Bosutinib versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial. Cortes, et al

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1 The following protocol information is provided solely to describe how the authors conducted the research underlying the published report associated with the following article: versus imatinib for newly diagnosed chronic myeloid leukemia: results from the randomized BFORE trial Cortes, et al DOI: /JCO The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Author Center ( only specific elements of the most recent version of the protocol are requested by JCO. The protocol information is not intended to replace good clinical judgment in selecting appropriate therapy and in determining drug doses, schedules, and dose modifications. The treating physician or other health care provider is responsible for determining the best treatment for the patient. ASCO and JCO assume no responsibility for any injury or damage to persons or property arising out of the use of these protocol materials or due to any errors or omissions. Individuals seeking additional information about the protocol are encouraged to consult with the corresponding author directly.

2 This supplement contains the following items: 1. Final study protocol...page 3 2. Final statistical analysis plan...page 126

3 Clinical Study Protocol Protocol Title: Protocol Number: Product: A Multicenter Phase 3 Randomized, Open-Label Study of versus Imatinib in Adult Patients with Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia AV001 EudraCT Number: Study Phase: Phase 3 Sponsor: Co-ordinating Investigators: Wyeth Pharmaceuticals, Inc. A wholly owned subsidiary of Pfizer Inc. 500 Arcola Road Collegeville, PA United States of America Europe: Prof. Dr. med. Tim H. Brümmendorf Klinik für Hämatologie, Onkologie und Stammzelltransplantation Uniklinik der RWTH Aachen Pauwelsstrasse Aachen Germany USA: Dr. Jorge Eduardo Cortes, M.D. The University of Texas MD Anderson Cancer Center Department of Leukemia 1515 Holcombe Blvd Unit Number: 428 Houston, TX USA Contract Research Organization: Protocol Version: Chiltern International Limited 171 Bath Road Slough Berkshire SL1 4AA United Kingdom Final including Amendment 3.1 (Global) Date of Protocol: 07 December 2016 Confidentiality Statement The confidential information in this document is provided to you as an Investigator or consultant for review by you, your staff, and the applicable Institutional Review Board/Independent Ethics Committee. Your acceptance of this document constitutes agreement that you will not disclose the information contained herein to others without written authorization from the Sponsor. This protocol has been written in accordance with current ICH-GCP guidelines. 07 December 2016 Page 1 of 123

4 Signature Page PROTOCOL TITLE: A Multicenter Phase 3 Randomized, Open-Label Study of versus Imatinib in Adult Patients with Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia PROTOCOL NO: AV001; Final Protocol including Amendment 3.1 This study protocol was subjected to critical review. The information it contains is consistent with the current risk/benefit evaluation of the test preparation as well as with the moral, ethical and scientific principles governing clinical research as set out in the Declaration of Helsinki and the International Conference on Harmonization (ICH) guidelines on Good Clinical Practice (GCP). This protocol is approved by: Signature: Witnessed by: Rocco J. Crescenzo, DO, FACOI Senior Director Global Clinical Lead, Pfizer Global Product Development Oncology 500 Arcola Road STE D-6256 Collegeville, PA USA Signature: Date Date: Date: Carlo Lanza, MD, PhD, MSc Senior Medical Officer Chiltern International Via General Guisan 6 Paradiso 6900 Switzerland The Investigator s Signature Page is provided in Section Details of study administrative structure are provided in Section December 2016 Page 2 of 123

5 SYNOPSIS Name of Sponsor: Name of Finished Product: Name of Active Ingredient: Title of Study: Protocol No: Co-ordinating Investigators: Pfizer Bosulif A Multicenter Phase 3 Randomized, Open-Label Study of versus Imatinib in Adult Patients with Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia AV001 Europe: Prof. Dr. med. Tim H. Brümmendorf Klinik für Hämatologie, Onkologie und Stammzelltransplantation Uniklinik der RWTH Aachen Pauwelsstrasse Aachen Germany USA: Dr. Jorge Eduardo Cortes, M.D. The University of Texas MD Anderson Cancer Center Department of Leukemia 1515 Holcombe Blvd Unit Number: 428 Houston, TX USA Study centers: The study will be performed in approximately 195 sites worldwide Study duration: All patients will be treated and/or followed for approximately 5 years Phase: 3 (240 weeks) after randomization until the study has closed. Objectives: Primary: To compare the proportion of patients demonstrating Major Molecular Response (MMR) at 12 months (48 weeks) in the bosutinib arm with that of the imatinib arm in newly diagnosed Philadelphia chromosome positive (Ph+) chronic phase (CP) chronic myelogenous leukemia (CML) patients harboring b2a2 and/or b3a2 transcripts. Secondary: To evaluate MMR by 18 months in the bosutinib treatment group compared with the imatinib treatment group. To evaluate the duration of MMR in the bosutinib treatment group compared with the imatinib treatment group. To estimate the proportion of patients demonstrating a cytogenic response (CCyR) by 12 months in both treatment groups. To evaluate the duration of CCyR in both treatment groups. To evaluate event free survival (EFS) in both treatment groups. To evaluate overall survival (OS) in both treatment groups. To assess the population pharmacokinetics (PK) of bosutinib administered once daily. To assess correlations between trough concentrations of bosutinib and key efficacy and safety parameters. To evaluate the safety profile of bosutinib and imatinib treatments. 07 December 2016 Page 3 of 123

