of 101

157 Clinical Study Protocol: COU-AA-302 April 2, 2012 Assuming an enrollment rate of 50 patients per month over 20 months, a total sample size of approximately 1000 patients is planned for the study. The OS endpoint will incorporate group sequential design by including 3 interim analyses and one final analysis using the O Brien-Fleming boundaries as implemented by Lan-DeMets alpha spending method. This method ensures that the type I error rate is not inflated. The interim analyses are planned at 15% (estimated), 40%, and 55% of the required number of events. The cumulative alpha spent will be <0.0001, , , and for each of the 4 analyses respectively. The exact timing of the first interim analysis will be determined according to the rpfs events required Hypothesized rpfs Hazard Ratio of Only one analysis will be conducted for rpfs. Assuming that the hazards for the two treatment groups follow a proportional hazard model, it is estimated that 378 rpfs events would be required to provide a 91% power in detecting a median rpfs of 4 months for the placebo group versus 6 months for the abiraterone group (HR=0.667) at a 2-tailed level of significance of 0.01; the same enrollment assumptions as described for OS is assumed. It is anticipated that at the time of observing the required rpfs events, approximately 680 patients will have been enrolled. At the conclusion of the rpfs analysis, including data review by the data monitoring committee, it is expected that nearly 1000 patients will have been enrolled. 9.3 Interim and Final Analyses Interim analysis for rpfs is not planned. The analysis of rpfs will be carried out at the twotailed 0.01 level of significance. The first interim analysis for OS will be timed according to the required number of events for rpfs. The alpha spent for OS will be adjusted accordingly using the alpha spending method as indicated above for all the analyses which should protect from inflating the type I error rate. 9.4 Analysis Populations Patient disposition and efficacy analyses will be performed on data from the intent-to-treat (ITT) population. All patients randomized into the study will be classified according to their assigned treatment group, regardless of the actual treatment received. The primary efficacy analyses will be on the ITT basis. All patients who receive any part of study drug will be included in the analysis of safety (Safety Population). 9.5 Demographics and Baseline Characteristics Demographic variables will include age, race, ethnicity, height, and weight. Baseline disease characteristics will include time from diagnosis, number of prior hormonal therapies, and other clinical characteristics as documented in the CRF. Confidential Page 59 of 101

158 Clinical Study Protocol: COU-AA-302 April 2, Study Endpoint(s) Efficacy Endpoint(s) Co-Primary efficacy endpoints: Overall survival Radiographic progression-free survival Secondary efficacy endpoints: Time to opiate use for cancer pain Time to initiation of cytotoxic chemotherapy Time to deterioration in ECOG performance score by 1 points Time-to-PSA progression based on PCWG2 criteria Other endpoints : PSA response rate [Proportion of patients achieving a PSA decline 50% according to Prostate Cancer Working Group (PCWG2) criteria] Objective response rate in patients with measurable disease (RECIST) Duration of response in patients with measurable disease QoL total score and each subscale score as assessed by FACT-P Time to pain progression Time to analgesic progression 9.7 Efficacy Analysis Population and Methods All randomized patients will be included in the intent-to-treat (ITT) population who will be classified according to their assigned treatment group, regardless of the actual treatment received. Overall survival is defined as the time from randomization to date of death from any cause. Radiographic progression-free survival is defined as the time from randomization to the occurrence of radiographic progression (Section 3.1.1) or death. The analysis of rpfs endpoint will use the centrally reviewed radiographic assessment of progression. The overall 5% level of significance will be used to compare the treatment effect with respect to both OS and rpfs endpoints. The OS and rpfs endpoints will be tested using 0.04 and 0.01 level of significance, respectively. The analyses of the primary endpoints for OS and rpfs are event driven according to the required number of events for each endpoint. If the rpfs endpoint is significant, the results will be summarized for regulatory review, along with the secondary endpoints. If the OS analysis is not significant, the study will continue and the patients will be followed for survival until the required number of events is observed. Confidential Page 60 of 101

159 Clinical Study Protocol: COU-AA-302 April 2, 2012 Distributions of time-to-event variables will be estimated using the Kaplan-Meier productlimit method. The median times to event with two-sided 95% confidence intervals will be estimated. The stratified logrank test will be used as the primary analysis for treatment comparison. The estimate of the hazard ratios and their 95% confidence intervals will also be provided. Response rate will be the proportion of patients fulfilling the respective criteria for response. The relative risk (treatment: control) will be reported along with the associated 95% confidence interval. Statistical inference will be evaluated using Chi-square statistic; the Fisher s exact test may be used if the expected counts in some cells are small. Sensitivity analysis for time to event endpoints using non-stratified logrank test and Cox proportional hazards model will also be performed as supportive analyses. Subgroup analyses will be carried out to assess if treatment effects are consistent within subgroup. A large number of patient crossover may confound the analysis of the primary endpoint of overall survival. Therefore a per-protocol analysis removing patients who crossover may be conducted. The accelerated failure time model with iterative parameter estimation method described by Branson and Whitehead (80) may also be used to obtain the point estimate of treatment effect and its associated confidence interval. If a large number of patients are censored, the rank preserving failure time model described by Robins and Tsiatis (81) may also be considered in the overall assessment of the survival endpoint. 9.8 Safety Evaluations Safety analysis will be summarized using the Safety Population. Extent of exposure to study drug will be summarized and details will be provided. Treatment emergent adverse events (AEs) are those events that occur or worsen on or after first dose of study drug up through 30 days post last dose. Adverse events will be coded using the MedDRA coding system and all AEs will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (NCI-CTCAE). Incidence of AEs will be summarized by system organ class (SOC) and preferred term (PT), and will be presented by treatment groups and overall. Adverse events will be summarized by grade, according to the worst grade experienced. In addition, most frequently observed AEs will be summarized by treatment groups. In the summary of AE, an AE occurs more than once within a SOC and PT will be counted only once using the worst grade experienced. Serious AE and deaths will be provided in a listing. All adverse events resulting in discontinuation, dose modification, dosing interruption, and/or treatment delay of study drug will also be listed and tabulated by preferred term. Clinical laboratory test results will be collected pretreatment and through 30 days post last dose of study treatment. All laboratory test results will be classified according to the NCI CTCAE v3.0 criteria. Standard reference ranges will be used for missing or discrepant Confidential Page 61 of 101

