Conditions: Stage IV Small Cell Lung Cancer
Keywords: Newly diagnosed Stage IV Small Cell Lung Cancer
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 172
Healthy volunteers: no

Brief summary:
The study consists of a Phase1b lead-in portion to determine the maximum tolerated dose (MTD) of OMP-59R5 (tarextumab) in combination with etoposide (EP) for 6 cycles followed a Phase 2, multi center, randomized, placebo-controlled portion comparing the efficacy and safety of OMP-59R5 in combination with EP for 6 cycles followed by single agent OMP-59R5 relative to EP alone for 6 cycles in subjects receiving first-line therapy for extensive stage small cell lung cancer.

Detailed description:
The Phase 1b lead-in portion of the study was conducted to determine the MTD of OMP-59R5 administered along with EP. The Phase 2 portion of the study was multi-center, randomized, and placebo-controlled. Subjects who qualified for enrollment into the Phase 2 portion of the study were randomized in a 1:1 ratio to receive study treatment of tarextumab along with EP (Arm A) or placebo along with EP (Arm B).

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: OMP-59R5 intervention 2: Etoposide intervention 3: Placebo intervention 4: Cisplatin or Carboplatin
Intervention descriptions: intervention 1: OMP-59R5 administered intravenously intervention 2: administered intravenously intervention 3: administered IV intervention 4: administered intravenously

Protocol document:
SAP_000.pdf: 
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 Drive
Redwood City, CA 94063
Phone: 650-995-8200
Prepared by:
SynteractHCR
Version Number
Date
Version 1
01SEP2016
Version 2
19SEP2016
Version 3
23MAR2017




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Statistical Analysis Plan 
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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: 
x 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). 
x 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: 
x Phase-1b and -2 portions: To determine the PK of tarextumab in combination with EP in 
subjects receiving first-line therapy for ES-SCLC 
x Phase-1b and -2 portions: To determine the immunogenicity of tarextumab in combination 
with EP in subjects receiving first-line therapy for ES-SCLC 
x 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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x 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 
x 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 
x 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: 
x 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 ߠଵ. 
The null hypotheses for testing homogeneity of PFS distributions across treatment arms is: 
ܪ଴ǣߠଵൌͲ 
And the alternative hypothesis is: 
ܪ஺ǣߠଵ൏Ͳ 
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. 
x 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. 
x 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. 
x 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 ൌ
ଷ଺ହǤଶହ
ଵଶ
 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, 
x 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. 
x 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. 
x 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. 
x 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. 
x 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 
ͳͲͲ ൬ܵܮܦ஼௫஽ଵെܵܮܦ௕௔௦௘௟௜௡௘
ܵܮܦ௕௔௦௘௟௜௡௘
൰݀ଶ
ൗ
 
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 
ͳͲͲ ൬ܵܮܦ௣௥௢௚௥௘௦௦௜௢௡െܵܮܦ௡௔ௗ௜௥
ܵܮܦ௡௔ௗ௜௥
൰݀ଵ
ൗ
 
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). 
͵ൌെͲǤͷ͸ͻȗ͸ȗ͵ ൅ͳǤͲ͹͸ȗͳȗ͸ȗ͵ 
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 intensity ൌ
Total 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 
3
21
21
21
Etop
Stop
Start
Stop
Start
Stop
Start
floor
h
floor

ª


º
§
·
§
·



¨
¸
¨
¸
«
»
©
¹
©
¹
¬
¼
, 
where 
1 if 21 x
0
( )
2 if 21 x
1
3 if 21 x
2
Etop
h
x

t
­
°
 

t
®
°

t
¯
 
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 
2
100
/
BSA
mg 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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1
21
21
21
Stop
Start
Stop
Start
Stop
Start
floor
h
floor

ª


º
§
·
§
·



¨
¸
¨
¸
«
»
©
¹
©
¹
¬
¼
, 
where 
^
( )
1 if 21 x
0
h x  

t
 
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
u

 
The mg amount of drug contained in a dose of Cisplatin is 
2
80
/
mg m
BSA
u
 
The amount of drug contained in a dose of study drug is 
15
/
weight
mg 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 ൌܰ௔ௗ௠௜௡௜௦௧௘௥௘ௗ
ܰ௣௟௔௡௡௘ௗ
ൈͳͲͲΨ 
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: 
x All TEAEs regardless of severity or presumed relationship to study drug 
x TEAEs judged related to tarextumab/placebo 
x TEAEs judged related to etoposide 
x TEAEs judged related to platinum therapy (cisplatin or carboplatin) 
x TEAEs judged related to any study drug 
x Treatment-emergent SAEs regardless of severity or presumed relationship to study drug  
x Treatment-emergent SAEs judged related to tarextumab  
x Treatment-emergent SAEs judged related to EP 
x Treatment-emergent SAEs judged related to any study drug 
x TEAEs leading to a delay/interruption in the administration of study drug 
x TEAEs leading to a reduction in the protocol-specified dose of study drug 
x TEAEs leading to discontinuation of study drug 
x TEAEs leading to withdrawal from the study 
x 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: 
x Systolic blood pressure: 90-120 mm Hg 
x Diastolic blood pressure: 60-80 mm Hg 
x Pulse rate: 60-100 beats/minute 
x Body temperature: 97.8-99.1 °F 
x 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: 
x QRS duration: 80-100 msec 
x PR interval: 120-200 msec 
x 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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23MAR2017 
 
Confidential 
 
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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) 


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Statistical Analysis Plan 
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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) 
 
 


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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 


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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 


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APPENDIX B. TABLE SHELLS 
 
 


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OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Table 14.1.1.1 
 
Subject Disposition 
 
All Subjects 
 
 
 
 
 
Placebo 
Tarextumab 
Total 
 
 
 
 
Subjects Randomized 
xx 
xx 
xx 
 
 
 
 
ITT Population[1] 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
Per-Protocol Population[2] 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
Safety Population[3] 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
Immunogenicity Population[4] 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
Pharmacokinetic Population[5] 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
Subjects Discontinued 
xx 
xx 
xx 
 
 
 
 
Primary Reason for Study Exit 
 
 
 
 
Death 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Lost to Follow-Up 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Study Terminated by OncoMed 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Withdrawal by Subject 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Other 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
Primary Reason for Discontinuing Study Drug [6] 
 
 
 
 
Adverse Event 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Death 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Lost to Follow-Up 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Disease Progression 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Study Terminated by OncoMed 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Withdrawal of Consent / Patient Decision 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Investigator Decision 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Other 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
Note: Denominators are based on the ITT population. 
[1] ITT = Intent-to-Treat. ITT population is comprised of all randomized subjects.  
[2] All randomized subjects who received at least one dose of study drug and had at least one post baseline tumor assessment. 
[3] All subjects who received at least one partial dose of tarextumab or placebo. 
[4] All subjects who had a baseline and at least one follow-up anti-tarextumab antibody sample obtained. 
[5] All subjects who received at least one dose of study drug and had at least one post-dose PK sample. 
[6] Study drug is Placebo or Tarextumab. 
[7] Platinum therapy is cisplatin or carboplatin. 
Programmer Notes: (a) add additional set of rows for (i) “Primary Reason for Discontinuing Etoposide” and (ii) “Primary Reason for Discontinuing Platinum Therapy [7]” 
 
 


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OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Table 14.1.1.2 
 
Platinum Therapy Randomization Strata Versus Actual Platinum Therapy Received 
 
ITT Population 
 
 
 
 
 
 
 
 
Actual Platinum Therapy Received 
 
 
 
 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
 
 
 
 
Cisplatin 
Carboplatin 
Cisplatin 
Carboplatin 
Cisplatin 
Carboplatin 
Platinum Therapy Randomization Strata 
 
 
 
 
 
 
 
Cisplatin 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Carboplatin 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan 
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OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Table 14.1.2.1 
 
Major Protocol Deviations 
 
ITT Population 
 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
Any Major Protocol Deviations [1] 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Deviation Category 1 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Deviation Category 2 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Deviation Category 3 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Etc. 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
[1] Subjects may be included in more than one protocol deviation category. 
 
Programmer note:  the actual categories of Major Protocol Deviation will be according to the external protocol deviation file received. 
 
 
 


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OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Table 14.1.3.1 
 
Demographic Characteristics 
 
ITT Population 
 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
Age  (years) [1] 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Median  
xx 
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
Sex 
 
 
 
 
Male 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Female 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
Child Bearing Potential  [2] 
 
 
 
 
 
 
Yes 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
No 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
Ethnicity 
 
 
 
 
Hispanic or Latino 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Not Hispanic or Latino 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
Race 
 
 
 
 
American Indian or Alaska Native 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Asian 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Black or African American 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Native Hawaiian or Other Pacific Islander xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
White 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 Multiple Races Checked 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
[1] Age on consent date. 
[2] For females only. 
Programmer notes: (a) percentages under Child Bearing Potential are percentages of female subjects, (b) repeat this table using the safety, per-protocol and immunogenicity populations (c) remove 
‘Multiple Races Checked’ row if all tables have zero count for total. 
 
 


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59R5-003 (Phase 2) 
Table 14.1.3.5 
 
Baseline Characteristics 
 
ITT Population 
 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
Height (cm) 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Median  
xx 
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
Weight (kg) 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Median  
xx 
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
Body Mass Index (kg/m2) [1] 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Median  
xx 
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
ECOG Performance Status 
 
 
 
 
0 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
1 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
2 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
Smoking History 
 
 
 
 
Never Smoked 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Ex Smoker 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Current Smoker 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
 [1] BMI (kg/m2) = weight (kg) / [height (cm)]2. 
 
Programmer notes: (a) repeat this table using the safety, per-protocol and immunogenicity populations 
 
 


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Page 1 of x 
59R5-003 (Phase 2) 
Table 14.1.3.9 
 
Small Cell Lung Cancer Disease Characteristics 
 
ITT Population 
 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
Months Since Diagnosis [1] 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Median  
xx 
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
Histological/Cytological Type 
 
 
 
 
Small Cell Only 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Mixed Type 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Other 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
Anatomical Location of Primary Cancer [1] 
 
 
 
 
Right Upper Lung 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Right Lower Lung 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Middle of Right Lung 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Left Upper Lung 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Other 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
Number of Sites of Disease at Study Entry 
 
 
 
 
1 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
2 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
≥3 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
Sites of Disease at Study Entry [2] 
 
 
 
 
Bone 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Brain 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Pleura 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Adrenal Gland 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Lymph Nodes 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
Other Nodes 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
[1] Months since diagnosis to the date of randomization. 
[2] Subjects may be included in more than one category. Therefore percentages may add to more than 100%. 
Programmer notes: (a) repeat this table using the safety population 
 
 


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59R5-003 (Phase 2) 
Table 14.1.3.11 
 
Prior Therapies for Small Cell Lung Cancer 
 
ITT Population 
 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
Prior Surgery for Lung Cancer 
 
 
 
 
Yes 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
No 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
Prior Radiotherapy for Lung Cancer 
 
 
 
 
Yes 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
No 
xx (xx.x%) xx (xx.x%) xx (xx.x%) 
 
 
 
 
Programmer notes: (a) repeat this table using the safety population 
 
 


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59R5-003 (Phase 2) 
Table 14.1.3.13 
 
Baseline Gene Expression 
 
ITT Population 
 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
Total 
(N=xx) 
 
 
 
 
Notch3 Expression 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Median  
xx 
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
Hes1 Expression 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Median  
xx 
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
Hey1 Expression 
 
 
 
 
n 
xx 
xx 
xx 
 
Mean (SD) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Median  
xx 
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
 
 
 
Programmer notes: (a) add additional rows for Hey2 Expression and Hes6 Expression, (b) repeat this table using the safety and per-protocol populations 
 
 


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59R5-003 (Phase 2) 
Table 14.1.3.16 
 
Prior and Concomitant Medications 
 
Safety Population 
 
 
 
ATC Class [1] 
 
Preferred Name 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Subjects Receiving any Prior or Concomitant Medications 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
ATC Class 1 
 
 
 
Preferred Name 1.1 
xx (xx.x%) 
xx (xx.x%) 
 
Preferred Name 1.2 
xx (xx.x%) 
xx (xx.x%) 
 
Preferred Name 1.3 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
ATC Class 2 
 
 
 
Preferred Name 2.1 
xx (xx.x%) 
xx (xx.x%) 
 
Preferred Name 2.2 
xx (xx.x%) 
xx (xx.x%) 
 
Preferred Name 2.3 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
ATC Class 3 
 
 
 
Preferred Name 3.1 
xx (xx.x%) 
xx (xx.x%) 
 
Preferred Name 3.2 
xx (xx.x%) 
xx (xx.x%) 
 
Preferred Name 3.3 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Note: At each level of summation (overall, ATC class and preferred name), subjects reporting more than one medication are counted only once. 
 
[1] ATC Class and Preferred Name are coded according to the WHO Drug Dictionary Enhanced (version March 1, 2014). 
 
 


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59R5-003 (Phase 2) 
Table 14.2.1.1 
 
Overall Survival 
 
ITT Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Total Follow-Up Time (person-years) [1] 
xxx.x 
xxx.x 
Number of Subjects who Died 
xx (xx.x%) 
xx (xx.x%) 
 Number of Subjects who did not Die (Censored) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Hazard [2] 
0.xx 
0.xx 
 
 
 
Kaplan-Meier Estimates: Quartiles [95% C.I.]  (days)  
 
 
 
25th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
50th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
75th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
 
 
Kaplan-Meier Estimate (# at risk) [SE] 
 
 
 
180 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
 
360 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
 
540 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
 
720 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
 
 
 
Range (Subjects who Died) (days) 
xxx, xxx 
xxx, xxx 
Range (All Subjects) (days) 
xxx, xxx 
xxx, xxx 
 
 
 
Hazard Ratio [95% C.I.] [3] 
 
x.xx [x.xx,x.xx] 
P-value [3] 
 
0.xxx 
 
 
 
Note: Overall Survival = Date of Documentation of Death – Randomization Date + 1. Subjects who had not experienced death by their last contact date were censored at that time. Subjects lacking 
data after randomization who do not die have their event time censored on the date of randomization with duration of 1 day. For detailed event and censoring rules, refer to protocol section 13.5.4 and 
SAP section 8.6.  C.I. = Confidence Interval. SE = Standard Error. 
[1] Sum of all individual follow-up times in days divided by 365.25. 
[2] Number of deaths / total follow-up time. 
[3] Hazard ratio, 95% C.I. and p-value from Cox proportional hazards model with main effects for treatment, platinum choice and prior treatment modality. 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 
 
 


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59R5-003 (Phase 2) 
Table 14.2.1.3 
 
Overall Survival for Subjects Receiving Cisplatin 
 
ITT Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Platinum Choice [1] 
 
 
 
Cisplatin 
xx (xx.x%) 
xx (xx.x%) 
 
Carboplatin 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Total Follow-Up Time (person-years) [2] 
xxx.x 
xxx.x 
 Number of Subjects who Died 
xx (xx.x%) 
xx (xx.x%) 
 Number of Subjects who did not Die (Censored) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Hazard [3] 
0.xx 
0.xx 
 
 
 
Kaplan-Meier Estimates:  Quartiles [95% C.I.] (days) 
 
 
 
25th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
50th Percentile  
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
75th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
 
 
Kaplan-Meier Estimate (# at risk) [SE] 
 
 
 
180 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
 
360 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
 
40 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
 
720 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
 
 
 
Range (Subjects who Died) (days) 
xxx, xxx 
xxx, xxx 
Range (All Subjects) (days) 
xxx, xxx 
xxx, xxx 
 
 
 
Hazard Ratio [95% C.I.] [4] 
 
x.xx [x.xx,x.xx] 
P-value [4] 
 
0.xxx 
 
 
 
Note: Overall Survival = Date of Documentation of Death – Randomization Date + 1. Subjects who had not experienced death by their last contact date were censored at that time. Subjects lacking 
data after randomization who do not die have their event time censored on the date of randomization with duration of 1 day. For detailed event and censoring rules, refer to protocol section 13.5.4 and 
SAP section 8.6.  C.I. = Confidence Interval. SE = Standard Error. 
 [1] Analyses presented in this table include only subjects who received cisplatin. Percentages below the first set of rows are based on subjects who received cisplatin. 
[2] Sum of all individual follow-up times in days divided by 365.25. 
[3] Number of deaths / total follow-up time. 
[4] Hazard ratio, 95% C.I. and p-value from Cox proportional hazards model with main effects for treatment and prior treatment modality. 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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Page 1 of x 
59R5-003 (Phase 2) 
Table 14.2.1.5 
 
Overall Survival for Subjects Receiving Carboplatin 
 
ITT Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Platinum Choice [1] 
 
 
 
Cisplatin 
xx (xx.x%) 
xx (xx.x%) 
 
Carboplatin 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Total Follow-Up Time (person-years) [2] 
xxx.x 
xxx.x 
Number of Subjects who Died 
xx (xx.x%) 
xx (xx.x%) 
Number of Subjects who did not Die (Censored) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Hazard [3] 
0.xx 
0.xx 
 
 
 
Kaplan-Meier Estimates: Quartiles [95% C.I.] (days) 
 
 
 
25th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
50th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
75th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
 
 
Kaplan-Meier Estimate (# at risk) [SE] 
 
 
 
180 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
 
360 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
 
540 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
 
720 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
 
 
 
Range (Subjects who Died) (days) 
xxx, xxx 
xxx, xxx 
Range (All Subjects) (days) 
xxx, xxx 
xxx, xxx 
 
 
 
Hazard Ratio [95% C.I.] [4] 
 
x.xx [x.xx,x.xx] 
P-value [4] 
 
0.xxx 
 
 
 
Note: Overall Survival = Date of Documentation of Death – Randomization Date + 1. Subjects who had not experienced death by their last contact date were censored at that time. Subjects lacking 
data after randomization who do not die have their event time censored on the date of randomization with duration of 1 day. For detailed event and censoring rules, refer to protocol section 13.5.4 and 
SAP section 8.6.  C.I. = Confidence Interval. SE = Standard Error. 
[1] Analyses presented in this table include only subjects who received carboplatin. Percentages below the first set of rows are based on subjects who received carboplatin. 
[2] Sum of all individual follow-up times in days divided by 365.25. 
[3] Number of deaths / total follow-up time. 
[4] Hazard ratio, 95% C.I. and p-value from Cox proportional hazards model with main effects for treatment and prior treatment modality. 
Programmer notes: (a) repeat this table using the per-protocol population 
 


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Statistical Analysis Plan 
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Page 1 of x 
59R5-003 (Phase 2) 
Table 14.2.1.7 
 
Overall Survival – Impact of Biomarker Expression 
 
ITT Population 
 
 
 
 
 
 
 
 
Model Coefficients (SE) [1]  
Hazard Ratio [95% Confidence Interval] [1] 
Biomarker 
Treatment 
Treatment x 
Biomarker 
Interaction 
 
At 25th 
Percentile 
At 50th 
Percentile 
At 75th 
Percentile 
 
 
 
 
 
 
 
Notch3 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
Hes1 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
Hey2 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
Hey1 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
Hes6 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
[1] Coefficients, hazard ratios and 95% confidence intervals are from Cox proportional hazards models with effects for treatment, biomarker and treatment-by-biomarker interaction. A separate model 
was used for each biomarker. 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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Statistical Analysis Plan 
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Page 1 of x 
59R5-003 (Phase 2) 
Table 14.2.1.9 
 
Overall Survival – Impact of Notch3 Expression in Subjects with High/Low Notch Pathway Markers 
 
ITT Population 
 
 
 
 
 
 
 
 
 
 
 
 
Model Coefficients (SE) [1]  
Hazard Ratio [95% Confidence Interval] [1] 
Biomarker 
Biomarker 
Level 
n 
Treatment 
Treatment x 
Notch3 
 
At Notch3 
25th Percentile 
At Notch3 
50th Percentile 
At Notch3 
75th Percentile 
 
 
 
 
 
 
 
 
 
N3RPI [2] 
High 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
Low 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
 
 
Hes1 
High 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
Low 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
 
 
Hey2 
High 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
Low 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
 
 
Hey1 
High 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
Low 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
 
 
Hes6 
High 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
Low 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
 
 
[1] Coefficients, hazard ratios and 95% confidence intervals are from Cox proportional hazards models with effects for treatment, Notch3 and treatment-by-Notch3 interaction. A separate model was 
used for each biomarker. 
[2] N3RPI is the Notch3-related PFS Index; N3RPI  = –0.569*HES6*NOTCH3 +1.076*HES1*HES6*NOTCH3 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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Statistical Analysis Plan 
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Confidential 
 
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Page 1 of x 
59R5-003 (Phase 2) 
Table 14.2.2.1 
 
Progression-Free Survival – Primary Analysis 
 
ITT Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Total Follow-Up Time (person-years) [1] 
xxx.x 
xxx.x 
Number of Subjects with Disease Progression or Death 
xx (xx.x%) 
xx (xx.x%) 
Number of Subjects who did not Progress or Die (Censored) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Hazard [2] 
0.xx 
0.xx 
 
 
 
Kaplan-Meier Estimates: Quartiles [95% C.I.] (days) 
 
 
 
25th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
50th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
75th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
 
 
Range (Subjects who Progressed or Died) (days) 
xxx, xxx 
xxx, xxx 
Range (All Subjects) (days) 
xxx, xxx 
xxx, xxx 
 
 
 
Hazard Ratio [95% C.I.] [3] 
 
x.xx [x.xx,x.xx] 
P-value [4] 
 
0.xxx 
 
 
 
Note: PFS= Date of Documentation of Death/Progression – Randomization Date + 1. Subjects who had not experienced death or progression by their last contact were censored at the time of their last 
radiographic response assessment. Subjects lacking a radiographic response assessment after randomization who do not progress or die have their event time censored on the date of randomization 
with duration of 1 day. For detailed event and censoring rules refer to protocol section 13.5.1 and SAP section 8.1. C.I. = Confidence Interval. 
 [1] Sum of all individual follow-up times in days divided by 365.25. 
[2] Number of Subjects with Disease Progression or Death/ Total Follow-up Time (Person-years). 
[3] Hazard ratio and 95% C.I. from Cox proportional hazards model with main effects for treatment, platinum choice and prior treatment modality. 
[4] P-value for treatment effect from stratified log rank test using platinum choice and prior treatment modality as stratification factors. 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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Statistical Analysis Plan 
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23MAR2017 
 
Confidential 
 
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Page 1 of x 
59R5-003 (Phase 2) 
Table 14.2.2.3 
 
Progression-Free Survival During Combination Chemotherapy 
 
ITT Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Total Follow-Up Time (person-years) [1] 
xxx.x 
xxx.x 
Number of Subjects with Disease Progression or Death  
xx (xx.x%) 
xx (xx.x%) 
Number of Subjects who did not Progress or Die (Censored) [2] 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Hazard [3] 
0.xx 
0.xx 
 
 
 
Kaplan-Meier Estimates: Quartiles [95% C.I.] (days) 
 
 
 
25th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
50th Percentile  
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
75th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
 
 
Range (Subjects who Progressed or Died) (days) 
xxx, xxx 
xxx, xxx 
Range (All Subjects) (days) 
xxx, xxx 
xxx, xxx 
 
 
 
Hazard Ratio [95% C.I.] [4] 
 
x.xx [x.xx,x.xx] 
P-value [5] 
 
0.xxx 
 
 
 
Note: PFS= Date of Documentation of Death/Progression – Randomization Date + 1. Subjects who had not experienced death or progression by their last contact were censored at the time of their last 
radiographic response assessment. Subjects lacking a radiographic response assessment after randomization who do not progress or die have their event time censored on the date of randomization 
with duration of 1 day. For detailed event and censoring rules refer to protocol section 13.5.1 and SAP section 8.1. C.I. = Confidence Interval. 
[1] Sum of all individual follow-up times in days divided by 365.25. 
[2] The same censoring mechanisms used in the primary analysis of PFS were employed here. Additionally, for this analysis, a subject’s PFS was censored 35 days (the scheduled time for 1 treatment 
cycle plus 7 days) following his or her last dose of etoposide or platinum. 
[3] Number of Subjects with Disease Progression or Death/ Total Follow-up Time (Person-years). 
[4] Hazard ratio and 95% C.I. from Cox proportional hazards model with main effects for treatment, platinum choice and prior treatment modality. 
[5] P-value for treatment effect from stratified log rank test using platinum choice and prior treatment modality as stratification factors. 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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Table 14.2.2.5 
 
Progression-Free Survival – Impact of Biomarker Expression 
 
ITT Population 
 
 
 
 
 
 
 
 
Model Coefficients (SE) [1]  
Hazard Ratio [95% Confidence Interval] [1] 
Biomarker 
Treatment 
Treatment x 
Biomarker 
Interaction 
 
At 25th 
Percentile 
At 50th 
Percentile 
At 75th 
Percentile 
 
 
 
 
 
 
 
Notch3 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
Hes1 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
Hey2 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
Hey1 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
Hes6 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
[1] Coefficients, hazard ratios and 95% confidence intervals are from Cox proportional hazards models with effects for treatment, biomarker and treatment-by-biomarker interaction. A separate model 
was used for each biomarker. 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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Table 14.2.2.7 
 
Progression-Free Survival – Impact of Notch3 Expression in Subjects with High/Low Notch Pathway Markers 
 
ITT Population 
 
 
 
 
 
 
 
 
 
 
 
 
Model Coefficients (SE) [1]  
Hazard Ratio [95% Confidence Interval] [1] 
Biomarker 
Biomarker 
Level 
n 
Treatment 
Treatment x 
Notch3 
 
At Notch3 
25th Percentile 
At Notch3 
50th Percentile 
At Notch3 
75th Percentile 
 
 
 
 
 
 
 
 
 
N3RPI [2] 
High 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
Low 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
 
 
Hes1 
High 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
Low 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
 
 
Hey2 
High 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
Low 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
 
 
Hey1 
High 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
Low 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
 
 
Hes6 
High 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
Low 
xx 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
 
 
[1] Coefficients, hazard ratios and 95% confidence intervals are from Cox proportional hazards models with effects for treatment, Notch3 and treatment-by-Notch3 interaction. A separate model was 
used for each biomarker. 
[2] N3RPI is the Notch3-related PFS Index; N3RPI  = –0.569*HES6*NOTCH3 +1.076*HES1*HES6*NOTCH3 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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Table 14.2.2.9 
 
Progression-Free Survival – Sensitivity Analysis 
 
Per-Protocol Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Total Follow-Up Time (person-years) [1] 
xxx.x 
xxx.x 
Number of Subjects with Disease Progression or Death 
xx (xx.x%) 
xx (xx.x%) 
Number of Subjects who did not Progress or Die 
(Censored) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Hazard [2] 
0.xx 
0.xx 
 
 
 
Kaplan-Meier Estimates: Quartiles [95% C.I.] (days) 
 
 
 
25th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
50th Percentile  
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
75th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
 
 
Range (Subjects who Progressed or Died) (days) 
xxx, xxx 
xxx, xxx 
Range (All Subjects) (days) 
xxx, xxx 
xxx, xxx 
 
 
 
Hazard Ratio [95% C.I.] [3] 
 
x.xx [x.xx,x.xx] 
P-value [4] 
 
0.xxx 
 
 
 
Note: PFS= Date of Documentation of Death/Progression – Randomization Date + 1. Subjects who had not experienced death or progression by their last contact were censored at the time of their last 
radiographic response assessment. Subjects lacking a radiographic response assessment after randomization who do not progress or die have their event time censored on the date of randomization 
with duration of 1 day. For detailed event and censoring rules refer to protocol section 13.5.1 and SAP section 8.1. C.I. = Confidence Interval. 
 [1] Sum of all individual follow-up times in days divided by 365.25. 
[2] Number of Subjects with Disease Progression or Death/ Total Follow-up Time (Person-years). 
[3] Hazard ratio and 95% C.I. from Cox proportional hazards model with treatment as the only explanatory variable. 
[4] P-value for treatment effect from unstratified log rank test. 
 
