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Confidential
Statistical Analysis Plan OncoMed Pharmaceuticals, Inc.
Study 59R5-003 (Phase 2 Portion)
A Phase-1b/2 Study of Tarextumab (OMP-59R5) in Combination with Etoposide and Platinum Therapy in Subjects with Untreated Extensive Stage Small Cell Lung Cancer
PINNACLE: Phase-1b/2 INvestigation of anti-Notch Antibody Therapy with Etoposide and Platinum Therapy in Small Cell Lung Carcinoma Safety and Efficacy
Sponsor: OncoMed Pharmaceuticals, Inc.800 Chesapeake DriveRedwood City, CA 94063Phone: 650-995-8200
Prepared by:SynteractHCR
Version Number DateVersion 1 01SEP2016Version 2 19SEP2016Version 3 23MAR2017
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TABLE OF CONTENTS List of Abbreviations ...................................................................................................................... 5
Definitions....................................................................................................................................... 6
1. Introduction ............................................................................................................................... 8
2. Study Objectives ....................................................................................................................... 8 2.1. Primary Objectives ........................................................................................................... 8 2.2. Secondary Objectives ....................................................................................................... 8 2.3. Exploratory Objective ...................................................................................................... 9
3. Study Design and Plan .............................................................................................................. 9 3.1. Blinded Treatment Phase ............................................................................................... 10 3.2. Follow-Up ...................................................................................................................... 11
4. Determination of Sample Size ................................................................................................ 11
5. General Analysis Considerations ............................................................................................ 15 5.1. Analysis Software .......................................................................................................... 15 5.2. Baseline Values .............................................................................................................. 16 5.3. Missing Values ............................................................................................................... 16 5.4. Subgroup Analyses ......................................................................................................... 16 5.5. Multiple Comparisons/Multiplicity ................................................................................ 16
6. Analysis Data Sets .................................................................................................................. 16 6.1. Analysis Populations ...................................................................................................... 17
7. Summaries of Patient Characteristics ..................................................................................... 18 7.1. Subject Disposition ........................................................................................................ 18 7.2. Protocol Deviations ........................................................................................................ 18 7.3. Demographics and Baseline Characteristics .................................................................. 18
8. Efficacy Endpoints .................................................................................................................. 19 8.1. Progression-Free Survival .............................................................................................. 19 8.2. Total Tumor Length ....................................................................................................... 21 8.3. Overall Response Rate ................................................................................................... 22 8.4. Duration of Response ..................................................................................................... 22 8.5. Sites of Progression ........................................................................................................ 23 8.6. Overall Survival ............................................................................................................. 23 8.7. Landmark Survival ......................................................................................................... 23
9. Exploratory Analyses .............................................................................................................. 24
10. Pharmacokinetic Endpoints .................................................................................................... 26
11. Safety Endpoints ..................................................................................................................... 27 11.1. Treatment Cycles and Dosing ........................................................................................ 27
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11.1.1. Dose Intensity ...................................................................................................... 27
11.1.2. Dosing Compliance ............................................................................................. 28
11.2. Adverse Events ............................................................................................................... 28 11.3. Clinical Laboratory Parameters ...................................................................................... 29 11.4. Vital Signs ...................................................................................................................... 30 11.5. Electrocardiogram Results ............................................................................................. 30 11.6. ECOG Performance Status ............................................................................................. 31 11.7. Immunogenicity ............................................................................................................. 31 11.8. Prior and Concomitant Medications ............................................................................... 31
12. References ............................................................................................................................... 31 Appendix A. List of Tables, Figures and Listings ........................................................................ 32
Appendix B. Table Shells ............................................................................................................. 44
Appendix C. Figure Shells .......................................................................................................... 101
Appendix D. Listing Shells ......................................................................................................... 106
FIGURES Figure 1. Enrollment, Progressions and Deaths over Time – Control Hazard of Progression of 0.1386 Beyond 9 months .......................................................................................................... 13
TABLES Table 1. Progression-Free Survival: Power for the Alternative Hypothesis ................................. 12
Table 2. Enrollment, Progressions and Deaths over Time – Control Hazard of Progression of 0.1386 Beyond 9 Months.......................................................................................................... 12
Table 3. Hazards for Piece-Wise Exponential Model of Progression Free Survival .................... 14
Table 4. Hazards for Piece-Wise Exponential Model of Overall Survival ................................... 14
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LIST OF ABBREVIATIONS
AE Adverse event ANCOVA Analysis of covariance ANOVA Analysis of variance ATC Anatomical/Therapeutic/Chemical (class) AUC Area under curve BMI Body mass index BSA Body surface area CRF Case report form CNS Central nervous system CR Complete response CSR Clinical study report CTCAE Common terminology criteria for adverse events DOR Duration of response DSMB Data Safety Monitoring Board ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group EP Etoposide and platinum (therapy) ES-SCLC Extensive stage small cell lung cancer HR Hazard ratio ITT Intent-to-treat (patient population) KM Kaplan-Meier MedDRA Medical Dictionary for Regulatory Activities MTD Maximum tolerated dose N3RPI NOTCH-3-ralated PFS index NE Inevaluable (by RECIST criteria) ORR Overall response rate OS Overall survival PCI Prophylactic cranial irradiation PD Progressive disease PFS Progression free survival PH Proportional hazards PK Pharmacokinetics PP Per-protocol (patient population) PR Partial response RECIST Response evaluation criteria in solid tumors (version 1.1) SAE Serious adverse event SAP Statistical analysis plan SD Stable disease SLD Sum of longest diameters TEAE Treatment-emergent adverse event TFLs Tables, figures and listings WBR Whole brain radiation WHO World Health Organization
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DEFINITIONS
Adverse event Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease temporally associated with the subject’s participation in the research, whether or not considered related to the subject’s participation in the research, or any baseline conditions that worsened during the study.
Baseline value The last non-missing value recorded prior to the first dose of study drug.
Best overall response Patient’s best investigator-assessed RECIST response to treatment category recorded since the start of the treatment.
On study tumor assessments
Tumor assessments that meet the following criteria: 1. No gap of ≥91 days between successive tumor assessments among those on or prior to the on study tumor assessment. (Note: a tumor assessment for which “Not Evaluated” is entered into the database does not qualify as a tumor assessment.) 2. No prior initiation of non-protocol anticancer therapy.
Overall response rate The proportion of patients achieving a complete response or partial response to treatment.
Dose intensity The total dose (in mg) a patient actually received divided by the total dose (in mg) the patient should have received had there been no missed doses, dosing delays or dosage reductions.
Intent-to-treat population All patients randomized to receive study drug regardless of whether they actually received study drug and regardless of whether evidence is found indicating they failed to meet study inclusion/exclusion criteria or had other protocol violations.
Last contact date The last contact date is the latest assessment/visit date recorded on any of the following case report forms: Discontinuation, Hematology, Chemistry, RECIST Overall Response Tumor Assessments, Survival Follow Up, Study Drug Infusion, Etoposide Infusion or Platinum Therapy Infusion.
Non-Protocol Anti-Cancer Therapy
Non-protocol anti-cancer therapies used by patients during their participation in this study, if any, will be identified by the sponsor after review of relevant data listings.
Per-protocol population The subset of safety population who either (a) have at least one response evaluation on study, or (b) die prior to their first scheduled response evaluation.
Platinum Therapy / Platinum Choice
The physician’s choice of platinum therapy (cisplatin or carboplatin) was used as a stratification variable by the dynamic randomization system. Discrepancies, if any, between the platinum therapy used to stratify a patient’s treatment assignment and the platinum therapy actually administered during the study will be dealt with as follows. Platinum choice entered in the dynamic randomization system will be used in all efficacy analyses where platinum choice is included as a model
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effect. However, actual platinum received (as documented on earliest Platinum Therapy Infusion CRF [e.g., Cycle 1, Day 1]) will be used when calculating dosing compliance.
Randomization Date Although each patient’s randomization date was recorded by site personnel on the Informed Consent case report form (CRF), the actual randomization date substantiated by the dynamic randomization system used to make blinded treatment assignments will be used in all analyses including calculations of times to events such as OS and PFS.
Randomized Study Drug Tarextumab or placebo Safety population The subset of the intent-to-treat population who received at least
one partial dose of tarextumab or Placebo and who have at least one post-dosing safety evaluation (labs, vital signs or adverse events).
Treatment-emergent adverse event
An adverse event that starts or increases in severity any time after the first administration of any randomized study drug (i.e., tarextumab or placebo) up to 30 days following the last administration of any study drug.
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1. INTRODUCTION This document outlines the statistical methods to be implemented for analyzing data collected within the phase-2 portion of OncoMed Pharmaceuticals, Inc. Protocol 59R5-003 (A Phase-1b/2 Study of Tarextumab [OMP-59R5] in Combination with Etoposide and Platinum Therapy in Subjects with Untreated Extensive Stage Small Cell Lung Cancer), amendment 6 dated 22 April 2016. The purpose of this statistical analysis plan (SAP) is to provide specific guidelines from which the statistical analyses will proceed. Any deviations from this plan will be documented in the clinical study report (CSR). The definitive analyses of efficacy data for making statistical inference with respect to the objectives the Phase-2 portion of the study and the definitive analyses of safety data will be performed using data from a formal data cut taken planned to occur in April 2017. Randomized treatment assignments will be unblinded at that time. Any subsequent data analyses that may be performed to include data accrued into the database following the April-2017 data cut will be considered secondary efficacy and/or safety analyses.
Investigating the pharmacokinetics (PK) of tarextumab in combination with EP is an objective of this study, but a detailed analysis plan is outside the scope of this document.
Throughout this SAP, the terms patient and subject are used synonymously to refer to an individual who was enrolled to participate in the clinical trial.
2. STUDY OBJECTIVES
2.1. Primary Objectives The primary objectives of this study are:
Phase-1b portion: To determine the maximum tolerated dose (MTD) of tarextumab when administered on Day 1 of each 21 day cycle along with etoposide 100 mg/m2 on Days 1, 2 and 3 and cisplatin 80 mg/m2 or carboplatin to an area under curve (AUC) of 5 mg/mL/min on Day 1 in subjects with untreated extensive stage small cell lung cancer (ES-SCLC).
Phase-2 portion: To determine the improvement in progression free survival (PFS) resulting from the addition of tarextumab to etoposide and platinum therapy (EP) in subjects receiving first-line therapy for ES- SCLC. (Platinum therapy for the phase-2 portion was similar to phase-1b [i.e., cisplatin or carboplatin], but the cisplatin dose was changed to 75 mg/m2.)
Statistical analyses concerning the primary objective for the phase-1b portion of this study will not be addressed in this SAP.
2.2. Secondary Objectives The secondary objectives of this study are:
Phase-1b and -2 portions: To determine the PK of tarextumab in combination with EP in subjects receiving first-line therapy for ES-SCLC
Phase-1b and -2 portions: To determine the immunogenicity of tarextumab in combination with EP in subjects receiving first-line therapy for ES-SCLC
Phase-2 portion: To estimate the improvement in overall survival (OS), 12-month survival and overall response rate (ORR) resulting from the addition of tarextumab to EP in subjects receiving first-line therapy for ES-SCLC
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Phase-2 portion: To correlate the treatment effect in PFS, OS, 12-month survival and ORR resulting from the addition of tarextumab to EP in subjects with Notch3, Hey2, Hes1, Hey1 and Hes6 expression
Phase-1b portion: To determine the safety and tolerability of tarextumab in combination with EP in subjects who are receiving first-line therapy for ES-SCLC
Phase-2 portion: To compare the safety and tolerability of tarextumab in combination with EP relative to EP alone in all subjects who are receiving first-line therapy for ES-SCLC
Statistical analyses concerning the secondary objectives for the phase-1b portion of this study will not be addressed in this SAP.
2.3. Exploratory Objective An exploratory objective of this study is:
Phase-1b and -2 portions: To describe the changes in exploratory pharmacodynamic biomarkers, including Notch pathway related genes and proteins and circulating tumor cells following tarextumab treatment
3. STUDY DESIGN AND PLAN The following descriptions of the study design and plan were copied from the study protocol. Since this SAP only covers analyses planned for the phase-2 portion of the study, some portions of the study design and plan related only to the phase-1b portion were omitted intentionally.
The study consists of a phase-1b lead-in portion to determine the MTD of tarextumab in combination with EP for 6 cycles followed by treatment with tarextumab alone until unacceptable toxicity or disease progression. The initial dose escalations of tarextumab will be conducted with etoposide and cisplatin. The dose of tarextumab will not exceed 15 mg/kg. Following the establishment of the highest tolerable dose of tarextumab in combination with etoposide and cisplatin, a cohort of 6 subjects will be treated at this dose in combination with etoposide and carboplatin. Once the safety and tolerability of tarextumab at this dose is also confirmed with etoposide and carboplatin, the protocol will transition to a phase-2, multicenter, randomized, placebo-controlled portion comparing the efficacy and safety of tarextumab at the highest tolerable dose in combination with EP for 6 cycles followed by single agent tarextumab relative to EP alone for 6 cycles in subjects receiving first-line therapy for ES-SCLC. However, if a DLT is observed in 2 or more subjects in the cohort of 6 subjects treated with the highest tolerable dose of tarextumab with etoposide and carboplatin, a new cohort of 3 to 6 subjects will be enrolled at the next lower dose level of tarextumab with etoposide and carboplatin. The highest tarextumab dose that is tolerable with both platinum options will be used in phase-2 portion of the study.
In phase-2 portion of the study, subjects may be treated with cisplatin or carboplatin as determined by the investigator prior to randomization. Alteration to the choice of platinum therapy is not permitted once the subject is randomized.
Etoposide 100 mg/m2 will be administered on Days 1, 2 and 3 along with cisplatin 80 mg/m2 for phase-1b and 75 mg/m2 for the phase-2 portion of the study or carboplatin to an AUC of 5 mg/mL/min on Day 1 of every 21-day cycle for 6 cycles, tarextumab or placebo will be given on Day 1 of every 21-day cycle prior to the administration of EP.
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Subjects may continue one of the chemotherapy drugs if the other is held or discontinued prior to completing 6 cycles of EP and prior to disease progression. Subjects should continue EP alone for a total of 6 cycles if tarextumab is held or discontinued prior to the completion of 6 cycles of EP. Subjects may continue study drug if one or both of the chemotherapy drugs is held or discontinued prior to completing 6 cycles of EP and prior to disease progression.
The phase-2 portion of the study may commence after the safety and tolerability of the highest tolerable dose of tarextumab has been confirmed in both cohorts of subjects with etoposide and cisplatin/carboplatin during phase-1b. The highest tarextumab dose that is tolerable with both platinum options will be used in the phase-2 portion of the study. For example: if tarextumab at 15 mg/kg is tolerable with etoposide and cisplatin, but not tolerable with etoposide and carboplatin; and tarextumab at 12.5 mg/kg is tolerable with etoposide and carboplatin, then tarextumab at 12.5 mg/kg will be the dose used in phase-2. The phase-2 portion includes a blinded treatment phase and follow-up phase. It is a multicenter, randomized, placebo-controlled portion evaluating the efficacy and safety of tarextumab in combination with etoposide and platinum therapy in subjects with previously untreated ES-SCLC. Subjects may be treated with cisplatin or carboplatin as determined by the Investigator prior to randomization. Alteration to the choice of platinum therapy is not permitted once the subject is randomized.
Approximately 135 evaluable subjects will be enrolled to the phase-2 portion of the study. Evaluable subjects are those who received at least one dose of study drug (either tarextumab or placebo).
Version 1.1 of standard response evaluation criteria in solid tumors (RECIST) criteria [Ref-1] was used to evaluate patients’ responses to treatment. RECIST response categories include complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). In addition to these four primary ratings, a patient’s response to treatment is classified as unevaluable (abbreviated NE) when no imaging/measurement is performed at a particular time point.
3.1. Blinded Treatment Phase Subjects who qualify for enrollment into the phase-2 portion of the study will be randomized in a 1:1 ratio to receive study treatment of EP with placebo or EP with tarextumab. The randomization will be balanced on the choice of platinum therapy (cisplatin versus carboplatin) and the prior use of whole brain radiation (WBR) or prophylactic cranial irradiation (PCI). Changing the choice of platinum therapy is not permitted once the subject is randomized. Treatment for each subject will begin on Cycle1, Day 1 (the first dosing day). Etoposide 100 mg/m2 will be given on Days 1, 2 and 3 and cisplatin 75 mg/m2 or carboplatin to an AUC of 5 mg/mL/min will be given on Day 1 of every 21-day cycle for 6 cycles. Subjects may remain in the blinded treatment phase to continue one of the chemotherapy drugs if the other is held or discontinued prior to completing 6 cycles of EP and prior to disease progression. For subjects who have study drug held or discontinued for tolerability reasons, EP chemotherapy should continue to the completion of 6 cycles. Subjects may continue study drug if one or both of the chemotherapy drugs is held or discontinued prior to completing 6 cycles of EP and prior to disease progression.
After the completion of 6 cycles of EP, subjects who do not have disease progression and have not had WBR or PCI prior to study entry and are good candidates for PCI according to the
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investigator should receive PCI within 8 weeks after the last dose of chemotherapy at a total dose of 25 Gy in 10 fractions. If subjects discontinue EP with treatment-related toxicities prior to completing 6 cycles and are good candidates for PCI per the investigator, PCI can be initiated at any time determined appropriate by the investigator. Subjects who do not receive PCI within 8 weeks after the last dose of chemotherapy can have PCI later during the study as determined by the investigator. Study drug (tarextumab or placebo) administration should continue at every 21-day cycle between the completion of chemotherapy and the initiation of PCI. PCI should not be initiated within 2 weeks of study drug administration and study drug will be held during the PCI treatment period. Subjects will resume study drug alone ≥14 days after completion of PCI, until disease progression or unacceptable treatment-related toxicities or withdrawal of consent. Subjects will discontinue study treatment if there is evidence of central nervous system (CNS) metastasis.
3.2. Follow-Up Subjects who discontinue study treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks (42 ±5 days) during follow-up until documented disease progression or initiation of new anti-cancer therapy, whichever is sooner. Additionally, subjects who are discontinued from study treatment will be followed for survival and any subsequent anti-cancer therapies. Survival follow-up information and subsequent anti-cancer therapies, including systemic therapies, surgery (resection of metastatic disease), and radiation therapy will be collected during telephone calls, through subjects medical records, and/or clinic visits every 3 months starting from the last study treatment until death, loss to follow-up, or study termination by the sponsor. The study staff may use a public information source (e.g., county records) to obtain information about survival status only.
4. DETERMINATION OF SAMPLE SIZE The following assumptions and methods for determining the sample size for the study were copied from the study protocol. Since this SAP only covers analyses planned for the phase-2 portion of the study, details on the determination of sample size for the phase-1b portion of the study have been omitted intentionally.
At the final analysis we will evaluate the effect of tarextumab on PFS in subjects in the intention to treat (ITT) population (defined in section 6.1). The final analysis will take place when 91 progression events have been observed or 10 months after the completion of enrollment whichever occurs first.
Denote the treatment effect in terms of the log of the hazard ratio (HR) by . The null hypotheses for testing homogeneity of PFS distributions across treatment arms is:
And the alternative hypothesis is:
The power and type-1 error rate for the log rank test of this hypothesis is presented in Table 1.
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Table 1. Progression-Free Survival: Power for the Alternative Hypothesis
Analysis 1 Analysis 2 Final Analysis Total Number of Events 61 76 91 Z-Statistic (reject the null) [1] 3.168 2.301 1.036 P-value (1 sided) 0.00077 0.011 0.15 Z statistic (reject the Alt) [2] -1.773 -1.486 -1.079 P-value (1 sided) 0.038 0.0690 0.1400 Cumulative Type 1 Error (1-sided) 8e-04 0.0107 0.1501 Cumulative Power HR=0.75 0.0204 0.1479 0.6318 HR=0.67 0.0543 0.2897 0.8090 HR=0.65 0.0687 0.3365 0.8460 HR=0.60 0.1204 0.4709 0.9194 HR=0.50 0.3223 0.7647 0.9884 Cumulative Probability of Stopping for Harm Alternative 4e-04 8e-04 0.0018 Null 0.0381 0.0762 0.1501 HR=1.33 (1/0.75) 0.2580 0.4246 0.6275 HR=1.49 (1/0.67) 0.4172 0.6170 0.8052 HR=2.00 (1/0.50) 0.8248 0.9412 0.9877 [1] The boundary for rejecting the null hypothesis for efficacy is obtained from the gamma(-16) alpha spending function. [2] The boundary for rejecting the null hypothesis for harm is obtained from the gamma(-4) alpha spending function.
With 91 events at the final analysis, there is 80% power with 0.15 type 1 error to detect an HR of 0.67. There is a 7.6% chance of stopping early for harm under the null hypothesis; a 42.5% chance of stopping early for harm if the HR=1.33 (1/0.75); a 61.7% chance of stopping early for harm if the HR=1.49 (1/0.67); and a 94.1% chance of stopping early for harm if the HR=2.00 (1/0.5).
Analyses 1 and 2 will take place at the last two quarterly safety review meeting of the Data Safety Monitoring Board (DSMB). The estimated numbers of events at these times are presented in Table 1. If the number of events differs from what is presented, then the efficacy and safety boundaries will be recalculated using the spending functions which are footnoted in Table 1.
Overall survival is a secondary endpoint in this study. An analysis of OS will take place at the time of each analysis for PFS as well as at the time that the final analysis of PFS takes place. The final analysis of OS will take place when there are 98 events or 6 months after the final analysis for PFS, whichever occurs first. Table 2 and Figure 1 present enrollment, PFS events and Deaths over time assuming a control hazard of progression beyond 9 months of 0.1386.
Table 2. Enrollment, Progressions and Deaths over Time – Control Hazard of Progression of 0.1386 Beyond 9 Months Study Time (months) 6 12 13 14 15 16 17 18 19 20 Cumulative Enrolment 22 77 85 89 91 105 119 133 134 134 Total PFS Events 5 31 38 43 49 55 62 69 75 80 Total PFS Events-2 [1] 6 35 42 48 54 61 68 76 82 87 Total Deaths 3 19 23 27 32 37 42 49 55 61 Total Deaths-2 [1] 4 22 27 32 37 42 49 56 63 69 Censored PFS (tarextumab) 1 5 6 7 8 9 10 11 12 13 Censored PFS (placebo) 1 4 5 6 7 8 9 9 10 11
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Study Time (months) 21 22 23 24 25 26 27 28 29 30 Cumulative Enrolment 134 134 134 134 134 134 134 134 134 134 Total PFS Events 85 90 94 96 97 98 99 99 100 100 Total PFS Events-2 [1] 92 98 101 103 104 104 105 105 105 106 Total Deaths 66 72 77 81 86 91 95 99 102 105 Total Deaths-2 [1] 75 81 86 91 96 100 104 108 111 114 Censored PFS (tarextumab) 14 15 15 16 16 16 16 16 16 17 Censored PFS (placebo) 12 12 13 13 13 13 13 13 13 13 [1] Total PFS Events-2 and Total Deaths-2 refer, respectively, to the expected numbers of progressions and deaths when tarextumab does not prolong progression or death.
Figure 1. Enrollment, Progressions and Deaths over Time – Control Hazard of Progression of 0.1386 Beyond 9 months
Calculations in Table 2 and Figure 1 take into account non constant hazards for PFS and OS described in Table 3 and Table 4, respectively. Estimates of non constant hazard are from Kaplan-Meier (KM) curves for PFS and Survival in Noda et al [Ref-2] and Hanna et al [Ref-3]. Regarding enrollment it was initially assumed that there is a ramp up time of 5 months with a starting enrollment of 4 subjects per months and that the maximum enrollment rate is 6 subjects per month. The enrollment in Table 10 and Figure 1 represents the observed enrollment up to January 2016 and the remaining enrollment is assumed to be 15 subjects per month.
The censoring rate was initially assumed to be 40% of the rate at which events occur in the control arm and 60% of the rate at which events occur in the tarextumab arm. When 79 PFS events accrued in the study, there were 39 censored observations for a censoring rate of 39/(39+79)=33%. This information was used to recalibrate the total number of events at the final analysis, the type 1 error rate and power.
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Table 3. Hazards for Piece-Wise Exponential Model of Progression Free Survival Period 0-5 months 5-7 months 7-8 months >8 months
% Change in Proportion without an event (Change in PFS)
0.50 (1.00 to 0.50)
0.50 (0.50 to 0.25)
0.50 (0.25 to 0.125)
0.50 (0.125 to 0.0625) 8-18 months [1] 8-11 months [2]
Hazard Control 0.1386 0.3466 0.6931 0.0693, 0.2310 Hazard Treatment 0.0901 0.2253 0.4505 0.0451, 0.1502 Hazard Ratio 0.65 0.65 0.65 0.65 [1] Noda et al [Ref-2] [2] Hanna et al [Ref-3]
Table 4. Hazards for Piece-Wise Exponential Model of Overall Survival Period 0-5 months 5-7 months 7-8 months >8 months
% Change in Proportion without an event
0.50 (1.00 to 0.50)
0.50 (0.50 to 0.25)
0.60 (0.25 to 0.10)
0.467 (0.15 to 0.08)
18-24 months [1] Hazard Control 0.07702 0.1155 0.1703 0.127 Hazard Treatment 0.05006 0.07509 0.1107 0.0825 Hazard Ratio 0.65 0.65 0.65 0.65 [1] Hanna et al [Ref-3]
We see from Table 2 that approximately 70% of the 98 deaths required for the final analysis of survival are expected to be observed at the time of the final analysis for PFS. Table 5 presents the power to detect benefit in OS for several HRs assuming that type 1 error is controlled at the 0.15 level and additional analyses take place at approximately 50%, 67% and 83% of full information. These additional analyses will take place at the quarterly DSMB review meetings. If the actual number of events at the review meetings differs from what is presented in the table, the efficacy and safety boundaries will be recalculated using the spending functions footnoted in Table 5.
Table 5. Overall Survival: Power for the Alternative Hypothesis
Analysis 1 Analysis 2 Analysis 3 Final Analysis Total Number of Events 49 66 81 98 Z-Statistic (reject the null) [1] 3.889 3.174 2.333 1.036 P-value (1 sided) 0.000050 0.00075 0.0098 0.15 Z statistic (reject the Alt) [2] -2.1 -1.848 -1.511 -1.082 P-value (1 sided) 0.018 0.032 0.0658 0.139 Cumulative Type 1 Error (1-sided) 1e-04 8e-04 0.0099 0.1501 Cumulative Power HR=0.75 0.0020 0.0226 0.1499 0.6511 HR=0.682 0.0054 0.0530 0.2711 0.8047 HR=0.65 0.0086 0.0777 0.3471 0.8637 HR=0.60 0.0178 0.1365 0. 4869 0.9324 HR=0.50 0.0717 0. 3610 0. 7846 0. 9918 Cumulative Probability of Stopping for Harm Alternative 3e-04 5e-04 9e-04 0.0019 Null 0.0179 0.0381 0.0744 0.1501 HR=1.33 (1/0.75) 0.1372 0.2660 0.4332 0.6470
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Analysis 1 Analysis 2 Analysis 3 Final Analysis HR=1.47 (1/0.682) 0.2235 0.4037 0.6007 0.8000 HR=2.00 (1/0.50) 0.6278 0.8426 0.9496 0.9911 [1] The boundary for rejecting the null hypothesis for efficacy is obtained from the gamma(-16) alpha spending function. [2] The boundary for rejecting the null hypothesis for harm is obtained from the gamma(-4) alpha spending function.
With 98 deaths at the final analysis, there is 80% power with 0.15 type 1 error to detect a HR of 0.682. There is a 7.4% chance of stopping early for harm under the null hypothesis, a 43.3% chance of stopping early for harm if the HR=1.33 (1/0.75); a 60.1% chance of stopping early for harm if the HR=1.47 (1/0.682); and a 95.0% chance of stopping early for harm if the HR=2.00 (1/0.5).
5. GENERAL ANALYSIS CONSIDERATIONS The statistical analyses will be reported using summary tables, figures and listings (TFLs). Unless otherwise noted, all statistical testing will be two-sided and will be performed at the 0.05 level of significance.
Continuous variables will be summarized with the number of non-missing values, estimated means, standard deviations, medians, 25th and 75th percentiles, and observed minimum and maximum values.
Categorical variables will be summarized by counts and by percentages. The percentage of patients within a category will be displayed in parentheses rounded to the nearest tenth of one percent. However, when the number of patients within a category is 0, then the percentage (i.e., 0.0%) will be omitted.
Time-to-event variables will be summarized by KM estimates of quartiles, observed minimum and maximum values, and the number of censored observations. The hazard will be estimated by the sum of all individual follow-up times in days divided by 365.25.
Any durations of time expressed in months will be reported in proportional “months” according to the formula
months days.
Summary tables will be presented by treatment group. Individual subject data will be presented in data listings.
The analyses described in this plan are considered a priori, in that they have been defined prior to database lock and prior to breaking the treatment blind. If any a posteriori analyses (i.e., analyses not included in this SAP) are performed, they will be identified as such in the CSR where the objective and rationale for executing any a posteriori analyses will be documented.
5.1. Analysis Software In general, data analyses and tabulations will be executed using SAS® version 9.2 or higher. SAS® programing statements will be validated by an independent programmer and SAS® output will undergo a senior-level statistical review to confirm that that all data manipulations and calculations are accurate and statistically valid methods have been implemented. Checks will be made to ensure accuracy and consistency with this plan and within and between TFLs. Upon
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completion of validation and quality-review procedures, all documentation will be collected and filed by the project statistician or designee.
5.2. Baseline Values Unless otherwise noted, baseline is defined as the last non-missing value recorded prior to the first dose of study drug. Therefore, data collected during any unscheduled visits will be used in the determination of baseline values, as applicable.
5.3. Missing Values No imputations will be made for missing values. Summaries will be based on observed data only.
5.4. Subgroup Analyses Plans for analyses of subgroups based on the presence or absence of anti-tarextumab antibodies are presented in section 11.7 below.
No analyses by baseline characteristics or study center are planned.
Subgroup analyses by baseline Notch3, Hes1, Hey2, Hey1 and Hes6 expression levels are not planned, but the impact these potentially important covariates have on the efficacy of tarextumab will be assessed through statistical modeling (see sections 8.1, 8.3, 8.6 and 8.7).
5.5. Multiple Comparisons/Multiplicity A gamma(-12) spending function will be used to control the type-1 error for the assessment of efficacy and a gamma(-4) spending function will be used to control the type-1 error for harm arising from multiple analyses of PFS (see Table 1). The same spending functions will be used to control for multiplicity when testing OS (see Table 5).
6. ANALYSIS DATA SETS The analysis set for the phase-2 portion of the study will include data from all subjects who were randomized in the phase-2 portion to receive either tarextumab or control. Data from subjects who were enrolled in the phase-1b portion of the study will be excluded from the analysis set.
The planned data cut for the formal final analysis of PFS will take place at the point where 91 PD events have occurred or 10 months after the completion of enrollment, whichever occurs first. However, the actual data cut for the final formal analysis of PFS may be extended beyond 10 months after the completion of enrollment for reasons concerning study conduct (e.g., if patients are randomized but not treated). This will ensure that the study will have 81% power to detect an HR of 0.67 (improvement in median PFS from 4.8 months to 7.2 months) with an associated total one sided type-1 error rate of 0.15 (see section 4).
When the data cut for the formal analysis of PFS is taken, the following rules will be applied to determine which data are included in statistical analyses and data summaries. The goal of these data filtering rules is to ensure that that only certain data records occurring after the cutoff date 01-DEC-2016 are included.
1. No filter will be applied to the Death Report CRF or Follow Up After Discontinuation of Study Treatment CRF.
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2. On CRF pages with a start/stop date (such as AE and CM), the data will be kept if either the start or stop date is on or prior to the cut off date. Note: if the start date is on or prior to the cut off, the record will be retained, therefore there may be stop dates that appear in listings that are post the cut off date.
3. If the outcome for an AE is death, the record will be retained even if the death occurred after the cut off date. Note: the record will be kept only for the purpose of preserving the death date (for efficacy analysis). The AE however will not be used in summaries of AEs.
4. In the event a partial date is reported and there is a chance the event/occurrence could be on or prior to the cutoff date, then that record will be kept for analyses and summaries. For instance, a record with a partial date of “2016” would be kept for analysis. Likewise, a record of “DEC-2016” would also be kept since the actual event date could have been 01DEC2016.
An additional data filtering rule specific to analyses of PFS and DOR is that deaths reported on the Death Report CRF and AE CRF where death is reported after the cut off date will not be considered.
Additional data filtering rules specific to analyses of OS are:
1. Death reported on Death Report CRF and AE CRF (end date of AE), regardless of date will be included in OS analyses. That is deaths reported after the cutoff date will not be filtered.
2. If the date of death reported on the Death Report CRF and an AE CRF is not the same, the date of death reported on the Death Report CRF will be used. SynteractHCR will notify the sponsor of the discrepancy.
3. The Follow-Up Discontinuation CRF does not explicitly collect date of death. The form only collects the Date of Survival Assessment and Last Known Survival Date. If a patient’s death is reported only on the Follow-Up Discontinuation CRF, then SynteractHCR will notify the sponsor, and the sponsor will advise SynteractHCR how to proceed.
Upon request, a listing of death dates can be generated to show which patients have died and which CRF page was used to acquire the death date.
The planned data cut for the final analysis of OS will be 6 months after the data cut for PFS or when 98 deaths have been observed, whichever occurs first. Once again, the actual data cut for the final formal analysis of OS may be extended beyond 6 months after the PFS data cut for reasons concerning study conduct.
6.1. Analysis Populations The following five groups of study patients will be used for statistical analyses.
1. The ITT patient population includes all patients randomized to receive study drug regardless of whether they actually received study drug and regardless of whether evidence is found indicating they failed to meet study inclusion/exclusion criteria or had other protocol violations. When the ITT patient population is analyzed, patients are grouped according to
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their randomized treatment regardless of actual treatment received. The ITT patient population is the analysis population for demographics and baseline characteristics and for all statistical inference and primary tests of hypotheses related to efficacy endpoints.
2. The safety patient population is the subset of ITT patients who received at least one dose of study drug. When the safety patient population is analyzed, patients are grouped according to actual treatment received. Tarextumab is considered a patient’s “treatment received” in the safety patient population if the patient received at least one dose of tarextumab (complete or incomplete dose) any time during the study. The safety patient population is the analysis population for all analyses of safety data.
3. The per-protocol (PP) patient population is the subset of safety patients who either (a) have at least one response evaluation on study, or (b) die prior to their first scheduled response evaluation. When the per-protocol patient population is analyzed, patients are grouped according to actual treatment received. The per-protocol population is used for sensitivity (secondary, supportive) analyses of efficacy endpoints.
