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: O Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triplenegative breast cancer. N Engl J Med 2011;364: DOI: /NEJMoa

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STATISTICAL ANALYSIS PLAN A Phase 2, Multi-center, Open-Label, Randomized Trial of Gemcitabine/ Carboplatin, with or without BSI-201, in Patients with ER, PR and HER2-negative Metastatic Breast

treated as confidential and shall remain the exclusive property of sanofi-aventis (or any of its affiliated companies).

132 STATISTICAL ANALYSIS PLAN A Phase 2, Multi-center, Open-Label, Randomized Trial of Gemcitabine/ Carboplatin, with or without BSI-201, in Patients with ER, PR and HER2-negative Metastatic Breast Cancer STUDY BIOSTATISTICIAN: Fong Clow DATE OF ISSUE: 22-Jun-2010 BSI-201 (SAR240550) (TCD11485) Total number of pages: 49 Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of sanofi-aventis (or any of its affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written consent of sanofi-aventis (or the concerned affiliated company); affiliated company means any corporation, partnership or other entity which at the date of communication or afterwards (i) controls directly or indirectly sanofi-aventis, (ii) is directly or indirectly controlled by sanofiaventis, with control meaning direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity According to template: QSD VERSION N 1.0 (22-JUL-2009) Page 1

133 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) TABLE OF CONTENTS TABLE OF CONTENTS...2 LIST OF TABLES...4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS OVERVIEW AND INVESTIGATIONAL PLAN STUDY DESIGN AND RANDOMIZATION Study design Randomization OBJECTIVES Primary objectives Secondary objectives Explorative objectives DETERMINATION OF SAMPLE SIZE STUDY PLAN MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL Additional secondary endpoints Informal interim analyses Primary analysis population Exploratory objectives MODIFICATIONS FROM THE APPROVED STATISTICAL ANALYSIS PLAN STATISTICAL AND ANALYTICAL PROCEDURE ANALYSIS VARIABLES Demographic and baseline characteristics Efficacy variables Primary efficacy variable Secondary efficacy variables Safety variables Adverse events Laboratory variables Vital signs Other safety variables...16 Property of the sanofi-aventis group - strictly confidential Page 2

134 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) Pharmacokinetic variables Pharmacodynamic variables Further therapies after stopping study treatment administration during the study ANALYSIS POPULATIONS Efficacy populations Intent to-treat (ITT) population Per-protocol population Efficacy population Safety populations Other analysis populations Protocol deviations Disposition of patients STATISTICAL METHODS Demographics and baseline characteristics Extent of study treatment exposure and compliance Gemcitabine, carboplatin and BSI-201 exposure Dose modification Concomitant medications Prior medications and prior anti-cancer therapies Post-treatment anti-cancer therapies Analyses of efficacy variables Analysis of primary efficacy variable Analyses of secondary efficacy variables Multiplicity issues Analyses of additional efficacy variable(s) Analyses of safety data Analyses of adverse events Analyses of clinical laboratory variables Analyses of vital signs Analyses of other safety variables Analyses of pharmacokinetic and pharmacodynamic variables Analyses of quality of life / health economics variables DATA HANDLING CONVENTIONS Cut-off Missing data Windows for time points Unscheduled visits Pooling of centers for statistical analyses Statistical technical issues...32 Property of the sanofi-aventis group - strictly confidential Page 3

135 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) 3 INTERIM ANALYSIS SOFTWARE DOCUMENTATION REFERENCE LIST OF APPENDICES...36 APPENDIX A DEFINITIONS...37 APPENDIX B MEDDRA SYSTEM ORGAN CLASS SORTING ORDER FOR REPORTING...41 APPENDIX C NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V3.0 (NCI-CTCAE) FOR LABORATORY TESTS...42 APPENDIX D RESPONSE EVALUATION CRITERIA IN SOLID TUMORS (RECIST) QUICK REFERENCE...44 APPENDIX E ADVERSE EVENTS AND LABORATORY DATA ANALYSIS BY CYCLE AND PATIENT...49 LIST OF TABLES Table 1 - Schedule of assessments...10 Table 2 - Gemcitabine dose reduction...20 Table 3 - Carboplatin dose reduction...20 Table 4 - Prognostic factor...22 Property of the sanofi-aventis group - strictly confidential Page 4

136 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) LIST OF ABBREVIATIONS AND DEFINITION OF TERMS AE: ALP: ALT: AST: ATC: AUC: BRCA: CBR: CR: CRF: CT: DBP: ECG: ECOG: ER: HER2: HLGT: HLT: INR: ITT: IV: LD: LLT: MedDRA: MRI: NCI-CTCAE: ORR: OS: PARP: PCSA: PD: PET: PFS: PK: PR: PT: PTT: RBC: RECIST: SAE: SAP: adverse event alkaline phosphatase alanine transaminase aspartate aminotransferase anatomical therapeutic chemical area under the curve a gene on chromosome 17 that normally helps to suppress cell growth clinical benefit rate = complete response + partial response + stable disease complete response case report form computed tomography diastolic blood pressure electrocardiogram Eastern Cooperative Oncology Group estrogen receptor human epidermal growth factor receptor high level group term high level term international normalized ratio intent-to-treat intravenous longest diameter lower level term Medical Dictionary for Regulatory Activities magnetic resonance imaging National Cancer Institute Common Terminology Criteria for Adverse Events objective response rate overall survival poly(adp-ribose)polymerase potentially clinically significant abnormality progressive disease positron emission tomography progression-free survival pharmacokinetics partial response, progesterone receptor prothrombin time partial thromboplastin time red blood cell Response Evaluation Criteria in Solid Tumors serious adverse event statistical analysis plan Property of the sanofi-aventis group - strictly confidential Page 5

