The following protocol information is provided solely to describe how the authors conducted

Transcription

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: Phase III Trial of Combined With Paclitaxel and Carboplatin in Advanced Squamous Non Small-Cell Lung Cancer 1.12/JCO The information provided may not reflect the complete protocol or any previous amendments or modifications. As described in the Information for Contributors ( 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 Page: Protocol Number: IND Number: Ex-US EUDRACT Number Date: Revised Date: 1 CA Non-IND Aug Apr-214 CA18414 Randomized, Multicenter, Double-Blind, Phase 3 Trial Comparing the Efficacy of in Addition to Paclitaxel and Carboplatin versus Placebo in Addition to Paclitaxel and Carboplatin in Subjects with Stage IV/Recurrent Non-Small Cell Lung Cancer (NSCLC) Revised Protocol Number: 6 Incorporates Amendment(s) 12 This document is the confidential and proprietary information of Bristol-Myers Squibb Company and its global affiliates (BMS). By reviewing this document, you agree to keep it confidential and to use and disclose it solely for the purpose of assessing whether your organization will participate in and/or the performance of the proposed BMS-sponsored study. Any permitted disclosures will be made only on a confidential "need to know" basis within your organization or to your independent ethics committee(s). Any other use, copying, disclosure or dissemination of this information is strictly prohibited unless expressly authorized in writing by BMS. Any supplemental information (eg, amendments) that may be added to this document is also confidential and proprietary to BMS and must Approved v

3 BMS CA18414 be kept in confidence in the same manner as the contents of this document. Any person who receives this document without due authorization from BMS is requested to return it to BMS or promptly destroy it. All other rights reserved. Replace all previous version(s) of the protocol with this revised protocol and please provide a copy of this revised protocol to all study personnel under your supervision, and archive the previous versions. Revised Protocol No.: 6 Date: 25-Apr Approved v

4 BMS CA18414 DOCUMENT HISTORY Document Date of Issue Summary of Change Revised Protocol 6 25-Apr-214 Incorporates Amendment 12 Amendment Apr-214 Updates study endpoints, adds 3-year dosing limit, updates the Global Medical Monitor, and makes other miscellaneous clarifications and corrections. Revised Protocol 5 4-Oct-212 Incorporates Amendment 9. Amendment 9 4-Oct-212 Updates to WOCBP language, informed consent and follow up after study treatment discontinuation, imar and irae language, inclusion and exclusion criteria modifications. Revised Protocol 4 21-Aug-211 Incorporates Amendment 7. Amendment 7 21-Aug-211 Changes placebo to IMP. Revised Protocol 3 15-Jul-211 Incorporates Amendment 6. Amendment 6 15-Jul-211 Moves randomization to Day 1 and removes the Lead-in Phase. Sample size changed to 92 randomized. CA18441 efficacy results updated. Added in secondary objective for OS in all blinded therapy treated subjects and moved outcomes objective to exploratory. Revised Protocol 2 25-Apr-211 Incorporates Administrative Letter 1 and Amendment 4. Amendment 4 25-Apr-211 Adds pre-dose TSH testing to the protocol in order to ensure consistency with the FDA approved label for ipilimumab. Administrative Letter 1 8-Feb-211 Expands the options listed in the protocol for the prevention of anaphylaxis and fluid retention associated with the administration of paclitaxel. Revised Protocol 1 11-Nov-21 Incorporates Amendment 2. Amendment 2 11-Nov-21 Grammatical and typographical errors corrected. Deleted optional re-induction sections, changed patient population to squamous only changed irrc to exploratory and patient management using mwho criteria. Original Protocol 1-Aug-21 Not applicable. Revised Protocol No.: 6 Date: 25-Apr Approved v

5 BMS CA18414 SYNOPSIS CA18414 Title of Study: Protocol CA18414: Randomized, Multicenter, Double-Blind, Phase 3 Trial Comparing the Efficacy of in Addition to Paclitaxel and Carboplatin versus Placebo in Addition to Paclitaxel and Carboplatin in Subjects with Stage IV/Recurrent Non-Small Cell Lung Cancer (NSCLC) Investigational Product(s), Dose and Mode of Administration, Duration of Treatment with Investigational Product(s): 1 mg/kg IV or placebo, Induction: q 3 weeks for up to 4 doses starting at Cycle 3, Maintenance: q 12 weeks for eligible subjects, for a maximum treatment period of 3 years from the first dose of blinded study therapy. 2 Paclitaxel 175 mg/m IV q 3 weeks for up to 6 doses starting at Day 1. Carboplatin AUC = 6 IV q 3 weeks for up to 6 doses starting at Day 1. Noninvestigational Product(s), Dose and Mode of Administration, Duration of Treatment with Noninvestigational Product(s): Not applicable. Study Phase: 3 Research Hypothesis: Among subjects with Stage IV or recurrent non-small cell lung cancer (NSCLC) of squamous histology, who are treated with paclitaxel, carboplatin and blinded study therapy, overall survival in subjects assigned to treatment with phased ipilimumab will be superior to overall survival in subjects assigned to treatment with phased placebo. Primary Objective: To compare Overall Survival (OS) of subjects with Stage IV/recurrent NSCLC of squamous histology who have been randomized to ipilimumab in addition to paclitaxel and carboplatin versus placebo in addition to paclitaxel and carboplatin, and have received at least one dose of blinded study therapy. Secondary Objectives: To compare Overall Survival in all randomized subjects To compare Progression-Free Survival (PFS) per mwho among randomized subjects who received at least one dose of blinded study therapy Study Design: This is a randomized, multicenter, double-blind Phase 3 study in chemotherapy naive subjects with Stage IV or recurrent NSCLC of squamous histology. The study will randomize approximately 92 eligible NSCLC subjects at a 1:1 ratio to 1 of 2 treatment arms, stratified by ECOG performance status, smoking status, gender, and region. Subjects will receive 1 of 2 treatment regimens: Arm A: Paclitaxel 175 mg/m IV q 3 weeks for up to 6 doses starting at randomization. Carboplatin AUC = 6 IV q 3 weeks for up to 6 doses starting at randomization. 1 mg/kg IV, Induction: q 3 weeks for up to 4 doses starting at Cycle 3, Maintenance: q 12 weeks for eligible subjects beginning 9 weeks after last ipilimumab induction dose. Arm B: Paclitaxel 175 mg/m2 IV q 3 weeks for up to 6 doses starting at randomization. Carboplatin AUC = 6 IV q 3 weeks for up to 6 doses starting at randomization. Placebo, Induction: q 3 weeks for up to 4 doses starting at Cycle 3, and Placebo Maintenance: q 12 weeks for eligible subjects beginning 9 weeks after last placebo induction dose. This study is divided into 4 phases: Screening, Induction, Maintenance and Follow-up (Toxicity/Progression Follow-up and Overall Survival Follow-up). Revised Protocol No.: 6 Date: 25-Apr Approved v

