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

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1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364: DOI: /NEJMoa

2 Clinical Protocol Page: 1 Protocol Number: IND Number: 9186 EUDRACT Number Date: 02-Dec-2005 A Multi-Center, Randomized, Double-Blind, Two-Arm, Phase III Study in Patients with Untreated Stage III (Unresectable) or IV Melanoma Receiving Dacarbazine Plus 10 mg/kg of Ipilimumab (MDX-010) vs. Dacarbazine With Placebo Revised Protocol 06 Incorporates Amendment 09 Medical Monitor - North America: Medical Monitor - International: Gabor Jurida, MD i3 Research 4206 Windy Chase Lane Katy, Texas Stefanella Bortini, MD PhD i3 Research V.le Algeria 93/a Roma Italy Telephone (office): Telephone (office): Fax: Fax: Central Medical Monitor: Sheena Demelo, MD i3 Research Sygnus Court, Market Street Maidenhead, Berkshire, SL6 8AD Telephone (office): +44 (0) Fax: +44 (0) BMS Medical Monitor BMS Study Director Ramy Ibrahim, MD Rachel Humphrey, MD 5 Research Parkway Wallingford, CT P.O. Box 4000 Princeton, NJ Telephone (office): (203) Telephone (office): (609) Fax: (203) Fax: (609) hr Emergency Telephone Number +44 (0) Bristol-Myers Squibb Pharmaceutical Research Institute Bristol-Myers Squibb 5 Research Parkway Wallingford, CT This protocol contains information that is confidential and proprietary to Medarex Inc. (MDX) and Bristol-Myers Squibb (BMS) Replace all previous version(s) of the protocol with Revised Protocol Number 06 supplied with this revision. Please provide a copy of this revised protocol to all study personnel under your supervision. Revised: 24-Mar-2009 Approved v

3 Ipilimumab (MDX-010) BMS Clinical Protocol DOCUMENT HISTORY Document Date of Issue Summary of Change Revised Protocol Mar-2009 Incorporates Amendment 09. Amendment Mar ) To modify the dose skipping criteria for ipilimumab/placebo. Current protocol indicates that dose skipping may be necessary for any Grade 3 skin-related adverse event that is deemed related to study drug. The dose skipping criteria for ipilimumab/placebo is being modified in order to make it more conservative. Dose skipping will be necessary in the presence of any Grade 3 skinrelated adverse event regardless of causality. 2) Update the contact details of the BMS Study Director. Revised Protocol Oct-2008 Incorporates Administrative Letter 04 and Amendment 08. Amendment Oct ) To change the primary objective to be a comparison of overall survival and rank secondary objectives. Current protocol has as its primary objective to compare progression- free survival (PFS) in patients treated with dacarbazine and placebo versus dacarbazine and ipilimumab. The proposed change to overall survival is based on data from concluded studies indicating a potential survival benefit in patients treated with ipilimumab. In addition, overall survival (OS) will be a better endpoint to capture different patterns of response observed with ipilimumab besides the conventional responses, such as late responses following an initial progression, slow steady decline in tumor burden with patients with SD and response in the presence of new lesions. All those different patterns of responses are poorly captured using PFS as the primary end point. The comparison of PFS will be the main secondary objective followed by comparisons of disease control rate and best overall response rate between the arms. PFS at Week 12 has been removed. 2) To add a Prohibited Therapies during the Follow-up Phase. Current protocol does not prohibit other therapies during the Follow-up Phase. Based on new available therapies for this patient population, anti-ctla-4 antagonists and CD137 agonists have been added as prohibited medications to the Follow-up Phase. These medications may have a cross over effect that can potentially affect the study endpoint of overall survival. This change will affect all subjects who enter the Follow-up Phase of the study. 3) To clarify analyses of time to response and duration of response. The following changes to the analyses of time to response and duration of response are incorporated in this amendment. The Revised Protocol No.: 06 Date: 24-Mar Approved v

4 Ipilimumab (MDX-010) BMS Clinical Protocol Document Date of Issue Summary of Change analysis of time to response will consider as a response a (confirmed) best overall response of CR or PR (based on pre-resection TAs); instead of censoring subjects who undergo tumor resection at the last TA prior to resection, all other subjects will be censored at the date of the maximum assessment time in all subjects in the treatment group (see Sections and ). An additional analysis of duration of response will be performed: time in response will be defined in all randomized subjects by assigning response duration of zero to non-responders (see Sections and ). The previous names, time to BOR and duration of BOR, will be replaced by the more accurate terms, time to response and duration of response, respectively. 4) Administrative. An update to the SAE Facsimile Transmission Number used to submit SAEs in the United States is provided. An update has been done on the cover page and Section 9.7 Handling of Serious Adverse Events, SAE telephone contact due to a change in North American Medical Monitor. An update to the protocol has been made based on updates to the Investigator Brochure. An update to the protocol has been made to clarify Section Follow-up Phase. Administrative Letter 04 Revised Protocol 04 Administrative Letter Nov-2007 An update to the protocol in order to be compliant with new regulatory guidelines. 1) Update CRO North American and International Medical Monitors on cover page. 2) Update CRO North American and International Medical Monitor SAE contact. 13-Jun-2007 Incorporates Administrative Letter 03 and Amendment Apr ) Update CRO North American Medical Monitor. 2) Update CRO North American and Russian/Ukraine Medical Monitor SAE Contact. 3) Indicates that additional treatment information for Section Immune Breakthrough Events can be found in the Investigator s Brochure. Revised Protocol No.: 06 Date: 24-Mar Approved v