137 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) SBP: SD: SDTM/ADS: SI: SOC: TEAEs: TNBC: UA: ULN: US: WBC: WHO: systolic blood pressure stable disease study data tabulation model/analysis data set system international system organ class treatment emergent adverse events triple-negative breast cancer urinalysis upper limit of normal ultrasound white blood cell World Health Organization Property of the sanofi-aventis group - strictly confidential Page 6

138 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) 1 OVERVIEW AND INVESTIGATIONAL PLAN Protocol is a phase 2, multi-center, open-label, randomized trial of gemcitabine/carboplatin, with or without BSI-201 (trial drug, a poly(adp-ribose)polymerase [PARP] inhibitor), in patients with estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) negative metastatic breast cancer. The statistical analysis plan (SAP) attempts to provide a thorough and concise description of the intended analyses of the study. The clinical, logistic, and experimental aspects of the study are described in the study protocol, a document originally issued on 13 June 2007 and amended twice since. Amendment 2, dated 28 January 2008 is hereafter referred to as the protocol. As a summary of the overall study, about 120 patients with metastatic breast cancer (Stage IV) with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria who consent to participate were to be randomized in a one-to-one ratio to receive either gemcitabine/carboplatin (Arm 1) or gemcitabine/carboplatin in combination with BSI-201 (Arm 2). More specifically, the patients from the both Arm 1 and Arm 2 received gemcitabine 1000 mg/m 2 as a 30-minute intravenous (IV) infusion and carboplatin AUC 2 as a 60-minute IV infusion on Days 1 and 8 of each 21-day cycle. Patients from Arm 2 received BSI-201 (5.6 mg/kg 60-minute IV infusion on Days 1, 4, 8 and 11 of each 21-day cycle. Notice that some patients started with BSI dose of 4.0 mg/kg since at the beginning of the study while the supported data from the phase 1 allowed 4.0 mg/kg BSI dose to be used. Subsequently, 5.6 mg/kg had been supported and was used in this study, which was done under protocol amendment 2. Patients were scheduled to receive the study drug until they experienced drug intolerance or disease progression or are discontinued for a specific reason ie, non compliance, physician decision or other. In Arm 1, at the time of disease progression, if any, patients were permitted to cross over to receive BSI-201 in combination with gemcitabine/carboplatin. Patients were scheduled to undergo end-of-treatment assessments 30 days after the last dose of study drug and every 90 days thereafter, for up to three years or until death whichever occurs first. During the study, tumors were to be assessed at baseline and then approximately every 6 weeks thereafter in the absence of progression of disease. Patients were to undergo safety evaluations and provide blood and urine for safety laboratory testing. Safety laboratory evaluations included blood chemistry, hematology, and urinalysis. Ongoing safety was assessed by physical examinations, collection of vital signs, adverse events (AEs) and concomitant medication use. Safety assessment was done in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 3.0 and analyzed using Medical Dictionary for Regulatory Activities (MedDRA) Version 12. Property of the sanofi-aventis group - strictly confidential Page 7

139 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) 1.1 STUDY DESIGN AND RANDOMIZATION Study design This was an open-label, randomized, multicenter study in adult patients with metastatic triplenegative breast cancer (TNBC), a subtype of breast cancer that is clinically negative for expression of ER, PR and HER Randomization Allocation to the two treatment arms was done centrally via electronic case report form (CRF) system, using a complete permuted-block randomization with block size of four without stratification. Approximately 120 patients (ie, 60 patients per treatment arm) were to be randomized from approximately 20 sites. 1.2 OBJECTIVES Primary objectives The primary objectives of this study are: 1. To evaluate the clinical benefit rate (CBR = complete response [CR] + partial response [PR] + stable disease [SD] 6 months) of gemcitabine/carboplatin/bsi-201 compared to gemcitabine/carboplatin; 2. To evaluate the safety and tolerability of BSI Secondary objectives The secondary objectives are: 1. To evaluate overall response rate 2. To evaluate progression free survival (PFS), 3. To evaluate the toxicity associated with each arm Explorative objectives The exploratory objectives of this trial are as follows: To characterize the inhibition of PARP activity by BSI-201 in peripheral blood mononuclear cells To characterize PARP activity in historic tumor tissues samples. To study the status of BRCA in TNBC. Property of the sanofi-aventis group - strictly confidential Page 8