6 BMS CA18414 Figure 1: Study Schematic PD or AE leading to DC Arm A Induction CC CCCC I I I I Screening CR PR SD Maintenance* I I I Toxicity Progression Follow-up Randomize Induction CC CCCC P PPP CR PR SD Maintenance* P P P Arm B I = ipilimumab Overall Survival PD or AE leading to DC P = placebo C = chemotherapy *For a maximum duration of 3 years from the first dose of blinded study therapy Study Population: Men and women who are 18 years old with histologically or cytologically confirmed Stage IV or recurrent NSCLC of predominantly squamous histology with ECOG performance 1, who have met screening requirements, and who have not previously received systemic therapy for locally advanced or metastatic lung cancer. Subjects with specific underlying autoimmune diseases (particularly gastrointestinal), history of motor neuropathy or toxic epidermal necrolysis (TEN) and brain metastases will be excluded. Study Assessments and Primary/Secondary Endpoints: Safety Assessments: All subjects who receive at least 1 dose of study treatment (ipilimumab, placebo, paclitaxel or carboplatin) will be evaluated for safety parameters. Efficacy Assessments: All randomized subjects who received at least one dose of blinded study therapy will be evaluated for efficacy analyses unless otherwise specified. In addition, a selected set of efficacy analyses will be performed on all randomized subjects. Overall survival will be defined as the time from the date of randomization until the date of death. For those subjects who have not died, OS will be censored on the last date the subject was known to be alive. Progression Free Survival (PFS) per mwho among the randomized subjects who received at least one dose of blinded study therapy will be analyzed as a secondary endpoint. Radiologic Assessments: CT/MRI imaging of the chest and abdomen is required at screening and every 6 weeks in the induction phase and every 12 weeks in the maintenance phase until no longer meeting criteria defined in Section Brain scan at screening is required to rule out the presence of brain metastases. A bone scan is required at screening except where prohibited by local regulations (until appropriate approvals are obtained). Statistical Methods: Sample size determination: This study will randomize approximately 92 subjects in a 1:1 ratio to ipilimumab + carboplatin/paclitaxel arm and placebo + carboplatin/paclitaxel arm. Assuming a 24% dropout rate during the first two cycles of chemotherapy alone period (i.e., the proportion of subjects who never receive blinded therapy due to any reason), it is estimated that approximately 7 randomized subjects will receive blinded study therapy. Due to slower enrollment of the Japanese subjects than expected and to ensure sufficient number of Japanese subjects will Revised Protocol No.: 6 Date: 25-Apr Approved v

7 BMS CA18414 be included in this trial, enrollment in Japan might be extended after the planned 92 subjects have been randomized. All events from all subjects, regardless of whether or not they will enter the study after Japan enrollment extension, will be taken into account for the primary and secondary analyses. In the primary endpoint of overall survival among the randomized subject who received at least one dose of blinded study therapy, an exponential distribution and a true hazard ratio [ipilimumab + carboplatin/paclitaxel vs placebo + carboplatin/paclitaxel] of.75 post chemotherapy alone period is assumed. It is also assumed that the median OS for chemotherapy alone arm after two cycle of chemotherapy is 1 months. A total of 518 events out of 7 randomized subjects who received blinded study therapy will be needed to ensure 9% power to detect a statistically significant difference in OS among randomized subjects who received blinded study therapy between treatment arms with a Type I error rate of 5% based on a 2-sided log-rank test. Based on the current design, the overall hazard ratio for OS among all randomized subjects is approximately.78 based on the simulation results with an estimated dropout rate of 24% during the first two cycles of chemotherapy. This assumes a piecewise exponential distribution with a hazard ratio of 1 during the first 2 cycles of chemotherapy alone and a true hazard ratio of.75 after that. The simulated overall hazard ratio would be.81. A total of 75 events out of 92 randomized subjects will provide 8% power to detect a statistically significant difference in OS among all randomized subjects between treatment arms with a Type I error rate of 5% based on a 2-sided log-rank test. Assuming that the enrollment follows a piecewise constant accrual rate (5 subjects per month during Months 1-3, 1 subjects per month during Months 4-6, and 28 subjects per month for the rest of the accrual period), it is estimated that total accrual will take approximately 38 months and the study will take 48 months to complete. Sample size calculation described above was based on 1, simulation results in which OS follows a piecewise exponential distribution. The statistical software R version was used for this exercise. Interim analysis Not applicable. Summary of Statistical Analyses All hypothesis testing will be two-sided. All hypothesis testing will be based on a significance level of.5. The analysis will not be conducted until the following 2 conditions have both been met: 1) 518 OS events have been observed in randomized subjects treated with at least one dose of blinded study therapy and 2) 75 OS events have been observed in all randomized subjects. The primary analysis will include all events available at the time of the database lock. Methods for Primary Endpoint The distribution of OS among the randomized subjects who received at least one dose of blinded study therapy will be compared between treatment arms using a two-sided unstratified log-rank test. The unstratified log-rank test p-value, hazard ratio and its associated two-sided 95% confidence interval will be estimated via an unstratified Cox model with treatment arm as the only covariate. The event-free OS probabilities for each treatment arm will be estimated and plotted using the Kaplan-Meier (KM) product-limit method. The estimates of medians and two-sided 95% CIs will be calculated via a log-log transformation. KM estimates of OS rates at 6 months, 1 year, 18 months, and 2 years and associated two-sided log-log transformed 95% confidence interval will be calculated. Methods for Time-to-Event Endpoints If superiority in OS among randomized subjects who received at least one dose of blinded study therapy is demonstrated, a hierarchical hypothesis testing approach for the secondary endpoints will be used to preserve an overall type I error rate at.5 for any included efficacy claims. The secondary efficacy endpoints will be tested in the following hierarchical order: OS in the population of all randomized subjects, followed by PFS per mwho among randomized subjects who received at least one dose of study therapy Overall Survival among all randomized subjects The distribution of overall survival among all randomized subjects will be compared between treatment arms using a two-sided log-rank test stratified by all randomization stratification factors (as defined in Section 4.2.3). The Revised Protocol No.: 6 Date: 25-Apr Approved v