 


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Table 14.2.3.1 
 
Landmark Survival at 180, 360, 540 and 720 Days 
 
ITT Population 
 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
P-Value 
 
 
 
 
Survival (# at risk) [SE] [1] 
 
 
 
 
180 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
0.xxx 
 
360 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
0.xxx 
 
540 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
0.xxx 
 
720 Days 
0.xx (xx) [x.xx] 0.xx (xx) [x.xx] 
0.xxx 
 
 
 
 
 
[1] Landmark survival p-values from independent Z tests. 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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Table 14.2.4.1 
Summary Assessment of Tumor Length (mm) 
 
ITT Population 
 
 
 
 
 
 
 
 
 
Placebo (N=xx) 
 
Tarextumab  (N=xx) 
 
Result 
Change 
from 
Baseline 
Percent 
Change 
 
Result 
Change 
from 
Baseline 
Percent 
Change 
 
 
 
 
 
 
 
 
Baseline Sum of Longest Diameters (SLD) 
 
 
 
 
 
 
 
 
n 
xx 
 
 
 
xx 
 
 
 
Mean (SD) 
xx.x (xx.xx) 
 
 
 xx.x (xx.xx) 
 
 
 
95% C.I. 
[xx.x, xx.x] 
 
 
 [xx.x, xx.x] 
 
 
 
Median  
xx 
 
 
 
xx 
 
 
 
25th, 75th Percentile 
xx, xx 
 
 
 
xx, xx 
 
 
 
Min, Max 
xx, xx 
 
 
 
xx, xx 
 
 
 
 
 
 
 
 
 
 
Cycle-3, Day-1 Sum of Longest Diameters (SLD) 
 
 
 
 
 
 
 
 
n 
xx 
xx 
xx 
 
xx 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx)  xx.x (xx.xx) xx.x (xx.xx) xx.x (xx.xx) 
 
95% C.I. 
[xx.x, xx.x] 
[xx.x, xx.x] 
[xx.x, xx.x]  [xx.x, xx.x] 
[xx.x, xx.x] [xx.x, xx.x] 
 
Median  
xx 
xx 
xx 
 
xx 
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
xx, xx 
 
ANCOVA p-values [1,2] 
 
 
 
 
 
0.xxx 
0.xxx 
 
 
 
 
 
 
 
 
Cycle-5, Day-1 Sum of Longest Diameters (SLD) 
 
 
 
 
 
 
 
 
[etcetera] 
[⁞] 
[⁞] 
[⁞] 
 
[⁞] 
[⁞] 
[⁞] 
 
 
 
 
 
 
 
 
Note: tumor length is calculated as the sum of the longest diameters (SLD) for the target lesions. SD = Standard Deviation; LS = Least Squares; SE = Standard Error; C.I. = Confidence Interval. 
[1] The difference between the follow-up and baseline SLD (e.g., SLDC3D1 – SLDbaseline) is the dependent variable in the ANCOVA model for change from baseline. 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. 
[2] The log of the ratio of follow-up to baseline SLD (e.g., log [SLDC3D1/SLDbaseline]) is the dependent variable in the ANCOVA model for percent change. Treatment, platinum choice and prior 
treatment modality will be categorical factors in the model, and log [SLDbaseline] will be included as a continuous covariate. 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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Table 14.2.4.3 
 
Rate of Change in Total Tumor Length at Progression 
 
ITT Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
SLD at Nadir 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
SLD at Progression 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Rate of SLD Change from Nadir to Progression (%/day) [1] 
 
 
 
N 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
P-value [2] 
 
0.xxx 
 
 
 
Note: SLD = Sum of Longest Diameters (i.e., total tumor length for target lesions as defined by RECIST criteria [version 1.1]). 
[1] Rate of Change in SLD at progression = 100 x (SLD at Progression – SLD at Nadir) / SLD at Nadir / (number of days between nadir and progression). 
[2] P-value for treatment effect from ANOVA model with treatment, platinum choice and prior treatment modality as categorical independent variables. 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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59R5-003 (Phase 2) 
Table 14.2.4.5 
 
Rate of Change from Total Tumor Length at Baseline 
 
ITT Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
SLD at Baseline 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
SLD at Cycle 3, Day 1 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Rate of SLD Change from Baseline to Cycle 3, Day 1Assessment (%/day) [1] 
 
 
 
N 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
P-value [2] 
 
0.xxx 
 
 
 
Note: SLD = Sum of Longest Diameters (i.e., total tumor length for target lesions as defined by RECIST criteria [version 1.1]). 
 [1] Rate of Change in SLD from baseline to CxD1 = 100 x (SLD at CxD1 – SLD at Baseline) / SLD at Baseline / (number of days between baseline and CxD1 assessment). 
[2]  P-value for treatment effect from ANOVA model with treatment, platinum choice and prior treatment modality as categorical independent variables. 
Programmer notes: (a) add rows for (i) SLD at Cycle 5, Day 1 and (ii) Rate of SLD Change from Baseline to Cycle 5, Day 1Assessment; (b) repeat this table using the per-protocol population 
 
 


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Table 14.2.5.1 
 
Best Overall Tumor Response Based on Investigator Assessment 
 
ITT Population 
 
 
 
 
 
 
 
Placebo (N=xx) 
 
Tarextumab (N=xx) 
 
Response 
Rate 
95% C.I.[2] 
 
Response 
Rate 
95% C.I.[2] 
 
 
 
 
 
 
Best Overall Tumor Response [1] 
 
 
 
 
 
 
Complete Response (CR) 
xx.x (xx.x%) [xx.x, xx.x]  xx.x (xx.x%) [xx.x, xx.x] 
 
Partial Response (PR) 
xx.x (xx.x%) [xx.x, xx.x]  xx.x (xx.x%) [xx.x, xx.x] 
 
Stable Disease (SD) 
xx.x (xx.x%) [xx.x, xx.x]  xx.x (xx.x%) [xx.x, xx.x] 
 
Progressive Disease (PD) 
xx.x (xx.x%) [xx.x, xx.x]  xx.x (xx.x%) [xx.x, xx.x] 
 
Not Evaluable (NE) 
xx.x (xx.x%) [xx.x, xx.x]  xx.x (xx.x%) [xx.x, xx.x] 
 
No Post-Baseline Tumor Assessment Collected 
xx.x (xx.x%) [xx.x, xx.x]  xx.x (xx.x%) [xx.x, xx.x] 
 
 
 
 
 
 
Overall Response Rate (CR or PR)  
xx.x (xx.x%) 
 
 xx.x (xx.x%) [xx.x, xx.x] 
Odds Ratio (Tarextumab/Placebo) [3] 
 
 
 
x.xx 
 
P-value [3] 
 
 
 
0.xxx 
 
 
 
 
 
 
 
[1] Tumor response based on RECIST criteria (version 1.1). 
[2] Two-sided exact 95% C.I.. 
[3] Odds ratio and p-value from logistic regression model including treatment, platinum choice and prior treatment modality as independent variables. 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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Table 14.2.5.3 
 
Best Overall Tumor Response Based on Investigator Assessment – Impact of Biomarker Expression 
 
ITT Population 
 
 
 
 
 
 
 
 
Model Coefficients (SE) [1]  
Odds Ratio [95% Confidence Interval] [1] 
Biomarker 
Treatment 
Treatment x 
Biomarker 
Interaction 
 
At 25th 
Percentile 
At 50th 
Percentile 
At 75th 
Percentile 
 
 
 
 
 
 
 
Notch3 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
Hes1 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
Hey2 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
Hey1 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
Hes6 
xx.x (xx.x) 
xx.x (xx.x) 
 x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] x.xx [x.xx,xx.xx] 
 
 
 
 
 
 
 
[1] Coefficients, odds ratio and 95% confidence interval from logistic regression models with effects for treatment, biomarker and treatment-by-biomarker interaction. A separate model was used for 
each biomarker. 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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Table 14.2.6.1 
 
Duration of Response 
 
ITT Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Number of Subjects with Objective Response (CR or PR) 
xx 
xx  
Total Follow-Up Time (person-years) [11] 
xxx.x 
xxx.x 
Number of Responders with Disease Progression or Death 
xx (xx.x%) 
xx (xx.x%) 
Number of Responders who did not Progress or Die (Censored) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Hazard [2] 
0.xx 
0.xx 
 
 
 
Kaplan-Meier Estimates: Quartiles [95% C.I.] (days) 
 
 
 
25th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
50th Percentile  
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
75th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
 
 
Range (Responders who Progressed or Died) (days) 
xx.x – xx.x 
xx.x – xx.x 
Range (All Responders) (days) 
xx.x – xx.x 
xx.x – xx.x 
 
 
 
Hazard Ratio [95% C.I.] [3] 
 
x.xx [x.xx,x.xx] 
P-value [2] 
 
0.xxx 
 
 
 
Note: For this table summary, Responders are those subjects who experienced an Objective Response. 
Note: Analyses presented in this table include only subjects who achieved a CR or PR. Percentages below the first row are based on subjects who achieved a CR or PR. 
Note: Duration of Response = Date of Documentation of Death/Progression – Date of First Partial (PR) or Complete Response (CR) + 1. Responders who had not experienced death or progression by 
their last contact were censored at the time of their last radiographic response assessment. Responders lacking a radiographic response assessment after first response who do not progress or die have 
their event time censored on the date of first response with duration of 1 day. For detailed event and censoring rules refer to protocol section 13.5.3 and SAP section 8.4. C.I. = Confidence Interval. 
[1] Sum of all individual follow-up times in days divided by 365.25. 
[2] Number of Subjects with Disease Progression or Death/ Total Follow-up Time (Person-years). 
[3] Hazard ratio, 95% C.I. and p-value from Cox proportional hazards model with main effects for treatment, platinum choice and prior treatment modality. 
Programmer notes: Percentages displayed to be based on number of subjects with an objective response. 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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Table 14.2.7.1 
 
Sites of Progression 
 
ITT Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Subjects with Progressive Disease [1] 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Progression based on… 
 
 
 
New Lesion 
xx (xx.x%) 
xx (xx.x%) 
 
Existing Lesion 
xx (xx.x%) 
xx (xx.x%) 
 
Chi-Square p-value [2] 
 
0.xxx 
 
 
 
Site of Progression 
 
 
 
Progression of existing lesion 
xx (xx.x%) 
xx (xx.x%) 
 
Liver 
xx (xx.x%) 
xx (xx.x%) 
 
Lung 
xx (xx.x%) 
xx (xx.x%) 
 
Lymph Node 
xx (xx.x%) 
xx (xx.x%) 
 
[…] 
[⁞] 
[⁞] 
 
More than one new lesion 
xx (xx.x%) 
xx (xx.x%) 
 
Chi-Square p-value [3] 
 
0.xxx 
 
 
 
[1] Analyses presented in this table include only subjects who had progressive disease during the study. Percentages below the first row are based on subjects who had progressive disease on study. 
[2] Hypothesis 1 is equivalent distributions of manner of disease progression (new lesion or progression of existing lesion). 
[3] Hypothesis 2 is equivalent distributions of site of progression with progression of an existing lesion grouped in a single category (i.e., regardless of site). 
Programmer notes: (a) repeat this table using the per-protocol population 
 
 


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59R5-003 (Phase 2) 
Table 14.3.1.1 
 
Overall Summary of Treatment-Emergent Adverse Events (TEAEs)  
 
Safety Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Subjects Reporting at Least One TEAE 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting at Least One TEAE 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting at Least One TEAE Related to Study Drug [1] 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting at Least One TEAE Related to Etoposide 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting at Least One  TEAE Related to Platinum Therapy 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting at Least One Serious TEAE 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting at Least One Serious TEAE Related to Study Drug [1] 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting at Least One Serious TEAE Related to Etoposide 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting at Least One Serious TEAE Related to Platinum Therapy 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting at Least One Grade 3 or Higher TEAE 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting at Least One Grade 4 or Higher TEAE 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting TEAE Leading to Delay/Interruption of Study Drug [1] 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting TEAE Leading to Delay/Interruption of Etoposide 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting TEAE Leading to Delay/Interruption of Platinum Therapy 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting TEAE Leading to Dose Reduction of Study Drug [1] 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting TEAE Leading to Dose Reduction of Etoposide 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting TEAE Leading to Dose Reduction of Platinum Therapy 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting TEAE Leading to Withdrawal of Study Drug [1] 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting TEAE Leading to Withdrawal of Etoposide 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting TEAE Leading to Withdrawal of Platinum Therapy 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting TEAE with Outcome of Death 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Maximum CTCAE Severity Grade [2] 
 
 
 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
 
Grade 3 
xx (xx.x%) 
xx (xx.x%) 
 
Grade 4 
xx (xx.x%) 
xx (xx.x%) 
 
Grade 5 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
[1] Study drug = tarextumab or placebo. 
[2] CTCAE = Common Terminology Criteria for Adverse Events (version 4.02). Subjects with more than one TEAE are counted only once at the highest CTCAE severity grade across all TEAEs. 
 
 


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59R5-003 (Phase 2) 
Table 14.3.1.2 
 
Treatment-Emergent Adverse Events (TEAEs) by System Organ Class and Preferred Term 
 
Safety Population 
 
 
 
System Organ Class / 
 
Preferred Term 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Subjects Reporting at Least One Qualifying TEAE  
xx (xx.x%) 
xx (xx.x%) 
 
 
 
System Organ Class 1 
xx (xx.x%) 
xx (xx.x%) 
 
Preferred Term 1.1 
xx (xx.x%) 
xx (xx.x%) 
 
Preferred Term 1.2 
xx (xx.x%) 
xx (xx.x%) 
 
Preferred Term 1.3 
xx (xx.x%) 
xx (xx.x%) 
 
[etcetera] 
[⁞] 
[⁞] 
 
 
 
System Organ Class 2 
xx (xx.x%) 
xx (xx.x%) 
 
Preferred Term 2.1 
xx (xx.x%) 
xx (xx.x%) 
 
Preferred Term 2.2 
xx (xx.x%) 
xx (xx.x%) 
 
Preferred Term 2.3 
xx (xx.x%) 
xx (xx.x%) 
 
[etcetera] 
[⁞] 
[⁞] 
 
 
 
Note: At each level of summation (overall, system organ class, preferred term), subjects reporting more than one adverse event are counted only once. 
Programmer notes: (a) primary sort order is descending SOC frequency under tarextumab, secondary sort order is descending PT frequency under tarextumab; (b) duplicate this table for the 
following TEAE subsets making the necessary changes to the table’s title – (i) TEAEs related to study drug, (ii) TEAEs related to etoposide, (iii) TEAEs related to platinum therapy, (iv) serious 
TEAEs, (v) serious TEAEs related to study drug, (vi) serious TEAEs related to etoposide, (vii) serious TEAEs related to platinum therapy, (viii) TEAEs leading to delay/interruption of study drug, (ix) 
TEAEs leading to delay/interruption of etoposide, (x) TEAEs leading to delay/interruption of platinum therapy, (xi) TEAEs leading to dose reduction of study drug, (xii) TEAEs leading to dose 
reduction of etoposide, (xiii) TEAEs leading to dose reduction of platinum therapy, (xiv) TEAEs leading to withdrawal of study drug, (xv) TEAEs leading to withdrawal of etoposide, (xvi) TEAEs 
leading to withdrawal of platinum therapy, (xvii) TEAEs leading to  discontinuation of study drug, (xviii) TEAEs with outcome of death 
 
 


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59R5-003 (Phase 2) 
Table 14.3.1.6 
 
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term and CTCAE Severity Grade 
 
Safety Population 
System Organ Class /  
  Preferred Term 
Placebo 
(N=   ) 
 
 
Tarextumab 
(N=   ) 
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
Total 
 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 
Total 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects Reporting at Least One Qualifying TEAE 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 1 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
Preferred Term 2 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%)  
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
n (%) 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = Severe; Grade 4 = Life Threatening; Grade 5 = Fatal.  
At each level of summation (overall, system organ class, and preferred term), subjects reporting more than one qualifying event are counted only once at the highest CTCAE severity grade. 
Programmer notes: (a) primary sort order is descending SOC frequency under tarextumab, secondary sort order is descending PT (total) frequency under tarextumab (total frequency [i.e., sum of 
frequencies for grades 1 through 5] even though total frequency is not displayed in table); (b) duplicate this table for the following TEAE subsets making the necessary changes to the table’s title – (i) 
TEAEs related to study drug, (ii) TEAEs related to etoposide, (iii) TEAEs related to platinum therapy, (iv) serious TEAEs, (v) serious TEAEs related to study drug, (vi) serious TEAEs related to 
etoposide, (vii) serious TEAEs related to platinum therapy 
 
 


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59R5-003 (Phase 2) 
Table 14.3.1.10 
 
Treatment-Emergent Adverse Events by Preferred Term 
 
Safety Population 
 
 
 
Preferred Term 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Subjects Reporting at Least One Qualifying TEAE 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Preferred Term 1 
xx (xx.x%) 
xx (xx.x%) 
Preferred Term 2 
xx (xx.x%) 
xx (xx.x%) 
Preferred Term 3 
xx (xx.x%) 
xx (xx.x%) 
Preferred Term 4 
xx (xx.x%) 
xx (xx.x%) 
Preferred Term 5 
xx (xx.x%) 
xx (xx.x%) 
Preferred Term 6 
xx (xx.x%) 
xx (xx.x%) 
[etcetera] 
[⁞] 
[⁞] 
 
 
 
 Note: At each level of summation (overall and preferred term), subjects reporting more than one qualifying event are counted only once. 
Programmer notes: (a) primary sort order is descending PT frequency under tarextumab; (b) duplicate this table for the following TEAE subsets making the necessary changes to the table’s title – (i) 
TEAEs related to study drug, (ii) TEAEs related to etoposide, (iii) TEAEs related to platinum therapy, (iv) serious TEAEs, (v) serious TEAEs related to study drug, (vi) serious TEAEs related to 
etoposide, (vii) serious TEAEs related to platinum therapy, (viii) TEAEs leading to delay/interruption of study drug, (ix) TEAEs leading to delay/interruption of etoposide, (x) TEAEs leading to 
delay/interruption of platinum therapy, (xi) TEAEs leading to dose reduction of study drug, (xii) TEAEs leading to dose reduction of etoposide, (xiii) TEAEs leading to dose reduction of platinum 
therapy, (xiv) TEAEs leading to withdrawal of study drug, (xv) TEAEs leading to withdrawal of etoposide, (xvi) TEAEs leading to withdrawal of platinum therapy, (xvii) TEAEs 
leading to  discontinuation of study drug, (xviii) TEAEs with outcome of death 
 
 


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Table 14.3.4.1 
 
Hematology 
 
Safety Population 
 
 
 
 
 
 
 
 
 
Placebo 
(N=xx) 
 
Tarextumab 
(N=xx) 
Laboratory Parameter Time Point 
Result 
Change from 
Baseline 
 
Result 
Change from 
Baseline 
 
 
 
 
 
 
 
Hemoglobin (g/dL) 
Baseline [1] 
 
 
 
 
 
 
 
n 
xx 
 
 
xx 
 
 
 
Mean (SD) 
xx.x (xx.xx) 
 
 
xx.x (xx.xx) 
 
 
 
Median  
xx 
 
 
xx 
 
 
 
25th, 75th Percentile 
xx, xx 
 
 
xx, xx 
 
 
 
Min, Max 
xx, xx 
 
 
xx, xx 
 
 
 
 
 
 
 
 
 
Maximum Post-Baseline 
 
 
 
 
 
 
 
n 
xx 
xx 
 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median  
xx 
xx 
 
xx 
xx 
 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Minimum Post-Baseline 
 
 
 
 
 
 
 
n 
xx 
xx 
 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median  
xx 
xx 
 
xx 
xx 
 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Last Observation Post-Baseline 
 
 
 
 
 
 
 
n 
xx 
xx 
 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median  
xx 
xx 
 
xx 
xx 
 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Hematocrit (%) 
Baseline [1] 
 
 
 
 
 
[etcetera] 
 
[⁞] 
[⁞] 
[⁞] 
 
[⁞] 
[⁞] 
 
 
 
 
 
 
 
[1] Baseline is defined as the last non-missing value prior to first dose of study drug. 
Programmer notes: (a) continue for all remaining hematology parameters; (b) duplicate table for (i) serum chemistry, (ii) coagulation tests (PT, aPTT and INR)  
 
 


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59R5-003 (Phase 2) 
Table 14.3.4.2 
 
Hematology – Shift from Baseline 
 
Safety Population 
 
Laboratory Parameter 
 
Shift from Baseline [1] 
 Placebo 
(N=   ) 
Tarextumab 
(N=   ) 
 
 
 
Hemoglobin (g/dL) 
Low or Normal to Any High Post-Baseline 
n (%) 
n (%) 
Normal or High to Any Low Post-Baseline 
n (%) 
n (%) 
 
 
Low or Normal to Last Observation High Post-Baseline 
n (%) 
n (%) 
Normal or High to Last Observation Low Post-Baseline 
n (%) 
n (%) 
 
 
 
 
Hematocrit (%) 
 
 
 
…. 
 
 
 
 
 
 
 
 [1] Baseline is defined as the last non-missing value prior to first dose of study drug. 
Programmer notes: (a) continue for all remaining hematology parameters; (b) duplicate table for (i) serum chemistry, (ii) coagulation tests (PT, aPTT and INR) 
 
 


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59R5-003 (Phase 2) 
Table 14.3.4.3 
 
Hematology – Range Change Abnormal – High 
 
Safety Population 
 
 
 
Laboratory Parameter 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Hemoglobin (g/dL) 
 
 
 
n 
xx (xx.x%) 
xx (xx.x%) 
 
Any Post-Baseline [1] 
 
 
 
 
Grade 4 
xx (xx.x%) 
xx (xx.x%) 
 
 
Grade 3 
xx (xx.x%) 
xx (xx.x%) 
 
 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
 
 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Last Observation Post-Baseline 
 
 
 
 
Grade 4 
xx (xx.x%) 
xx (xx.x%) 
 
 
Grade 3 
xx (xx.x%) 
xx (xx.x%) 
 
 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
 
 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Platelets (x10^9/L) 
 
 
[etcetera] 
[⁞] 
[⁞] 
 
 
 
[1] Subjects are counted only once using their highest post-baseline CTCAE severity grade. Only patients who have an increase in CTCAE grade severity from baseline are considered for counts of 
Grades 1 through 4.  Subjects who have a baseline result and at least one post-baseline result for a particular analyte are considered when determining percentages, regardless of whether the patient 
had a CTCAE grade counted for the analyte. 
Programmer notes: (a) continue for all remaining hematology parameters with CTCAE severity grading criteria; (b) duplicate table for (i) serum chemistry, (ii) coagulation tests (PT, aPTT and INR) 
 
 


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59R5-003 (Phase 2) 
Table 14.3.4.13 
 
Urinalysis – Shift from Baseline 
 
Safety Population 
Laboratory Parameter 
 
Time Point 
 Placebo 
(N=   ) 
Tarextumab 
(N=   ) 
 
 
 
Protein 
n 
 
 
Any Post-Baseline 
 
 
   Absent to Present 
n (%) 
n (%) 
 
 
 
Last Observation Post-Baseline 
 
 
   Absent to Present 
n (%) 
n (%) 
 
 
 
Glucose 
n 
 
 
Any Post-Baseline 
 
 
   Absent to Present 
n (%) 
n (%) 
 
 
 
Last Observation Post-Baseline 
 
 
   Absent to Present 
n (%) 
n (%) 
 
 
 
pH 
n 
 
 
Any Post-Baseline 
 
 
   Low or Normal to High 
n (%) 
n (%) 
   Normal or High to Low 
n (%) 
n (%) 
 
 
 
Last Observation Post-Baseline 
 
 
   Low or Normal to High 
n (%) 
n (%) 
   Normal or High to Low 
n (%) 
n (%) 
 
 
 
 
Specific Gravity 
 
 
 
… 
 
 
 
 
 
 
[1] Baseline is defined as the last non-missing value prior to first dose of study drug. 
 