4. The pharmacokinetic (PK) patient population is comprised of all subjects who received at least one complete dose of tarextumab and have at least one post-dose PK sample.
5. The immunogenicity patient population is comprised of all subjects who had a baseline and one or more follow-up samples obtained for quantifying anti-tarextumab antibody.
7. SUMMARIES OF PATIENT CHARACTERISTICS
7.1. Subject Disposition Subject disposition information will be summarized for all subjects by treatment arm. Summaries will include the number of subjects randomized, the number of subjects in each analysis population, the primary reason for stopping each study drug (randomized treatment [tarextumab or placebo], selected platinum therapy [cisplatin or carboplatin] and etoposide), and the primary reason for withdrawing from the study.
The physician’s choice of platinum therapy (cisplatin or carboplatin) was used as a stratification variable by the dynamic randomization system. The actual platinum received (as documented on earliest Platinum Therapy Infusion CRF [e.g., Cycle 1, Day 1]) will be summarized in a 2x2 frequency table against the platinum-therapy strata under which a patient was randomized.
7.2. Protocol Deviations Protocol deviations will be collected and provided by the sponsor. Major protocol deviations that could potentially affect the integrity of efficacy/safety analysis results will be identified prior to database lock and categorized. Major protocol deviations categories may include, but are not limited to enrollment violations, dosing violations, prohibited concomitant therapy violations, and continuation of therapy when treatment should have been discontinued. Major protocol deviations will be summarized by deviation category and treatment group.
7.3. Demographics and Baseline Characteristics Demographic variables include age, sex, child-bearing potential for females, ethnicity and race. Age will be calculated in years relative to the informed consent date. Baseline characteristics include height, weight, body mass index (BMI), smoking history and Eastern Cooperative
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Oncology Group (ECOG) performance status. Descriptive statistics will be presented for age, height and weight; and frequency counts and percentages will be presented for sex, child-bearing potential, ethnicity, race, smoking history (never smoked, ex-smoker, or current smoker) and ECOG performance status. Demographic and baseline characteristics will be summarized for the ITT, safety, PP and immunogenicity populations.
ES-SCLC history, including time since ES-SCLC diagnosis, histological/cytological type (small cell only, mixed type, or other), anatomical location of primary tumor, and number of disease sites (1, 2 or ≥3) at study entry will be summarized by treatment group for the ITT and safety populations. The time from ES-SCLC diagnosis to randomization will be quantified in months according to the formula shown in section 5. Summary statistics for baseline values of total tumor length (abbreviated SLD for sum of longest diameters) will be included in the analyses of efficacy endpoints.
Baseline levels of Notch3, Hes1, Hey2, Hey1 and Hes6 will be summarized as a continuous variable in the ITT, safety and per-protocol populations.
Prior therapies (surgeries and radiotherapies) for ES-SCLC will be summarized for the ITT and safety populations.
Patients’ medical and surgical histories will be displayed in a data listing.
8. EFFICACY ENDPOINTS Primary analyses of efficacy endpoints will use data from the ITT population. Additional efficacy analyses will be performed using data from only the PP population, but these analyses are considered secondary.
Efficacy endpoints include investigator-assessed PFS, assessment of SLD as a continuous variable, ORR defined as the proportion of patients achieving a CR or PR, duration of response (DOR), sites of progression, OS and landmark survival at 180, 360, 540 and 720 days.
As mentioned in section 5 above,
Continuous variables will be summarized with the number of non-missing values, estimated means, standard deviations, medians, 25th and 75th percentiles, and observed minimum and maximum values.
Categorical variables will be summarized by counts and by percentages. The percentage of patients within a category will be displayed in parentheses rounded to the nearest tenth of one percent. However, when the number of patients within a category is 0, then the percentage (i.e., 0.0%) will be omitted.
Time-to-event variables will be summarized by KM estimates of quartiles, observed minimum and maximum values, and the number of censored observations. The hazard will be estimated by the sum of all individual follow-up times in days divided by 365.25.
8.1. Progression-Free Survival On study tumor assessments are those that meet the following criteria:
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1. No gap of >91 days between successive tumor assessments among those on or prior to the on study tumor assessment. (Note: a tumor assessment for which “Not Evaluated” is entered into the database does not qualify as a tumor assessment.)
2. No prior initiation of non-protocol anticancer therapy.
PFS, the primary endpoint of the study, is defined as the time from randomization (Day 1) until the first occurrence of death or disease progression based on investigator assessments of tumor response per the RECIST criteria. Progressions that are not determined from on study tumor assessments as well as deaths occurring more than 49 days from the last on-study tumor assessment are not treated as progression events. Subjects without a progression event will be censored at their last on study tumor assessment.
In addition two special cases will be handled in a manner consistent with the above rules as follows:
1. Patients whose first tumor assessment is >91 days from randomization will be censored on the date of randomization with a PFS of 1 day.
2. Patients who never had an on study tumor assessment and who did not die within 49 days (the scheduled time between tumor assessments plus 7 days) after randomization will be censored on the date of randomization with a PFS of 1 day.
The KM method will be used to estimate the proportions of subjects over time without progression or death and the median progression-free survival time. KM curves will be plotted by treatment group. The 95% confidence intervals for median progression-free survival time will also be calculated for each treatment arm. The p-value for treatment effect will be generated using a stratified log rank test using platinum choice (cisplatin or carboplatin; see page 6) and prior treatment modality (WBRT or PCI) as stratification factors. The HR and its 95% confidence interval will be estimated using a Cox proportional hazards (PH) model with main effects for treatment and the aforementioned stratification factors.
According to the study design, administrations of randomized treatment (tarextumab or placebo only; without EP) may continue in 21-day cycles from the completion of 6 cycles of EP until the initiation of PCI. The following analysis of PFS will be conducted in order to determine if there is a treatment benefit when tarextumab is administered in combination with EP. Subjects who have not progressed will have their PFS censored 35 days (the scheduled time for 1 treatment cycle plus 7 days) following the last dose of Carboplatin/Cisplatin or EP. KM and Cox PH analyses will be the same as those described above.
The impact of the biomarkers Notch3, Hes1, Hey2, Hey1 and Hes6 on PFS will be evaluated with a Cox PH model with treatment, biomarker and treatment-by-biomarker interaction included in the model as independent variables. A separate Cox PH model will be used for each biomarker.
Sensitivity analyses for PFS include replicating the primary log-rank analysis using the PP population and unstratified log-rank tests using the ITT and PP populations.
The planned timing for the primary analysis of PFS is stated in section 5.5 above.
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8.2. Total Tumor Length Total tumor length is the sum of the longest diameters (SLD) for the target lesions as defined by RECIST criteria. Standard summary statistics for a continuous variable (identified in section 5) will be computed for SLD at baseline and the Cycle-3, Day-1 (C3D1) and Cycle-5, Day-1 (C5D1) assessments. Summary statistics will also be presented for changes from baseline at the C3D1 and C5D1 tumor assessments. Ninety-five percent confidence intervals for the mean SLD at each time point will also be computed. Two analysis of covariance (ANCOVA) models for SLD will be used to test the hypothesis that there is no difference between treatment arms with regard to changes in tumor length from baseline at the C3D1 assessment.
The difference between the follow-up and baseline SLD (e.g., SLDC3D1 – SLDbaseline) will be the dependent variable in the first ANCOVA model. Treatment, platinum choice (cisplatin versus carboplatin) and prior treatment modality (WBRT or PCI) will be categorical factors in the model, and SLDbaseline will be included as a continuous covariate.
The log of the ratio of follow-up to baseline SLD (e.g., log [SLDC3D1/SLDbaseline]) is the dependent variable in the ANCOVA model. Treatment, platinum choice and prior treatment modality will be categorical factors in the model, and log SLDbaseline will be included as a continuous covariate.
Missing values will not be imputed.
Separate but similar analyses will be performed for changes in tumor length from baseline at the C5D1 assessment.
A waterfall plot of best percent change in SLD across all tumor assessments relative to baseline will be presented.
Rates of change in SLD from baseline to C3D1, C5D1 and at progression will be evaluated.
The rate of change in SLD at CxD1 is defined as
where d2 is the number of days between the baseline assessment (Day 1) and the CxD1 assessment.
Rate of change in SLD at CxD1 will be missing for subjects who did not have a RECIST assessment corresponding to the CxD1 visit.
The rate of change in SLD from its on-study nadir to progression is defined as
where d1 is the number of days between the on-study SLD nadir and progression.
Rate of change in SLD at progression will be missing for subjects who did not have a RECIST assessment of PD on study and for subjects whose on-study SLDnadir = 0.
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Comparisons of these rates of change between the two treatment arms will be made using an analysis of variance (ANOVA) model with treatment, platinum choice (cisplatin versus carboplatin) and prior treatment modality (WBRT or PCI) as categorical independent variables.
8.3. Overall Response Rate A patient’s best overall response is defined as the best investigator-assessed RECIST response to treatment category recorded since the start of the treatment. The hierarchy of response ratings, best to worst, is CR, PR, SD, PD, followed by NE. The numbers and percentages of subjects achieving each of these response categories will be summarized within treatment group.
The ORR, defined as the proportion of patients achieving a CR or PR, and its 95% confidence interval will be computed within treatment group. The p-value for equality between treatment groups will be calculated for the two groups using a logistic regression model including treatment, platinum choice (cisplatin versus carboplatin) and prior treatment modality (WBRT or PCI) as categorical independent variables. Patients without any post-baseline tumor assessments will be classified among those never achieving a CR or PR.
The impact of the biomarkers Notch3, Hes1, Hey2, Hey1 and Hes6 on ORR will be evaluated with a logistic regression model with treatment, biomarker and treatment-by-biomarker interaction included in the model as independent variables. A separate logistic regression model will be used for each biomarker.
8.4. Duration of Response Analyses of DOR include only patients who achieved a CR or PR; patients failing to achieve a CR or PR during the study are omitted from analyses of DOR. If the number of patients achieving a CR or PR is not sufficient to produce meaningful KM curves, then the planned analyses for DOR may be abandoned.
DOR is defined as the number of days from the first CR or PR until the first occurrence of death or disease progression based on investigator assessments of tumor response per the RECIST criteria. Progressions that are not determined from on study tumor assessments as well as deaths occurring more than 49 days from the last on-study tumor assessment are not treated as progression events. Subjects achieving a CR/PR but without a subsequent progression event will be censored at their last on study tumor assessment.
In addition two special cases will be handled in a manner consistent with the above rules as follows:
1. Patients whose next tumor assessment (following the first CR/PR) is >91 days after the first CR/PR will be censored on the date of the first CR/PR with a DOR of 1 day.
2. Patients who never had an on study tumor assessment after the first CR/PR and who did not die within 49 days (the scheduled time between tumor assessments plus 7 days) after the first CR/PR will be censored on the date of first CR/PR with a DOR of 1 day.
The KM method will be used to estimate the proportions of CR/PR patients over time who have not experienced RECIST disease progression and the median DOR. KM curves will be plotted and 95% confidence intervals for median DOR will also be calculated for each treatment arm. The HR, its 95% confidence interval and the p-value for testing the statistical significance of the
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treatment effect will be generated using a Cox PH model with main effects for treatment, platinum choice (cisplatin versus carboplatin) and prior treatment modality (WBRT or PCI).
8.5. Sites of Progression Sites of progression will be categorized as stemming from (1) a new lesion or (2) progression of an existing lesion. Treatment-group distributions based on this binomial categorization will be tested using a chi-square test. Then “new lesions” will be further categorized by anatomical site. Patients with new lesions at multiple anatomical locations will be classified as a single category. The resulting multinomial distributions will also be compared across treatment groups using a chi-square test.
8.6. Overall Survival OS is defined as the number of days from randomization (Day 1) until death. The following rules will be used to define censored observations and censoring times for OS.
1. A patient for whom no death date is reported will have OS censored on the last contact date (defined on page 6). When evaluating the last contact date using the ‘Follow-Up After Discontinuation of Study Treatment’ CRF, both of the ‘date of survival assessment’ (if checked ‘alive’ for ‘subject status’) and the ‘last known survival date’ (if checked ‘alive or ‘lost to follow-up’ for ‘subject status) will be considered.
2. Patients lacking data after randomization who do not die have their event time censored on the date of randomization with duration of 1 day.
3. All patients alive on the date of the 98th sequential patient death will have their OS censored on the day following the date on which the 98th patient died. All patient deaths will be counted towards the total of 98, independent of which treatment arm the deceased patients were randomized to.
The KM method will be used to estimate survival proportions over time. KM survival curves will be plotted and 95% confidence intervals for median OS will also be calculated for each treatment arm. The HR, its 95% confidence interval and the p-value for testing the statistical significance of the treatment effect will be generated using a Cox PH model with main effects for treatment, platinum choice (cisplatin versus carboplatin) and prior treatment modality (WBRT or PCI).
OS will also be analyzed separately for two subsets of ITT patients defined by platinum choice (cisplatin or carboplatin). In this case, the p-value for testing the statistical significance of the treatment effect will be generated using a Cox PH model with main effects for treatment and prior treatment modality only.
The impact of the biomarkers Notch3, Hes1, Hey2, Hey1 and Hes6 on OS will be evaluated with a Cox PH model with treatment, biomarker and treatment-by-biomarker interaction included in the model as independent variables. A separate Cox PH model will be used for each biomarker.
The planned timing for the primary analysis of OS is stated in section 5.5 above.
8.7. Landmark Survival KM estimates of OS at 180, 360, 540 and 720 days will be summarized. Comparisons between the two treatment groups will be made using independent Z tests.
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9. EXPLORATORY ANALYSES An exploratory analysis was undertaken by the sponsor using blinded data to examine the relationship between PFS and the Notch pathway markers HES1, HES6 and NOTCH3. The biomarker values were normalized so that the distributions had mean 0 and variance 1, then a Cox PH model was fit using the three main effects, the three two-way interactions, and the three-way interaction as independent variables. Estimated coefficients are show in Table 6.
Table 6. Cox PH Model between Progression-Free Survival and Three Biomarkers
Independent Variable Estimated Coefficient
Exponentiated Coefficient
Standard Error Z-Score P-Value
HES6 0.17396 1.190 0.192 0.9059 0.3700 HES1 0.00154 1.002 0.134 0.0115 0.9900 NOTCH3 0.01248 1.013 0.189 0.0660 0.9500 HES6*HES1 0.68087 1.976 0.241 2.8300 0.0047 HES6*NOTCH3 –0.56935 0.566 0.247 –2.3021 0.0210 HES1*NOTCH3 0.15654 1.169 0.191 0.8215 0.4100 HES6* HES1*NOTCH3 1.07604 2.933 0.357 3.0175 0.0025 Model notes: n=89 (56 observations deleted due to missing values); number of events=58; Likelihood ratio test=16.3 (7 degrees of freedom); p=0.0222
Judging statistical significance at the two-sided 0.05 level, the two statistically significant terms which included NOTCH3 were used to establish a NOTCH-3-ralated PFS index (N3RPI).
Patients were then split into two groups (High N3RPI or Low N3RPI) based on whether their score was above or below the median N3RPI (0.066), respectively. A patient whose N3RPI was equal to the median was placed into the Low N3RPI group. Patients in each of these two groups were then split into two additional groups (High NOTCH3 or Low NOTCH3) based on whether their score was above or below the overall median NOTCH3 value (–0.046), respectively. A patient whose NOTCH3 was equal to the median was placed into the Low NOTCH3 group.
The KM curves for PFS and for OS in these four subgroups are presented in Figure 2 and Figure 3, respectively. For patients with an N3RPI above the median N3RPI (i.e., High N3RPI), the difference in PFS between the High and Low NOTCH3 groups is associated with a p-value of 0.09.
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Figure 2. Progression-Free Survival Kaplan-Meier Curves for Patients with High and Low N3RPI
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Figure 3. Overall Survival Kaplan-Meier Curves for Patients with High and Low N3RPI
It is noteworthy that high NOTCH3 is trending to be beneficial for patients with low N3RPI, whereas high NOTCH3 appears to be detrimental when N3RPI is high. This prompted the exploratory hypothesis that NOTCH 3 inhibition with tarextumab will improve PFS and OS in patients who have high N3RPI. In the case where N3RPI is high, tarextumab may be able to reduce the detrimental effects associated with high Notch 3 expression.
The following exploratory analyses will be carried out to test this hypothesis. The analysis population (ITT or per-protocol) will be divided into two N3RPI groups: High N3RPI and Low N3RPI (as defined above). Independent Cox PH models will be fit to data from each of the two groups. The models will include effects for treatment (tarextumab or placebo), NOTCH3 value, and the interaction between treatment and NOTCH3. The treatment HR and a 95% CI for the HR will be estimated at the quartiles of the NOTCH3 distribution. The same analysis will be carried out for “high” and “low” patient subgroups based on each of the biomarkers (Hes1, Hes6, Hey1 and Hey2).
10. PHARMACOKINETIC ENDPOINTS Investigating the PK of tarextumab in combination with EP is an objective of this study, but a detailed analysis plan is outside the scope of this document. Therefore, no PK analyses are discussed here.
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11. SAFETY ENDPOINTS Analyses of safety endpoints will use data from the safety population. Safety endpoints listed in the study protocol include adverse events (AEs), serious adverse events (SAEs), clinical laboratory parameters, and results from testing for anti-tarextumab antibodies. Other safety endpoints include vital signs and electrocardiogram (ECG) results.
11.1. Treatment Cycles and Dosing Dosing with tarextumab (or placebo), etoposide and EP will be summarized by the number of cycles of treatment administered (duration of treatment), the number of doses of each study medication, and the extent of exposure to each study medication. Placebo exposure will be summarized in tarextumab-equivalent units, that is, by the number of milligrams of tarextumab the placebo “replaced” during treatment-blinded dosing.
Body surface area (BSA) is determined for each visit. The latest assessment of BSA on or before each visit will be used to determine the protocol-specified amount of drug (mg) in a dose.
11.1.1. Dose Intensity Dose intensity is defined as the total dose a patient actually received divided by the total dose the patient should have received had there been no missed doses, dosing delays or dosage reductions.
Dose intensityTotal amount of drug received (mg)
protocol-specified, planned amount of drug (mg)
The actual amount of drug received is obtained from the dosing records.
The protocol specified amount of drug to be received for each treatment is provided below.
Etoposide The number of doses of Etoposide that should be administered per protocol is
321 21 21Etop
Stop Start Stop Start Stop Startfloor h floor ,
where
1 if 21 x 0( ) 2 if 21 x 1
3 if 21 x 2Etoph x
Start is the date of the first dose of treatment. Stop is the last dose of treatment.
The amount of drug contained in a dose of Etoposide is 2100 / BSAmg m
Carboplatin/Cisplatin/Study Drug The number of doses of Carboplatin, Cisplatin or Study Drug that should be administered per protocol is
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121 21 21
Stop Start Stop Start Stop Startfloor h floor ,
where
( ) 1 if 21 x 0h x
Start is the date of the first dose of treatment and Stop is the last dose of treatment for the respective drugs. Treatment period is (last treatment date – first treatment date + 2), allowing 2 extra days to cover any following early visits.
The mg amount of drug contained in a dose of Carboplatin is
AUC of 5 ( 25)GFR
The mg amount of drug contained in a dose of Cisplatin is 280 /mg m BSA
The amount of drug contained in a dose of study drug is
15 / weightmg kg
Weight, BSA and GFR are to be determined at each visit. Use the latest weight, BSA and/or GFR on or before each dose to determine the amount of drug (mg) in a dose.
11.1.2. Dosing Compliance Dosing compliance is defined as the ratio of the number of doses administered to the number of doses planned according to the schedule outlined in the study protocol.
Dosing compliance
where Nplanned is the number of doses planned according to the schedule outlined in the study protocol and Nadministered is the number of doses the patient received.
Dosing compliance will be summarized as a continuous variable (see Section 5) and by the numbers of patients with 0% to <20%; 20% to <40%; 40% to <60%; 60% to <80%; 80% to <100%; and 100% compliance. The reasons for delaying and/or withholding doses randomized study drug, selected platinum agent and etoposide will also be summarized.
11.2. Adverse Events Reported AE terms will be mapped to preferred terminology using Medical Dictionary for Regulatory Activities (MedDRA) version 17.1. All reported events will appear in AE listings, however only treatment-emergent adverse events will be summarized. A treatment-emergent adverse event (TEAE) is an AE that starts or increases in severity any time after the first administration of any randomized study drug (i.e., tarextumab or placebo) up to 30 days following the last administration of any study drug. AE severity was rated by the investigator according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 criteria.
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A high-level safety summary will display the numbers of patients within each treatment arm who experience one or more AEs in each of the following categories:
All TEAEs regardless of severity or presumed relationship to study drug
TEAEs judged related to tarextumab/placebo
TEAEs judged related to etoposide
TEAEs judged related to platinum therapy (cisplatin or carboplatin)
TEAEs judged related to any study drug
Treatment-emergent SAEs regardless of severity or presumed relationship to study drug
Treatment-emergent SAEs judged related to tarextumab
Treatment-emergent SAEs judged related to EP
Treatment-emergent SAEs judged related to any study drug
TEAEs leading to a delay/interruption in the administration of study drug
TEAEs leading to a reduction in the protocol-specified dose of study drug
TEAEs leading to discontinuation of study drug
TEAEs leading to withdrawal from the study
TEAEs leading to death The base summary of TEAEs will show treatment-arm incidence rates for each MedDRA primary system organ class (SOC) and/or preferred term (PT) sorted by descending incidence in the tarextumab treatment group. A separate summary will be produced for each of the AE subsets listed above. Additional summaries will be produced by CTCAE severity grade. Patients may have more than one TEAE per MedDRA SOC and/or PT. At each level of summarization, a patient is counted once if he or she reported one or more TEAEs at that level. In AE summaries by CTCAE severity grade, patients will be classified according to the highest reported CTCAE severity for a qualifying event.
11.3. Clinical Laboratory Parameters Clinical laboratory results (serum chemistry, hematology, coagulation and urinalysis) will be valued using conventional units of measurement and summarized by treatment group using descriptive statistics for baseline, maximum post baseline, minimum post baseline, and last observed values. Changes from baseline will also be summarized. All clinical laboratory results will be listed by patient.
The numbers of patients shifting from a ‘low’ or ‘normal’ test result at baseline to ‘high’ result at any post-baseline assessment will be summarized, as will the numbers of patients shifting from a ‘normal’ or ‘high’ result at baseline to ‘low’ result post baseline. Laboratory parameters with a CTCAE grading scale will be summarized in Range Change Abnormal (RCA) tables which categorize patients according to (1) their most extreme post-baseline severity grade, and (2) the severity grade at their last post-baseline evaluation. Parameters with a CTCAE grading scale for high values and a second scale for low values will be summarized in both directions. Some
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urinalysis parameters with categorical outcomes will be summarized with the numbers of patients shifting from normal at baseline (e.g., negative or absent) to an abnormal result post baseline (e.g., positive or present).
11.4. Vital Signs Vital signs (systolic and diastolic blood pressures, pulse, body temperature and respiration rate) will be summarized by treatment group using descriptive statistics for baseline, maximum post baseline, minimum post baseline, and last observed values. Changes from baseline will also be summarized. All vital signs will be listed by patient.
The numbers of patients with a result above the normal range at any post-baseline assessment will be summarized, as will the numbers of patients with a result below the normal range at any post-baseline visit. Normal ranges are:
Systolic blood pressure: 90-120 mm Hg
Diastolic blood pressure: 60-80 mm Hg
Pulse rate: 60-100 beats/minute
Body temperature: 97.8-99.1 °F
Respiratory rate: 12-18 breaths/minute
11.5. Electrocardiogram Results ECG results (QRS duration, PR interval and QTc Interval) will be summarized by treatment group using descriptive statistics for baseline, maximum post baseline, minimum post baseline, and last observed values. Changes from baseline will also be summarized. All ECG results will be listed by patient.
The numbers of patients with a result above the normal range at any post-baseline assessment will be summarized, as will the numbers of patients with a result below the normal range at any post-baseline visit. Normal ranges are:
QRS duration: 80-100 msec
PR interval: 120-200 msec
QTc interval (Bazett or Fridericia formula): ≤430 msec for males; ≤450 msec for females The numbers of QTc values in the ranges <480 msec; 480-500 msec; and >500 msec will be presented for the categories baseline, worst (maximum) post-baseline assessment, and last post-baseline assessment.
The overall clinical interpretation of each ECG acquisition will be classified on the ordinal scale normal, abnormal but not clinically significant, and abnormal with clinical significance. Overall clinical interpretation will then be summarized (1) for the categories baseline, worst (maximum) post-baseline assessment, and last post-baseline assessment and (2) in a shift table pairing the baseline and most extreme post-baseline classifications.
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11.6. ECOG Performance Status ECOG performance status will be summarized (1) for the categories baseline, minimum post-baseline value, maximum post-baseline value, and last post-baseline value and (2) in a shift table pairing the baseline assessment and most extreme post-baseline values.
11.7. Immunogenicity The incidence of anti-tarextumab antibody development in the tarextumab treatment group will be summarized with counts and proportions. In addition, the impact of detectable anti-tarextumab antibodies and neutralizing anti-tarextumab antibodies on the efficacy of tarextumab will be assessed by summarizing PFS and OS in the subgroups of patients with and without these anti-tarextumab antibodies. The impact of detectable anti-tarextumab antibodies and neutralizing anti-tarextumab antibodies on the safety of tarextumab will be assessed by comparing AE incidence rates in the subgroups of patients with and without these anti-tarextumab antibodies. However, these subgroup analyses may not be carried out if the number of subjects with or without anti-tarextumab antibodies does not provide reasonable estimates of PFS and ORR.
11.8. Prior and Concomitant Medications Medications recorded on case report forms will be mapped to Anatomical/Therapeutic/Chemical (ATC) classes and preferred names in the World Health Organization (WHO) Drug Dictionary Enhanced (version March 1, 2014).
Prior and concomitant medications will be summarized for each treatment group by WHO ATC class and preferred name. Patients may have used more than one prior/concomitant medication per ATC class and preferred name. At each level of summarization, a patient is counted once if he or she reported one or more medications at that level. Summaries will be ordered by descending order of incidence of ATC class and preferred name within each ATC class. All prior and concomitant medications will be listed by patient.
12. REFERENCES 1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid
tumors: Revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
2. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002;346(2): 85-91.
3. Hanna N, Bunn PA Jr, Langer C, et al. Randomized Phase III Trial Comparing Irinotecan/Cisplatin With Etoposide/Cisplatin in Patients With Previously Untreated Extensive-Stage Disease Small-Cell Lung Cancer. J Clin Oncol. 2006;24(13):2038-2043.