160 Clinical Study Protocol: COU-AA-302 April 2, 2012 normal ranges. Baseline laboratory test values are the results from the last blood samples drawn on or prior to the first day of study treatment. On-study laboratory test values are those results from blood samples drawn after the first study treatment up until 30 days after the last dose of study treatment. Mean change from baseline in laboratory test values at each visit will be provided. On-study clinical laboratory test abnormalities will be summarized. Shifts in laboratory test values will also be summarized Safety Analysis Population and Methods: All patients who receive any part of a dose of abiraterone acetate or placebo will be analyzed for safety. Safety endpoints will be summarized descriptively for vital signs, adverse events, clinical laboratory parameters, and ECG. Serious adverse events and deaths, and patients discontinued from study treatment will be listed. 9.9 Pharmacokinetics Analysis Approximately patients are scheduled to be enrolled at selected sites for the PK assessment. Based on the 1:1 randomization, this should yield approximately patients on active treatment (abiraterone acetate). Nonlinear mixed effects modeling will be used to develop a population PK model for abiraterone acetate and abiraterone plasma concentrations in CRPC patients. A covariate analysis will be performed to investigate the influence of patient factors on the apparent clearance of abiraterone. Patient factors will include, but are not limited to, body weight, calculated creatinine clearance, liver function, sex, age, race, and time of meal relative to the time of dose administration. Patient factors on other disposition (e.g., apparent volume of distribution) and absorption parameters will be tested in a secondary fashion. A separate report will be generated summarizing the results from the PK modeling and covariate analysis Other Assessments or Analyses In addition, analysis of pharmacoeconomic data and production of a final pharmacoeconomic report will be handled separately from the final clinical study report. Information obtained from the collection of medical resource utilization data may be combined with other data, such as cost data or other clinical parameters, in the production of final pharmacoeconomic report. Confidential Page 62 of 101

161 Clinical Study Protocol: COU-AA-302 April 2, ADMINISTRATIVE CONSIDERATIONS 10.1 Investigators and Study Administrative Structure Investigator Responsibilities The investigator undertakes to perform the study in accordance with ICH Guidelines per Good Clinical Practice (GCP) and the applicable regulatory requirements. A copy of the guidelines will be available in the Investigator Site File. It is the investigator s responsibility to ensure that adequate time and appropriate resources are available at the investigational site prior to commitment to participate in this study. The investigator should also be able to demonstrate a potential for recruiting the required number of suitable patients within the agreed recruitment period. The investigator will maintain a list of appropriately qualified persons to whom the investigator has delegated significant study-related tasks. An up-to-date copy of the curriculum vitae for the investigator and sub-investigator(s) will be provided to Cougar (or its representative) before starting the study. The investigator will inform Cougar of any updates to the list of sub-investigators after the start of the study. If the patient has a primary physician, the investigator should, with the patient s consent, inform them of the patient s participation in the study. Agreement with the final clinical study report will be documented by the signed and dated signature of the principal or coordinating investigator in compliance with ICH E Protocol Adherence and Investigator Agreement The investigator must adhere to the protocol as detailed in this document. The investigator will be responsible for enrolling only those patients who have met protocol eligibility criteria. The investigators will be required to sign an investigator agreement to confirm acceptance and willingness to comply with the study protocol. It is the investigator s responsibility to communicate with their local IRB/IEC to ensure accurate and timely information is provided at all phases during the study. In particular, the appropriate approvals must be in place prior to recruitment, and the IRB/IEC must be informed of study completion. The investigator should also notify the appropriate IRB or EC of serious adverse events occurring at the site and other adverse event reports received from Cougar Biotechnology, in accordance with local procedures and statutes Institutional Review Board (IRB) or Independent Ethics Committee (IEC) Approval It is the responsibility of the investigator to submit this protocol, the final approved informed consent document (approved by Cougar or its representative), relevant supporting information, and all types of patient recruitment or advertisement information (approved by Cougar or its representative) to the IRB/IEC for review and it must be approved before the Confidential Page 63 of 101

162 Clinical Study Protocol: COU-AA-302 April 2, 2012 study is initiated. Prior to implementing changes in the study, Cougar will produce a protocol amendment and the IRB/IEC must also approve any amendments to the protocol. On the approval letter, the study (title, protocol number and version), the documents reviewed (protocol, informed consent material, amendments) and the date of review should be clearly stated. Drug supplies will not be released and the patient recruitment will not begin until this written approval has been received by Cougar or its designee. The investigator is responsible for keeping the IRB/IEC apprised of the progress of the study and of any changes made to the protocol as deemed appropriate, but in any case at least once a year. The investigator must also keep the IRB/IEC informed of any serious and significant adverse events Ethical Conduct of the Study This protocol accords with the principles of the Declaration of Helsinki as set forth at the 18th World Medicines Association (Helsinki 1964) and amendments of the 29th (Tokyo 1975), the 35th (Venice 1983), the 41st (Hong Kong 1989), the 48th, and the 52nd (Edinburgh 2000) World Medicines Association. As these accords are reviewed and amended periodically, the most current amended version will be in effect Patient Information and Consent It is the responsibility of the investigator to obtain written informed consent from patients. Each patient is requested to sign the Patient Information and Consent Form after the patient has received written information and an explanation of what the study involves, i.e., the objectives, potential benefits and risk, inconveniences and the patient s rights and responsibilities. A copy of the Patient Information and signed Consent Form must be given to the patient. If applicable, it will be provided in a certified translation of the local language. Signed consent forms must remain in each patient s study file and must be available for verification by study monitors at any time. If the IRB/IEC requires modification of this form, the documentation supporting this requirement must be provided to Cougar along with the new version. Cougar reserves the right to reject these modifications, should they not cover the minimum information required by ICH GCP Patient Confidentiality Data collected during this study may be used to support the development, registration or marketing of abiraterone acetate. All data collected during the study will be controlled by Cougar or designee and Cougar will abide by all relevant data protection laws. After patients have consented to take part in the study, their medical records and the data collected during the study will be reviewed by representatives of Cougar and/or the company organizing the research on Cougar s behalf to confirm that the data collected are accurate and for the purpose of analyzing the results. These records and data may additionally be reviewed by Confidential Page 64 of 101