 


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59R5-003 (Phase 2) 
Table 14.3.4.14 
 
Vital Signs 
 
Safety Population 
 
 
 
 
 
 
 
 
 
Placebo (N=xx) 
 
Tarextumab (N=xx) 
Parameter 
Time Point 
Result 
Change from 
Baseline 
 
Result 
Change from 
Baseline 
 
 
 
 
 
 
 
Systolic Blood Pressure (mmHg) 
Baseline [1] 
 
 
 
 
 
 
 
n 
xx 
 
 
xx 
 
 
 
Mean (SD) 
xx.x (xx.xx) 
 
 
xx.x (xx.xx) 
 
 
 
Median  
xx 
 
 
xx 
 
 
 
25th, 75th Percentile 
xx, xx 
 
 
xx, xx 
 
 
 
Min, Max 
xx, xx 
 
 
xx, xx 
 
 
 
 
 
 
 
 
 
Maximum Post-Baseline 
 
 
 
 
 
 
 
n 
xx 
xx 
 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median  
xx 
xx 
 
xx 
xx 
 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Minimum Post-Baseline 
 
 
 
 
 
 
 
n 
xx 
xx 
 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median  
xx 
xx 
 
xx 
xx 
 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Last Observation Post-Baseline 
 
 
 
 
 
 
 
n 
xx 
xx 
 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median  
xx 
xx 
 
xx 
xx 
 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
Diastolic Blood Pressure (mmHg) 
Baseline [1] 
 
 
 
 
 
[etcetera] 
 
[⁞] 
[⁞] 
[⁞] 
 
[⁞] 
[⁞] 
 
 
 
 
 
 
 
[1] Baseline is defined as the last non-missing value prior to first dose of study drug. 
Programmer notes: (a) continue for all vital sign parameters (systolic and diastolic blood pressures, pulse, body temperature and respiration rate) 
 
 


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59R5-003 (Phase 2) 
Table 14.3.4.15 
 
Vital Signs – Range Change Abnormal (RCA) 
 
Safety Population 
 
 
 
Vital Signs Parameter 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
n 
xx 
xx 
Any Post-Baseline 
 
 
 
High [1] 
 
 
 
 
Temperature 
xx (xx.x%) 
xx (xx.x%) 
 
 
Pulse Rate 
xx (xx.x%) 
xx (xx.x%) 
 
 
Respiratory Rate 
xx (xx.x%) 
xx (xx.x%) 
 
 
SBP 
xx (xx.x%) 
xx (xx.x%) 
 
 
DBP 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Low [1] 
 
 
 
 
Temperature 
xx (xx.x%) 
xx (xx.x%) 
 
 
Pulse Rate 
xx (xx.x%) 
xx (xx.x%) 
 
 
Respiratory Rate  
xx (xx.x%) 
xx (xx.x%) 
 
 
SBP 
xx (xx.x%) 
xx (xx.x%) 
 
 
DBP 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Last Post-Baseline Visit 
 
 
 
High[1] 
 
 
 
 
Temperature  
xx (xx.x%) 
xx (xx.x%) 
 
 
Pulse Rate  
xx (xx.x%) 
xx (xx.x%) 
 
 
Respiratory Rate  
xx (xx.x%) 
xx (xx.x%) 
 
 
SBP 
xx (xx.x%) 
xx (xx.x%) 
 
 
DBP 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Low[1] 
 
 
 
 
Temperature 
xx (xx.x%) 
xx (xx.x%) 
 
 
Pulse Rate  
xx (xx.x%) 
xx (xx.x%) 
 
 
Respiratory Rate  
xx (xx.x%) 
xx (xx.x%) 
 
 
SBP 
xx (xx.x%) 
xx (xx.x%) 
 
 
DBP 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Note: SBP=Systolic Blood Pressure. DBP=Diastolic Blood Pressure. Normal Range Temperature: 36.6°C to 37.3°C. Normal Range SBP: 90-120 mmHg. Normal Range DBP: 60-80 mmHg. Normal 
Range Respiratory Rate: 12-18 breaths per minute. Normal Range Pulse Rate: 60-100 beats per minute. 
 [1] Each subject is represented once by their worst change. A range change can be either a change in a vital sign parameter value from baseline low or normal to post-baseline high or a change from 
baseline high or normal to post-baseline low. A subject can be included in both ‘High’ and ‘Low’ categories if applicable. 
 
 


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59R5-003 (Phase 2) 
Table 14.3.4.16 
 
12-Lead Electrocardiogram (ECG) 
 
Safety Population 
 
 
 
 
 
 
 
 
 
Placebo (N=xx) 
 
Tarextumab (N=xx) 
Parameter 
Time Point 
Result 
Change from 
Baseline 
 
Result 
Change from 
Baseline 
 
 
 
 
 
 
 
QRS Duration (msec) 
Baseline [1] 
 
 
 
 
 
 
 
n 
xx 
 
 
xx 
 
 
 
Mean (SD) 
xx.x (xx.xx) 
 
 
xx.x (xx.xx) 
 
 
 
Median  
xx 
 
 
xx 
 
 
 
25th, 75th Percentile 
xx, xx 
 
 
xx, xx 
 
 
 
Min, Max 
xx, xx 
 
 
xx, xx 
 
 
 
 
 
 
 
 
 
Maximum Post-Baseline 
 
 
 
 
 
 
 
n 
xx 
xx 
 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median  
xx 
xx 
 
xx 
xx 
 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Minimum Post-Baseline 
 
 
 
 
 
 
 
n 
xx 
xx 
 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median  
xx 
xx 
 
xx 
xx 
 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
 
Last Observation Post-Baseline 
 
 
 
 
 
 
 
n 
xx 
xx 
 
xx 
xx 
 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
Median  
xx 
xx 
 
xx 
xx 
 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
Min, Max 
xx, xx 
xx, xx 
 
xx, xx 
xx, xx 
 
 
 
 
 
 
 
PR Interval (msec) 
Baseline [1] 
 
 
 
 
 
[etcetera] 
 
[⁞] 
[⁞] 
[⁞] 
 
[⁞] 
[⁞] 
 
 
 
 
 
 
 
[1] Baseline is defined as the last non-missing value prior to first dose of study drug. 
Programmer notes: (a) continue for all electrocardiogram parameters (QRS duration, PR interval, QTc Interval) 
 
 


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59R5-003 (Phase 2) 
Table 14.3.4.17 
 
12-Lead Electrocardiogram (ECG) – Range Change Abnormal 
 
Safety Population 
 
 
 
ECG Parameter 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
 n 
xx 
xx 
Any Post-Baseline 
 
 
 
High [1] 
 
 
 
 
QRS Duration (msec) 
xx (xx.x%) 
xx (xx.x%) 
 
 
PR Interval (msec) 
xx (xx.x%) 
xx (xx.x%) 
 
 
QTc Interval (msec) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Low [1] 
 
 
 
 
QRS Duration (msec) 
xx (xx.x%) 
xx (xx.x%) 
 
 
PR Interval (msec) 
xx (xx.x%) 
xx (xx.x%) 
 
 
QTc Interval (msec) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Last Observation Post-Baseline 
 
 
 
High[1] 
 
 
 
 
QRS Duration (msec) 
xx (xx.x%) 
xx (xx.x%) 
 
 
PR Interval (msec) 
xx (xx.x%) 
xx (xx.x%) 
 
 
QTc Interval (msec) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Low[1] 
 
 
 
 
QRS Duration (msec) 
xx (xx.x%) 
xx (xx.x%) 
 
 
PR Interval (msec) 
xx (xx.x%) 
xx (xx.x%) 
 
 
QTc Interval (msec) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Note: Reference ranges: QRS duration 80-100 msec; PR interval 120-200 msec; QTc interval ≤430 msec (males), ≤450 msec (females). 
[1] Each subject is represented once by their worst change. A range change can be either a change in an ECG parameter value from baseline low or normal to post-baseline high or a change from 
baseline high or normal to post-baseline low. A subject can be included in both ‘High’ and ‘Low’ categories if fits both categories. 
 
 
 


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59R5-003 (Phase 2) 
Table 14.3.4.18 
 
12-Lead Electrocardiogram (ECG) – QTc Interval 
 
Safety Population 
 
 
 
Time Point 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Baseline [1] 
 
 
 
<480 
xx (xx.x%) 
xx (xx.x%) 
 
480-500 msec 
xx (xx.x%) 
xx (xx.x%) 
 
>500 msec 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Worst (Maximum)  Post-Baseline 
 
 
 
<480 
xx (xx.x%) 
xx (xx.x%) 
 
480-500 msec 
xx (xx.x%) 
xx (xx.x%) 
 
>500 msec 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Last Observation Post-Baseline 
 
 
 
<480 
xx (xx.x%) 
xx (xx.x%) 
 
480-500 msec 
xx (xx.x%) 
xx (xx.x%) 
 
>500 msec 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 [1] Baseline is defined as the last non-missing value prior to first dose of study drug. 
 
 
 


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Table 14.3.4.19 
 
12-Lead Electrocardiogram (ECG) – Overall Interpretation 
 
Safety Population 
Time Point 
Placebo 
(N=   ) 
Tarextumab 
(N=   ) 
 
 
Baseline [1] 
 
 
   n 
n 
n 
   Normal 
n (%) 
n (%) 
   Abnormal NCS 
n (%) 
n (%) 
   Abnormal CS 
n (%) 
n (%) 
 
 
Worst Post-Baseline 
 
 
n 
n 
n 
Normal 
n (%) 
n (%) 
Abnormal NCS 
n (%) 
n (%) 
Abnormal CS 
n (%) 
n (%) 
 
 
Last Observation Post-Baseline  
 
 
n 
n 
n 
Normal 
n (%) 
n (%) 
Abnormal NCS 
n (%) 
n (%) 
Abnormal CS 
n (%) 
n (%) 
 
 
 
 
Note: NCS = Not clinically significant, CS = Clinically significant. Percentages are based on the number of subjects with a non-missing response at each visit. 
[1] Baseline is defined as the last non-missing value prior to first dose of study drug. 
 
 


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Table 14.3.4.20 
 
12-Lead Electrocardiogram (ECG) – Overall Interpretation Shift from Baseline 
 
Safety Population 
 
 
 
 
Baseline [1] 
Most Extreme Post-Baseline 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
 
Normal 
Normal 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal - Not Clinically Significant 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal - Clinically Significant 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Abnormal - Not Clinically Significant Normal 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal - Not Clinically Significant 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal - Clinically Significant 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
Abnormal - Clinically Significant 
Normal 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal - Not Clinically Significant 
xx (xx.x%) 
xx (xx.x%) 
 
Abnormal - Clinically Significant 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
[1] Baseline is defined as the last non-missing value prior to first dose of study drug. 
 
 


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Table 14.3.4.21 
 
ECOG Performance Status 
 
Safety Population 
 
 
 
Performance Status Score [1] 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Baseline [2] 
 
 
 
n 
xx 
xx 
 
0 
xx (xx.x%) 
xx (xx.x%) 
 
1 
xx (xx.x%) 
xx (xx.x%) 
 
2 
xx (xx.x%) 
xx (xx.x%) 
 
3 
xx (xx.x%) 
xx (xx.x%) 
 
4 
xx (xx.x%) 
xx (xx.x%) 
 
5 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Maximum Post-Baseline 
 
 
 
n 
xx 
xx 
 
0 
xx (xx.x%) 
xx (xx.x%) 
 
1 
xx (xx.x%) 
xx (xx.x%) 
 
2 
xx (xx.x%) 
xx (xx.x%) 
 
3 
xx (xx.x%) 
xx (xx.x%) 
 
4 
xx (xx.x%) 
xx (xx.x%) 
 
5 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Minimum Post-Baseline 
 
 
 
n 
xx 
xx 
 
0 
xx (xx.x%) 
xx (xx.x%) 
 
1 
xx (xx.x%) 
xx (xx.x%) 
 
2 
xx (xx.x%) 
xx (xx.x%) 
 
3 
xx (xx.x%) 
xx (xx.x%) 
 
4 
xx (xx.x%) 
xx (xx.x%) 
 
5 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Last Observation Post-Baseline 
 
 
 
n 
xx 
xx 
 
0 
xx (xx.x%) 
xx (xx.x%) 
 
1 
xx (xx.x%) 
xx (xx.x%) 
 
2 
xx (xx.x%) 
xx (xx.x%) 
 
3 
xx (xx.x%) 
xx (xx.x%) 
 
4 
xx (xx.x%) 
xx (xx.x%) 
 
5 
xx (xx.x%) 
xx (xx.x%) 
Note: Percentages are based on the number of patients with a non-missing response at each visit.  
[1] For complete definitions of each activity status code, reference Appendix D of the clinical protocol. 
[2] Baseline is defined as the last non-missing value prior to first dose of study drug. 


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59R5-003 (Phase 2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 14.3.4.22 
ECOG Performance Status – Shift from Baseline 
Safety Population 
 
Performance Status Score [1] 
Placebo (N=   ) 
Baseline [2] 
 
Tarextumab (N=   ) 
Baseline [2] 
0 
1 
 
0 
1 
 
 
 
 
 
Maximum Post-Baseline 
 
 
 
 
 
 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 (%) 
 
 
 
 
 
Minimum Post-Baseline 
 
 
 
 
 
   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] For complete definitions of each activity status code, reference Appendix D of the clinical protocol. 
[2] Baseline is defined as the last non-missing value prior to first dose of study drug. 
 
Programming note: Continue for Last Observation Post-Baseline. 
Programming note: Add additional baseline columns as needed. 
 
 


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59R5-003 (Phase 2) 
Table 14.3.4.23 
 
Anti-Tarextumab Antibodies 
 
Immunogenicity Population 
 
 
Time Point 
Tarextumab 
(N=xx) 
 
 
Any Positive Sample During Study 
xx (xx.x%) 
 
 
Cycle 1, Day 1 
 
 
Positive 
xx (xx.x%) 
 
Negative 
xx (xx.x%) 
 
Viable Sample Not Available 
xx (xx.x%) 
 
 
Cycle 3, Day 1 
 
 
Positive 
xx (xx.x%) 
 
Negative 
xx (xx.x%) 
 
Viable Sample Not Available 
xx (xx.x%) 
 
 
Cycle 5, Day 1 
 
 
Positive 
xx (xx.x%) 
 
Negative 
xx (xx.x%) 
 
Viable Sample Not Available 
xx (xx.x%) 
 
 
Treatment Termination 
 
 
Positive 
xx (xx.x%) 
 
Negative 
xx (xx.x%) 
 
Viable Sample Not Available 
xx (xx.x%) 
 
 
 
 


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Table 14.3.4.24 
 
Impact of Anti-Tarextumab Antibodies on Progression-Free Survival 
 
Immunogenicity Population 
 
 
 
 
Tarextumab (N=xx) 
 
Anti-Tarextumab 
Antibody Negative 
(N=xx) 
Anti-Tarextumab 
Antibody Positive 
(N=xx) 
 
 
 
Total Follow-Up Time (person-years) [1] 
xxx.x 
xxx.x 
Number of Subjects with Disease Progression or Death 
xx (xx.x%) 
xx (xx.x%) 
Number of Subjects who did not Progress or Die (Censored) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Hazard [2] 
0.xx 
0.xx 
 
 
 
Kaplan-Meier Estimates: Quartiles [95% C.I.] (days) 
 
 
 
25th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
50th Percentile  
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
75th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
 
 
Range (Subjects who Progressed or Died) (days) 
xxx, xxx 
xxx, xxx 
Range (All Subjects) (days) 
xxx, xxx 
xxx, xxx 
 
 
 
Hazard Ratio [95% C.I.] [3] 
 
x.xx [x.xx,x.xx] 
P-value [4] 
 
0.xxx 
 
 
 
Note: PFS= Date of Documentation of Death/Progression – Randomization Date + 1. Subjects who had not experienced death or progression by their last contact were censored at the time of their last 
radiographic response assessment. Subjects lacking a radiographic response assessment after randomization who do not progress or die have their event time censored on the date of randomization 
with duration of 1 day. For detailed event and censoring rules refer to protocol section 13.5.1 and SAP section 8.1. C.I. = Confidence Interval. 
 [1] Sum of all individual follow-up times in days divided by 365.25. 
[2] Number of Subjects with Disease Progression or Death/ Total Follow-up Time (Person-years).  
[3] Hazard ratio and 95% C.I. from Cox proportional hazards model with main effects for anti-tarextumab antibody status (positive or negative). 
[4] P-value for treatment effect from unstratified log rank test. 
Programmer notes: (a) percentages are based on the numbers of subjects who are antibody negative and antibody positive, not on the number of subjects receiving tarextumab 
 
 


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Table 14.3.4.25 
 
Impact of Anti-Tarextumab Antibodies on Overall Survival 
 
Immunogenicity Population 
 
 
 
 
Tarextumab (N=xx) 
 
Anti-Tarextumab 
Antibody Negative 
(N=xx) 
Anti-Tarextumab 
Antibody Positive 
(N=xx) 
 
 
 
Total Follow-Up Time (person-years) [1] 
xxx.x 
xxx.x 
Number of Subjects who Died 
xx (xx.x%) 
xx (xx.x%) 
Number of Subjects who did not Die (Censored) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Hazard [2] 
0.xx 
0.xx 
 
 
 
Kaplan-Meier Estimates: [95% C.I.] (days) 
 
 
 
25th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
50th Percentile (Median) 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
75th Percentile 
xxx [xxx,xxx] 
xxx [xxx,xxx] 
 
 
 
Kaplan-Meier  Estimate (# at risk) [SE] 
 
 
 
180 Days 
0.xx (xx) [x.xx] 
0.xx (xx) [x.xx] 
 
360 Days 
0.xx (xx) [x.xx] 
0.xx (xx) [x.xx] 
 
540 Days 
0.xx (xx) [x.xx] 
0.xx (xx) [x.xx] 
 
720 Days 
0.xx (xx) [x.xx] 
0.xx (xx) [x.xx] 
 
 
 
Range (Subjects who Died) (days) 
xxx, xxx 
xxx, xxx 
Range (All Subjects) (days) 
xxx, xxx 
xxx, xxx 
 
 
 
Hazard Ratio [95% C.I.] [3] 
 
x.xx [x.xx,x.xx] 
P-value [4] 
 
0.xxx 
 
 
 
Note: Overall Survival = Date of Documentation of Death – Randomization Date + 1. Subjects who had not experienced death by their last contact date were censored at that time. Subjects lacking 
data after randomization who do not die have their event time censored on the date of randomization with duration of 1 day. For detailed event and censoring rules refer to protocol section 13.5.4 and 
SAP section 8.6.  C.I. = Confidence Interval. SE = Standard Error. 
[1] Sum of all individual follow-up times in days divided by 365.25. 
[2] Number of Subjects who Died/ Total Follow-up Time (Person-years). 
[3] Hazard ratio and 95% C.I. from Cox proportional hazards model with main effects for anti-tarextumab antibody status (positive or negative). 
[4] P-value for treatment effect from unstratified log rank test. 
Programmer notes: (a) percentages are based on the numbers of subjects who are antibody negative and antibody positive, not on the number of subjects receiving tarextumab 
 
 


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Table 14.3.4.26 
 
Overall Summary of Impact of Anti-Tarextumab Antibodies on Treatment-Emergent Adverse Events (TEAEs) 
 
Immunogenicity Population 
 
 
 
 
Tarextumab (N=xx) 
 
Anti-Tarextumab 
Antibody Negative 
(N=xx) 
Anti-Tarextumab 
Antibody Positive 
(N=xx) 
 
 
 
Subjects Reporting at Least One TEAE 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting at Least One Serious TEAE 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting at Least One Serious TEAE Related to Tarextumab 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting at Least One Serious TEAE Related to Etoposide 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting at Least One Serious TEAE Related to Platinum Therapy 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting at Least One Grade 3 or Higher TEAE 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting at Least One Grade 4 or Higher TEAE 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting TEAE Leading to Delay/Interruption of Tarextumab 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting TEAE Leading to Delay/Interruption of Etoposide 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting TEAE Leading to Delay/Interruption of Platinum Therapy 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting TEAE Leading to Dose Reduction of Tarextumab 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting TEAE Leading to Dose Reduction of Etoposide 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting TEAE Leading to Dose Reduction of Platinum Therapy 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting TEAE Leading to Withdrawal of Tarextumab 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting TEAE Leading to Withdrawal of Etoposide 
xx (xx.x%) 
xx (xx.x%) 
Subjects Reporting TEAE Leading to Withdrawal of Platinum Therapy 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Subjects Reporting TEAE with Outcome of  Death 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Maximum CTCAE Severity Grade [1] 
 
 
 
Grade 1 
xx (xx.x%) 
xx (xx.x%) 
 
Grade 2 
xx (xx.x%) 
xx (xx.x%) 
 
Grade 3 
xx (xx.x%) 
xx (xx.x%) 
 
Grade 4 
xx (xx.x%) 
xx (xx.x%) 
 
Grade 5 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 [1] CTCAE = Common Terminology Criteria for Adverse Events (version 4.02). Subjects with more than one TEAE are counted only once at the highest CTCAE severity grade across all TEAEs. 
Programmer notes: (a) percentages are based on the numbers of subjects who are antibody negative and antibody positive, not on the number of subjects receiving tarextumab 


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Table 14.3.4.27 
 
Impact of Anti-Tarextumab Antibodies Treatment-Emergent Adverse Events (TEAEs) 
 
Safety Population 
 
 
 
 
Tarextumab (N=xx) 
Preferred Term 
Anti-Tarextumab 
Antibody Negative 
(N=xx) 
Anti-Tarextumab 
Antibody Positive 
(N=xx) 
 
 
 
Subjects Reporting at Least One TEAE 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Preferred Term 1 
xx (xx.x%) 
xx (xx.x%) 
Preferred Term 2 
xx (xx.x%) 
xx (xx.x%) 
Preferred Term 3 
xx (xx.x%) 
xx (xx.x%) 
Preferred Term 4 
xx (xx.x%) 
xx (xx.x%) 
Preferred Term 5 
xx (xx.x%) 
xx (xx.x%) 
Preferred Term 6 
xx (xx.x%) 
xx (xx.x%) 
[etcetera] 
[⁞] 
[⁞] 
 
 
 
 Note: At each level of summation (overall and preferred term), subjects reporting more than one qualifying event are counted only once. 
Programmer notes: (a) percentages are based on the numbers of subjects who are antibody negative and antibody positive, not on the number of subjects receiving tarextumab 
 
 


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59R5-003 (Phase 2) 
Table 14.3.5.1 
 
Study Drug Exposure – Tarextumab/Placebo 
 
Safety Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Treatment Cycles 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Number of Infusions Administered 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Total Dose Administered (mg) [1] 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Duration of Treatment (days) [2] 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Dose Intensity 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
[1] Placebo exposure is summarized in tarextumab-equivalent units (i.e., the number of milligrams of tarextumab the placebo “replaced” during treatment-blinded dosing). 
[2] Duration of treatment = number of days from the first dose (Day 1) until the last dose. 
 
 


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Table 14.3.5.2 
 
Dosing Compliance – Tarextumab/Placebo 
 
Safety Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Dosing Compliance (%) [1] 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
0% to <20% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
20% to <40% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
40% to <60% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
60% to <80% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
80% to <100% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
100% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Number of Missed Doses 
xx 
xx 
Reason for Missed Dose 
 
 
 
Adverse Event 
xx 
xx 
 
Other 
xx 
xx 
 
 
 
Number of Delayed Doses 
xx 
xx 
Reason for Delayed Dose 
 
 
 
Adverse Event 
xx 
xx 
 
Other 
xx 
xx 
 
 
 
Number of Reduced Doses 
xx 
xx 
Reason for Reduced Dose 
 
 
 
Adverse Event 
xx 
xx 
 
Other 
xx 
xx 
 
 
 
 
[1] Dosing compliance = (number of doses administered) / number of planned doses x 100. 
 
 


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59R5-003 (Phase 2) 
Table 14.3.5.3 
 
Study Drug Exposure – Etoposide 
 
Safety Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Treatment Cycles 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Number of Infusions Administered 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Total Dose Administered (mg) 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Duration of Treatment (days) [1] 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Dose Intensity 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
[1] Duration of treatment = number of days from the first dose (Day 1) until the last dose. 
 