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Appendix A. List of Tables, Figures and Listings
List of Tables
Table Number
Table Description
14.1 DEMOGRAPHIC DATA 14.1.1.1 Subject Disposition (All Subjects) 14.1.1.2 Platinum Therapy Randomization Strata Versus Actual Platinum Therapy
Received (ITT Population) 14.1.2 Protocol Deviations 14.1.2.1 Major Protocol Deviations (ITT Population) 14.1.3 Demographics and Baseline 14.1.3.1 Demographic Characteristics (ITT Population) 14.1.3.2 Demographic Characteristics (Safety Population) 14.1.3.3 Demographic Characteristics (Per-Protocol Population) 14.1.3.4 Demographic Characteristics (Immunogenicity Population) 14.1.3.5 Baseline Characteristics (ITT Population) 14.1.3.6 Baseline Characteristics (Safety Population) 14.1.3.7 Baseline Characteristics (Per-Protocol Population) 14.1.3.8 Baseline Characteristics (Immunogenicity Population) 14.1.3.9 Small Cell Lung Cancer Disease Characteristics (ITT Population) 14.1.3.10 Small Cell Lung Cancer Disease Characteristics (Safety Population) 14.1.3.11 Prior Therapies for Small Cell Lung Cancer (ITT Population) 14.1.3.12 Prior Therapies for Small Cell Lung Cancer (Safety Population) 14.1.3.13 Baseline Gene Expression (ITT Population) 14.1.3.14 Baseline Gene Expression (Safety Population) 14.1.3.15 Baseline Gene Expression (Per-Protocol Population) 14.1.3.16 Prior and Concomitant Medications (Safety Population) 14.2 EFFICACY DATA 14.2.1 Overall Survival 14.2.1.1 Overall Survival (ITT Population) 14.2.1.2 Overall Survival (Per-Protocol Population) 14.2.1.3 Overall Survival for Patients Receiving Cisplatin (ITT Population) 14.2.1.4 Overall Survival for Patients Receiving Cisplatin (Per-Protocol Population) 14.2.1.5 Overall Survival for Patients Receiving Carboplatin (ITT Population) 14.2.1.6 Overall Survival for Patients Receiving Carboplatin (Per-Protocol
Population) 14.2.1.7 Overall Survival – Impact of Biomarker Expression (ITT Population) 14.2.1.8 Overall Survival – Impact of Biomarker Expression (Per-Protocol
Population) 14.2.1.9 Overall Survival – Impact of Notch3 Expression in Subjects with
High/Low Notch Pathway Markers (ITT Population) 14.2.1.10 Overall Survival – Impact of Notch3 Expression in Subjects with
High/Low Notch Pathway Markers (Per-Protocol Population) 14.2.2 Progression-Free Survival
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Table Number
Table Description
14.2.2.1 Progression-Free Survival – Primary Analysis (ITT Population) 14.2.2.2 Progression-Free Survival – Primary Analysis (Per-Protocol Population) 14.2.2.3 Progression-Free Survival During Combination Chemotherapy (ITT
Population) 14.2.2.4 Progression-Free Survival During Combination Chemotherapy (Per-
Protocol Population) 14.2.2.5 Progression-Free Survival – Impact of Biomarker Expression (ITT
Population) 14.2.2.6 Progression-Free Survival – Impact of Biomarker Expression (Per-Protocol
Population) 14.2.2.7 Progression-Free Survival – Impact of Notch3 Expression in Subjects with
High/Low Notch Pathway Markers (ITT Population) 14.2.2.8 Progression-Free Survival – Impact of Notch3 Expression in Subjects with
High/Low Notch Pathway Markers (Per-Protocol Population) 14.2.2.9 Progression-Free Survival – Sensitivity Analysis (Per-Protocol Population) 14.2.3 Landmark Survival 14.2.3.1 Landmark Survival at 180, 360, 540 and 720 Days (ITT Population) 14.2.3.2 Landmark Survival at 180, 360, 540 and 720 Days (Per-Protocol
Population) 14.2.4 Tumor Length 14.2.4.1 Summary Assessment of Tumor Length (ITT Population) 14.2.4.2 Summary Assessment of Tumor Length (Per-Protocol Population) 14.2.4.3 Rate of Change in Total Tumor Length at Progression (ITT Population) 14.2.4.4 Rate of Change in Total Tumor Length at Progression (Per-Protocol
Population) 14.2.4.5 Rate of Change from Total Tumor Length at Baseline (ITT Population) 14.2.4.6 Rate of Change from Total Tumor Length at Baseline (Per-Protocol
Population) 14.2.5 Best Overall Tumor Response 14.2.5.1 Best Overall Tumor Response Based on Investigator Assessment (ITT
Population) 14.2.5.2 Best Overall Tumor Response Based on Investigator Assessment (Per-
Protocol Population) 14.2.5.3 Best Overall Tumor Response Based on Investigator Assessment – Impact
of Biomarker Expression (ITT Population) 14.2.5.4 Best Overall Tumor Response Based on Investigator Assessment – Impact
of Biomarker Expression (Per-Protocol Population) 14.2.6 Duration of Response 14.2.6.1 Duration of Response (ITT Population) 14.2.6.2 Duration of Response (Per-Protocol Population) 14.2.7 Sites of Progression 14.2.7.1 Sites of Progression (ITT Population) 14.2.7.2 Sites of Progression (Per-Protocol Population)
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Table Number
Table Description
14.3 SAFETY DATA 14.3.1 Displays of Adverse Events 14.3.1.1 Overall Summary of Treatment-Emergent Adverse Events (TEAEs)
(Safety Population) 14.3.1.2 Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and
Preferred Term (Safety Population) 14.3.1.3 Treatment-Emergent Adverse Events (TEAEs) Related to Study Drug by
MedDRA System Organ Class and Preferred Term (Safety Population) 14.3.1.4 Treatment-Emergent Adverse Events (TEAEs) Related to Etoposide by
MedDRA System Organ Class and Preferred Term (Safety Population) 14.3.1.5 Treatment-Emergent Adverse Events (TEAEs) Related to Platinum
Therapy by MedDRA System Organ Class and Preferred Term (Safety Population)
14.3.1.6 Treatment-Emergent Adverse Events (TEAEs) by System Organ Class, Preferred Term and CTCAE Severity Grade (Safety Population)
14.3.1.7 Treatment-Emergent Adverse Events (TEAEs) Related to Study Drug by System Organ Class, Preferred Term and CTCAE Severity Grade (Safety Population)
14.3.1.8 Treatment-Emergent Adverse Events (TEAEs) Related to Etoposide by System Organ Class, Preferred Term and CTCAE Severity Grade (Safety Population)
14.3.1.9 Treatment-Emergent Adverse Events (TEAEs) Related to Platinum Therapy by System Organ Class, Preferred Term and CTCAE Severity Grade (Safety Population)
14.3.1.10 Treatment-Emergent Adverse Events (TEAEs) by Preferred Term (Safety Population)
14.3.1.11 Treatment-Emergent Adverse Events (TEAEs) Related to Study Drug by Preferred Term (Safety Population)
14.3.1.12 Treatment-Emergent Adverse Events (TEAEs) Related to Etoposide by Preferred Term (Safety Population)
14.3.1.13 Treatment-Emergent Adverse Events (TEAEs) Related to Platinum Therapy by Preferred Term (Safety Population)
14.3.2 Deaths, Other Serious and Significant Adverse Events 14.3.2.1 Treatment-Emergent Adverse Events (TEAEs) with Outcome of Death by
System Organ Class and Preferred Term (Safety Population) 14.3.2.2 Serious Treatment-Emergent Adverse Events (TEAEs) by System Organ
Class and Preferred Term (Safety Population) 14.3.2.3 Serious Treatment-Emergent Adverse Events (TEAEs) Related to Study
Drug by System Organ Class and Preferred Term (Safety Population) 14.3.2.4 Serious Treatment-Emergent Adverse Events (TEAEs) Related to
Etoposide by System Organ Class and Preferred Term (Safety Population) 14.3.2.5 Serious Treatment-Emergent Adverse Events (TEAEs) Related to Platinum
Therapy by System Organ Class and Preferred Term (Safety Population)
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Table Number
Table Description
14.3.2.6 Treatment-Emergent Adverse Events (TEAEs) Leading to Delay/Interruption of Study Drug by System Organ Class and Preferred Term (Safety Population)
14.3.2.7 Treatment-Emergent Adverse Events (TEAEs) Leading to Delay/Interruption of Etoposide by System Organ Class and Preferred Term (Safety Population)
14.3.2.8 Treatment-Emergent Adverse Events (TEAEs) Leading to Delay/Interruption of Platinum Therapy by System Organ Class and Preferred Term (Safety Population)
14.3.2.9 Treatment-Emergent Adverse Events (TEAEs) Leading to Dose Reduction of Study Drug by System Organ Class and Preferred Term (Safety Population)
14.3.2.10 Treatment-Emergent Adverse Events (TEAEs) Leading to Dose Reduction of Etoposide by System Organ Class and Preferred Term (Safety Population)
14.3.2.11 Treatment-Emergent Adverse Events (TEAEs) Leading to Dose Reduction of Platinum Therapy by System Organ Class and Preferred Term (Safety Population)
14.3.2.12 Treatment-Emergent Adverse Events (TEAEs) Leading to Withdrawal of Study Drug by System Organ Class and Preferred Term (Safety Population)
14.3.2.13 Treatment-Emergent Adverse Events (TEAEs) Leading to Withdrawal of Etoposide by System Organ Class and Preferred Term (Safety Population)
14.3.2.14 Treatment-Emergent Adverse Events (TEAEs) Leading to Withdrawal of Platinum Therapy by System Organ Class and Preferred Term (Safety Population)
14.3.2.15 Treatment-Emergent Adverse Events (TEAEs) Leading to Discontinuation of Study Drug by System Organ Class and Preferred Term (Safety Population)
14.3.2.16 Treatment-Emergent Adverse Events (TEAEs) with Outcome of Death by Preferred Term (Safety Population)
14.3.2.17 Serious Treatment-Emergent Adverse Events (TEAEs) by Preferred Term (Safety Population)
14.3.2.18 Serious Treatment-Emergent Adverse Events (TEAEs) Related to Study Drug by Preferred Term (Safety Population)
14.3.2.19 Serious Treatment-Emergent Adverse Events (TEAEs) Related to Etoposide by Preferred Term (Safety Population)
14.3.2.20 Serious Treatment-Emergent Adverse Events (TEAEs) Related to Platinum Therapy by Preferred Term (Safety Population)
14.3.2.21 Treatment-Emergent Adverse Events (TEAEs) Leading to Delay/Interruption of Study Drug by Preferred Term (Safety Population)
14.3.2.22 Treatment-Emergent Adverse Events (TEAEs) Leading to Delay/Interruption of Etoposide by Preferred Term (Safety Population)
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Table Number
Table Description
14.3.2.23 Treatment-Emergent Adverse Events (TEAEs) Leading to Delay/Interruption of Platinum Therapy by Preferred Term (Safety Population)
14.3.2.24 Treatment-Emergent Adverse Events (TEAEs) Leading to Dose Reduction of Study Drug by Preferred Term (Safety Population)
14.3.2.25 Treatment-Emergent Adverse Events (TEAEs) Leading to Dose Reduction of Etoposide by Preferred Term (Safety Population)
14.3.2.26 Treatment-Emergent Adverse Events (TEAEs) Leading to Dose Reduction of Platinum Therapy by Preferred Term (Safety Population)
14.3.2.27 Treatment-Emergent Adverse Events (TEAEs) Leading to Withdrawal of Study Drug by Preferred Term (Safety Population)
14.3.2.28 Treatment-Emergent Adverse Events (TEAEs) Leading to Withdrawal of Etoposide by Preferred Term (Safety Population)
14.3.2.29 Treatment-Emergent Adverse Events (TEAEs) Leading to Withdrawal of Platinum Therapy by Preferred Term (Safety Population)
14.3.2.30 Treatment-Emergent Adverse Events (TEAEs) Leading to Discontinuation of Study Drug by Preferred Term (Safety Population)
14.3.2.31 Serious Treatment-Emergent Adverse Events (TEAEs) by System Organ Class, Preferred Term and CTCAE Severity Grade (Safety Population)
14.3.2.32 Serious Treatment-Emergent Adverse Events (TEAEs) Related to Study Drug by System Organ Class, Preferred Term and CTCAE Severity Grade (Safety Population)
14.3.2.33 Serious Treatment-Emergent Adverse Events (TEAEs) Related to Etoposide by System Organ Class, Preferred Term and CTCAE Severity Grade (Safety Population)
14.3.2.34 Serious Treatment-Emergent Adverse Events (TEAEs) Related to Platinum Therapy by System Organ Class, Preferred Term and CTCAE Severity Grade (Safety Population)
14.3.4 Laboratory and Other Data 14.3.4.1 Hematology (Safety Population) 14.3.4.2 Hematology – Shift from Baseline (Safety Population) 14.3.4.3 Hematology – Range Change Abnormal – High (Safety Population) 14.3.4.4 Hematology – Range Change Abnormal – Low (Safety Population) 14.3.4.5 Serum Chemistry (Safety Population) 14.3.4.6 Serum Chemistry – Shift from Baseline (Safety Population) 14.3.4.7 Serum Chemistry – Range Change Abnormal – High (Safety Population) 14.3.4.8 Serum Chemistry – Range Change Abnormal – Low (Safety Population) 14.3.4.9 Coagulation (Safety Population) 14.3.4.10 Coagulation– Shift from Baseline (Safety Population) 14.3.4.11 Coagulation– Range Change Abnormal – High (Safety Population) 14.3.4.12 Urinalysis (Safety Population) 14.3.4.13 Urinalysis – Shift from Baseline (Safety Population) 14.3.4.14 Vital Signs (Safety Population)
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Table Number
Table Description
14.3.4.15 Vital Signs – Range Change Abnormal (RCA) (Safety Population) 14.3.4.16 12-Lead Electrocardiogram (ECG) (Safety Population) 14.3.4.17 12-Lead Electrocardiogram (ECG) – Range Change Abnormal (RCA)
(Safety Population) 14.3.4.18 12-Lead Electrocardiogram (ECG) – QTc Interval (Safety Population) 14.3.4.19 12-Lead Electrocardiogram (ECG) – Overall Interpretation (Safety
Population) 14.3.4.20 12-Lead Electrocardiogram (ECG) – Overall Interpretation Shift from
Baseline (Safety Population) 14.3.4.21 ECOG Performance Status (Safety Population) 14.3.4.22 ECOG Performance Status – Shift from Baseline (Safety Population) 14.3.4.23 Anti-Tarextumab Antibodies (Immunogenicity Population) 14.3.4.24 Impact of Anti-Tarextumab Antibodies on Progression-Free Survival
(Immunogenicity Population) 14.3.4.25 Impact of Anti-Tarextumab Antibodies on Overall Survival
(Immunogenicity Population) 14.3.4.26 Overall Summary of Impact of Anti-Tarextumab Antibodies on Treatment-
Emergent Adverse Events (TEAEs) (Immunogenicity Population) 14.3.4.27 Impact of Anti-Tarextumab Antibodies Treatment-Emergent Adverse
Events (TEAEs) (Immunogenicity Population) 14.3.5 Extent of Exposure 14.3.5.1 Study Drug Exposure – Tarextumab/Placebo (Safety Population) 14.3.5.2 Dosing Compliance – Tarextumab/Placebo (Safety Population) 14.3.5.3 Study Drug Exposure – Etoposide (Safety Population) 14.3.5.4 Dosing Compliance – Etoposide (Safety Population) 14.3.5.5 Study Drug Exposure – Cisplatin (Safety Population) 14.3.5.6 Dosing Compliance – Cisplatin (Safety Population) 14.3.5.7 Study Drug Exposure – Carboplatin (Safety Population) 14.3.5.8 Dosing Compliance – Carboplatin (Safety Population)
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List of Figures
Figure Number
Figure Description
14.2.1.1 Overall Survival (ITT Population) 14.2.1.2 Overall Survival (ITT Population with Notch3 >25th Percentile) 14.2.1.3 Overall Survival (ITT Population with Notch3 >50th Percentile) 14.2.1.4 Overall Survival (ITT Population with Notch3 >75th Percentile) 14.2.1.5 Overall Survival (ITT Population with Hes1 >25th Percentile) 14.2.1.6 Overall Survival (ITT Population with Hes1 >50th Percentile) 14.2.1.7 Overall Survival (ITT Population with Hes1 >75th Percentile) 14.2.1.8 Overall Survival (ITT Population with Hes6 >25th Percentile) 14.2.1.9 Overall Survival (ITT Population with Hes6 >50th Percentile) 14.2.1.10 Overall Survival (ITT Population with Hes6 >75th Percentile) 14.2.1.11 Overall Survival (ITT Population with Hey1 >25th Percentile) 14.2.1.12 Overall Survival (ITT Population with Hey1 >50th Percentile) 14.2.1.13 Overall Survival (ITT Population with Hey1 >75th Percentile) 14.2.1.14 Overall Survival (ITT Population with Hey2 >25th Percentile) 14.2.1.15 Overall Survival (ITT Population with Hey2 >50th Percentile) 14.2.1.16 Overall Survival (ITT Population with Hey2 >75th Percentile) 14.2.1.17 Overall Survival (Per-Protocol Population) 14.2.2.1 Progression-Free Survival (ITT Population) 14.2.2.2 Progression-Free Survival (ITT Population with Notch3 >25th Percentile) 14.2.2.3 Progression-Free Survival (ITT Population with Notch3 >50th Percentile) 14.2.2.4 Progression-Free Survival (ITT Population with Notch3 >75th Percentile) 14.2.2.5 Progression-Free Survival (ITT Population with Hes1 >25th Percentile) 14.2.2.6 Progression-Free Survival (ITT Population with Hes1 >50th Percentile) 14.2.2.7 Progression-Free Survival (ITT Population with Hes1 >75th Percentile) 14.2.2.8 Progression-Free Survival (ITT Population with Hes6 >25th Percentile) 14.2.2.9 Progression-Free Survival (ITT Population with Hes6 >50th Percentile) 14.2.2.10 Progression-Free Survival (ITT Population with Hes6 >75th Percentile) 14.2.2.11 Progression-Free Survival (ITT Population with Hey1 >25th Percentile) 14.2.2.12 Progression-Free Survival (ITT Population with Hey1 >50th Percentile) 14.2.2.13 Progression-Free Survival (ITT Population with Hey1 >75th Percentile) 14.2.2.14 Progression-Free Survival (ITT Population with Hey2 >25th Percentile) 14.2.2.15 Progression-Free Survival (ITT Population with Hey2 >50th Percentile) 14.2.2.16 Progression-Free Survival (ITT Population with Hey2 >75th Percentile) 14.2.2.17 Progression-Free Survival (Per-Protocol Population) 14.2.4.1 Waterfall Plot of Best Percentage Change from Baseline Total Tumor
Length [ITT Population] 14.2.4.2 Waterfall Plot of Best Percentage Change from Baseline Total Tumor
Length [Per-Protocol Population] 14.2.6.1 Duration of Response (ITT Population) 14.2.6.2 Duration of Response (Per-Protocol Population) 14.3.4.1 Box Plot of Hemoglobin by Visit (Safety Population)
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Figure Number
Figure Description
14.3.4.2 Box Plot of Change from Baseline Hemoglobin by Visit (Safety Population)
14.3.4.3 Box Plot of Hematocrit by Visit (Safety Population) 14.3.4.4 Box Plot of Change from Baseline Hematocrit by Visit (Safety Population) 14.3.4.5 Box Plot of Platelets by Visit (Safety Population) 14.3.4.6 Box Plot of Change from Baseline Platelets by Visit (Safety Population) 14.3.4.7 Box Plot of Red Blood Cells by Visit (Safety Population) 14.3.4.8 Box Plot of Change from Baseline Red Blood Cells by Visit (Safety
Population) 14.3.4.9 Box Plot of White Blood Cells by Visit (Safety Population) 14.3.4.10 Box Plot of Change from Baseline White Blood Cells by Visit (Safety
Population) 14.3.4.11 Box Plot of Absolute Neutrophil Count by Visit (Safety Population) 14.3.4.12 Box Plot of Change from Baseline Absolute Neutrophil Count by Visit
(Safety Population) 14.3.4.13 Box Plot of Albumin by Visit (Safety Population) 14.3.4.14 Box Plot of Change from Baseline Albumin by Visit (Safety Population) 14.3.4.15 Box Plot of Alkaline Phosphatase by Visit (Safety Population) 14.3.4.16 Box Plot of Change from Baseline Alkaline Phosphatase by Visit (Safety
Population) 14.3.4.17 Box Plot of Total Bilirubin by Visit (Safety Population) 14.3.4.18 Box Plot of Change from Baseline Total Bilirubin by Visit (Safety
Population) 14.3.4.19 Box Plot of Direct Bilirubin by Visit (Safety Population) 14.3.4.20 Box Plot of Change from Baseline Direct Bilirubin by Visit (Safety
Population) 14.3.4.21 Box Plot of Bicarbonate by Visit (Safety Population) 14.3.4.22 Box Plot of Change from Baseline Bicarbonate by Visit (Safety
Population) 14.3.4.23 Box Plot of Blood Urea Nitrogen by Visit (Safety Population) 14.3.4.24 Box Plot of Change from Baseline Blood Urea Nitrogen by Visit (Safety
Population) 14.3.4.25 Box Plot of Calcium by Visit (Safety Population) 14.3.4.26 Box Plot of Change from Baseline Calcium by Visit (Safety Population) 14.3.4.27 Box Plot of Chloride by Visit (Safety Population) 14.3.4.28 Box Plot of Change from Baseline Chloride by Visit (Safety Population) 14.3.4.29 Box Plot of Creatinine by Visit (Safety Population) 14.3.4.30 Box Plot of Change from Baseline Creatinine by Visit (Safety Population) 14.3.4.31 Box Plot of Glucose by Visit (Safety Population) 14.3.4.32 Box Plot of Change from Baseline Glucose by Visit (Safety Population) 14.3.4.33 Box Plot of Lactic Dehydrogenase by Visit (Safety Population) 14.3.4.34 Box Plot of Change from Baseline Lactic Dehydrogenase by Visit (Safety
Population)
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Figure Number
Figure Description
14.3.4.35 Box Plot of Magnesium by Visit (Safety Population) 14.3.4.36 Box Plot of Change from Baseline Magnesium by Visit (Safety Population) 14.3.4.37 Box Plot of Phosphorus by Visit (Safety Population) 14.3.4.38 Box Plot of Change from Baseline Phosphorus by Visit (Safety Population) 14.3.4.39 Box Plot of Potassium by Visit (Safety Population) 14.3.4.40 Box Plot of Change from Baseline Potassium by Visit (Safety Population) 14.3.4.41 Box Plot of Total Protein by Visit (Safety Population) 14.3.4.42 Box Plot of Change from Baseline Total Protein by Visit (Safety
Population) 14.3.4.43 Box Plot of AST (SGOT) by Visit (Safety Population) 14.3.4.44 Box Plot of Change from Baseline AST (SGOT) by Visit (Safety
Population) 14.3.4.45 Box Plot of ALT (SGPT) by Visit (Safety Population) 14.3.4.46 Box Plot of Change from Baseline ALT (SGPT) by Visit (Safety
Population) 14.3.4.47 Box Plot of Sodium by Visit (Safety Population) 14.3.4.48 Box Plot of Change from Baseline Sodium by Visit (Safety Population) 14.3.4.49 Box Plot of Phosphorus by Visit (Safety Population) 14.3.4.50 Box Plot of Change from Baseline Phosphorus by Visit (Safety Population) 14.3.4.51 Box Plot of International Normalized Ratio by Visit (Safety Population) 14.3.4.52 Box Plot of Change from Baseline International Normalized Ratio by Visit
(Safety Population) 14.3.4.53 Box Plot of Prothrombin Time by Visit (Safety Population) 14.3.4.54 Box Plot of Change from Baseline Prothrombin Time by Visit (Safety
Population) 14.3.4.55 Box Plot of Activated Partial Thromboplastin Time by Visit (Safety
Population) 14.3.4.56 Box Plot of Change from Baseline Activated Partial Thromboplastin Time
by Visit (Safety Population) 14.3.4.57 Box Plot of pH by Visit (Safety Population) 14.3.4.58 Box Plot of Change from Baseline pH by Visit (Safety Population) 14.3.4.59 Box Plot of Specific Gravity by Visit (Safety Population) 14.3.4.60 Box Plot of Change from Baseline Specific Gravity by Visit (Safety
Population) 14.3.4.61 Box Plot of Temperature by Visit (Safety Population) 14.3.4.62 Box Plot of Change from Baseline Temperature by Visit (Safety
Population) 14.3.4.63 Box Plot of Pulse Rate by Visit (Safety Population) 14.3.4.64 Box Plot of Change from Baseline Pulse Rate by Visit (Safety Population) 14.3.4.65 Box Plot of Respiratory Rate by Visit (Safety Population) 14.3.4.66 Box Plot of Change from Baseline Respiratory Rate by Visit (Safety
Population) 14.3.4.67 Box Plot of Systolic Blood Pressure by Visit (Safety Population)
OncoMed Pharmaceuticals, Inc. Statistical Analysis Plan 59R5-003 (Phase 2) 23MAR2017
Confidential Page 41/149
Figure Number
Figure Description
14.3.4.68 Box Plot of Change from Baseline Systolic Blood Pressure by Visit (Safety Population)
14.3.4.69 Box Plot of Diastolic Blood Pressure by Visit (Safety Population) 14.3.4.70 Box Plot of Change from Baseline Diastolic Blood Pressure by Visit
(Safety Population) 14.3.4.71 Box Plot of Weight by Visit (Safety Population) 14.3.4.72 Box Plot of Change from Baseline Weight by Visit (Safety Population) 14.3.4.73 Box Plot of QRS Duration by Visit (Safety Population) 14.3.4.74 Box Plot of Change from Baseline QRS Duration by Visit (Safety
Population) 14.3.4.75 Box Plot of PR Interval by Visit (Safety Population) 14.3.4.76 Box Plot of Change from Baseline PR Interval by Visit (Safety Population) 14.3.4.77 Box Plot of QTc Interval by Visit (Safety Population) 14.3.4.78 Box Plot of Change from Baseline QTc Interval by Visit (Safety
Population)
OncoMed Pharmaceuticals, Inc. Statistical Analysis Plan 59R5-003 (Phase 2) 23MAR2017
Confidential Page 42/149
List of Listings
Listing Number
Listing Description
16.2.1 Discontinued Subjects 16.2.1.1 Subject Disposition 16.2.1.2 Informed Consent 16.2.2 Protocol Deviations 16.2.2.1 Major Protocol Deviations 16.2.3 Subjects Excluded from Efficacy Analyses 16.2.3.1 Inclusion/Exclusion Criteria 16.2.4 Demographics and Other Data 16.2.4.1 Demographics and Baseline Characteristics 16.2.4.2 Medical/Surgical History 16.2.4.3 Extensive Small Cell Lung Cancer History 16.2.4.4 Prior Surgery for Lung Cancer 16.2.4.5 Prior Radiotherapy for Lung Cancer 16.2.4.6 Baseline Gene Expression 16.2.4.7 FFPE Tissue Sample 16.2.4.8 Prior and Concomitant Medications 16.2.4.9 Concomitant Procedures 16.2.5 Compliance and Drug Concentration Data 16.2.5.1 Study Drug Infusion 16.2.5.2 Etoposide Infusion 16.2.5.3 Platinum Therapy Infusion 16.2.5.4 Doses Delayed, Interrupted, Reduced and Not Administered 16.2.5.5 Pre-dose, Post-dose and Single PK Samples 16.2.6 Efficacy Data 16.2.6.2 Tumor Evaluations – Target Lesions 16.2.6.3 Tumor Evaluations – Non-target Lesions 16.2.6.4 Tumor Evaluations – New Lesions 16.2.6.5 Tumor Assessments (RECIST Overall Response) 16.2.6.6 Derived Efficacy Data 16.2.6.7 End of Treatment 16.2.7 Adverse Events 16.2.7.1 Adverse Events 16.2.7.2 Deaths 16.2.7.3 Serious Adverse Events 16.2.7.4 Adverse Events Leading to Study Drug Discontinuation 16.2.8 Laboratory and Other Data 16.2.8.1 Hematology 16.2.8.2 PT/INR and aPTT 16.2.8.3 Serum Chemistry 16.2.8.4 Urinalysis 16.2.8.5 Vital Signs
OncoMed Pharmaceuticals, Inc. Statistical Analysis Plan 59R5-003 (Phase 2) 23MAR2017
Confidential Page 43/149
Listing Number
Listing Description
16.2.8.6 ECOG Performance Status 16.2.8.7 12-Lead ECG 16.2.8.8 Physical Examination 16.2.8.9 Optional Blood for Pharmacogenomics 16.2.8.10 CA19-9 Tumor Marker 16.2.8.11 Anti-Tarextumab Antibodies 16.2.8.12 Blood for Biomarkers 16.2.8.13 Serum Pregnancy Test 16.2.8.14 Optional Tumor Core Biopsy 16.2.8.15 On Study PCI or WBRT (PCI) 16.2.8.16 Follow up after Discontinuation of Study Treatment 16.2.8.17 Treatments and Procedures for Extensive Small Cell Lung Cancer During
Follow-Up Period
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 4
4/14
9
APP
EN
DIX
B. T
AB
LE
SH
EL
LS
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 4
5/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.1.
1.1
Su
bjec
t Dis
posi
tion
A
ll Su
bjec
ts
Pl
aceb
o Ta
rext
umab
To
tal
Subj
ects
Ran
dom
ized
xx
xx
xx
IT
T Po
pula
tion[1
] xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Per-P
roto
col P
opul
atio
n[2]
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
) Sa
fety
Pop
ulat
ion[3
] xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Imm
unog
enic
ity P
opul
atio
n[4]
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
) Ph
arm
acok
inet
ic P
opul
atio
n[5]
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Su
bjec
ts D
isco
ntin
ued
xx
xx
xx
Prim
ary
Rea
son
for S
tudy
Exi
t
D
eath
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Lo
st to
Fol
low
-Up
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Stud
y Te
rmin
ated
by
Onc
oMed
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
W
ithdr
awal
by
Subj
ect
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Oth
er
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Pr
imar
y R
easo
n fo
r Dis
cont
inui
ng S
tudy
Dru
g [6
]
A
dver
se E
vent
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
D
eath
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Lo
st to
Fol
low
-Up
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Dis
ease
Pro
gres
sion
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
St
udy
Term
inat
ed b
y O
ncoM
ed
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
With
draw
al o
f Con
sent
/ Pa
tient
Dec
isio
n xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
In
vest
igat
or D
ecis
ion
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Oth
er
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
N
ote:
Den
omin
ator
s are
bas
ed o
n th
e IT
T po
pula
tion.
[1
] ITT
= In
tent
-to-T
reat
. ITT
pop
ulat
ion
is c
ompr
ised
of a
ll ra
ndom
ized
subj
ects
. [2
] All
rand
omiz
ed su
bjec
ts w
ho re
ceiv
ed a
t lea
st o
ne d
ose
of st
udy
drug
and
had
at l
east
one
pos
t bas
elin
e tu
mor
ass
essm
ent.
[3] A
ll su
bjec
ts w
ho re
ceiv
ed a
t lea
st o
ne p
artia
l dos
e of
tare
xtum
ab o
r pla
cebo
. [4
] All
subj
ects
who
had
a b
asel
ine
and
at le
ast o
ne fo
llow
-up
anti-
tare
xtum
ab a
ntib
ody
sam
ple
obta
ined
. [5
] All
subj
ects
who
rece
ived
at l
east
one
dos
e of
stud
y dr
ug a
nd h
ad a
t lea
st o
ne p
ost-d
ose
PK sa
mpl
e.
[6] St
udy
drug
is P
lace
bo o
r Tar
extu
mab
. [7
] Plat
inum
ther
apy
is c
ispl
atin
or c
arbo
plat
in.
Prog
ram
mer
Not
es: (
a) a
dd a
dditi
onal
set o
f row
s for
(i) “
Prim
ary
Reas
on fo
r Dis
cont
inui
ng E
topo
side”
and
(ii)
“Pri
mar
y Re
ason
for D
isco
ntin
uing
Pla
tinum
The
rapy
[7] ”
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 4
6/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.1.
1.2
Pl
atin
um T
hera
py R
ando
miz
atio
n St
rata
Ver
sus A
ctua
l Pla
tinum
The
rapy
Rec
eive
d
ITT
Pop
ulat
ion
Act
ual P
latin
um T
hera
py R
ecei
ved
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
To
tal
(N=x
x)
Cis
plat
in
Car
bopl
atin
C
ispl
atin
C
arbo
plat
in
Cis
plat
in
Car
bopl
atin
Pl
atin
um T
hera
py R
ando
miz
atio
n St
rata
Cis
plat
in
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
C
arbo
plat
in
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 4
7/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.1.
2.1
M
ajor
Pro
toco
l Dev
iatio
ns
IT
T P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
To
tal
(N=x
x)
Any
Maj
or P
roto
col D
evia
tions
[1]
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Dev
iatio
n C
ateg
ory
1 xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
D
evia
tion
Cat
egor
y 2
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Dev
iatio
n C
ateg
ory
3 xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Et
c.
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
[1
] Su
bjec
ts m
ay b
e in
clud
ed in
mor
e th
an o
ne p
roto
col d
evia
tion
cate
gory
. Pr
ogra
mm
er n
ote:
the
act
ual c
ateg
orie
s of M
ajor
Pro
toco
l Dev
iatio
n wi
ll be
acc
ordi
ng to
the
exte
rnal
pro
toco
l dev
iatio
n fil
e re
ceiv
ed.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 4
8/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.1.
3.1
D
emog
raph
ic C
hara
cter
istic
s
ITT
Pop
ulat
ion
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
To
tal
(N=x
x)
Age
(ye
ars)
[1]
n xx
xx
xx
Mea
n (S
D)
xx (x
x.x)
xx
(xx.
x)
xx (x
x.x)
Med
ian
xx
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
xx, x
x
Se
x
M
ale
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Fem
ale
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
C
hild
Bea
ring
Pote
ntia
l [2
]
Y
es
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
No
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Et
hnic
ity
His
pani
c or
Lat
ino
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Not
His
pani
c or
Lat
ino
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
R
ace
Am
eric
an In
dian
or A
lask
a N
ativ
e xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
A
sian
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
B
lack
or A
frica
n A
mer
ican
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
N
ativ
e H
awai
ian
or O
ther
Pac
ific
Isla
nder
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
W
hite
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Mul
tiple
Rac
es C
heck
ed
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
[1
] Age
on
cons
ent d
ate.
[2
] For f
emal
es o
nly.
Prog
ram
mer
not
es: (
a) p
erce
ntag
es u
nder
Chi
ld B
eari
ng P
oten
tial a
re p
erce
ntag
es o
f fem
ale
subj
ects,
(b) r
epea
t thi
s tab
le u
sing
the
safe
ty, p
er-p
roto
col a
nd im
mun
ogen
icity
pop
ulat
ions
(c) r
emov
e ‘M
ultip
le R
aces
Che
cked
’ row
if a
ll ta
bles
hav
e ze
ro c
ount
for t
otal
.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 4
9/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.1.
3.5
B
asel
ine
Cha
ract
eris
tics
IT
T P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
To
tal
(N=x
x)
Hei
ght (
cm)
n xx
xx
xx
Mea
n (S
D)
xx (x
x.x)
xx
(xx.
x)
xx (x
x.x)
Med
ian
xx
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
xx, x
x
W
eigh
t (kg
)
n
xx
xx
xx
M
ean
(SD
) xx
(xx.
x)
xx (x
x.x)
xx
(xx.
x)
M
edia
n xx
xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x xx
, xx
Bod
y M
ass I
ndex
(kg/
m2 ) [1
]
n
xx
xx
xx
M
ean
(SD
) xx
(xx.
x)
xx (x
x.x)
xx
(xx.
x)
M
edia
n xx
xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x xx
, xx
ECO
G P
erfo
rman
ce S
tatu
s
0
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
1 xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
2
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Sm
okin
g H
isto
ry
Nev
er S
mok
ed
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Ex S
mok
er
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Cur
rent
Sm
oker
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
[1]
BM
I (kg
/m2 ) =
wei
ght (
kg) /
[hei
ght (
cm)]
2 . Pr
ogra
mm
er n
otes
: (a)
repe
at th
is ta
ble
usin
g th
e sa
fety
, per
-pro
toco
l and
imm
unog
enic
ity p
opul
atio
ns
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 5
0/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.1.
3.9
Sm
all C
ell L
ung
Can
cer
Dis
ease
Cha
ract
eris
tics
IT
T P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
To
tal
(N=x
x)
Mon
ths S
ince
Dia
gnos
is [1
]
n
xx
xx
xx
M
ean
(SD
) xx
(xx.
x)
xx (x
x.x)
xx
(xx.
x)
M
edia
n xx
xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x xx
, xx
His
tolo
gica
l/Cyt
olog
ical
Typ
e
Sm
all C
ell O
nly
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Mix
ed T
ype
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Oth
er
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
A
nato
mic
al L
ocat
ion
of P
rimar
y C
ance
r [1]
Rig
ht U
pper
Lun
g xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
R
ight
Low
er L
ung
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Mid
dle
of R
ight
Lun
g xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Le
ft U
pper
Lun
g xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
O
ther
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Num
ber o
f Site
s of D
isea
se a
t Stu
dy E
ntry
1
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
2 xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
≥3
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Site
s of D
isea
se a
t Stu
dy E
ntry
[2]
Bon
e xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
B
rain
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Pl
eura
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
A
dren
al G
land
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Ly
mph
Nod
es
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Oth
er N
odes
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
[1] M
onth
s sin
ce d
iagn
osis
to th
e da
te o
f ran
dom
izat
ion.
[2
] Su
bjec
ts m
ay b
e in
clud
ed in
mor
e th
an o
ne c
ateg
ory.
The
refo
re p
erce
ntag
es m
ay a
dd to
mor
e th
an 1
00%
.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
safe
ty p
opul
atio
n
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 5
1/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.1.
3.11
Prio
r T
hera
pies
for
Smal
l Cel
l Lun
g C
ance
r
ITT
Pop
ulat
ion
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
To
tal
(N=x
x)
Prio
r Sur
gery
for L
ung
Can
cer
Yes
xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
N
o xx
(xx.
x%)
xx (x
x.x%
) xx
(xx.
x%)
Prio
r Rad
ioth
erap
y fo
r Lun
g C
ance
r
Y
es
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
No
xx (x
x.x%
) xx
(xx.
x%)
xx (x
x.x%
)
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
safe
ty p
opul
atio
n
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 5
2/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.1.
3.13
Bas
elin
e G
ene
Exp
ress
ion
IT
T P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
To
tal
(N=x
x)
Not
ch3
Expr
essi
on
n xx
xx
xx
Mea
n (S
D)
xx (x
x.x)
xx
(xx.
x)
xx (x
x.x)
Med
ian
xx
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
xx, x
x
H
es1
Expr
essi
on
n xx
xx
xx
Mea
n (S
D)
xx (x
x.x)
xx
(xx.
x)
xx (x
x.x)
Med
ian
xx
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
xx, x
x
H
ey1
Expr
essi
on
n xx
xx
xx
Mea
n (S
D)
xx (x
x.x)
xx
(xx.
x)
xx (x
x.x)
Med
ian
xx
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
xx, x
x
Prog
ram
mer
not
es: (
a) a
dd a
dditi
onal
row
s for
Hey
2 Ex
pres
sion
and
Hes
6 Ex
pres
sion
, (b)
repe
at th
is ta
ble
usin
g th
e sa
fety
and
per
-pro
toco
l pop
ulat
ions
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 5
3/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.1.
3.16
Prio
r an
d C
onco
mita
nt M
edic
atio
ns
Sa
fety
Pop
ulat
ion
A
TC C
lass
[1]
Pr
efer
red
Nam
e Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Subj
ects
Rec
eivi
ng a
ny P
rior o
r Con
com
itant
Med
icat
ions
xx
(xx.
x%)
xx (x
x.x%
)
ATC
Cla
ss 1
Pref
erre
d N
ame
1.1
xx (x
x.x%
) xx
(xx.
x%)
Pr
efer
red
Nam
e 1.
2 xx
(xx.
x%)
xx (x
x.x%
)
Pref
erre
d N
ame
1.3
xx (x
x.x%
) xx
(xx.
x%)
A
TC C
lass
2
Pr
efer
red
Nam
e 2.
1 xx
(xx.
x%)
xx (x
x.x%
)
Pref
erre
d N
ame
2.2
xx (x
x.x%
) xx
(xx.
x%)
Pr
efer
red
Nam
e 2.
3 xx
(xx.
x%)
xx (x
x.x%
)
ATC
Cla
ss 3
Pref
erre
d N
ame
3.1
xx (x
x.x%
) xx
(xx.
x%)
Pr
efer
red
Nam
e 3.
2 xx
(xx.
x%)
xx (x
x.x%
)
Pref
erre
d N
ame
3.3
xx (x
x.x%
) xx
(xx.
x%)
N
ote:
At e
ach
leve
l of s
umm
atio
n (o
vera
ll, A
TC c
lass
and
pre
ferr
ed n
ame)
, sub
ject
s rep
ortin
g m
ore
than
one
med
icat
ion
are
coun
ted
only
onc
e.
[1] A
TC C
lass
and
Pre
ferr
ed N
ame
are
code
d ac
cord
ing
to th
e W
HO
Dru
g D
ictio
nary
Enh
ance
d (v
ersi
on M
arch
1, 2
014)
.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 5
4/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
1.1
O
vera
ll Su
rviv
al
IT
T P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Tota
l Fol
low
-Up
Tim
e (p
erso
n-ye
ars)
[1]
xxx.
x xx
x.x
Num
ber o
f Sub
ject
s who
Die
d xx
(xx.
x%)
xx (x
x.x%
) N
umbe
r of S
ubje
cts w
ho d
id n
ot D
ie (C
enso
red)
xx
(xx.
x%)
xx (x
x.x%
)
Haz
ard
[2]
0.xx
0.
xx
K
apla
n-M
eier
Est
imat
es: Q
uarti
les [
95%
C.I.