5 Ipilimumab (MDX-010) BMS Clinical Protocol Document Date of Issue Summary of Change Amendment Jan ) Specify that a 1.2 µm in-line filter must be used during ipilimumab/placebo infusion. 2) Adverse event and safety lab parameters for dose skipping and dose discontinuation have been changed based on current safety data. 3) Refer to the current Investigator Brochure for information on the treatment of Immune Related Adverse Events and delete outdated treatment guidelines. 4) Update the Flow Chart to include mandated review of safety labs (ie, chemistry and hematology) prior to all study drug treatments. (Section 7.1) 5) Clarify storage requirements and additional vial size of investigational product and provide information regarding the placebo arm. 6) Updated the primary US medical contact and Serious Adverse Event mailing address. Revised Protocol 25-May-2006 Incorporates Administrative Letter 02 and Amendment a Amendment 06 a 25-May-2006 To add an interim analysis of overall survival (OS), to be conducted at the same time as the analyses of other efficacy endpoints, ie when at least 416 events for Progression Free Survival (PFS) have been observed in the study and all patients have been followed for at least 12 weeks. The previous protocol did not mandate an analysis of OS at this time; To clarify that the comparison of OS between treatment arms will be the main secondary analysis and to describe the testing procedure to be followed in order to maintain the overall significance level; To enhance safety controls for patients with ocular toxicity by excluding patients with a Grade 3 ocular toxicity from continuing study drug dosing, even after having a positive response to topical therapy; To mandate that safety labs (ie, chemistry and hematology labs) be collected and reviewed prior to all study drug treatments to allow for observation of any safety laboratory abnormalities prior to dosing. The previous protocol did not mandate a review of safety labs prior to dosing; To correct the description of dacarbazine under the Product Identification Table to note that dacarbazine will be provided as a white powder; To correct grammatical errors. a There were multiple revisions of this document prior to 25-May-2006, however Amendment 06 and Revised Protocol 03 where the first fully approved versions that were in place for the enrollment of the first patient. This document history only includes the history of the protocol from this date forward. Revised Protocol No.: 06 Date: 24-Mar Approved v

6 Ipilimumab (MDX-010) BMS Clinical Protocol SYNOPSIS Clinical Protocol Title of Study: Protocol : A Multi-Center, Randomized, Double-Blind, Two-Arm, Phase III Study in Patients with Untreated Stage III (Unresectable) or IV Melanoma Receiving Dacarbazine Plus 10 mg/kg of Ipilimumab (MDX-010) vs. Dacarbazine With Placebo Estimated Number of Study Centers and Countries/Regions: Approximately 150 Sites including, but potentially not limited to, sites in the United States, Canada, South America, Europe, Africa and Australia. Study Phase: III Research Hypothesis: Among patients with previously untreated Stage IIIc, N3 (unresectable) or Stage IV melanoma (AJCC 2001 and measurable per modified World Health Organization [WHO] criteria), overall survival (OS) in patients receiving dacarbazine plus 10 mg/kg ipilimumab (MDX-010) BMS will be superior to that in patients receiving dacarbazine with placebo. Primary Objective: To compare overall survival (OS) in patients with previously untreated Stage IIIc, N3 (unresectable) or Stage IV melanoma receiving dacarbazine plus 10mg/kg ipilimumab (MDX-010) vs. dacarbazine with placebo. Secondary Objectives: 1) To compare progression -free survival (PFS) between two arms; 2) To compare disease control rate (proportion with best overall response of complete response [CR] or partial response [PR] or stable disease [SD]) between two arms; 3) To compare best overall response rate (BORR) between two arms; 4) To estimate survival rate at 1 year, 18 months, and 2 years for each treatment arm 5) To estimate duration of response for each treatment arm; 6) To estimate time to response for each treatment arm; 7) To evaluate the safety profile for each treatment arm; 8) To evaluate Health Related Quality of Life (HRQoL) for each treatment arm; 9) To obtain serum samples for population pharmacokinetics (PK). Study Design: This study is divided into four phases: the Screening Phase, the Induction Phase, the Maintenance Phase, and the Follow-Up Phase. After informed consent is obtained, patients will enter the Screening Phase to assess eligibility criteria. Upon meeting criteria, eligible patients will be randomized into the Induction Phase to receive placebo or active ipilimumab and dacarbazine treatment (4 separate infusions of either placebo or active 10 mg/kg dose of ipilimumab and dacarbazine infusions at 3 week intervals) and tumor assessments. Tumor response and patient tolerability to placebo or active ipilimumab will determine whether, and in what capacity, patients will be allowed to continue in the Maintenance Phase (continued placebo or active ipilimumab dosing in 12 week intervals until PD, drug intolerance, withdrawal of consent or study closure). Patients who show PD or who do not wish to continue study phase assessments in the Induction or Maintenance Phase, will enter the Follow-Up Phase. Revised Protocol No.: 06 Date: 24-Mar Approved v