8 BMS CA18414 stratified log-rank test p-value, hazard ratio and its associated two-sided 95% CI will be presented The hazard ratio and associated two-sided 95% CI will be estimated via a stratified Cox model with treatment arm as the only covariate in the model. PFS The distributions of PFS per mwho among randomized subjects who received at least one dose of blinded study therapy will be compared between treatment arms using a two-sided unstratified log-rank test. The log-rank test p-value, hazard ratio and its associated two sided 95% confidence interval (CI) will be presented unless otherwise indicated. For OS among all Randomized subjects,and PFS per mwho among randomized subjects who received at least one dose of blinded study therapy, the event-free probabilities for each treatment arm will be estimated and plotted using the Kaplan-Meier (KM) product-limit method. The estimates of medians and two-sided 95% CI will be calculated via complementary log-log transformation. Safety Descriptive statistics of safety will be presented for all treated subjects who received at least one dose of blinded study therapy using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3. by treatment arm. All on study AEs, drug-related AEs, immune-mediated adverse reactions, immune-related AEs, SAEs, drug-related SAEs and immune-mediated adverse reactions will be tabulated using worst grade per NCI CTCAE v3. criteria by system organ class and by preferred term. The listings by subject will be produced for all deaths, all SAEs, and all AEs leading to discontinuation of study drug. On-study laboratory parameters, including hematology, serum chemistry, liver function, and renal function will be summarized using worst grade per NCI CTCAE v3. criteria. The reporting period for these subjects will be from the first dose of blinded study therapy to 9 days after the last dose is received. A selected set of the safety analyses described above will be repeated for all treated subjects including those who never received blinded study therapy due to reasons such as, but not limited to, death, disease progression or intolerable adverse events occurred during the first two cycles of chemotherapy. The reporting period for safety data will be from the first dose of study medication to 9 days (> 5 half lives) after the last dose is received. Pharmacokinetics Pharmacokinetic (PK) data obtained from this study may be pooled with data from other studies to perform an integrated population PK analysis (including assessment of covariate effects on PK), as well as exposure-response analysis for selected safety and efficacy endpoints. Pharmacodynamics Pharmacodynamic analyses will examine the patterns of change in ALC over time, and how these patterns might differ between treatment arms. Predictive analyses will examine potential relationships between ALC and measures of response such as overall survival. Two (2) types of ALC analyses will be done: pharmacodynamic and predictive. Pharmacogenomics Not applicable. Outcomes Research Among subjects who received at least one dose of blinded study therapy, the distribution of time to symptom progression (defined as an increase of at least 15 mm from baseline prior to receiving any study drug in any of the three symptoms (cough, pain and dyspnea)) will be estimated using KM method. Subjects who do not show deterioration in symptoms will be censored on the last assessment date that all three symptoms (dyspnea, cough and pain) were assessed. The estimates of medians and two-sided 95% CIs will be calculated via complementary log-log transformation. Revised Protocol No.: 6 Date: 25-Apr Approved v

9 BMS CA18414 TABLE OF CONTENTS TITLE PAGE... DOCUMENT HISTORY... SYNOPSIS... TABLE OF CONTENTS... 1 INTRODUCTION AND STUDY RATIONALE Study Rationale Immune Therapy Development Rationale Lung Cancer Background Unmet Medical Need Investigational Product Characteristics: Key Elements of s Background Clinical Data Melanoma Program Development Experience in Lung Cancer Research Hypothesis Objectives Primary Objective Secondary Objectives Exploratory Objectives Product Development Background Overall Risk/Benefit Assessment... 2 ETHICAL CONSIDERATIONS Good Clinical Practice Institutional Review Board/Independent Ethics Committee Informed Consent... 3 INVESTIGATIONAL PLAN Study Design and Duration Treatment Arms Treatment Flow Screening Phase Induction Phase Maintenance Phase End of Treatment Visit Toxicity/Progression Follow-up Phase Overall Survival Follow-up Phase Post Study Access to Therapy Study Population Inclusion Criteria Exclusion Criteria Women of Childbearing Potential Concomitant Treatments Prohibited and/or Restricted Treatments Other Restrictions and Precautions Discontinuation of Subjects from Treatment Revised Protocol No.: 6 Date: 25-Apr Approved v