] (d
ays)
25th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
50
th P
erce
ntile
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
75th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
K
apla
n-M
eier
Est
imat
e (#
at r
isk)
[SE]
180
Day
s 0.
xx (x
x) [x
.xx]
0.
xx (x
x) [x
.xx]
360
Day
s 0.
xx (x
x) [x
.xx]
0.
xx (x
x) [x
.xx]
540
Day
s 0.
xx (x
x) [x
.xx]
0.
xx (x
x) [x
.xx]
720
Day
s 0.
xx (x
x) [x
.xx]
0.
xx (x
x) [x
.xx]
Ran
ge (S
ubje
cts w
ho D
ied)
(day
s)
xxx,
xxx
xx
x, x
xx
Ran
ge (A
ll Su
bjec
ts) (
days
) xx
x, x
xx
xxx,
xxx
Haz
ard
Rat
io [9
5% C
.I.] [3
]
x.xx
[x.x
x,x.
xx]
P-va
lue
[3]
0.
xxx
N
ote:
Ove
rall
Surv
ival
= D
ate
of D
ocum
enta
tion
of D
eath
– R
ando
miz
atio
n D
ate
+ 1.
Sub
ject
s who
had
not
exp
erie
nced
dea
th b
y th
eir l
ast c
onta
ct d
ate
wer
e ce
nsor
ed a
t tha
t tim
e. S
ubje
cts l
acki
ng
data
afte
r ran
dom
izat
ion
who
do
not d
ie h
ave
thei
r eve
nt ti
me
cens
ored
on
the
date
of r
ando
miz
atio
n w
ith d
urat
ion
of 1
day
. For
det
aile
d ev
ent a
nd c
enso
ring
rule
s, re
fer t
o pr
otoc
ol se
ctio
n 13
.5.4
and
SA
P se
ctio
n 8.
6. C
.I. =
Con
fiden
ce In
terv
al. S
E =
Stan
dard
Erro
r. [1
] Su
m o
f all
indi
vidu
al fo
llow
-up
times
in d
ays d
ivid
ed b
y 36
5.25
. [2
] N
umbe
r of d
eath
s / to
tal f
ollo
w-u
p tim
e.
[3] H
azar
d ra
tio, 9
5% C
.I. a
nd p
-val
ue fr
om C
ox p
ropo
rtion
al h
azar
ds m
odel
with
mai
n ef
fect
s for
trea
tmen
t, pl
atin
um c
hoic
e an
d pr
ior t
reat
men
t mod
ality
.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 5
5/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
1.3
O
vera
ll Su
rviv
al fo
r Su
bjec
ts R
ecei
ving
Cis
plat
in
IT
T P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Plat
inum
Cho
ice
[1]
C
ispl
atin
xx
(xx.
x%)
xx (x
x.x%
)
Car
bopl
atin
xx
(xx.
x%)
xx (x
x.x%
)
Tota
l Fol
low
-Up
Tim
e (p
erso
n-ye
ars)
[2]
xxx.
x xx
x.x
Num
ber o
f Sub
ject
s who
Die
d xx
(xx.
x%)
xx (x
x.x%
) N
umbe
r of S
ubje
cts w
ho d
id n
ot D
ie (C
enso
red)
xx
(xx.
x%)
xx (x
x.x%
)
Haz
ard
[3]
0.xx
0.
xx
K
apla
n-M
eier
Est
imat
es:
Qua
rtile
s [95
% C
.I.] (
days
)
25th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
50
th P
erce
ntile
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
75th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
K
apla
n-M
eier
Est
imat
e (#
at r
isk)
[SE]
180
Day
s 0.
xx (x
x) [x
.xx]
0.
xx (x
x) [x
.xx]
360
Day
s 0.
xx (x
x) [x
.xx]
0.
xx (x
x) [x
.xx]
40 D
ays
0.xx
(xx)
[x.x
x]
0.xx
(xx)
[x.x
x]
72
0 D
ays
0.xx
(xx)
[x.x
x]
0.xx
(xx)
[x.x
x]
R
ange
(Sub
ject
s who
Die
d) (d
ays)
xx
x, x
xx
xxx,
xxx
R
ange
(All
Subj
ects
) (da
ys)
xxx,
xxx
xx
x, x
xx
H
azar
d R
atio
[95%
C.I.
] [4]
x.
xx [x
.xx,
x.xx
] P-
valu
e [4
]
0.xx
x
Not
e: O
vera
ll Su
rviv
al =
Dat
e of
Doc
umen
tatio
n of
Dea
th –
Ran
dom
izat
ion
Dat
e +
1. S
ubje
cts w
ho h
ad n
ot e
xper
ienc
ed d
eath
by
thei
r las
t con
tact
dat
e w
ere
cens
ored
at t
hat t
ime.
Sub
ject
s lac
king
da
ta a
fter r
ando
miz
atio
n w
ho d
o no
t die
hav
e th
eir e
vent
tim
e ce
nsor
ed o
n th
e da
te o
f ran
dom
izat
ion
with
dur
atio
n of
1 d
ay. F
or d
etai
led
even
t and
cen
sorin
g ru
les,
refe
r to
prot
ocol
sect
ion
13.5
.4 a
nd
SAP
sect
ion
8.6.
C.I.
= C
onfid
ence
Inte
rval
. SE
= St
anda
rd E
rror.
[1] A
naly
ses p
rese
nted
in th
is ta
ble
incl
ude
only
subj
ects
who
rece
ived
cis
plat
in. P
erce
ntag
es b
elow
the
first
set o
f row
s are
bas
ed o
n su
bjec
ts w
ho re
ceiv
ed c
ispl
atin
. [2
] Su
m o
f all
indi
vidu
al fo
llow
-up
times
in d
ays d
ivid
ed b
y 36
5.25
. [3
] N
umbe
r of d
eath
s / to
tal f
ollo
w-u
p tim
e.
[4] H
azar
d ra
tio, 9
5% C
.I. a
nd p
-val
ue fr
om C
ox p
ropo
rtion
al h
azar
ds m
odel
with
mai
n ef
fect
s for
trea
tmen
t and
prio
r tre
atm
ent m
odal
ity.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 5
6/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
1.5
O
vera
ll Su
rviv
al fo
r Su
bjec
ts R
ecei
ving
Car
bopl
atin
ITT
Pop
ulat
ion
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Plat
inum
Cho
ice
[1]
C
ispl
atin
xx
(xx.
x%)
xx (x
x.x%
)
Car
bopl
atin
xx
(xx.
x%)
xx (x
x.x%
)
Tota
l Fol
low
-Up
Tim
e (p
erso
n-ye
ars)
[2]
xxx.
x xx
x.x
Num
ber o
f Sub
ject
s who
Die
d xx
(xx.
x%)
xx (x
x.x%
) N
umbe
r of S
ubje
cts w
ho d
id n
ot D
ie (C
enso
red)
xx
(xx.
x%)
xx (x
x.x%
)
Haz
ard
[3]
0.xx
0.
xx
K
apla
n-M
eier
Est
imat
es: Q
uarti
les [
95%
C.I.
] (da
ys)
25
th P
erce
ntile
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
50th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
75
th P
erce
ntile
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
Kap
lan-
Mei
er E
stim
ate
(# a
t ris
k) [S
E]
18
0 D
ays
0.xx
(xx)
[x.x
x]
0.xx
(xx)
[x.x
x]
36
0 D
ays
0.xx
(xx)
[x.x
x]
0.xx
(xx)
[x.x
x]
54
0 D
ays
0.xx
(xx)
[x.x
x]
0.xx
(xx)
[x.x
x]
72
0 D
ays
0.xx
(xx)
[x.x
x]
0.xx
(xx)
[x.x
x]
R
ange
(Sub
ject
s who
Die
d) (d
ays)
xx
x, x
xx
xxx,
xxx
R
ange
(All
Subj
ects
) (da
ys)
xxx,
xxx
xx
x, x
xx
H
azar
d R
atio
[95%
C.I.
] [4]
x.
xx [x
.xx,
x.xx
] P-
valu
e [4
]
0.xx
x
Not
e: O
vera
ll Su
rviv
al =
Dat
e of
Doc
umen
tatio
n of
Dea
th –
Ran
dom
izat
ion
Dat
e +
1. S
ubje
cts w
ho h
ad n
ot e
xper
ienc
ed d
eath
by
thei
r las
t con
tact
dat
e w
ere
cens
ored
at t
hat t
ime.
Sub
ject
s lac
king
da
ta a
fter r
ando
miz
atio
n w
ho d
o no
t die
hav
e th
eir e
vent
tim
e ce
nsor
ed o
n th
e da
te o
f ran
dom
izat
ion
with
dur
atio
n of
1 d
ay. F
or d
etai
led
even
t and
cen
sorin
g ru
les,
refe
r to
prot
ocol
sect
ion
13.5
.4 a
nd
SAP
sect
ion
8.6.
C.I.
= C
onfid
ence
Inte
rval
. SE
= St
anda
rd E
rror.
[1] A
naly
ses p
rese
nted
in th
is ta
ble
incl
ude
only
subj
ects
who
rece
ived
car
bopl
atin
. Per
cent
ages
bel
ow th
e fir
st se
t of r
ows a
re b
ased
on
subj
ects
who
rece
ived
car
bopl
atin
. [2
] Su
m o
f all
indi
vidu
al fo
llow
-up
times
in d
ays d
ivid
ed b
y 36
5.25
. [3
] N
umbe
r of d
eath
s / to
tal f
ollo
w-u
p tim
e.
[4] H
azar
d ra
tio, 9
5% C
.I. a
nd p
-val
ue fr
om C
ox p
ropo
rtion
al h
azar
ds m
odel
with
mai
n ef
fect
s for
trea
tmen
t and
prio
r tre
atm
ent m
odal
ity.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 5
7/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
1.7
O
vera
ll Su
rviv
al –
Impa
ct o
f Bio
mar
ker
Exp
ress
ion
IT
T P
opul
atio
n
M
odel
Coe
ffici
ents
(SE)
[1]
H
azar
d R
atio
[95%
Con
fiden
ce In
terv
al] [1
]
Bio
mar
ker
Trea
tmen
t
Trea
tmen
t x
Bio
mar
ker
Inte
ract
ion
A
t 25th
Pe
rcen
tile
At 5
0th
Perc
entil
e A
t 75th
Pe
rcen
tile
N
otch
3 xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
H
es1
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
Hey
2 xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
H
ey1
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
Hes
6 xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
[1] C
oeffi
cien
ts, h
azar
d ra
tios a
nd 9
5% c
onfid
ence
inte
rval
s are
from
Cox
pro
porti
onal
haz
ards
mod
els w
ith e
ffec
ts fo
r tre
atm
ent,
biom
arke
r and
trea
tmen
t-by-
biom
arke
r int
erac
tion.
A se
para
te m
odel
w
as u
sed
for e
ach
biom
arke
r.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 5
8/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
1.9
O
vera
ll Su
rviv
al –
Impa
ct o
f Not
ch3
Exp
ress
ion
in S
ubje
cts w
ith H
igh/
Low
Not
ch P
athw
ay M
arke
rs
IT
T P
opul
atio
n
M
odel
Coe
ffici
ents
(SE)
[1]
H
azar
d R
atio
[95%
Con
fiden
ce In
terv
al] [1
]
Bio
mar
ker
Bio
mar
ker
Leve
l n
Trea
tmen
t Tr
eatm
ent x
N
otch
3
At N
otch
3 25
th P
erce
ntile
A
t Not
ch3
50th
Per
cent
ile
At N
otch
3 75
th P
erce
ntile
N3R
PI [2
] H
igh
xx
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
Lo
w
xx
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
H
es1
Hig
h xx
xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
Low
xx
xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
Hey
2 H
igh
xx
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
Lo
w
xx
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
H
ey1
Hig
h xx
xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
Low
xx
xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
Hes
6 H
igh
xx
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
Lo
w
xx
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
[1
] C
oeffi
cien
ts, h
azar
d ra
tios a
nd 9
5% c
onfid
ence
inte
rval
s are
from
Cox
pro
porti
onal
haz
ards
mod
els w
ith e
ffec
ts fo
r tre
atm
ent,
Not
ch3
and
treat
men
t-by-
Not
ch3
inte
ract
ion.
A se
para
te m
odel
was
us
ed fo
r eac
h bi
omar
ker.
[2] N
3RPI
is th
e N
otch
3-re
late
d PF
S In
dex;
N3R
PI =
–0.
569*
HES
6*N
OTC
H3
+1.0
76*H
ES1*
HES
6*N
OTC
H3
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 5
9/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
2.1
Pr
ogre
ssio
n-Fr
ee S
urvi
val –
Pri
mar
y A
naly
sis
IT
T P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Tota
l Fol
low
-Up
Tim
e (p
erso
n-ye
ars)
[1]
xxx.
x xx
x.x
Num
ber o
f Sub
ject
s with
Dis
ease
Pro
gres
sion
or D
eath
xx
(xx.
x%)
xx (x
x.x%
) N
umbe
r of S
ubje
cts w
ho d
id n
ot P
rogr
ess o
r Die
(Cen
sore
d)
xx (x
x.x%
) xx
(xx.
x%)
H
azar
d [2
] 0.
xx
0.xx
Kap
lan-
Mei
er E
stim
ates
: Qua
rtile
s [95
% C
.I.] (
days
)
25th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
50
th P
erce
ntile
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
75th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
R
ange
(Sub
ject
s who
Pro
gres
sed
or D
ied)
(day
s)
xxx,
xxx
xx
x, x
xx
Ran
ge (A
ll Su
bjec
ts) (
days
) xx
x, x
xx
xxx,
xxx
Haz
ard
Rat
io [9
5% C
.I.] [3
]
x.xx
[x.x
x,x.
xx]
P-va
lue
[4]
0.
xxx
N
ote:
PFS
= D
ate
of D
ocum
enta
tion
of D
eath
/Pro
gres
sion
– R
ando
miz
atio
n D
ate
+ 1.
Sub
ject
s who
had
not
exp
erie
nced
dea
th o
r pro
gres
sion
by
thei
r las
t con
tact
wer
e ce
nsor
ed a
t the
tim
e of
thei
r las
t ra
diog
raph
ic re
spon
se a
sses
smen
t. Su
bjec
ts la
ckin
g a
radi
ogra
phic
resp
onse
ass
essm
ent a
fter r
ando
miz
atio
n w
ho d
o no
t pro
gres
s or d
ie h
ave
thei
r eve
nt ti
me
cens
ored
on
the
date
of r
ando
miz
atio
n w
ith d
urat
ion
of 1
day
. For
det
aile
d ev
ent a
nd c
enso
ring
rule
s ref
er to
pro
toco
l sec
tion
13.5
.1 a
nd S
AP
sect
ion
8.1.
C.I.
= C
onfid
ence
Inte
rval
. [1
] Sum
of a
ll in
divi
dual
follo
w-u
p tim
es in
day
s div
ided
by
365.
25.
[2] N
umbe
r of S
ubje
cts w
ith D
isea
se P
rogr
essi
on o
r Dea
th/ T
otal
Fol
low
-up
Tim
e (P
erso
n-ye
ars)
. [3
] H
azar
d ra
tio a
nd 9
5% C
.I. fr
om C
ox p
ropo
rtion
al h
azar
ds m
odel
with
mai
n ef
fect
s for
trea
tmen
t, pl
atin
um c
hoic
e an
d pr
ior t
reat
men
t mod
ality
. [4
] P-
valu
e fo
r tre
atm
ent e
ffec
t fro
m st
ratif
ied
log
rank
test
usi
ng p
latin
um c
hoic
e an
d pr
ior t
reat
men
t mod
ality
as s
tratif
icat
ion
fact
ors.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 6
0/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
2.3
Pr
ogre
ssio
n-Fr
ee S
urvi
val D
urin
g C
ombi
natio
n C
hem
othe
rapy
ITT
Pop
ulat
ion
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Tota
l Fol
low
-Up
Tim
e (p
erso
n-ye
ars)
[1]
xxx.
x xx
x.x
Num
ber o
f Sub
ject
s with
Dis
ease
Pro
gres
sion
or D
eath
xx
(xx.
x%)
xx (x
x.x%
) N
umbe
r of S
ubje
cts w
ho d
id n
ot P
rogr
ess o
r Die
(Cen
sore
d) [2
] xx
(xx.
x%)
xx (x
x.x%
)
Haz
ard
[3]
0.xx
0.
xx
K
apla
n-M
eier
Est
imat
es: Q
uarti
les [
95%
C.I.
] (da
ys)
25
th P
erce
ntile
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
50th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
75
th P
erce
ntile
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
Ran
ge (S
ubje
cts w
ho P
rogr
esse
d or
Die
d) (d
ays)
xx
x, x
xx
xxx,
xxx
R
ange
(All
Subj
ects
) (da
ys)
xxx,
xxx
xx
x, x
xx
H
azar
d R
atio
[95%
C.I.
] [4]
x.
xx [x
.xx,
x.xx
] P-
valu
e [5
]
0.xx
x
Not
e: P
FS=
Dat
e of
Doc
umen
tatio
n of
Dea
th/P
rogr
essi
on –
Ran
dom
izat
ion
Dat
e +
1. S
ubje
cts w
ho h
ad n
ot e
xper
ienc
ed d
eath
or p
rogr
essi
on b
y th
eir l
ast c
onta
ct w
ere
cens
ored
at t
he ti
me
of th
eir l
ast
radi
ogra
phic
resp
onse
ass
essm
ent.
Subj
ects
lack
ing
a ra
diog
raph
ic re
spon
se a
sses
smen
t afte
r ran
dom
izat
ion
who
do
not p
rogr
ess o
r die
hav
e th
eir e
vent
tim
e ce
nsor
ed o
n th
e da
te o
f ran
dom
izat
ion
with
dur
atio
n of
1 d
ay. F
or d
etai
led
even
t and
cen
sorin
g ru
les r
efer
to p
roto
col s
ectio
n 13
.5.1
and
SA
P se
ctio
n 8.
1. C
.I. =
Con
fiden
ce In
terv
al.
[1] Su
m o
f all
indi
vidu
al fo
llow
-up
times
in d
ays d
ivid
ed b
y 36
5.25
. [2
] Th
e sa
me
cens
orin
g m
echa
nism
s use
d in
the
prim
ary
anal
ysis
of P
FS w
ere
empl
oyed
her
e. A
dditi
onal
ly, f
or th
is a
naly
sis,
a su
bjec
t’s P
FS w
as c
enso
red
35 d
ays (
the
sche
dule
d tim
e fo
r 1 tr
eatm
ent
cycl
e pl
us 7
day
s) fo
llow
ing
his o
r her
last
dos
e of
eto
posi
de o
r pla
tinum
. [3
] N
umbe
r of S
ubje
cts w
ith D
isea
se P
rogr
essi
on o
r Dea
th/ T
otal
Fol
low
-up
Tim
e (P
erso
n-ye
ars)
. [4
] H
azar
d ra
tio a
nd 9
5% C
.I. fr
om C
ox p
ropo
rtion
al h
azar
ds m
odel
with
mai
n ef
fect
s for
trea
tmen
t, pl
atin
um c
hoic
e an
d pr
ior t
reat
men
t mod
ality
. [5
] P-
valu
e fo
r tre
atm
ent e
ffec
t fro
m st
ratif
ied
log
rank
test
usi
ng p
latin
um c
hoic
e an
d pr
ior t
reat
men
t mod
ality
as s
tratif
icat
ion
fact
ors.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 6
1/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
2.5
Pr
ogre
ssio
n-Fr
ee S
urvi
val –
Impa
ct o
f Bio
mar
ker
Exp
ress
ion
IT
T P
opul
atio
n
M
odel
Coe
ffici
ents
(SE)
[1]
H
azar
d R
atio
[95%
Con
fiden
ce In
terv
al] [1
]
Bio
mar
ker
Trea
tmen
t
Trea
tmen
t x
Bio
mar
ker
Inte
ract
ion
A
t 25th
Pe
rcen
tile
At 5
0th
Perc
entil
e A
t 75th
Pe
rcen
tile
N
otch
3 xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
H
es1
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
Hey
2 xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
H
ey1
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
Hes
6 xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
[1] C
oeffi
cien
ts, h
azar
d ra
tios a
nd 9
5% c
onfid
ence
inte
rval
s are
from
Cox
pro
porti
onal
haz
ards
mod
els w
ith e
ffec
ts fo
r tre
atm
ent,
biom
arke
r and
trea
tmen
t-by-
biom
arke
r int
erac
tion.
A se
para
te m
odel
w
as u
sed
for e
ach
biom
arke
r.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 6
2/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
2.7
Pr
ogre
ssio
n-Fr
ee S
urvi
val –
Impa
ct o
f Not
ch3
Exp
ress
ion
in S
ubje
cts w
ith H
igh/
Low
Not
ch P
athw
ay M
arke
rs
IT
T P
opul
atio
n
M
odel
Coe
ffici
ents
(SE)
[1]
H
azar
d R
atio
[95%
Con
fiden
ce In
terv
al] [1
]
Bio
mar
ker
Bio
mar
ker
Leve
l n
Trea
tmen
t Tr
eatm
ent x
N
otch
3
At N
otch
3 25
th P
erce
ntile
A
t Not
ch3
50th
Per
cent
ile
At N
otch
3 75
th P
erce
ntile
N3R
PI [2
] H
igh
xx
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
Lo
w
xx
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
H
es1
Hig
h xx
xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
Low
xx
xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
Hey
2 H
igh
xx
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
Lo
w
xx
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
H
ey1
Hig
h xx
xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
Low
xx
xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
Hes
6 H
igh
xx
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
Lo
w
xx
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
[1
] C
oeffi
cien
ts, h
azar
d ra
tios a
nd 9
5% c
onfid
ence
inte
rval
s are
from
Cox
pro
porti
onal
haz
ards
mod
els w
ith e
ffec
ts fo
r tre
atm
ent,
Not
ch3
and
treat
men
t-by-
Not
ch3
inte
ract
ion.
A se
para
te m
odel
was
us
ed fo
r eac
h bi
omar
ker.
[2] N
3RPI
is th
e N
otch
3-re
late
d PF
S In
dex;
N3R
PI =
–0.
569*
HES
6*N
OTC
H3
+1.0
76*H
ES1*
HES
6*N
OTC
H3
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 6
3/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
2.9
Pr
ogre
ssio
n-Fr
ee S
urvi
val –
Sen
sitiv
ity A
naly
sis
Pe
r-Pr
otoc
ol P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Tota
l Fol
low
-Up
Tim
e (p
erso
n-ye
ars)
[1]
xxx.
x xx
x.x
Num
ber o
f Sub
ject
s with
Dis
ease
Pro
gres
sion
or D
eath
xx
(xx.
x%)
xx (x
x.x%
) N
umbe
r of S
ubje
cts w
ho d
id n
ot P
rogr
ess o
r Die
(C
enso
red)
xx
(xx.
x%)
xx (x
x.x%
)
H
azar
d [2
] 0.
xx
0.xx
Kap
lan-
Mei
er E
stim
ates
: Qua
rtile
s [95
% C
.I.] (
days
)
25th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
50
th P
erce
ntile
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
75th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
R
ange
(Sub
ject
s who
Pro
gres
sed
or D
ied)
(day
s)
xxx,
xxx
xx
x, x
xx
Ran
ge (A
ll Su
bjec
ts) (
days
) xx
x, x
xx
xxx,
xxx
Haz
ard
Rat
io [9
5% C
.I.] [3
]
x.xx
[x.x
x,x.
xx]
P-va
lue
[4]
0.
xxx
N
ote:
PFS
= D
ate
of D
ocum
enta
tion
of D
eath
/Pro
gres
sion
– R
ando
miz
atio
n D
ate
+ 1.
Sub
ject
s who
had
not
exp
erie
nced
dea
th o
r pro
gres
sion
by
thei
r las
t con
tact
wer
e ce
nsor
ed a
t the
tim
e of
thei
r las
t ra
diog
raph
ic re
spon
se a
sses
smen
t. Su
bjec
ts la
ckin
g a
radi
ogra
phic
resp
onse
ass
essm
ent a
fter r
ando
miz
atio
n w
ho d
o no
t pro
gres
s or d
ie h
ave
thei
r eve
nt ti
me
cens
ored
on
the
date
of r
ando
miz
atio
n w
ith d
urat
ion
of 1
day
. For
det
aile
d ev
ent a
nd c
enso
ring
rule
s ref
er to
pro
toco
l sec
tion
13.5
.1 a
nd S
AP
sect
ion
8.1.
C.I.
= C
onfid
ence
Inte
rval
. [1
] Sum
of a
ll in
divi
dual
follo
w-u
p tim
es in
day
s div
ided
by
365.
25.
[2] N
umbe
r of S
ubje
cts w
ith D
isea
se P
rogr
essi
on o
r Dea
th/ T
otal
Fol
low
-up
Tim
e (P
erso
n-ye
ars)
. [3
] H
azar
d ra
tio a
nd 9
5% C
.I. fr
om C
ox p
ropo
rtion
al h
azar
ds m
odel
with
trea
tmen
t as t
he o
nly
expl
anat
ory
varia
ble.
[4
] P-
valu
e fo
r tre
atm
ent e
ffec
t fro
m u
nstra
tifie
d lo
g ra
nk te
st.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 6
4/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
3.1
L
andm
ark
Surv
ival
at 1
80, 3
60, 5
40 a
nd 7
20 D
ays
IT
T P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
P-
Val
ue
Surv
ival
(# a
t ris
k) [S
E] [1
]
18
0 D
ays
0.xx
(xx)
[x.x
x]
0.xx
(xx)
[x.x
x]
0.xx
x
360
Day
s 0.
xx (x
x) [x
.xx]
0.
xx (x
x) [x
.xx]
0.
xxx
54
0 D
ays
0.xx
(xx)
[x.x
x]
0.xx
(xx)
[x.x
x]
0.xx
x
720
Day
s 0.
xx (x
x) [x
.xx]
0.
xx (x
x) [x
.xx]
0.
xxx
[1] La
ndm
ark
surv
ival
p-v
alue
s fro
m in
depe
nden
t Z te
sts.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 6
5/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
T
able
14.
2.4.
1 Su
mm
ary
Ass
essm
ent o
f Tum
or L
engt
h (m
m)
IT
T P
opul
atio
n
Plac
ebo
(N=x
x)
Ta
rext
umab
(N
=xx)
R
esul
t
Cha
nge
from
B
asel
ine
Perc
ent
Cha
nge
R
esul
t
Cha
nge
from
B
asel
ine
Perc
ent
Cha
nge
Bas
elin
e Su
m o
f Lon
gest
Dia
met
ers (
SLD
)
n
xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx
.x (x
x.xx
)
95%
C.I.
[x
x.x,
xx.
x]
[x
x.x,
xx.
x]
M
edia
n xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx
, xx
M
in, M
ax
xx, x
x
xx, x
x
C
ycle
-3, D
ay-1
Sum
of L
onge
st D
iam
eter
s (SL
D)
n xx
xx
xx
xx
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
95
% C
.I.
[xx.
x, x
x.x]
[x
x.x,
xx.
x]
[xx.
x, x
x.x]
[xx.
x, x
x.x]
[x
x.x,
xx.
x]
[xx.
x, x
x.x]
Med
ian
xx
xx
xx
xx
xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
xx, x
x
xx, x
x xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x xx
, xx
xx
, xx
xx, x
x xx
, xx
A
NC
OV
A p
-val
ues [1
,2]
0.
xxx
0.xx
x
C
ycle
-5, D
ay-1
Sum
of L
onge
st D
iam
eter
s (SL
D)
[etc
eter
a]
[⁞]
[⁞]
[⁞]
[⁞]
[⁞]
[⁞]
N
ote:
tum
or le
ngth
is c
alcu
late
d as
the
sum
of t
he lo
nges
t dia
met
ers (
SLD
) for
the
targ
et le
sion
s. SD
= S
tand
ard
Dev
iatio
n; L
S =
Leas
t Squ
ares
; SE
= St
anda
rd E
rror
; C.I.
= C
onfid
ence
Inte
rval
. [1
] The
diff
eren
ce b
etw
een
the
follo
w-u
p an
d ba
selin
e SL
D (e
.g.,
SLD
C3D
1 – S
LDba
selin
e) is
the
depe
nden
t var
iabl
e in
the
AN
CO
VA
mod
el fo
r cha
nge
from
bas
elin
e. T
reat
men
t, pl
atin
um c
hoic
e (c
ispl
atin
ver
sus c
arbo
plat
in) a
nd p
rior t
reat
men
t mod
ality
(WB
RT
or P
CI)
will
be
cate
goric
al fa
ctor
s in
the
mod
el, a
nd S
LDba
selin
e will
be
incl
uded
as a
con
tinuo
us c
ovar
iate
. [2
] The
log
of th
e ra
tio o
f fol
low
-up
to b
asel
ine
SLD
(e.g
., lo
g [S
LDC
3D1/S
LDba
selin
e]) is
the
depe
nden
t var
iabl
e in
the
AN
CO
VA
mod
el fo
r per
cent
cha
nge.
Tre
atm
ent,
plat
inum
cho
ice
and
prio
r tre
atm
ent m
odal
ity w
ill b
e ca
tego
rical
fact
ors i
n th
e m
odel
, and
log
[SLD
base
line]
will
be
incl
uded
as a
con
tinuo
us c
ovar
iate
.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 6
6/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
4.3
R
ate
of C
hang
e in
Tot
al T
umor
Len
gth
at P
rogr
essi
on
IT
T P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
SLD
at N
adir
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
SLD
at P
rogr
essi
on
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
Rat
e of
SLD
Cha
nge
from
Nad
ir to
Pro
gres
sion
(%/d
ay) [1
]
N
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
P-va
lue
[2]
0.
xxx
N
ote:
SLD
= S
um o
f Lon
gest
Dia
met
ers (
i.e.,
tota
l tum
or le
ngth
for t
arge
t les
ions
as d
efin
ed b
y R
ECIS
T cr
iteria
[ver
sion
1.1
]).
[1] R
ate
of C
hang
e in
SLD
at p
rogr
essi
on =
100
x (S
LD a
t Pro
gres
sion
– S
LD a
t Nad
ir) /
SLD
at N
adir
/ (nu
mbe
r of d
ays b
etw
een
nadi
r and
pro
gres
sion
). [2
] P-
valu
e fo
r tre
atm
ent e
ffec
t fro
m A
NO
VA
mod
el w
ith tr
eatm
ent,
plat
inum
cho
ice
and
prio
r tre
atm
ent m
odal
ity a
s cat
egor
ical
inde
pend
ent v
aria
bles
.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 6
7/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
4.5
R
ate
of C
hang
e fr
om T
otal
Tum
or L
engt
h at
Bas
elin
e
ITT
Pop
ulat
ion
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
SLD
at B
asel
ine
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
SLD
at C
ycle
3, D
ay 1
n xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
M
edia
n xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
R
ate
of S
LD C
hang
e fro
m B
asel
ine
to C
ycle
3, D
ay 1
Ass
essm
ent (
%/d
ay) [1
]
N
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th
Perc
entil
e xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
P-va
lue
[2]
0.
xxx
N
ote:
SLD
= S
um o
f Lon
gest
Dia
met
ers (
i.e.,
tota
l tum
or le
ngth
for t
arge
t les
ions
as d
efin
ed b
y R
ECIS
T cr
iteria
[ver
sion
1.1
]).
[1] R
ate
of C
hang
e in
SLD
from
bas
elin
e to
CxD
1 =
100
x (S
LD a
t CxD
1 –
SLD
at B
asel
ine)
/ SL
D a
t Bas
elin
e / (
num
ber o
f day
s bet
wee
n ba
selin
e an
d C
xD1
asse
ssm
ent).
[2
] P-
valu
e fo
r tre
atm
ent e
ffect
from
AN
OV
A m
odel
with
trea
tmen
t, pl
atin
um c
hoic
e an
d pr
ior t
reat
men
t mod
ality
as c
ateg
oric
al in
depe
nden
t var
iabl
es.
Prog
ram
mer
not
es: (
a) a
dd ro
ws f
or (i
) SLD
at C
ycle
5, D
ay 1
and
(ii)
Rate
of S
LD C
hang
e fro
m B
asel
ine
to C
ycle
5, D
ay 1
Asse
ssm
ent;
(b) r
epea
t thi
s tab
le u
sing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 6
8/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
5.1
B
est O
vera
ll T
umor
Res
pons
e B
ased
on
Inve
stig
ator
Ass
essm
ent
IT
T P
opul
atio
n
Plac
ebo
(N=x
x)
Ta
rext
umab
(N=x
x)
R
espo
nse
Rat
e 95
% C
.I.[2
]
Res
pons
e R
ate
95%
C.I.
[2]
Bes
t Ove
rall
Tum
or R
espo
nse
[1]
Com
plet
e R
espo
nse
(CR
) xx
.x (x
x.x%
) [x
x.x,
xx.
x]
xx
.x (x
x.x%
) [x
x.x,
xx.
x]
Pa
rtial
Res
pons
e (P
R)
xx.x
(xx.
x%)
[xx.
x, x
x.x]
xx.x
(xx.
x%)
[xx.
x, x
x.x]
Stab
le D
isea
se (S
D)
xx.x
(xx.
x%)
[xx.
x, x
x.x]
xx.x
(xx.
x%)
[xx.
x, x
x.x]
Prog
ress
ive
Dis
ease
(PD
) xx
.x (x
x.x%
) [x
x.x,
xx.
x]
xx
.x (x
x.x%
) [x
x.x,
xx.
x]
N
ot E
valu
able
(NE)
xx
.x (x
x.x%
) [x
x.x,
xx.
x]
xx
.x (x
x.x%
) [x
x.x,
xx.
x]
N
o Po
st-B
asel
ine
Tum
or A
sses
smen
t Col
lect
ed
xx.x
(xx.
x%)
[xx.
x, x
x.x]
xx.x
(xx.
x%)
[xx.
x, x
x.x]
O
vera
ll R
espo
nse
Rat
e (C
R o
r PR)
xx
.x (x
x.x%
)
xx
.x (x
x.x%
) [x
x.x,
xx.
x]
Odd
s Rat
io (T
arex
tum
ab/P
lace
bo) [3
]
x.xx
P-va
lue
[3]
0.
xxx
[1
] Tu
mor
resp
onse
bas
ed o
n R
ECIS
T cr
iteria
(ver
sion
1.1
). [2
] Tw
o-si
ded
exac
t 95%
C.I.