140 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) To study the response in patients with cancer and known BRCA mutations compared to patients without these mutations. To classify breast cancer tissue as either basal or luminal. 1.3 DETERMINATION OF SAMPLE SIZE The primary objective of the trial was to estimate the CBR in the BSI-201 arm. With a sample size of 60 patients per arm, under the assumption that the observed CBR in the BSI-201 arm will be approximately 0.60 (60%), the half-width of the exact 90% binomial confidence interval will be approximately equal to In particular, for an observed CBR of 0.6, the exact 90% binomial confidence interval will be (0.49, 0.71). In contrast, the anticipated CBR in the control arm is assumed to be approximately If the CBR in the BSI-201 arm is or larger, then based on a one-sided test of equality of proportions at the 5% level of significance, the trial will have at least 80% power to detect an increase from a control arm CBR of STUDY PLAN Patients were to be randomized in a 1:1 ratio into 1 of 2 treatment arms: Arm 1: Patients receive gemcitabine and carboplatin on Days 1 and 8 of a 21-day cycle. Arm 2: Patients receive gemcitabine and carboplatin on Days 1 and 8 with BSI-201 on Days 1, 4, 8, and 11 of a 21-day cycle. BSI-201 (Arm 2 or Arm 1 after crossover) was to be administered at 5.6 mg/kg as a 60-minute IV infusion. Patients were to receive BSI-201 infusions twice weekly (Days 1, 4, 8, and 11) during the first 2 weeks of a 21-day cycle. As noted earlier, some patients started with BSI dose of 4.0 mg/kg prior the protocol amendment 2. In both arms gemcitabine will be administered at 1000 mg/m 2 as a 30-minute IV infusion and carboplatin dosed to achieve AUC 2 as a 60-minute IV infusion. Patients will receive gemcitabine/carboplatin infusions once weekly (Days 1 and 8) during the first 2 weeks of a 21-day cycle, with treatment modifications for toxicity as specified per protocol. In both arms, treatment was to continue until disease progression or unacceptable toxicity. Patients who are discontinued from study treatment were to undergo end-of-treatment assessments 30 days after the last dose of study drug, and then will be followed every 90 (±20) days for overall survival (OS) and PFS. Table 1 contains the study schedule of assessments. It is noted that cycles are defined in terms of consecutive 21-day time periods (possibly with small gaps between them as a result of dosing delays due to AEs irrespective of a possible failure to dose one or more of the 3 study drugs during a numbered cycle. Gemcitabine and/or carboplatin may be delayed up to a maximum of 3 weeks, or skipped, due to toxicity observed in a given treatment cycle. Property of the sanofi-aventis group - strictly confidential Page 9

141 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) Table 1 - Schedule of assessments Informed consent Assessments Medical/Cancer History & Demographics Screening Within 14 days of First Dose X X Day 1 CYCLE 1 21-Day Regimen Day 4 Day 8 Day 11 Day 1 CYCLE 2 21-Day Regimen Day 4 Day 8 Day 11 Day 1 Subsequent Cycles 21-Day Regimen Physical examination X X Symptom-directed examination X X X X X X Height X Weight X X X X X Vital signs (Pre / Post Dose) X X X X X X ECOG performance status X X X X X X X X PT/PTT or INR X X Hematology, Serum chemistry & UA X X X X X X X X 12-Lead ECG X X Gemcitabine / Carboplatin Administration (ARM 1 & 2) Day 4 X X X X X X BSI-201 Administration (ARM 2) X X X X X X X X X X X X PK Samples (Arm 2 and Crossover Subjects) PARP Inhibition (Arm 2 and Crossover Subjects) Tumor Samples Tumor assessment Archived Within 21 - days Pre /Post Dose Pre /Post Dose Pre Dose Pre Dose Pre /Post Dose Pre/ Post Dose Post Cycle PET Scan (Cross Over Pts Only) Prior to first BSI-201 dose & Start of Next Cycle Pregnancy test X X Day 8 Day 11 Even Cycle End of Treatment 30 Days from last Dose Follow-Up Every 90-Days ±20 days Property of the sanofi-aventis group - strictly confidential Page 10

142 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) Screening Assessments Within 14 days of First Dose CYCLE 1 CYCLE 2 Subsequent Cycles End of 21-Day Regimen 21-Day Regimen 21-Day Regimen Treatment Day Day Day Day Day Day Day Day Day Day Day Day Adverse events X X X X X X X X X X X X X Concomitant medications X X X X X X X X X X X X X X Survival and Treatment Status 30 Days from last Dose Follow-Up Every 90-Days ±20 days X Property of the sanofi-aventis group - strictly confidential Page 11

143 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) 1.5 MODIFICATIONS FROM THE STATISTICAL SECTION OF THE PROTOCOL Additional secondary endpoints Overall survival will be analyzed as a secondary efficacy endpoint. The survival analyses provide supportive efficacy information. In addition, time to response and duration of response will also be used as the secondary efficacy endpoints Informal interim analyses No formal interim analysis was planned for the study. However, 9 and 7 informal interim analyses were performed for time to progression and OS, respectively, prior to the final data cut-off on 16 November It is noticed that the time to progression results were reported as the PFS for all those interim analyses. There were as many as interim analyses for CBR, the primary endpoint defined by the protocol. There is no interim analysis for the confirmed objective response rate (ORR); though, CBR is correlated with the confirmed ORR Primary analysis population The protocol specified that the efficacy population was the primary analysis population; while the SAP is specifying the intent-to-treat (ITT) population is the primary analysis population Exploratory objectives All analyses to assess the exploratory objectives described in the protocol will not be performed since the trial has not collected adequate data to allow for performing the analyses. 1.6 MODIFICATIONS FROM THE APPROVED STATISTICAL ANALYSIS PLAN Not applicable. Property of the sanofi-aventis group - strictly confidential Page 12