10 BMS Post Treatment Study Follow up Withdrawal of Consent Lost to Follow-Up... 4 TREATMENTS Study Treatments Investigational Product (BMS-73416) Paclitaxel Carboplatin Non-investigational Product Handling and Dispensing Packaging and Labeling Method of Assigning Subject Identification Enrollment Randomization Selection and Timing of Dose for Each Subject Dose Modifications of Blinded (Active or Placebo) Liver Function Tests (LFTs) Required Prior to Blinded Study Drug Administration Delay of One Dose of Blinded Study Drug Criteria to Resume Treatment with Blinded Study Drug Treatment of Blinded Study Drug Related Infusion Reactions Re-treatment with Blinded Study Drug Following Infusion Reactions Treatment of Blinded Study Drug Related Isolated Drug Fever Dose Modifications of Chemotherapy Recommended Dose Modifications for Hematologic Toxicity Recommended Dose Modifications for Non-hematologic Toxicities Discontinuation of Study Treatment (Treatment Stopping Criteria) Discontinuation of All Study Treatment Permanent Discontinuation of Blinded Study Drug () Permanent Discontinuation of Paclitaxel Permanent Discontinuation of Carboplatin Blinding/Unblinding Treatment Compliance Destruction and Return of Study Drug Destruction of Study Drug Return of Study Drug... 5 STUDY ASSESSMENTS AND PROCEDURES Flow Chart/Time and Events Schedule Study Materials Safety Assessments Medical History, Physical Exam, Physical Measurements Vital Signs Electrocardiogram (ECG)... CA Revised Protocol No.: 6 Date: 25-Apr Approved v

11 BMS Pregnancy Testing ECOG Performance Status Laboratory Testing Chemistry Hematology Urinalysis HIV and Hepatitis Panel Specialty Labs Imaging Assessment for the Study Efficacy Assessments Primary Efficacy Assessment Secondary/Exploratory Efficacy Assessments Radiological Assessment of Tumor Lesions Definition of Measurable/Non-measurable Lesions Definition of Index/Non-index Lesions Definition of Tumor Response using mwho Pharmacokinetic Assessments PK and Anti Drug Antibody (ADA) Assessments Pharmacodynamic Assessments Pharmacogenomic/Pharmacogenetic Assessments Outcomes Research Assessments Other Assessments Healthcare Resource Utilization... 6 ADVERSE EVENTS Serious Adverse Events Serious Adverse Event Collection and Reporting Clinical Safety Program Nonserious Adverse Events Nonserious Adverse Event Collection and Reporting Adverse Events of Interest Laboratory Test Abnormalities Pregnancy Overdose Other Safety Considerations... 7 DATA MONITORING COMMITTEE AND OTHER ETERNAL COMMITTEES... 8 STATISTICAL CONSIDERATIONS Sample Size Determination Populations for Analyses Endpoints Primary Endpoint Secondary Endpoints OS in All Randomized Subjects Progression-free Survival Per mwho Exploratory Endpoints... CA Revised Protocol No.: 6 Date: 25-Apr Approved v

12 BMS Best Overall Response Rate per mwho and Duration of Response per mwho among randomized subjects who received at least one dose of blinded study therapy Safety Endpoints Disease Control Rate per mwho Time to Symptom Progression Analyses Demographics and Baseline Characteristics Efficacy Analyses Methods for Primary Endpoint Methods for Secondary and Exploratory Time-to-event Endpoints Efficacy Subset Analysis Sensitivity Analysis Safety Analyses Pharmacokinetic Analyses Pharmacodynamic Analyses Pharmacogenomic Analyses Outcomes Research Analyses Other Analyses Interim Analyses... 9 STUDY MANAGEMENT Compliance Compliance with the Protocol and Protocol Revisions Monitoring Investigational Site Training Records Records Retention Study Drug Records Case Report Forms Publications... 1 GLOSSARY OF TERMS LIST OF ABBREVIATIONS REFERENCES... APPENDI 1 ECOG PERFORMANCE STATUS... APPENDI 2 LUNG CANCER SYMPTOM SCALE (LCSS)... CA Revised Protocol No.: 6 Date: 25-Apr Approved v

13 BMS CA INTRODUCTION AND STUDY RATIONALE 1.1 Study Rationale Immune Therapy Development Rationale The immune system s ability to control the development of tumors and the potential of 1 immunotherapy to provide clinical benefit to cancer patients are now well established. The immune response to tumors is a complex, multi-stage process that begins with tumor 2 associated antigen recognition and T-cell activation. Full activation of naive T-cells requires not only stimulation of the antigen receptor by peptide/major histocompatibility complexes, but also by co-stimulatory signals. These signals are provided by the engagement of CD28, which is constitutively expressed on T-cell surfaces by CD8 (B7.1) and CD86 (B7.2) molecules, which are present on antigen presenting cells. CD28-B7 co-stimulatory signals are critical for the induction of T-cell proliferation, cytokine secretion, and effector functions, which ultimately translate into clinical effects. Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) is an activation-induced T-cell surface molecule that binds CD8 and CD86, but with greater avidity than CD28. CTLA-4 ligation down-regulates T-cell responses, which results in an abrogation of the clinical effects provided 3 by T-cell activation. Reciprocally, the blockade of CTLA-4 interactions with CD28 results in an increase of T cell activation. Several in vitro studies have demonstrated that monoclonal antibodies against CTLA-4 enhance T-cell responses, whereas direct cross-linking of CTLA-4 with B7.1 and B7.2 results in a blockade of cell cycle progression, diminished cytokine expression, and decreased T-cell proliferation. In vivo, CTLA-4 blockade results in a significant 4 inhibition of tumor growth. In addition, the activity of CTLA-4 blockage can be enhanced in a number of non-clinical xenograft models by priming the immune system with tumor cells using 5 6 tumor-associated antigen vaccination, administration of irradiated tumor cells, or external 7 irradiation of pre-existing tumor. Similar improvement of the antitumor effects of CTLA-4 8 blockade can also result from antigen release after chemotherapy induced cell death Lung Cancer Background Lung cancer is the leading cause of cancer-related death in both men and women. In the US, 9 there were 157,2 projected deaths in the year 28 and in Europe, lung cancer accounted for 12% of approximately 3.2 million new cancer cases, and 19.7% (334,8) of cancer-related 1 deaths. Approximately 8-85% of these patients have Non Small Cell Lung Cancer (NSCLC), with the majority presenting with locally advanced or distant metastatic disease not amenable to cure by surgery and/or radiotherapy and therefore eligible for systemic medical treatment. The National Comprehensive Cancer Network (NCCN) developed guidelines for the first-line 11 treatment of patients with recurrent or metastatic NSCLC. The treatment of patients with recurrent or metastatic NSCLC who present with an Eastern Cooperative Oncology Group Revised Protocol No.: 6 Date: 25-Apr Approved v