7 Ipilimumab (MDX-010) BMS Clinical Protocol Study Phases are further detailed below: Screening Phase: Begins after the patient signs the informed consent form (ICF); Ends upon randomization into the treatment phase (Induction Phase); Establishes patient eligibility; Provides characteristics, including the baseline disease status for the response assessment. Induction Phase: Begins on Day 1 (randomization) and ends at Week 24 or upon PD occurring between Week 12 and 24; One single dose of placebo or active ipilimumab to be administered at Weeks 1, 4, 7 and 10, for a total of four doses; Open-label dacarbazine to be administered at 3-week intervals, starting at Week 1 and continuing until Week 22; Four tumor assessments (TAs) (radiographic and photographic) to be performed at Weeks 12, 16, 20 and 24. Randomization will be stratified by: Baseline distant metastasis (M) stage (M0 versus M1a versus M1b versus M1c) (see Appendix 5); Eastern Cooperative Oncology Group (ECOG) performance status (0 vs. 1); Study site. Maintenance Phase: Begins at Week 24 (note that all assessments at Week 24 are counted as Induction Phase assessments, any dosing at Week 24 is considered to be Maintenance Phase dosing); Includes two categories of patients (defined further in Sections 3.1 and ): On Treatment: patients without PD who continue to tolerate placebo or active ipilimumab (refer to Section 6.2.4) will continue dosing in 12 week intervals until PD, withdrawal of consent or study closure; TA Only: Patients without PD who discontinue placebo or active ipilimumab dosing due to toxicity will continue with Maintenance Phase tumor assessments and study procedures until PD, withdrawal of consent or study closure, but will receive no further dosing. All patients in this Phase will have TAs (radiographic and photographic) performed every 6 weeks at Weeks 30, 36, 42 and 48. After Week 48, TAs will be performed every 12 weeks. Follow-Up Phase: Begins for the patients when they: Withdraw consent from study procedures but not from Follow-Up; Experience PD, on or after Week 12. No further placebo or active ipilimumab or dacarbazine dosing; No TAs; Revised Protocol No.: 06 Date: 24-Mar Approved v

8 Ipilimumab (MDX-010) BMS Clinical Protocol Telephone contact every 12 weeks to evaluate OS, obtain information regarding disease progression, inquire about current anti-cancer regimens and AEs. Tumor Assessments To ensure a uniform tumor assessment schedule, radiographic imaging (e.g., MRI/CT of brain, chest, abdomen, pelvis, other soft tissue and bone scans, as applicable) and digital photographs of skin lesions will be performed for all patients at Screening and subsequently in the Induction Phase at Week 12. All non-progressing patients, will continue Induction Phase assessments at Weeks 16, 20 and 24 and every 6 weeks through Week 48 (e.g., Weeks 30, 36, 42 and 48) in the Maintenance Phase. For non-progressing patients who continue in the Maintenance Phase beyond Week 48, tumor assessments will be done every 12 weeks. For patients who experience Investigator-determined disease progression and enter the Follow-Up Phase, it is recommended that at least two additional tumor assessments, obtained as a standard-of-care in Follow-Up, be submitted to the Independent Review Committee (IRC) for assessment. Tumor Assessments Scheduling Rationale Ipilimumab is expected to trigger immune-mediated responses, which require activation of the immune system prior to the observation of clinical responses. Such immune activation may take weeks to months to be evident. Some patients with advanced melanoma may have objective volume increase of tumor lesions within 12 weeks following start of ipilimumab dosing. Such patients may have not had sufficient time to develop the required immune activation or, in some patients, tumor volume increases may represent infiltration of lymphocytes into the original tumor. In conventional studies, such tumor volume increases during the first 12 weeks of the study would constitute PD and lead to discontinuation of imaging to detect response, thus disregarding the potential for subsequent immune-mediated clinical response. Therefore, in this study, patients with tumor volume increase detected prior to Week 12 but without rapid clinical deterioration will continue to be treated with study drug and clinically observed with a stringent imaging schedule to allow detection of a subsequent tumor response. This will improve the overall assessment of the clinical activity of ipilimumab and more likely capture its true potential to induce clinical responses. Tumor assessments will be made using modified WHO criteria. Additionally, patients with progressive disease in the Follow-Up Phase will be asked to have additional tumor assessments that are performed as standard-of-care, submitted to the IRC so as to allow for a more comprehensive assessment of the kinetics of disease progression. Data Monitoring Committee (DMC) To provide independent oversight for safety, study conduct and risk-benefit ratio, a DMC will be instituted. To ensure the safety of patients, the DMC will review the safety data after 60 patients are randomized and followed for at least 4 weeks. Following review, the DMC will recommend continuation, modification, or discontinuation of the study based on observed toxicities. A separate charter will describe the activities of this committee. Duration of Study: Approximately 17 months of accrual and an additional 17 months of follow-up (34 months total) are required to observe the necessary number of events for full information on the primary endpoint of survival. Number of Patients per Group: Approximately 500 patients will be randomized, 250 patients in each of the two arms. Study Population: Patients with previously untreated unresectable Stage III melanoma with N3 macroscopic lymph nodes or intransit/satellite metastases or Stage IV melanoma (see Appendix 5 for TNM classification) are potentially eligible if they meet Inclusion/Exclusion Criteria (see Sections 5.1 and 5.2). All patients must have measurable disease per modified WHO criteria (See Section 3.3). Revised Protocol No.: 06 Date: 24-Mar Approved v