163 Clinical Study Protocol: COU-AA-302 April 2, 2012 auditors or by regulatory authorities. The patient s name, however, will not be disclosed outside the hospital. They will be known by a unique patient number. The results of this study may be used in other countries throughout the world that have ensured an adequate level of protection for personal data. Written Authorization (US sites only) or Data Protection Consent (European sites only) is to be obtained from each patient prior to enrollment into the study, and/or from the patient's legally authorized representative in accordance with the applicable privacy requirements [eg, the Health Insurance Portability and Accountability Act of 1996 Standards for Privacy of Individually Identifiable Health Information ( HIPAA ), European Union Data Protection Directive 95/46/EC ( EU Directive ) and any other state and country privacy requirements] Study Monitoring To ensure compliance with relevant regulations, data generated by this study must be available for inspection upon request by representatives of regulatory authorities, Cougar and its representatives, and the IRB/EC for each study site. As a sponsor of this study, Cougar may delegate some administrative aspects of this study to a duly authorized representative including, but not limited to, study initiation, monitoring, and management of SAE reports. Cougar or representative s monitor is responsible for verifying the ecrfs at regular intervals (approximately every 6-8 weeks) throughout the study to verify adherence to the protocol; completeness, accuracy, and consistency of the data; and adherence to local regulations on the conduct of clinical research. The monitor should have access to the patients medical records and other study-related records needed to verify the entries on the ecrfs Case Report Forms Electronic Case Report Forms (ecrfs) will be provided by Cougar or its representative and should be handled in accordance with instructions from Cougar or its representative. The investigator is responsible for maintaining adequate and accurate ecrfs which have been designed to record all observations and other data pertinent to the clinical investigation. Each ecrf should be filled out completely by the investigator or delegate as stated in the Site Delegation List. All data captured for the study is planned to be electronic. However, if necessary, data capture may be performed using paper CRFs. If paper CRFs are used, then all CRFs should be completed in a neat legible manner to ensure accurate interpretation of the data; a black ball-point pen should be used to ensure the clarity of reproduced copies of all CRFs. Incorrect entries should be crossed out with a single line. Corrections must be made adjacent to the item to be altered, initialed and dated with the reason for the correction if necessary, by an authorized (investigator/co-worker) person. Overwriting of this information or use of liquid correcting fluid is not allowed. The ecrfs should be reviewed, signed and dated by the investigator. Confidential Page 65 of 101

164 Clinical Study Protocol: COU-AA-302 April 2, 2012 Once the site monitor has verified the contents of the completed ecrf pages against the source data, the EDC system will be locked for those pages. Queries may be raised if the data are unclear or contradictory, which must be addressed by the investigator Laboratory Assessments A Central Laboratory will be used to analyze all lab specimens collected for the study. In the rare instance when it is not possible for the site to send a sample to the central lab, the local laboratory results will be captured on supplemental lab ecrfs Independent Data Monitoring Committee (IDMC) An external Independent Data Monitoring Committee (IDMC) will monitor and advise on interim safety and efficacy aspects of the study and relevance of new external information as specified in the IDMC charter. Key safety and efficacy (e.g. SAEs) data will be provided to the IDMC with treatment groups randomly identified (from meeting to meeting) as either X or Y. Treatment group identification may be obtained from the Independent Biostatistician if the IDMC determines that unblinding is necessary to determine whether the study should be stopped early for either safety or efficacy Central Radiologic Review All CT, MRI, and bone scans will be collected centrally for independent review of radiographic progression (a primary endpoint in this study) Protocol Violations/Deviations Protocol violations and deviations should be reported to Cougar (or designee) as they occur or are discovered and should be captured in ecrfs at the time of monitoring Access to Source Documentation Source data to be reviewed during this study will include, but is not restricted to: original source data such as the patient s medical file, patient s diary cards (if applicable), and laboratory test, histology, and pathology reports. All key data must be recorded in the patient s hospital notes/medical chart. The investigator will permit authorized representatives of Cougar, the respective national or local health authorities, and auditors to inspect facilities and records relevant to this study. The monitor (or auditors or regulatory inspectors) will check the CRF entries against the source documents. The consent form will include a statement by which the patients allow the monitor/auditor/inspector from the IEC/IRB or regulatory authority access to source data (eg, patient s medical file, appointment books, original laboratory test reports, X rays etc) that substantiate information in the CRFs. These personnel, bound by professional secrecy, will not disclose any personal information. Confidential Page 66 of 101

165 Clinical Study Protocol: COU-AA-302 April 2, Retention of Data As described in the ICH GCP Guidelines, essential documents, including CRFs, source documents, consent forms, laboratory test results, and drug inventory records, should be retained by the investigator until at least 2 years after the last approval of a marketing application in an ICH region and until there are no pending or contemplated marketing applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. These documents should be retained for a longer period however if required by the applicable regulatory requirements or by an agreement with Cougar. The investigator should obtain written permission from Cougar prior to the destruction of any study document. These records should be made available at reasonable times for inspection and duplication by a properly authorized representative of the Regulatory Authorities Financial Disclosure The investigator will be required to disclose any financial arrangement whereby the value of the compensation for conducting the study could be influenced by the outcome of the study; any significant payments of other sorts from Cougar, such as a grant to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation, or honoraria; any proprietary interest in abiraterone acetate; any significant equity interest in Cougar as defined in the US Code of Federal Regulations [21 CFR 54 2(b)]. In consideration of participation in the study, Cougar will pay the investigator, or nominated payee the sums set out in the payment schedule attached to the Investigator Agreement Study Publication Guidelines and Disclosure Policy Cougar Biotechnology ( Sponsor ) encourages publication of results derived from the clinical research it sponsors. Publication includes publication of a paper in a peer-reviewed medical journal, abstract submission with a poster or oral presentation at a scientific meeting, or making results public by some other means. Sponsor will retain the right to review all material prior to presentation or submission for publication, and neither institution(s) nor Study Co-Chairs/Principal Investigator(s) is/are permitted to publish/present the results of the study, in part or in their entirety, without the written authorization of the Sponsor. The review is aimed at complying with 21CFR312.7 (non promotion of investigational drugs) as well as the intellectual property rights and commercial interests of the Sponsor First Publication The results of the entire multi-center study shall be presented in a first publication upon completion of the entire multi-center study (data lock), with authorship being determined by the Sponsor and Protocol Steering Committee using the criteria defined by the International Committee of Medical Journal Editors. At least 2 Sponsor representatives will also be included as coauthors on the first publication of the results of the entire multi-center study to allow recognition of the Sponsor s involvement in the design and execution of the study. Confidential Page 67 of 101