6 Exploratory: To evaluate MMR at 3, 6 and 9 months and at 18 months in both treatment groups. To evaluate MMR at 12 months in both treatment groups in the Philadelphia chromosome unrestricted (i.e., Ph+ and Philadelphia chromosome negative [Ph-]) patient population. To evaluate MR 1 and MR 2 at 3 months and 6 months respectively in both treatment groups. To evaluate MR 4 and MR 4.5 at 3, 6, 9 and 12 months in both treatment groups. To evaluate time to MMR in the bosutinib treatment group compared with the imatinib treatment group. To evaluate the proportion of patients with cumulative complete hematologic response (CHR) in both treatment groups in both Ph+ and Philadelphia chromosome unrestricted (i.e., Ph+ and Ph-) patient population. To evaluate the time to CCyR in both treatment groups. To estimate the time to transformation to accelerated phase (AP) and blast phase (BP) on treatment in both treatment groups. To evaluate patient-reported outcomes, including quality of life (QoL), using Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and EuroQol-5D (EQ-5D), in both treatment groups. To evaluate the type of BCR-ABL mutations present at treatment completion or discontinuation, or in case of suboptimal response in both treatment groups. To investigate the presence of newly observed BCR-ABL mutations in patients with sub-optimal response in both treatment groups. Study Design: Phase 3, 2-arm, randomized, open label trial. Patients will be randomized (1:1) to receive bosutinib or imatinib for the dur ation of the study. The study will be open for enrollment until the planned number of approximately 500 Ph+ patients have been randomized (approximately 250 Ph+ patients in each treatment arm; a total of approximately 530 Ph+ and Ph- patients). All patients will be treated and/or followed for approximately 5 years (240 weeks) after randomization until the study has closed. Patients who discontinue study therapy early due to disease progression or intolerance to study medication will continue to be followed yearly for survival for up to approximately 5 years (240 weeks) after randomization. Planned number of patients: It is planned to enroll a sufficient number of patients to randomize approximately 500 Ph+ patients (a total of approximately 530 Ph+ and Phpatients). Diagnosis and main criteria for inclusion: Main Inclusion Criteria: 1. Molecular diagnosis of CP CML of 6 months (from initial diagnosis). Diagnosis of CP CML with molecular confirmation by detection of BCR-ABL rearrangement at screening (cytogenetic assessment for Philadelphia chromosome is not required for enrollment); diagnosis of CP CML will be defined as all of the following, per ELN criteria: (a) <15% blasts in peripheral blood and bone marrow; (b) <30% blasts plus promyelocytes in peripheral blood and bone marrow; (c) <20% basophils in peripheral blood; (d) 100 x 10 9 /L platelets ( 100,000/mm 3 ); (e) No evidence of extramedullary disease except hepatosplenomegaly; AND (f) No prior diagnosis of AP or BP CML. Philadelphia chromosome status will be identified at screening. Both Philadelphia positive (Ph+) and Philadelphia negative (Ph-) patients may be included. 2. Adequate hepatic, renal and pancreatic function defined as: Aspartate aminotransferase (AST)/Alanine aminotransferase 07 December 2016 Page 4 of 123

7 (ALT) 2.5 x upper limit of normal (ULN) or 5 x ULN if attributable to liver involvement of leukemia. Total bilirubin 2.0 x ULN (unless associated with Gilbert s syndrome). Creatinine 1.5 x ULN. 3. Ability to take oral tablets. 4. Eastern Cooperative Oncology Group (ECOG) Performance status of 0 or Age 18 years. 6. Negative serum pregnancy test within 2 weeks of the first dose of study drug if the patient is a woman of childbearing potential. A woman of childbearing potential is defined as a woman who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives. Patients and patients partners of childbearing potential (physically able to have children) and who are sexually active, must agree to use double barrier contraception, oral contraceptives, intrauterine device, intra-muscular contraceptive, vasectomy/surgical sterilization, true abstinence or other approved method of birth control consistently and correctly during the study and for at least 28 days after they have stopped taking the study drug. 7. Ability to provide written informed consent prior to any study related screening procedures being performed. Main Exclusion Criteria: 1. Any prior medical treatment for CML, including tyrosine kinase inhibitors (TKIs), with the exception of hydroxyurea and/or anagrelide treatment, which are permitted for up to 6 months prior to study entry (signature of ICF) if suitably approved for use in the subject s region. 2. Any past or current CNS involvement, including leptomeningeal leukemia. 3. Hypersensitivity to the active substance or to any of the following excipients: Microcrystalline cellulose (E460), croscarmellose sodium (E468), poloxamer 188, povidone (E1201), magnesium stearate (E470b), polyvinyl alcohol, titanium dioxide (E171), macrogol 3350, Talc (E553b), iron oxide yellow (E172). 4. Extramedullary disease only. 5. Major surgery or radiotherapy within 14 days of randomization. 6. Concomitant use of or need for medications known to prolong the QT interval. 7. History of clinically significant or uncontrolled cardiac disease, including: History of, or active, congestive heart failure. Uncontrolled angina or hypertension within 3 months. Myocardial infarction (within 12 months). Clinically significant ventricular arrhythmia (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes). Diagnosed or suspected congenital or acquired prolonged QT history or prolonged QTc (QTcF should not exceed 500 msec). Unexplained syncope. 07 December 2016 Page 5 of 123