9 Ipilimumab (MDX-010) BMS Clinical Protocol Test Product, Dose and Mode of Administration, Duration of Treatment: During the Induction Phase patients will receive the following: Open-label dacarbazine at a dose of 850 mg/m 2 as tolerated, administered by intravenous (IV) infusion, starting at Week 1. Dacarbazine dosing will continue every 3 weeks until Week 22 (see Sections and 6.2.6), until disease progression, unacceptable toxicity or withdrawal of consent. Placebo or active ipilimumab at a dose of 10 mg/kg, administered as tolerated by IV infusion, one single dose during Weeks 1, 4, 7 and 10 for a total of four separate doses, until disease progression, unacceptable toxicity or withdrawal of consent. Placebo or active ipilimumab should be dosed prior to dacarbazine when both study drugs are administered together on Weeks 1, 4, 7, and 10. Because there may be overlapping toxicities between ipilimumab and dacarbazine, dose modifications at time points where combination therapy is administered (ipilimumab plus dacarbazine or placebo plus dacarbazine; at Weeks 1, 4, 7 and 10 in the Induction Phase), will be governed by the criteria established for ipilimumab. At these time points, the administration of both agents is linked and the skipping or discontinuation of one agent will necessitate the skipping or discontinuation of the other agent (refer to Section ). At time points where dacarbazine is administered alone (Weeks 13, 16, 19 and 22 of the Induction Phase), dacarbazine-specific treatment modification criteria will be used (refer to Section ). In the Maintenance Phase (on and following Week 24), when ipilimumab or placebo is given alone, the same combination treatment modification guidelines as established for ipilimumab will govern treatment modification (refer to Section ). During the Maintenance Phase non-progressing patients will receive the following: Continued placebo or active ipilimumab at a dose of 10 mg/kg every 12 weeks, beginning at Week 24, until disease progression, study drug-associated toxicity, withdrawal of consent or study closure; No dacarbazine dosing. Re-Induction with ipilimumab following Maintenance will not be permitted within this study. Follow-Up Phase: No placebo, active ipilimumab or dacarbazine dosing. Patients may develop study drug related toxicities that will require skipping doses or dose discontinuation. Some of these adverse events may be consistent with potentially drug-related immune-mediated phenomena, termed Immune Breakthrough Events (IBEs) (refer to Section and Appendix 1). Details of how to dose study medication in the presence of adverse drug reactions that may or may not be IBEs, are addressed in Section Criteria for Evaluation: Efficacy Measures: Investigator and Independent Review Committee (IRC) tumor evaluations will be based on modified WHO criteria. Throughout the study each respective Investigator will determine disease status of patients at the defined time points and as clinically indicated. For the purpose of final analysis of study results, an IRC will review all images from all time points for all patients and assess response parameters as specified. Pharmacokinetics: Blood draws to assess the serum PK of ipilimumab will be drawn at the time points listed in Table Serum concentration data will be used in conjunction with samples from other studies as part of the population PK assessment. Serum Human Anti-Human Antibodies (HAHA) will be Revised Protocol No.: 06 Date: 24-Mar Approved v