144 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) 2 STATISTICAL AND ANALYTICAL PROCEDURE 2.1 ANALYSIS VARIABLES This section contains detailed definitions of many analysis variables. Appendix A contains additional definitions (typically of less important analysis variables or other items whose definitions would not readily fit in this section) Demographic and baseline characteristics Age and age group (<50 versus 50, <65 versus 65) Race Ethnicity Height Weight Body surface area Eastern Cooperative Oncology Group (ECOG) performance status Malignancy history, including time from diagnosis to randomization, primary site, histological classification, BRCA mutation, metastatic sites (number and description) Prior anti-cancer treatment, time from last prior anti-cancer therapy administration to randomization. Prior anti-cancer surgeries, radiotherapies, and hormonal treatment Past medical history other than metastatic TNBC Laboratory measurements at baseline Vital signs and electrocardiogram (ECG) measurements at baseline Efficacy variables Primary efficacy variable Clinical benefit rate (CBR): CBR is defined as CR+PR+SD 6 months Tumor assessments will be performed at screening, post-dose at the end of Cycle 2 and every other cycle thereafter, approximately every 6 8 weeks, and end of treatment. Response is integrated response from target, non-target and new lesions, will be derived using investigatorreported tumor assessments according to RECIST 1.0. To be assigned a status of confirmed PR or CR. The tumor assessments must be confirmed by repeat tumor assessments that should be performed 30 days after the criteria for response are first met. Property of the sanofi-aventis group - strictly confidential Page 13

145 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) Secondary efficacy variables The following secondary efficacy variables will be examined: Objective response rate: ORR is defined as the percentage of patients with confirmed PR or CR based on the investigator tumor assessments. Progression-Free Survival: PFS is defined as the time interval from the date of randomization to the date of investigator assess disease progression based upon RECIST Version 1.0 (1) or the date of death due to any cause, whichever comes first: PFS (months) = [earlier of (date of disease progression, date of death) date of randomization +1](12/365.25) In the absence of disease progression or death before the analysis cut-off date, PFS will be censored at the date of the last valid tumor assessment showing CR, PR, or SD performed before the cut-off date. If a patient received other therapy for breast cancer during this study before progression the patient will be censored at the date of the last tumor assessment before the start of the first such therapy. Patients who crossed over before disease progression will be censored at the date of last tumor assessment before crossover. Overall Survival: OS is defined as the time interval from the date of randomization to the date of death due to any cause: OS (months) = (date of death date of randomization + 1)(12/365.25) In the absence of confirmation of death before the analysis cut-off date, OS will be censored at the last date the patient was known to be alive, or at the analysis cut-off date, whichever is earlier. Duration of response: duration of response will be calculated on patients with ORR and is defined as the time interval from the date of first documented CR or PR to the date of subsequent progressive disease (PD) or death, whichever is earlier: Duration of response (months) = [date of first documented CR or PR - earlier of (date of subsequent documented disease progression, date of death) +1](12/365.25) Duration of response is determined only for patients who have a confirmed CR or PR. In the absence of disease progression or death before the analysis cut-off date, duration of response will be censored at the date of the last valid tumor assessment before the cut-off date. Time to response: time to response is defined as the time from the date of randomization to the date of the first documented RECIST defined response (CR or PR). Time to response is determined only for patients who have a confirmed CR or PR. Property of the sanofi-aventis group - strictly confidential Page 14

146 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) Safety variables Adverse events The study will use Version 3.0 of the NCI-CTCAE experienced by patients. All AEs will be coded to a lower level term (LLT), preferred term, high level term (HLT), high level group term (HLGT), and associated system organ class (SOC) using the MedDRA Version 12. The observation period will be divided into 4 segments: The pre-treatment period is defined as the time between the patients giving informed consent and the start of any study drug The on-treatment period is the period from first dose of any study treatment up to 30 days after the last dose of any study drug. For patients in the gemcitabine/carboplatin arm who crossed over, all AEs up to the crossover date (ie, date of first dose after crossover) will be part of the on-treatment period The post-crossover on-treatment period is the period from first dose of study medication after crossover up to 30 days after the last dose of any study drug The post-treatment period is defined as the period starting from 31 days after last dose of any study drug (after the on-treatment period or the post-crossover on-treatment period) until the end of the follow-up period. Treatment emergent adverse events (TEAEs) are defined as any AE that developed or worsened in severity compared to baseline during the on-treatment period (or the post-cross-over period for patients who crossed over). An AE will be regarded as treatment-related based on a positive answer to any one or more of the 3 separate CRF questions asking if there is a reasonable possibility the AE may have been caused by gemcitabine, carboplatin, or BSI Laboratory variables Laboratory variables include: Hematology: white blood cell (WBC), red blood cell (RBC), hemoglobin, hematocrit, platelets, neutrophils, lymphocytes, monocytes, eosinophils, basophils Chemistry: albumin, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transaminase (ALT), calcium, sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, glucose, total protein, lactate dehydrogenase, gamma glutamyl transferase, phosphorus, total bilirubin. Urinalysis: appearance, color, ph, specific gravity, ketones, protein, glucose, bilirubin, nitrite, and occult blood. Property of the sanofi-aventis group - strictly confidential Page 15