166 Clinical Study Protocol: COU-AA-302 April 2, Subsequent Publications Results from data subsets should not be published in advance of and must make reference to the first publication. Publications must include at least 2 Sponsor authors to allow recognition of the Sponsor s involvement. In all publications, the study is to be identified as COU-AA REFERENCE LIST 1. Kamangar F, Dores G.M, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol 2006;24: Jemal A., Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin 2008;58: Jacobs SC. Spread of Prostatic Cancer to Bone. Urology 1983;21(4): Scher, HI, Morris MJ, Kelly WK, Schwartz LH, Heller G. Prostate cancer clinical trial end points: "RECIST"ing a step backwards. Clin Cancer Res 2005;11: Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989;321: Eisenberger MA, Blumenstein BA, Crawford ED, Miller G, McLeod DG, Loehrer PJ, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998;339: Schmitt B, Wilt TJ, Schellhammer PF, DeMasi V, Sartor O, Crawford ED, et al. Combined androgen blockade with nonsteroidal antiandrogens for advanced prostate cancer: a systematic review. Urology 2001;57: Forti G, Salerno R, Moneti G, Zoppi S, Fiorelli G, Marinoni T, et al. Three-month treatment with a long-acting gonadotropin-releasing hormone agonist of patients with benign prostatic hyperplasia: effects on tissue androgen concentration, 5 alphareductase activity and androgen receptor content. J Clin Endocrinol Metab 1989;68: Mohler JL, Gregory CW, Ford OH 3rd, Kim D, Weaver CM, Petrusz P, et al. The androgen axis in recurrent prostate cancer. Clin Cancer Res 2004;10: Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R et al. Molecular determinants of resistance to antiandrogen therapy. Nat Med 2004;10:33-9. Confidential Page 68 of 101

167 Clinical Study Protocol: COU-AA-302 April 2, Stigliano A, Gandini O, Cerquetti L, Gazzaniga P, Misiti S, Monti S, et al. Increased metastatic lymph node 64 and CYP17 expression are associated with high stage prostate cancer. J Endocrinol 2007;194: Montgomery RB, Mostaghel EA, Vessella R, Hess DL, Kalhorn TF, Higano CS, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 2008; 68: Logothetis CJ, Wen S, Molina A, Chieffo N, Smith P, Troncoso E, et al. Identification of an androgen withdrawal responsive phenotype in castrate resistant prostate cancer (CRPC) patients (pts) treated with abiraterone acetate (AA). ASCO 2008; 26:Abstract Taplin, ME, Rajeshkumar B, Halabi S, Werner CP, Woda BA, Picus J, et al. Androgen receptor mutations in androgen-independent prostate cancer: Cancer and Leukemia Group B Study J Clin Oncol 2003;21: Tomlin SA, Rhodes DR, Perner S, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005;310: Setlur SR, Mertz KD, Hoshida Y, Demichelis F, Lupien M, Perner S, et al. Estrogendependent signaling in a molecularly distinct subclass of aggressive prostate cancer. J Natl Cancer Institute 2008;100: Hegelson BE, Tomlins SA, Shah N, et al. Characterization of TMPRSS2:ETV5 and SLC45A3:ETV5 gene fusion in prostate cancer. Cancer Res 2008;68: Perner S, Demichelis F, Beroukhim R, et al. TMPRSS2-ERG fusion associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res 2006; 66: Demichelis F, Fall K, Perner S, et al. TMPRSS2-ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene 2007; 26: Mehra R, Han B, Tomlins SA, et al. Heterogeneity of TMPRSS2 gene rearrangements in multifocal prostate adenocarcinoma: Molecular evidence for an independent group of diseases. Cancer Res 2007; 67: Attard G, Clark J, Ambroisine L, et al. Duplication of the fusion TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene 2008; 27: Attard G, Reid AH, Yap TA, Raynaud F, Dowsett M, Settatree S, et al. Phase I clinical trial of a selective inhibitor of CYP17, arbiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol (in press). 23. Logothetis C, Provenge, FDA Presentation, Mar 29, 2007, Confidential Page 69 of 101

168 Clinical Study Protocol: COU-AA-302 April 2, Nabhan C, Is Chemotherapy the standard for asymptomatic androgen-independent prostate cancer? J.Clin.Oncol. 2008; 26: Calabro F, Sternberg CN. Current indications for chemotherapy in prostate cancer patients. Eur Urol 2007; 51: Basch EM, Somerfield MR, Beer TM, Carducci MA, Higano CS, Scher HI. American Society of Clinical Oncology Endorsement of the Cancer Care Ontario Practice Guidelines on Nonhormonal Therapy for Men With Metastatic Hormone_Refractory (Castration-Resistant) Prostate Cancer. J Clin Oncol 2007; 25: Heidenreich A, Aus G, Abbou CC, Bolla M, Joniau S, Matveev V, et al. Guidelines on Prostate Cancer. European Association of Urology ESMO Clinical Recommendations. Annals of Oncology: 19:Supplement 2, May, Carducci MA, Saad F, Abrahamsson P-A et al: A phase 3 randomized controlled trial of the efficacy and safety of Atrasentan in men with metastatic hormone-refractory prostate cancer. Cancer 2007; 110: Sleep D. Atrasentan, ODAC Presentation, Sept 13, 2005, Small EJ, Sceilhammer PF, Higano CS et al. Placebo-controlled Phase III trial of immunologic therapy with sipuleucel-t CAPC8015 in patients with metastatic, asymptomatic hormone refractory prostate cancer. J.Clin.Oncol 2006; 24: Huggins C, Bergenstal DM. Inhibition of human mammary and prostatic cancers by adrenalectomy. Cancer Res 1952;12: Kruit WH, Stoter G, Klijn JG. Effect of combination therapy with aminoglutethimide and hydrocortisone on prostate-specific antigen response in metastatic prostate cancer refractory to standard endocrine therapy. Anticancer Drugs 2004;15: Dawson N, Figg WD, Brawley OW, Bergan R, Cooper MR, Senderowicz A, et al. Phase II study of suramin plus aminoglutethimide in two cohorts of patients with androgen-independent prostate cancer: simultaneous antiandrogen withdrawal and prior antiandrogen withdrawal. Clin Cancer Res 1998;4: Small EJ, Baron A, Bok R. Simultaneous antiandrogen withdrawal and treatment with ketoconazole and hydrocortisone in patients with advanced prostate carcinoma. Cancer 1997;80: Millikan R. Baez,L, Banerjee T, Wade J, Edwards K, Winn R, et al. Randomized Phase 2 trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate cancer. Urol Oncol 2001;6: Confidential Page 70 of 101