10 Ipilimumab (MDX-010) BMS Clinical Protocol collected as per Table Safety Measures: Safety will be evaluated for all treated patients using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events v3.0 (CTCAE). Safety assessments will be based on medical review of AE reports and the results of vital sign measurements, physical examinations and clinical laboratory tests. The incidence of AEs will be tabulated and reviewed for potential significance and clinical importance. The reporting period for safety data will be from the date of first on-study dose to 70 days (5 half-lives) after the last dose is received. Health-related quality of life (HRQoL) will be assessed as measured by the European Organization for Research and Treatment of Cancer Quality of Life questionnaire (EORTC) and will be administered at multiple time-points throughout the study. Statistical Methods: Following completion of all Screening Phase evaluations, all eligible patients will be randomized to one of the two arms in a 1:1 ratio. The randomization procedure will dynamically minimize the imbalance between treatment arms within the levels of each of the following stratification factors: baseline M stage (M0 versus M1a versus M1b versus M1c) (see Appendix 5 for staging) and ECOG performance status (0 vs. 1) as defined at the time of randomization, and by study site. PFS, OS, survival rates at 1 year, 18 months and 2 years, BORR, disease control rate and time to response will be evaluated for all randomized patients. Duration of response and time to response will be evaluated for all patients with BOR. The primary efficacy analyses will be based on OS. A two-sided, α = 0.05 level, log-rank test will be performed, stratified by baseline M stage (M0 versus M1a versus M1b versus M1c) and ECOG performance status (0 versus 1), as defined at the time of randomization. Assuming a median survival of 8 months for dacarbazine with placebo and 500 randomized patients (250 per arm) a total of 416 deaths are needed to provide approximately 90% power to detect a 38% increase in median OS to 11 months for dacarbazine plus 10 mg/kg ipilimumab. This corresponds to a hazard ratio of 0.727, or a 27% reduction in hazard rate. Secondary efficacy endpoints include PFS, survival rates at one year, 18 months and 2 years, BORR, disease control rate, time to response, and duration of response. The main secondary analysis is the comparison of PFS between treatment arms, for which a two-sided, α = 0.05 level, log-rank test will be performed, stratified by baseline M stage (M0 versus M1a versus M1b versus M1c) and ECOG performance status (0 vs. 1) as defined at the time of randomization. A hierarchical approach to statistical testing will be adopted. Following the primary efficacy analysis of OS, the test for superiority of the main secondary endpoint, PFS, will be conducted. This will be followed by tests of disease control rate and then of BORR. Demographic, baseline laboratory results and HRQoL will be summarized using descriptive statistics. The primary comparison of HRQoL between treatment arms will be a Wei-Lachin test on differences from baseline. A Wei-Lachin test will be conducted for each scale. Worst toxicity grades per patient will be tabulated for selected AEs and laboratory measurements. Revised Protocol No.: 06 Date: 24-Mar Approved v

11 Ipilimumab (MDX-010) BMS Clinical Protocol TABLE OF CONTENTS TITLE PAGE DOCUMENT HISTORY SYNOPSIS TABLE OF CONTENTS INTRODUCTION Research Hypothesis Product Development Rationale Immunotherapy for Malignant Melanoma CTLA-4 and T Cell Activation Summary of Results of Investigational Program Pharmacology Pre-Clinical Toxicology Summary of Pre-clinical Pharmacology Data for ipilimumab (MDX-010) In-vivo Evaluation of Anti-murine CTLA-4 mab in Mouse Tumor Models In-vivo Evaluation of ipilimumab (MDX-010) in Mouse Tumor Models In-vivo Evaluation of ipilimumab (MDX-010) in Cynomolgus Monkeys Clinical Safety Data to Date Details of Intestinal Perforations or Serious Bleeding Details of Drug-Related Deaths Revised Protocol No.: 06 Date: 24-Mar Approved v

12 Ipilimumab (MDX-010) BMS Clinical Protocol Safety of 10 mg/kg of Ipilimumab (MDX-010) Every 3 Weeks x 4 Doses Clinical Efficacy to Date Expected Toxicities Pharmacokinetics of Ipilimumab (MDX-010) in Patients Rationale Overall Risk/Benefit Assessment STUDY OBJECTIVES Primary Objective Secondary Objectives STUDY DESIGN AND EVALUATION Study Design Tumor Assessments Tumor Assessments Scheduling Rationale Independent Review Committee (IRC) Additional Outcome Assessments Health-related Quality of Life (HRQoL) Resource Utilization Duration of Study Study Population Criteria for Evaluation Method of Tumor Response Assessment Radiographic Assessments Non-radiographic Assessments Revised Protocol No.: 06 Date: 24-Mar Approved v

13 Ipilimumab (MDX-010) BMS Clinical Protocol Definition of Measurable/Non-Measurable and Index/Non-Index Lesions Definition of Measurable/Non-Measurable Lesions Definition of Index/Non-Index Lesions Definition of Response Index Lesions Non -Index Lesions Response Per Time Point Best Overall Response (BOR) per Patient (Including all Time Points) Response Assessments The Best Overall Response Rate (BORR) Duration of Response Time to Response Disease Control Rate Progression Free Survival (PFS) Duration of Stable Disease Overall Survival (OS) Survival Rate at Specified Time Points Pharmacokinetic and Immunogenicity Evaluation Sample Size Determination Interim Analyses Data Monitoring Committee (DMC) STATISTICAL METHODOLOGY Data Set Descriptions Analyses Revised Protocol No.: 06 Date: 24-Mar Approved v

14 Ipilimumab (MDX-010) BMS Clinical Protocol Demographics and Baseline Characteristics Efficacy Analyses Primary Efficacy Analyses Secondary Efficacy Analyses Safety Analyses Pharmacokinetic Analyses Health-related Quality of Life Analyses Resource Utilization PATIENT SELECTION CRITERIA Inclusion Criteria Exclusion Criteria STUDY CONDUCT Ethics Study Therapy Treatment Group Assignment Treatment Administration Ipilimumab Dacarbazine Treatment Administration Ipilimumab (MDX-010) Dacarbazine Administration Criteria for Treatment Modifications Treatment Modification Criteria for Combination Therapy (Dacarbazine Plus Placebo or Dacarbazine Plus Ipilimumab) in the Induction Phase and or Placebo or Ipilimumab Alone in the Maintenance Phase Revised Protocol No.: 06 Date: 24-Mar Approved v