 


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59R5-003 (Phase 2) 
Table 14.3.5.4 
 
Dosing Compliance – Etoposide 
 
Safety Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Dosing Compliance [1] 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
0% to <20% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
20% to <40% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
40% to <60% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
60% to <80% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
80% to <100% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
100% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Number of Missed Doses 
xx 
xx 
Reason for Missed Dose 
 
 
 
Adverse Event 
xx 
xx 
 
Other 
xx 
xx 
 
 
 
Number of Delayed Doses 
xx 
xx 
Reason for Delayed Dose 
 
 
 
Adverse Event 
xx 
xx 
 
Other 
xx 
xx 
 
 
 
[1] Dosing compliance = (number of doses administered) / number of planned doses. 
 
 


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Table 14.3.5.5 
 
Study Drug Exposure – Cisplatin 
 
Safety Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Platinum Therapy [1] 
 
 
 
Cisplatin 
xx (xx.x%) 
xx (xx.x%) 
 
Carboplatin 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Treatment Cycles 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Number of Infusions Administered 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Total Dose Administered (mg) 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Duration of Treatment (days) [2] 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
Dose Intensity 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 99/149 
[1] Analyses presented in this table include only subjects who received cisplatin as their platinum therapy. Percentages below the first set of rows are based on subjects who received cisplatin. 
[2] Duration of treatment = number of days from the first dose (Day 1) until the last dose. 
Programmer notes: (a) produce the same table replacing “cisplatin” with “carboplatin” in the title and footnote 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 100/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Table 14.3.5.6 
 
Dosing Compliance – Cisplatin 
 
Safety Population 
 
 
 
 
Placebo 
(N=xx) 
Tarextumab 
(N=xx) 
 
 
 
Dosing Compliance [1] 
 
 
 
n 
xx 
xx 
 
Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
Median  
xx 
xx 
 
25th, 75th Percentile 
xx, xx 
xx, xx 
 
Min, Max 
xx, xx 
xx, xx 
 
 
 
0% to <20% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
20% to <40% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
40% to <60% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
60% to <80% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
80% to <100% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
100% Dosing Compliance 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Number of Missed Doses 
xx 
xx 
Reason for Missed Dose 
 
 
 
Adverse Event 
xx 
xx 
 
Other 
xx 
xx 
 
 
 
Number of Delayed Doses 
xx 
xx 
Reason for Delayed Dose 
 
 
 
Adverse Event 
xx 
xx 
 
Other 
xx 
xx 
 
 
 
[1] Dosing compliance = (number of doses administered) / number of planned doses. 
 Programmer notes: (a) produce the same table replacing “cisplatin” with “carboplatin” in the title 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 101/149 
 
APPENDIX C. FIGURE SHELLS 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 102/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Figure 14.2.1.1 
 
Overall Survival 
 
ITT Population 
 
Programmer notes: (a) replace “Treatment A” with “Placebo”; (b) replace “Treatment B” with “Tarextumab”; (c) include “at risk” counts beneath the x-axis (see secondary figure mock below); 
(d) delete “Treatment C”; (e) duplicate figure using per-protocol population and all gene-expression subsets of the ITT population; (f) duplicate figure for progression-free survival using the ITT 
population; (f) duplicate figure for overall survival using the per-protocol population and all gene-expression subsets of the ITT population 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 103/149 
Secondary figure mock showing format for “at risk” summary: 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 104/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Figure 14.2.4.1 
 
Waterfall Plot of Best Percentage Change from Baseline Total Tumor Length 
 
ITT Population 
 
Programmer notes: (a) replace “screening” in the y-axis label with “Baseline”; (b) delete the footnote marker “[1]” from the y-axis label; (c) duplicate figure using per-protocol population 
 
 
CR
PR
SD
PD
%-Change from Screening [1]
-100
-90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
20
30
40
50
60
70
80
90
100


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 105/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Figure 14.3.4.63 
 
Box Plot of Pulse Rate by Visit 
 
Safety Population 
 
Programmer notes: (a) replace “Cohort 1” with “Placebo”; (b) replace “Cohort 2” with “Tarextumab”; (c) delete “Cohort 3” and “Cohort 4”; (d) duplicate figure for all clinical laboratory, vital 
sign and ECG parameters (see Planned Tables, Figures and Listings [Appendix A] for complete list); (e) duplicate all figures for “Box Plot of Change from Baseline Parameter by Visit” – remember 
to (i) remove the “Baseline” marker from the x-axis and (ii) replace the y-axis label “Parameter (unit)” with “Change from Baseline Parameter (unit)” 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 106/149 
APPENDIX D. LISTING SHELLS 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 107/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.1.1 
 
Subject Disposition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
 
Subject 
ID 
ITT 
Population 
Per-Protocol 
Population 
Safety 
Population 
Immuno- 
genicity 
Population 
Pharmaco-
kinetic 
Population 
Treatment 
Start Date 
Treatment 
End Date 
Primary Reason for Ending 
Study Treatment 
Study Exit 
Date 
Primary Reason for 
Study Exit 
Placebo | 
Tarextumab 
003-xxx-xxx 
Y | N 
Y | N 
Y | N 
Y | N 
Y | N 
ddmmmyyyy ddmmmyyyy Lost to follow-up | 
Withdrawal of 
consent/Patient decision | 
Death | 
Adverse Event #xx: Adverse 
Event term | Disease 
Progression | Investigator 
decision based on 
patient's best interest  
Study Terminated by 
OncoMed | Other: Other 
term 
 
ddmmmyyyy Death | 
Lost to Follow-Up | 
Study Terminated by 
OncoMed | Withdrawal 
by Subject | Other: Other 
term 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 108/149 
 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.1.2 
 
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Informed 
Consent 
Date 
Randomization 
Date 
Consented 
to Optional 
Tumor 
Biopsy 
If Yes, Date 
Optional 
Tumor Biopsy 
Consent Date 
Consented to 
Optional 
Pharmacogenomics 
Blood Sample 
If Yes,  
Optional 
Pharmaco- 
genomics 
Blood Sample 
Consent Date 
Consented to 
DNA 
Testing on 
Blood 
Sample 
If Yes,  
DNA Testing 
on Blood 
Sample 
Consent Date 
Consented to 
DNA Testing 
on Tumor 
Tissue 
Sample 
If Yes,  
DNA Testing 
on Tumor 
Tissue Consent 
Date 
Placebo | 
Tarextumab 
003-xxx-xxx ddmmmyyyy 
ddmmmyyyy 
Yes | No 
ddmmmyyyy 
Yes | No 
ddmmmyyyy 
Yes | No 
ddmmmyyyy 
Yes | No 
ddmmmyyyy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 109/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.2.1 
 
Major Protocol Deviations 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Protocol Deviation 
Description 
Deviation Code 
Placebo | 
Tarextumab 
003-xxx-xxx Description 
xx-Deviation 
Code 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 110/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.3.1 
 
Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Protocol Version Date 
Did the subject meet all 
eligibility criteria? 
Criteria Type 
Criterion Number 
Reason Not Met 
Placebo  | 
Tarextumab  
003-xxx-xxx 
ddmmmyyyy 
Ye s | No 
Inclusion | Exclusion | None 
xx 
Reason 
 
 
 
 
 
 
 
Programmer notes: (a) all subjects should be listed; (b) Display “None” for Criteria Type as appropriate 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 111/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.4.1 
 
Demographics and Baseline Characteristics 
Part 1 of 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
 
Date of Birth 
Age 
(years)[1] 
Sex 
If Female, 
Child-Bearing 
Potential? 
Race 
Ethnicity 
 
 
 
 
Placebo | 
Tarextumab  
003-xxx-xxx 
 
ddmmmyyyy 
xx.x 
Male |  
Female 
Yes | No 
American Indian or 
Alaska Native | 
Asian | Black or 
African American | 
Native Hawaiian or Oth
er Pacific Islander | 
White 
Hispanic 
or 
Latino | 
Not Hisp
anic or L
atino 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<second part of listing> 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.4.1 
 
Demographics and Baseline Characteristics 
 
Part 2 of 2 
 
 
  
 
 
 
 
 
 
Treatment Group 
Subject ID 
 
Height 
(cm) 
Weight 
(kg) 
Body Mass 
Index [2] 
(mg/m2) 
ECOG 
Smoking History 
If Ex-Smoker or Current Smoker, 
number of pack years 
If Ex-Smoker, 
Stop Date 
Placebo |  
Tarextumab 
003-xxx-xxx  
xxx 
xx.x 
x.xx 
0 | 1 | 2 
Never Smoked | 
Ex Smoker | 
Current Smoker 
xx 
ddmmmyyyy 
 
[1] Age at time informed consent was signed. 
[2] BMI (kg/m2) = weight (kg) / [height (cm)]2. 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 112/149 
 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.4.2 
 
Medical/Surgical History 
 
 
 
 
 
 
 
Treatment Group 
Subject ID 
Any past and/or concomitant diseases or past surgeries? Description of Medical Condition/Event 
Onset Date 
End Date 
Ongoing/ 
Resolved 
Placebo |  
Tarextumab  
003-xxx-xxx 
Yes | No 
Description 
ddmmmyyyy ddmmmyyyy Ongoing | Resolved 
 
 
 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 113/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.4.3 
 
Extensive Small Cell Lung Cancer History  
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Date of 
Diagnosis 
(Study Day) 
Months 
Since 
Diagnosis 
Histological/ 
Cytological 
Type 
Anatomical 
Location of 
Primary Cancer 
Number of 
Sites of Disease 
at Study Entry 
Sites of Disease at Study 
Entry 
Placebo | 
Tarextumab  
003-xxx-xxx 
ddmmmyyyy 
(xx) 
xx 
Small Cell 
Only | 
Mixed Type 
| Other: 
Other term 
Right Upper Lung | 
Right Lower Lung | 
Middle of Right 
Lung | 
Left Upper Lung | 
Other: Other term 
x 
Bone | Brain: 
Symptomatic/ 
Asymptomatic | 
Pleura | Adrenal Gland | 
Lymph Nodes: Specify 
Lymph Nodes | 
Other Nodes: Other 
location 
 
 
 
 
 
 
 
 
Programmer notes: (a) for Sites of Disease at Study Entry, list all that apply 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 114/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.4.4 
 
Prior Surgery for Lung Cancer  
 
 
 
 
 
 
Treatment Group 
Subject ID 
Prior Surgery for 
Lung Cancer 
Surgery Date 
Description of Surgery 
Location of Surgery 
Placebo | 
Tarextumab 
003-xxx-xxx 
Yes | No 
ddmmmyyyy 
Description 
Location 
 
 
 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 115/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.4.5 
 
Prior Radiotherapy for Lung Cancer  
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Prior 
Radiotherapy for 
Lung Cancer 
Start Date 
End Date 
Site of Treatment 
Total cGY 
Placebo | 
Tarextumab 
003-xxx-xxx 
Yes | No 
ddmmmyyyy 
ddmmmyyyy 
Site of Treatment 
xx | Unknown 
 
 
 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 116/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.4.6 
 
Baseline Gene Expression 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Notch3 Expression Hes1 Expression Hey1 Expression Hey2 Expression Hes6 Expression 
Placebo | 
Tarextumab  
003-xxx-xxx 
Yes | No 
Yes | No 
Yes | No 
Yes | No 
Yes | No 
 
 
 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 117/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.4.7 
 
FFPE Tissue Sample 
Part 1 of 2 
 
 
 
 
 
 
 
 
 
Archival Tissue 
Treatment Group 
Subject ID 
Sample 
submitted? 
Biopsy Date 
(Study Day) 
Date of Submission 
to OncoMed 
(Study Day) 
 
Anatomical Location 
 
Location Description  
Placebo | 
Tarextumab 
 
003-xxx-xxx 
Yes | No 
ddmmmyyyy 
(xx) 
ddmmmyyyy 
(xx) 
Liver | Lymph Nodes | 
Peritoneum | 
Chest Wall | Abdomen | 
Pelvis | Breast | Skin | 
Kidney | Lung | 
Other: Other organ 
Description 
 
[1] If archival tissue was not submitted. 
<second part of listing> 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.4.7 
 
FFPE Tissue Sample 
Part 2 of 2 
 
 
 
 
 
 
 
 
 
Fresh Tumor Core Biopsies 
Treatment Group 
Subject ID 
Biopsies 
Performed?[1] 
Biopsies Date 
(Study Day) 
Date of Submission 
to OncoMed  
(Study Day) 
Anatomical Location 
Location Description  
Placebo | 
Tarextumab 
 
003-xxx-xxx 
Yes | No 
ddmmmyyyy 
(xx) 
ddmmmyyyy 
(xx) 
Liver | Lymph Nodes | 
Peritoneum | 
Chest Wall | Abdomen | 
Pelvis | Breast | Skin | 
Kidney | Lung | 
Other: Other organ 
Description 
 
[1] If archival tissue was not submitted.  
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 118/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.4.8 
 
Prior and Concomitant Medications 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Verbatim Term // 
Preferred Name  // 
ATC Class[1] 
Start Date 
(Study Day) 
End Date 
(Study Day)  
Route 
Indication 
 
Placebo | 
Tarextumab 
003-xxx-xxx Verbatim Term // 
Preferred Name  // 
 ATC Class  
ddmmmyyyy 
(xx) 
ddmmmyyyy 
(xx) | 
Ongoing 
 
Inhalation | 
Intra-arterial | 
Intralesional | 
Intramuscular | 
Intraocular | 
Intraperitoneal | 
Intravenous | 
Nasal | 
Oral | 
Rectal | 
Subcutaneous | 
Topical | 
Transdermal | 
Vaginal | 
Other: Other 
term 
Medical History #xx: MH 
term | 
Adverse Event #xx: AE 
term | 
Other: Other term 
 
 
 
 
 
 
 
 
 
 
[1] ATC Class and Preferred Name are coded using WHO Drug Dictionary Enhanced (version March 1, 2014). 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 119/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.4.9 
 
Concomitant Procedures 
 
 
 
 
 
 
 
  
 
Treatment Group Subject ID 
Any Concomitant 
Procedures? 
Procedure 
Anatomical 
Location 
Start Date 
(Study Day) 
End Date 
(Study Day) 
 Indication 
 
Placebo | 
Tarextumab 
003-xxx-xxx 
Yes | No 
Procedure 
Location 
ddmmmyyyy (xx) ddmmmyyyy (xx)  Medical History #xx: MH term | 
Adverse Event #xx: AE term | 
Other: Other term 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 120/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.5.1 
 
Study Drug Infusion 
 
Part 1 of 3: Infusion Administration 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Infusion 
Performed? 
If Infusion Was Not 
Performed, 
Specify Reason 
If AE, 
Specify 
Date  
of Infusion 
(Study Day) 
Infusion 
Start / 
Stop Times 
Intended 
Dose Per 
Protocol 
(mg) 
What Weight 
Was Used to 
Calculate Dose? 
Infusion 
Dose 
(mg) 
Placebo | 
Tarextumab 
003-xxx-xxx CYCLE X 
DAY X 
Yes | No 
Adverse Event | Other: 
Other term 
AE term 
ddmmmyyyy 
(xx) 
xx:xx / 
xx:xx 
xx.xx 
Weight at Current 
Visit | 
Weight at Baseline | 
Other: Other term 
 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
<second part of listing> 
 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.5.1 
 
Study Drug Infusion 
 
Part 2 of 3: Infusion Reduced or Delayed 
 
 
 
 
 
 
  
 
 
 
 
 
Dose Reduced 
 
Infusion Delayed 
Treatment 
Group 
Subject ID 
Visit 
Dose reduced 
since last 
infusion? 
 
Specify Reason 
If AE, 
Specify 
 
Infusion 
Delayed? 
 
Specify Reason 
If AE, 
Specify 
Placebo | 
Tarextumab 
003-xxx-xxx CYCLE X DAY X 
Yes | No 
Adverse Event | Other: Other 
term 
AE term 
 
Yes | No 
Adverse Event | Other: Other 
term 
AE term 
 
 
 
 
 
 
  
 
 
<third part of listing on next page> 
 
OncoMed Pharmaceuticals, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.5.1 
 
Study Drug Infusion 
 
Part 3 of 3: Infusion Interrupted or Restarted 
 
 
 
 
 
 
  
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Infusion Interrupted 
 
Restart after Interruption 
Completed 
After Restart 
Total Dose 
Administered 
(mg) 
Infusion 
Interrupted? 
 
Specify Reason 
If AE, 
Specify 
Infusion 
Restarted? 
Start / Stop 
Times  
Dose 
(mg) 
Placebo | 
Tarextumab 
003-xxx-xxx CYCLE X 
DAY X 
Yes | No 
Adverse Event | Other: 
Other term 
AE term 
 
Yes | No 
xx:xx / xx:xx 
xxxx 
Infusion was 
completed | 
Infusion was 
interrupted again 
xxxx 
 
 
 
 
 
 
  
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 121/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.5.2 
 
Etoposide Infusion 
 
Part 1 of 3: Infusion Administration 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Infusion 
Performed? 
If Infusion Was Not 
Performed, 
Specify Reason 
If AE, 
Specify 
Date  
of Infusion 
(Study Day) 
Infusion 
Start / 
Stop Times 
Intended 
Dose Per 
Protocol 
(mg) 
What Weight 
Was Used to 
Calculate Dose? 
BSA 
(m2) 
Actual 
Dose 
(mg) 
Placebo | 
Tarextumab 
003-xxx-xxx CYCLE X 
DAY X 
Yes | No 
Adverse Event | Other: 
Other term 
AE term 
ddmmmyyyy 
(xx) 
xx:xx / 
xx:xx 
xx.xx 
Weight at Current 
Visit | 
Weight at Baseline | 
Other: Other term 
 
xx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
<second part of listing> 
 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.5.2 
 
Etoposide Infusion 
 
Part 2 of 3: Infusion Reduced or Delayed 
 
 
 
 
 
 
  
 
 
 
 
 
Dose Reduced 
 
Infusion Delayed 
Treatment 
Group 
Subject ID 
Visit 
Dose reduced 
since last 
infusion? 
 
Specify Reason 
If AE, 
Specify 
 
Infusion 
Delayed? 
 
Specify Reason 
If AE, 
Specify 
Placebo | 
Tarextumab 
003-xxx-xxx CYCLE X DAY X 
Yes | No 
Adverse Event | Other: Other 
term 
AE term 
 
Yes | No 
Adverse Event | Other: Other 
term 
AE term 
 
 
 
 
 
 
  
 
 
<third part of listing> 
 
OncoMed Pharmaceuticals, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of x 
59R5-003 (Phase 2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.5.2 
 
Etoposide Infusion 
 
Part 3 of 3: Infusion Interrupted or Restarted 
 
 
 
 
 
 
  
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Infusion Interrupted 
 
Restart after Interruption 
Completed 
After Restart 
Total Dose 
Administered 
(mg) 
Infusion 
Interrupted? 
 
Specify Reason 
If AE, 
Specify 
Infusion 
Restarted? 
Start / Stop 
Times  
Dose 
(mg) 
Placebo | 
Tarextumab 
003-xxx-xxx CYCLE X 
DAY X 
Yes | No 
Adverse Event | Other: 
Other term 
AE term 
 
Yes | No 
xx:xx / xx:xx 
xxxx 
Infusion was 
completed | 
Infusion was 
interrupted again 
xxxx 
 
 
 
 
 
 
  
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 122/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.5.3 
 
Platinum Therapy Infusion 
 
Part 1 of 3: Infusion Administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Infusion 
Performed? 
If Yes, Specify 
therapy 
If Infusion Was 
Not Performed, 
Specify Reason 
If AE, 
Specify 
Date  
of Infusion 
(Study Day) 
Infusion 
Start / 
Stop 
Times 
Intended 
Dose Per 
Protocol 
What Weight 
Was Used to 
Calculate Dose? 
BSA 
(m2) 
GFR 
(mL/min/ 
1.73 m2) 
Actual 
Dose 
(mg) 
Placebo | 
Tarextumab 
003-xxx-xxx CYCLE X 
DAY X 
Yes | No 
Cisplatin | 
Carboplatin 
Adverse Event | 
Other: Other 
term 
AE term 
ddmmmyyyy 
(xx) 
xx:xx / 
xx:xx 
xx.xx 
mg/m2 | 
xx.xx 
mg/mL-
min 
Weight at 
Current Visit | 
Weight at 
Baseline | 
Other: Other 
term 
 
xx 
xx 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<second part of listing> 
 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.5.3 
 
Platinum Therapy Infusion 
 
Part 2 of 3: Infusion Reduced or Delayed 
 
 
 
 
 
 
  
 
 
 
 
 
Dose Reduced 
 
Infusion Delayed 
Treatment 
Group 
Subject ID 
Visit 
Dose reduced 
since last 
infusion? 
 
Specify Reason 
If AE, 
Specify 
 
Infusion 
Delayed? 
 
Specify Reason 
If AE, 
Specify 
Placebo | 
Tarextumab 
003-xxx-xxx CYCLE X DAY X 
Yes | No 
Adverse Event | Other: Other 
term 
AE term 
 
Yes | No 
Adverse Event | Other: Other 
term 
AE term 
 
 
 
 
 
 
  
 
 
<third part of listing> 
 
OncoMed Pharmaceuticals, Inc.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of x 
59R5-003 (Phase 2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 16.2.5.3 
 
Platinum Therapy Infusion 
 
Part 3 of 3: Infusion Interrupted or Restarted 
 
 
 
 
 
 
  
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Infusion Interrupted 
 
Restart after Interruption 
Completed 
After Restart 
Total Dose 
Administered 
(mg) 
Total 
Planned Dose 
(mg) 
Infusion 
Interrupted? 
 
Specify Reason 
If AE, 
Specify 
Infusion 
Restarted? 
Start / Stop 
Times  
Dose 
(mg) 
Placebo | 
Tarextumab 
003-xxx-xxx CYCLE X 
DAY X 
Yes | No 
Adverse Event | 
Other: Other term 
AE term 
 
Yes | No 
xx:xx / 
xx:xx 
xxxx 
Infusion was 
completed | 
Infusion was 
interrupted again 
xxxx 
xxxx 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 123/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.5.4 
 
Doses Delayed, Interrupted, Reduced and Not Administered 
 
 
 
 
 
 
 
Treatment Group Subject ID 
Visit 
Date 
(Study Day) 
Dosing 
Reason 
Adverse Event/Other Reason 
Placebo | 
Tarextumab 
003-xxx-xxx CYCLE X DAY X 
Yes | No 
Dose Delayed |  
Dose Interrupted | 
Dose Reduced |  
Not Administered 
Adverse Event | Other Adverse Event #xx: AE term | Other term 
 
 
 
 
 
 
 
 
Note: This listing is sorted by Treatment, Dosing, Reason, and Subject. 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 124/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.5.5 
 
Pre-dose, Post-dose and Single PK Samples 
 
 
  
 
 
 
 
Treatment Group 
Subject ID 
 Visit 
Was PK Sample Drawn? 
Draw Date 
(Study Day) Time Point Draw Time 
Placebo | 
Tarextumab  
003-xxx-xxx  SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
Pre-dose |  
Post-dose |  
[blank] 
xx:xx 
 
 
  
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 125/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.6.2 
 
Tumor Evaluations – Target Lesions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Was 
radiographic 
evaluation 
performed? 
Date 
Performed 
(Study Day) 
Location 
Number Location 
Location 
Description 
(Position within
 Organ) 
Technique 
Used 
Thickness 
of slice 
(mm)[1] 
Longest 
Diameter 
(mm)[2] 
Baseline 
Sum of 
Longest 
Diameters 
(mm) 
Visit 
Sum of 
Longest 
Diameters 
(mm) 
Percent 
Change 
from 
Baseline 
Placebo | 
Tarextumab 
003-xxx-xxx 
SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
1 | 2 | 3, 
etc. 
Pancreas | 
Liver | 
Lymph Nod
es | 
Peritoneum | 
Chest Wall | 
Abdomen | 
Pelvis | 
Breast | 
Skin | 
Kidney | 
Lung | 
Other: Other 
location 
Position 
MRI | 
Conventio
nal CT | 
Spiral CT | 
PET CT | 
Bone Scan 
| Other: 
Other 
technique 
xx.x 
xx.x | 
Unable to 
Evaluate 
[blank] 
[blank] 
[blank] 
 
 
 
 
 
 
⁞ 
⁞ 
⁞ 
 
⁞ 
 
 
 
 
 
 
 
 
 
Visit 
Summary 
[blank] 
[blank] 
 
[blank] 
xx.x 
xx.x | NA 
xx.x% 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] If Spiral or Conventional CT Scan. 
[2] If lymph node, short axis measurement is recorded. 
Note: CT = Computed Tomography, NA = Not Applicable. 
 