8 Study Drug, dose and mode of administration: Reference therapy, dose, and mode of administration: 8. Known seropositivity to human immunodeficiency virus (HIV), current acute or chronic hepatitis B (hepatitis B surface-antigen positive), hepatitis C, cirrhosis or evidence of decompensated liver disease. Patients with resolved Hepatitis B can be included. 9. Recent or ongoing clinically significant gastrointestinal (GI) disorder e.g. Crohn s Disease, Ulcerative Colitis or prior total or partial gastrectomy. 10. History of another malignancy within 5 years with the exception of basal cell carcinoma or cervical carcinoma in situ or stage 1 or 2 cancer that is considered adequately treated and currently in complete remission for at least l2 months. 11. Uncontrolled hypomagnesemia or uncorrected hypokalemia, due to potential effects on the QT interval. 12. Current, or recent (within 30 days, or 5 half-lives of investigational product) participation in other clinical trials of investigational agents and/or containing interventional procedures deemed contrary to the objectives and conduct of this trial. 13. Women who are pregnant, planning to become pregnant during the study or are breastfeeding a child, or men who are planning to father a child during their participation in this study., 400 mg, oral administration once a day Imatinib, 400 mg, oral administration once a day Criteria for evaluation: Efficacy: Efficacy will be determined by analysis of physical examination findings, peripheral blood and bone marrow; the primary efficacy analysis will be performed at the end of the Core Treatment Phase of the study. The Core Treatment Phase is the first 12 months (48 weeks) of the study on a per patient basis. Automated complete blood counts (CBCs), differential counts (with manual confirmation of abnormalities), bone marrow differentials, cytogenetics, and mortality will be used to determine the response to treatment. Cytogenetic, molecular, and hematologic response rates will be estimated for all randomized patients. Primary Efficacy Endpoint: The primary efficacy endpoint is MMR at 12 months (48 weeks) in Ph+ CML patients harboring b2a2 and/or b3a2 transcripts. MMR is defined as 0.1% BCR-ABL on the international scale (IS) by real-time quantitative polymerase chain reaction (RQ-PCR). Secondary Efficacy Endpoints: MMR by 18 months. Duration of MMR. CCyR by 12 months. Duration of CCyR. EFS. OS. Exploratory Efficacy Endpoints: MMR at 3, 6, 9 and 18 months. MMR at 12 months in the Philadelphia chromosome unrestricted (i.e., Ph+ and Ph-) patient population. MR 1 and MR 2 at 3 months and 6 months respectively. 07 December 2016 Page 6 of 123

9 MR 4 and MR 4.5 at 3, 6, 9 and 12 months. Time to MMR. Cumulative CHR in both Ph+ and Philadelphia chromosome unrestricted (Ph+ and Ph-) patient population. Time to CCyR. Time to transformation to AP and blast phase BP on treatment. Type of mutations present at treatment completion/discontinuation or suboptimal response in each treatment group. Presence of newly observed BCR-ABL mutations in patients post-baseline and correlation with response to treatment in imatinib and bosutinib treatment groups. Pharmacokinetic Data (bosutinib treatment group only): A total of 4 PK samples per patient will be drawn. All patients will provide pre-dose blood samples on Day 1, Day 28, Day 56, and Day 84. Pharmacokinetic Endpoints (secondary endpoints) Population PK of bosutinib. Correlations between trough concentrations of bosutinib and key efficacy and safety parameters. Safety: Safety will be assessed on an ongoing basis by physical examination including measurement of vital signs, laboratory assessments, standard safety evaluations (electrocardiograms [ECGs] for monitoring of QTc interval changes and echocardiograms/muga scans for monitoring ventricular function) and recording of adverse events (AEs) and serious adverse events (SAEs). Adverse events will be graded according to the NCI CTC version 4. Discontinuations due to AEs will be considered the main comparative safety endpoint for AEs. In addition standard laboratory assessments will be performed. Quality of Life: Patient reported health outcomes and QoL will be assessed using Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and EuroQol-5D (EQ-5D). Statistical Methods The primary efficacy endpoint, MMR at 12 months (48 weeks) in Ph+ patients harboring b2a2 and/or b3a2 transcripts, will be analyzed using a Cochran-Mantel-Haenszel test, adjusted for the stratification factors, Sokal score and geographical region. MMR will be also assessed in the Philadelphia chromosome unrestricted population (both Ph- and Ph+ patients) as an exploratory endpoint All secondary and exploratory endpoints based on response rate will be analyzed in the same way. Secondary and exploratory endpoints based on time to event data or duration of response data will be analyzed either by a Cox s proportional hazards model and Kaplan-Meier plots or, as appropriate, cumulative incidence curves and Gray s test. Kaplan-Meier plots will be presented for OS. The null hypothesis for the primary efficacy comparison will be that there is no difference in the proportion of patients demonstrating MMR at 12 months (48 weeks) in the bosutinib treatment group compared to the imatinib arm, taking into account region and Sokal score. The alternative hypothesis will be that the proportion of patients demonstrating MMR at 12 months (48 weeks) is higher in the bosutinib arm compared to the imatinib arm. Rejecting the null hypothesis and accepting the alternative hypothesis, for the modified intent-to-treat (mitt) population, will be considered to be a successful demonstration of efficacy for this study. The primary outcome measure will be analyzed using a CMH test, adjusted for the stratification factors Sokal score and geographical region. The study, with approximately 500 Ph+ patients to be enrolled, is powered at greater than 90% to detect a 15% difference (assuming 25% in the imatinib arm vs. 40% in the bosutinib arm) in the proportion of patients demonstrating MMR at 12 months (48 weeks) with a 1-sided alpha of December 2016 Page 7 of 123

10 TABLE OF CONTENTS SIGNATURE PAGE LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS INTRODUCTION Indication Background and Rationale Treatment Options for CML Imatinib (Glivec/Gleevec, Novartis Pharmaceuticals) Second Generation TK1s (BOSULIF, Pfizer) as first-line treatment for CP CML Rationale for Use of Imatinib as Comparator Study Rationale Risk/Benefit Statement STUDY OBJECTIVES Primary Objective Secondary Objectives Exploratory Objectives INVESTIGATIONAL PLAN Summary of Study Design Study Procedures Screening Visit Patient Enrollment / Randomization Core Treatment Phase Visits Extension Phase Early Discontinuation Visit Long-Term Follow-Up Treatment Completion Visit Discussion of Study Design Selection of Study Population Inclusion Criteria Exclusion Criteria Patient Withdrawal Termination of the Trial Regular Termination of Study Premature Termination of Study Further Treatment After the End of the Study December 2016 Page 8 of 123