14 BMS CA18414 (ECOG) Performance Status (PS) - 1 should consist of a platinum-based chemotherapy unless the patient is known to have activated EGFR mutation or gene amplification or is a never smoker and present with an adenocarcinoma. Indeed, platinum-based chemotherapy was proven to prolong survival, improve symptom control and to result in a superior quality of life compared to best supportive care. Platinum salts (carboplatin or cisplatin) have been combined with a number of agents (paclitaxel, docetaxel, gemcitabine, vinorelbine, irinotecan, etoposide, vinblastine and pemetrexed). Until recently, there was no evidence that one platinum-based regimen was superior to another in terms of efficacy. 12 However, recent results from a randomized Phase 3 study suggest that pemetrexed/cisplatin may provide improved overall survival (OS) when compared with gemcitabine/cisplatin in subjects with non-squamous histology. 13 In addition, targeted therapies have been approved in the EU and in the US to be used as first line agents for advanced/metastatic lung cancer either in combination with a platinum-containing therapy or as a single agent. Bevacizumab, a recombinant monoclonal antibody that blocks the vascular endothelial growth factor (VEGF) was approved in 26 in the US for patients with unresectable, locally advanced, recurrent, or metastatic non-squamous NSCLC and in 27 in the EU for first-line treatment of patients with unresectable advanced, metastatic or recurrent non small cell lung cancer other than predominantly squamous cell histology. In Study E4599, 14 the median overall survival was significantly extended by 2 months and median progression-free survival was significantly increased by 1.7 months when intravenous bevacizumab, 15 mg/kg once every 3 weeks, was added to first-line carboplatin/paclitaxel therapy compared with carboplatin/paclitaxel alone. In the AVAiL study, 15 median progression-free survival was significantly increased (by.6 and.4 months) by the addition of intravenous bevacizumab, 7.5 or 15 mg/kg once every 3 weeks, to first-line cisplatin/gemcitabine therapy, when compared with placebo plus cisplatin/gemcitabine. However, median overall survival duration was not significantly improved (13.6 and 13.4 months vs 13.1 months). Overall, bevacizumab is not widely used in NSCLC patients outside the US, presumably as a consequence of additional toxicities that were observed in the bevacizumab arms in AVAil and in E4599, as well as a consequence of the absence of statistically significant OS improvement reported in the AVAil study. Gefitinib was approved in the EU for the treatment of adult patients with locally advanced or metastatic NSCLC with activating mutations of EGFR TK on the basis of a randomized Phase 3 study that demonstrated that in a population of patients known to be prone to have tumors with activating EGFR mutations (adenocarcinoma, nonsmokers or light smokers or former light smokers). 16 Patients with activating EGFR mutations assigned to gefitinib clearly experienced longer PFS than those assigned to chemotherapy alone. Conversely, those without activating mutation progressed quickly when assigned to gefitinib. Overall, these data suggest limiting the use of gefitinib as a first line agent only to patients for which the existence of EGFR activating mutations has been established. However, the technical platform required for the determination of activating EGFR TK mutations is not yet widely available. Revised Protocol No.: 6 Date: 25-Apr Approved v

15 BMS CA18414 The combination of cetuximab with cisplatin and vinorelbine was evaluated in the FLE study in subjects with EGFR-positive tumors. Patients assigned to the cetuximab arm experienced a modest but significant improvement in OS (11.3 vs 1.1 months; p =.441) Unmet Medical Need Despite the availability of new agents, the prognosis for patients with advanced NSCLC is still poor. Recent large, randomized Phase 3 trials have demonstrated that platinum-based chemotherapy combinations yield a median survival time of 8 to 11 months, a 1-year survival rate of 3% to 45% and a 2-year survival rate of 1% to 2%. 18 While the administration of pemetrexed and cisplatin results in a better survival than the administration of gemcitabine and cisplatin for patients with non-squamous histology, pemetrexed/cisplatin was inferior than gemcitabine/cisplatin for patients with squamous histology. Cetuximab did demonstrate a survival benefit but this was modest and only patients with EGFR positive tumor should receive cetuximab in combination with a platinum-containing regimen. 19 Indeed, the management of patients with tumor of non-squamous histologies has been improved by the availability of bevacizumab and gefitinib. However, no progress has been made for that of patients with squamous histology. Maintenance therapy and second-line therapies have been demonstrated to provide additional survival benefits, but only in a subset of patients. Better first line therapies are still needed. Overall, new treatment strategies that could enhance the clinical benefit provided by platinumbased doublets are eagerly awaited by the community Investigational Product Characteristics: Key Elements of s Background Clinical Data The data supporting the dose of 1 mg/kg of ipilimumab were generated in metastatic melanoma subjects as well as in the CA18441 Phase 2 lung study. All safety data on ipilimumab monotherapy at a dose of 1 mg/kg came from these studies. Safety data on ipilimumab in combination with paclitaxel and carboplatin were generated both in subjects with NSCLC and in subjects with SCLC. This combination is also being evaluated in metastatic melanoma as part of a drug-drug interaction study Melanoma Program has been evaluated in a number of indications, at different doses, as a single agent or in combination with other agents in studies that enrolled more than 3 subjects. The clinical efficacy of ipilimumab as a single agent at a dose of 3 mg/kg administered every 3 weeks for 4 doses has been established in MD1-2 (a randomized, controlled study in second line, locally advanced/metastatic melanoma). The rationale supporting the dose and schedule of ipilimumab used during the Phase 2 study in lung cancer (CA18441), and CA18414, comes from pharmacokinetic, pharmacodynamic, and clinical data (efficacy and safety) that were Revised Protocol No.: 6 Date: 25-Apr Approved v