Programmer notes: (a) place a “Visit Summary” row following the last line for each time point; (b) leave blank the cells for Baseline Sum of Longest Diameters, Visit Sum of Longest Diameters, and 
Percent Change from  Baseline in each row except for the Visit Summary row described in note (a) 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 126/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.6.3 
 
Tumor Evaluations – Non-target Lesions 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Was 
radiographic 
evaluation 
performed? 
Date 
Performed 
(Study Day) Location 
Location Description 
(Position within Organ) 
Technique Used 
Lesion Status [1] 
Placebo | 
Tarextumab 
003-xxx-xxx 
Baseline | 
Cycle x 
Yes | No 
ddmmmyyyy 
(xx) 
Pancreas | 
Liver | 
Lymph Nodes | 
Peritoneum | 
Chest Wall | 
Abdomen | 
Pelvis | 
Breast | 
Skin | 
Kidney | 
Lung | Other: 
Other location 
Position 
MRI | 
Conventional CT | 
Spiral CT | 
PET CT | 
Bone Scan | 
Other: Other 
technique 
CR | 
Non-CR/Non-PD | 
PD | 
Unable to Evaluate 
 
 
 
 
 
 
 
 
 
[1] CR = complete response; PD = progressive disease 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 127/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.6.4 
 
Tumor Evaluations – New Lesions 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Was 
radiographic 
evaluation 
performed? 
Date 
Performed 
(Study Day) Location 
Location Description 
(Position within Organ) 
Technique Used 
Lesion Status [1] 
Placebo | 
Tarextumab  
003-xxx-xxx 
Baseline | 
Cycle x 
Yes | No 
ddmmmyyyy 
(xx) 
Pancreas | 
Liver | 
Lymph 
Nodes | 
Peritoneum | 
Chest Wall | 
Abdomen | 
Pelvis | 
Breast | 
Skin | 
Kidney | 
Lung | 
Bone | 
CNS | 
Other: Other 
location 
Position 
MRI | 
Conventional 
CT | 
Spiral CT | 
PET-CT | 
Bone Scan | 
X-Ray | 
Physical Exam | 
Other: Other 
technique 
CR | 
Non-CR/Non-PD | 
PD | 
Unable to Evaluate 
 
 
 
 
 
 
 
 
 
[1] CR = complete response; PD = progressive disease 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 128/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.6.5 
 
Tumor Assessments (RECIST Overall Response) 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Response 
Date 
(Study Day) 
Target 
Lesion 
Response [1] 
Target 
Lesion 
Response [1] 
New 
Lesions 
Overall Response 
Assessment [1] 
If Overall Response is 
Progressive Disease, 
was it non-radiographic 
clinical progression? 
Placebo | 
Tarextumab  
003-xxx-xxx 
SCREENING | 
CYCLE X 
DAY X 
ddmmmyyyy 
(xx) 
CR | PR | SD | PD | 
Unable to Evaluate: 
Reason | Not 
Evaluated 
No Lesions at Baseline | 
CR | PR | SD | PD | 
Unable to Evaluate: 
Reason | Not Evaluated 
Yes | 
No 
CR | PR | SD | PD | 
PD | 
Not Evaluated 
Yes | No 
 
 
 
 
 
 
 
 
 
 
[1] CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 129/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.6.6 
 
Derived Efficacy Data 
 
 
 
 
 
 
 
 
 
 
 
RECIST v1.1 Assessment 
 
PFS[2] 
 
OS[3] 
 
DOR[4] 
Treatment Group 
Subject ID 
Best Tumor Response 
Objective Response[1] 
 
Censored 
Days 
 
Censored 
Days 
 
Censored 
Days 
Placebo | 
Tarextumab  
003-xxx-xxx 
CR | PR | SD | PD | NE 
Yes | No 
 
Yes | No 
xxx 
 
Yes | No 
xxx 
 
Yes | No 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = Not Evaluated. 
[1] Best response of CR or PR. 
[2] Progression-Free Survival (PFS) = Date of Documentation of Death/Progression – Randomization Date + 1. Subjects who had not experienced death or progression by their last contact were censored 
at the time of their last radiographic response assessment. Subjects lacking a radiographic response assessment after randomization who do not progress or die have their event time censored on the date 
of randomization with duration of 1 day. 
[3] Overall Survival (OS) = Date of Documentation of Death – Randomization Date + 1. Subjects who had not experienced death by their last contact were censored at the time. Subjects lacking data after 
randomization who do not die have their event time censored on the date of randomization with duration of 1 day. 
[4] Duration of Response (DOR) = Date of Documentation of Death/Progression – Date of First Partial (PR) or Complete Response (CR) + 1. Patients who discontinue the study without disease 
progression or death while on study are censored on the date of the last on study tumor assessment documenting the absence of progressive disease. Patients lacking a tumor assessment after first dose 
who do not progress or die while on study have their event time censored on the date of first dose with duration of 1 day. 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 130/149 
 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.21 
 
End of Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
 
Study Drug 
 
 
 
Etoposide 
 
 
 
Platinum Therapy 
 
Date 
of Last Dose 
(Study Day) 
Primary Reason for 
Ending 
Primary 
Associated 
AE 
Date 
of Last Dose 
(Study Day) 
Primary Reason for 
Ending 
Primary 
Associated 
AE 
Date 
of Last Dose 
(Study Day) 
Primary Reason for 
Ending 
Primary 
Associated 
AE 
Placebo | 
Tarextumab 
003-xxx-xxx ddmmmyyyy 
(xx) 
Lost  to follow-up | 
Withdrawal of 
consent/Patient 
Decision | 
Death | 
Adverse Event | 
Disease progression | 
Investigator decision 
based on 
patient's best interest 
| 
Study Terminated by 
OncoMed | 
Other: Other term 
 
Adverse 
Event #xx: 
AE term 
 ddmmmyyyy 
(xx) 
Lost  to follow-up | 
Withdrawal of 
consent/Patient 
Decision | 
Death | 
Adverse Event | 
Disease 
progression | 
Investigator 
decision based on 
patient's best 
interest | 
Study Terminated 
by OncoMed | 
Other: Other term 
 
Adverse 
Event #xx: 
AE term 
 
ddmmmyyyy 
(xx) 
Lost  to follow-up | 
Withdrawal of 
consent/Patient 
Decision | 
Death | 
Adverse Event | 
Disease 
progression | 
Investigator 
decision based on 
patient's best 
interest | 
Study Terminated 
by OncoMed | 
Other: Other term 
 
Adverse 
Event #xx: 
AE term 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 131/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.7.1 
 
Adverse Events 
 
Part 1 of 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
AE 
# 
Verbatim Term // 
MedDRA Preferred Term // 
System Organ Class 
Onset Date 
(Study Day) 
End Date 
(Study Day) 
On-
going 
Severity 
(CTCAE 
V4.02 
Grade) 
Treatment 
of Event 
Infusion 
Reaction 
Outcome  
Caused 
Study Drug 
Discon- 
tinuation 
Serious 
Event 
Serious 
Event 
Type 
Placebo 
|Tarextumab 
003-xxx-x
xx 
xx 
Verbatim Term // 
MedDRA Preferred Term // 
System Organ Class 
ddmmmyyyy 
(xx) 
ddmmmyyy
y 
(xx) 
Yes | 
No 
x 
None | 
Medication | 
Non-Drug 
Treatment | 
Hospitalizati
on 
Yes | No 
Recovered/R
esolved 
without 
Sequelae | 
Recovered/R
esolved with 
Sequelae | 
Not 
Recovered/N
ot Resolved | 
Fatal | 
Unknown 
Yes | No 
Yes | No 
Yes | No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
<second part of listing> 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.7.1 
 
Adverse Events 
Part 2 of 2 
 
 
 
 
 
 
  
 
 
  
 
 
Treatment 
Group 
Subject ID 
AE 
# 
Relationship to 
 
Initial Action Taken with 
 
Action Taken with 
Tarextumab 
Etoposide 
Platinum 
Therapy 
Tarextumab 
Etoposide 
Platinum 
Therapy 
Tarextumab 
Etoposide 
Platinum 
Therapy 
Placebo | 
Tarextumab  
003-xxx-xxx 
xx 
Related | 
Not Related 
Related | 
Not 
Related 
Related | Not 
Related 
 None | 
Dose Reduced | 
Dose Delayed | 
Infusion 
Interrupted | 
Withdrawn | 
Not Applicable 
None | 
Dose Reduced | 
Dose Delayed | 
Infusion 
Interrupted | 
Withdrawn | 
Not Applicable 
None | 
Dose Reduced | 
Dose Delayed | 
Infusion 
Interrupted | 
Withdrawn | 
Not Applicable 
 None | 
Dose Reduced | 
Dose Delayed | 
Infusion 
Interrupted | 
Withdrawn | 
Not Applicable 
None | 
Dose Reduced | 
Dose Delayed | 
Infusion 
Interrupted | 
Withdrawn | 
Not Applicable 
None | 
Dose Reduced | 
Dose Delayed | 
Infusion 
Interrupted | 
Withdrawn | 
Not Applicable 
 
 
 
 
 
 
  
 
 
  
 
 
 
Programmer notes: (a) Duplicate this listing to create Listing 16.2.7.3 of “Serious Adverse Events” and Listing 16.2.7.4 of “Adverse Events Leading to Study Drug Discontinuation” 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 132/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.7.2 
 
Deaths 
 
 
 
 
 
Treatment Group 
Subject ID 
Date of Death 
(Study Day) 
Cause of Death 
Primary Associated AE 
Placebo | 
Tarextumab  
003-xxx-xxx 
ddmmmyyyy (xx) 
Adverse Event | 
Progressive Disease 
Unknown | 
Other: Other term 
AE term 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 133/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.1 
 
Hematology 
 
Part 1 of 2 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Sample 
collected? 
Collection 
Date 
(Study Day) 
Collection 
Time 
Hemoglobin 
(g/dL) 
Hematocrit 
(%) 
Platelets 
(x103/uL) 
RBC 
(x106/uL) 
WBC 
(x103/uL) 
ANC 
(x103/uL) 
Placebo | 
Tarextumab  
003-xxx-xxx 
 SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
xx:xx 
xx.xL/H, G1/G2/G3/G4 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: RBC = Red Blood Cells, WBC = White Blood Cell, ANC = Absolute Neutrophil Count, ND = Not Done. L = Low, H = High, with respect to laboratory reference ranges. Grades are according 
to NCI Common Terminology Criteria Adverse Events (CTCAE) version 4.03 
 
Programming notes: Display L/H, G1/G2/G3/G4/G5 for each lab test result, where applicable. 
 
<second part of listing> 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.1 
 
Hematology 
 
Part 2 of 2 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Sample 
collected? 
Collection 
Date 
(Study 
Day) 
Collection 
Time 
Neutrophils 
(%) 
Bands 
(%) 
Lymphocytes 
(%) 
Eosinophils 
(%) 
Monocytes 
(%) 
Basophils 
(%) 
Placebo | 
Tarextumab  
003-xxx-xxx 
 SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyy
yy (xx) 
xx:xx 
xx.xL/H, G1/G2/G3/G4 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
Note: RBC = Red Blood Cells, WBC = White Blood Cell, ANC = Absolute Neutrophil Count, ND = Not Done. L = Low, H = High, with respect to laboratory reference ranges. Grades are according 
to NCI Common Terminology Criteria Adverse Events (CTCAE) version 4.03 
 
Programming notes: Display L/H, G1/G2/G3/G4/G5 for each lab test result, where applicable. 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 134/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.2 
 
PT/INR and aPTT 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Sample 
collected? 
Collection 
Date 
(Study Day) 
Collection 
Time 
Prothrombin Time (PT) 
(sec) 
International 
Normalized 
Ratio (INR) 
Activated Partial 
Thromboplastin 
Time (aPTT) 
(sec) 
Placebo | 
Tarextumab  
003-xxx-xxx 
 SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
xx:xx 
xx.xL/H, G1/G2/G3/G4 
 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
Note: ND = Not Done. L = Low, H = High, with respect to laboratory reference ranges. Grades are according to NCI Common Terminology Criteria Adverse Events (CTCAE) version 4.03 
 
Programming notes: Display L/H, G1/G2/G3/G4 for each lab test result, where applicable. 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 135/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.3 
 
Serum Chemistry 
 
Part 1 of 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Sample 
collected? 
Collection 
Date 
(Study Day) 
Collection 
Time 
Fasting 
for at least 
6 hours? 
Albumin 
(g/dL) 
Alkaline 
Phosphatase 
(U/L) 
Total 
Bilirubin 
(mg/dL) 
Direct 
Bilirubin 
(mg/dL) Bicarbonate 
(mEq/L) 
Blood 
Urea 
Nitrogen 
(mg/dL) 
Calcium 
(mg/dL) 
Chloride 
(mEq/L) 
Placebo | 
Tarextumab  
003-xxx-xxx  SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
xx:xx 
Yes | No 
xx.xL/H, 
G1/G2/G3/G4 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: LDH = Lactic Dehydrogenase, ND = Not Done. L = Low, H = High, with respect to laboratory reference ranges. Grades are according to NCI Common Terminology Criteria Adverse Events 
(CTCAE) version 4.03 
 
Programming notes: Display L/H, G1/G2/G3/G4/G5 for each lab test result, where applicable. 
 
<second part of listing> 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.3 
 
Serum Chemistry 
 
Part 2 of 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Sample 
collected? 
Collection 
Date 
(Study Day) 
Collection 
Time 
Fasting 
for at 
least 6 
hours? 
Creatin-
ine 
(mg/dL) 
Blood 
Glucose 
(mg/dL) 
LDH 
(U/L) 
Magnes-
ium 
(mg/dL) 
Phosph-
orus 
(mg/dL) Potassium 
(mEq/L) 
Total 
Protein 
(g/dL) 
AST 
(SGOT) 
(U/L) 
ALT 
(SGPT) 
(U/L) 
Sodium 
(mEq/L) 
Placebo | 
Tarextumab  
003-xxx-xxx  SCREENING 
| CYCLE X 
DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
xx:xx 
Yes | 
No 
xx.xL/H, 
G1/G2/G3/G4 
 
xx.x 
 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: LDH = Lactic Dehydrogenase, ND = Not Done. L = Low, H = High, with respect to laboratory reference ranges. Grades are according to NCI Common Terminology Criteria Adverse Events 
(CTCAE) version 4.03 
Programming notes: Display L/H, G1/G2/G3/G4/G5 for each lab test result, where applicable. 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 136/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.4 
 
Urinalysis 
 
Part 1 of 2 
 
 
  
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
 Visit 
Sample 
collected? 
Collection 
Date 
(Study Day) 
Collect- 
ion 
Time 
Protein 
Glucose 
Ketones 
Blood 
Bilirubin 
pH 
Specific 
Gravity 
Placebo | 
Tarextumab 
003-xxx-xxx  SCREENING | 
CYCLE 1 DAY 1 
Yes | No 
ddmmmyyyy 
(xx) 
xx:xx 
Negative | 
Positive: 
Trace/ 
1+/ 
2+/ 
3+/ 
4+/ 
Unknown | 
Not Done 
Negative | 
Positive | Not 
Done 
Negative | 
Positive | Not 
Done 
Negative | 
Positive | Not 
Done 
Negative | 
Positive | Not 
Done 
x.x 
x.xx 
 
 
  
 
 
 
 
 
 
 
 
 
 
<second part of listing> 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.4 
 
Urinalysis 
 
Part 2 of 2 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
 Visit 
Sample 
collected? 
Collection 
Date 
(Study Day) 
Collection 
Time 
Microscopic 
Exam 
Performed? 
Bacteria 
Casts 
Crystals 
RBC 
(cells/hpf) 
WBC 
(cells/hpf) Other 
test 
Result 
(units) 
Reference 
Range 
Placebo | 
Tarextumab  
003-xxx-xxx  SCREENING | 
CYCLE 1 DAY 
1 
Yes | No 
ddmmmyyyy 
(xx) 
xx:xx 
Yes | No 
Absent | 
Present | 
Not Done 
Absent | 
Present | 
Not 
Done 
Absent | 
Present | 
Not Done 
xx 
xx 
x.xx 
xx 
units 
xx-xx 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 137/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.5 
 
Vital Signs 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
 Visit 
Vital Signs 
Measured? 
Date (Study 
Day) 
Time 
Temperature 
(°C) 
Pulse Rate 
(beast/min) 
Respiratory Rate 
(beats/min) 
Blood Pressure 
(Systolic/ 
Diastolic) 
(mmHg) 
Height 
(cm) 
Weight 
(kg) 
Placebo | 
Tarextumab 
003-xxx-xxx  SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
xx:xx 
xx.x 
xx 
xx 
xxx/xx 
xxx.x 
xx.x 
 
 
  
 
 
 
 
 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 138/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.6 
 
ECOG Performance Status 
 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
ECOG 
Assessment 
Performed? 
Assessment 
Date 
(Study Day) 
Score[1] 
 
 
Placebo | 
Tarextumab  
003-xxx-xxx 
SCREENING | CYCLE 
X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
x 
 
 
 
 
 
 
 
 
 
 
 
[1] 0 = Fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light housework, office work; 2 = Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% 
of waking hour; 3 = Capable of only limited self-care, confined to bed or chair more than 50% of waking hour; 4 = Completely disabled. Cannot carry on any self-care. Totally 
confined to bed or chair; 5 = Dead. 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 139/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.7 
 
12-Lead ECG 
 
Part 1 of 2 
 
 
 
 
 
 
 
 
 
Treatment Group 
Subject ID 
Visit 
Was ECG 
Performed? 
Date of 
Assessment 
(Study Day) 
PR Interval 
(msec) 
QRS Duration (msec) 
QTc 
Interval 
(msec) 
QTc Interval 
Formula 
Placebo |  
Tarextumab  
003-xxx-xxx 
SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
xxx 
xxx  
xxx 
Bazett | 
Fridericia 
 
 
 
 
 
 
 
 
 
   
Note: MH = Medical History 
<second part of listing> 
 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.7 
 
12-Lead ECG 
 
Part 2 of 2 
 
 
  
 
 
 
 
 
 
 
Treatment Group 
Subject ID 
 Visit 
Was ECG 
Performed? 
Date of 
Assessment 
(Study Day) 
Interpretation 
If Abnormal, 
Describe 
Abnormality 
If Abnormal, 
Clinically 
Significant? 
Primary 
Associated 
AE 
Primary 
Associated 
MH 
Placebo | 
Tarextumab  
003-xxx-xxx  SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
Normal | 
Abnormal 
Description  
Yes | No 
AE term 
MH term 
 
 
  
 
 
 
 
 
 
 
 
Note: MH = Medical History 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 140/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.8 
 
Physical Examination 
 
 
  
 
 
 
 
 
 
 
Treatment Group 
Subject ID 
 Visit 
Was Physical Exam 
Performed? 
Date of 
Exam 
(Study Day) 
Abnormal 
Findings? 
If Abnormal, 
Clinically 
Significant? 
If Yes, 
Primary 
MH 
If Yes, 
Primary 
AE 
If No, 
Description of Non-
Clinically 
Significant Abnormality 
Placebo | 
Tarextumab  
003-xxx-xxx  SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
Yes | No 
Yes | No 
MH term 
AE term 
Description 
 
 
  
 
 
 
 
 
 
 
 
Note: MH = Medical History  
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 141/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.9 
 
Optional Blood for Pharmacogenomics 
 
 
  
 
 
Treatment Group 
Subject ID 
 Visit 
Was optional blood sample collected for 
pharmacogenomics? 
PG Blood Date of Collection 
(Study Day) 
Placebo | 
Tarextumab  
003-xxx-xxx  SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
 
 
  
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 142/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.10 
 
CA 19-9 Tumor Marker 
 
 
  
 
 
 
Treatment Group 
Subject ID 
 Visit 
Was the CA19-9 Tumor Marker 
Sample Collected? 
Collection Date 
(Study Day) 
Result (Units) 
Placebo | 
Tarextumab  
003-xxx-xxx  SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
xxxxx.x units 
 
 
  
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 143/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.11 
 
Anti-Tarextumab Antibodies 
 
 
  
 
 
Treatment Group 
Subject ID 
 Visit 
Was the Anti-Tarextumab Antibody 
Sample Collected? 
Collection Date 
(Study Day) 
Placebo | 
Tarextumab  
003-xxx-xxx  SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
 
 
  
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 144/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.12 
 
Blood for Biomarkers 
 
 
 
 
 
 
 
 
 
Treatment 
Group 
Subject ID 
Visit 
Was Blood Sample for 
Plasma Biomarkers 
Collected? 
Blood Sample for 
Plasma Biomarkers 
Collection Date 
(Study Day) 
Was Blood Sample for 
mRNA Biomarkers 
Collected? 
Blood Sample for 
mRNA Biomarkers 
Collection Date 
(Study Day) 
Was Blood 
Sample for CTCs 
Collected? 
Blood Sample for 
CTCs Collection 
Date 
(Study Day) 
Placebo | 
Tarextumab  
003-xxx-xxx SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
Yes | No 
ddmmmyyyy 
(xx) 
Yes | No 
ddmmmyyyy 
(xx) 
 
 
 
 
 
 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 145/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.13 
 
Serum Pregnancy Test 
 
 
 
 
 
 
 
Treatment Group 
Subject ID 
Visit 
Was the Pregnancy Test performed? If No, Specify Reason 
Date of Assessment 
(Study Day) 
 
Result 
Placebo | 
Tarextumab 
003-xxx-xxx SCREENING | 
UNSCHEDULED 
Yes | No 
Prior Hysterectomy | 
Other Reason: 
ddmmmyyyy 
(xx) 
Positive | Negative 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 146/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.14 
 
Optional Tumor Core Biopsy 
 
 
 
 
 
 
 
 
Treatment Group 
Subject ID 
Visit 
Was an Optional Tumor Core 
Biopsy Sample Collected? 
Date of Collection 
(Study Day) 
Time of Collection Location 
Location Description 
(Position within Organ) 
Placebo | 
Tarextumab 
003-xxx-xxx 
SCREENING | 
CYCLE X DAY X 
Yes | No 
ddmmmyyyy 
(xx) 
xx:xx 
Pancreas | 
Liver | 
Lymph | 
Nodes | 
Peritoneum | 
Chest Wall | 
Abdomen | 
Pelvis | 
Breast | 
Skin | 
Kidney | 
Lung | 
Other: Other 
organ 
Description 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 147/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.15 
 
On Study PCI or WBRT (PCI) 
Treatment 
Group 
Subject ID 
Visit 
Prophylactic Cranial Irradiation (PCI) 
 
Whole Brain Radiation [WBRT (PCI)] 
Administered 
during study? 
Total 
cGY 
Start Date 
(Study Day) 
Stop Date 
(Study Day) 
 
Administered 
during study? 
Total 
cGY  
Start Date 
(Study Day) 
Stop Date 
(Study Day) 
Placebo | 
Tarextumab  
003-xxx-xxx SCREENING | 
CYCLE X 
DAY X 
Yes | No 
xx | 
Unknown 
ddmmmyyyy 
(xx) 
ddmmmyyyy 
(xx) 
 
Yes | No 
xx | 
Unknown 
ddmmmyyyy 
(xx) 
ddmmmyyyy 
(xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 148/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.8.16 
 
Follow-Up After Discontinuation of Study Treatment 
 
 
 
 
 
 
 
 
Treatment Group 
Subject ID 
Visit 
Was a Survival Follow-Up Done? 
Date of 
Survival Assessment 
(Study Day) 
Subject Status 
Last Known 
Survival Date 
(Study Day) 
 
Placebo | 
Tarextumab 
003-xxx-xxx X MONTH SURVIVAL FOLLOW-UP 
Yes | No 
ddmmmyyyy (xx) 
Alive | 
Dead | 
Lost to Follow-Up 
ddmmmyyyy (xx)  
 
 
 
 
 
 
 
 
 
 
 


OncoMed Pharmaceuticals, Inc. 
 
Statistical Analysis Plan 
59R5-003 (Phase 2) 
 
23MAR2017 
 
Confidential 
 
Page 149/149 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.17 
 
Treatments and Procedures for Extensive Small Lung Cancer During Follow-Up Period 
Part 1 of 3: Surgery 
 
 
 
 
 
 
 
 
Treatment Group 
Subject ID 
Visit 
Any surgeries for the 
treatment of lung cancer 
during follow-up period? 
Surgery Description 
Location 
Surgery Date 
(Study Day) 
 
Placebo | 
Tarextumab 
003-xxx-xxx 
X MONTH SURVIVAL 
FOLLOW-UP 
Yes | No 
Description 
Location 
ddmmmyyyy (xx) 
 
 
 
 
 
 
 
 
 
<second part of listing> 
 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.17 
 
Treatments and Procedures for Extensive Small Lung Cancer During Follow-Up Period 
Part 2 of 3: Radiotherapy 
 
 
 
 
 
 
 
 
 
Treatment Group 
Subject ID 
Visit 
Any radiotherapy 
for the treatment of 
lung cancer during 
follow-up period? 
Site of Treatment 
Total cGY 
Start Date 
(Study Day) 
Stop Date 
(Study Day) 
Systemic Therapy? 
Placebo | 
Tarextumab 
003-xxx-xxx 
X MONTH SURVIVAL 
FOLLOW-UP 
Yes | No 
Site 
xx | Unknown 
ddmmmyyyy (xx) 
ddmmmyyyy (xx) 
Yes | No 
 
 
 
 
 
 
 
 
 
<third part of listing> 
 
OncoMed Pharmaceuticals, Inc. 
 