11 5.0 STUDY TREATMENTS Treatments Administered Identity of the Investigational Product Identity of the Comparator Treatment Method of Assigning Patients to Treatment Group Selection of Doses in the Study Selection and Timing of Dose for Each Patient Dose Escalation for and Imatinib Dose Reductions Blinding Prior and Concomitant Treatments Prior Treatment Concomitant Treatment Excluded Medications Allowed Medications Other Treatment Considerations Treatment Compliance Study Medication Accountability EFFICACY, SAFETY, PHARMACOKINETIC, AND HEALTH OUTCOME ASSESSMENTS Efficacy Sample Collection for Molecular Response Mutation Analysis PCR laboratory and supplies Primary Efficacy Endpoint Secondary Efficacy Endpoints Exploratory Efficacy Endpoints Safety Adverse Events Abnormal Test Finding Reporting Period Adverse Event Reporting Requirements Serious Adverse Events Hospitalization Events Due to Disease Progression Reporting Period for Serious Adverse Events Non Serious Adverse Event Reporting Requirements Serious Adverse Event Reporting Requirements Potential Cases of Drug Induced Liver Injury Medication Errors Severity Assessment December 2016 Page 9 of 123

12 6.5.6 Causality Assessment Exposure During Pregnancy Sponsor Reporting Requirements to Regulatory Authorities Clinical Laboratory Evaluations Lipase and Pancreatitis Monitoring Vital Signs, Physical Findings, and Other Safety Assessments Vital Signs Physical Examination Chest X-ray ECG Monitoring ECHO / MUGA Scan Safety Reporting During Follow-up Period Withdrawal Due to Adverse Events Patient Reported Assessments Functional Assessment of Cancer Therapy Leukemia (FACT-Leu) EuroQol Health Utilities Index (EQ-5D) Pharmacokinetics Blood Collection for Plasma PK Appropriateness of Measurements Biological Sample Storage QUALITY CONTROL AND QUALITY ASSURANCE STATISTICS Determination of Sample Size Statistical Methods Analysis Populations Primary efficacy analysis Secondary efficacy analyses Exploratory Efficacy Analyses Efficacy Endpoint and Efficacy Variables Primary Efficacy Variables Secondary Variables Other Measures of MMR and Reductions in BCR-ABL transcript Cytogenetic Response Assessment Event Free Survival and Overall Survival Time to Response Duration of Response Time to Transformation in AP/BP Exploratory Efficacy Endpoints December 2016 Page 10 of 123

13 Plots Safety Adverse Events Clinical Laboratory Evaluations Vital Signs Measurements, Physical Findings and Other Safety Evaluations Health Outcomes Analyses Pharmacokinetic Analyses Interim Analyses Data Monitoring Committee Study Management Committee Data to be Analyzed ETHICS Institutional Review Board or Independent Ethics Committee Ethical Conduct of the Study Patient Information and Informed Consent General Process for all Countries Patient Data Protection STUDY ADMINISTRATION ADMINISTRATIVE STRUCTURE Direct Access, Data Handling and Record Keeping Investigator Sponsor Investigator Information Investigator Obligations Protocol Signatures Reporting Safety Issues and Serious Breaches of the Protocol or ICH-GCP Publication Policy Sponsor s Publication Policy Investigator s Ability to Publish Patient Injury, Financing and Insurance Reporting of Safety Issues and Serious Breaches of the Protocol or ICH-GCP PRESTUDY DOCUMENTATION RECORDS RETENTION Process for all Countries CLINICAL STUDY REPORT PROTOCOL AMENDMENTS December 2016 Page 11 of 123

14 11.0 REFERENCES APPENDICES SIGNATURE OF INVESTIGATOR December 2016 Page 12 of 123

15 LIST OF TABLES Table 1: Schedule of Events...31 Table 2: Pharmacokinetics Flowchart ( Treatment Group)...36 Table 3: Dose Modifications for and Imatinib...54 Table 4: Management of Treatment Based on Non-hematologic Treatment-related Toxicity...57 Table 5: Hematologic Treatment-related Toxicity...58 Table 6: Administrative Structure...97 LIST OF APPENDICES Appendix 1: Response Definitions Appendix 2: FACT-Leu, Version Appendix 3: EQ-5D Health Questionnaire Appendix 4: Sample Drug Diary Cards Appendix 5: Eastern Cooperative Oncology Group (ECOG) Performance Appendix 6: Status Summary of Drugs that are Generally Accepted to Have a Risk of Causing QTc Prolongation Potentially Causing Torsades de Pointes Appendix 7: List of Cytochrome P4503A Inducers/Inhibitors Appendix 8: Laboratory Tests Appendix 9: Guidelines for the Management of Diarrhea December 2016 Page 13 of 123

16 1.0 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS Abbreviation AE AIDS ALT ANC AP aptt ASCO AST AUC BELA (trial) BCR-ABL BP BUN CBA CBC CCyR CHR CI CK CL/F C max CMH CML CMR CNS CP CSA CTC CYP DIR Term Adverse event Acquired immune deficiency syndrome Alanine aminotransferase Absolute neutrophil count Accelerated phase Activated partial thromboplastin time American Society of Clinical Oncology Aspartate aminotransferase Area under the concentration-time curve Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (trial) Fusion transcript or protein resulting from the 9;22 chromosomal translocation responsible for formation of the Philadelphia Chromosome Blast phase Blood urea nitrogen Chromosome Banding Analysis Complete blood count Complete cytogenetic response Complete hematologic response Confidence interval Creatine kinase Clearance Maximum concentration Cochran-Mantel-Haenszel Chronic myelogenous leukemia Complete molecular response Central nervous system Chronic phase Clinical study agreement Common terminology criteria Cytochrome P450 Dispensing and inventory record 07 December 2016 Page 14 of 123