147 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) Laboratory results will all be expressed in system international (SI) units, have local normal ranges provided by the various local laboratories providing the data, and be graded according to the NCI-CTCAE Version 3.0 (see Appendix C), when applicable Vital signs Weight on Day 1 and 8 of each treatment cycle and at end-of-treatment 5-minute sitting systolic and diastolic blood pressure Pulse Respiratory rate Oral temperature Other safety variables 12-lead ECGs Physical examination and symptom-directed examination findings ECOG performance status Pharmacokinetic variables None Pharmacodynamic variables None Further therapies after stopping study treatment administration during the study Further therapies after stopping study treatment administration (ie, last dose of BSI-201, gemcitabine or carboplatin, whichever is last), such as surgery, chemotherapy, immunotherapy, biologics, and hormonal therapy will be analyzed as well. 2.2 ANALYSIS POPULATIONS Inclusion in the analysis populations will be determined according to the following definitions Efficacy populations Intent to-treat (ITT) population The ITT population will consist of all randomized patients. All efficacy analyses will be conducted using the ITT population. Property of the sanofi-aventis group - strictly confidential Page 16

148 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) All analyses using this population will be based on the treatment group assigned at randomization. If patients were randomized but not treated, then they will be reported under their randomized treatment group for efficacy analyses. However, they are by definition excluded from the safety analyses. If patients were randomized but took incorrect treatment, then they will be reported under their randomized treatment group for all efficacy analyses, but will be reported under the treatment they actually received for all safety analyses Per-protocol population No per-protocol population has been defined Efficacy population The efficacy population will consist of all subjects who completed at least one cycle treatment AND have a baseline assessment of tumor size AND have a post-treatment assessment of tumor size Safety populations The safety population will consist of all patients who received at least 1 dose of any of the 3 study drugs. All analyses using this population will be based on the treatment actually received, ie, as treated. The crossover safety population will include all patients from the gemcitabine/carboplatin arm who crossed over to receive gemcitabine/carboplatin + BSI-201. This population will be used for analysis of exposure and safety data after the crossover date Other analysis populations Not applicable Protocol deviations All major protocol deviations potentially impacting efficacy analyses, for example, No metastatic TNBC More than 2 previous chemotherapies for metastatic disease Use of other anti-cancer drug therapy during treatment More than 2 missing or non-adequate tumor assessments Crossover before documented disease progression Non-measureable disease per RECIST 1.0 Property of the sanofi-aventis group - strictly confidential Page 17

149 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) Randomization and/or drug dispensing irregularities (eg, patient treated with incorrect treatment, randomized twice, treated but not randomized), will be summarized for the ITT population using frequencies and percentages by treatment group. Minor protocol deviations will be summarized separately. A listing of protocol deviations will be presented including patient, treatment group, date, and a description of the deviation Disposition of patients Patients inclusion in the ITT, safety, and crossover safety populations will be summarized by treatment group. Number (%) of patients randomized in each site will also be summarized. Separate summaries will be provided of treatment discontinuation and study discontinuation and the reasons for each type of discontinuation in the ITT population. Disposition-related listings will include listings related to treatment discontinuation, study discontinuation, population membership, and treatment crossover. 2.3 STATISTICAL METHODS Descriptive statistics for all demographic, safety, and efficacy variables will be provided in tables. For continuous variables, descriptive statistics will include number of observations, mean, standard deviation, median, and range (minimum and maximum). For categorical variables, descriptive statistics will include frequency and percentage. Percentages will be calculated using as the denominator the number of patients with non-missing data in the considered population. For time to event variables (ie, survival), the estimates of the 25 th and 75th percentiles as well as median with 95% confidence interval will be calculated using the Kaplan-Meier Life Test Methods. The hazard ratio and its 95% confidence interval will be estimated using the Cox proportional hazards regression model. A graph of the probability of the events over time will be presented Important data listings will be provided, for example, patient disposition, demographics, AEs leading to discontinuation, serious adverse events (SAEs), deaths, and AEs of special interest. Listings will be sorted by site and patient number within treatment group. Repeated values of these key variables will be blanked out in the listings. Missing values will be presented by blank spaces. For partially missing dates, the information present will be printed; eg, --/05/2000. All raw data will be presented to the original number of decimal places. The means and medians will be presented to 1 more decimal place than the raw data. The standard deviations will be presented to 2 more decimal places than the raw data. For tables where rounding is required, rounding will be done to the nearest round-off unit. For example, if the round-off unit is the ones place (ie, integers), values XX.5 will be rounded up to XX+1 while values < XX.5 will be rounded down to XX. Property of the sanofi-aventis group - strictly confidential Page 18