15 Ipilimumab (MDX-010) BMS Clinical Protocol Dacarbazine Treatment Modification (When Administered Alone) Discontinuation of Placebo or Active Ipilimumab and Dacarbazine Therapy Treatment Compliance Immune Breakthrough Events (IBEs): Definition, Monitoring, Treatment Other Guidance Infusion Reactions Associated with Ipilimumab (MDX-010) Treatment of Ipilimumab (MDX-010) Related Isolated Drug Fever Surgical Resection Following Initial Response Local Radiotherapy for Symptomatic Bone Lesions Toxicity Associated With Dacarbazine Therapy Blinding/Unblinding Blinding Ipilimumab or Placebo: Dacarbazine: Unblinding Prohibited and Restricted Therapies During the Study Prohibited Therapies Precautions Non-therapy Precautions and Restrictions Precautions Restrictions Withdrawal of Patients from Study Revised Protocol No.: 06 Date: 24-Mar Approved v

16 Ipilimumab (MDX-010) BMS Clinical Protocol 7 STUDY PROCEDURES AND OBSERVATIONS Flow Chart/Time and Events Schedule Procedures by Visit Screening Phase Pre-study (Day -28 to Day -1) Induction Phase (Week 1 [Day 1] to Week 24 tumor assessment) Maintenance Phase Criteria for Entry into the Maintenance Phase for Treatment Follow-Up Phase Study Completion or Early Withdrawal Visit Study Drug Discontinuation Details of Procedures Study Materials Safety Assessments Medical History, Physical Exam, Physical Measurements Vital Signs Pregnancy Testing ECOG Status Assessment of Baseline Symptoms Adverse Event Monitoring Other Assessments Laboratory Test Assessments Dacarbazine Specific Laboratory Assessments Serum Chemistry Revised Protocol No.: 06 Date: 24-Mar Approved v

17 Ipilimumab (MDX-010) BMS Clinical Protocol Hematology Urinalysis HIV and Hepatitis Panel Autoimmune and Endocrine Panels Stool Calprotectin Pharmacokinetics Assessments Pharmacokinetics: Blood Collection and Processing Pharmacokinetic Sample Analysis Immunogenicity Testing Human Leukocyte Antigen Typing Labeling and Shipping of Biological Samples Additional Outcome Assessments Health Related Quality of Life Assessment Resource Utilization Image Acquisition, Monitoring, Quality Control and Transfer Imaging Site Operations Site Qualification - Radiographic Images Submission of Image Data - Radiographic Images Site Monitoring - Radiographic Images Site Operations - Photographic Images Imaging Parameters for Tumor Assessments Baseline: Screening Phase, (Day 28 to Day 1) Prior to First Treatment Induction Phase, Weeks 12, 16, 20 and 24 and Unscheduled Time Points Revised Protocol No.: 06 Date: 24-Mar Approved v

18 Ipilimumab (MDX-010) BMS Clinical Protocol Maintenance Phase: Weeks, 30, 36, 42, and 48 and Every 12 Weeks Thereafter and at Unscheduled Time Points INVESTIGATIONAL PRODUCT Investigational Product Identification Packaging and Labeling Handling and Dispensing of Investigational Product Investigational Product Records at Investigational Site(s) Return and Destruction of Investigational Product Return of Investigational Product Destruction of Investigational Product Retained Samples for Bioavailability/Bioequivalence Studies ADVERSE EVENT REPORTING IN CLINICAL TRIALS Importance of Adverse Event Reporting Collection of Safety Information Adverse Events Related to Study Conditions Overdose AE Follow-up Reporting of AE Information Following Study Completion Handling of Serious Adverse Events (SAEs) Laboratory Test Abnormalities Revised Protocol No.: 06 Date: 24-Mar Approved v

19 Ipilimumab (MDX-010) BMS Clinical Protocol 9.9 Other Safety Considerations Pregnancy ADMINISTRATIVE SECTION Compliance with the Protocol and Protocol Revisions Informed Consent Informed Consent Procedures Patients Unable to Give Informed Consent Minors Patients Experiencing Acute Events or Emergencies Mentally Impaired or Incapacitated Patients Other Circumstances Illiterate Patients Update of Informed Consent Monitoring for Protocol Compliance Records and Reports Institutional Review Board/Independent Ethics Committee (IRB/IEC) Records Retention GLOSSARY OF TERMS AND LIST OF ABBREVIATIONS Glossary of Terms List of Abbreviations REFERENCES Revised Protocol No.: 06 Date: 24-Mar Approved v

20 Ipilimumab (MDX-010) BMS Clinical Protocol APPENDIX 1 SUGGESTED WORK-UP AND TREATMENT FOR IMMUNE BREAKTHROUGH EVENTS (IBE)S APPENDIX 2 DIARRHEA MANAGEMENT ALGORITHM APPENDIX 3 ECOG PERFORMANCE STATUS APPENDIX 4 DACARBAZINE LABEL INFORMATION APPENDIX 5 MELANOMA TUMOR STAGING APPENDIX 6 GLOSSARY OF COMMONLY USED TERMS. 150 Revised Protocol No.: 06 Date: 24-Mar Approved v