169 Clinical Study Protocol: COU-AA-302 April 2, Small EJ, Baron AD, Fippin L, Apodaca D.: Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol 1997;157: Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, et al. Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a Phase 3 trial (CALGB 9583). J Clin Oncol 2004;22: Itakura H, Vaughn D, Haller DG, O'Dwyer PJ. Rhabdomyolysis from cytochrome p- 450 interaction of ketoconazole and simvastatin in prostate cancer. J Urol 2003;169: Tannock I, Gospodarowicz M, Meakin W, Panzarella T, Stewart L, Rider W. Treatment of metastatic prostatic cancer with low-dose prednisone: evaluation of pain and quality of life as pragmatic indices of response Journal of Clinical Oncology 1989, Vol 7, Nishimura K, Nonomura N, Satoh E, et al. Potential mechanisms for the effects of dexamethasone on growth of androgen-independent prostate cancer. JNCI 2001; 93: Li Z, Chen Y, Cao D et al. Glucocorticoid up-regulates transforming growth factor- {beta} (TGF-{beta}) type II receptor and enhances TGF-{beta} signaling in human prostate cancer PC-3 cells. Endocrinology 2006; 147: Tannock IF, Osoba D, Stockler MR, Ernst DS, Neville AJ, Moore MJ, et al. Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone resistant prostate cancer: a Canadian randomized trial with palliative endpoints. J Clin Oncol 1996; 14: Fossa SD, Slee PH, Brausi M, Horenblas S, Hall RR, Hetherington JW, et al. Flutamide versus prednisone in patients with prostate cancer symptomatically progressing after androgen-ablative therapy: a Phase 3 study of the European organization for research and treatment of cancer genitourinary group. J Clin Oncol 2001;19: Small EJ, Meyer M, Marshall ME, Reyno LM, Meyers FJ, Natale RB, et al. Suramin therapy for patients with symptomatic hormone-refractory prostate cancer: results of a randomized Phase 3 trial comparing suramin plus hydrocortisone to placebo plus hydrocortisone. J Clin Oncol 2000;18: Kantoff PW, Halabi S, Conaway M, Picus J, Kirshner J, Hars V, et al. Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999;17: Confidential Page 71 of 101

170 Clinical Study Protocol: COU-AA-302 April 2, Morioka M, Kobayashi T, Furukawa Y, Jo Y, Shinkai M, Matsuki, T, et al. Prostatespecific antigen levels and prognosis in patients with hormone-refractory prostate cancer treated with low-dose dexamethasone. Urol Int 2002;68: Saika T, Kusaka N, Tsushima T, Yamato T, Ohashi T, Suyama B, et al. Treatment of androgen-independent prostate cancer with dexamethasone: a prospective study in stage D2 patients. Int J Urol 2001;8: Storlie JA, Buckner JC, Wiseman GA, Burch PA, Hartmann LC, Richardson RL. Prostate specific antigen levels and clinical response to low dose dexamethasone for hormone-refractory metastatic prostate carcinoma. Cancer 1995;76: Smith DC, Redman BG, Flaherty LE, Li L, Strawderman M, Pienta KJ. A phase II trial of oral diethylbestrol as a second line hormonal agent in advanced prostate cancer. Urology 1998; 52: Klotz L, McNeill I, Fleshner N. A phase 1-2 trial of diethylbestrol plus low dose warfarin in advanced prostate carcinoma. J Urol 1999; 161: Oh WK, Kanthoff PW, Weinberg V, Jones G, Rini BI, Derynck MK, et al. Prospective, multicentre, randomized phase II trial of the herbal supplement PC-SPES and diethylbestrol in patients with androgen-independent prostate cancer. J Clin Oncol 2004; 22: Hedlund PO, Jacobsson H, Vaage S, Hahne B, Sandin T, Kontturi, M, et al. Treatment of high-grade, high-stage prostate cancer with estramustine phosphate or diethylstilbestrol. A double-blind study. The SPCG-1 Study Group. Scandinavian Prostate Cancer Group. Scand J Urol Nephrol 1997;31: Saad F, Gleason DM, Murray R, Tchekmedyian S, Venner P, Lacombe L, et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96: Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004;351: Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351: Berthold DR, Pond G, DeWit R, Eisenberger M, Tannock IF. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival of the TAX-327 study. Journal of Clinical Oncology 2007;25:Abstract Confidential Page 72 of 101