150 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) All confidence intervals, statistical tests, and resulting p-values will be reported as 2-sided and will be assessed at the 5% significance level. All p-values will be displayed to 3 decimal places and rounded up (eg, 0.XXX). For frequency counts of categorical variables, categories whose counts are zero will be displayed for the sake of completeness. For example, if none of the patients discontinue due to lack of efficacy, this reason will still be included in the table with a count of Demographics and baseline characteristics Patient demographic and baseline characteristics will be summarized using frequency counts for categorical variables (age category, race, ethnicity, ECOG performance status), and descriptive statistics for quantitative variables (age, weight, height). History of malignancy and prior anti-cancer treatment will be summarized by treatment group Extent of study treatment exposure and compliance Extent of study treatment exposure will be analyzed on the safety population (ie, taking into account all cycles administered before the crossover date) and the safety crossover population Gemcitabine, carboplatin and BSI-201 exposure Overall study treatment exposure (over all 3 study medications together) will be summarized with summary statistics for the number of study cycles started (cycle started if 1 or more of the 3 study drugs administered) and duration of exposure in weeks [(first day of last cycle first day of first cycle + 21 days)/7] by treatment group. Summary statistics will be provided for the following for each of the 3 study drugs separately by treatment group: Number of study cycles started and duration of exposure in weeks Cumulative dose entire study: Separately for gemcitabine, carboplatin, BSI-201 sum of all doses administered over the entire study in units of mg/m 2, AUC 2, and mg/kg Relative dose intensity: Cumulative dose entire study/[(duration of exposure)(planned dose intensity]. Planned dose intensity is (2000 mg/m 2 /3 weeks) for gemcitabine, (AUC 4/3 weeks) for carboplatin, and (22.4 mg/kg/3 weeks) for BSI Dose modification Dose modification can occur in the form of (1) delay and (2) reduction, which will be derived as described below. Property of the sanofi-aventis group - strictly confidential Page 19

151 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) Delay A dose delay is defined as a cycle starting 4 or more days late, that is, Day 1 of the current cycle Day 1 of the previous cycle >24 days. Number of days of delay is calculated as (Day 1 of the current cycle Day 1 of the previous cycle -21). Reduction Dose reduction is not permitted for BSI-201. For gemcitabine, dose reduction is defined as: Table 2 - Gemcitabine dose reduction Category Actual dose level (mg/m²) Actual dose administered (mg/m²) Initial dose Dose < 1100 Dose reduction Dose < 900 Dose reduction Dose < 700 For carboplatin, dose reduction is defined as: Table 3 - Carboplatin dose reduction Category Actual dose level (AUC) Actual dose administered (AUC) Initial dose Dose < 2.2 Dose reduction Dose < 1.8 Analysis of dose modification Summary statistics will be provided for dose modification for each of the 3 study drugs separately as follows: Number (%) of patients and cycles with dose delayed. The summary will also include the number (%) of cycles with 4-7 days >7 days delay Number (%) of patients with 1 or 2 dose reductions. The summary will also include number (%) of cycles with drug administered at a reduced dose (dose< initial dose) Concomitant medications Concomitant medications are defined as medications taken from the first administration of study drug (including medications ongoing from before first administration that continued) to 30 days post-treatment. Concomitant medications will be coded according to the World Health Organization (WHO) Drug Dictionary. Property of the sanofi-aventis group - strictly confidential Page 20

152 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) Non-cancer and cancer concomitant medications will be summarized by treatment group, anatomical therapeutic chemical (ATC) classes, and WHO preferred term. A patient will be counted at most once for each concomitant medication, even if the patient took the same medication on multiple occasions. Notice that patients receiving any anti-cancer concomitant medication during the treatment period will be defined as the protocol violations Prior medications and prior anti-cancer therapies Prior medications and prior anti-cancer therapies are defined as medications and therapies taken before the first administration of study drug. Prior medications will be coded according to the WHO Drug Dictionary and will be summarized by treatment group, ATC classes, and WHO preferred term. The prior anti-cancer therapies will be summarized by treatment group Post-treatment anti-cancer therapies Post-treatment anti-cancer therapies are defined as anti-cancer therapies taken 30 days after the last dose administration of study drug. The post anti-cancer therapies will be summarized by treatment group Analyses of efficacy variables Efficacy analysis will include Primary variables: CBR Secondary analysis variables: OS, PFS, best overall response, ORR, duration of response and time to response Analysis of primary efficacy variable Primary analysis of clinical benefit rate Clinical benefit rate, which is the achievement of either CR or PR or SD 6 months, will be for the ITT population. The number and percent of patients achieving CR and PR separately will be summarized. The number and percent of patients achieving CBR will be summarized with corresponding exact 2-sided 95% confidence intervals. The difference between treatments, a 95% confidence interval for the difference based on a normal distribution, and a p-value based on the Pearson chi-square test will be provided. Property of the sanofi-aventis group - strictly confidential Page 21