21 Ipilimumab (MDX-010) BMS Clinical Protocol 1 INTRODUCTION 1.1 Research Hypothesis Among patients with previously untreated Stage IIIc, N3 (unresectable) or Stage IV melanoma (AJCC 2001 and measurable per modified WHO criteria), OS in patients receiving dacarbazine plus 10 mg/kg ipilimumab (MDX-010) BMS , will be superior to that in patients receiving dacarbazine with placebo. 1.2 Product Development Rationale In the last 50 years (i.e., ), the incidence of malignant melanoma has risen 690% while mortality rate increased by 165%. Even with the recent decline in the incidence of several cancer types, the incidence of malignant melanoma is continuing to rise. 1 Despite this, overall survival has improved for early stage tumors because of early detection and improved surgical treatment, the only currently available curative therapy. Recurrent and/or metastatic melanoma remains largely a fatal disease with a median survival of 3-11 months. High-dose interferon alfa-2b (IFN-α) is currently approved by US Food and Drug Administration (FDA) for use as adjuvant therapy in patients with high risk of relapse. Treatment with high-dose IFN-α is associated with only a 10% improvement in recurrence-free survival, 0-10% improvement in overall survival and very significant toxicities that limit compliance with its use. 2,3,4 Dacarbazine is the only FDA-approved chemotherapeutic agent in this setting and provides an objective tumor response in only 5% to 20% of patients but these responses are short-lived (e.g. median duration of response = 6 months) and there is no associated increase in survival. 5 Over the last 30 years many chemotherapeutic drugs, including the aggressive Dartmouth combination regimen (dacarbazine, cisplatin, carmustine, and tamoxifen) 6 and newer drugs such as temozolamide, 7 have not resulted in significant improvement in survival when compared to dacarbazine. Fotemustine, with an overall response rate of 15%, 6 months median duration of response and 2 months median time to progression, is approved in parts of Europe for use in metastatic melanoma. 8 Interleukin-2 (IL-2) was approved by the FDA in 1998 for treatment of metastatic melanoma based on data suggesting a 16% overall objective response rate with a 6% complete response. Toxicities Revised Protocol No.: 06 Date: 24-Mar Approved v

22 Ipilimumab (MDX-010) BMS Clinical Protocol of high-dose IL-2 therapy are severe (e.g., capillary leak, sepsis, and hypotension). Additionally, 2% of patients died from such associated AEs. 9 Malignant melanoma continues to be a considerable unmet medical need based on the unsatisfactory efficacy and significant toxicities of the currently available drugs and the rising incidence of the disease throughout the world Immunotherapy for Malignant Melanoma Malignant melanoma is an immune responsive disease. The earliest evidence, provided by epidemiological observations, suggest that immunosuppressed patients have an increased incidence of melanoma and in some (< 1%) immunocompetent patients the primary melanoma lesions spontaneously regressed. Infiltration of melanoma lesions by T lymphocytes has been shown to be associated with a better clinical prognosis. 10 Immunologic interventions to treat cancer can potentially be achieved through the induction of an immune response (active immunotherapy), administration of antibodies (passive immunotherapy) and/or stimulation of effector cells with cytokines or antibodies. All of these approaches have been investigated in melanoma and have shown early promise. Immune-modulating agents such as IFN-α and IL-2 have shown efficacy against melanoma and have been approved by the FDA for the treatment of various stages of melanoma. In addition to a direct cytotoxic effect, IFN-α is able to stimulate natural killer (NK) cell activity and to regulate the expression of histocompatibility antigens or tumor-associated antigens to demonstrate a 15% response rate in metastatic melanoma but a less than 5% complete response. The median duration of response ranged from 6-12 months. IFN-α treatment is also associated with significant toxicities. 11 Interleukin-2 modulates the immune system by stimulating the growth and activity of T-lymphocytes, human lymphocyte antigen (HLA)-restricted or non-restricted cytotoxic T cells and induces the production of many cytokines, such as tumor necrosis factor (TNF), IFN-γ and IL-1. IL-2 is currently approved for treatment of Stage IV melanoma; however its usage is also limited due to significant toxicities. 8 Various combinations of IL-2, IFN-α, TNF-α and chemotherapy drugs have failed to significantly improve survival or quality of life. Revised Protocol No.: 06 Date: 24-Mar Approved v