17 Abbreviation ECG ECHO ECOG ecrf EDTA EFS EGFR egfr EIU EMA ENESTnd (trial) EQ-5D EU FACT-Leu FDA GCP G-CSF GI HDPE HgB HIV HSCT ICF ICH IDMC INR IP IPAL IRB/IEC IRIS (trial) IS ITT Term Electrocardiogram Echocardiogram Eastern Cooperative Oncology Group Electronic case report form Ethylenediaminetetraacetic acid Event free survival Epidermal growth factor receptor Estimated glomerular filtration rate Exposure in-utero European Medicines Agency Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Philadelphia Chromosome Positive (trial) EuroQol-5D European Union Functional Assessment of Cancer Therapy-Leukemia Food and Drug Administration Good clinical practice Granulocyte colony-stimulating factor Gastrointestinal High density polyethylene Hemoglobin Human immunodeficiency virus Hematopoietic stem cell transplantation Informed consent form International Conference on Harmonization Independent data monitoring committee International normalized ratio Investigational product Investigational product accountability log Institutional review board/independent ethics committee International Randomized Study of Interferon versus STI571 (trial) International scale Intent-to-treat 07 December 2016 Page 15 of 123

18 Abbreviation LC/MS/MS LFT LLN MAR MCyR MedDRA MHR MI MMR mrna MUGA NCCN NCI NICE OS PCR P-gp Ph+ Ph- PK PPI PT PTT QoL RBC RQ-PCR RT-PCR RT-qPCR SAE SAP SMC SRM SUSAR Term Validated liquid chromatography/tandem mass spectrometry Liver function test Lower limit of normal Missing at random Major cytogenetic response Medical Dictionary for Regulatory Activities Major hematologic response Multiple imputation Major molecular response Messenger ribonucleic acid Multiple gated acquisition National Comprehensive Cancer Network National Cancer Institute National Institute of Clinical Excellence Overall survival Polymerase chain reaction P-glycoprotein Philadelphia chromosome positive Philadelphia chromosome negative Pharmacokinetics Proton pump inhibitors Prothrombin time Partial thromboplastin time Quality of life Red blood cell Real-time quantitative polymerase chain reaction Reverse transcriptase polymerase chain reaction Quantitative reverse transcriptase polymerase chain reaction Serious adverse event Statistical analysis plan Study Management Committee Study reference manual Suspected unexpected serious adverse reactions 07 December 2016 Page 16 of 123

19 Abbreviation TEAE TKI ULN VAS V/F WBC Term Treatment-emergent adverse event Tyrosine kinase inhibitor Upper limit of normal Visual analogue scale Volume of distribution White blood cell Term Regulation Regulatory agency Sponsor Patient Study Drug Definition The term regulation refers to all applicable regulations, laws, and guidelines. The regulations may be international, national, or local and may include but are not limited to the Code of Federal Regulations; the European Clinical Trials Directive; the Good Clinical Practice (GCP): Consolidated Guideline (Canada); the International Conference on Harmonization Guideline for Good Clinical Practice; the Therapeutic Goods Administration Annotated International Conference on Harmonization Guidelines (Australia); and the World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Subjects. The term regulatory agency refers to all health and regulatory agencies with oversight responsibility for the study. These may be international, national, or local and may include but are not limited to the Australian Therapeutic Goods Administration; the Canadian Health Products and Food Branch; the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). The term Sponsor refers but is not limited to the Sponsor listed in the front of this document. A participant with a disease in a clinical study. For obtaining informed consent, this term also includes a legally acceptable representative where applicable. Any drug, comparator, placebo, nutritional product, dietary supplement, herbal product, vaccine, biologic product, or device used in clinical studies. For study drug accountability, this term applies to such articles when they are required by the protocol and supplied (shipped) by the Sponsor (including diluents such as sterile water for injection). 07 December 2016 Page 17 of 123

20 2.0 INTRODUCTION 2.1 Indication (Bosulif ) is an orally bioavailable, potent, multi-targeted, dual Src-Abl tyrosine kinase inhibitor (TKI) that has been approved for the treatment of adult patients with Philadelphia positive (Ph+) chronic phase (CP), accelerated phase (AP) and blast phase (BP) chronic myelogenous leukemia (CML) previously treated with other TKI inhibitor therapy.[1] This study will investigate the use of bosutinib as first-line treatment for patients with Ph+ CP CML. 2.2 Background and Rationale CML is the fourth most commonly occurring adult leukemia. CML is a clonal myeloid neoplasm in which the leukemic cells in over 95% patients have a reciprocal translocation between chromosomes 9 and 22 t(9;22)(q34;q11), the consequence of which is the generation of the Philadelphia (Ph) chromosome. The molecular product of the t(9;22) translocation is the BCR-ABL oncogene, which encodes the constitutively activated BCR-ABL kinase that activates several downstream signaling pathways that mediate myeloproliferation, resistance to apoptosis and genetic instability. The transition of patients with CML from CP to BP with an intermediate AP is becoming less standard with the chief determinants of survival being disease stage and TKI responsiveness. 2.3 Treatment Options for CML Hematopoietic stem cell transplantation (HSCT) is the only curative strategy for CML. Other treatments including chemotherapy, interferon alpha, and TKIs are effective in controlling the disease to varying degrees in all populations. The utility of HSCT is largely limited to pediatric and younger adult patients, especially those with matched donors. In addition to its limited use, HSCT is associated with a substantial morbidity and mortality. The risks accompanying HSCT and the delay in finding or nonavailability of matched donors have necessitated an alternate treatment paradigm wherein agents targeting the BCR-ABL fusion protein, such as TKIs, are considered frontline therapy. The first such TKI to be used successfully as a therapeutic agent was imatinib. Imatinib was granted approval by the European Commission in November 2001 and by the United States Food and Drug Administration (FDA) in December 2002 for the treatment of newly diagnosed patients with CP CML. However, despite the overall success of imatinib, some patients fail to achieve the desired response, experience disease progression, or are intolerant to imatinib treatment. Between 17% and 25% of patients either fail or become intolerant to imatinib during the first 5 years of treatment. The estimated annual rate of treatment failure 07 December 2016 Page 18 of 123