Page 1 of x 
59R5-003 (Phase 2) 
Listing 16.2.17 
 
Treatments and Procedures for Extensive Small Lung Cancer During Follow-Up Period 
Part 3 of 3: Systemic Therapy 
 
 
 
 
 
 
 
Treatment Group 
Subject ID 
Visit 
Any systemic therapy for the 
treatment of lung cancer 
during follow-up period? 
Regimen 
Start Date 
(Study Day) 
End Date 
(Study Day) 
Placebo | 
Tarextumab 
003-xxx-xxx 
X MONTH SURVIVAL 
FOLLOW-UP 
Yes | No 
Regimen 
ddmmmyyyy (xx) 
ddmmmyyyy (xx) 
 
 
 
 
 
 
 
 

Prot_ICF_001.pdf: 
OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6
Page 1 of 235 
22 April 2016 
CONFIDENTIAL 
CLINICAL PROTOCOL 
 
Protocol No. 
59R5-003 
Title: 
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 
Version: 
18 December 2012 
Amendment 1: 09 May 2013 
Amendment 2:  19 August 2013 
Amendment 3: 23 October 2013 
Amendment 4: 17 April 2014 
Amendment 5:  10 September 2014 
Amendment 6:  22 April 2016 
IND Number: 
106826 
Sponsor: 
OncoMed Pharmaceuticals, Inc. 
800 Chesapeake 
Redwood City, CA 94063 
Phone: 650-995-8200 
 
 
CONFIDENTIAL 
This document contains proprietary and confidential information of OncoMed Pharmaceuticals, Inc.  Acceptance of 
this document constitutes agreement by the recipient that no previously unpublished information contained herein 
will be published or disclosed without the prior written approval of OncoMed Pharmaceuticals, Inc. with the 
exception that this document may be disclosed to study personnel under your supervision who need to know the 
contents for conducting the study and appropriate Institutional Review Boards/Ethics Committees under the 
condition that the personnel have agreed to keep this information confidential.  The foregoing shall not apply to 
disclosure required by governmental regulations or laws; however, OncoMed Pharmaceuticals, Inc. shall be 
promptly notified of any such disclosure. 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6
Page 2 of 235 
22 April 2016 
 
CONFIDENTIAL 
SPONSOR CONTACTS 
 
Medical Monitor: 
Primary:  
 
 
 
 
 
 
 
 
 
 
 
 
 
Backup: 
 
 
 
 
 
 
 
 
 
OncoMed Pharmaceuticals, Inc. 
 
 
 
 
 
800 Chesapeake Drive 
 
 
 
 
 
Redwood City, CA  94063 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6
Page 3 of 235 
22 April 2016 
 
CONFIDENTIAL 
INVESTIGATOR SIGNATURE PAGE 
 
OncoMed Pharmaceuticals, Inc. 
Protocol No. 59R5-003 
Amendment 6:  22 April 2016 
I will provide copies of the protocol, any subsequent protocol amendments, and access to all 
information provided by the Sponsor to the study personnel under my supervision.  I will discuss 
this material with them to ensure that they are fully informed about the investigational drug and 
the study protocol. 
I agree to conduct this clinical trial according to the attached protocol.  I also agree to conduct 
this study in compliance with Good Clinical Practice (GCP), all federal, state, and local 
regulations as well as with the requirements of the appropriate Institutional Review Board or 
Ethics Committee and any other institutional requirements. 
 
 
 
Principal Investigator 
 
Date 
Printed Name: 
 
Institution: 
 
Address: 
 
 
 
Telephone Number: 
 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6
Page 4 of 235 
22 April 2016 
 
CONFIDENTIAL 
 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6
Page 5 of 235 
22 April 2016 
 
CONFIDENTIAL 
SYNOPSIS 
Title of Study: 
A Phase 1b/2 Study of Tarextumab in Combination with Etoposide and Platinum Therapy in Subjects with Untreated 
Extensive Stage Small Cell Lung Cancer  
INNACLE:  
Phase 1b/2 INvestigation of anti-Notch Antibody Therapy with Etoposide and Platinum Therapy in 
Small Cell Lung Carcinoma Safety and Efficacy 
Study Period:  Approximately 36 months 
Development Phase:  Phase 1b/2 
Objectives: 
Primary Objectives: 
•
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 area under the 
curve (AUC) of 5 mg/mL•min on Day 1  in subjects with untreated extensive stage small cell lung cancer 
(Phase 1b 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 extensive stage small cell lung 
cancer (Phase 2 portion) 
Secondary Objectives: 
•
To determine the pharmacokinetics of tarextumab in combination with EP in subjects receiving first-line therapy 
for extensive stage small cell lung cancer (Phase 1b and 2 portion) 
•
To determine the immunogenicity of tarextumab in combination with EP in subjects receiving first-line therapy 
for extensive stage small cell lung cancer (Phase 1b and 2 portions) 
•
To estimate the improvement in overall survival (OS), 12 months OS, and the overall response rate (ORR) 
resulting from the addition of tarextumab to EP in subjects receiving first-line therapy for extensive stage small 
cell lung cancer (Phase 2 portion) 
•
To correlate the treatment effect in PFS and OS, 12 month OS and ORR resulting from the addition of tarextumab 
to EP in subjects receiving first-line therapy for extensive stage small cell lung cancer in subjects with Notch3, 
Hes 1, Hey 2, Hey 1 and Hes 6 expression (Phase 2 portion) 
•
To determine the safety and tolerability of tarextumab in combination with EP in subjects who are receiving 
first-line therapy for extensive stage small cell lung cancer (Phase 1b 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 extensive stage small cell lung cancer (Phase 2 portion) 
Exploratory Objective: 
•
To describe the changes in exploratory pharmacodynamic (PD) biomarkers, including Notch pathway related 
genes and proteins and circulating tumor cells following tarextumab treatment (Phase 1b and 2 portions) 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6
Page 6 of 235 
22 April 2016 
 
CONFIDENTIAL 
Study Design: 
The study consists of a Phase1b 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 progression of disease.  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 of the highest tolerable dose is confirmed with etoposide and cisplatin/carboplatin, 
the protocol will explore a Phase 2, multicenter, randomized, placebo-controlled portion comparing the efficacy and 
safety of tarextumab at this 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 extensive stage small cell lung 
cancer. 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.  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 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 or with carboplatin area 
under the curve (AUC) of 5 mg/mL•min on Day 1 of every 21-day cycle for 6 cycles in Phase 1b.  In Phase 2 portion of 
the study, cisplatin dose will be 75 mg/m2, etoposide and carboplatin dose will the same as the one used in Phase 1b.  
tarextumab or Placebo will be given on Day 1 of every 21-day cycle prior to the administration of EP.   
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 study drug 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. 
After the completion of 6 cycles of EP, subjects who do not have disease progression and have not had prophylactic 
cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study entry and are good candidates for PCI per the 
Investigators 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 Investigators, PCI can be initiated at the time that is determined appropriated per 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 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 (APPENDIX A). Subjects will discontinue study treatment if there is evidence of central 
nervous system (CNS) metastasis. 
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 approximately 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.   
Additionally, subjects who discontinue study treatment for any reason other than disease progression will be followed 
with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up until documented disease progression or 
initiation of new anti-cancer therapy, whichever is sooner. 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6
Page 7 of 235 
22 April 2016 
 
CONFIDENTIAL 
Study Population and Number of Subjects: 
Subjects must have previously untreated extensive stage small cell lung cancer proven either by histology or cytology. 
In addition, subjects must have Formalin-Fixed, Paraffin-Embedded (FFPE) tumor tissue, either archived or fresh 
biopsied for Notch3, Hes1, Hey2, Hey1 and Hes6 analysis.  In the Phase 2 portion, subjects must have measurable 
disease by RECIST 1.1 criteria in order to be eligible.  
Approximately 30 subjects will be enrolled into Phase 1b portion of the study, the exact number will depend on the 
number of dose levels assessed and the toxicities observed. 
For the Phase 2 portion of the trial, approximately 135 subjects will be treated with at least one dose of study drug 
(either tarextumab or placebo). 
Diagnosis and Main Criteria for Eligibility: 
Inclusion Criteria: 
1.
Histologically or cytologically documented extensive stage small cell lung cancer (combined small cell carcinoma 
is allowed); extensive stage is defined as disease beyond the ipsilateral hemithorax, including malignant pleural or 
pericardial effusion or hematogenous metastases (contralateral mediastinal and ipsilateral supraclavicular 
lymphadenopathy are generally classified as limited disease).   
2.
Adults of 18 years of age or older. 
3.
Performance Status (ECOG) of 0 or 1. 
4.
FFPE tumor tissue, either fresh core needle biopsied (two fresh cores preferred whenever possible), or archived 
available for Notch3, Hes1, Hey2, Hey1 and Hes6 analysis  
5.
Adequate organ function: 
a.
Adequate hematologic function (absolute neutrophil count [ANC]  1,500 cells/ȝL; hemoglobin  9 g/dL, 
platelets  100,000/ȝL). 
b.
Adequate renal function (serum creatinine  1.5 mg/dL or calculated creatinine clearance  60 mL/min using 
Cockroft Gault formula).  
c.
Adequate hepatic function (alanine aminotransferase [ALT]  3 x upper limit of normal [ULN],  
ALT may be  5 x ULN if due to liver metastases but cannot be associated with concurrent elevated 
bilirubin >1.5xULN unless it is approved by the Sponsor’s Medical Monitor). 
d.
Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated partial thromboplastin 
time (aPTT) 1.5 × ULN. 
6.
Written consent on an IRB/IEC-approved Informed Consent Form prior to any study-specific evaluation. 
7.
For women of child-bearing potential, negative serum pregnancy test at screening and use of physician-approved 
method of birth control from 30 days prior to the first study drug administration to 30 days following the last study 
drug administration or the last EP in the study, whichever is discontinued last. 
8.
Male subjects must be surgically sterile or must agree to use physician-approved contraception during the study 
and for 30 days following the last study drug administration or the last EP in the study, whichever is discontinued 
last. 
Additionally, for individuals eligible to participate in Phase 2 portion of the study: 
9.
Subject must have evidence of measurable disease per RECIST 1.1 criteria. 
Exclusion Criteria: 
1.
Limited stage small cell lung cancer appropriate for radical treatment with chemoradiation. 
2.
Prior therapy including radiation, chemotherapy or surgery for newly diagnosed extensive stage small cell lung 
cancer.  Exceptions to this exclusion criterion include: 1) prophylactic cranial irradiation or whole brain radiation 
(WBRT) prior to the first administration of study drug provided that the subject has stable neurologic condition for 
at least 2 weeks after the completion of the radiation, adverse event that is related to the radiation has recovered to 
be  Grade 1, and is not receiving corticosteroid of > 40 mg prednisone daily equivalent dose to control the 
symptoms, 2) focused radiation for symptomatic relief for isolated bone metastases; 3) bisphosphonate or 
denosumab therapy for bone metastasis initiated prior to study entry. 
3.
Presence of uncontrolled Grade  1 diarrhea within 4 weeks prior to the first study drug administration. 
4.
Presence of any serious or uncontrolled illness including, but not limited to:  ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, uncontrolled 
arterial thrombosis, symptomatic pulmonary embolism, and psychiatric illness that would limit compliance with 
study requirement. 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6
Page 8 of 235 
22 April 2016 
 
CONFIDENTIAL 
Diagnosis and Main Criteria for Eligibility: (Cont’d) 
5.
History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty 
and/or stenting within 6 months prior to the first administration of study drug. 
6.
A history of malignancy with the exception of: 
a.
Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer 
b.
Superficial bladder cancer 
c.
Adequately treated stage I cancer from which the subject is currently in remission, or  
d.
Any other cancer from which the subject has been disease-free for  3 years 
7.
Known human immunodeficiency virus (HIV) infection. 
8.
Females who are pregnant or breastfeeding. 
9.
Concurrent use of therapeutic warfarin (prophylactic low dose of warfarin, i.e., 1 mg daily for port catheter is 
allowed). 
Additionally, individuals ineligible to participate in Phase 2 portion of the study if : 
10. Subjects have relapsed after treatment for limited disease 
Test Product, Dose, and Mode of Administration 
Study drug will be either tarextumab or Placebo (Phase 2, only).  Study drug will be given intravenously on Day 1 of 
every 21-day cycle.  The subject should not receive two consecutive doses of study drug within 18 days.  
Tarextumab is an IgG2 fully human monoclonal antibody that is directed against the Notch2/3 receptors.  Tarextumab 
is supplied at a concentration of 10 mg/mL in 25mL single-use glass vial filled to 20 mL to deliver at total of 200 mg 
per vial.  Tarextumab vials must be stored at 2°C–8°C.  DO NOT FREEZE.  DO NOT SHAKE. 
Please refer to the Pharmacy Manual for the details on tarextumab preparation and administration. Placebo is a 
formulation of 50mM Histidine, 100mM Sodium Chloride, 45mM Sucrose and 0.01% (v/v) Polysorbate-20, pH 6.0.  
Placebo will be administered in the same manner as tarextumab. Please refer to the Pharmacy Manual for details 
regarding Placebo preparation and administration. 
Etoposide will be administered by IV infusion at a dose of 100 mg/m2 over 30 to 60 minutes on Days 1, 2 and 3 of each 
21-day treatment cycle for 6 cycles in accordance with institutional standard of care.  The subject should not receive 
two Day 1 consecutive doses of etoposide within 18 days.  A one day window will be allowed for each consecutive day 
of etoposide dosing (e.g. Day 2 and 3 dosing may occur on Day 3 and 4, or Day 3 and 5). 
Cisplatin or carboplatin will be the choice of platinum therapy.  Initially, all subjects in Phase 1b will receive cisplatin 
until the MTD/highest tolerable dose is determined with tarextumab in combination with etoposide and cisplatin.  After 
that, a cohort of 6 subjects will be enrolled to receive tarextumab at the MTD/highest tolerable dose with etoposide and 
carboplatin.  Subjects in Phase 2 will receive cisplatin or carboplatin as determined by the Investigator prior to 
randomization.  
Cisplatin will be administered by IV infusion at a dose of 80 mg/m2 over 30 minutes to 2 hours on Day 1 of each 21-
day treatment cycle for 6 cycles in accordance with institutional standard of care in Phase 1b and at a dose of 75 mg/m2 
in Phase 2 portion of the study. The subject should not receive two consecutive doses of cisplatin within 18 days. 
Carboplatin will be administered by IV infusion at AUC of 5 mg/mL•min over 15 minutes or longer on Day 1 of each 
21-day treatment cycle for 6 cycles in accordance with institutional standard of care.  The subject should not receive 
two consecutive doses of carboplatin within 18 days. 
On days when study drug is given together with etoposide and platinum therapy, study drug should be given prior to 
etoposide and platinum therapy administration.  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. 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. 
Duration of Treatment: 
In the absence of unacceptable study drug treatment-related toxicity or disease progression, subjects may receive study 
treatment for up to 1 year at the discretion of the Investigator and beyond 1 year with the agreement of the Investigator 
and the Sponsor. 
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Safety Evaluation: 
Safety will be assessed by adverse event monitoring (including attribution of adverse events and serious adverse 
events), physical examination, vital signs, clinical laboratory testing and anti-tarextumab testing on an ongoing basis as 
outlined in the Schedule of Assessments. 
Efficacy Evaluation: 
Subjects will be assessed for response using Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1.  The 
first response assessment will occur approximately 6 weeks/42 days (± 5 days) after the first dose of the study drug.  
Subsequent response assessments will occur every 6 weeks/42 days (± 5 days).  Subjects who discontinue study 
treatment for any reason other than disease progression will be followed with tumor assessment every 6 weeks/42 days 
(±5 days) during Follow-up until documented disease progression or initiation of new anti-cancer therapy, whichever is 
sooner. 
Immunogenicity: 
During Phase 1b, serum samples will be obtained for immunogenicity assessment prior to study drug administration on 
Day 1 of Cycle 1, every three cycles thereafter (Day 1 of Cycle 4, 7, 10, etc.), at other times as clinically indicated such 
as when significant toxicities occur and at the time of treatment termination for all subjects enrolled in Phase 1b. 
Samples that test positive will be assessed for neutralizing capability.  
During Phase 2, serum samples will be obtained for immunogenicity assessment prior to study drug administration on 
Day 1 of Cycle 1, every other cycle thereafter (Day 1 of Cycle 3, 5, 7, etc.), at other times as clinically indicated such 
as when significant toxicities occur and at the time of treatment termination for all subjects enrolled in Phase 2. 
Samples that test positive will be assessed for neutralizing capability. 
Pharmacokinetic Evaluation: 
For subjects enrolled in Phase 1b portion only:  Plasma samples from all subjects enrolled in Phase 1b portion will be 
obtained for pharmacokinetic analysis of tarextumab at pre-dose and 5 minutes post infusion on Day 1 of Cycles 1 and 
3, on Days 3 and 8 of Cycles 1 and 3, at other times as clinically indicated such as when significant toxicities occur as 
well as at the time of treatment termination, as outlined in the Schedule of Assessments (APPENDIX B).   
For subjects enrolled in Phase 2 portion only: Plasma samples from all subjects enrolled in Phase 2 portion will be 
obtained for pharmacokinetic analysis of tarextumab on Day 1 of Cycles 1 and 3, at  pre-dose and 5 minutes post 
tarextumab infusion;  Day 3 of Cycle 1 and Cycle 3 prior to etoposide administration; Day 8 of Cycle 1 and Cycle 3 
when blood sample is taken for biomarker evaluation;  Day 1 of every other cycle starting from Cycle 5 prior to study 
drug administration and, at other times as clinically indicated such as when significant toxicities occur as well as at the 
time of treatment termination, as outlined in the Schedule of Assessments (APPENDIX C). Pharmacokinetic 
parameters (i.e. area under the curve [AUC], clearance, volume of distribution and apparent half life) of tarextumab 
will be assessed for each evaluable subject. 
Biomarker Evaluation: 
Samples will be obtained for biomarker evaluations as outlined in the Schedule of Assessments (APPENDIX B and 
APPENDIX C). 
Notch3, Hes1, Hey2, Hey1, and Hes6 expression levels (e.g., protein and/or RNA) will be assessed in FFPE tumor 
specimens to correlate the treatment effect in relation to these gene expressions. The expression level of additional 
proteins and genes may be evaluated and correlated with clinical benefit. Additionally, DNA testing may be done on 
subjects who consent to have the optional DNA testing on FFPE tumor specimens collected. 
Exploratory pharmacodynamics assays to confirm target engagement will include assessments of hair follicles (Phase 
1b portion only), plasma proteins, and blood mRNA.  Circulating tumor cells (CTCs) will also be monitored to explore 
the effects of treatment on CTCs.  In addition, a pharmacogenomic blood sample will be collected on Day 1 of Cycle 1 
prior to dosing from subjects who give informed consent to assess Notch target- or pathway-related genes.   
Optional tumor biopsies will be obtained to assess tumor biomarkers before and during tarextumab treatment and at the 
time of progression in subjects who are consented to provide pre- and post-treatment tumor biopsies, provided it is 
feasible. 
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CONFIDENTIAL 
1.0
TABLE OF CONTENTS 
SPONSOR CONTACTS ...............................................................................................................2 
INVESTIGATOR SIGNATURE PAGE......................................................................................3 
SPONSOR SIGNATURE PAGE ..................................................................................................4 
SYNOPSIS ......................................................................................................................................5 
1.0 
TABLE OF CONTENTS ................................................................................................10 
LIST OF TABLES .......................................................................................................................14 
LIST OF FIGURES .....................................................................................................................15 
LIST OF APPENDICES .............................................................................................................15 
2.0 
LIST OF ABBREVIATIONS .........................................................................................16 
3.0 
BACKGROUND ..............................................................................................................19 
3.1 
Investigational Medicinal Product .........................................................................19 
3.2 
Disease Background...............................................................................................19 
3.3 
Nonclinical Data ....................................................................................................19 
3.4 
Clinical Background ..............................................................................................23 
3.5 
Dose Rationale .......................................................................................................27 
3.6 
Study Conduct ........................................................................................................28 
3.7 
Subject Population .................................................................................................28 
4.0 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................29 
4.1 
Study Objectives ....................................................................................................29 
5.0 
OVERALL STUDY DESIGN AND PLAN DESCRIPTION.......................................30 
5.1 
Phase 1b Portion ....................................................................................................31 
5.2 
Dose Limiting Toxicity ..........................................................................................32 
5.3 
Dose Escalation Plan..............................................................................................32 
5.4 
Maximum Tolerated Dose .....................................................................................33 
5.4.1 
Follow-Up .............................................................................................34 
5.5 
Phase 2 Portion ......................................................................................................35 
5.5.1 
Blinded Treatment Phase ......................................................................35 
5.5.2 
Follow-up ..............................................................................................36 
6.0 
SELECTION OF STUDY POPULATION ...................................................................36 
6.1 
Inclusion Criteria ...................................................................................................36 
6.2 
Exclusion Criteria ..................................................................................................37 
6.3 
Removal of Subjects from Study Treatment ..........................................................39 
6.4 
Subject Identification and Replacement of Subjects .............................................40 
7.0 
TREATMENT OF SUBJECTS ......................................................................................40 
7.1 
Study Drug (tarextumab or Placebo) .....................................................................41 
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7.1.1 
Study Drug Administration ...................................................................41 
7.1.2 
Study Drug Description ........................................................................42 
7.1.3 
Study Drug Packaging ..........................................................................42 
7.1.4 
Study Drug Ordering, Storage, and Accountability ..............................42 
7.1.5 
Study Drug Preparation .........................................................................42 
7.2 
Etoposide................................................................................................................42 
7.2.1 
Administration ......................................................................................42 
7.2.2 
Description ............................................................................................43 
7.2.3 
Storage ..................................................................................................43 
7.2.4 
Packaging ..............................................................................................43 
7.3 
Cisplatin .................................................................................................................43 
7.3.1 
Administration ......................................................................................43 
7.3.2 
Description ............................................................................................43 
7.3.3 
Storage ..................................................................................................43 
7.3.4 
Packaging ..............................................................................................43 
7.4 
Carboplatin .............................................................................................................44 
7.4.1 
Administration ......................................................................................44 
7.4.2 
Description ............................................................................................44 
7.4.3 
Storage ..................................................................................................44 
7.4.4 
Packaging ..............................................................................................44 
7.5 
Dose Modifications or Delay for Treatment-Related Toxicities ...........................44 
7.5.1 
Infusion Reaction Management ............................................................54 
7.6 
Anti-Emetics, Anti-diarrhea and Hematopoietic Supportive Care ........................54 
7.7 
Concomitant and Prohibited Therapy ....................................................................55 
7.8 
Treatment Compliance ...........................................................................................55 
8.0 
SAFETY ASSESSMENTS ..............................................................................................56 
8.1 
Adverse Events Definitions and Reporting Procedures .........................................56 
8.1.1 
Definition of Adverse Event .................................................................56 
8.1.2 
Adverse Event -Causality rating ...........................................................56 
8.1.3 
Definition of Serious Adverse Event ....................................................57 
8.1.3.1 
Disease Progression and Death ......................................................57 
8.1.4 
Serious Adverse Event Reporting Procedures ......................................57 
8.2 
Clinical Laboratory Assessments ...........................................................................58 
8.2.1 
Hematology ...........................................................................................58 
8.2.2 
Chemistry ..............................................................................................58 
8.2.3 
Urinalysis ..............................................................................................58 
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8.3 
Vital Signs and Other Physical Findings ...............................................................59 
8.4 
Cardiac Studies ......................................................................................................59 
8.5 
Immunogenicity Assessments ................................................................................59 
8.6 
Pharmacokinetic Assessments ...............................................................................59 
9.0 
EFFICACY ASSESSMENTS .........................................................................................60 
10.0 
BIOMARKERS AND EXPLORATORY ASSESSMENTS ........................................60 
11.0 
STUDY VISIT SCHEDULE AND ASSESSMENTS ....................................................61 
11.1 
Screening................................................................................................................62 
11.2 
Treatment Visits – Phase 1b ..................................................................................63 
11.2.1 
Cycle 1 ..................................................................................................64 
11.2.1.1 
Cycle 1 Day 1.................................................................................64 
11.2.1.2 
Cycle 1 Day 2.................................................................................65 
11.2.1.3 
Cycle 1 Day 3.................................................................................65 
11.2.1.4 
Cycle 1 Day 8.................................................................................66 
11.2.2 
Cycles 2-6 .............................................................................................66 
11.2.2.1 
Day 1 (± 1 day) of Cycles 2-6 ........................................................66 
11.2.2.2 
Day 2 of Cycles 2-6 .......................................................................67 
11.2.2.3 
Day 3 of Cycles 2-6 .......................................................................68 
11.2.2.4 
Day 8 of Cycles 2 and 3 Only ........................................................68 
11.2.3 
After Cycle 6 of etoposide and cisplatin/carboplatin with 
tarextumab .............................................................................................69 
11.2.4 
Cycle 7 and every cycle thereafter ........................................................69 
11.2.4.1 
Day 1 (± 1 day) of Cycle 7 and every cycle thereafter ..................69 
11.3 
Treatment Visits – Phase 2 ....................................................................................70 
11.3.1 
Cycle 1 ..................................................................................................71 
11.3.1.1 
Cycle 1 Day 1.................................................................................71 
11.3.1.2 
Cycle 1 Day 2.................................................................................72 
11.3.1.3 
Cycle 1 Day 3.................................................................................73 
11.3.1.4 
Cycle 1 Day 8.................................................................................73 
11.3.2 
Cycles 2-6 .............................................................................................73 
11.3.2.1 
Day 1 (± 1 day) of Cycles 2-6 ........................................................73 
11.3.2.2 
Day 2 of Cycles 2-6 .......................................................................74 
11.3.2.3 
Day 3 of Cycles 2-6 .......................................................................75 
11.3.2.4 
Day 8 of Cycles 2 and 3 Only ........................................................75 
11.3.3 
After Cycle 6 - Planned EP Treatment cycles .......................................76 
11.3.4 
Subsequent Cycles After Cycle 6 ..........................................................76 
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11.3.4.1 
Day 1 (± 1 day) of Subsequent Cycles After Completion of 
Planned EP Cycles .........................................................................76 
11.4 
Treatment Termination ..........................................................................................77 
11.5 
Follow up ...............................................................................................................78 
12.0 
DATA QUALITY ASSURANCE ...................................................................................78 
13.0 
STATISTICAL PLAN .....................................................................................................79 
13.1 
Power and Sample Size ..........................................................................................79 
13.1.1 
Phase 1b ................................................................................................79 
13.1.2 
Sample Size Justification – Phase 2 ......................................................79 
13.1.3 
Randomization and Blinding ................................................................87 
13.1.4 
Procedures for Unblinding ....................................................................87 
13.2 
Phase 1b .................................................................................................................87 
13.3 
Phase 2 ...................................................................................................................88 
13.3.1 
Subject Populations for Analysis ..........................................................88 
13.3.2 
Analysis Set ...........................................................................................88 
13.4 
Endpoints ...............................................................................................................88 
13.4.1 
Efficacy Endpoints ................................................................................88 
13.4.2 
Safety Endpoints ...................................................................................89 
13.4.3 
Immunogenicity Endpoints ...................................................................90 
13.4.4 
Pharmacokinetic Endpoints ...................................................................90 
13.4.5 
Exploratory Endpoints ..........................................................................90 
13.5 
Statistical Methods .................................................................................................90 
13.5.1 
Progression-Free Survival .....................................................................91 
13.5.2 
Response Rate (Best Overall Response) ...............................................92 
13.5.3 
Duration of Response ............................................................................93 
13.5.4 
Overall Survival ....................................................................................93 
13.5.5 
Landmark Survival ................................................................................93 
13.5.6 
Correlation of Biomarkers with Efficiacy Endpoints ............................94 
13.6 
Demographics and Baseline Characteristics ..........................................................94 
13.7 
Treatment Exposure ...............................................................................................94 
13.8 
Termination Criteria...............................................................................................94 
13.9 
Deviation Reporting ...............................................................................................95 
13.10 Data Safety Monitory Board ..................................................................................95 
13.11 Analysis of PFS and OS Prior to the Final Analysis .............................................95 
13.12 DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ................................95 
14.0 
ETHICAL CONSIDERATIONS ....................................................................................96 
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15.0 
INVESTIGATOR REQUIREMENTS ..........................................................................96 
15.1 
Informed Consent...................................................................................................96 
15.2 
Institutional Review Board/Ethics Committee Approval ......................................96 
15.3 
Study Monitoring ...................................................................................................97 
15.4 
Auditing Procedures...............................................................................................97 
15.5 
Data Collection ......................................................................................................97 
15.6 
Investigational Medicinal Product Accountability ................................................98 
15.7 
Disclosure of Data and Publication ........................................................................98 
15.8 
Retention of Records ..............................................................................................99 
16.0 
REFERENCES ...............................................................................................................100 
  