153 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) Subgroup analysis will performed for the CBR using baseline characteristics and medical history variables. Summary statistics showing number of patients, percent of event, odd ratio and its 95% confidence intervals for each subgroup will be presented using forest plot. The subgroup variables are: Table 4 - Prognostic factor Prognostic Factor Line of therapy: Age category : Race: ECOG performance score: Time since diagnosis of TNBC: Burden of disease Visceral disease: Description (Coding) 0= No previous chemo, 1=one or more previous chemo in metastatic setting 0= <50y, 1= 50y 0= Other (Black or African American), 1=White 0= ECOG 1, 1=ECOG=0 0= <= 24 months, 1= > 24 months 0= 0-2 metastatic sites, 1=>2 metastatic sites 0= others, 1= Main metastatic sites is visceral In addition, the potential influence of baseline characteristics and medical history on the CBR will be evaluated using the logistic regression model. The baseline factors are the same as the subgroup defined Table 4. The odds ratio will be modeled using above baseline variables as covariates. A two-step selection process will be applied to these baseline characteristics to identify the final set of relevant factors. Each the baseline factor will be preliminarily evaluated by including treatment and that factor in the logistic regression model. Only the variable significant at a 10% level will be considered in building the multivariate model. A backward elimination process will be applied to these variables including treatment, using a 5% level to stay in the model, to identify the final set of relevant factors. Treatment-by-factor interactions may also be explored only for the set of factors included in the final model. The estimated odd ratio and 95% confidence interval of the treatment and factors will be provided. As an exploratory analysis, CBR will be analyzed using the efficacy population Analyses of secondary efficacy variables Analyses of overall response ORR, that is the achievement of either CR or PR, will be for the ITT population. As an exploratory analysis, ORR will be analyzed using the efficacy population. The number and percent of patients achieving objective response (CR or PR) will be summarized with corresponding exact 2-sided 95% confidence intervals. The difference between treatments, a 95% confidence interval for the difference based on a normal distribution, and a p-value based on the Pearson chi-square test will be provided. Similar analysis for CBR will be also performed for ORR. Property of the sanofi-aventis group - strictly confidential Page 22

154 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) Duration of response and time to response will be analyzed in for the responders only. Kaplan-Meier estimates of the 25 th, 50 th, and 75 th percentiles and the 95% confidence intervals of median will be provided. Analyses of progressive-free survival The analysis for the endpoint PFS will be similar to that described for OS below, but exclude any separate analysis of crossover patients. Events contributing to PFS (ie, disease progression or death without progression) will be described. Sensitivity analysis of progressive-free survival A sensitivity analysis will be performed to assess the robustness of the primary analysis of PFS in the ITT population. The proposed censorship criteria for the sensitivity analysis are as follows: Situation Date of Progression or Censoring Outcome No baseline assessment Randomization Censored Progression documented between scheduled visits Treatment discontinuation for undocumented progression Earliest of: Date of radiological assessment showing new lesion (if progression is based on new lesion); or Date of last radiological assessment of measured lesions (if progression is based on increase in sum of measured lesions) Date of last radiological assessment of measured lesions Progressed Censored Treatment discontinuation for toxicity or other reason Date of last radiological assessment of measured lesions Censored New anticancer treatment started with no claim of progression Date of last visit with adequate assessment Censored Death after an extended lost-to-follow-up time (2 or more missed assessments) Last visit with adequate assessment Censored Analyses of overall survival Overall survival will be analyzed using Kaplan-Meier method by treatment group in the ITT population. Kaplan-Meier estimates of the 25 th, 50 th, and 75 th percentiles and the 95% confidence intervals of median will be provided. In addition, probabilities of surviving at 3, 6, 9, and 12 months will be provided for each treatment group. The hazard ratio and its 95% confidence interval will be estimated using the Cox proportional hazards regression model. Kaplan-Meier curves will be plotted. Underlying assumptions of the Cox proportional hazard model will be checked by graphical methods. The 2-sided log-rank test in the ITT population will be used to compare treatment groups. Property of the sanofi-aventis group - strictly confidential Page 23

155 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) The hazard rate as a function of OS time t from randomization will be modeled as a function of a baseline hazard function λ 0 (t) and covariate TRT (indicating treatment: 0=gemcitabine/carboplatin, 1=gemcitabine/carboplatin + BSI-201): λ(t TRT)= λ 0 (t)exp(βtrt) which implies log{ λ(t TRT)/ λ 0 (t)}= βtrt=β*1=β The baseline hazard λ 0 (t) corresponds to the hazard function for a patient treated with gemcitabine/carboplatin. Hence, log{hazard (gemcitabine/carboplatin + BSI-201)/ hazard(gemcitabine/carboplatin)}= β. So, hazard (gemcitabine/carboplatin + BSI-201)/ hazard (gemcitabine/carboplatin) =e β. Hence, e β is the hazard ratio of death for patients treated with gemcitabine/carboplatin + BSI-201 compared to those treated with gemcitabine/carboplatin. If β <0 then the hazard for patients treated with gemcitabine/carboplatin + BSI-201 is lower (better survival) since e β <1 showing the beneficial effect of BSI-201. If β >0 then the hazard for patients treated with gemcitabine/carboplatin + BSI-201 is higher (poorer survival) since e β >1. If β=0 then there is no association between hazard (survival) and treatment with gemcitabine/carboplatin + BSI-201 since e β =1. Follow-up duration (months) will be defined as the time interval from the date of randomization to the date of death or the date of last contact with the patient. Median follow-up duration will be estimated using the Kaplan-Meier method. Reasons for censoring for OS (patient alive at the cutoff date, lost to follow-up, withdrew consent) will be also summarized. The potential influence of the following baseline patient factors on OS will be evaluated using the Cox proportional hazards model: STRTA (indicating stratification factor: 0 = no previous chemotherapy in the metastatic setting for TNBC, 1= one or more previous chemotherapies in the metastatic setting for TNBC) AGEGRP (indicating age group: 0 = age <50 years, 1 = age 50 years) ECOG (indicating ECOG performance status: 0 = ECOG score 1 or above, 1 = ECOG score 0) RACE (indicating ethnic origin: 0 = Non-white, 1 = white) TIMSIN (indicating time since diagnosis of TNBC: 0 = 24 months or less, 1 = more than 24 months) BURDEN (indicating burden of disease: 0 = 0-2 metastatic sites, 1 = >2 metastatic sites) VISCERAL (indication visceral disease: 0 = others, 1 = Main metastatic sites is visceral) For each factor listed above, a Cox proportional hazards model including the treatment effect, the factor effect, and the treatment-by-factor interaction, that is, λ (t TRT, FACTOR)= λ 0 (t)exp(β 1 TRT + β 2 FACTOR + β 3 TRT*FACTOR), Property of the sanofi-aventis group - strictly confidential Page 24