16 BMS CA18414 generated from Phase 2 melanoma studies CA18422, 8, 4, and 7. After completion of the lung Phase 2 study, results from a second Phase 3 study in previously untreated melanoma became available (CA18424). In this study, the addition of 1 mg/kg ipilimumab to dacarbazine led to a prolongation of overall survival, and was feasible with an acceptable safety profile. These studies best characterized ipilimumab clinical activity at a dose of 1 mg/kg and their characteristics are summarized in the table below (Table ). Table : Characteristics of Melanoma Studies CA18422 CA1848 MD1 CA1844 (N = 217) (N = 155) -2 (N = 82) Pretreated Pretreated CA1847 (N = 115) Pre- Pretreated/ treated Untreated Pretreated Dose mg/kg placebo Subjects Untreated budesonide placebo budesonide In addition, a specific response pattern in metastatic melanoma was observed and led to the development of immune-related response criteria (irrc) that were used prospectively to measure treatment activity in CA MD1-2 (Phase 3, 3 mg/kg, previously treated melanoma) MD1-2 was a large (676 randomized subjects), multinational, double-blind, randomized Phase 3 study that compared ipilimumab 3 mg/kg in combination with gp1 melanoma peptide vaccine (gp1), ipilimumab 3 mg/kg monotherapy, or gp1 alone (randomized in a 3:1:1 ratio) in HLA-A2*21-positive subjects with pretreated advanced melanoma. The primary endpoint of this study was the comparison of overall survival (OS) in subjects randomized to ipilimumab + gp1 vs gp1. Key secondary endpoints included the comparison of OS in subjects randomized to ipilimumab monotherapy vs gp1 and ipilimumab + gp1 vs ipilimumab monotherapy. The hazard ratio (HR) for comparison of OS between the ipilimumab + gp1 and gp1 groups was.68 (95% confidence interval [CI]:.55,.85; p =.4). The HR for comparison of OS between the ipilimumab monotherapy and gp1 groups was.66 (95% CI:.51,.87; p =.26), indicating a clinically meaningful and statistically significant hazard reduction for death of 32% in the ipilimumab + gp1 group and 34% in the ipilimumab monotherapy group compared with gp1. There was no difference between ipilimumab monotherapy + gp1 vs ipilimumab monotherapy. Median OS was 9.95 months (95% CI: 8.48, 11.5) in the ipilimumab + gp1 group, 1.12 months (95% CI: 8.2, 13.8) in the ipilimumab monotherapy group, and 6.44 months (95% CI: 5.49, 8.71) in the gp1 group (Figure ). Revised Protocol No.: 6 Date: 25-Apr Approved v

17 BMS Figure : CA18414 MD1-2 - Overall Survival by Treatment (ITT Population) Program Source: S:\project\mdx-1\mdx1-2\program\govsurv111.sas 1:2 Tuesday, January 12, 21 Secondary endpoints were Best Overall Response Rate (BORR), Disease Control Rate (DCR) and Progression-Free Survival (PFS). Response was assessed by the investigators, and the highest activity was observed in the ipilimumab monotherapy group (1.9%). BORR was 5.7% and 1.5% in the ipilimumab + gp1 and gp1 groups, respectively (Table ). BORR was significantly higher in the ipilimumab + gp1 and ipilimumab monotherapy groups as compared with the gp1 group (p =.433 and p =.12, respectively) and in the ipilimumab monotherapy group as compared with ipilimumab + gp1 (p =.42). Similarly, for DCR, the highest activity was observed in the ipilimumab monotherapy group (28.5%). DCR was 2.1% and 11.% in the ipilimumab + gp1 and gp1 groups, respectively. The median PFS was similar in all 3 treatment groups (~2.8 months), reflecting the timing of the first scheduled tumor assessment at Week 12. There was a separation of curves shortly thereafter (Figure ). The HR for comparison of PFS between the ipilimumab + gp1 and gp1 groups was.81 (95% CI:.66, 1.; p =.464), between the ipilimumab and gp1 groups was.64 (95% CI:.5,.83; p =.7), and between the ipilimumab + gp1 and ipilimumab monotherapy groups was 1.25 (95% CI: 1.1, 1.53; p =.371). Revised Protocol No.: 6 Date: 25-Apr Approved v