21 after the start of imatinib therapy, including progression during the CP and transformation to more advanced phases of CML, was 3.3% after 1 year of treatment, 7.5% in the second year, 4.8% in the third year, 1.5% in the fourth year, and 0.9% after 5 years of treatment.[2,3] Second generation TKIs, dasatinib and nilotinib, were initially developed and approved in 2006 and 2007, respectively, for the treatment of patients with resistance or intolerance to prior therapy, including imatinib. In 2010, both dasatinib and nilotinib were additionally approved for adult patients with newly diagnosed Ph+ CML in CP on the basis of phase 3 studies that demonstrated favorable results compared with imatinib.[4,5] In 2012, the International Randomized Study of Interferon versus STI571 (IRIS trial) established that complete cytogenetic response (CCyR) and major molecular response (MMR) are critical therapeutic milestones associated with good long-term outcomes in CML.[2,6,7,8,9] The IRIS trial was the first randomized trial to demonstrate the prognostic significance of monitoring BCR-ABL transcripts by real-time quantitative polymerase chain reaction (RQ-PCR) Imatinib (Glivec/Gleevec, Novartis Pharmaceuticals) Imatinib mesylate (referred to in this protocol as imatinib) is an inhibitor of the BCR-ABL kinase and been the standard first-line therapy for patients with chronic-phase CML. Imatinib was granted approval by the European Commission in November 2001 and by the FDA in December 2002 for the treatment of newly diagnosed patients with CP Ph+ CML based on results from the IRIS trial. However, after 8 years of follow-up, only 55% of the patients originally randomized to the imatinib treatment group remain on study drug. This was primarily due to failure to achieve CCyR (17%), loss of CCyR (15%) and intolerance to imatinib (approximately 5%).[10] While several mechanisms of imatinib resistance have been proposed, the best known and possibly the most clinically prevalent are lack of adherence/compliance (which may reflect adverse events [AEs] in some patients) and/or the development of BCR-ABL mutations, which alter drug sensitivity and can be detected in approximately 40% to 50% of patients with CP CML in which imatinib has failed.[10] In order to overcome these mechanisms of resistance, second-generation TKIs have been developed and approved. These products are discussed below. 07 December 2016 Page 19 of 123

22 2.3.2 Second Generation TK1s Dasatinib (Sprycel, Bristol-Myers Squibb) DASISION, the first line study of dasatinib versus imatinib was a multinational study including 519 patients with newly diagnosed CP CML.[11] Patients were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). Data were evaluated after all patients had at least 12 months of follow-up; over 80% of patients were on-going at the time of analysis. The median duration of treatment was approximately 14 months. Results showed a confirmed CCyR rate that was higher with dasatinib than with imatinib (77% vs. 66%, p=0.007). Dasatinib had higher thrombocytopenia than imatinib (19% versus 10%) and 10% of patients on dasatinib developed pleural effusions versus none on imatinib. Nilotinib (Tasigna, Novartis) The first study in the use of nilotinib as first-line therapy evaluated 51 patients with newly diagnosed CML in chronic phase treated with nilotinib 400 mg twice daily in the front-line setting.[12] At 24 months, 93% of patients achieved a CCyR and 79% had a MMR. Notably, the projected event free survival was 90% at 24 months. Treatment was well tolerated, the most frequent Grade 3/4 AEs being neutropenia (12%) and thrombocytopenia (11%). A phase 3 randomized trial, ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials Newly Diagnosed Philadelphia Chromosome Positive) compared imatinib 400 mg twice daily with nilotinib 300 mg or 400 mg twice daily as first-line therapy in patients with CML in early chronic phase.[13] At 12 months, MMR rates for nilotinib (44% for the 300 mg dose and 43% for the 400 mg dose) were significantly superior to that for imatinib (22%, p<0.001). The more frequent AEs were skin rash, myalgia, and increases in bilirubin, lipase and blood glucose on nilotinib. Fatigue, myalgia, and fluid retention were the most frequent AEs in the imatinib group (BOSULIF, Pfizer) (SKI-606) is an oral, dual Src/Abl TKI with more potent inhibitory activity against BCR-ABL than imatinib in CML cell lines[14,15], with minimal inhibitory activity against c-kit or platelet-derived growth factor receptor.[15,16] These are 2 nonspecific targets potentially associated with toxicities reported for other second-generation TKIs. 07 December 2016 Page 20 of 123