156 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) will be examined using the ITT population. Number of patients, number (%) of deaths, median OS estimated with the Kaplan-Meier method, and 95% confidence limits will be provided for each treatment. Within each selected subgroup, the treatment effect hazard ratio and its 95% confidence limits will be estimated using a Cox proportional hazards model. For each subgroup and for the overall population, hazard ratios and 95% confidence interval will be displayed using forest plots. Following examination of these factors individually, a multivariate Cox proportional hazards model will be examined involving factors significant at a 10% level based on a Wald chi-square test in a single-factor model. If all factors did qualify, the hazard function as a function of OS time t from randomization will be modeled as a function of a baseline hazard function λ 0 (t) and covariates λ (t TRT, STRTA, AGEGRP, ECOG, RACE)= λ 0 (t)exp(β 1 TRT + β 2 STRTA + β 3 AGEGRP + β 4 ECOG + β 5 RACE + β 6 TIMSIN). The baseline hazard λ 0 (t) corresponds to the hazard function for a patient who had no previous chemotherapy treatment for TNBC, age <50 years, ECOG performance score of 1, non-white, treated with gemcitabine/carboplatin, time since diagnosis 12 months or less, tumor burden, and visceral disease. In an ITT population analysis, a backward elimination process will be applied to the eligible factors (including treatment), requiring a 5% level of a Wald chi-square test to stay in the model, to identify the final set of relevant factors. Treatment-by-factor interactions will also be explored for the set of factors included in the final model. The estimated hazard ratio, 2-sided 95% confidence interval, and Wald chi-square test p-values will be provided throughout these analyses of the impact of baseline patient factors. Exploratory analysis of overall survival The impact of crossover patients on OS will be examined by splitting the gemcitabine/carboplatin arm into (1) patients who received gemcitabine/carboplatin only and (2) patients who crossed over and received BSI-201 and repeating the primary analysis of OS with 3 treatment groups. However, it is recognized that these comparisons are not based on randomization and therefore will be considered descriptive only Multiplicity issues All statistical analyses in this study are descriptive, no multiplicity will be considered for the primary and secondary efficacy variables Analyses of additional efficacy variable(s) There are no additional efficacy variables. Property of the sanofi-aventis group - strictly confidential Page 25

157 Statistical Analysis Plan 22-Jun (TCD11485) Version number: 2 (electronic: 1.0) Analyses of safety data Safety analysis will be based on the safety population and the crossover safety population. For patients who crossed over, analyses on the safety population will include all data reported up to the crossover date. Summaries for the crossover safety population will only be provided where specifically indicated. Analysis of safety will include: AEs Clinical laboratory variables Vital signs Other safety variables, including ECGs, physical examinations, and ECOG performance status Analyses of adverse events In all TEAE summary tables involving summary by SOC, the SOC will be sorted by internationally agreed order (see Appendix B). Unless otherwise stated, HLGTs, HLTs, and preferred terms will be sorted by alphabetical order. Overview of treatment emergent adverse events An overall summary of TEAEs will be provided. The number and percentage of patients who experienced any: TEAE Grade 3 or higher TEAE TEAE leading to permanent treatment discontinuation Serious TEAE Fatal TEAE, will be summarized by treatment. This summary will also be provided for the crossover safety population. A summary of TEAEs with an incidence 5% in any treatment group presented by preferred term sorted by decreasing order of frequency in test arm and presented by all grade and Grade 3 will be provided. TEAEs with a difference of 2 percentage points between treatment groups (by 4-level MedDRA terms of SOC, HLGT, HLT, and preferred term) will be summarized by arm. Property of the sanofi-aventis group - strictly confidential Page 26

Sponsor / Company: Sanofi Drug substance(s): SAR (iniparib)

These results are supplied for informational purposes only. Prescribing decisions should be made based on the approved package insert in the country of prescription. Sponsor / Company: Sanofi Drug substance(s):