171 Clinical Study Protocol: COU-AA-302 April 2, Attard G, Reid A, Barrett M, Karavasilis V, Molife R, Thompson E, et al. Inhibition of androgen synthesis results in a high response rate in castration refractory prostate cancer. In: American Association for Cancer Research Annual Meeting: Proceedings; 2007 Apr 14-18; Los Angeles, CA. Philadelphia (PA): AACR; 2007, Abstract LB Barrie, SE, Potter GA, Goddard PM, Haynes BP, Dowsett M, Jarman M, et al. Pharmacology of novel steroidal inhibitors of cytochrome P450(17) alpha (17 alphahydroxylase/c17-20 lyase). J Steroid Biochem Mol Biol 1994;50: O'Donnell A, Judson I, Dowsett M, Raynaud F, Dearnaley D, Mason, M, et al. Hormonal impact of the 17alpha-hydroxylase/C(17,20)-lyase inhibitor abiraterone acetate (CB7630) in patients with prostate cancer. Br J Cancer 2004;90: Attard G, Reid A, Yap TA, Raynaud F, Dowsett M, Settatree1 S, et al. Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven. J Clin Oncol2008 Oct 1;26(28): Ryan CJ, Rosenberg J, Lin AM, Huey V, Kim JJ, Martins V, et al. C2 Effect of concomitant food intake on pharmacokinetics of abiraterone acetate, a 17 alphahydroxylase C17,20-lyase inhibitor in castration-resistant prostate cancer (CRPC). AACR-EORTC Meeting Abstract C2, Ryan CJ, Rosenberg J, Lin A, Valiente J, Kim J, and Small, EJ. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings 2007;Part I (25)18S (June 20 Supplement): Auchus RJ. The genetics, pathophysiology, and management of human deficiencies of P450c17. Endocrinol Metab Clin North Am 2001;30(1): de Bono JS, Attard G, Adjei A, et al. Potential applications for circulating tumor cells expressing the insulin-like growth factor-i receptor. Clin Cancer Res 2007;13: de Bono JS, Attard G, Reid A, Parker C, Dowsett M, Mollife R, et al. Abiraterone acetate (AA), a CYP17 inhibitor of androgen synthesis, has significant and durable anti-tumor activity in both chemotherapy naïve and docetaxel pre-treated castration resistant prostate cancer (CRPC). J Clin Oncol 2008 ASCO Annual Meeting Proceedings; 26:Abstract Ryan CJ, Rosenberg J, Lin A, and Small EJ. Phase I evaluation of abiraterone acetate (CB7630), a 17-alpha hydroxylase C17,20-lyase inhibitor in androgen-independent prostate cancer (AiPCa). J Clin Oncol 2007 ASCO Annual Meeting Proceedings; 25:Abstract Sandblom G, Carlsson P, Sennfalt K, Varenhorst E. A population-based study of pain and quality of life during the year before death in men with prostate cancer. Br J Cancer 2004;90: Confidential Page 73 of 101

172 Clinical Study Protocol: COU-AA-302 April 2, Litwin MS, Lubeck DP, Stoddard ML, Pasta DJ, Flanders SC, Henning JM. Quality of life before death for men with prostate cancer: results from the CaPSURE database. J Urol 2001;165: Melmed GY, Kwan L, Reid K. Litwin MS. Quality of life at the end of life: trends in patients with metastatic prostate cancer. Urology 2002;59: Berry DL, Moinpour CM, Jiang CS, Ankerst DP, Petrylak DP, Vinson L. Quality of life and pain in advanced stage prostate cancer: results of a Southwest Oncology Group randomized trial comparing docetaxel and estramustine to mitoxantrone and prednisone. J Clin Oncol 2006;24: Osoba D, Tannock IF, Ernst DS, Neville AJ. Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol 1999;17: Esper P, Mo F, Chodak G, Sinner M, Cella D, Pienta KJ. Measuring quality of life in men with prostate cancer using the functional assessment of cancer therapy-prostate instrument. Urology 1997;50: Carducci M, Nelson JB, Vogelzang NJ, Mulani P. Determination of Clinically Meaningful Change (CMC) for Functional Assessment of Cancer Therapy-Prostate (FACT-P). Journal of Clinical Oncology, 2005 ASCO Annual Meeting Proceedings. Abstract 8077;23: Scher HI, Halabi S, Tannock I, Morris M, Sternberg CN, Carducci MA, et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008; 26: Pollen JJ, Witztum KF, Ashburn WL. The flare phenomenon on radionuclide bone scan in metastatic prostate cancer. AJR Am J Roentgenol 1984; 142: Scher HI, Warren M, Heller G. The association between measures of progression and survival in castrate-metastatic prostate cancer. Clin Cancer Res 2007;13: Brundage MD, Crook JM, Lukka H. Use of strontium-89 in endocrine-refractory prostate cancer metastatic to bone. Provincial Genitourinary Cancer Disease Site Group. Cancer Prev Control 1998; 2: Rajan R, Elliott DJ, Robson CN, Leung HY. Alternative splicing and biological heterogeneity in prostate cancer. Nature Reviews Urology 2009; 6: Branson M and Whitehead J. Estimating a treatment effect in survival studies in which patients switch treatment. Stat Med 2002; 21: Confidential Page 74 of 101

173 Clinical Study Protocol: COU-AA-302 April 2, Robins JM and Tsiatis AA. Correcting for non-compliance in randomized trials using Rank Preserving Structural Failure Time models. Commun Statist Theory Meth 1991; 20: Confidential Page 75 of 101

174 Clinical Study Protocol: COU-AA-302 April 2, 2012 Appendix 1: Schedule of Events Evaluation Screening Day -14 to 1 Table of Scheduled Events 1 Day 1 of Cycle 1 Day 15 of Cycle 1 2 Day 1 of Cycles 2, 4, 6, 8, 9, 11, 12 Treatment Phase Day 15 of Cycles 2 and 3 2 Day 1 of Cycles 3, 5, 7, 10, and at Treatment Discontinuation 3 End of Study Treatment Visit 4 X Procedures Signed consent X 17 form Medical history, X demographics, prior prostate therapies QOL - FACT-P X X X BPI-SF, analgesic X X X X X usage Physical exam X X X X and Weight 5 Vital signs 6 X X X X X X ECOG X X X X X X 12 Lead ECG 7 X X X MUGA Scan or X Cardiac ECHO 8 Dosing X X X X compliance Concomitant X X X X X X medications Adverse events X 9 X X X X X 10 Laboratory Assessments Hematology X X X X X Coagulation X X Factors- PT/PTT (INR) Serum chemistry, X X X X X X electrolytes Fasting Glucose X X X Serum Lipids X X X Follow-Up Phase Q3 Months up to Month 60 Confidential Page 76 of 101

175 Clinical Study Protocol: COU-AA-302 April 2, 2012 Evaluation Screening Day -14 to 1 Table of Scheduled Events 1 Day 1 of Cycle 1 Day 15 of Cycle 1 2 Day 1 of Cycles 2, 4, 6, 8, 9, 11, 12 Treatment Phase Day 15 of Cycles 2 and 3 2 Day 1 of Cycles 3, 5, 7, 10, and at Treatment Discontinuation 3 End of Study Treatment Visit 4 X 16 Liver function tests 16 PSA 11 X X X X Serum X testosterone Urinalysis X (dipstick) Tumor Assessments CT / MRI /other X 12 X imaging procedure Bone Scan X 12 X 13 Disease X progression assessment TMPRSS2-ERG and other biomarkers (at selected study centers) X 18 PK 14 Sampling at Select Study Centers Pre-dose PK X 14 X 14 X 14 Follow-Up Phase Q3 Months up to Month 60 X 15 In Clinic Dosing X 14 X 14 X 14 of Study Treatment for PK Post-dose 12- X 14 X 14 X 14 Lead ECG Post dose PK X 14 X 14 X 14 Follow-Up Period Assessments Follow-Up Assessments 15 Confidential Page 77 of 101