. [3
] O
dds r
atio
and
p-v
alue
from
logi
stic
regr
essi
on m
odel
incl
udin
g tre
atm
ent,
plat
inum
cho
ice
and
prio
r tre
atm
ent m
odal
ity a
s ind
epen
dent
var
iabl
es.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 6
9/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
5.3
B
est O
vera
ll T
umor
Res
pons
e B
ased
on
Inve
stig
ator
Ass
essm
ent –
Impa
ct o
f Bio
mar
ker
Exp
ress
ion
IT
T P
opul
atio
n
M
odel
Coe
ffici
ents
(SE)
[1]
O
dds R
atio
[95%
Con
fiden
ce In
terv
al] [1
]
Bio
mar
ker
Trea
tmen
t
Trea
tmen
t x
Bio
mar
ker
Inte
ract
ion
A
t 25th
Pe
rcen
tile
At 5
0th
Perc
entil
e A
t 75th
Pe
rcen
tile
N
otch
3 xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
H
es1
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
Hey
2 xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
H
ey1
xx.x
(xx.
x)
xx.x
(xx.
x)
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
Hes
6 xx
.x (x
x.x)
xx
.x (x
x.x)
x.xx
[x.x
x,xx
.xx]
x.
xx [x
.xx,
xx.x
x]
x.xx
[x.x
x,xx
.xx]
[1] C
oeffi
cien
ts, o
dds r
atio
and
95%
con
fiden
ce in
terv
al fr
om lo
gist
ic re
gres
sion
mod
els w
ith e
ffect
s for
trea
tmen
t, bi
omar
ker a
nd tr
eatm
ent-b
y-bi
omar
ker i
nter
actio
n. A
sepa
rate
mod
el w
as u
sed
for
each
bio
mar
ker.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 7
0/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
6.1
D
urat
ion
of R
espo
nse
IT
T P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Num
ber o
f Sub
ject
s with
Obj
ectiv
e R
espo
nse
(CR
or P
R)
xx
xx
Tota
l Fol
low
-Up
Tim
e (p
erso
n-ye
ars)
[11]
xx
x.x
xxx.
x N
umbe
r of R
espo
nder
s with
Dis
ease
Pro
gres
sion
or D
eath
xx
(xx.
x%)
xx (x
x.x%
) N
umbe
r of R
espo
nder
s who
did
not
Pro
gres
s or D
ie (C
enso
red)
xx
(xx.
x%)
xx (x
x.x%
)
Haz
ard
[2]
0.xx
0.
xx
K
apla
n-M
eier
Est
imat
es: Q
uarti
les [
95%
C.I.
] (da
ys)
25
th P
erce
ntile
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
50th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
75
th P
erce
ntile
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
Ran
ge (R
espo
nder
s who
Pro
gres
sed
or D
ied)
(day
s)
xx.x
– x
x.x
xx.x
– x
x.x
Ran
ge (A
ll R
espo
nder
s) (d
ays)
xx
.x –
xx.
x xx
.x –
xx.
x
Haz
ard
Rat
io [9
5% C
.I.] [3
]
x.xx
[x.x
x,x.
xx]
P-va
lue
[2]
0.
xxx
N
ote:
For
this
tabl
e su
mm
ary,
Res
pond
ers a
re th
ose
subj
ects
who
exp
erie
nced
an
Obj
ectiv
e R
espo
nse.
N
ote:
Ana
lyse
s pre
sent
ed in
this
tabl
e in
clud
e on
ly su
bjec
ts w
ho a
chie
ved
a C
R o
r PR.
Per
cent
ages
bel
ow th
e fir
st ro
w a
re b
ased
on
subj
ects
who
ach
ieve
d a
CR
or P
R.
Not
e: D
urat
ion
of R
espo
nse
= D
ate
of D
ocum
enta
tion
of D
eath
/Pro
gres
sion
– D
ate
of F
irst P
artia
l (PR
) or C
ompl
ete
Res
pons
e (C
R) +
1. R
espo
nder
s who
had
not
exp
erie
nced
dea
th o
r pro
gres
sion
by
thei
r las
t con
tact
wer
e ce
nsor
ed a
t the
tim
e of
thei
r las
t rad
iogr
aphi
c re
spon
se a
sses
smen
t. R
espo
nder
s lac
king
a ra
diog
raph
ic re
spon
se a
sses
smen
t afte
r firs
t res
pons
e w
ho d
o no
t pro
gres
s or d
ie h
ave
thei
r eve
nt ti
me
cens
ored
on
the
date
of f
irst r
espo
nse
with
dur
atio
n of
1 d
ay. F
or d
etai
led
even
t and
cen
sorin
g ru
les r
efer
to p
roto
col s
ectio
n 13
.5.3
and
SA
P se
ctio
n 8.
4. C
.I. =
Con
fiden
ce In
terv
al.
[1] Su
m o
f all
indi
vidu
al fo
llow
-up
times
in d
ays d
ivid
ed b
y 36
5.25
. [2
] N
umbe
r of S
ubje
cts w
ith D
isea
se P
rogr
essi
on o
r Dea
th/ T
otal
Fol
low
-up
Tim
e (P
erso
n-ye
ars)
. [3
] H
azar
d ra
tio, 9
5% C
.I. a
nd p
-val
ue fr
om C
ox p
ropo
rtion
al h
azar
ds m
odel
with
mai
n ef
fect
s for
trea
tmen
t, pl
atin
um c
hoic
e an
d pr
ior t
reat
men
t mod
ality
.
Prog
ram
mer
not
es: P
erce
ntag
es d
ispl
ayed
to b
e ba
sed
on n
umbe
r of s
ubje
cts w
ith a
n ob
ject
ive
resp
onse
.
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 7
1/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.2.
7.1
Si
tes o
f Pro
gres
sion
ITT
Pop
ulat
ion
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Subj
ects
with
Pro
gres
sive
Dis
ease
[1]
xx (x
x.x%
) xx
(xx.
x%)
Pr
ogre
ssio
n ba
sed
on…
New
Les
ion
xx (x
x.x%
) xx
(xx.
x%)
Ex
istin
g Le
sion
xx
(xx.
x%)
xx (x
x.x%
)
Chi
-Squ
are
p-va
lue
[2]
0.
xxx
Si
te o
f Pro
gres
sion
Prog
ress
ion
of e
xist
ing
lesi
on
xx (x
x.x%
) xx
(xx.
x%)
Li
ver
xx (x
x.x%
) xx
(xx.
x%)
Lu
ng
xx (x
x.x%
) xx
(xx.
x%)
Ly
mph
Nod
e xx
(xx.
x%)
xx (x
x.x%
)
[…]
[⁞]
[⁞]
M
ore
than
one
new
lesi
on
xx (x
x.x%
) xx
(xx.
x%)
C
hi-S
quar
e p-
valu
e [3
]
0.xx
x
[1] A
naly
ses p
rese
nted
in th
is ta
ble
incl
ude
only
subj
ects
who
had
pro
gres
sive
dis
ease
dur
ing
the
study
. Per
cent
ages
bel
ow th
e fir
st ro
w a
re b
ased
on
subj
ects
who
had
pro
gres
sive
dis
ease
on
stud
y.
[2] H
ypot
hesi
s 1 is
equ
ival
ent d
istri
butio
ns o
f man
ner o
f dis
ease
pro
gres
sion
(new
lesi
on o
r pro
gres
sion
of e
xist
ing
lesi
on).
[3] H
ypot
hesi
s 2 is
equ
ival
ent d
istri
butio
ns o
f site
of p
rogr
essi
on w
ith p
rogr
essi
on o
f an
exis
ting
lesi
on g
roup
ed in
a si
ngle
cat
egor
y (i.
e., r
egar
dles
s of s
ite).
Prog
ram
mer
not
es: (
a) re
peat
this
tabl
e us
ing
the
per-
prot
ocol
pop
ulat
ion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 7
2/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
1.1
O
vera
ll Su
mm
ary
of T
reat
men
t-E
mer
gent
Adv
erse
Eve
nts (
TE
AE
s)
Sa
fety
Pop
ulat
ion
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Subj
ects
Rep
ortin
g at
Lea
st O
ne T
EAE
xx (x
x.x%
) xx
(xx.
x%)
Su
bjec
ts R
epor
ting
at L
east
One
TEA
E xx
(xx.
x%)
xx (x
x.x%
) Su
bjec
ts R
epor
ting
at L
east
One
TEA
E R
elat
ed to
Stu
dy D
rug
[1]
xx (x
x.x%
) xx
(xx.
x%)
Subj
ects
Rep
ortin
g at
Lea
st O
ne T
EAE
Rel
ated
to E
topo
side
xx
(xx.
x%)
xx (x
x.x%
) Su
bjec
ts R
epor
ting
at L
east
One
TEA
E R
elat
ed to
Pla
tinum
The
rapy
xx
(xx.
x%)
xx (x
x.x%
)
Subj
ects
Rep
ortin
g at
Lea
st O
ne S
erio
us T
EAE
xx (x
x.x%
) xx
(xx.
x%)
Subj
ects
Rep
ortin
g at
Lea
st O
ne S
erio
us T
EAE
Rel
ated
to S
tudy
Dru
g [1
] xx
(xx.
x%)
xx (x
x.x%
) Su
bjec
ts R
epor
ting
at L
east
One
Ser
ious
TEA
E R
elat
ed to
Eto
posid
e xx
(xx.
x%)
xx (x
x.x%
) Su
bjec
ts R
epor
ting
at L
east
One
Ser
ious
TEA
E R
elat
ed to
Pla
tinum
The
rapy
xx
(xx.
x%)
xx (x
x.x%
)
Subj
ects
Rep
ortin
g at
Lea
st O
ne G
rade
3 o
r Hig
her T
EAE
xx (x
x.x%
) xx
(xx.
x%)
Subj
ects
Rep
ortin
g at
Lea
st O
ne G
rade
4 o
r Hig
her T
EAE
xx (x
x.x%
) xx
(xx.
x%)
Su
bjec
ts R
epor
ting
TEA
E Le
adin
g to
Del
ay/In
terr
uptio
n of
Stu
dy D
rug
[1]
xx (x
x.x%
) xx
(xx.
x%)
Subj
ects
Rep
ortin
g TE
AE
Lead
ing
to D
elay
/Inte
rrup
tion
of E
topo
side
xx (x
x.x%
) xx
(xx.
x%)
Subj
ects
Rep
ortin
g TE
AE
Lead
ing
to D
elay
/Inte
rrup
tion
of P
latin
um T
hera
py
xx (x
x.x%
) xx
(xx.
x%)
Su
bjec
ts R
epor
ting
TEA
E Le
adin
g to
Dos
e R
educ
tion
of S
tudy
Dru
g [1
] xx
(xx.
x%)
xx (x
x.x%
) Su
bjec
ts R
epor
ting
TEA
E Le
adin
g to
Dos
e R
educ
tion
of E
topo
side
xx (x
x.x%
) xx
(xx.
x%)
Subj
ects
Rep
ortin
g TE
AE
Lead
ing
to D
ose
Red
uctio
n of
Pla
tinum
The
rapy
xx
(xx.
x%)
xx (x
x.x%
)
Subj
ects
Rep
ortin
g TE
AE
Lead
ing
to W
ithdr
awal
of S
tudy
Dru
g [1
] xx
(xx.
x%)
xx (x
x.x%
) Su
bjec
ts R
epor
ting
TEA
E Le
adin
g to
With
draw
al o
f Eto
posid
e xx
(xx.
x%)
xx (x
x.x%
) Su
bjec
ts R
epor
ting
TEA
E Le
adin
g to
With
draw
al o
f Pla
tinum
The
rapy
xx
(xx.
x%)
xx (x
x.x%
)
Subj
ects
Rep
ortin
g TE
AE
with
Out
com
e of
Dea
th
xx (x
x.x%
) xx
(xx.
x%)
M
axim
um C
TCA
E Se
verit
y G
rade
[2]
G
rade
1
xx (x
x.x%
) xx
(xx.
x%)
G
rade
2
xx (x
x.x%
) xx
(xx.
x%)
G
rade
3
xx (x
x.x%
) xx
(xx.
x%)
G
rade
4
xx (x
x.x%
) xx
(xx.
x%)
G
rade
5
xx (x
x.x%
) xx
(xx.
x%)
[1
] St
udy
drug
= ta
rext
umab
or p
lace
bo.
[2] C
TCA
E =
Com
mon
Ter
min
olog
y C
riter
ia fo
r Adv
erse
Eve
nts (
vers
ion
4.02
). Su
bjec
ts w
ith m
ore
than
one
TEA
E ar
e co
unte
d on
ly o
nce
at th
e hi
ghes
t CTC
AE
seve
rity
grad
e ac
ross
all
TEA
Es.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 7
3/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
1.2
T
reat
men
t-E
mer
gent
Adv
erse
Eve
nts (
TE
AE
s) b
y Sy
stem
Org
an C
lass
and
Pre
ferr
ed T
erm
Safe
ty P
opul
atio
n
Syst
em O
rgan
Cla
ss /
Pr
efer
red
Term
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Subj
ects
Rep
ortin
g at
Lea
st O
ne Q
ualif
ying
TEA
E
xx (x
x.x%
) xx
(xx.
x%)
Sy
stem
Org
an C
lass
1
xx (x
x.x%
) xx
(xx.
x%)
Pr
efer
red
Term
1.1
xx
(xx.
x%)
xx (x
x.x%
)
Pref
erre
d Te
rm 1
.2
xx (x
x.x%
) xx
(xx.
x%)
Pr
efer
red
Term
1.3
xx
(xx.
x%)
xx (x
x.x%
)
[etc
eter
a]
[⁞]
[⁞]
Sy
stem
Org
an C
lass
2
xx (x
x.x%
) xx
(xx.
x%)
Pr
efer
red
Term
2.1
xx
(xx.
x%)
xx (x
x.x%
)
Pref
erre
d Te
rm 2
.2
xx (x
x.x%
) xx
(xx.
x%)
Pr
efer
red
Term
2.3
xx
(xx.
x%)
xx (x
x.x%
)
[etc
eter
a]
[⁞]
[⁞]
N
ote:
At e
ach
leve
l of s
umm
atio
n (o
vera
ll, sy
stem
org
an c
lass
, pre
ferr
ed te
rm),
subj
ects
repo
rting
mor
e th
an o
ne a
dver
se e
vent
are
cou
nted
onl
y on
ce.
Prog
ram
mer
not
es: (
a) p
rim
ary
sort
ord
er is
des
cend
ing
SOC
freq
uenc
y un
der t
arex
tum
ab, s
econ
dary
sort
ord
er is
des
cend
ing
PT fr
eque
ncy
unde
r tar
extu
mab
; (b)
dup
licat
e th
is ta
ble
for t
he
follo
wing
TEA
E su
bset
s mak
ing
the
nece
ssar
y ch
ange
s to
the
tabl
e’s t
itle
– (i)
TEA
Es re
late
d to
stud
y dr
ug, (
ii) T
EAEs
rela
ted
to e
topo
side
, (iii
) TEA
Es re
late
d to
pla
tinum
ther
apy,
(iv)
seri
ous
TEAE
s, (v
) ser
ious
TEA
Es re
late
d to
stud
y dr
ug, (
vi) s
erio
us T
EAEs
rela
ted
to e
topo
side,
(vii)
seri
ous T
EAEs
rela
ted
to p
latin
um th
erap
y, (v
iii) T
EAEs
lead
ing
to d
elay
/inte
rrup
tion
of st
udy
drug
, (ix
) TE
AEs l
eadi
ng to
del
ay/in
terr
uptio
n of
eto
posi
de, (
x) T
EAEs
lead
ing
to d
elay
/inte
rrup
tion
of p
latin
um th
erap
y, (x
i) TE
AEs l
eadi
ng to
dos
e re
duct
ion
of st
udy
drug
, (xi
i) TE
AEs l
eadi
ng to
dos
e re
duct
ion
of e
topo
side,
(xiii
) TEA
Es le
adin
g to
dos
e re
duct
ion
of p
latin
um th
erap
y, (x
iv) T
EAEs
lead
ing
to w
ithdr
awal
of s
tudy
dru
g, (x
v) T
EAEs
lead
ing
to w
ithdr
awal
of e
topo
side,
(xvi
) TEA
Es
lead
ing
to w
ithdr
awal
of p
latin
um th
erap
y, (x
vii)
TEAE
s lea
ding
to d
isco
ntin
uatio
n of
stud
y dr
ug, (
xviii
) TEA
Es w
ith o
utco
me
of d
eath
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 7
4/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
1.6
T
reat
men
t-E
mer
gent
Adv
erse
Eve
nts b
y Sy
stem
Org
an C
lass
, Pre
ferr
ed T
erm
and
CT
CA
E S
ever
ity G
rade
Safe
ty P
opul
atio
n Sy
stem
Org
an C
lass
/
Pr
efer
red
Term
Plac
ebo
(N=
)
Tare
xtum
ab
(N=
)
Gra
de 1
G
rade
2
Gra
de 3
G
rade
4
Gra
de 5
To
tal
G
rade
1
Gra
de 2
G
rade
3
Gra
de 4
G
rade
5
Tota
l
Su
bjec
ts R
epor
ting
at L
east
One
Qua
lifyi
ng T
EAE
n (%
) n
(%)
n (%
) n
(%)
n (%
) n
(%)
n
(%)
n (%
) n
(%)
n (%
) n
(%)
n (%
)
Sy
stem
Org
an C
lass
1
n (%
) n
(%)
n (%
) n
(%)
n (%
) n
(%)
n
(%)
n (%
) n
(%)
n (%
) n
(%)
n (%
) Pr
efer
red
Term
1
n (%
) n
(%)
n (%
) n
(%)
n (%
) n
(%)
n
(%)
n (%
) n
(%)
n (%
) n
(%)
n (%
) Pr
efer
red
Term
2
n (%
) n
(%)
n (%
) n
(%)
n (%
) n
(%)
n
(%)
n (%
) n
(%)
n (%
) n
(%)
n (%
) .
.
Sy
stem
Org
an C
lass
2
n (%
) n
(%)
n (%
) n
(%)
n (%
) n
(%)
n
(%)
n (%
) n
(%)
n (%
) n
(%)
n (%
) Pr
efer
red
Term
1
n (%
) n
(%)
n (%
) n
(%)
n (%
) n
(%)
n
(%)
n (%
) n
(%)
n (%
) n
(%)
n (%
) Pr
efer
red
Term
2
n (%
) n
(%)
n (%
) n
(%)
n (%
) n
(%)
n
(%)
n (%
) n
(%)
n (%
) n
(%)
n (%
) .
.
N
ote:
Gra
de 1
= M
ild; G
rade
2 =
Mod
erat
e; G
rade
3 =
Sev
ere;
Gra
de 4
= L
ife T
hrea
teni
ng; G
rade
5 =
Fat
al.
At e
ach
leve
l of s
umm
atio
n (o
vera
ll, sy
stem
org
an c
lass
, and
pre
ferr
ed te
rm),
subj
ects
repo
rting
mor
e th
an o
ne q
ualif
ying
eve
nt a
re c
ount
ed o
nly
once
at t
he h
ighe
st C
TCA
E se
verit
y gr
ade.
Prog
ram
mer
not
es: (
a) p
rim
ary
sort
ord
er is
des
cend
ing
SOC
freq
uenc
y un
der t
arex
tum
ab, s
econ
dary
sort
ord
er is
des
cend
ing
PT (t
otal
) fre
quen
cy u
nder
tare
xtum
ab (t
otal
freq
uenc
y [i.
e., s
um o
f fr
eque
ncie
s for
gra
des 1
thro
ugh
5] e
ven
thou
gh to
tal f
requ
ency
is n
ot d
ispl
ayed
in ta
ble)
; (b)
dup
licat
e th
is ta
ble
for t
he fo
llow
ing
TEAE
subs
ets m
akin
g th
e ne
cess
ary
chan
ges t
o th
e ta
ble’
s titl
e –
(i)
TEAE
s rel
ated
to st
udy
drug
, (ii)
TEA
Es re
late
d to
eto
posi
de, (
iii) T
EAEs
rela
ted
to p
latin
um th
erap
y, (i
v) se
riou
s TEA
Es, (
v) se
riou
s TEA
Es re
late
d to
stu
dy d
rug,
(vi)
seri
ous T
EAEs
rela
ted
to
etop
osid
e, (v
ii) se
riou
s TEA
Es re
late
d to
pla
tinum
ther
apy
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 7
5/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
1.10
Tre
atm
ent-
Em
erge
nt A
dver
se E
vent
s by
Pref
erre
d T
erm
Safe
ty P
opul
atio
n
Pref
erre
d Te
rm
Plac
ebo
(N=x
x)
Tare
xtum
ab
(N=x
x)
Su
bjec
ts R
epor
ting
at L
east
One
Qua
lifyi
ng T
EAE
xx (x
x.x%
) xx
(xx.
x%)
Pr
efer
red
Term
1
xx (x
x.x%
) xx
(xx.
x%)
Pref
erre
d Te
rm 2
xx
(xx.
x%)
xx (x
x.x%
) Pr
efer
red
Term
3
xx (x
x.x%
) xx
(xx.
x%)
Pref
erre
d Te
rm 4
xx
(xx.
x%)
xx (x
x.x%
) Pr
efer
red
Term
5
xx (x
x.x%
) xx
(xx.
x%)
Pref
erre
d Te
rm 6
xx
(xx.
x%)
xx (x
x.x%
) [e
tcet
era]
[⁞]
[⁞]
Not
e: A
t eac
h le
vel o
f sum
mat
ion
(ove
rall
and
pref
erre
d te
rm),
subj
ects
repo
rting
mor
e th
an o
ne q
ualif
ying
eve
nt a
re c
ount
ed o
nly
once
.
Prog
ram
mer
not
es: (
a) p
rim
ary
sort
ord
er is
des
cend
ing
PT fr
eque
ncy
unde
r tar
extu
mab
; (b)
dup
licat
e th
is ta
ble
for t
he fo
llow
ing
TEAE
subs
ets m
akin
g th
e ne
cess
ary
chan
ges t
o th
e ta
ble’
s titl
e –
(i)
TEAE
s rel
ated
to st
udy
drug
, (ii)
TEA
Es re
late
d to
eto
posi
de, (
iii) T
EAEs
rela
ted
to p
latin
um th
erap
y, (i
v) se
riou
s TEA
Es, (
v) se
riou
s TEA
Es re
late
d to
stud
y dr
ug, (
vi) s
erio
us T
EAEs
rela
ted
to
etop
osid
e, (v
ii) se
riou
s TEA
Es re
late
d to
pla
tinum
ther
apy,
(viii
) TEA
Es le
adin
g to
del
ay/in
terr
uptio
n of
stud
y dr
ug, (
ix) T
EAE
s lea
ding
to d
elay
/inte
rrup
tion
of e
topo
side,
(x) T
EAEs
lead
ing
to
dela
y/in
terr
uptio
n of
pla
tinum
ther
apy,
(xi)
TEAE
s lea
ding
to d
ose
redu
ctio
n of
stud
y dr
ug, (
xii)
TEAE
s lea
ding
to d
ose
redu
ctio
n of
eto
posid
e, (x
iii) T
EAEs
lead
ing
to d
ose
redu
ctio
n of
pla
tinum
th
erap
y, (x
iv) T
EAEs
lead
ing
to w
ithdr
awal
of s
tudy
dru
g, (x
v) T
EAEs
lead
ing
to w
ithdr
awal
of e
topo
side
, (xv
i) TE
AEs l
eadi
ng to
with
draw
al o
f pla
tinum
ther
apy,
(xvi
i) TE
AEs
lead
ing
to d
isco
ntin
uatio
n of
stud
y dr
ug, (
xviii
) TEA
Es w
ith o
utco
me
of d
eath
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 7
6/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.1
H
emat
olog
y
Safe
ty P
opul
atio
n
Plac
ebo
(N=x
x)
Ta
rext
umab
(N
=xx)
Labo
rato
ry P
aram
eter
Ti
me
Poin
t R
esul
t C
hang
e fro
m
Bas
elin
e
Res
ult
Cha
nge
from
B
asel
ine
H
emog
lobi
n (g
/dL)
B
asel
ine
[1]
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
)
xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
Max
imum
Pos
t-Bas
elin
e
n xx
xx
xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
xx
.x (x
x.xx
) xx
.x (x
x.xx
)
M
edia
n xx
xx
xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
xx
, xx
xx, x
x
M
in, M
ax
xx, x
x xx
, xx
xx
, xx
xx, x
x
M
inim
um P
ost-B
asel
ine
n
xx
xx
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
Med
ian
xx
xx
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
xx, x
x xx
, xx
Min
, Max
xx
, xx
xx, x
x
xx, x
x xx
, xx
Last
Obs
erva
tion
Post
-Bas
elin
e
n xx
xx
xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
xx
.x (x
x.xx
) xx
.x (x
x.xx
)
M
edia
n xx
xx
xx
xx
25th
, 75th
Perc
entil
e xx
, xx
xx, x
x
xx, x
x xx
, xx
Min
, Max
xx
, xx
xx, x
x
xx, x
x xx
, xx
H
emat
ocrit
(%)
Bas
elin
e [1
]
[etc
eter
a]
[⁞]
[⁞]
[⁞]
[⁞]
[⁞]
[1
] B
asel
ine
is d
efin
ed a
s the
last
non
-mis
sing
val
ue p
rior t
o fir
st d
ose
of st
udy
drug
.
Prog
ram
mer
not
es: (
a) c
ontin
ue fo
r all
rem
aini
ng h
emat
olog
y pa
ram
eter
s; (b
) dup
licat
e ta
ble
for (
i) se
rum
che
mis
try,
(ii)
coag
ulat
ion
test
s (PT
, aPT
T an
d IN
R)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 7
7/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.2
H
emat
olog
y –
Shift
from
Bas
elin
e
Safe
ty P
opul
atio
n
Labo
rato
ry P
aram
eter
Shift
from
Bas
elin
e [1
] P
lace
bo
(N=
)
Tare
xtum
ab
(N=
)
Hem
oglo
bin
(g/d
L)
Low
or N
orm
al to
Any
Hig
h Po
st-B
asel
ine
n (%
) n
(%)
N
orm
al o
r Hig
h to
Any
Low
Pos
t-Bas
elin
e n
(%)
n (%
)
Low
or N
orm
al to
Las
t Obs
erva
tion
Hig
h Po
st-B
asel
ine
n (%
) n
(%)
N
orm
al o
r Hig
h to
Las
t Obs
erva
tion
Low
Pos
t-Bas
elin
e n
(%)
n (%
)
H
emat
ocrit
(%)
…
.
[1] B
asel
ine
is d
efin
ed a
s the
last
non
-mis
sing
val
ue p
rior t
o fir
st d
ose
of st
udy
drug
.
Prog
ram
mer
not
es: (
a) c
ontin
ue fo
r all
rem
aini
ng h
emat
olog
y pa
ram
eter
s; (b
) dup
licat
e ta
ble
for (
i) se
rum
che
mis
try,
(ii)
coag
ulat
ion
test
s (PT
, aPT
T an
d IN
R)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 7
8/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.3
H
emat
olog
y –
Ran
ge C
hang
e A
bnor
mal
– H
igh
Sa
fety
Pop
ulat
ion
Labo
rato
ry P
aram
eter
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Hem
oglo
bin
(g/d
L)
n
xx (x
x.x%
) xx
(xx.
x%)
A
ny P
ost-B
asel
ine
[1]
Gra
de 4
xx
(xx.
x%)
xx (x
x.x%
)
G
rade
3
xx (x
x.x%
) xx
(xx.
x%)
Gra
de 2
xx
(xx.
x%)
xx (x
x.x%
)
G
rade
1
xx (x
x.x%
) xx
(xx.
x%)
Last
Obs
erva
tion
Post
-Bas
elin
e
G
rade
4
xx (x
x.x%
) xx
(xx.
x%)
Gra
de 3
xx
(xx.
x%)
xx (x
x.x%
)
G
rade
2
xx (x
x.x%
) xx
(xx.
x%)
Gra
de 1
xx
(xx.
x%)
xx (x
x.x%
)
Plat
elet
s (x1
0^9/
L)
[etc
eter
a]
[⁞]
[⁞]
[1
] Sub
ject
s are
cou
nted
onl
y on
ce u
sing
thei
r hig
hest
pos
t-bas
elin
e C
TCA
E se
verit
y gr
ade.
Onl
y pa
tient
s who
hav
e an
incr
ease
in C
TCA
E gr
ade
seve
rity
from
bas
elin
e ar
e co
nsid
ered
for c
ount
s of
Gra
des 1
thro
ugh
4. S
ubje
cts w
ho h
ave
a ba
selin
e re
sult
and
at le
ast o
ne p
ost-b
asel
ine
resu
lt fo
r a p
artic
ular
ana
lyte
are
con
side
red
whe
n de
term
inin
g pe
rcen
tage
s, re
gard
less
of w
heth
er th
e pa
tient
ha
d a
CTC
AE
grad
e co
unte
d fo
r the
ana
lyte
.
Prog
ram
mer
not
es: (
a) c
ontin
ue fo
r all
rem
aini
ng h
emat
olog
y pa
ram
eter
s with
CTC
AE s
ever
ity g
radi
ng c
rite
ria;
(b) d
uplic
ate
tabl
e fo
r (i)
seru
m c
hem
istr
y, (i
i) co
agul
atio
n te
sts (
PT, a
PTT
and
INR)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 7
9/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.13
Uri
naly
sis –
Shi
ft fr
om B
asel
ine
Sa
fety
Pop
ulat
ion
Labo
rato
ry P
aram
eter
Tim
e Po
int
Pla
cebo
(N
= )
Ta
rext
umab
(N
= )
Pr
otei
n n
A
ny P
ost-B
asel
ine
Abs
ent t
o Pr
esen
t n
(%)
n (%
)
Last
Obs
erva
tion
Post
-Bas
elin
e
A
bsen
t to
Pres
ent
n (%
) n
(%)
Glu
cose
n
A
ny P
ost-B
asel
ine
Abs
ent t
o Pr
esen
t n
(%)
n (%
)
Last
Obs
erva
tion
Post
-Bas
elin
e
A
bsen
t to
Pres
ent
n (%
) n
(%)
pH
n
Any
Pos
t-Bas
elin
e
L
ow o
r Nor
mal
to H
igh
n (%
) n
(%)
Nor
mal
or H
igh
to L
ow
n (%
) n
(%)
La
st O
bser
vatio
n Po
st-B
asel
ine
Low
or N
orm
al to
Hig
h n
(%)
n (%
)
N
orm
al o
r Hig
h to
Low
n
(%)
n (%
)
Sp
ecifi
c G
ravi
ty
…
[1] B
asel
ine
is d
efin
ed a
s the
last
non
-mis
sing
val
ue p
rior t
o fir
st d
ose
of st
udy
drug
.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 8
0/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.14
Vita
l Sig
ns
Sa
fety
Pop
ulat
ion
Pl
aceb
o (N
=xx)
Tare
xtum
ab (N
=xx)
Para
met
er
Tim
e Po
int
Res
ult
Cha
nge
from
B
asel
ine
R
esul
t C
hang
e fro
m
Bas
elin
e
Syst
olic
Blo
od P
ress
ure
(mm
Hg)
B
asel
ine
[1]
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
)
xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
Max
imum
Pos
t-Bas
elin
e
n xx
xx
xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
xx
.x (x
x.xx
) xx
.x (x
x.xx
)
M
edia
n xx
xx
xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
xx
, xx
xx, x
x
M
in, M
ax
xx, x
x xx
, xx
xx
, xx
xx, x
x
M
inim
um P
ost-B
asel
ine
n
xx
xx
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
Med
ian
xx
xx
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
xx, x
x xx
, xx
Min
, Max
xx
, xx
xx, x
x
xx, x
x xx
, xx
Last
Obs
erva
tion
Post
-Bas
elin
e
n xx
xx
xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
xx
.x (x
x.xx
) xx
.x (x
x.xx
)
M
edia
n xx
xx
xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
xx
, xx
xx, x
x
M
in, M
ax
xx, x
x xx
, xx
xx
, xx
xx, x
x
Dia
stol
ic B
lood
Pre
ssur
e (m
mH
g)
Bas
elin
e [1
]
[etc
eter
a]
[⁞]
[⁞]
[⁞]
[⁞]
[⁞]
[1
] B
asel
ine
is d
efin
ed a
s the
last
non
-mis
sing
val
ue p
rior t
o fir
st d
ose
of st
udy
drug
.
Prog
ram
mer
not
es: (
a) c
ontin
ue fo
r all
vita
l sig
n pa
ram
eter
s (sy
stol
ic a
nd d
iasto
lic b
lood
pre
ssur
es, p
ulse
, bod
y te
mpe
ratu
re a
nd re
spir
atio
n ra
te)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 8
1/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.15
Vita
l Sig
ns –
Ran
ge C
hang
e A
bnor
mal
(RC
A)
Sa
fety
Pop
ulat
ion
Vita
l Sig
ns P
aram
eter
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
n xx
xx
A
ny P
ost-B
asel
ine
H
igh
[1]
Tem
pera
ture
xx
(xx.
x%)
xx (x
x.x%
)
Pu
lse
Rat
e xx
(xx.
x%)
xx (x
x.x%
)
R
espi
rato
ry R
ate
xx (x
x.x%
) xx
(xx.
x%)
SBP
xx (x
x.x%
) xx
(xx.
x%)
DB
P xx
(xx.
x%)
xx (x
x.x%
)
Lo
w [1
]
Te
mpe
ratu
re
xx (x
x.x%
) xx
(xx.
x%)
Puls
e R
ate
xx (x
x.x%
) xx
(xx.
x%)
Res
pira
tory
Rat
e
xx (x
x.x%
) xx
(xx.
x%)
SBP
xx (x
x.x%
) xx
(xx.
x%)
DB
P xx
(xx.
x%)
xx (x
x.x%
)
Last
Pos
t-Bas
elin
e V
isit
H
igh[1
]
Te
mpe
ratu
re
xx (x
x.x%
) xx
(xx.
x%)
Puls
e R
ate
xx
(xx.
x%)
xx (x
x.x%
)
R
espi
rato
ry R
ate
xx
(xx.
x%)
xx (x
x.x%
)
SB
P xx
(xx.
x%)
xx (x
x.x%
)
D
BP
xx (x
x.x%
) xx
(xx.
x%)
Low
[1]
Tem
pera
ture
xx
(xx.
x%)
xx (x
x.x%
)
Pu
lse
Rat
e
xx (x
x.x%
) xx
(xx.
x%)
Res
pira
tory
Rat
e
xx (x
x.x%
) xx
(xx.
x%)
SBP
xx (x
x.x%
) xx
(xx.
x%)
DB
P xx
(xx.
x%)
xx (x
x.x%
)
Not
e: S
BP=S
ysto
lic B
lood
Pre
ssur
e. D
BP=
Dia
stol
ic B
lood
Pre
ssur
e. N
orm
al R
ange
Tem
pera
ture
: 36.
6°C
to 3
7.3°
C. N
orm
al R
ange
SB
P: 9
0-12
0 m
mH
g. N
orm
al R
ange
DB
P: 6
0-80
mm
Hg.
Nor
mal
R
ange
Res
pira
tory
Rat
e: 1
2-18
bre
aths
per
min
ute.