23 In preclinical studies, oral bosutinib was well tolerated with bioavailability of 50% to 60%. No drug related hematologic toxicities were seen. Gastrointestinal toxicities of emesis and fecal alteration (soft or mucoid) were considered dose limiting. To date, approximately 1994 subjects, including 1460 patients with cancer, have received at least 1 dose of bosutinib in 24 clinical studies. These included 14 clinical pharmacology studies (12 studies in healthy volunteers, 1 study in patients with hepatic impairment and 1 study in patients with renal impairment). On 04 September 2012 bosutinib (500 mg) was approved by the US FDA for the treatment of adult patients with CP, AP, or BP Ph+ CML with resistance or intolerance to prior therapy. More recently, on 27 March 2013, the European Medicines Agency (EMA) granted conditional marketing authorization in the European Union (EU), for the treatment of adult patients with CP, AP, and BP Ph+ CML previously treated with 1 or more TKIs, and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options. Both approvals were granted based on the results obtained from the phase 1/2 study single arm study (3160A4-200-WW, Study 200 ) in adult patients with Ph+ leukemias who had failed prior TKI therapy, with the support of the safety results obtained as part of the phase 3 study (3160A WW) comparing bosutinib with imatinib in newly diagnosed CP Ph+ CML patients (described below). In addition, the EMA was provided descriptive narrative information from the bosutinib compassionate use program in patients with Ph+ CML who had received at least 1 prior TKI treatment and progressed or were intolerant, and otherwise not considered suitable for other TKI therapy. Analyses were also provided from a subset of Study 200 patients who had failed prior imatinib, or imatinib and nilotinib or dasatinib as first-line treatment for CP CML In the phase 3 study (3160A WW, Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia [BELA]), bosutinib (500 mg) was compared to imatinib in the first-line treatment of CP Ph+ CML. The primary objective of the study was to compare the complete CCyR at 1 year in CP patients receiving bosutinib alone versus patients receiving imatinib alone. The study enrolled 502 patients (250 on bosutinib and 252 on imatinib). No statistically significant difference was observed at 12 months of treatment between the bosutinib and imatinib groups regarding rates of CCyR (70% vs. 68%). Similarly, the cumulative CCyR rates by 24 months were virtually identical at 79% and 81%, respectively. However, on an intent-to treat (ITT) analysis, the MMR rates at 12 months for bosutinib and imatinib were 41% and 27%, and the cumulative MMR rates by 24 months were 61% versus 52%, respectively (p <0.05 for both comparisons). Time to CCyR and 07 December 2016 Page 21 of 123

24 MMR was shorter with bosutinib compared to imatinib (p <0.001 for both comparisons). Furthermore, the percentage of patients who experienced treatment failure (4% vs. 13%), progression to AP or BP (2% vs. 5%) or death (3% vs. 5%) was lower among those receiving bosutinib compared to those treated with imatinib. The shorter time to response is important for patients as it means they have a shorter time when they are vulnerable to potential progression to either AP or BP. Results after a minimum follow-up of 24 months showed that 66% of patients receiving bosutinib and 45% of those treated with imatinib had dose interruptions. Dose reductions were required in 43% and 21% of patients, respectively. The rates of treatment discontinuation were 37% and 29%, respectively. Importantly, treatment discontinuations due to AEs or disease progression in the bosutinib and imatinib groups were 24% versus 4% and 7% versus 13%, respectively. Compared with imatinib, bosutinib was associated with higher incidences of Grade 3-4 gastrointestinal (GI) toxicities, including diarrhea (12% vs. 1%), vomiting (3% vs. 0%) and abdominal pain (1% vs. <1%), although these AEs were usually transient and manageable. Notably, diarrhea occurred mostly in the first 1-2 months of therapy and improved or subsided spontaneously over time. Grade 3 and Grade 4 elevations of alanine aminotransferase (ALT) (23% vs. 4%), aspartate aminotransferase (AST) (12% vs. 4%) or lipase (11% vs. 6%) were more frequent among patients treated with bosutinib compared to imatinib. Of those patients experiencing Grade 3-4 elevations in transaminase levels in the bosutinib treatment group of this study, 91% were rechallenged. Of these patients, 80% were successfully re-challenged. Overall, 14% of patients were discontinued from bosutinib treatment due to unacceptable transaminase elevations. Grade 3-4 neutropenia, thrombocytopenia and anemia in the bosutinib and imatinib treatment groups were 10% vs. 24%, 14% vs. 15% and 8% vs. 8%, respectively, indicating that bosutinib is at least as safe as imatinib regarding hematologic toxicity. In summary, bosutinib was associated with a toxicity profile distinct from that of imatinib. A higher number of patients (n=48, 19%) were discontinued from bosutinib treatment as a result of an AE, including 15 (31%) of 48 patients who discontinued before their first post baseline assessment. One of the goals of this study is to assess safety of bosutinib treatment compared with imatinib treatment. Early discontinuations as a result of toxicity may have contributed to the lower rate of CCyR associated with bosutinib in the ITT population, which included these patients as non-responders. Although bosutinib therapy was associated with greater rates of diarrhea, vomiting, and aminotransferase elevations compared with imatinib, most instances were transient and, in the case of diarrhea, frequently self-limiting after the first 2 to 3 months of therapy. Fluid 07 December 2016 Page 22 of 123