18 BMS Table : CA18414 MD1-2 - Secondary Efficacy Endpoints (ITT Population) 3 mg/kg + gp1 N = 43 3 mg/kg N = 137 gp1 N = (5.7) (3.7, 8.4) 15 (1.9) (6.3, 17.4) 2 (1.5) (.2, 5.2) 81 (2.1) (16.3, 24.3) 39 (28.5) (21.1, 36.8) 15 (11.) (6.3, 17.5) CR 1 (.2) 2 (1.5) PR 22 (5.5) 13 (9.5) 2 (1.5) SD 58 (14.4) 24 (17.5) 13 (9.6) PD 239 (59.3) 7 (51.1) 89 (65.4) Not evaluated (missing or unknown) 83 (2.6) 28 (2.4) 32 (23.5) 2.76 (2.73, 2.79) 2.86 (2.76, 3.2) 2.76 (2.73, 2.83) BORR (CR and PR) N (%) (95% CI) p-value Treatment comparison for BORR a + gp1 vs gp1.433 vs gp gp1 vs.42 DCR (CR, PR, SD) N (%) (95% CI) BOR, N (%) PFS Median (months) (95% CI) Hazard Ratio (95% CI) Treatment comparison for PFS a b c b p-value c + gp1 vs gp1.81 (.66, 1.).464 vs gp1.64 (.5,.83).7 + gp1 vs 1.25 (1.1, 1.53).371 Cochran-Mantel-Haenszel test stratified by M-stage and prior IL-2 at randomization Stratified Cox model Stratified Log-rank test Revised Protocol No.: 6 Date: 25-Apr Approved v

19 BMS Figure : CA18414 MD1-2 - Progression-free Survival by Treatment (ITT Population) The safety profile of ipilimumab at 3 mg/kg in MD1-2 is consistent with that observed at 3 mg/kg in the Phase 2 studies. Additionally, the 3 mg/kg safety profile observed in MD1-2 (see Table ) does not greatly differ from the experience at 1 mg/kg in the Phase 2 program. A set of pre-defined AEs based on the mechanism of action of ipilimumab are called immune-related adverse events (iraes). The iraes arising in these studies were generally manageable with either symptomatic treatment or immunosuppressive therapy such as corticosteroids. Recommended irae management guidelines (see ipilimumab Investigators Brochure) have been developed to minimize the risk for complications from these iraes. Although the rate of Grade 3-4 iraes is higher at the 1 mg/kg dose, the rates of deaths due to iraes is comparable. Across the studies, most iraes involved the skin (eg, pruritus and rash) and GI tract (eg, diarrhea and colitis). Further, iraes affecting the liver (eg, increased ALT and AST) and endocrine system (eg, hypothyroidism and hypopituitarism) were less frequent than those affecting the skin and GI tract. Immune-related AEs were managed with symptomatic therapy (Grade 1-2 events), systemic corticosteroids (Grade 3-4 events), other immunosuppressants (eg, infliximab, mycophenolate) for steroid-unresponsive GI or hepatic iraes, or hormone replacement therapy, as appropriate. With few exceptions, iraes were manageable and reversible within days to weeks. Severe complications of iraes, such as GI perforation/colectomy or treatment-related deaths, were infrequent. Revised Protocol No.: 6 Date: 25-Apr Approved v

20 BMS CA18414 Table : MD1-2: Summary of Drug-related and Immune-related Adverse Events Number of Subjects (%) 3 mg/kg + gp1 N = mg/kg gp1 N = 131 N = (77.4) 13 (78.6) 85 (64.9) Grade 3 55 (14.4) 24 (18.3) 15 (11.5) Grade 4 4 (1.) 5 (3.8) Grade 5 7 (1.8) 4 (3.1) 1 (.8) 22 (57.7) 81 (61.8) 42 (32.1) Grade 3 39 (1.2) 16 (12.2) 4 (3.1) Grade 4 2 (.5) 3 (2.3) Parameter a Drug-related AEs b iraes Grade 5 3 (.8) 2 (1.5) 122 (32.) 39 (29.8) 19 (14.5) Grade 3 21 (5.5) 1 (7.6) 1 (.8) Grade 4 2 (.5) GI iraes Grade 5 2 (.5) 1 (.8) Liver iraes 8 (2.1) 5 (3.8) 6 (4.6) Grade 3 4 (1.) 3 (2.3) Grade 4 Grade 5 1 (.8) 16 (4.2) 1 (7.6) 2 (1.5) Grade 3 4 (1.) 3 (2.3) Grade 4 2 (1.5) Endocrine iraes Grade (39.9) 56 (42.7) 25 (19.1) Grade 3 8 (2.1) 2 (1.5) Grade 4 1 (.3) Skin iraes Grade 5 administered once every 3 weeks for 4 doses; re-induction of the original regimen offered for subjects with SD or better after induction who progressed after Week 12. Safety data for MD1-2 were analyzed for treated subjects as randomized. AEs occurring 7 days or more after the last dose of study medication that were considered drug-related are included. a b Drug-related AEs are only those AEs considered by the investigator to be study therapy-related. All iraes, including the subcategories of iraes displayed in this table (ie, GI iraes, liver iraes, endocrine iraes, and skin iraes). CA18424 (Phase 3, previously untreated melanoma, 1 mg/kg) CA18424 evaluated the addition of 1 mg/kg ipilimumab to dacarbazine in patients with previously untreated, metastatic melanoma. A total of 52 patients were randomized to receive Revised Protocol No.: 6 Date: 25-Apr Approved v

21 BMS CA up to 8 cycles of dacarbazine 85 mg/m q3w, either with ipilimumab 1 mg/kg or placebo given at Cycles 1-4 and as maintenance after completion of chemotherapy. The two arms were well balanced regarding most baseline characteristics, as shown in Table Table : CA18424 Baseline Characteristics + DTIC n = 25 Placebo + DTIC n = Male Female M M1a M1b M1c ULN > ULN x ULN > 2x ULN Age (years) Mean Gender (%) M Stage (%) ECOG PS (%) LDH (%) Prior adjuvant therapy (%) Prior therapy for advanced disease (%) Patients on the ipilimumab arm received a median of 3 ipilimumab induction doses, versus 4 placebo induction doses on the placebo arm. A total of 17.4% and 21.1% of patients continued to receive maintenance ipilimumab or placebo, for a median of 4 and 2 doses, respectively. The number of patients who received all 8 dacarbazine doses was 12.2% in the ipilimumab arm, and 21.5% in the placebo arm. The Overall Survival Kaplan-Meier plot is in Figure Revised Protocol No.: 6 Date: 25-Apr Approved v