Nor
mal
Ran
ge P
ulse
Rat
e: 6
0-10
0 be
ats p
er m
inut
e.
[1]
Each
subj
ect i
s rep
rese
nted
onc
e by
thei
r wor
st c
hang
e. A
rang
e ch
ange
can
be
eith
er a
cha
nge
in a
vita
l sig
n pa
ram
eter
val
ue fr
om b
asel
ine
low
or n
orm
al to
pos
t-bas
elin
e hi
gh o
r a c
hang
e fro
m
base
line
high
or n
orm
al to
pos
t-bas
elin
e lo
w. A
subj
ect c
an b
e in
clud
ed in
bot
h ‘H
igh’
and
‘Low
’ cat
egor
ies
if ap
plic
able
.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 8
2/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.16
12-L
ead
Ele
ctro
card
iogr
am (E
CG
)
Safe
ty P
opul
atio
n
Plac
ebo
(N=x
x)
Ta
rext
umab
(N=x
x)
Para
met
er
Tim
e Po
int
Res
ult
Cha
nge
from
B
asel
ine
R
esul
t C
hang
e fro
m
Bas
elin
e
QR
S D
urat
ion
(mse
c)
Bas
elin
e [1
]
n xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
M
edia
n xx
xx
25th
, 75th
Per
cent
ile
xx, x
x
xx
, xx
M
in, M
ax
xx, x
x
xx
, xx
M
axim
um P
ost-B
asel
ine
n
xx
xx
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
Med
ian
xx
xx
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
xx, x
x xx
, xx
Min
, Max
xx
, xx
xx, x
x
xx, x
x xx
, xx
Min
imum
Pos
t-Bas
elin
e
n xx
xx
xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
xx
.x (x
x.xx
) xx
.x (x
x.xx
)
M
edia
n xx
xx
xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
xx
, xx
xx, x
x
M
in, M
ax
xx, x
x xx
, xx
xx
, xx
xx, x
x
La
st O
bser
vatio
n Po
st-B
asel
ine
n
xx
xx
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
Med
ian
xx
xx
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
xx, x
x xx
, xx
Min
, Max
xx
, xx
xx, x
x
xx, x
x xx
, xx
PR
Inte
rval
(mse
c)
Bas
elin
e [1
]
[etc
eter
a]
[⁞]
[⁞]
[⁞]
[⁞]
[⁞]
[1
] B
asel
ine
is d
efin
ed a
s the
last
non
-mis
sing
val
ue p
rior t
o fir
st d
ose
of st
udy
drug
.
Prog
ram
mer
not
es: (
a) c
ontin
ue fo
r all
elec
troc
ardi
ogra
m p
aram
eter
s (Q
RS d
urat
ion,
PR
inte
rval
, QTc
Inte
rval
)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 8
3/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.17
12-L
ead
Ele
ctro
card
iogr
am (E
CG
) – R
ange
Cha
nge
Abn
orm
al
Sa
fety
Pop
ulat
ion
ECG
Par
amet
er
Plac
ebo
(N=x
x)
Tare
xtum
ab
(N=x
x)
n
xx
xx
Any
Pos
t-Bas
elin
e
Hig
h [1
]
Q
RS
Dur
atio
n (m
sec)
xx
(xx.
x%)
xx (x
x.x%
)
PR
Inte
rval
(mse
c)
xx (x
x.x%
) xx
(xx.
x%)
QTc
Inte
rval
(mse
c)
xx (x
x.x%
) xx
(xx.
x%)
Low
[1]
QR
S D
urat
ion
(mse
c)
xx (x
x.x%
) xx
(xx.
x%)
PR In
terv
al (m
sec)
xx
(xx.
x%)
xx (x
x.x%
)
Q
Tc In
terv
al (m
sec)
xx
(xx.
x%)
xx (x
x.x%
)
Last
Obs
erva
tion
Post
-Bas
elin
e
Hig
h[1]
QR
S D
urat
ion
(mse
c)
xx (x
x.x%
) xx
(xx.
x%)
PR In
terv
al (m
sec)
xx
(xx.
x%)
xx (x
x.x%
)
Q
Tc In
terv
al (m
sec)
xx
(xx.
x%)
xx (x
x.x%
)
Lo
w[1
]
Q
RS
Dur
atio
n (m
sec)
xx
(xx.
x%)
xx (x
x.x%
)
PR
Inte
rval
(mse
c)
xx (x
x.x%
) xx
(xx.
x%)
QTc
Inte
rval
(mse
c)
xx (x
x.x%
) xx
(xx.
x%)
N
ote:
Ref
eren
ce ra
nges
: QR
S du
ratio
n 80
-100
mse
c; P
R in
terv
al 1
20-2
00 m
sec;
QTc
inte
rval
≤43
0 m
sec
(mal
es), ≤4
50 m
sec
(fem
ales
). [1
] Ea
ch su
bjec
t is r
epre
sent
ed o
nce
by th
eir w
orst
cha
nge.
A ra
nge
chan
ge c
an b
e ei
ther
a c
hang
e in
an
ECG
par
amet
er v
alue
from
bas
elin
e lo
w o
r nor
mal
to p
ost-b
asel
ine
high
or a
cha
nge
from
ba
selin
e hi
gh o
r nor
mal
to p
ost-b
asel
ine
low
. A su
bjec
t can
be
incl
uded
in b
oth
‘Hig
h’ a
nd ‘L
ow’ c
ateg
orie
s if f
its b
oth
cate
gorie
s.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 8
4/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.18
12-L
ead
Ele
ctro
card
iogr
am (E
CG
) – Q
Tc
Inte
rval
Safe
ty P
opul
atio
n
Tim
e Po
int
Plac
ebo
(N=x
x)
Tare
xtum
ab
(N=x
x)
B
asel
ine
[1]
<4
80
xx (x
x.x%
) xx
(xx.
x%)
48
0-50
0 m
sec
xx (x
x.x%
) xx
(xx.
x%)
>5
00 m
sec
xx (x
x.x%
) xx
(xx.
x%)
W
orst
(Max
imum
) Po
st-B
asel
ine
<4
80
xx (x
x.x%
) xx
(xx.
x%)
48
0-50
0 m
sec
xx (x
x.x%
) xx
(xx.
x%)
>5
00 m
sec
xx (x
x.x%
) xx
(xx.
x%)
La
st O
bser
vatio
n Po
st-B
asel
ine
<4
80
xx (x
x.x%
) xx
(xx.
x%)
48
0-50
0 m
sec
xx (x
x.x%
) xx
(xx.
x%)
>5
00 m
sec
xx (x
x.x%
) xx
(xx.
x%)
[1
] Bas
elin
e is
def
ined
as t
he la
st n
on-m
issi
ng v
alue
prio
r to
first
dos
e of
stud
y dr
ug.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 8
5/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.19
12-L
ead
Ele
ctro
card
iogr
am (E
CG
) – O
vera
ll In
terp
reta
tion
Sa
fety
Pop
ulat
ion
Tim
e Po
int
Plac
ebo
(N=
)
Tare
xtum
ab
(N=
)
B
asel
ine
[1]
n
n
n
Nor
mal
n
(%)
n (%
)
Abn
orm
al N
CS
n (%
) n
(%)
A
bnor
mal
CS
n (%
) n
(%)
W
orst
Pos
t-Bas
elin
e
n
n n
Nor
mal
n
(%)
n (%
) A
bnor
mal
NC
S n
(%)
n (%
)
Abn
orm
al C
S n
(%)
n (%
)
La
st O
bser
vatio
n Po
st-B
asel
ine
n
n n
Nor
mal
n
(%)
n (%
) A
bnor
mal
NC
S n
(%)
n (%
)
Abn
orm
al C
S n
(%)
n (%
)
N
ote:
NC
S =
Not
clin
ical
ly si
gnifi
cant
, CS
= C
linic
ally
sign
ifica
nt. P
erce
ntag
es a
re b
ased
on
the
num
ber o
f sub
ject
s with
a n
on-m
issi
ng re
spon
se a
t eac
h vi
sit.
[1] B
asel
ine
is d
efin
ed a
s the
last
non
-mis
sing
val
ue p
rior t
o fir
st d
ose
of st
udy
drug
.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 8
6/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.20
12-L
ead
Ele
ctro
card
iogr
am (E
CG
) – O
vera
ll In
terp
reta
tion
Shift
from
Bas
elin
e
Safe
ty P
opul
atio
n
Bas
elin
e [1
] M
ost E
xtre
me
Post
-Bas
elin
e Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
N
orm
al
Nor
mal
xx
(xx.
x%)
xx (x
x.x%
)
Abn
orm
al -
Not
Clin
ical
ly S
igni
fican
t xx
(xx.
x%)
xx (x
x.x%
)
Abn
orm
al -
Clin
ical
ly S
igni
fican
t xx
(xx.
x%)
xx (x
x.x%
)
A
bnor
mal
- N
ot C
linic
ally
Sig
nific
ant
Nor
mal
xx
(xx.
x%)
xx (x
x.x%
)
Abn
orm
al -
Not
Clin
ical
ly S
igni
fican
t xx
(xx.
x%)
xx (x
x.x%
)
Abn
orm
al -
Clin
ical
ly S
igni
fican
t xx
(xx.
x%)
xx (x
x.x%
)
A
bnor
mal
- C
linic
ally
Sig
nific
ant
Nor
mal
xx
(xx.
x%)
xx (x
x.x%
)
Abn
orm
al -
Not
Clin
ical
ly S
igni
fican
t xx
(xx.
x%)
xx (x
x.x%
)
Abn
orm
al -
Clin
ical
ly S
igni
fican
t xx
(xx.
x%)
xx (x
x.x%
)
[1
] B
asel
ine
is d
efin
ed a
s the
last
non
-mis
sing
val
ue p
rior t
o fir
st d
ose
of st
udy
drug
.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 8
7/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.21
EC
OG
Per
form
ance
Sta
tus
Sa
fety
Pop
ulat
ion
Perfo
rman
ce S
tatu
s Sco
re [1
] Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Bas
elin
e [2
]
n xx
xx
0 xx
(xx.
x%)
xx (x
x.x%
)
1 xx
(xx.
x%)
xx (x
x.x%
)
2 xx
(xx.
x%)
xx (x
x.x%
)
3 xx
(xx.
x%)
xx (x
x.x%
)
4 xx
(xx.
x%)
xx (x
x.x%
)
5 xx
(xx.
x%)
xx (x
x.x%
)
Max
imum
Pos
t-Bas
elin
e
n xx
xx
0 xx
(xx.
x%)
xx (x
x.x%
)
1 xx
(xx.
x%)
xx (x
x.x%
)
2 xx
(xx.
x%)
xx (x
x.x%
)
3 xx
(xx.
x%)
xx (x
x.x%
)
4 xx
(xx.
x%)
xx (x
x.x%
)
5 xx
(xx.
x%)
xx (x
x.x%
)
Min
imum
Pos
t-Bas
elin
e
n xx
xx
0 xx
(xx.
x%)
xx (x
x.x%
)
1 xx
(xx.
x%)
xx (x
x.x%
)
2 xx
(xx.
x%)
xx (x
x.x%
)
3 xx
(xx.
x%)
xx (x
x.x%
)
4 xx
(xx.
x%)
xx (x
x.x%
)
5 xx
(xx.
x%)
xx (x
x.x%
)
Last
Obs
erva
tion
Post
-Bas
elin
e
n xx
xx
0 xx
(xx.
x%)
xx (x
x.x%
)
1 xx
(xx.
x%)
xx (x
x.x%
)
2 xx
(xx.
x%)
xx (x
x.x%
)
3 xx
(xx.
x%)
xx (x
x.x%
)
4 xx
(xx.
x%)
xx (x
x.x%
)
5 xx
(xx.
x%)
xx (x
x.x%
) N
ote:
Per
cent
ages
are
bas
ed o
n th
e nu
mbe
r of p
atie
nts w
ith a
non
-mis
sing
resp
onse
at e
ach
visi
t.
[1] F
or c
ompl
ete
defin
ition
s of e
ach
activ
ity st
atus
cod
e, re
fere
nce
App
endi
x D
of t
he c
linic
al p
roto
col.
[2] B
asel
ine
is d
efin
ed a
s the
last
non
-mis
sing
val
ue p
rior t
o fir
st d
ose
of st
udy
drug
.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 8
8/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.22
E
CO
G P
erfo
rman
ce S
tatu
s – S
hift
from
Bas
elin
e Sa
fety
Pop
ulat
ion
Pe
rform
ance
Sta
tus S
core
[1]
Plac
ebo
(N=
)
Bas
elin
e [2
]
Tare
xtum
ab (N
= )
B
asel
ine
[2]
0 1
0
1
M
axim
um P
ost-B
asel
ine
n
n
n
n n
0
n
(%)
n (%
)
n (%
) n
(%)
1
n
(%)
n (%
)
n (%
) n
(%)
2
n
(%)
n (%
)
n (%
) n
(%)
3
n
(%)
n (%
)
n (%
) n
(%)
4
n
(%)
n (%
)
n (%
) n
(%)
5
n
(%)
n (%
)
n (%
) n
(%)
Min
imum
Pos
t-Bas
elin
e
n
n
n
n n
0
n
(%)
n (%
)
n (%
) n
(%)
1
n
(%)
n (%
)
n (%
) n
(%)
2
n
(%)
n (%
)
n (%
) n
(%)
3
n
(%)
n (%
)
n (%
) n
(%)
4
n
(%)
n (%
)
n (%
) n
(%)
5
n
(%)
n (%
)
n (%
) n
(%)
[1] F
or c
ompl
ete
defin
ition
s of e
ach
activ
ity st
atus
cod
e, re
fere
nce
App
endi
x D
of t
he c
linic
al p
roto
col.
[2]
Bas
elin
e is
def
ined
as t
he la
st n
on-m
issi
ng v
alue
prio
r to
first
dos
e of
stud
y dr
ug.
Prog
ram
min
g no
te: C
ontin
ue fo
r Las
t Obs
erva
tion
Post
-Bas
elin
e.
Prog
ram
min
g no
te: A
dd a
dditi
onal
bas
elin
e co
lum
ns a
s nee
ded.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 8
9/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.23
Ant
i-Tar
extu
mab
Ant
ibod
ies
Im
mun
ogen
icity
Pop
ulat
ion
Tim
e Po
int
Tare
xtum
ab
(N=x
x)
Any
Pos
itive
Sam
ple
Dur
ing
Stud
y xx
(xx.
x%)
Cyc
le 1
, Day
1
Posi
tive
xx (x
x.x%
)
Neg
ativ
e xx
(xx.
x%)
V
iabl
e Sa
mpl
e N
ot A
vaila
ble
xx (x
x.x%
)
C
ycle
3, D
ay 1
Po
sitiv
e xx
(xx.
x%)
N
egat
ive
xx (x
x.x%
)
Via
ble
Sam
ple
Not
Ava
ilabl
e xx
(xx.
x%)
Cyc
le 5
, Day
1
Posi
tive
xx (x
x.x%
)
Neg
ativ
e xx
(xx.
x%)
V
iabl
e Sa
mpl
e N
ot A
vaila
ble
xx (x
x.x%
)
Tr
eatm
ent T
erm
inat
ion
Posi
tive
xx (x
x.x%
)
Neg
ativ
e xx
(xx.
x%)
V
iabl
e Sa
mpl
e N
ot A
vaila
ble
xx (x
x.x%
)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 9
0/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.24
Impa
ct o
f Ant
i-Tar
extu
mab
Ant
ibod
ies o
n Pr
ogre
ssio
n-Fr
ee S
urvi
val
Im
mun
ogen
icity
Pop
ulat
ion
Tare
xtum
ab (N
=xx)
Ant
i-Tar
extu
mab
A
ntib
ody
Neg
ativ
e (N
=xx)
Ant
i-Tar
extu
mab
A
ntib
ody
Posi
tive
(N=x
x)
To
tal F
ollo
w-U
p Ti
me
(per
son-
year
s) [1
] xx
x.x
xxx.
x N
umbe
r of S
ubje
cts w
ith D
isea
se P
rogr
essi
on o
r Dea
th
xx (x
x.x%
) xx
(xx.
x%)
Num
ber o
f Sub
ject
s who
did
not
Pro
gres
s or D
ie (C
enso
red)
xx
(xx.
x%)
xx (x
x.x%
)
Haz
ard
[2]
0.xx
0.
xx
K
apla
n-M
eier
Est
imat
es: Q
uarti
les [
95%
C.I.
] (da
ys)
25
th P
erce
ntile
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
50th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
75
th P
erce
ntile
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
Ran
ge (S
ubje
cts w
ho P
rogr
esse
d or
Die
d) (d
ays)
xx
x, x
xx
xxx,
xxx
R
ange
(All
Subj
ects
) (da
ys)
xxx,
xxx
xx
x, x
xx
H
azar
d R
atio
[95%
C.I.
] [3]
x.
xx [x
.xx,
x.xx
] P-
valu
e [4
]
0.xx
x
Not
e: P
FS=
Dat
e of
Doc
umen
tatio
n of
Dea
th/P
rogr
essi
on –
Ran
dom
izat
ion
Dat
e +
1. S
ubje
cts w
ho h
ad n
ot e
xper
ienc
ed d
eath
or p
rogr
essi
on b
y th
eir l
ast c
onta
ct w
ere
cens
ored
at t
he ti
me
of th
eir l
ast
radi
ogra
phic
resp
onse
ass
essm
ent.
Subj
ects
lack
ing
a ra
diog
raph
ic re
spon
se a
sses
smen
t afte
r ran
dom
izat
ion
who
do
not p
rogr
ess o
r die
hav
e th
eir e
vent
tim
e ce
nsor
ed o
n th
e da
te o
f ran
dom
izat
ion
with
dur
atio
n of
1 d
ay. F
or d
etai
led
even
t and
cen
sorin
g ru
les r
efer
to p
roto
col s
ectio
n 13
.5.1
and
SA
P se
ctio
n 8.
1. C
.I. =
Con
fiden
ce In
terv
al.
[1] Su
m o
f all
indi
vidu
al fo
llow
-up
times
in d
ays d
ivid
ed b
y 36
5.25
. [2
] N
umbe
r of S
ubje
cts w
ith D
isea
se P
rogr
essi
on o
r Dea
th/ T
otal
Fol
low
-up
Tim
e (P
erso
n-ye
ars)
. [3
] H
azar
d ra
tio a
nd 9
5% C
.I. fr
om C
ox p
ropo
rtion
al h
azar
ds m
odel
with
mai
n ef
fect
s for
ant
i-tar
extu
mab
ant
ibod
y st
atus
(pos
itive
or n
egat
ive)
. [4
] P-
valu
e fo
r tre
atm
ent e
ffec
t fro
m u
nstra
tifie
d lo
g ra
nk te
st.
Prog
ram
mer
not
es: (
a) p
erce
ntag
es a
re b
ased
on
the
num
bers
of s
ubje
cts w
ho a
re a
ntib
ody
nega
tive
and
antib
ody
posit
ive,
not
on
the
num
ber o
f sub
ject
s rec
eivi
ng ta
rext
umab
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 9
1/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.25
Impa
ct o
f Ant
i-Tar
extu
mab
Ant
ibod
ies o
n O
vera
ll Su
rviv
al
Im
mun
ogen
icity
Pop
ulat
ion
Tare
xtum
ab (N
=xx)
Ant
i-Tar
extu
mab
A
ntib
ody
Neg
ativ
e (N
=xx)
Ant
i-Tar
extu
mab
A
ntib
ody
Posi
tive
(N=x
x)
To
tal F
ollo
w-U
p Ti
me
(per
son-
year
s) [1
] xx
x.x
xxx.
x N
umbe
r of S
ubje
cts w
ho D
ied
xx (x
x.x%
) xx
(xx.
x%)
Num
ber o
f Sub
ject
s who
did
not
Die
(Cen
sore
d)
xx (x
x.x%
) xx
(xx.
x%)
H
azar
d [2
] 0.
xx
0.xx
Kap
lan-
Mei
er E
stim
ates
: [95
% C
.I.] (
days
)
25th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
50
th P
erce
ntile
(Med
ian)
xx
x [x
xx,x
xx]
xxx
[xxx
,xxx
]
75th
Per
cent
ile
xxx
[xxx
,xxx
] xx
x [x
xx,x
xx]
K
apla
n-M
eier
Est
imat
e (#
at r
isk)
[SE]
180
Day
s 0.
xx (x
x) [x
.xx]
0.
xx (x
x) [x
.xx]
360
Day
s 0.
xx (x
x) [x
.xx]
0.
xx (x
x) [x
.xx]
540
Day
s 0.
xx (x
x) [x
.xx]
0.
xx (x
x) [x
.xx]
720
Day
s 0.
xx (x
x) [x
.xx]
0.
xx (x
x) [x
.xx]
Ran
ge (S
ubje
cts w
ho D
ied)
(day
s)
xxx,
xxx
xx
x, x
xx
Ran
ge (A
ll Su
bjec
ts) (
days
) xx
x, x
xx
xxx,
xxx
Haz
ard
Rat
io [9
5% C
.I.] [3
]
x.xx
[x.x
x,x.
xx]
P-va
lue
[4]
0.
xxx
N
ote:
Ove
rall
Surv
ival
= D
ate
of D
ocum
enta
tion
of D
eath
– R
ando
miz
atio
n D
ate
+ 1.
Sub
ject
s who
had
not
exp
erie
nced
dea
th b
y th
eir l
ast c
onta
ct d
ate
wer
e ce
nsor
ed a
t tha
t tim
e. S
ubje
cts l
acki
ng
data
afte
r ran
dom
izat
ion
who
do
not d
ie h
ave
thei
r eve
nt ti
me
cens
ored
on
the
date
of r
ando
miz
atio
n w
ith d
urat
ion
of 1
day
. For
det
aile
d ev
ent a
nd c
enso
ring
rule
s ref
er to
pro
toco
l sec
tion
13.5
.4 a
nd
SAP
sect
ion
8.6.
C.I.
= C
onfid
ence
Inte
rval
. SE
= St
anda
rd E
rror.
[1] Su
m o
f all
indi
vidu
al fo
llow
-up
times
in d
ays d
ivid
ed b
y 36
5.25
. [2
] Num
ber o
f Sub
ject
s who
Die
d/ T
otal
Fol
low
-up
Tim
e (P
erso
n-ye
ars)
. [3
] H
azar
d ra
tio a
nd 9
5% C
.I. fr
om C
ox p
ropo
rtion
al h
azar
ds m
odel
with
mai
n ef
fect
s for
ant
i-tar
extu
mab
ant
ibod
y st
atus
(pos
itive
or n
egat
ive)
. [4
] P-
valu
e fo
r tre
atm
ent e
ffec
t fro
m u
nstra
tifie
d lo
g ra
nk te
st.
Prog
ram
mer
not
es: (
a) p
erce
ntag
es a
re b
ased
on
the
num
bers
of s
ubje
cts w
ho a
re a
ntib
ody
nega
tive
and
antib
ody
posit
ive,
not
on
the
num
ber o
f sub
ject
s rec
eivi
ng ta
rext
umab
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 9
2/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.26
Ove
rall
Sum
mar
y of
Im
pact
of A
nti-T
arex
tum
ab A
ntib
odie
s on
Tre
atm
ent-
Em
erge
nt A
dver
se E
vent
s (T
EA
Es)
Imm
unog
enic
ity P
opul
atio
n
Ta
rext
umab
(N=x
x)
Ant
i-Tar
extu
mab
A
ntib
ody
Neg
ativ
e (N
=xx)
Ant
i-Tar
extu
mab
A
ntib
ody
Posi
tive
(N=x
x)
Su
bjec
ts R
epor
ting
at L
east
One
TEA
E xx
(xx.
x%)
xx (x
x.x%
)
Subj
ects
Rep
ortin
g at
Lea
st O
ne S
erio
us T
EAE
xx (x
x.x%
) xx
(xx.
x%)
Subj
ects
Rep
ortin
g at
Lea
st O
ne S
erio
us T
EAE
Rel
ated
to T
arex
tum
ab
xx (x
x.x%
) xx
(xx.
x%)
Subj
ects
Rep
ortin
g at
Lea
st O
ne S
erio
us T
EAE
Rel
ated
to E
topo
side
xx (x
x.x%
) xx
(xx.
x%)
Subj
ects
Rep
ortin
g at
Lea
st O
ne S
erio
us T
EAE
Rel
ated
to P
latin
um T
hera
py
xx (x
x.x%
) xx
(xx.
x%)
Su
bjec
ts R
epor
ting
at L
east
One
Gra
de 3
or H
ighe
r TEA
E xx
(xx.
x%)
xx (x
x.x%
) Su
bjec
ts R
epor
ting
at L
east
One
Gra
de 4
or H
ighe
r TEA
E xx
(xx.
x%)
xx (x
x.x%
)
Subj
ects
Rep
ortin
g TE
AE
Lead
ing
to D
elay
/Inte
rrup
tion
of T
arex
tum
ab
xx (x
x.x%
) xx
(xx.
x%)
Subj
ects
Rep
ortin
g TE
AE
Lead
ing
to D
elay
/Inte
rrup
tion
of E
topo
side
xx (x
x.x%
) xx
(xx.
x%)
Subj
ects
Rep
ortin
g TE
AE
Lead
ing
to D
elay
/Inte
rrup
tion
of P
latin
um T
hera
py
xx (x
x.x%
) xx
(xx.
x%)
Su
bjec
ts R
epor
ting
TEA
E Le
adin
g to
Dos
e R
educ
tion
of T
arex
tum
ab
xx (x
x.x%
) xx
(xx.
x%)
Subj
ects
Rep
ortin
g TE
AE
Lead
ing
to D
ose
Red
uctio
n of
Eto
posid
e xx
(xx.
x%)
xx (x
x.x%
) Su
bjec
ts R
epor
ting
TEA
E Le
adin
g to
Dos
e R
educ
tion
of P
latin
um T
hera
py
xx (x
x.x%
) xx
(xx.
x%)
Su
bjec
ts R
epor
ting
TEA
E Le
adin
g to
With
draw
al o
f Tar
extu
mab
xx
(xx.
x%)
xx (x
x.x%
) Su
bjec
ts R
epor
ting
TEA
E Le
adin
g to
With
draw
al o
f Eto
posid
e xx
(xx.
x%)
xx (x
x.x%
) Su
bjec
ts R
epor
ting
TEA
E Le
adin
g to
With
draw
al o
f Pla
tinum
The
rapy
xx
(xx.
x%)
xx (x
x.x%
)
Subj
ects
Rep
ortin
g TE
AE
with
Out
com
e of
Dea
th
xx (x
x.x%
) xx
(xx.
x%)
M
axim
um C
TCA
E Se
verit
y G
rade
[1]
G
rade
1
xx (x
x.x%
) xx
(xx.
x%)
G
rade
2
xx (x
x.x%
) xx
(xx.
x%)
G
rade
3
xx (x
x.x%
) xx
(xx.
x%)
G
rade
4
xx (x
x.x%
) xx
(xx.
x%)
G
rade
5
xx (x
x.x%
) xx
(xx.
x%)
[1
] CTC
AE
= C
omm
on T
erm
inol
ogy
Crit
eria
for A
dver
se E
vent
s (ve
rsio
n 4.
02).
Subj
ects
with
mor
e th
an o
ne T
EAE
are
coun
ted
only
onc
e at
the
high
est C
TCA
E se
verit
y gr
ade
acro
ss a
ll TE
AEs
.
Prog
ram
mer
not
es: (
a) p
erce
ntag
es a
re b
ased
on
the
num
bers
of s
ubje
cts w
ho a
re a
ntib
ody
nega
tive
and
antib
ody
posit
ive,
not
on
the
num
ber o
f sub
ject
s rec
eivi
ng ta
rext
umab
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 9
3/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
4.27
Impa
ct o
f Ant
i-Tar
extu
mab
Ant
ibod
ies T
reat
men
t-E
mer
gent
Adv
erse
Eve
nts (
TE
AE
s)
Sa
fety
Pop
ulat
ion
Tare
xtum
ab (N
=xx)
Pref
erre
d Te
rm
Ant
i-Tar
extu
mab
A
ntib
ody
Neg
ativ
e (N
=xx)
Ant
i-Tar
extu
mab
A
ntib
ody
Posi
tive
(N=x
x)
Su
bjec
ts R
epor
ting
at L
east
One
TEA
E xx
(xx.
x%)
xx (x
x.x%
)
Pref
erre
d Te
rm 1
xx
(xx.
x%)
xx (x
x.x%
) Pr
efer
red
Term
2
xx (x
x.x%
) xx
(xx.
x%)
Pref
erre
d Te
rm 3
xx
(xx.
x%)
xx (x
x.x%
) Pr
efer
red
Term
4
xx (x
x.x%
) xx
(xx.
x%)
Pref
erre
d Te
rm 5
xx
(xx.
x%)
xx (x
x.x%
) Pr
efer
red
Term
6
xx (x
x.x%
) xx
(xx.
x%)
[etc
eter
a]
[⁞]
[⁞]
N
ote:
At e
ach
leve
l of s
umm
atio
n (o
vera
ll an
d pr
efer
red
term
), su
bjec
ts re
porti
ng m
ore
than
one
qua
lifyi
ng e
vent
are
cou
nted
onl
y on
ce.
Prog
ram
mer
not
es: (
a) p
erce
ntag
es a
re b
ased
on
the
num
bers
of s
ubje
cts w
ho a
re a
ntib
ody
nega
tive
and
antib
ody
posit
ive,
not
on
the
num
ber o
f sub
ject
s rec
eivi
ng ta
rext
umab
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 9
4/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
5.1
St
udy
Dru
g Ex
posu
re –
Tar
extu
mab
/Pla
cebo
Safe
ty P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Trea
tmen
t Cyc
les
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
Num
ber o
f Inf
usio
ns A
dmin
iste
red
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
Tota
l Dos
e A
dmin
iste
red
(mg)
[1]
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
Dur
atio
n of
Tre
atm
ent (
days
) [2]
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
Dos
e In
tens
ity
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
[1] Pl
aceb
o ex
posu
re is
sum
mar
ized
in ta
rext
umab
-equ
ival
ent u
nits
(i.e
., th
e nu
mbe
r of m
illig
ram
s of t
arex
tum
ab th
e pl
aceb
o “r
epla
ced”
dur
ing
treat
men
t-blin
ded
dosi
ng).
[2] D
urat
ion
of tr
eatm
ent =
num
ber o
f day
s fro
m th
e fir
st d
ose
(Day
1) u
ntil
the
last
dos
e.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 9
5/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
5.2
D
osin
g C
ompl
ianc
e –
Tar
extu
mab
/Pla
cebo
Safe
ty P
opul
atio
n
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Dos
ing
Com
plia
nce
(%) [1
]
n xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
M
edia
n xx
xx
25th
, 75t
h Pe
rcen
tile
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
0%
to <
20%
Dos
ing
Com
plia
nce
xx (x
x.x%
) xx
(xx.
x%)
20%
to <
40%
Dos
ing
Com
plia
nce
xx (x
x.x%
) xx
(xx.
x%)
40%
to <
60%
Dos
ing
Com
plia
nce
xx (x
x.x%
) xx
(xx.
x%)
60%
to <
80%
Dos
ing
Com
plia
nce
xx (x
x.x%
) xx
(xx.
x%)
80%
to <
100%
Dos
ing
Com
plia
nce
xx (x
x.x%
) xx
(xx.
x%)
100%
Dos
ing
Com
plia
nce
xx (x
x.x%
) xx
(xx.
x%)
N
umbe
r of M
isse
d D
oses
xx
xx
R
easo
n fo
r Mis
sed
Dos
e
Adv
erse
Eve
nt
xx
xx
O
ther
xx
xx
Num
ber o
f Del
ayed
Dos
es
xx
xx
Rea
son
for D
elay
ed D
ose
A
dver
se E
vent
xx
xx
Oth
er
xx
xx
N
umbe
r of R
educ
ed D
oses
xx
xx
R
easo
n fo
r Red
uced
Dos
e
Adv
erse
Eve
nt
xx
xx
O
ther
xx
xx
[1] D
osin
g co
mpl
ianc
e =
(num
ber o
f dos
es a
dmin
iste
red)
/ nu
mbe
r of p
lann
ed d
oses
x 1
00.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 9
6/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
5.3
St
udy
Dru
g Ex
posu
re –
Eto
posi
de
Sa
fety
Pop
ulat
ion
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Trea
tmen
t Cyc
les
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
Num
ber o
f Inf
usio
ns A
dmin
iste
red
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
Tota
l Dos
e A
dmin
iste
red
(mg)
n xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
M
edia
n xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
D
urat
ion
of T
reat
men
t (da
ys) [1
]
n xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
M
edia
n xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
D
ose
Inte
nsity
n xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
M
edia
n xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
[1
] D
urat
ion
of tr
eatm
ent =
num
ber o
f day
s fro
m th
e fir
st d
ose
(Day
1) u
ntil
the
last
dos
e.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 9
7/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
5.4
D
osin
g C
ompl
ianc
e –
Eto
posi
de
Sa
fety
Pop
ulat
ion
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Dos
ing
Com
plia
nce
[1]
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
0% to
<20
% D
osin
g Co
mpl
ianc
e xx
(xx.
x%)
xx (x
x.x%
) 20
% to
<40
% D
osin
g C
ompl
ianc
e xx
(xx.
x%)
xx (x
x.x%
) 40
% to
<60
% D
osin
g C
ompl
ianc
e xx
(xx.
x%)
xx (x
x.x%
) 60
% to
<80
% D
osin
g C
ompl
ianc
e xx
(xx.
x%)
xx (x
x.x%
) 80
% to
<10
0% D
osin
g Co
mpl
ianc
e xx
(xx.
x%)
xx (x
x.x%
) 10
0% D
osin
g C
ompl
ianc
e xx
(xx.
x%)
xx (x
x.x%
)
Num
ber o
f Mis
sed
Dos
es
xx
xx
Rea
son
for M
isse
d D
ose
A
dver
se E
vent
xx
xx
Oth
er
xx
xx
N
umbe
r of D
elay
ed D
oses
xx
xx
R
easo
n fo
r Del
ayed
Dos
e
Adv
erse
Eve
nt
xx
xx
O
ther
xx
xx
[1] D
osin
g co
mpl
ianc
e =
(num
ber o
f dos
es a
dmin
iste
red)
/ nu
mbe
r of p
lann
ed d
oses
.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 9
8/14
9
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
5.5
St
udy
Dru
g Ex
posu
re –
Cis
plat
in
Sa
fety
Pop
ulat
ion
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Plat
inum
The
rapy
[1]
C
ispl
atin
xx
(xx.
x%)
xx (x
x.x%
)
Car
bopl
atin
xx
(xx.
x%)
xx (x
x.x%
)
Trea
tmen
t Cyc
les
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
Num
ber o
f Inf
usio
ns A
dmin
iste
red
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
Tota
l Dos
e A
dmin
iste
red
(mg)
n xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
M
edia
n xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
D
urat
ion
of T
reat
men
t (da
ys) [2
]
n xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
M
edia
n xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
D
ose
Inte
nsity
n xx
xx
Mea
n (S
D)
xx.x
(xx.
xx)
xx.x
(xx.
xx)
M
edia
n xx
xx
25th
, 75th
Per
cent
ile
xx, x
x xx
, xx
M
in, M
ax
xx, x
x xx
, xx
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 9
9/14
9
[1] A
naly
ses p
rese
nted
in th
is ta
ble
incl
ude
only
subj
ects
who
rece
ived
cis
plat
in a
s the
ir pl
atin
um th
erap
y. P
erce
ntag
es b
elow
the
first
set o
f row
s are
bas
ed o
n su
bjec
ts w
ho re
ceiv
ed c
ispl
atin
. [2
] D
urat
ion
of tr
eatm
ent =
num
ber o
f day
s fro
m th
e fir
st d
ose
(Day
1) u
ntil
the
last
dos
e.