25 retention, which has commonly been observed with dasatinib[17-24] and imatinib [17,25,26] occurred infrequently with bosutinib. Despite the occurrence of liver function test abnormalities with bosutinib treatment, no cases were associated with permanent liver injury. Low rates of Grade 3 or Grade 4 (all causality) anemia (6%), neutropenia (11%), and thrombocytopenia (14%) were reported with bosutinib. The minimal inhibition of c-kit by bosutinib may have contributed to the low incidence of myelosuppressive events, particularly Grade 3 or Grade 4 neutropenia.[27] Overall, there were fewer deaths in the bosutinib treatment group, with no treatment-related deaths and few CML-related deaths in either treatment group. The trends in toxicity profile observed for bosutinib in this study are similar to those previously observed for bosutinib in CP CML after failure of imatinib treatment.[28] Complete information for bosutinib may be found in the Single Reference Safety Document, which for this study is the EU Summary of Product Characteristics or the United States Package Insert. 2.4 Rationale for Use of Imatinib as Comparator According to the National Comprehensive Cancer Network (NCCN) Version 2, 2014 guidelines[29] and European Leukaemia Net Recommendation[30], imatinib, dasatinib or nilotinib are considered the standard of care in newly diagnosed patients with Ph+ CML who are not eligible for stem cell transplant. Imatinib has been used as the active comparator in investigations of both dasatinib and nilotinib. Both the NCCN and the National Institute of Clinical Excellence (NICE) recommend starting imatinib at 400 mg and report experience with doses up to 800 mg for CP patients in cases of inadequate responses, provided there is no severe adverse drug reaction. 2.5 Study Rationale Patients with CML are now able to be treated and their disease controlled for long periods of time. The other approved agents have been demonstrated to be associated with significant toxicities for which some patients might be particularly susceptible and other patients might not be expected to be able to tolerate due to the presence of relevant comorbidities. may represent an additional choice for such patients for treatment of their CML in the first line setting, which could offer these patients a better tolerated and possibly sustainable treatment option than other available therapies. In the phase 3 BELA study, which evaluated the effect of treatment in a first-line setting, bosutinib at 500 mg did not achieve the primary efficacy end point of a superior rate of CCyR at 12 months versus imatinib. However, bosutinib did demonstrate superiority across many other efficacy end points including MMR at 12 months, and importantly for patients, 07 December 2016 Page 23 of 123

26 the percentage of patients with transformation to AP or BP was lower for bosutinib than imatinib. In addition, the safety profile of bosutinib was distinct from that of imatinib in terms of increased gastrointestinal (GI) toxicity especially diarrhea and increased values for liver function tests (LFTs). However, there were fewer patients with hematological toxicities. Detailed management guidelines for diarrhea have been added to this protocol to help the management of the AE profile of this drug (Appendix 9). In addition, the Investigators will receive careful training to ensure appropriate understanding of the bosutinib side effect profile. Prior clinical studies with bosutinib in CML have used a starting dose of bosutinib of 500 mg daily. In both studies, a substantial number of patients reported toxicities. The incidence of treatment emergent AEs (TEAEs) overall as well as unique TEAEs were lower following dose reduction from 500 mg to 400 mg, while the efficacy of bosutinib in patients who received dose reductions to 400 mg remained favorable. Therefore, it was concluded that a starting dose of 400 mg daily in this phase 3 study comparing bosutinib to imatinib in the first-line CML setting, will result in better tolerability and similar efficacy as a starting dose of 500 mg daily. The discussion of study design is provided in Section Risk/Benefit Statement To date, approximately 1994 subjects, including 1460 patients with cancer, have received at least 1 dose of bosutinib in 24 clinical studies. These included 14 clinical pharmacology studies (12 studies in healthy volunteers, 1 study in patients with hepatic impairment and 1 study in patients with renal impairment). Together, these data provide evidence that bosutinib is overall well tolerated and efficacious. This evidence base has resulted in a conditional marketing authorization for second line CML patients being granted in the EU for the treatment of adult patients with CP, AP, and BP Ph+ CML previously treated with 1 or more TKIs, and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options. The present study has been designed to investigate the safety and efficacy of bosutinib as first-line treatment for patients with CP CML. The efficacy of bosutinib compared with imatinib treatment as a first line treatment will be investigated in terms of the proportion of patients demonstrating MMR at 12 months (48 weeks) in patients with newly diagnosed Philadelphia chromosome positive CP CML and in a combined population of BCR-ABL positive, Ph+ and Philadelphia chromosome negative (Ph-) CP CML patients. 07 December 2016 Page 24 of 123

27 Safety of bosutinib treatment compared with imatinib treatment will also be investigated in terms of the proportion of patients demonstrating a CCyR by 12 months and evaluate the duration of CCyR in both treatment groups. Approximately 530 patients in total (sufficient to provide 500 Ph+ patients) will be randomized. The planned Ph+ patient population (adults with newly diagnosed Ph+ CP CML) corresponds to the target population for this drug. The efficacy and safety endpoints are standard for evaluation of this drug class. Patients will be closely monitored throughout the study and evaluated by the Investigator. The reference product imatinib is the longest established TKI treatment for CML patients and is approved as standard first-line therapy for patients with chronic-phase CML; however between 17% and 25% of patients either fail or become intolerant to imatinib during the first 5 years of treatment. In the previous phase 3 study (3160A WW, Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia [BELA]), bosutinib (500 mg) was compared to imatinib in the first-line treatment of CP Ph+ CML. The primary objective of the study was to compare the complete CCyR at 1 year in CP patients receiving bosutinib alone versus patients receiving imatinib alone. In the BELA study, bosutinib at 500 mg did not achieve the primary efficacy end point of a statistically significant superior rate of CCyR at 12 months versus imatinib in the ITT population (it achieved it in the PP population). However, bosutinib did demonstrate statistically significant superiority across many other efficacy end points including MMR at 12 months, and importantly for patients, the percentage of patients with transformation to AP or BP was lower for bosutinib than imatinib. The incidence of TEAEs overall as well as unique TEAEs were lower following dose reduction from 500 mg to 400 mg, while the efficacy of bosutinib in patients who received dose reductions to 400 mg remained favorable. Therefore, it was concluded that a starting dose of 400 mg daily in the current phase 3 study comparing bosutinib to imatinib in the first-line CML setting, will result in better tolerability while retaining similar efficacy as a starting dose of 500 mg daily. In addition, the safety profile of bosutinib was distinct from that of imatinib in terms of increased GI toxicity especially diarrhea and increased values for LFTs. However, there were fewer patients with hematological toxicities. Detailed management guidelines for diarrhea (Appendix 9) have been added to this protocol to help the management of the AE profile of this. In addition, the Investigators will receive careful training to ensure appropriate understanding of the bosutinib side effect profile. 07 December 2016 Page 25 of 123