22 BMS CA18414 Figure : CA18424 Kaplan-Meier Plot of Overall Survival - All Randomized Subjects 1. + DTIC.9 Placebo + DTIC.8 PROPORTION ALIVE Months MONTHS S UBJE CT S AT R ISK The study met its primary endpoint of prolonging overall survival in patients treated with ipilimumab (HR.72 (95% CI, ), median OS 11.2 vs 9.1 months, p =.9). The overall survival (OS) Kaplan Meier curve is presented in the Figure One, two and three year survival rates were 47.3% 28.5% and 2.8% in the ipilimumab arm, and 36.3% 17.9% and 12.2% in the placebo arm. PFS, a secondary endpoint, was also prolonged by the addition ipilimumab, HR.76 (95% CI, ). The median PFS was 2.8 months in the ipilimumab arm vs 2.6 months in the placebo arm, p =.6. BORR was increased from 1.3% in the placebo arm to 15.2% in the ipilimumab arm (see Table ). More importantly, duration of response was more than twice as long in the ipilimumab arm (19.3 months) than in the placebo arm (8.1 months). Table : CA18424 Tumor Response + DTIC n = 25 Placebo + DTIC n = 252 Disease Control Rate, n (%) 83 (33.2) 76 (3.2) BORR (CR + PR), n (%) 38 (15.2) 26 (1.3) 4 (1.6) 2 (.8) Partial response 34 (13.6) 24 (9.5) Stable disease 45 (18.) 5 (19.8) Progressive disease 111 (44.4) 131 (52.) Complete response Duration of response, months Revised Protocol No.: 6 Date: 25-Apr Approved v

23 BMS CA18414 In terms of safety, the types of ipilimumab AEs were consistent with previous studies and predominantly affected: skin, GI tract, liver, endocrine system. This is consistent with the immune-based mechanism of action. Events were managed with established guidelines and were generally responsive to dose interruption/discontinuation, corticosteroids and/or other immunosuppressants. The rates of events differed slightly from the ones observed in Phase 2: there were more AST/ALT elevations, but less diarrhea and colitis, and no GI perforations. Drug related Grade 3/4 events occurred in 5.6% of patients in the ipilimumab arm and 11.6% of patients in the placebo arm. No treatment related deaths occurred in the ipilimumab arm versus 1 death in the placebo arm. Select adverse events associated with the mechanism of action of ipilimumab (but regardless of attribution by the investigator) are shown in Table : Table : CA18424 Select Adverse Events + DTIC n = 247 Total Placebo + DTIC n = 251 Grade 3-4 Total Grade 3-4 % Patients Dermatologic Pruritis Rash Diarrhea Colitis Increased ALT Increased AST Hypothyroidism Autoimmune thyroiditis.8 Hyperthyroidism.4.4 Gastrointestinal (GI) GI perforation Hepatic Endocrine a Hypophysitis a 1 (.4%) hypophysitis was reported on Day 364. Rationale supporting the dose and schedule of ipilimumab Melanoma data demonstrating that ipilimumab improves survival are available at a dose of 3 mg/kg (MD1-2) and 1 mg/kg (CA18424). In lung cancer, only a dose of 1 mg/kg of Revised Protocol No.: 6 Date: 25-Apr Approved v

24 BMS CA18414 ipilimumab, added to carboplatin/paclitaxel, has been tested in the previous Phase 2 study. A dose of 1 mg/kg of ipilimumab administered once every 3 weeks in the induction phase and every 12 weeks for a maximum treatment period of 3 years from the first dose in the maintenance phase is considered appropriate for CA18414 based on the following: A dose of 1 mg/kg is necessary to ensure a blockade of the CTLA-4 pathway: an in vitro assay that measures the CTLA-4 binding to B7-1 and B7-2 was developed and demonstrated that a concentration of 2 g/ml of ipilimumab was the minimal concentration able to fully abrogate the binding of CTLA-4 to B7.1 and B7.2. The trough concentration of ipilimumab was determined during the Phase 2 studies performed in advanced/metastatic melanoma and compared to the threshold for optimal CTLA-4 blockade. While a dose of 3 mg/kg administered every 3 weeks was able to yield a concentration of ipilimumab greater than 2 g/ml in 3% of the subjects, a dose of 1 mg/kg was able to result in a trough concentration greater than 2 g/ml in 95% of the subjects. These data suggest that a dose of 1 mg/kg administered once every 3 weeks is, among the 3 doses tested, the only dose that results in a trough concentration of ipilimumab higher than the threshold for optimal blockade. The total duration of ipilimumab treatment is limited to a maximum of 3 years from the first dose. The optimal duration for ipilimumab treatment is currently unknown. In MD1-2 an overall survival benefit was observed with 4 induction doses only. Recently, a large metaanalysis of ipilimumab-treated patients with advanced melanoma (n=1861) demonstrated a plateau in OS Kaplan-Meier curve at year 3 that appears flat up to year 1, regardless of the 2 use of maintenance therapy. Therefore, while continued treatment between end of induction and year 3, where patients continue to die from melanoma, might affect outcome, a benefit from treatment beyond 3 years is unlikely. The contribution of maintenance, or optimal duration in other tumor types, or in different disease settings is currently unknown. Data indicate that the dynamics and timing of immune activation are similar regardless of tumor type: for example, increases in pharmacodynamic markers of ipilimumab activity (eg, absolute lymphocyte count, activation of specific T cell subsets, presence of antibodies to tumor antigens), is comparable across tumor types, and also appears to be independent of other anti-cancer therapy, eg, concomitant chemotherapy. Revised Protocol No.: 6 Date: 25-Apr Approved v