Prog
ram
mer
not
es: (
a) p
rodu
ce th
e sa
me
tabl
e re
plac
ing
“cis
plat
in”
with
“ca
rbop
latin
” in
the
title
and
foot
note
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
00/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Tab
le 1
4.3.
5.6
D
osin
g C
ompl
ianc
e –
Cis
plat
in
Sa
fety
Pop
ulat
ion
Pl
aceb
o (N
=xx)
Ta
rext
umab
(N
=xx)
Dos
ing
Com
plia
nce
[1]
n
xx
xx
M
ean
(SD
) xx
.x (x
x.xx
) xx
.x (x
x.xx
)
Med
ian
xx
xx
25
th, 7
5th P
erce
ntile
xx
, xx
xx, x
x
Min
, Max
xx
, xx
xx, x
x
0% to
<20
% D
osin
g Co
mpl
ianc
e xx
(xx.
x%)
xx (x
x.x%
) 20
% to
<40
% D
osin
g C
ompl
ianc
e xx
(xx.
x%)
xx (x
x.x%
) 40
% to
<60
% D
osin
g C
ompl
ianc
e xx
(xx.
x%)
xx (x
x.x%
) 60
% to
<80
% D
osin
g C
ompl
ianc
e xx
(xx.
x%)
xx (x
x.x%
) 80
% to
<10
0% D
osin
g Co
mpl
ianc
e xx
(xx.
x%)
xx (x
x.x%
) 10
0% D
osin
g C
ompl
ianc
e xx
(xx.
x%)
xx (x
x.x%
)
Num
ber o
f Mis
sed
Dos
es
xx
xx
Rea
son
for M
isse
d D
ose
A
dver
se E
vent
xx
xx
Oth
er
xx
xx
N
umbe
r of D
elay
ed D
oses
xx
xx
R
easo
n fo
r Del
ayed
Dos
e
Adv
erse
Eve
nt
xx
xx
O
ther
xx
xx
[1] D
osin
g co
mpl
ianc
e =
(num
ber o
f dos
es a
dmin
iste
red)
/ nu
mbe
r of p
lann
ed d
oses
.
Prog
ram
mer
not
es: (
a) p
rodu
ce th
e sa
me
tabl
e re
plac
ing
“cis
plat
in”
with
“ca
rbop
latin
” in
the
title
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
01/1
49
APP
EN
DIX
C. F
IGU
RE
SH
EL
LS
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
02/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Figu
re 1
4.2.
1.1
O
vera
ll Su
rviv
al
IT
T P
opul
atio
n
Prog
ram
mer
not
es: (
a) re
plac
e “T
reat
men
t A”
with
“Pl
aceb
o”; (
b) re
plac
e “T
reat
men
t B”
with
“Ta
rext
umab
”; (c
) inc
lude
“at
risk
” co
unts
ben
eath
the
x-ax
is (s
ee se
cond
ary
figur
e m
ock
belo
w);
(d
) del
ete
“Tre
atm
ent C
”; (e
) dup
licat
e fig
ure
usin
g pe
r-pr
otoc
ol p
opul
atio
n an
d al
l gen
e-ex
pres
sion
subs
ets o
f the
ITT
popu
latio
n; (f
) dup
licat
e fig
ure
for p
rogr
essi
on-fr
ee su
rviv
al u
sing
the
ITT
popu
latio
n; (f
) dup
licat
e fig
ure
for o
vera
ll su
rviv
al u
sing
the
per-
prot
ocol
pop
ulat
ion
and
all g
ene-
expr
essi
on su
bset
s of t
he IT
T po
pula
tion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
03/1
49
Seco
ndar
y fig
ure
moc
k sh
owin
g fo
rmat
for “
at ri
sk”
sum
mar
y:
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
04/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Figu
re 1
4.2.
4.1
W
ater
fall
Plot
of B
est P
erce
ntag
e C
hang
e fr
om B
asel
ine
Tot
al T
umor
Len
gth
IT
T P
opul
atio
n
Prog
ram
mer
not
es: (
a) re
plac
e “s
cree
ning
” in
the
y-ax
is la
bel w
ith “
Base
line”
; (b)
del
ete
the
foot
note
mar
ker “
[1]”
from
the
y-ax
is la
bel;
(c) d
uplic
ate
figur
e us
ing
per-
prot
ocol
pop
ulat
ion
CR
PRSD
PD
%-Change from Screening [1]
-100-90
-80
-70
-60
-50
-40
-30
-20
-100102030405060708090100
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
05/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Figu
re 1
4.3.
4.63
Box
Plo
t of P
ulse
Rat
e by
Vis
it
Safe
ty P
opul
atio
n
Prog
ram
mer
not
es: (
a) re
plac
e “C
ohor
t 1”
with
“Pl
aceb
o”; (
b) re
plac
e “C
ohor
t 2”
with
“Ta
rext
umab
”; (c
) del
ete
“Coh
ort 3
” an
d “C
ohor
t 4”;
(d) d
uplic
ate
figur
e fo
r all
clin
ical
labo
rato
ry, v
ital
sign
and
EC
G p
aram
eter
s (se
e Pl
anne
d Ta
bles
, Fig
ures
and
Lis
tings
[App
endi
x A]
for c
ompl
ete
list);
(e) d
uplic
ate
all f
igur
es fo
r “Bo
x Pl
ot o
f Cha
nge
from
Bas
elin
e Pa
ram
eter
by
Visi
t” –
rem
embe
r to
(i) r
emov
e th
e “B
asel
ine”
mar
ker f
rom
the
x-ax
is a
nd (i
i) re
plac
e th
e y-
axis
labe
l “Pa
ram
eter
(uni
t)” w
ith “
Chan
ge fr
om B
asel
ine
Para
met
er (u
nit)”
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
06/1
49
APP
EN
DIX
D. L
IST
ING
SH
EL
LS
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
07/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.1.1
Subj
ect D
ispo
sitio
n
Trea
tmen
t G
roup
Subj
ect
ID
ITT
Popu
latio
n Pe
r-Pro
toco
l Po
pula
tion
Safe
ty
Popu
latio
n
Imm
uno-
ge
nici
ty
Popu
latio
n
Phar
mac
o-ki
netic
Po
pula
tion
Trea
tmen
t St
art D
ate
Trea
tmen
t En
d D
ate
Prim
ary
Rea
son
for E
ndin
g St
udy
Trea
tmen
t St
udy
Exit
Dat
e Pr
imar
y R
easo
n fo
r St
udy
Exit
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x Y
| N
Y
| N
Y
| N
Y
| N
Y
| N
dd
mm
myy
yy
ddm
mm
yyyy
Lo
st to
follo
w-u
p |
With
draw
al o
f co
nsen
t/Pat
ient
dec
isio
n |
Dea
th |
Adv
erse
Eve
nt #
xx: A
dver
se
Even
t ter
m |
Dis
ease
Pr
ogre
ssio
n | I
nves
tigat
or
deci
sion
bas
ed o
n pa
tient
's be
st in
tere
st
Stud
y Te
rmin
ated
by
Onc
oMed
| O
ther
: Oth
er
term
ddm
mm
yyyy
D
eath
| Lo
st to
Fol
low
-Up
| St
udy
Term
inat
ed b
y O
ncoM
ed |
With
draw
al
by S
ubje
ct |
Oth
er: O
ther
te
rm
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
08/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.1.2
Info
rmed
Con
sent
Trea
tmen
t G
roup
Su
bjec
t ID
Info
rmed
C
onse
nt
Dat
e R
ando
miz
atio
n D
ate
Con
sent
ed
to O
ptio
nal
Tum
or
Bio
psy
If Y
es, D
ate
Opt
iona
l Tu
mor
Bio
psy
Con
sent
Dat
e
Con
sent
ed to
O
ptio
nal
Phar
mac
ogen
omic
s B
lood
Sam
ple
If Y
es,
Opt
iona
l Ph
arm
aco-
ge
nom
ics
Blo
od S
ampl
e C
onse
nt D
ate
Con
sent
ed to
D
NA
Te
stin
g on
B
lood
Sa
mpl
e
If Y
es,
DN
A T
estin
g on
Blo
od
Sam
ple
Con
sent
Dat
e
Con
sent
ed to
D
NA
Tes
ting
on T
umor
Ti
ssue
Sa
mpl
e
If Y
es,
DN
A T
estin
g on
Tum
or
Tiss
ue C
onse
nt
Dat
e Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
ddm
mm
yyyy
dd
mm
myy
yy
Yes
| N
o dd
mm
myy
yy
Yes
| N
o dd
mm
myy
yy
Yes
| N
o dd
mm
myy
yy
Yes
| N
o dd
mm
myy
yy
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
09/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.2.1
Maj
or P
roto
col D
evia
tions
Tr
eatm
ent
Gro
up
Subj
ect I
D
Prot
ocol
Dev
iatio
n D
escr
iptio
n D
evia
tion
Cod
e
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x D
escr
iptio
n xx
-Dev
iatio
n C
ode
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
10/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.3.1
Incl
usio
n/E
xclu
sion
Cri
teri
a
Trea
tmen
t G
roup
Su
bjec
t ID
Pr
otoc
ol V
ersi
on D
ate
Did
the
subj
ect m
eet a
ll el
igib
ility
crit
eria
? C
riter
ia T
ype
Crit
erio
n N
umbe
r R
easo
n N
ot M
et
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x dd
mm
myy
yy
Ye
s | N
o In
clus
ion
| Exc
lusi
on |
Non
e xx
R
easo
n
Prog
ram
mer
not
es: (
a) a
ll su
bjec
ts sh
ould
be
liste
d; (b
) Dis
play
“N
one”
for C
rite
ria
Type
as a
ppro
pria
te
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
11/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.4.1
Dem
ogra
phic
s and
Bas
elin
e C
hara
cter
istic
s Pa
rt 1
of 2
Trea
tmen
t G
roup
Su
bjec
t ID
Dat
e of
Birt
h A
ge
(yea
rs)[1
] Se
x
If Fe
mal
e,
Chi
ld-B
earin
g Po
tent
ial?
R
ace
Ethn
icity
Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
dd
mm
myy
yy
xx.x
M
ale
| Fe
mal
e Y
es |
No
Am
eric
an In
dian
or
Ala
ska
Nat
ive
| A
sian
| B
lack
or
Afri
can
Am
eric
an |
Nat
ive
Haw
aiia
n or
Oth
er P
acifi
c Is
land
er |
Whi
te
His
pani
c or
La
tino
| N
ot H
isp
anic
or L
atin
o
<s
econ
d pa
rt o
f lis
ting>
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.4.1
Dem
ogra
phic
s and
Bas
elin
e C
hara
cter
istic
s
Part
2 o
f 2
Trea
tmen
t Gro
up
Subj
ect I
D
H
eigh
t (c
m)
Wei
ght
(kg)
Bod
y M
ass
Inde
x [2
]
(mg/
m2 )
ECO
G
Smok
ing
His
tory
If
Ex-S
mok
er o
r Cur
rent
Sm
oker
, nu
mbe
r of p
ack
year
s If
Ex-S
mok
er,
Stop
Dat
e Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
xx
x xx
.x
x.xx
0
| 1 |
2 N
ever
Sm
oked
| Ex
Sm
oker
| C
urre
nt S
mok
er
xx
ddm
mm
yyyy
[1] A
ge a
t tim
e in
form
ed c
onse
nt w
as si
gned
. [2
] BM
I (kg
/m2 ) =
wei
ght (
kg) /
[hei
ght (
cm)]
2 .
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
12/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.4.2
Med
ical
/Sur
gica
l His
tory
Trea
tmen
t Gro
up
Subj
ect I
D
Any
pas
t and
/or c
onco
mita
nt d
isea
ses o
r pas
t sur
gerie
s?
Des
crip
tion
of M
edic
al C
ondi
tion/
Even
t O
nset
Dat
e En
d D
ate
Ong
oing
/ R
esol
ved
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x Y
es |
No
Des
crip
tion
ddm
mm
yyyy
dd
mm
myy
yy
Ong
oing
| R
esol
ved
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
13/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.4.3
Ext
ensi
ve S
mal
l Cel
l Lun
g C
ance
r H
isto
ry
Trea
tmen
t G
roup
Su
bjec
t ID
Dat
e of
D
iagn
osis
(S
tudy
Day
)
Mon
ths
Sinc
e D
iagn
osis
His
tolo
gica
l/ C
ytol
ogic
al
Type
Ana
tom
ical
Lo
catio
n of
Pr
imar
y C
ance
r
Num
ber o
f Si
tes o
f Dis
ease
at
Stu
dy E
ntry
Si
tes o
f Dis
ease
at S
tudy
En
try
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x dd
mm
myy
yy
(xx)
xx
Sm
all C
ell
Onl
y |
Mix
ed T
ype
| Oth
er:
Oth
er te
rm
Rig
ht U
pper
Lun
g |
Rig
ht L
ower
Lun
g |
Mid
dle
of R
ight
Lu
ng |
Left
Upp
er L
ung
| O
ther
: Oth
er te
rm
x B
one
| Bra
in:
Sym
ptom
atic
/ A
sym
ptom
atic
| Pl
eura
| A
dren
al G
land
| Ly
mph
Nod
es: S
peci
fy
Lym
ph N
odes
| O
ther
Nod
es: O
ther
lo
catio
n
Prog
ram
mer
not
es: (
a) fo
r Site
s of D
isea
se a
t Stu
dy E
ntry
, lis
t all
that
app
ly
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
14/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.4.4
Prio
r Su
rger
y fo
r L
ung
Can
cer
Trea
tmen
t Gro
up
Subj
ect I
D
Prio
r Sur
gery
for
Lung
Can
cer
Surg
ery
Dat
e D
escr
iptio
n of
Sur
gery
Lo
catio
n of
Sur
gery
Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
Yes
| N
o dd
mm
myy
yy
Des
crip
tion
Loca
tion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
15/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.4.5
Prio
r R
adio
ther
apy
for
Lun
g C
ance
r
Trea
tmen
t G
roup
Su
bjec
t ID
Prio
r R
adio
ther
apy
for
Lung
Can
cer
Star
t Dat
e En
d D
ate
Site
of T
reat
men
t To
tal c
GY
Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
Yes
| N
o dd
mm
myy
yy
ddm
mm
yyyy
Si
te o
f Tre
atm
ent
xx |
Unk
now
n
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
16/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.4.6
Bas
elin
e G
ene
Exp
ress
ion
Tr
eatm
ent
Gro
up
Subj
ect I
D
Not
ch3
Expr
essi
on
Hes
1 Ex
pres
sion
H
ey1
Expr
essi
on
Hey
2 Ex
pres
sion
H
es6
Expr
essi
on
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x Y
es |
No
Yes
| N
o Y
es |
No
Yes
| N
o Y
es |
No
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
17/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.4.7
FFPE
Tis
sue
Sam
ple
Part
1 o
f 2
A
rchi
val T
issu
e
Trea
tmen
t Gro
up
Subj
ect I
D
Sam
ple
subm
itted
? B
iops
y D
ate
(Stu
dy D
ay)
Dat
e of
Sub
mis
sion
to
Onc
oMed
(S
tudy
Day
) A
nato
mic
al L
ocat
ion
Loca
tion
Des
crip
tion
Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
Yes
| N
o dd
mm
myy
yy
(xx)
dd
mm
myy
yy
(xx)
Li
ver |
Lym
ph N
odes
| Pe
riton
eum
| C
hest
Wal
l | A
bdom
en |
Pelv
is |
Bre
ast |
Ski
n |
Kid
ney
| Lun
g |
Oth
er: O
ther
org
an
Des
crip
tion
[1] If
arch
ival
tiss
ue w
as n
ot su
bmitt
ed.
<sec
ond
part
of l
istin
g>
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.4.7
FFPE
Tis
sue
Sam
ple
Part
2 o
f 2
Fr
esh
Tum
or C
ore
Bio
psie
s
Trea
tmen
t Gro
up
Subj
ect I
D
Bio
psie
s Pe
rform
ed?[1
] B
iops
ies D
ate
(Stu
dy D
ay)
Dat
e of
Sub
mis
sion
to
Onc
oMed
(S
tudy
Day
) A
nato
mic
al L
ocat
ion
Loca
tion
Des
crip
tion
Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
Yes
| N
o dd
mm
myy
yy
(xx)
dd
mm
myy
yy
(xx)
Li
ver |
Lym
ph N
odes
| Pe
riton
eum
| C
hest
Wal
l | A
bdom
en |
Pelv
is |
Bre
ast |
Ski
n |
Kid
ney
| Lun
g |
Oth
er: O
ther
org
an
Des
crip
tion
[1] If
arch
ival
tiss
ue w
as n
ot su
bmitt
ed.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
18/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.4.8
Prio
r an
d C
onco
mita
nt M
edic
atio
ns
Trea
tmen
t G
roup
Su
bjec
t ID
Ver
batim
Ter
m //
Pr
efer
red
Nam
e //
A
TC C
lass
[1]
Star
t Dat
e (S
tudy
Day
) En
d D
ate
(Stu
dy D
ay)
R
oute
In
dica
tion
Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
Ver
batim
Ter
m //
Pr
efer
red
Nam
e //
A
TC C
lass
ddm
mm
yyyy
(x
x)
ddm
mm
yyyy
(x
x) |
Ong
oing
In
hala
tion
| In
tra-a
rteria
l |
Intra
lesi
onal
| In
tram
uscu
lar |
In
traoc
ular
| In
trape
riton
eal |
In
trave
nous
| N
asal
| O
ral |
R
ecta
l |
Subc
utan
eous
| To
pica
l |
Tran
sder
mal
| V
agin
al |
Oth
er: O
ther
te
rm
Med
ical
His
tory
#xx
: MH
te
rm |
Adv
erse
Eve
nt #
xx: A
E te
rm |
Oth
er: O
ther
term
[1
] A
TC C
lass
and
Pre
ferr
ed N
ame
are
code
d us
ing
WH
O D
rug
Dic
tiona
ry E
nhan
ced
(ver
sion
Mar
ch 1
, 201
4).
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
19/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.4.9
Con
com
itant
Pro
cedu
res
Trea
tmen
t Gro
up
Subj
ect I
D
Any
Con
com
itant
Pr
oced
ures
? Pr
oced
ure
Ana
tom
ical
Lo
catio
n St
art D
ate
(Stu
dy D
ay)
End
Dat
e (S
tudy
Day
)
Indi
catio
n
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x Y
es |
No
Proc
edur
e Lo
catio
n dd
mm
myy
yy (x
x)
ddm
mm
yyyy
(xx)
Med
ical
His
tory
#xx
: MH
term
| A
dver
se E
vent
#xx
: AE
term
| O
ther
: Oth
er te
rm
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
20/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.5.1
Stud
y D
rug
Infu
sion
Part
1 o
f 3: I
nfus
ion
Adm
inis
trat
ion
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Infu
sion
Pe
rform
ed?
If In
fusi
on W
as N
ot
Perfo
rmed
, Sp
ecify
Rea
son
If A
E,
Spec
ify
Dat
e
of In
fusi
on
(Stu
dy D
ay)
Infu
sion
St
art /
St
op T
imes
Inte
nded
D
ose
Per
Prot
ocol
(m
g)
Wha
t Wei
ght
Was
Use
d to
C
alcu
late
Dos
e?
Infu
sion
D
ose
(mg)
Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
CY
CLE
X
DA
Y X
Y
es |
No
Adv
erse
Eve
nt |
Oth
er:
Oth
er te
rm
AE
term
dd
mm
myy
yy
(xx)
xx
:xx
/ xx
:xx
xx.x
x W
eigh
t at C
urre
nt
Vis
it |
Wei
ght a
t Bas
elin
e |
Oth
er: O
ther
term
xxxx
<
seco
nd p
art o
f lis
ting>
O
ncoM
ed P
harm
aceu
tical
s, In
c.
Pa
ge 1
of x
59
R5-
003
(Pha
se 2
) L
istin
g 16
.2.5
.1
St
udy
Dru
g In
fusi
on
Pa
rt 2
of 3
: Inf
usio
n R
educ
ed o
r D
elay
ed
D
ose
Red
uced
Infu
sion
Del
ayed
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Dos
e re
duce
d si
nce
last
in
fusi
on?
Spec
ify R
easo
n If
AE,
Sp
ecify
In
fusi
on
Del
ayed
?
Spec
ify R
easo
n If
AE,
Sp
ecify
Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
CY
CLE
X D
AY
X
Yes
| N
o A
dver
se E
vent
| O
ther
: Oth
er
term
A
E te
rm
Y
es |
No
Adv
erse
Eve
nt |
Oth
er: O
ther
te
rm
AE
term
<th
ird p
art o
f lis
ting
on n
ext p
age>
O
ncoM
ed P
harm
aceu
tical
s, In
c.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.5.1
Stud
y D
rug
Infu
sion
Part
3 o
f 3: I
nfus
ion
Inte
rrup
ted
or R
esta
rted
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Infu
sion
Inte
rrup
ted
R
esta
rt af
ter I
nter
rupt
ion
Com
plet
ed
Afte
r Res
tart
Tota
l Dos
e A
dmin
iste
red
(mg)
In
fusi
on
Inte
rrup
ted?
Spec
ify R
easo
n If
AE,
Sp
ecify
In
fusi
on
Res
tarte
d?
Star
t / S
top
Tim
es
Dos
e (m
g)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x C
YC
LE X
D
AY
X
Yes
| N
o A
dver
se E
vent
| O
ther
: O
ther
term
A
E te
rm
Y
es |
No
xx:x
x / x
x:xx
xx
xx
Infu
sion
was
co
mpl
eted
| In
fusi
on w
as
inte
rrup
ted
agai
n
xxxx
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
21/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.5.2
Eto
posi
de In
fusi
on
Pa
rt 1
of 3
: Inf
usio
n A
dmin
istr
atio
n
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Infu
sion
Pe
rform
ed?
If In
fusi
on W
as N
ot
Perfo
rmed
, Sp
ecify
Rea
son
If A
E,
Spec
ify
Dat
e
of In
fusi
on
(Stu
dy D
ay)
Infu
sion
St
art /
St
op T
imes
Inte
nded
D
ose
Per
Prot
ocol
(m
g)
Wha
t Wei
ght
Was
Use
d to
C
alcu
late
Dos
e?
BSA
(m
2 )
Act
ual
Dos
e (m
g)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x C
YC
LE X
D
AY
X
Yes
| N
o A
dver
se E
vent
| O
ther
: O
ther
term
A
E te
rm
ddm
mm
yyyy
(x
x)
xx:x
x /
xx:x
x xx
.xx
Wei
ght a
t Cur
rent
V
isit
| W
eigh
t at B
asel
ine
| O
ther
: Oth
er te
rm
xx
xxxx
<se
cond
par
t of l
istin
g>
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.5.2
Eto
posi
de In
fusi
on
Pa
rt 2
of 3
: Inf
usio
n R
educ
ed o
r D
elay
ed
D
ose
Red
uced
Infu
sion
Del
ayed
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Dos
e re
duce
d si
nce
last
in
fusi
on?
Spec
ify R
easo
n If
AE,
Sp
ecify
In
fusi
on
Del
ayed
?
Spec
ify R
easo
n If
AE,
Sp
ecify
Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
CY
CLE
X D
AY
X
Yes
| N
o A
dver
se E
vent
| O
ther
: Oth
er
term
A
E te
rm
Y
es |
No
Adv
erse
Eve
nt |
Oth
er: O
ther
te
rm
AE
term
<th
ird p
art o
f lis
ting>
O
ncoM
ed P
harm
aceu
tical
s, In
c.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
L
istin
g 16
.2.5
.2
E
topo
side
Infu
sion
Part
3 o
f 3: I
nfus
ion
Inte
rrup
ted
or R
esta
rted
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Infu
sion
Inte
rrup
ted
R
esta
rt af
ter I
nter
rupt
ion
Com
plet
ed
Afte
r Res
tart
Tota
l Dos
e A
dmin
iste
red
(mg)
In
fusi
on
Inte
rrup
ted?
Spec
ify R
easo
n If
AE,
Sp
ecify
In
fusi
on
Res
tarte
d?
Star
t / S
top
Tim
es
Dos
e (m
g)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x C
YC
LE X
D
AY
X
Yes
| N
o A
dver
se E
vent
| O
ther
: O
ther
term
A
E te
rm
Y
es |
No
xx:x
x / x
x:xx
xx
xx
Infu
sion
was
co
mpl
eted
| In
fusi
on w
as
inte
rrup
ted
agai
n
xxxx
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
22/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.5.3
Plat
inum
The
rapy
Infu
sion
Part
1 o
f 3: I
nfus
ion
Adm
inis
trat
ion
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Infu
sion
Pe
rform
ed?
If Y
es, S
peci
fy
ther
apy
If In
fusi
on W
as
Not
Per
form
ed,
Spec
ify R
easo
n If
AE,
Sp
ecify
Dat
e
of In
fusi
on
(Stu
dy D
ay)
Infu
sion
St
art /
St
op
Tim
es
Inte
nded
D
ose
Per
Prot
ocol
Wha
t Wei
ght
Was
Use
d to
C
alcu
late
Dos
e?
BSA
(m
2 )
GFR
( m
L/m
in/
1.73
m2 )
Act
ual
Dos
e (m
g)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x C
YC
LE X
D
AY
X
Yes
| N
o C
ispl
atin
| C
arbo
plat
in
Adv
erse
Eve
nt |
Oth
er: O
ther
te
rm
AE
term
dd
mm
myy
yy
(xx)
xx
:xx
/ xx
:xx
xx.x
x m
g/m
2 | xx
.xx
mg/
mL-
min
Wei
ght a
t C
urre
nt V
isit
| W
eigh
t at
Bas
elin
e |
Oth
er: O
ther
te
rm
xx
xx
xxxx
<se
cond
par
t of l
istin
g>
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.5.3
Plat
inum
The
rapy
Infu
sion
Part
2 o
f 3: I
nfus
ion
Red
uced
or
Del
ayed
Dos
e R
educ
ed
In
fusi
on D
elay
ed
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Dos
e re
duce
d si
nce
last
in
fusi
on?
Spec
ify R
easo
n If
AE,
Sp
ecify
In
fusi
on
Del
ayed
?
Spec
ify R
easo
n If
AE,
Sp
ecify
Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
CY
CLE
X D
AY
X
Yes
| N
o A
dver
se E
vent
| O
ther
: Oth
er
term
A
E te
rm
Y
es |
No
Adv
erse
Eve
nt |
Oth
er: O
ther
te
rm
AE
term
<th
ird p
art o
f lis
ting>
O
ncoM
ed P
harm
aceu
tical
s, In
c.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
L
istin
g 16
.2.5
.3
Pl
atin
um T
hera
py In
fusi
on
Pa
rt 3
of 3
: Inf
usio
n In
terr
upte
d or
Res
tart
ed
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Infu
sion
Inte
rrup
ted
Res
tart
afte
r Int
erru
ptio
n C
ompl
eted
A
fter R
esta
rt
Tota
l Dos
e A
dmin
iste
red
(mg)
Tota
l Pl
anne
d D
ose
(mg)
In
fusi
on
Inte
rrup
ted?
Spec
ify R
easo
n If
AE,
Sp
ecify
In
fusi
on
Res
tarte
d?
Star
t / S
top
Tim
es
Dos
e (m
g)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x C
YC
LE X
D
AY
X
Yes
| N
o A
dver
se E
vent
| O
ther
: Oth
er te
rm
AE
term
Yes
| N
o xx
:xx
/ xx
:xx
xxxx
In
fusi
on w
as
com
plet
ed |
Infu
sion
was
in
terr
upte
d ag
ain
xxxx
xx
xx
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
23/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.5.4
Dos
es D
elay
ed, I
nter
rupt
ed, R
educ
ed a
nd N
ot A
dmin
iste
red
Trea
tmen
t Gro
up
Subj
ect I
D
Vis
it D
ate
(Stu
dy D
ay)
Dos
ing
Rea
son
Adv
erse
Eve
nt/O
ther
Rea
son
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x C
YC
LE X
DA
Y X
Y
es |
No
Dos
e D
elay
ed |
D
ose
Inte
rrup
ted
| D
ose
Red
uced
|
Not
Adm
inis
tere
d
Adv
erse
Eve
nt |
Oth
er
Adv
erse
Eve
nt #
xx: A
E te
rm |
Oth
er te
rm
N
ote:
Thi
s lis
ting
is so
rted
by T
reat
men
t, D
osin
g, R
easo
n, a
nd S
ubje
ct.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
24/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.5.5
Pre-
dose
, Pos
t-do
se a
nd S
ingl
e PK
Sam
ples
Trea
tmen
t Gro
up
Subj
ect I
D
V
isit
Was
PK
Sam
ple
Dra
wn?
D
raw
Dat
e (S
tudy
Day
) Ti
me
Poin
t D
raw
Tim
e
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x
SCR
EEN
ING
| C
YC
LE X
DA
Y X
Y
es |
No
ddm
mm
yyyy
(x
x)
Pre-
dose
|
Post
-dos
e |
[bla
nk]
xx:x
x
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
25/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.6.2
Tum
or E
valu
atio
ns –
Tar
get L
esio
ns
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Was
ra
diog
raph
ic
eval
uatio
n pe
rform
ed?
Dat
e Pe
rform
ed
(Stu
dy D
ay)
Loca
tion
Num
ber
Loca
tion
Loca
tion
Des
crip
tion
(Pos
ition
with
in O
rgan
) Te
chni
que
Use
d
Thic
knes
s of
slic
e (m
m)[1
]
Long
est
Dia
met
er
(mm
)[2]
Bas
elin
e Su
m o
f Lo
nges
t D
iam
eter
s (m
m)
Vis
it Su
m o
f Lo
nges
t D
iam
eter
s (m
m)
Perc
ent
Cha
nge
from
B
asel
ine
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x SC
REE
NIN
G |
CY
CLE
X D
AY
X
Yes
| N
o dd
mm
myy
yy
(xx)
1
| 2 |
3,
etc.
Pa
ncre
as |
Live
r |
Lym
ph N
odes
| Pe
riton
eum
| C
hest
Wal
l |
Abd
omen
| Pe
lvis
| B
reas
t |
Skin
| K
idne
y |
Lung
| O
ther
: Oth
er
loca
tion
Posi
tion
MR
I |
Con
vent
iona
l CT
| Sp
iral C
T |
PET
CT
| B
one
Scan
| O
ther
: O
ther
te
chni
que
xx.x
xx
.x |
Una
ble
to
Eval
uate
[bla
nk]
[bla
nk]
[bla
nk]
⁞ ⁞
⁞
⁞
Vis
it Su
mm
ary
[bla
nk]
[bla
nk]
[b
lank
] xx
.x
xx.x
| N
A
xx.x
%
[1] If
Spi
ral o
r Con
vent
iona
l CT
Scan
. [2
] If ly
mph
nod
e, sh
ort a
xis m
easu
rem
ent i
s rec
orde
d.
Not
e: C
T =
Com
pute
d To
mog
raph
y, N
A =
Not
App
licab
le.
Prog
ram
mer
not
es: (
a) p
lace
a “
Visi
t Sum
mar
y” ro
w fo
llow
ing
the
last
line
for e
ach
time
poin
t; (b
) lea
ve b
lank
the
cells
for B
asel
ine
Sum
of L
onge
st D
iam
eter
s, Vi
sit S
um o
f Lon
gest
Dia
met
ers,
and
Perc
ent C
hang
e fr
om B
asel
ine
in e
ach
row
exc
ept f
or th
e Vi
sit S
umm
ary
row
des
crib
ed in
not
e (a
)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
26/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.6.3
Tum
or E
valu
atio
ns –
Non
-tar
get L
esio
ns
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Was
ra
diog
raph
ic
eval
uatio
n pe
rform
ed?
Dat
e Pe
rform
ed
(Stu
dy D
ay)
Loca
tion
Loca
tion
Des
crip
tion
(Pos
ition
with
in O
rgan
) Te
chni
que
Use
d Le
sion
Sta
tus [1
]
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x B
asel
ine
| C
ycle
x
Yes
| N
o dd
mm
myy
yy
(xx)
Pa
ncre
as |
Live
r |
Lym
ph N
odes
| Pe
riton
eum
| C
hest
Wal
l |
Abd
omen
| Pe
lvis
| B
reas
t |
Skin
| K
idne
y |
Lung
| O
ther
: O
ther
loca
tion
Posi
tion
MR
I |
Con
vent
iona
l CT
| Sp
iral C
T |
PET
CT
| B
one
Scan
| O
ther
: Oth
er
tech
niqu
e
CR
| N
on-C
R/N
on-P
D |
PD |
Una
ble
to E
valu
ate
[1
] C
R =
com
plet
e re
spon
se; P
D =
pro
gres
sive
dis
ease
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
27/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.6.4
Tum
or E
valu
atio
ns –
New
Les
ions
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Was
ra
diog
raph
ic
eval
uatio
n pe
rform
ed?