LIST OF TABLES 
Table 1: 
Summary of the Activity of Tarextumab in SCLC Xenografts .................20 
Table 2: 
Study 59R5-001:  Worse Grade Treatment Related Diarrhea 
(N=34/42) ...................................................................................................24 
Table 3: 
Study 59R5-001: Grade 3 Treatment Related Adverse Events by Body 
System (N=39) ...........................................................................................25 
Table 4: 
Maximum Tolerated Dose Determination and Cohort Expansion ............33 
Table 5: 
Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy 
Dose Modification and Delay ....................................................................46 
Table 6: 
Power to Declare a Dose as Exceeding the MTD for Various Incidence 
Rates ...........................................................................................................79 
Table 7: 
PFS: Power for H1 ....................................................................................80 
Table 8: 
Hazards for Piece-Wise Exponential Model of Progression Free 
Survival ......................................................................................................81 
Table 9: 
Hazards for Piece-wise Exponential Model of Survival ............................82 
Table 10: 
Enrollment, Progressions and Deaths over Time – Control Hazard of 
Progression of 0.1386 beyond 9 months ....................................................85 
Table 11: 
Power for OS..............................................................................................86 
  
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LIST OF FIGURES 
Figure 1: 
Activity of Tarextumab in Lu68 SCLC Tumor Recurrence Model ...........21 
Figure 2: 
Activity of Tarextumab in 87 SCLC Tumor Recurrence Model in 
Combination with Carboplatin plus Irinotecan ..........................................22 
Figure 3: 
Tarextumab Inhibits Growth of Lu40 SCLC Tumors in Combination 
with Taxol ..................................................................................................22 
Figure 4: 
Tarextumab Inhibits Growth of Lu61 SCLC Tumors ................................23 
Figure 5: 
Notch Genes and Overall Survival ............................................................27 
Figure 6: 
PFS in Subjects Treated with Etoposide plus Cisplatin. from Noda et al..82 
Figure 7: 
PFS in Subjects Treated with Etoposide plus Cisplatin - Hanna ...............83 
Figure 8: 
Survival in Subjects Treated with Etoposide plus Cisplatin(from Noda 
et al.) ..........................................................................................................83 
Figure 9: 
Survival in Subjects Treated with Etoposide plus Cisplatin (from 
Hanna et al.) ...............................................................................................84 
Figure 10: 
Enrollment, Progressions and Deaths over Time – Control Hazard of 
Progression of 0.1386 Beyond 9 months ...................................................84 
  
LIST OF APPENDICES 
APPENDIX A: 
STUDY SCHEMA...................................................................................102 
APPENDIX B: 
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 1B ....103 
APPENDIX C  
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 2 .......108 
APPENDIX D: 
ECOG PERFORMANCE STATUS CRITERIA.....................................113 
APPENDIX E: 
RECIST CRITERIA 1.1 ..........................................................................114 
APPENDIX F: 
SAMPLE INFORMED CONSENT – Phase 1b ......................................120 
APPENDIX G: 
SAMPLE INFORMED CONSENT – Phase 2 ........................................143 
APPENDIX H: 
SAMPLE PHARMACOGENOMICS/DNA INFORMED CONSENT ..166 
APPENDIX I: 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..................171 
AMENDMENT 1: 
09 MAY 2013 ..........................................................................................171 
AMENDMENT 2: 
19 AUGUST 2013 ...................................................................................197 
AMENDMENT 3: 
23 OCTOBER 2013 .................................................................................218 
AMENDMENT 4: 
17 APRIL 2014 ........................................................................................231 
AMENDMENT 5: 
10 SEPTEMBER 2014 ............................................................................233 
AMENDMENT 6: 
22 APRIL 2016 ........................................................................................235 
  
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2.0
LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
aPTT 
activated partial thromboplastin time 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
absolute neutrophil count 
AST (SGOT) 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
AUC 
area under the curve 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CR 
complete response 
CRA 
clinical research associate 
CRF 
case report form 
CT 
computed tomography (scan) 
CTC 
circulating tumor cell 
CTCAE 
common toxicity criteria for adverse events (National Cancer Institute) 
D5W 
5% dextrose in water  
dL 
deciliter(s) 
DLT 
dose-limiting toxicity 
DSMB 
data safety monitoring board 
ECG 
electrocardiogram 
ECOG 
eastern cooperative oncology group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EP 
etoposide and platinum therapy (cisplatin or carboplatin) 
FACS 
fluorescent-activated cell sorting 
FFPE 
formalin-fixed, paraffin-embedded 
GI 
gastrointestinal 
GCP 
good clinical practice 
HIPAA 
health insurance portability and accountability act OF 1996 
IEC 
independent ethics committee 
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Abbreviation or Term 
Definition/Explanation 
IMP 
investigational medicinal product 
INR 
international normalized ration 
IRB 
institutional review board 
ITT 
intent-to-treat (population) 
L 
liter(s) 
LFT(s) 
liver function test(s) 
IV 
Intravenous 
IWRS  
Interactive Web-based randomization system 
Kg 
kilogram(s) 
Kaplan-Meier 
KM 
LD 
longest diameter (of a lesion), or limited disease 
LDH 
lactic dehydrogenase 
MedDRA 
medical dictionary for regulatory activities 
Mg 
milligram(s) 
Min 
minute(s) 
mL 
milliliter(s) 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCI 
national cancer institute 
NE 
not evaluable 
NOAEL 
no observed adverse effect level 
ORR 
overall response rate 
OS 
overall survival 
PCI 
prophylactic cranial irradiation 
PD 
progressive disease or pharmacodynamic 
PK 
pharmacokinetics 
PFS 
progression free survival 
PR 
partial response 
PVC 
polyvinyl chloride 
RECIST 
response evaluation criteria in solid tumors 
SAE 
serious adverse event 
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Abbreviation or Term 
Definition/Explanation 
SCLC 
small cell lung cancer 
SD 
stable disease 
SLD 
sum of longest diameter 
ULN 
upper limit of normal 
US 
Ultrasound 
WBRT 
whole brain radiation therapy 
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3.0
BACKGROUND 
3.1
Investigational Medicinal Product 
Investigational Medicinal Product is either tarextumab or Placebo. 
Tarextumab is a fully human IgG2 monoclonal antibody that inhibits the function of both Notch2 
and Notch3 receptors.  Tarextumab is supplied at a concentration of 10 mg/mL in 25-mL single-
use glass vial filled to 20 mL to deliver at total of 200 mg per vial.  Tarextumab vials must be 
stored at 2°C–8°C.  DO NOT FREEZE.  DO NOT SHAKE. 
Placebo is a formulation of 50mM Histidine, 100mM Sodium Chloride, 45mM Sucrose and 
0.01% (v/v) Polysorbate-20, pH 6.0.  Placebo will be handled the same way as tarextumab. 
3.2
Disease Background 
Small cell lung cancer (SCLC) comprises ~ 15% of the total cases of lung cancer in the US  
(Ref 1) and Europe.  At the time of diagnosis, approximately 30% of patients with SCLC will 
have tumors confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph 
nodes. These patients are designated as having limited-stage disease (LD) while patients with 
tumors that have spread beyond the supraclavicular areas are said to have extensive-stage disease 
(ED). SCLC is more responsive to chemotherapy and radiation therapy than other cell types of 
lung cancer; however, a cure is difficult to achieve because SCLC has a greater tendency to be 
widely disseminated by the time of diagnosis. Chemotherapy is the main treatment for ED-
SCLC.  Combination therapy with EP is considered the standard first line regimen and results in 
a high response rate (60-70%), but tumor recurrence after therapy is very common and the five 
year survival rate is only ~ 5% (Ref 2).  Development of new and effective therapies for this 
disease has been lacking, and consequently, there is a significant need to develop novel 
approaches for the treatment of SCLC.   
3.3
Nonclinical Data   
Many current cancer treatments, while producing an initial reduction in tumor burden, have not 
resulted in a long-term benefit.  A possible explanation for this observation is the presence of 
cancer stem cells (Ref 3, Ref 4), which represent a small percentage of the tumor, but are the 
most tumorigenic component driving growth and metastasis and are more resistant to traditional 
cytotoxic therapy, including both radiotherapy (Ref 5) and chemotherapy (Ref 6), than the 
remaining bulk of the tumor.  Like normal stem cells, cancer stem cells may be characterized by 
three properties:  self-renewal, the capacity to develop into multiple lineages, and the ability to 
proliferate extensively (Ref 7).  Cancer stem cells (CSCs) have been most extensively studied in 
hematologic malignancy, but have now also been identified in many solid tumors, including 
breast, colon, lung, head and neck, glioblastoma, and pancreatic cancers. CSCs rely on the 
activation of developmental pathways including the Notch pathway and several new therapies, 
including tarextumab, are being developed to target these pathways (Ref 8).  
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CONFIDENTIAL 
SCLC is characterized by expression of Notch receptors and Notch target genes indicating that 
the pathway is likely to be activated in this disease. OncoMed Pharmaceuticals has established a 
collection of patient derived xenografts, including several from small cell lung cancer patients, 
that retain much of the cellular heterogeneity of the patient’s tumor and which enable the pre-
clinical study of potential therapeutics in models that better represent the clinical setting than 
traditional xenografts from cell lines that have passaged in tissue culture (Ref 9). We have found 
that these xenograft models express various levels of Notch1, Notch2 or Notch3 as shown by 
immunohistochemistry. In addition, we have also shown elevated expression of various Notch 
target genes in SCLC including PBX1, HEYL, HEY2, and HES6 (data not shown). 
Additionally, we have tested the effects of anti-Notch2/3 (tarextumab) in eight SCLC patient 
derived models and tarextumab was found to be active in seven of these models (Table 1) 
Table 1: 
Summary of the Activity of Tarextumab in SCLC Xenografts 
SCLC Tumor 
Efficacy 
Lu40 
+ 
Lu61 
+ 
Lu65 
+ 
Lu66 
+ 
Lu67 
- 
Lu68 
+ 
Lu87 
+ 
Lu90 
+ 
SCLC patient derived xenografts were tested with tarextumab in combination with chemotherapeutic treatment. 
A “+” indicates a reduction in tumor volume by tarextumab plus chemotherapy (p < 0.05) relative to the group 
treated with chemotherapy alone. The asterisk indicates that tarextumab also exhibited single agent activity in 
Lu61.  
 
We also tested the activity of tarextumab in SCLC in a tumor recurrence experiment that was 
meant to recapitulate some of the clinical features of the response of SCLC to chemotherapeutic 
treatment.  Our initial tumor recurrence experiment was carried out in OMP-Lu68 tumors, a 
patient derived SCLC tumor which expresses Notch3 and Notch2, the targets of tarextumab. The 
experiment had two treatments phases – an “induction phase” where tumor bearing mice were 
treated with a high dose of chemotherapy with or without tarextumab and a “maintenance phase” 
where either tarextumab or control antibody treatments were continued. Established Lu68 lung 
tumors were treated with cisplatin or cisplatin plus tarextumab and it was observed that co-
administration of tarextumab with cisplatin led to an increased rate of tumor regression relative 
to cisplatin alone (Figure 1). Continued treatment with tarextumab during the maintenance phase 
significantly delayed the rate of tumor recurrence (Figure1).  
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CONFIDENTIAL 
A similar experiment was carried on the Lu87 SCLC xenograft model. In this case we used 
carboplatin plus irinotecan as the chemotherapeutic regimen. We found that tarextumab 
treatment led to a significant delay in tumor regrowth after the initial response to 
chemotherapeutic treatment Figure 2. The design of these pre-clinical tumor recurrence 
experiments was intended to model the PINNACLE trial design - combination of tarextumab 
plus chemotherapy followed by tarextumab only in the maintenance phase. Irinotecan was 
chosen as a chemotherapeutic agent for these pre-clinical studies because both irinotecan and 
etoposide are topoisomerase inhibitors and irinotecan is much better tolerated in mice than 
etoposide. Similarly, we have found that carboplatin is generally better tolerated than cisplatin in 
our pre-clinical studies. These data in Lu87 establish that tarextumab can be efficacious in 
combination with chemotherapeutic regimens that include carboplatin. Additional studies in 
several other SCLC tumors also showed that tarextumab was efficacious in combination with 
carboplatin (data not shown). In addition to these tumor recurrence experiments, we also found 
that tarextumab inhibited tumor growth in combination with Taxol in Lu40 SCLC tumors  
(Figure 3) and as a single agent in Lu61 SCLC tumors (Figure 4). 
Figure 1: 
Activity of Tarextumab in Lu68 SCLC Tumor Recurrence Model 
 
Legend:  Lu68 tumor cells were implanted in Nod-Scid mice and allowed to grow until the average tumor volume 
was ~ 250 mm3. Tumor bearing mice were randomized into two groups and treated with either cisplatin plus control 
antibody or cisplatin plus tarextumab. After three weeks, the cisplatin treatments were discontinued and the antibody 
treatment schedule was maintained. tarextumab was dosed at 40 mg/kg every two weeks and cisplatin was dosed at 
2.5 mg/kg twice per week. There were 10 animals per group. The mean + SEM for each group is shown.  
 
0
5
10 15 20 25 30 35 40 45 50 55
0
300
600
900
1200
1500
1800
Control Ab + cisplatin -> Control Ab
OMP-59R5 + cisplatin -> OMP-59R5
Antibodies
+ chemo
Abs only
Days
tumor volume (mm3)
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Tarextumab (OMP-59R5) 
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CONFIDENTIAL 
Figure 2: 
Activity of Tarextumab in 87 SCLC Tumor Recurrence Model in 
Combination with Carboplatin plus Irinotecan 
 
Legend:  Lu87 tumor cells were implanted in Nod-Scid mice and allowed to grow until the average tumor volume 
was ~ 180 mm3. Tumor bearing mice were randomized into two groups and treated with either carboplatin and 
irinoecan plus control antibody or carboplatin and irinotecan plus tarextumab. After three weeks, the carboplatin and 
irinotecan treatments were discontinued and the antibody treatment schedule was maintained. Tarextumab was 
dosed at 40 mg/kg every two weeks. Carboplatin and irinotecan were dosed at 20 mg/kg once per week for the first 
two week and 10 mg/kg once per week for the third dose. There were 8 animals per in control group and seven 
animals in the 59R5. The mean + SEM for each group is shown.  
Figure 3: 
Tarextumab Inhibits Growth of Lu40 SCLC Tumors in Combination 
with Taxol 
 
Legend:  Lu40 tumor cells were implanted in Nod-Scid mice and allowed to grow until the average tumor volume 
was ~ 150 mm3. Tumor bearing mice were randomized into four groups (n = 10 per group) and treated with either 
Control Ab, tarextumab, Taxol, or the combination of tarextumab and Taxol. Tarextumab was dosed at 40 mg/kg 
every two weeks and Taxol was dosed at 10 mg/kg once per week. Tumor measurements were taken on the 
indicated days and the mean + SEM for each group is shown. 
 
0
10
20
30
40
50
60
70
0
300
600
900
1200
1500
OMP-59R5 + carbo/irino->OMP-59R5
Control Ab + carbo/irino->Control Ab
 Abs +
chemo
 Abs only
Days
tumor volume (mm3)
 
0
5
10
15
20
25
30
0
200
400
600
800
1000
Control Ab
OMP-59R5
Taxol
OMP-59R5 + Taxol
Days
tumor volume (mm3)
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Figure 4: 
Tarextumab Inhibits Growth of Lu61 SCLC Tumors 
 
Legend:  Lu61 SCLC tumor cells were implanted in Nod-Scid mice and allowed to grow until the average tumor 
volume was ~ 150 mm3. Tumor bearing mice were randomized into two groups (n = 10 per group) and treated with 
either Control Ab or tarextumab. Tarextumab was dosed at 40 mg/kg every two weeks. Tumor measurements were 
taken on the indicated days and the mean + SEM for each group is shown. 
Summary 
Collectively, our data show that inhibiting Notch signaling with tarextumab results in anti-tumor 
activity in several SCLC xenografts. Importantly, tarextumab treatment can increase response to 
chemotherapy treatment and delay tumor re-growth after initial tumor shrinkage in response to 
chemotherapy. Given the urgent need for new therapeutic options for treatment of SCLC, we 
plan to explore the utility of this antibody in clinical testing in SCLC in combination with 
chemotherapy.  
3.4
Clinical Background 
The first-in-human clinical trial of tarextumab (Study 59R5-001) began with a single-agent 
multiple dose escalation study in subjects with solid tumors.  Subjects were treated in escalating 
dose cohorts of 0.5, 1, 2.5, and 5 mg/kg administered IV weekly.  Additionally, escalating dose 
cohorts of 5, 7.5, and 10mg/kg administered IV every other week, and 7.5mg/kg every three 
weeks were tested as well.  
As of April 25, 2013, a total of forty-two subjects have been treated in Study 59R5-001: three at 
0.5 mg/kg weekly, three at 1 mg/kg weekly, six at 2.5 mg/kg weekly, nine at 5 mg/kg weekly, six 
at 5 mg/kg every other week, six at 7.5mg/kg every other week, three at 10 mg/kg every other 
week, and six at 7.5mg/kg every three weeks. 
 
0
5
10
15
20
25
30
35
0
200
400
600
800
1000
Control Ab
OMP-59R5
Days
tumor volume (mm3)
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Two DLTs occurred in two of nine subjects treated at 5 mg/kg weekly: one Grade 3 hypokalemia 
secondary to Grade 3 diarrhea in one subject and one Grade 3 diarrhea in another subject, which 
led to the MTD for weekly dosing schedule to be 2.5 mg/kg.  No DLTs occurred in 6 subjects 
treated at 7.5 mg/kg every three weeks that led to the MTD for every three week schedule to be 
7.5 mg/kg.  Two DLTs both Grade 3 diarrhea, occurred in two of three subjects treated with a 
single dose of tarextumab at 10 mg/kg every other week and no DLTs occurred in 6 subjects 
treated at 7.5 mg/kg every other week, which led to the MTD for every other week schedule to 
be 7.5 mg/kg every other week. 
Toxicities observed to date have been mostly Grades 1 and 2, and were manageable with 
supportive care and/or interruption or dose reduction of tarextumab.  There were no AEs of a 
Grade 4 severity reported.  AEs with a severity of Grade 3 were uncommon and have been 
primarily diarrhea.  
Diarrhea has been the most common adverse event, occurring in 81% (34 of 42) of subjects 
treated on the study regardless of schedule, which was expected based on the observance of 
diarrhea in the cynomolgus monkey toxicology study.  Diarrhea was observed at 2.5 mg/kg 
weekly and above dose cohorts, and was dose dependent.  Table 2 below tabulates the incidence 
and worse severity of diarrhea occurred while receiving tarextumab among dose levels according 
NCI-CTCAE criteria v4.02.   
Table 2: 
Study 59R5-001:  Worse Grade Treatment Related Diarrhea 
(N=34/42) 
Diarrhea 
Grade 
0.5 mg/kg  
QW  
(n=2/3) 
1 mg/kg  
QW  
(n=0/3) 
2.5 mg/kg 
QW  
(n=6/6) 
5 mg/kg 
QW  
(n=8/9) 
5 mg/kg 
QoW  
(n=4/6) 
10 mg/kg 
QoW 
(n=3/3) 
7.5 mg/kg 
Q3W 
(n=5/6) 
7.5 mg/kg 
QoW 
(n=6/6) 
1 
1 
- 
3 
4 
3 
- 
4 
3 
2 
1 
- 
3 
2 
- 
- 
1 
3 
3 
- 
- 
- 
2 
1 
3 
- 
 
 
Additional common treatment-related adverse events included (as of November 17, 2012 data 
cutoff with 39 subjects treated) fatigue (30.8%), nausea (28.2%), decreased appetite (17.9%), 
vomiting (15.4%), increased alanine transaminase (ALT) (10.3%), hypokalemia (15.4 and 
dizziness (10.3%). 
Table 2 and Table 3 summarize all treatment related CTC Grade 3 adverse events that occurred 
in Study 59R5-001 by body system as of November 17, 2012; there were no Grade 4 or 5 events 
on study. 
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Table 3: 
Study 59R5-001: Grade 3 Treatment Related Adverse Events by Body 
System (N=39) 
Body System  
Preferred Term 
Number of Subjects 
Gastrointestinal Disorders 
Diarrhea 
6 (15.4%) 
Blood and Lymphatic System Disorders 
Anemia 
2 (5.1%) 
Investigations 
Alanine Aminotransferase 
Increased  
Aspartate Aminotransferase 
Increase 
1 (2.6%) 
1 (2.6%) 
Metabolism and Nutrition Disorders 
Hypokalaemia 
2 (5.1%) 
General Disorders and Administration Site 
Conditions 
Fatigue 
1 (2.6%) 
 
No RECIST complete or partial responses have been noted on this Phase 1 study.  However, six 
subjects have had RECIST stable disease (SD) lasting greater than 56 days (ranging from 
61 days to 165 days, all of them have come off the study).  
As of November 17, 2015, twenty seven subjects have been treated in the current study 
(Study 59R5-003): three, three, six, three and six each at 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 12.5 
mg/kg and 15 mg/kg dose cohorts respectively with etoposide and cisplatin; one DLT of Grade 3 
nausea was reported from a subject at 10 mg/kg dose cohort that lasted more than 48 hours 
despite daily IV fluids and antiemetics. The dose cohort of 10 mg/kg was expanded to enroll a 
total of 6 subjects. 15 mg/kg of tarextumab was the highest dose tested in Phase 1b and was 
selected for the Phase 2 portion of the study.  To establish the safety and tolerability of this 
selected dose, tarextumab 15 mg/kg was administered in combination with etoposide and 
cisplatin to a cohort of 6 subjects.  An additional 6 subjects were treated with tarextumab 
15 mg/kg in combination with etoposide and carboplatin.  As of April 19, 2016 a total of 119 
subjects have been treated in Study 59R5-003 Phase 2 portion.  4 of these subjects have been 
treated with tarextumab 15 mg/kg or placebo in combination with etoposide and cisplatin and 
115 subjects have been treated with tarextumab 15 mg/kg or placebo in combination with 
etoposide and carboplatin.  
 