176 Clinical Study Protocol: COU-AA-302 April 2, The Cycle 1 Day 1 visit may occur on the same day as the Screening Visit provided that all screening assessments have been completed and results reviewed prior to the commencement of Cycle 1 Day1 assessments. 2 If patients continue on study without disease progression or discontinuation of treatment beyond Cycle 12, they should receive visit assessments as follows: - At Cycle 13 and every third cycle thereafter (i.e. Cycles 13, 16, 19, 22 ), patients should receive the same assessments as indicated for Cycles 3, 5, 7, and At all other cycles (i.e. Cycles 14, 15, 17, 18, 20, 21 ) they should receive the same assessments as indicated for Cycles 2, 4, 6, 8, 9, 11, and Treatment Discontinuation Visit can occur at any scheduled or unscheduled visit when applicable. At this visit, documentation to confirm progressive disease is required. 4 End of Study Treatment Visit should be scheduled to collect safety assessments between 15 to 28 days after the patient stops treatment. Patients will enter Follow up Phase at that time. 5 Weight will be recorded at every indicated visit. Height will be measured at Screening visit only. 6 Vitals include upright blood pressure, heart rate, respiratory rate, and oral or aural body temperature. 7 ECGs should not be obtained when serum potassium is < 3.5mg/mL. Hypokalemia should be corrected prior to ECG collection. 8 A MUGA scan should be obtained at baseline (up to 28 days prior to Cycle 1 Day 1). A cardiac ECHO can be used if MUGA is not available or when ECHO is standard of care at the study site. 9 Pre-Treatment SAEs should be reported from time patient signs a consent form up to Cycle 1 Day 1 treatment administration. 10 Adverse event follow-up is required for 30 days following last dose to determine if any new or ongoing drug related AE or any SAE regardless of relationship to drug exists. Follow-up could be conducted by sites via telephone attempts and must be documented in source notes. 11 If patient undergoes a digital rectal exam (DRE), PSA must be sampled prior to the DRE 12 Scans (CT, MRI, and Bone) performed up to 28 days prior to Cycle 1 Day 1 can be used for baseline assessments. 13 If disease progression is observed on the bone scan, confirmatory bone scan is required at least 6 weeks later. Study treatment should be continued in the interim unless there is unequivocal clinical progression as defined in Section 6.6. If the confirmatory scan is negative (does not confirm PD), then the patient should be seen again at the next scheduled study visit as specified in the protocol. 14 Selected Study Centers Only: PK blood samples collected pre and post dose at the following visits: Cycle 1 Day 1, Cycle 2 Day 1, and Cycle 5 Day 1. Patients will be asked to withhold their daily dose and take study treatment following pre-dose PK collection. 15 Follow-up assessments may be collected by telephone interview or chart review. Information will be collected on overall survival, opiate use, ECOG performance status, next therapy for prostate cancer (including dose and treatment duration of cytotoxic chemotherapy), and study treatment related SAEs. 16 Liver function tests include: ALK-P, ALT (SGPT), AST (SGOT), LDH, and direct and total bilirubin 17 Informed consent may be obtained prior to Day -14, as long as it is obtained before any study-specific procedures are completed. 18 Shipment of samples to the central laboratory for biomarker analysis can be completed at any point after Screening. Confidential Page 78 of 101

177 Clinical Study Protocol: COU-AA-302 April 2, 2012 Appendix 2: Study Treatment Preparation and Dispensing Instructions Labeling/Packaging Study treatment (abiraterone acetate and placebo) will be provided to each site packaged for patient assignment at the time of randomization. Packaging includes a 30-day supply. Site pharmacist will dispense the study treatment to each patient in accordance with this protocol under the guidelines of the site s dispensation standard operating procedure. Storage of Study Treatments The study treatment must be stored in a secure area and administered only to patients who entered into the clinical study, at no cost to the patient, in accordance with the conditions specified in this protocol. Investigational product should be stored at the study site at a room temperature between 15ºC to 30º C; 59º-86º F. Bottles of study drug should be stored with the cap on tightly and should not be refrigerated as this is a high relative humidity environment. Clinical Supply Inventory The investigator must keep an accurate accounting of the number of investigational units received from Cougar Biotechnology, Inc., dispensed to the patients, the number of units returned to the investigator by the patient, and the number of units returned to Cougar Biotechnology, Inc. during and at the completion of the study. A detailed inventory must be completed for the study treatment. The study treatment must be dispensed only by an appropriately qualified person to patients in the study. The treatment is to be used in accordance with the protocol by patients who are under the direct supervision of an investigator. Return or Disposal of Study Medications/Treatments All clinical study treatments will be returned to Cougar Biotechnology, Inc. or destroyed at the site as specified in writing by Cougar Biotechnology, Inc. Destruction of study treatments at the site should be done in the presence of a Cougar Biotechnology, Inc. representative. Alternatively, destruction of the treatments may be carried out by a suitably qualified person based on written instructions from Cougar Biotechnology, Inc. Confidential Page 79 of 101

178 Clinical Study Protocol: COU-AA-302 April 2, 2012 Appendix 3: Protocol-Specific PCWG2 Criteria Progressive Disease after Androgen Deprivation Eligibility Criteria: The reference value (#1) is the last PSA measured before increases are documented, with subsequent values obtained a minimum of 1 week apart. If the PSA at time point 3 (value #3A) is greater than that at point 2, then eligibility has been met. If the PSA is not greater than point 2 (value #3B), but value #4 is, the patient is eligible assuming that other criteria are met, if values 3A or #4 are 2 ng/ml or higher. Figure A3.1. Eligibility Based on PSA Confidential Page 80 of 101