Dat
e Pe
rform
ed
(Stu
dy D
ay)
Loca
tion
Loca
tion
Des
crip
tion
(Pos
ition
with
in O
rgan
) Te
chni
que
Use
d Le
sion
Sta
tus [1
]
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x B
asel
ine
| C
ycle
x
Yes
| N
o dd
mm
myy
yy
(xx)
Pa
ncre
as |
Live
r |
Lym
ph
Nod
es |
Perit
oneu
m |
Che
st W
all |
A
bdom
en |
Pelv
is |
Bre
ast |
Sk
in |
Kid
ney
| Lu
ng |
Bon
e |
CN
S |
Oth
er: O
ther
lo
catio
n
Posi
tion
MR
I |
Con
vent
iona
l C
T |
Spira
l CT
| PE
T-C
T |
Bon
e Sc
an |
X-R
ay |
Phys
ical
Exa
m |
Oth
er: O
ther
te
chni
que
CR
| N
on-C
R/N
on-P
D |
PD |
Una
ble
to E
valu
ate
[1
] C
R =
com
plet
e re
spon
se; P
D =
pro
gres
sive
dis
ease
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
28/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.6.5
Tum
or A
sses
smen
ts (R
EC
IST
Ove
rall
Res
pons
e)
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Res
pons
e D
ate
(Stu
dy D
ay)
Targ
et
Lesi
on
Res
pons
e [1
]
Targ
et
Lesi
on
Res
pons
e [1
] N
ew
Lesi
ons
Ove
rall
Res
pons
e A
sses
smen
t [1]
If O
vera
ll R
espo
nse
is
Prog
ress
ive
Dis
ease
, w
as it
non
-rad
iogr
aphi
c cl
inic
al p
rogr
essi
on?
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x SC
REE
NIN
G |
CY
CLE
X
DA
Y X
ddm
mm
yyyy
(x
x)
CR
| PR
| SD
| PD
| U
nabl
e to
Eva
luat
e:
Reas
on |
Not
Ev
alua
ted
No
Lesi
ons a
t Bas
elin
e |
CR
| PR
| SD
| PD
| U
nabl
e to
Eva
luat
e:
Reas
on |
Not
Eva
luat
ed
Yes
| N
o C
R |
PR |
SD |
PD |
PD |
Not
Eva
luat
ed
Yes
| N
o
[1
] CR
= c
ompl
ete
resp
onse
; PR
= p
artia
l res
pons
e; S
D =
stab
le d
isea
se; P
D =
pro
gres
sive
dis
ease
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
29/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.6.6
Der
ived
Eff
icac
y D
ata
R
ECIS
T v1
.1 A
sses
smen
t
PFS[2
]
OS[3
]
DO
R[4
]
Trea
tmen
t Gro
up
Subj
ect I
D
Bes
t Tum
or R
espo
nse
Obj
ectiv
e R
espo
nse[1
]
Cen
sore
d D
ays
C
enso
red
Day
s
Cen
sore
d D
ays
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x C
R |
PR |
SD |
PD |
NE
Yes
| N
o
Yes
| N
o xx
x
Yes
| N
o xx
x
Yes
| N
o xx
x
Not
e: C
R =
com
plet
e re
spon
se; P
R =
par
tial r
espo
nse;
SD
= st
able
dis
ease
; PD
= p
rogr
essi
ve d
isea
se; N
E =
Not
Eva
luat
ed.
[1] B
est r
espo
nse
of C
R o
r PR
. [2
] Pro
gres
sion
-Fre
e Su
rviv
al (P
FS) =
Dat
e of
Doc
umen
tatio
n of
Dea
th/P
rogr
essi
on –
Ran
dom
izat
ion
Dat
e +
1. S
ubje
cts w
ho h
ad n
ot e
xper
ienc
ed d
eath
or p
rogr
essi
on b
y th
eir l
ast c
onta
ct w
ere
cens
ored
at
the
time
of th
eir l
ast r
adio
grap
hic
resp
onse
ass
essm
ent.
Subj
ects
lack
ing
a ra
diog
raph
ic re
spon
se a
sses
smen
t afte
r ran
dom
izat
ion
who
do
not p
rogr
ess o
r die
hav
e th
eir e
vent
tim
e ce
nsor
ed o
n th
e da
te
of ra
ndom
izat
ion
with
dur
atio
n of
1 d
ay.
[3] O
vera
ll Su
rviv
al (O
S) =
Dat
e of
Doc
umen
tatio
n of
Dea
th –
Ran
dom
izat
ion
Dat
e +
1. S
ubje
cts w
ho h
ad n
ot e
xper
ienc
ed d
eath
by
thei
r las
t con
tact
wer
e ce
nsor
ed a
t the
tim
e. S
ubje
cts l
acki
ng d
ata
afte
r ra
ndom
izat
ion
who
do
not d
ie h
ave
thei
r eve
nt ti
me
cens
ored
on
the
date
of r
ando
miz
atio
n w
ith d
urat
ion
of 1
day
. [4
] Dur
atio
n of
Res
pons
e (D
OR
) = D
ate
of D
ocum
enta
tion
of D
eath
/Pro
gres
sion
– D
ate
of F
irst P
artia
l (PR
) or C
ompl
ete
Res
pons
e (C
R) +
1. P
atie
nts w
ho d
isco
ntin
ue th
e st
udy
with
out d
isea
se
prog
ress
ion
or d
eath
whi
le o
n st
udy
are
cens
ored
on
the
date
of t
he la
st o
n st
udy
tum
or a
sses
smen
t doc
umen
ting
the
abse
nce
of p
rogr
essi
ve d
isea
se. P
atie
nts l
acki
ng a
tum
or a
sses
smen
t afte
r firs
t dos
e w
ho d
o no
t pro
gres
s or d
ie w
hile
on
study
hav
e th
eir e
vent
tim
e ce
nsor
ed o
n th
e da
te o
f firs
t dos
e w
ith d
urat
ion
of 1
day
.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
30/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.21
E
nd o
f Tre
atm
ent
Trea
tmen
t G
roup
Su
bjec
t ID
St
udy
Dru
g
Etop
osid
e
Plat
inum
The
rapy
Dat
e of
Las
t Dos
e (S
tudy
Day
) Pr
imar
y R
easo
n fo
r En
ding
Prim
ary
Ass
ocia
ted
AE
Dat
e of
Las
t Dos
e (S
tudy
Day
) Pr
imar
y R
easo
n fo
r En
ding
Prim
ary
Ass
ocia
ted
AE
Dat
e of
Las
t Dos
e (S
tudy
Day
) Pr
imar
y R
easo
n fo
r En
ding
Prim
ary
Ass
ocia
ted
AE
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x dd
mm
myy
yy
(xx)
Lo
st t
o fo
llow
-up
| W
ithdr
awal
of
cons
ent/P
atie
nt
Dec
isio
n |
Dea
th |
Adv
erse
Eve
nt |
Dis
ease
pro
gres
sion
| In
vest
igat
or d
ecis
ion
base
d on
pa
tient
's be
st in
tere
st
| Stud
y Te
rmin
ated
by
Onc
oMed
| O
ther
: Oth
er te
rm
Adv
erse
Ev
ent #
xx:
AE
term
dd
mm
myy
yy
(xx)
Lo
st t
o fo
llow
-up
| W
ithdr
awal
of
cons
ent/P
atie
nt
Dec
isio
n |
Dea
th |
Adv
erse
Eve
nt |
Dis
ease
pr
ogre
ssio
n |
Inve
stig
ator
de
cisi
on b
ased
on
patie
nt's
best
in
tere
st |
Stud
y Te
rmin
ated
by
Onc
oMed
| O
ther
: Oth
er te
rm
Adv
erse
Ev
ent #
xx:
AE
term
dd
mm
myy
yy
(xx)
Lo
st t
o fo
llow
-up
| W
ithdr
awal
of
cons
ent/P
atie
nt
Dec
isio
n |
Dea
th |
Adv
erse
Eve
nt |
Dis
ease
pr
ogre
ssio
n |
Inve
stig
ator
de
cisi
on b
ased
on
patie
nt's
best
in
tere
st |
Stud
y Te
rmin
ated
by
Onc
oMed
| O
ther
: Oth
er te
rm
Adv
erse
Ev
ent #
xx:
AE
term
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
31/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.7.1
Adv
erse
Eve
nts
Pa
rt 1
of 2
Trea
tmen
t G
roup
Su
bjec
t ID
A
E #
Ver
batim
Ter
m //
M
edD
RA
Pre
ferr
ed T
erm
//
Syst
em O
rgan
Cla
ss
Ons
et D
ate
(Stu
dy D
ay)
End
Dat
e (S
tudy
Day
) O
n-go
ing
Seve
rity
(CTC
AE
V4.
02
Gra
de)
Trea
tmen
t of
Eve
nt
Infu
sion
R
eact
ion
Out
com
e
Cau
sed
Stud
y D
rug
Dis
con-
tin
uatio
n Se
rious
Ev
ent
Serio
us
Even
t Ty
pe
Plac
ebo
|Tar
extu
mab
00
3-xx
x-x
xx
xx
Ver
batim
Ter
m //
M
edD
RA
Pre
ferr
ed T
erm
//
Syst
em O
rgan
Cla
ss
ddm
mm
yyyy
(x
x)
ddm
mm
yyy
y (xx)
Yes
| N
o x
Non
e |
Med
icat
ion
| N
on-D
rug
Trea
tmen
t |
Hos
pita
lizat
ion
Yes
| N
o R
ecov
ered
/Res
olve
d w
ithou
t Se
quel
ae |
Rec
over
ed/R
esol
ved
with
Se
quel
ae |
Not
R
ecov
ered
/Not
Res
olve
d |
Fata
l |
Unk
now
n
Yes
| N
o Y
es |
No
Yes
| N
o
<sec
ond
part
of l
istin
g>
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.7.1
Adv
erse
Eve
nts
Part
2 o
f 2
Trea
tmen
t G
roup
Su
bjec
t ID
A
E #
Rel
atio
nshi
p to
Initi
al A
ctio
n Ta
ken
with
Act
ion
Take
n w
ith
Tare
xtum
ab
Etop
osid
e Pl
atin
um
Ther
apy
Tare
xtum
ab
Etop
osid
e Pl
atin
um
Ther
apy
Tare
xtum
ab
Etop
osid
e Pl
atin
um
Ther
apy
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x xx
R
elat
ed |
Not
Rel
ated
R
elat
ed |
Not
R
elat
ed
Rel
ated
| N
ot
Rel
ated
Non
e |
Dos
e R
educ
ed |
Dos
e D
elay
ed |
Infu
sion
In
terr
upte
d |
With
draw
n |
Not
App
licab
le
Non
e |
Dos
e R
educ
ed |
Dos
e D
elay
ed |
Infu
sion
In
terr
upte
d |
With
draw
n |
Not
App
licab
le
Non
e |
Dos
e R
educ
ed |
Dos
e D
elay
ed |
Infu
sion
In
terr
upte
d |
With
draw
n |
Not
App
licab
le
N
one
| D
ose
Red
uced
| D
ose
Del
ayed
| In
fusi
on
Inte
rrup
ted
| W
ithdr
awn
| N
ot A
pplic
able
Non
e |
Dos
e R
educ
ed |
Dos
e D
elay
ed |
Infu
sion
In
terr
upte
d |
With
draw
n |
Not
App
licab
le
Non
e |
Dos
e R
educ
ed |
Dos
e D
elay
ed |
Infu
sion
In
terr
upte
d |
With
draw
n |
Not
App
licab
le
Prog
ram
mer
not
es: (
a) D
uplic
ate
this
listi
ng to
cre
ate
List
ing
16.2
.7.3
of “
Seri
ous A
dver
se E
vent
s” a
nd L
istin
g 16
.2.7
.4 o
f “Ad
vers
e Ev
ents
Lea
ding
to S
tudy
Dru
g D
iscon
tinua
tion”
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
32/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.7.2
Dea
ths
Trea
tmen
t Gro
up
Subj
ect I
D
Dat
e of
Dea
th
(Stu
dy D
ay)
Cau
se o
f Dea
th
Prim
ary
Ass
ocia
ted
AE
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x dd
mm
myy
yy (x
x)
Adv
erse
Eve
nt |
Prog
ress
ive
Dis
ease
U
nkno
wn
| O
ther
: Oth
er te
rm
AE
term
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
33/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.1
Hem
atol
ogy
Pa
rt 1
of 2
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Sam
ple
colle
cted
?
Col
lect
ion
Dat
e (S
tudy
Day
) C
olle
ctio
n Ti
me
Hem
oglo
bin
(g/d
L)
Hem
atoc
rit
(%)
Plat
elet
s (x
103 /u
L)
RB
C
(x10
6 /uL)
W
BC
(x
103 /u
L)
AN
C
(x10
3 /uL)
Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
SC
REE
NIN
G |
CY
CLE
X D
AY
X
Yes
| N
o dd
mm
myy
yy
(xx)
xx
:xx
xx.x
L/H
, G1/
G2/
G3/
G4
xx
.x
xx.x
xx
.x
xx.x
xx
.x
Not
e: R
BC
= R
ed B
lood
Cel
ls, W
BC
= W
hite
Blo
od C
ell,
AN
C =
Abs
olut
e N
eutro
phil
Cou
nt, N
D =
Not
Don
e. L
= L
ow, H
= H
igh,
with
resp
ect t
o la
bora
tory
refe
renc
e ra
nges
. Gra
des a
re a
ccor
ding
to
NC
I Com
mon
Ter
min
olog
y C
riter
ia A
dver
se E
vent
s (C
TCA
E) v
ersi
on 4
.03
Prog
ram
min
g no
tes:
Dis
play
L/H
, G1/
G2/
G3/
G4/
G5
for e
ach
lab
test
resu
lt, w
here
app
licab
le.
<se
cond
par
t of l
istin
g>
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.1
Hem
atol
ogy
Pa
rt 2
of 2
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Sam
ple
colle
cted
?
Col
lect
ion
Dat
e (S
tudy
D
ay)
Col
lect
ion
Tim
e N
eutro
phils
(%
) B
ands
(%
) Ly
mph
ocyt
es
(%)
Eosi
noph
ils
(%)
Mon
ocyt
es
(%)
Bas
ophi
ls
(%)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x S
CR
EEN
ING
| C
YC
LE X
DA
Y X
Y
es |
No
ddm
mm
yyyy
(xx)
xx
:xx
xx.x
L/H
, G1/
G2/
G3/
G4
xx
.x
xx.x
xx
.x
xx.x
xx
.x
Not
e: R
BC
= R
ed B
lood
Cel
ls, W
BC
= W
hite
Blo
od C
ell,
AN
C =
Abs
olut
e N
eutro
phil
Cou
nt, N
D =
Not
Don
e. L
= L
ow, H
= H
igh,
with
resp
ect t
o la
bora
tory
refe
renc
e ra
nges
. Gra
des a
re a
ccor
ding
to
NC
I Com
mon
Ter
min
olog
y C
riter
ia A
dver
se E
vent
s (C
TCA
E) v
ersi
on 4
.03
Prog
ram
min
g no
tes:
Dis
play
L/H
, G1/
G2/
G3/
G4/
G5
for e
ach
lab
test
resu
lt, w
here
app
licab
le.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
34/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.2
PT/I
NR
and
aPT
T
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Sam
ple
colle
cted
?
Col
lect
ion
Dat
e (S
tudy
Day
) C
olle
ctio
n Ti
me
Prot
hrom
bin
Tim
e (P
T)
(sec
)
Inte
rnat
iona
l N
orm
aliz
ed
Rat
io (I
NR
)
Act
ivat
ed P
artia
l Th
rom
bopl
astin
Ti
me
(aPT
T)
(sec
)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x S
CR
EEN
ING
| C
YC
LE X
DA
Y X
Y
es |
No
ddm
mm
yyyy
(x
x)
xx:x
x xx
.xL/
H, G
1/G
2/G
3/G
4
xx
.x
xx.x
N
ote:
ND
= N
ot D
one.
L =
Low
, H =
Hig
h, w
ith re
spec
t to
labo
rato
ry re
fere
nce
rang
es. G
rade
s are
acc
ordi
ng to
NC
I Com
mon
Ter
min
olog
y C
riter
ia A
dver
se E
vent
s (C
TCA
E) v
ersi
on 4
.03
Prog
ram
min
g no
tes:
Dis
play
L/H
, G1/
G2/
G3/
G4
for e
ach
lab
test
resu
lt, w
here
app
licab
le.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
35/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.3
Seru
m C
hem
istr
y
Part
1 o
f 2
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Sam
ple
colle
cted
?
Col
lect
ion
Dat
e (S
tudy
Day
) C
olle
ctio
n Ti
me
Fast
ing
for a
t lea
st
6 ho
urs?
A
lbum
in
(g/d
L)
Alk
alin
e Ph
osph
atas
e (U
/L)
Tota
l B
iliru
bin
(mg/
dL)
Dire
ct
Bili
rubi
n (m
g/dL
) B
icar
bona
te
(mEq
/L)
Blo
od
Ure
a N
itrog
en
(mg/
dL)
Cal
cium
(m
g/dL
) C
hlor
ide
(mEq
/L)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x S
CR
EEN
ING
| C
YC
LE X
DA
Y X
Y
es |
No
ddm
mm
yyyy
(x
x)
xx:x
x Y
es |
No
xx.x
L/H
,
G1/
G2/
G3/
G4
xx.x
xx
.x
xx.x
xx
.x
xx.x
xx
.x
xx.x
N
ote:
LD
H =
Lac
tic D
ehyd
roge
nase
, ND
= N
ot D
one.
L =
Low
, H =
Hig
h, w
ith re
spec
t to
labo
rato
ry re
fere
nce
rang
es. G
rade
s are
acc
ordi
ng to
NC
I Com
mon
Ter
min
olog
y C
riter
ia A
dver
se E
vent
s (C
TCA
E) v
ersi
on 4
.03
Prog
ram
min
g no
tes:
Dis
play
L/H
, G1/
G2/
G3/
G4/
G5
for e
ach
lab
test
resu
lt, w
here
app
licab
le.
<se
cond
par
t of l
istin
g>
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.3
Seru
m C
hem
istr
y
Part
2 o
f 2
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Sam
ple
colle
cted
?
Col
lect
ion
Dat
e (S
tudy
Day
) C
olle
ctio
n Ti
me
Fast
ing
for a
t le
ast 6
ho
urs?
Cre
atin
-in
e (m
g/dL
)
Blo
od
Glu
cose
(m
g/dL
) LD
H
(U/L
)
Mag
nes-
ium
(m
g/dL
)
Phos
ph-
orus
(m
g/dL
) Po
tass
ium
(m
Eq/L
)
Tota
l Pr
otei
n (g
/dL)
AST
(S
GO
T)
(U/L
)
ALT
(S
GPT
) (U
/L)
Sodi
um
(mEq
/L)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x S
CR
EEN
ING
| C
YC
LE X
D
AY
X
Yes
| N
o dd
mm
myy
yy
(xx)
xx
:xx
Yes
| N
o xx
.xL/
H,
G1/
G2/
G3/
G4
xx.x
xx
.x
xx.x
xx
.x
xx.x
xx
.x
xx.x
xx
.x
Not
e: L
DH
= L
actic
Deh
ydro
gena
se, N
D =
Not
Don
e. L
= L
ow, H
= H
igh,
with
resp
ect t
o la
bora
tory
refe
renc
e ra
nges
. Gra
des a
re a
ccor
ding
to N
CI C
omm
on T
erm
inol
ogy
Crit
eria
Adv
erse
Eve
nts
(CTC
AE)
ver
sion
4.0
3
Prog
ram
min
g no
tes:
Dis
play
L/H
, G1/
G2/
G3/
G4/
G5
for e
ach
lab
test
resu
lt, w
here
app
licab
le.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
36/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.4
Uri
naly
sis
Pa
rt 1
of 2
Trea
tmen
t G
roup
Su
bjec
t ID
Vis
it Sa
mpl
e co
llect
ed?
Col
lect
ion
Dat
e (S
tudy
Day
)
Col
lect
- io
n Ti
me
Prot
ein
Glu
cose
K
eton
es
Blo
od
Bili
rubi
n pH
Sp
ecifi
c G
ravi
ty
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x
SCR
EEN
ING
| C
YC
LE 1
DA
Y 1
Y
es |
No
ddm
mm
yyyy
(x
x)
xx:x
x N
egat
ive
| Po
sitiv
e:
Trac
e/
1+/
2+/
3+/
4+/
Unk
now
n |
Not
Don
e
Neg
ativ
e |
Posi
tive
| Not
D
one
Neg
ativ
e |
Posi
tive
| Not
D
one
Neg
ativ
e |
Posi
tive
| Not
D
one
Neg
ativ
e |
Posi
tive
| Not
D
one
x.x
x.xx
<se
cond
par
t of l
istin
g>
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.4
Uri
naly
sis
Pa
rt 2
of 2
Trea
tmen
t G
roup
Su
bjec
t ID
Vis
it Sa
mpl
e co
llect
ed?
Col
lect
ion
Dat
e (S
tudy
Day
) C
olle
ctio
n Ti
me
Mic
rosc
opic
Ex
am
Perfo
rmed
? B
acte
ria
Cas
ts
Cry
stal
s R
BC
(c
ells
/hpf
) W
BC
(c
ells
/hpf
) O
ther
te
st
Res
ult
(uni
ts)
Ref
eren
ce
Ran
ge
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x
SCR
EEN
ING
| C
YC
LE 1
DA
Y
1
Yes
| N
o dd
mm
myy
yy
(xx)
xx
:xx
Yes
| N
o A
bsen
t |
Pres
ent |
N
ot D
one
Abs
ent |
Pr
esen
t |
Not
D
one
Abs
ent |
Pr
esen
t |
Not
Don
e
xx
xx
x.xx
xx
un
its
xx-x
x
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
37/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.5
Vita
l Sig
ns
Trea
tmen
t G
roup
Su
bjec
t ID
Vis
it V
ital S
igns
M
easu
red?
D
ate
(Stu
dy
Day
) Ti
me
Tem
pera
ture
(°
C)
Puls
e R
ate
(bea
st/m
in)
Res
pira
tory
Rat
e (b
eats
/min
)
Blo
od P
ress
ure
(Sys
tolic
/ D
iast
olic
) (m
mH
g)
Hei
ght
(cm
) W
eigh
t (k
g)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x
SCR
EEN
ING
| C
YC
LE X
DA
Y X
Y
es |
No
ddm
mm
yyyy
xx
:xx
xx.x
xx
xx
xx
x/xx
xx
x.x
xx.x
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
38/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.6
EC
OG
Per
form
ance
Sta
tus
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
ECO
G
Ass
essm
ent
Perfo
rmed
?
Ass
essm
ent
Dat
e (S
tudy
Day
) Sc
ore[1
]
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x SC
REE
NIN
G |
CY
CLE
X
DA
Y X
Y
es |
No
ddm
mm
yyyy
(x
x)
x
[1] 0
= F
ully
act
ive,
abl
e to
car
ry o
n al
l pre
-dis
ease
per
form
ance
with
out r
estri
ctio
n; 1
= R
estri
cted
in p
hysi
cally
stre
nuou
s act
ivity
, but
am
bula
tory
and
abl
e to
car
ry o
ut w
ork
of a
lig
ht o
r sed
enta
ry n
atur
e (e
.g.,
light
hou
sew
ork,
off
ice
wor
k; 2
= A
mbu
lato
ry a
nd c
apab
le o
f all
self
-car
e, b
ut u
nabl
e to
car
ry o
ut a
ny w
ork
activ
ities
. Up
and
abou
t mor
e th
an 5
0%
of w
akin
g ho
ur; 3
= C
apab
le o
f onl
y lim
ited
self-
care
, con
fined
to b
ed o
r cha
ir m
ore
than
50%
of w
akin
g ho
ur; 4
= C
ompl
etel
y di
sabl
ed. C
anno
t car
ry o
n an
y se
lf-ca
re. T
otal
ly
conf
ined
to b
ed o
r cha
ir; 5
= D
ead.
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
39/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.7
12-L
ead
EC
G
Pa
rt 1
of 2
Trea
tmen
t Gro
up
Subj
ect I
D
Vis
it W
as E
CG
Pe
rform
ed?
Dat
e of
A
sses
smen
t (S
tudy
Day
) PR
Inte
rval
(m
sec)
Q
RS
Dur
atio
n (m
sec)
QTc
In
terv
al
(mse
c)
QTc
Inte
rval
Fo
rmul
a
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x SC
REE
NIN
G |
CY
CLE
X D
AY
X
Yes
| N
o dd
mm
myy
yy
(xx)
xx
x xx
x
xxx
Baz
ett |
Fr
ider
icia
Not
e: M
H =
Med
ical
His
tory
<se
cond
par
t of l
istin
g>
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.7
12-L
ead
EC
G
Pa
rt 2
of 2
Trea
tmen
t Gro
up
Subj
ect I
D
V
isit
Was
EC
G
Perfo
rmed
?
Dat
e of
A
sses
smen
t (S
tudy
Day
) In
terp
reta
tion
If A
bnor
mal
, D
escr
ibe
Abn
orm
ality
If A
bnor
mal
, C
linic
ally
Si
gnifi
cant
?
Prim
ary
Ass
ocia
ted
AE
Prim
ary
Ass
ocia
ted
MH
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x
SCR
EEN
ING
| C
YC
LE X
DA
Y X
Y
es |
No
ddm
mm
yyyy
(x
x)
Nor
mal
| A
bnor
mal
D
escr
iptio
n
Yes
| N
o A
E te
rm
MH
term
N
ote:
MH
= M
edic
al H
isto
ry
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
40/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.8
Phys
ical
Exa
min
atio
n
Trea
tmen
t Gro
up
Subj
ect I
D
V
isit
Was
Phy
sica
l Exa
m
Perfo
rmed
?
Dat
e of
Ex
am
(Stu
dy D
ay)
Abn
orm
al
Find
ings
?
If A
bnor
mal
, C
linic
ally
Si
gnifi
cant
?
If Y
es,
Prim
ary
MH
If Y
es,
Prim
ary
AE
If N
o,
Des
crip
tion
of N
on-
Clin
ical
ly
Sign
ifica
nt A
bnor
mal
ity
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x
SCR
EEN
ING
| C
YC
LE X
DA
Y X
Y
es |
No
ddm
mm
yyyy
(x
x)
Yes
| N
o Y
es |
No
MH
term
A
E te
rm
Des
crip
tion
N
ote:
MH
= M
edic
al H
isto
ry
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
41/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.9
Opt
iona
l Blo
od fo
r Ph
arm
acog
enom
ics
Trea
tmen
t Gro
up
Subj
ect I
D
V
isit
Was
opt
iona
l blo
od sa
mpl
e co
llect
ed fo
r ph
arm
acog
enom
ics?
PG
Blo
od D
ate
of C
olle
ctio
n (S
tudy
Day
) Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
SC
REE
NIN
G |
CY
CLE
X D
AY
X
Yes
| N
o dd
mm
myy
yy
(xx)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
42/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.1
0
CA
19-
9 T
umor
Mar
ker
Trea
tmen
t Gro
up
Subj
ect I
D
V
isit
Was
the
CA
19-9
Tum
or M
arke
r Sa
mpl
e C
olle
cted
? C
olle
ctio
n D
ate
(Stu
dy D
ay)
Res
ult (
Uni
ts)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x
SCR
EEN
ING
| C
YC
LE X
DA
Y X
Y
es |
No
ddm
mm
yyyy
(x
x)
xxxx
x.x
units
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
43/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.1
1
Ant
i-Tar
extu
mab
Ant
ibod
ies
Trea
tmen
t Gro
up
Subj
ect I
D
V
isit
Was
the
Ant
i-Tar
extu
mab
Ant
ibod
y Sa
mpl
e C
olle
cted
? C
olle
ctio
n D
ate
(Stu
dy D
ay)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x
SCR
EEN
ING
| C
YC
LE X
DA
Y X
Y
es |
No
ddm
mm
yyyy
(x
x)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
44/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.1
2
Blo
od fo
r B
iom
arke
rs
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Was
Blo
od S
ampl
e fo
r Pl
asm
a B
iom
arke
rs
Col
lect
ed?
Blo
od S
ampl
e fo
r Pl
asm
a B
iom
arke
rs
Col
lect
ion
Dat
e (S
tudy
Day
)
Was
Blo
od S
ampl
e fo
r m
RN
A B
iom
arke
rs
Col
lect
ed?
Blo
od S
ampl
e fo
r m
RN
A B
iom
arke
rs
Col
lect
ion
Dat
e (S
tudy
Day
)
Was
Blo
od
Sam
ple
for C
TCs
Col
lect
ed?
Blo
od S
ampl
e fo
r C
TCs C
olle
ctio
n D
ate
(Stu
dy D
ay)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x SC
REE
NIN
G |
CY
CLE
X D
AY
X
Yes
| N
o dd
mm
myy
yy
(xx)
Y
es |
No
ddm
mm
yyyy
(x
x)
Yes
| N
o dd
mm
myy
yy
(xx)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
45/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.1
3
Seru
m P
regn
ancy
Tes
t
Trea
tmen
t Gro
up
Subj
ect I
D
Vis
it W
as th
e Pr
egna
ncy
Test
per
form
ed?
If N
o, S
peci
fy R
easo
n D
ate
of A
sses
smen
t (S
tudy
Day
)
Res
ult
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x SC
REE
NIN
G |
UN
SCH
EDU
LED
Y
es |
No
Prio
r Hys
tere
ctom
y |
Oth
er R
easo
n:
ddm
mm
yyyy
(x
x)
Posi
tive
| Neg
ativ
e
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
46/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.1
4
Opt
iona
l Tum
or C
ore
Bio
psy
Trea
tmen
t Gro
up
Subj
ect I
D
Vis
it W
as a
n O
ptio
nal T
umor
Cor
e B
iops
y Sa
mpl
e C
olle
cted
? D
ate
of C
olle
ctio
n (S
tudy
Day
) Ti
me
of C
olle
ctio
n Lo
catio
n Lo
catio
n D
escr
iptio
n (P
ositi
on w
ithin
Org
an)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x SC
REE
NIN
G |
CY
CLE
X D
AY
X
Yes
| N
o dd
mm
myy
yy
(xx)
xx
:xx
Panc
reas
| Li
ver |
Ly
mph
| N
odes
| Pe
riton
eum
| C
hest
Wal
l |
Abd
omen
| Pe
lvis
| B
reas
t |
Skin
| K
idne
y |
Lung
| O
ther
: Oth
er
orga
n
Des
crip
tion
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
47/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.1
5
On
Stud
y PC
I or
WB
RT
(PC
I)
Trea
tmen
t G
roup
Su
bjec
t ID
V
isit
Prop
hyla
ctic
Cra
nial
Irra
diat
ion
(PC
I)
Who
le B
rain
Rad
iatio
n [W
BR
T (P
CI)]
A
dmin
iste
red
durin
g st
udy?
To
tal
cGY
St
art D
ate
(Stu
dy D
ay)
Stop
Dat
e (S
tudy
Day
)
Adm
inis
tere
d du
ring
stud
y?
Tota
l cG
Y
Star
t Dat
e (S
tudy
Day
) St
op D
ate
(Stu
dy D
ay)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x SC
REE
NIN
G |
CY
CLE
X
DA
Y X
Yes
| N
o xx
| U
nkno
wn
ddm
mm
yyyy
(x
x)
ddm
mm
yyyy
(x
x)
Y
es |
No
xx |
Unk
now
n dd
mm
myy
yy
(xx)
dd
mm
myy
yy
(xx)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
48/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.8.1
6
Follo
w-U
p A
fter
Dis
cont
inua
tion
of S
tudy
Tre
atm
ent
Trea
tmen
t Gro
up
Subj
ect I
D
Vis
it W
as a
Sur
viva
l Fol
low
-Up
Don
e?
Dat
e of
Su
rviv
al A
sses
smen
t (S
tudy
Day
) Su
bjec
t Sta
tus
Last
Kno
wn
Surv
ival
Dat
e (S
tudy
Day
)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x X
MO
NTH
SU
RV
IVA
L FO
LLO
W-U
P Y
es |
No
ddm
mm
yyyy
(xx)
A
live
| D
ead
| Lo
st to
Fol
low
-Up
ddm
mm
yyyy
(xx)
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Stat
istic
al A
naly
sis P
lan
59R
5-00
3 (P
hase
2)
23
MA
R20
17
Conf
iden
tial
Pa
ge 1
49/1
49
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.17
T
reat
men
ts a
nd P
roce
dure
s for
Ext
ensi
ve S
mal
l Lun
g C
ance
r D
urin
g Fo
llow
-Up
Peri
od
Part
1 o
f 3: S
urge
ry
Trea
tmen
t Gro
up
Subj
ect I
D
Vis
it
Any
surg
erie
s for
the
treat
men
t of l
ung
canc
er
durin
g fo
llow
-up
perio
d?
Surg
ery
Des
crip
tion
Loca
tion
Surg
ery
Dat
e (S
tudy
Day
)
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x X
MO
NTH
SU
RV
IVA
L FO
LLO
W-U
P Y
es |
No
Des
crip
tion
Loca
tion
ddm
mm
yyyy
(xx)
<se
cond
par
t of l
istin
g>
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.17
T
reat
men
ts a
nd P
roce
dure
s for
Ext
ensi
ve S
mal
l Lun
g C
ance
r D
urin
g Fo
llow
-Up
Peri
od
Part
2 o
f 3: R
adio
ther
apy
Trea
tmen
t Gro
up
Subj
ect I
D
Vis
it
Any
radi
othe
rapy
fo
r the
trea
tmen
t of
lung
can
cer d
urin
g fo
llow
-up
perio
d?
Site
of T
reat
men
t To
tal c
GY
St
art D
ate
(Stu
dy D
ay)
Stop
Dat
e (S
tudy
Day
) Sy
stem
ic T
hera
py?
Plac
ebo
| Ta
rext
umab
00
3-xx
x-xx
x X
MO
NTH
SU
RV
IVA
L FO
LLO
W-U
P Y
es |
No
Site
xx
| U
nkno
wn
ddm
mm
yyyy
(xx)
dd
mm
myy
yy (x
x)
Yes
| N
o
<
third
par
t of l
istin
g>
Onc
oMed
Pha
rmac
eutic
als,
Inc.
Page
1 o
f x
59R
5-00
3 (P
hase
2)
Lis
ting
16.2
.17
T
reat
men
ts a
nd P
roce
dure
s for
Ext
ensi
ve S
mal
l Lun
g C
ance
r D
urin
g Fo
llow
-Up
Peri
od
Part
3 o
f 3: S
yste
mic
The
rapy
Trea
tmen
t Gro
up
Subj
ect I
D
Vis
it
Any
syst
emic
ther
apy
for t
he
treat
men
t of l
ung
canc
er
durin
g fo
llow
-up
perio
d?
Reg
imen
St
art D
ate
(Stu
dy D
ay)
End
Dat
e (S
tudy
Day
) Pl
aceb
o |
Tare
xtum
ab
003-
xxx-
xxx
X M
ON
TH S
UR
VIV
AL
FOLL
OW
-UP
Yes
| N
o R
egim
en
ddm
mm
yyyy
(xx)
dd
mm
myy
yy (x
x)