23 Ipilimumab (MDX-010) BMS CTLA-4 and T Cell Activation Clinical Protocol Figure 1.2.2: Mechanism of Action Advances in the understanding of the mechanisms that regulate T cell activation have allowed the rational design of new strategies for immunotherapy for tumors, including melanoma. It has been known for some time that engagement of the T cell antigen receptor by itself is not sufficient for full T cell activation; a second co-stimulatory signal is required for induction of IL-2 production, proliferation and differentiation to effector function of naive T cells. Abundant data now indicates that the primary source of this co-stimulation is mediated by engagement of CD28 on the T cell surface by members of the B7 family on the antigen-presenting cell (APC). 12 Refer to Figure Expression of B7 has been shown to be limited to professional antigen presenting cells; that is, specialized cells of the hematopoietic lineage, including dendritic cells, activated macrophages, and activated B cells. It has been suggested that this sharply-defined restriction of B7 expression is a fail-safe mechanism for maintenance of peripheral T cell tolerance, ensuring that T cell activation can only be stimulated by appropriate APCs. 13 The fact that tumor cells do not express B7 contributes to their poor capacity to elicit immune responses. 14,15 The demonstration that induction of expression of B7 on many tumor cells by transfection, transduction or other mechanisms can heighten tumor immunogenicity, led to great interest in pursuing this as an approach to tumor immunotherapy. As demonstrated in-vivo in murine tumor models, the utility of B7 Revised Protocol No.: 06 Date: 24-Mar Approved v

24 Ipilimumab (MDX-010) BMS Clinical Protocol expression as a vaccination approach is limited by the following factors: (1) B7-expressing tumor cell vaccines are only effective when the tumor cells have a high degree of inherent immunogenicity; (2) while B7-expressing vaccines have been shown in many cases to be effective in inducing protective immune responses, they have demonstrated only limited utility in inducing responses to established tumors; and (3) inactivation of tumor cells by radiation has been shown to destroy the immunoenhancing activity of the B7 gene product. 16,17 In the past few years it has become apparent that co-stimulation is even more complex than originally thought. Refer to Figure After activation, T cells express CTLA-4, a close homologue to CD28. CTLA-4 binds members of the B7 family with a much higher affinity than CD Although there was initially some controversy as to the role of CTLA-4 in regulating T cell activation, it has become clear that CTLA-4 down-regulates T cell responses. 19 This was initially suggested by the following in-vitro observations: (1) blockade of CTLA-4/B7 interactions with antibody enhanced T cell responses; (2) cross-linking of CTLA-4 with CD3 and CD28 inhibited T cell responses; and (3) administration of antibodies to CTLA-4 in-vivo enhanced the immune response to peptide antigens or superantigens in mice. 20,21,22,23 Blocking CTLA-4-B7 interaction while preserving signaling via CD28 resulted in enhanced T cell responses in-vitro. 21 Perhaps the most convincing demonstration of the down-regulatory role of CTLA-4 came from examination of mice with a null mutation. 24,25,26 CTLA-4 knockout mice appear to have spontaneously activated T cells evident at approximately 1 week after birth, followed by rampant lymphoproliferation and lymphadenopathy. These mice die at approximately 3 weeks of age, either as a result of polyclonal T cell expansion and tissue destruction or as a result of toxic shock resulting from lymphokine production by the T cells. Since thymocyte differentiation and selection proceed normally in CTLA-4-deficient mice, the rampant T cell expansion that occurs in the mice indicates that CTLA-4 plays a critical role in down-regulating T cell responses in the periphery. 23 Revised Protocol No.: 06 Date: 24-Mar Approved v

25 Ipilimumab (MDX-010) BMS Summary of Results of Investigational Program Pharmacology Clinical Protocol Ipilimumab (MDX-010) is a human Immunoglobulin G (IgG1)κ anti-ctla-4 monoclonal antibody (mab). In-vitro studies were performed with ipilimumab (MDX-010) to demonstrate that it is specific for CTLA-4, actively inhibits CTLA-4 interactions with B7.1 and B7.2, does not show any cross-reactivity with human B7.1 or B7.2 negative cell lines and stains the appropriate cells without non-specific cross-reactivity in normal human tissues as demonstrated by immunohistochemistry. Ipilimumab (MDX-010) does cross-react with CTLA-4 in non-human primates including cynomolgus monkeys. Ipilimumab (MDX-010) was originally produced and purified from a hybridoma clone. Subsequently, a transfectoma Chinese Hamster Ovary cell (CHO) has been generated that is capable of producing more ipilimumab (MDX-010) on a per cell basis than the hybridoma. Material from the transfectoma will be utilized in this and future ipilimumab (MDX-010) clinical studies. Biochemical, immunologic and in-vivo preclinical primate assessments demonstrated similarity between hybridoma and transfectoma-derived ipilimumab (MDX-010) Pre-Clinical Toxicology Complete information on the pre-clinical toxicology studies can be found in the ipilimumab (MDX-010) Investigator Brochure (IB). Non-clinical toxicity assessments included in-vitro evaluation for the potential of ipilimumab (MDX-010) to mediate complement-dependent cellular cytotoxicity (CDCC) or antibody-dependent cellular cytotoxicity (ADCC), and toxicology assessments in cynomolgus monkeys alone and in the presence of vaccines. The in-vitro studies demonstrated that ipilimumab (MDX-010) did not mediate CDCC or ADCC of PHA- or complement dependent (CD)3-activated human T cells. These data are consistent with the requirement of high levels of antigen expression on the surface of target cells for efficient ADCC or CDCC. Since ipilimumab (MDX-010) is a human IgG1, an isotype generally capable of mediating CDCC and ADCC, the lack of these Revised Protocol No.: 06 Date: 24-Mar Approved v