179 Clinical Study Protocol: COU-AA-302 April 2, 2012 Appendix 4: Modified Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference for the COU-AA-302 study: A Phase 3, Randomized, Double-blind, Placebo Controlled Study of Abiraterone Acetate (CB7630) Plus Prednisone in Asymptomatic or Mildly Symptomatic Patients with Metastatic Castration-Resistant Prostate Cancer Eligibility RECIST criteria will be used on measurable soft tissue and visceral lesions Measurable disease - the presence of at least one measurable lesion. If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology. Measurable lesions Visceral or extranodal lesions need to be at least 10 mm in one dimension using spiral CT; however, lymph nodes need to be 20 mm in at least one dimension to be considered as target or evaluable lesions to assess changes in size. Non-measurable lesions - all other lesions, including small lesions (longest diameter [LD] <20 mm), i.e., leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, cystic lesions, and also abdominal masses that are not confirmed and followed by imaging techniques. For this study, bone lesions are not considered non-measurable lesions for RECIST. Bone lesions will be assessed by bone scan only. All measurements should be taken and recorded in metric notation, using a ruler or calipers. All baseline evaluations should be performed as closely as possible to the beginning of treatment and never more than 28 days before the beginning of the treatment; nodal and visceral/extra-nodal disease will be recorded separately. The same method of assessment and the same technique should be used to characterize each identified and reported lesion at baseline and during follow-up. Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules and palpable lymph nodes). For the case of skin lesions, documentation by color photography, including a ruler to estimate the size of the lesion, is recommended. Confidential Page 81 of 101

180 Clinical Study Protocol: COU-AA-302 April 2, 2012 Methods of Measurement CT and MRI are the best currently available and reproducible methods to measure target lesions selected for response assessment. Conventional CT and MRI should be performed with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm contiguous reconstruction algorithm. Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung. However, CT is preferable. Ultrasound (US), endoscopy and laparoscopy should not be used to measure tumor lesions. Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., after treatment to differentiate between residual benign lesions and residual malignant lesions. Baseline Documentation of Target and Non-Target Lesions All measurable lesions up to a maximum of 5 lesions per organ and 10 lesions in total, representative of all involved organs should be identified as target lesions and recorded and measured at baseline. Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically). A sum of the LD for all target lesions will be calculated and reported as the baseline sum LD. The baseline sum LD will be used as reference by which to characterize the objective tumor. All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at baseline. Measurements of these lesions are not required, but the presence or absence of each should be noted throughout follow-up. Evaluation of Target Lesions * Complete Response (CR): Disappearance of all target lesions * Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD * Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions * Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Confidential Page 82 of 101

181 Clinical Study Protocol: COU-AA-302 April 2, 2012 Evaluation of Non-Target Lesions * Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker level * Incomplete Response/ Stable Disease (SD): Persistence of one or more non-target lesion(s) or/and maintenance of tumor marker level above the normal limits * Progressive Disease (PD): Appearance of new lesions and/or unequivocal progression of existing non-target lesions (1) (1) Although a clear progression of non target lesions only is exceptional, in such circumstances, the opinion of the treating physician should prevail. Evaluation of Best Overall Response The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for PD the smallest measurements recorded since the treatment started). In general, the patient's best response assignment will depend on the achievement of both measurement and confirmation criteria Response Criteria Target lesions Non-Target lesions New Lesions Overall Response CR CR No CR CR Incomplete No PR response/sd PR Non-PD No PR SD Non-PD No SD PD Any Yes or No PD Any PD Yes or No PD Any Any Yes PD Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence of disease progression at that time should be classified as having symptomatic deterioration. Every effort should be made to document the objective progression even after discontinuation of treatment. In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the evaluation of complete response depends on this determination, it is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status. Confidential Page 83 of 101

182 Clinical Study Protocol: COU-AA-302 April 2, 2012 Duration of Overall Response The duration of overall response is measured from the time measurement criteria are met for CR or PR (whichever status is recorded first) until the first date that recurrence or PD is objectively documented, taking as reference for PD the smallest measurements recorded since the treatment started. Duration of Stable Disease Stable disease is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started. Reporting of Results All patients included in the study must be assessed for response to treatment, even if there are major protocol treatment deviations or if they are ineligible. Each patient will be assigned one of the following categories: 1) complete response, 2) partial response, 3) stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, insufficient data). All of the patients who met the eligibility criteria should be included in the main analysis of the response rate. Patients in response categories 4-9 should be considered as failing to respond to treatment (disease progression). Thus, an incorrect treatment schedule or drug administration does not result in exclusion from the analysis of the response rate. Precise definitions for categories 4-9 will be protocol specific. All conclusions should be based on all eligible patients. Sub-analyses may then be performed on the basis of a subset of patients, excluding those for whom major protocol deviations have been identified. However, these subanalyses may not serve as the basis for drawing conclusions concerning treatment efficacy, and the reasons for excluding patients from the analysis should be clearly reported. The 95% confidence intervals should be provided Confidential Page 84 of 101

183 Clinical Study Protocol: COU-AA-302 April 2, 2012 Appendix 5: National Cancer Institute Common Terminology Criteria for AEs V3.0 (CTCAE): publish date August 9, 2006: Confidential Page 85 of 101

184 Clinical Study Protocol: COU-AA-302 April 2, 2012 Appendix 6: ECOG Performance Status ECOG Grade Scale (with Karnofsky conversion) 0 Fully active, able to carry on all pre-disease performance without restriction. (Karnofsky ) 1 Restricted in physically strenuous activity but ambulatory and able to carry out work on a light or sedentary nature, eg., light housework, office work. (Karnofsky 70-80) 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. (Karnofsky 50-60) 3 Capable of only limited self-care; confined to bed or chair more than 50% of waking hours. (Karnofsky 30-40) 4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair. (Karnofsky 10-20) 5 Dead Confidential Page 86 of 101

185 Clinical Study Protocol: COU-AA-302 April 2, 2012 Appendix 7: Creatinine Clearance Creatinine clearance (CrCl) is to be estimated by using the following formula: Adult male CrCl = (140 - age) x weight measured in kg (72 x serum creatinine measured in mg/deciliter) Confidential Page 87 of 101

186 Clinical Study Protocol: COU-AA-302 April 2, 2012 Appendix 8: Brief Pain Inventory (Short Form) Confidential Page 88 of 101

187 Clinical Study Protocol: COU-AA-302 April 2, 2012 Confidential Page 89 of 101