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CONFIDENTIAL 
Tarextumab has been studied in a Phase 1b/2 study in combination with nab-paclitaxel and 
gemcitabine in subjects with previously untreated stage IV pancreatic cancer (Study 59R5-002, 
ALPINE).  The study was initially conducted in combination with gemcitabine alone and was 
amended to incorporate nab-paclitaxel into the chemotherapy backbone in response to the 
changes in standard of care in this disease population.  As of November 17, 2015, forty subjects 
have been treated in Phase 1b of Study 59R5-002:  five and four at 2.5 mg/kg and 5.0 mg/kg 
respectively every other week in combination with gemcitabine at 1000 mg/m2 on Days 1, 8 and 
15 of every 28 day cycle, four, six, six, three  and twelve at 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 12.5 
mg/kg and 15 mg/kg respectively every other week in combination with nab-paclitaxel at 125 
mg/m2 and gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle.  No DLTs 
have been reported in the first 35 subjects. Dose escalation stopped at tarextumab 15 mg/kg as 
the highest dose tested in Phase 1b portion of the study.  Tarextumab 15 mg/kg dose cohort was 
then expanded with 5 additional subjects treated, one of which had Grade 3 diarrhea that lasted 
for 5 days during the first cycle. Overall, tarextumab in combination with nab-paclitaxel and 
gemcitabine continued to be well tolerated up to 15 mg/kg.  15 mg/kg has been selected as the 
Phase 2 dose in ALPINE study.  As of November 17, 2015, 177 subjects have been randomized 
with 172 subjects treated in Phase 2 portion of Alpine study.  
To date, tarextumab has been well tolerated up to 15 mg/kg.  Among the 356 subjects treated 
through 17 November 2015, 23 (6.5%) subjects discontinued tarextumab/placebo treatment due 
to AEs, regardless of relationship.  Toxicities observed to date have been mostly Grades 1 and 2, 
and manageable with supportive care and/or interruption or dose reduction of tarextumab.  The 
most common (occurring in 25% of subjects) treatment emergent events are diarrhea (62.6%), 
nausea (49.2%), thrombocytopenia (45.2%), neutropenia (26.7%), anemia (48%), vomiting 
(31.5%), fatigue (57.0%) and decreased appetite (28.7%).  The most common (occurring in 
 25% of subjects) treatment related events are diarrhea (53.1%), fatigue (41.6%), 
thrombocytopenia (26.7%) and nausea (27.2%).  Adverse events with a severity of Grade 3 that 
were considered related were uncommon and have been primarily diarrhea (9.6%), anemia 
(12.1%), thrombocytopenia (10.1%), neutropenia (7.6%) and fatigue (7.6%).  Please refer to the 
updated Investigator Brochure for more details. 
Exploratory Phase 1b Biomarker Data 
Exploratory biomarker data from the phase1b portion of the PINNACLE study shows a trend of 
improved outcome in patients with high Notch target genes i.e. Hes1, Hey2, Hey1 and Hes6 in 
the 12.5 mg/kg and 15 mg/kg cohorts. 
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CONFIDENTIAL 
Figure 5: 
Notch Genes and Overall Survival 
 
Legend: Notch genes and overall survival. Expression of Notch3 gene levels and Notch target genes (Hes1, Hey2, 
Hey1, Hes6) was measured in FFPE tissues from 19 patients in the Phase1b portion of the trial. Biomarker 
high vs. low was set at a 50th percentile.  Red lines include patients in the 5, 7.5, and 10 mg/kg cohorts and blue 
lines indicate patient in the 12.5 and 15 mg/kg cohorts.  
 
3.5
Dose Rationale 
Treatment with EP is the standard of care for subjects with untreated extended stage small cell 
lung cancer.  The most common AE of tarextumab is diarrhea, whereas cytopenia and 
nephrotoxicity (with cisplatin) are the most common adverse event with EP administration.  
Therefore, the most common AEs of tarextumab and EP do not overlap, providing the 
justification for investigating this combination in the study.  The initial dose escalations of 
tarextumab will be conducted with etoposide and cisplatin.  Subjects enrolled in this study will 
receive a starting dose of 5 mg/kg of tarextumab once every three weeks, which is one dose 
below the MTD of 7.5 mg/kg every three weeks in Study 59R5-001.  Dose escalation will be 
2.5 mg/kg per increment and will not exceed an tarextumab dose of 15 mg/kg. 15 mg/kg is twice 
of the single agent MTD of 7.5 mg/kg every three weeks established in Study 59R5-001 and 
pharmacodynamics modulation of the notch pathway was seen at 1 mg/kg above in tumor 
biopsies and surrogate tissues in Study 59R5-001, and at 7.5 mg/kg above in hair follicles in 
Study 59R5-002(Investigator Brochure Edition 04 dated January 15, 2014).   
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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 highest tolerable dose in 
combination with etoposide and carboplatin.  Once the safety and tolerability of tarextumab at 
this dose is confirmed with etoposide and cisplatin/carboplatin, the protocol will explore 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 extensive stage small cell lung cancer. 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.  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 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 will be administered by IV infusion at a dose of 
100 mg/m2 on Days 1, 2, and 3 of every 21-day cycle.  Cisplatin will be administered by IV 
infusion at a dose of 80 mg/m2 in Phase 1b and 75 mg/m2 in Phase 2 portion of the study or 
carboplatin at AUC of 5 mg/mL•min on Day 1 of every 21-day cycle.  This is the dose regimen 
for etoposide and platinum therapy commonly used in first line treatment for extensive stage 
small cell lung cancer.  tarextumab has an estimated apparent half-life of 2 to 3 days at 7.5 mg/kg 
in Study 59R5-001, subjects will not receive PCI within 2 weeks of study drug administration 
and will not receive tarextumab during the radiation to alleviate any potential interaction 
between the study drug and the radiation.  Therefore, risks and potential benefits of participation 
have been appropriately mitigated for this patient population. 
3.6
Study Conduct 
This study will be conducted in compliance with the protocol approved by the Institutional 
Review Board (IRB) or Independent Ethics Committee (IEC), and in accordance with Good 
Clinical Practice (GCP) standards and all applicable regulatory requirements.  No deviation from 
the protocol will be implemented without the prior review and approval of the IRB/IEC except 
where it may be necessary to eliminate an immediate hazard to a research subject.  In such a 
case, the deviation will be reported to the IRB or IEC as soon as possible. 
3.7
Subject Population 
Subjects must be at least 18 years of age, have adequate organ and marrow function, have an 
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, have untreated 
extensive stage small cell lung cancer, and FFPE tumor tissue, either archived or fresh core 
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CONFIDENTIAL 
needle biopsied for Notch3, Hes1, Hey2, Hey1 and Hes6 analysis.  Additionally for the Phase 2 
portion of the study, subjects must have evidence of measurable disease by RECIST 1.1 criteria. 
4.0
STUDY OBJECTIVES AND ENDPOINTS 
4.1
Study Objectives 
Primary Objectives: 
•
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 AUC of 5 mg/mL•min on Day 1  in subjects with untreated 
extensive stage small cell lung cancer (Phase 1b 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 extensive stage small cell lung cancer (Phase 2 portion) 
Secondary Objectives: 
•
To determine the pharmacokinetics of tarextumab in combination with EP in subjects 
receiving first-line therapy for extensive stage small cell lung cancer (Phase 1b and 2 
portions) 
•
To determine the immunogenicity of tarextumab in combination with EP in subjects 
receiving first-line therapy for extensive stage small cell lung cancer (Phase 1b and 2 
portions) 
•
To estimate the improvement in overall survival (OS), 12 months OS, and the overall 
response rate (ORR) resulting from the addition of tarextumab to EP in subjects receiving 
first-line therapy for extensive stage small cell lung cancer (Phase 2 portion) 
•
To correlate the treatment effect in PFS, OS, 12 month OS and the ORR resulting from the 
addition of tarextumab to EP in subjects with Notch 3,  Hey2, Hes1, Hey1 and Hes6 
expression (Phase 2 portion) 
•
To determine the safety and tolerability of tarextumab in combination with EP in subjects 
who are receiving first-line therapy for extensive stage small cell lung cancer (Phase 1b 
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 extensive stage small cell lung 
cancer with Phase 2 portion) 
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CONFIDENTIAL 
Exploratory Objective: 
•
To describe the changes in exploratory pharmacodynamic (PD) biomarkers, including Notch 
pathway related genes and proteins and circulating tumor cells following tarextumab 
treatment. (Phase 1b and 2 portions) 
5.0
OVERALL STUDY DESIGN AND PLAN DESCRIPTION 
The study consists of a Phase1b 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 progression of disease.  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 explore 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 extensive stage small 
cell lung cancer. 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 1 b and 75 mg/m2 for Phase 2 portion of the study or carboplatin at 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.   
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. 
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5.1
Phase 1b Portion 
The Phase 1b portion is to determine the MTD of tarextumab in combination with etoposide and 
cisplatin/carboplatin in subjects with previously untreated extensive stage small cell lung cancer.  
Initially, cohorts of 3 to 6 subjects with previously untreated extensive stage small cell lung 
cancer will be enrolled sequentially into successively higher tarextumab dose level in 
combination with etoposide 100 mg/m2 on Days 1, 2 and 3 and cisplatin 80 mg/m2 on Day 1 of 
every 21-day cycle for 6 cycles.  The starting dose of OMP59R5 is 5 mg/kg.  Dose escalation 
will be 2.5 mg/kg per increment and will not exceed an tarextumab dose of 15 mg/kg.  Subjects 
at each dose level will be treated and observed for DLT through the end of the first cycle (21 
days).  Each subject will participate in only 1 cohort.  Once the highest tolerable dose is 
determined with tarextumab in combination with etoposide and cisplatin, a cohort of 6 subjects 
will be treated at this dose with etoposide and carboplatin to confirm the safety and tolerability of 
this dose with etoposide and carboplatin. Carboplatin will be given at AUC of 5 mg/mL•min on 
Day 1 of every 21- day cycle for 6 cycles in combination with etoposide 100 mg/m2 on Days 1, 
2, and 3.  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.  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.  For subjects 
who have tarextumab 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 prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study 
entry and are good candidates for PCI per the Investigators should receive PCI within 8 weeks 
after the last dose of chemotherapy at a total dose of 25 Gy in 10 fractions.  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.  Tarextumab 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 tarextumab alone 14 days after completion of PCI, 
until disease progression or unacceptable treatment-related toxicities or withdrawal of consent  
(Appendix A).  Subjects will discontinue study treatment if there is evidence of central nervous 
system (CNS) metastasis.   
Approximately 30 subjects will be enrolled into Phase 1b portion of the study, the exact number 
will depend on the number of dose levels assessed and the toxicities observed. 
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5.2
Dose Limiting Toxicity 
Adverse events will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 4.02 (see Study Reference Binder).  
Doselimiting- toxicity (DLT) is defined as either of the following tarextumab treatment-related 
toxicities occurring within the first 21 days (Cycle 1): 
•
 Grade 3 non-hematologic toxicity except for Grade 3 electrolyte disturbances that respond 
to correction within 24 hours, or Grade 3 rash, diarrhea, nausea, vomiting, and mucositis that 
responds to standard medical supportive care within 48 hours; 
•
Grade 3 thrombocytopenia associated with Grade 2 hemorrhage or any Grade 4 
thrombocytopenia; 
•
Grade 4 neutropenia lasting >7 days  
•
Grade 3 or 4 neutropenia of any duration associated with fever ≥ 38.3°C (101°F); 
•
Grade 4 anemia; 
•
Any clinically significant toxicity that occurs during the first 21 days or beyond Day 21 that 
in the judgment of the Investigators and Sponsor is dose-limiting. 
5.3
Dose Escalation Plan 
Initially, cohorts of 3 to 6 evaluable subjects with previously untreated extensive stage small cell 
lung cancer will be enrolled sequentially into successively higher tarextumab dose level in 
combination with etoposide 100 mg/m2 on Days 1, 2 and 3, and cisplatin 80 mg/m2 on Day 1 of 
every 21-day cycle for 6 cycles.  Subjects at each dose level will be treated and observed for 
DLT through the end of the first cycle (21 days) to be considered evaluable for DLT 
determination.  Each subject will participate in only 1 cohort.   
The starting dose of tarextumab is 5 mg/kg on Day 1 of each 21-day cycle.  The subsequent dose 
level will be increased in 2.5 mg/kg increments (i.e., 7.5 mg/kg, 10 mg/kg, etc) until the MTD is 
reached but will not exceed an tarextumab dose of 15 mg/kg.  Dose escalation will only proceed 
if no DLT is observed in a cohort of at least 3 subjects after discussion and agreement between 
the participating Investigators and Sponsor’s Medical Monitor.   
If a DLT is observed in only 1 subject in a cohort of 3 subjects, an additional 3 subjects may be 
enrolled up to a total of 6 subjects at this dose level.  Dose escalation will then proceed only if no 
more than 1 subject in the cohort of six subjects has experienced a DLT during the first cycle of 
treatment and after discussion and agreement between the participating Investigators and 
Sponsor’s Medical Monitor.   
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If a DLT is observed in 2 or more subjects in a cohort of 3 or 6 subjects, an additional 3 subjects 
will be enrolled for a total of 6 subjects at the previous lower dose level, if only 3 subjects were 
treated at that lower dose level.  The Investigators and Sponsor, after their safety review, may 
elect to study a dose level that is intermediate to the current dose level and the next lower dose 
level previously studied, e.g. 6 mg/kg as an intermediate dose between 5 mg/kg and 7.5mg/kg.  
The level of dose de-escalation and a decision to go to an intermediate dose level will be 
determined after discussion between the participating Investigators and Sponsor’s Medical 
Monitor prior to dose escalation.  If a DLT is observed in 2 or more subjects in a cohort of 3 to 
6 subjects treated with the starting dose of 5 mg/kg, a new cohort of 3 to 6 subjects will be 
enrolled at either 2.5 mg/kg or an intermediate dose level between 2.5 mg/kg and 5 mg/kg.  
Table 4 below provides a summary of the dose escalation decision rules for determination of the 
MTD. 
5.4
Maximum Tolerated Dose 
The MTD is defined as the highest dose level of tarextumab at which no more than 1 out of 
6 subjects experiences DLT during the first cycle (21 days) of therapy with etoposide and 
cisplatin.  Dose escalation will not continue beyond 15 mg/kg of tarextumab.  Table 4 provides a 
summary of the dose escalation decision rules for determination of the MTD. 
Table 4: 
Maximum Tolerated Dose Determination and Cohort Expansion 
Number of Subjects per Cohort With 
a DLT During Cycle 1 (Days 1 to 21) 
Dose Escalation Decision Rule 
0 out of 3 
Enter at least 3 subjects at the next dose level. 
1 out of 3 
Enter up to 3 more subjects at this dose level. 
If none of the 3 additional subjects has a DLT, proceed to the 
next dose level. 
If 1 or more of the 3 additional subjects has a DLT, then dose 
escalation will be stopped, and the MTD will have been 
exceeded.  Up to 3 additional subjects may be entered at a lower 
dose level if only 3 subjects were treated previously at that dose 
or a new cohort of 3 subjects at an intermediate dose level may 
be evaluated. 
≥2 
Dose escalation will be stopped, and the MTD will have been 
exceeded.  Up to 3 additional subjects may be entered at a lower 
dose level if only 3 subjects were treated previously at that dose 
or a new cohort of 3 subjects at an intermediate dose level may 
be evaluated. 
≤1 out of 6 at the highest dose 
evaluated. 
This is generally the MTD.   
Abbreviations:  DLT = dose limiting toxicity; MTD = maximum tolerated dose. 
 
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All participating sites are required to send in DLT Notification Forms within 24 hours of 
learning of the event.  Participating investigators and the Sponsor’s Medical Monitor will review 
study drug-related toxicities from the current dose before escalating to the next dose.  
Once the highest tolerable dose is determined with tarextumab in combination with etoposide 
and cisplatin with 15 mg/kg as the highest dose of tarextumab being tested, a cohort of 6 subjects 
will be treated at this dose with etoposide and carboplatin (AUC 5 mg/mL•min on on Day 1 of 
every 21-day cycle for 6 cycles) to confirm the safety and tolerability of this dose with etoposide 
and carboplatin before commencing the Phase 2 portion of the study.  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.  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 portion of the study. 
5.4.1
Follow-Up 
Subjects who discontinue study treatment for any reason other than disease progression will be 
followed with tumor assessment every 6 weeks/42 days (±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. 
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5.5
Phase 2 Portion 
Phase 2 portion may commence after the safety and tolerability of the highest tolerable dose of 
OMP 59R5 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 portion of the study.  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 extensive stage small cell 
lung cancer.  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). 
5.5.1
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 or prophylactic cranial irradiation).  Alteration to the 
choice of platinum therapy is not permitted once the subject is randomized. Treatment for each 
subject will begin on Study 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 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. 
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After the completion of 6 cycles of EP, subjects who do not have disease progression and have 
not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study 
entry and are good candidates for PCI per the Investigators 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 Investigators, PCI can be initiated at the time that is determined 
appropriated per 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  
(Appendix A).  Subjects will discontinue study treatment if there is evidence of central nervous 
system (CNS) metastasis.   
5.5.2
Follow-up  
Subjects who discontinue study treatment for any reason other than disease progression will be 
followed with tumor assessment every 6 weeks/42 days (±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. 
6.0
SELECTION OF STUDY POPULATION 
6.1
Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for the study: 
1. Histologically or cytologically documented extensive stage small cell lung cancer (combined 
small cell carcinoma is allowed); extensive stage is defined as disease beyond the ipsilateral 
hemithorax, including malignant pleural or pericardial effusion or hematogenous metastases 
(contralateral mediastinal and ipsilateral supraclavicular lymphadenopathy are generally 
classified as limited disease).   
2. Adults of 18 years of age or older. 
3. Performance Status (ECOG) of 0 or 1. 
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4. FFPE tumor tissue, either fresh core needle biopsied (two fresh cores preferred whenever 
possible), or archived available for Notch3, Hes1, Hey2, Hey1 and Hes6 analysis.   
5. Adequate organ function: 
a.
Adequate hematologic function (absolute neutrophil count [ANC]  1,500 cells/ȝL; 
hemoglobin  9 g/dL, platelets  100,000/ȝL). 
b. Adequate renal function (serum creatinine  1.5 mg/dL or calculated creatinine clearance 
 60 mL/min using Cockroft Gault formula). 
c.
Adequate hepatic function (alanine aminotransferase [ALT]  3 x upper limit of normal 
[ULN], ALT may be  5 x ULN if due to liver metastases but cannot be associated with 
concurrent elevated bilirubin > 1.5xULN unless it is approved by the Sponsor’s Medical 
Monitor). 
d. Prothrombin Time (PT)/International Normalized Ration (INR)  1.5 × ULN, activated 
partial thromboplastin time (aPTT)  1.5 × ULN. 
6. Written consent on an IRB/IEC-approved Informed Consent Form prior to any study-specific 
evaluation. 
7. For women of child-bearing potential, negative serum pregnancy test at screening and use of 
physician-approved method of birth control from 30 days prior to the first study drug 
administration to 30 days following the last study drug administration or the last EP in the 
study, whichever is discontinued last. 
8. Male subjects must be surgically sterile or must agree to use physician-approved 
contraception during the study and for 30 days following the last study drug administration or 
the last EP in the study, whichever is discontinued last. 
Additionally, for individuals eligible to participate in Phase 2 portion of the study: 
9. Subject must have evidence of measurable disease per RECIST 1.1 criteria. 
6.2
Exclusion Criteria 
Subjects who meet any of the following criteria will not be eligible for participation in the study: 
1. Limited stage small cell lung cancer appropriate for radical treatment with chemoradiation. 
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2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed extensive 
stage small cell lung cancer. Exceptions to this exclusion criterion include: 1) prophylactic 
cranial irradiation or whole brain radiation (WBRT) prior to the first administration of study 
drug provided that the subject has stable neurologic condition for at least 2 weeks after the 
completion of the radiation, adverse event that is related to the radiation has recovered to be 
 Grade 1, and is not requiring corticosteroid of > 40 mg prednisone daily equivalent dose to 
control the symptoms, 2) focused radiation for symptomatic relief for isolated bone 
metastases; 3) bisphosphonate or denosumab therapy for bone metastasis initiated prior to 
study entry. 
3. Presence of uncontrolled Grade  1 diarrhea within 4 weeks prior to the first study drug 
administration. 
4. Presence of any serious or uncontrolled illness including, but not limited to:  ongoing or 
active infection, symptomatic congestive heart failure unstable angina pectoris, uncontrolled 
cardiac arrhythmia, uncontrolled arterial thrombosis, symptomatic pulmonary embolism, and 
psychiatric illness that would limit compliance with study requirement. 
5. History of myocardial infarction, acute coronary syndromes (including unstable angina), 
coronary angioplasty and/or stenting within 6 months prior to the first administration of study 
drug. 
6. A history of malignancy with the exception of: 
a. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ 
cervical cancer 
b. Superficial bladder cancer 
c. Adequately treated stage I cancer from which the subject is currently in remission, or  
d. Any other cancer from which the subject has been disease-free for  3 years 
7. Known human immunodeficiency virus (HIV) infection. 
8. Females who are pregnant or breastfeeding. 
9. Concurrent use of therapeutic warfarin (prophylactic low dose of warfarin, i.e., 1 mg daily 
for port catheter is allowed) 
Additionally, individuals ineligible to participate in Phase 2 portion of the study if: 
10. Subjects have relapsed after treatment for limited disease 
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6.3
Removal of Subjects from Study Treatment 
Each subject has the right to withdraw from the study at any time without prejudice to further 
treatment.  The Investigator must withdraw from the study any subjects who request to be 
withdrawn.  A subject’s participation in the study may be discontinued at any time at the 
discretion of the Investigator and in accordance with his/her clinical judgment.  When possible, 
tests and evaluations listed for the treatment termination visit should be carried out 
approximately 4 weeks after the last administration of tarextumab or Placebo, etoposide, or 
platinum therapy, whichever is discontinued last, but before the initiation of new anti-cancer 
therapy.  The sponsor must be notified of all subjects’ withdrawals as soon as possible.  The 
sponsor also reserves the right to discontinue participation by an individual Investigator or site 
for poor enrollment or noncompliance.  If a subject fails to return for scheduled visits, a 
documented effort must be made to determine the reason.  If the subject cannot be reached by 
telephone after 2 attempts, a certified letter should be send to the subjects requesting contact with 
the Investigator.  This information should be recorded in the study records. 
Prior to enrollment into the study, the Investigator or designee must explain to each subject, that 
the subject’s protected health information obtained during the study may be shared with the 
study sponsor, regulatory agencies, and IRB/EC in order to analyze and evaluate study results.  It 
is the Investigator’s responsibility to obtain written permission to use protected health 
information per country-specific regulations.  If permission to use protected health information is 
withdrawn, it is the Investigator’s responsibility to obtain a written request, to ensure that no 
further data will be collected from the subject and the subject will be removed from the study. 
Subjects may terminate study treatment due to: 
•
Disease progression  
•
Initiation of new anti-cancer therapy including surgical resection of tumor, palliative 
radiation (prophylactic cranial irradiation, according to standard of care, is permitted for 
subjects who are without progression following 6 cycles of etoposide and cisplatin treatment; 
subjects may have prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) 
prior to study entry) and/or a new systemic anti-cancer therapy. 
•
Initiation of a new intravenous bisphosphonate or denosumab more than 30 days after the 
first administration of study drug  
•
Development of toxicity that, in the Investigator’s judgment, precludes further study 
participation 
•
Significant protocol violations or noncompliance on the part of the subject or Investigator 
•
Discontinuation is in the subject’s best interest and/or in the judgment of the Investigator 
•
Lost to follow-up 
•
Pregnancy 
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6.4
Subject Identification and Replacement of Subjects 
Each subject will be assigned a unique subject identifier.  This unique identifier will be on all 
electronic case report form (eCRF) pages.  In Phase 1b, subjects who withdraw from the study 
prior to completing Day 21 of Cycle 1 for reasons other than study drug-related toxicities will be 
replaced.  In Phase 2, subjects who are randomized, but not dosed, will not be replaced.  
However, enrollment in the study will continue until 135 subjects are randomized and treated. 
7.0
TREATMENT OF SUBJECTS 
Subjects will be given study drug in combination with EP. 
Study drug will be tarextumab in the Phase 1b portion, and either tarextumab or Placebo in the 
Phase 2 portion.  Study drug will be administered by IV infusion on Day 1 of every 21-day cycle.  
The subject should not take two consecutive doses of study drug within 18 days.  
Etoposide will be administered by IV infusion at a dose of 100 mg/m2 over 30 to 60 minutes on 
Days 1, 2 and 3 of each 21-day treatment cycle for 6 cycles in accordance with institutional 
standard of care.  The subject should not receive two Day 1 consecutive doses of etoposide 
within 18 days.  A one day window will be allowed for each consecutive day of etoposide dosing 
(e.g. Day 2 and 3 dosing may occur on Day 3 and 4, or Day 3 and 5). 
Cisplatin or carboplatin will be the choice of platinum therapy.  Initially, all subjects in Phase 1b 
will receive cisplatin until the MTD/highest tolerable dose is determined with tarextumab in 
combination with etoposide and cisplatin.  After that, a cohort of 6 subjects will be enrolled to 
receive tarextumab at the MTD/highest tolerable dose with etoposide and carboplatin.  Subjects 
in Phase 2 will receive cisplatin or carboplatin as determined by the Investigator prior to 
randomization. 
Cisplatin will be administered by IV infusion at a dose of 80 mg/m2 over 30 minutes to 2 hours 
on Days 1 of each 21-day treatment cycle for 6 cycles in accordance with institutional standard 
of care in Phase 1b and at 75 mg/m2 in Phase 2 portion of the study.  The subject should not 
receive two cisplatin doses within 18 days. 
Carboplatin will be administered by IV infusion at a dose of AUC of 5 mg/mL•min over 
15 minutes or longer on Days 1 of each 21-day treatment cycle for 6 cycles in accordance with 
institutional standard of care.  The subject should not receive two carboplatin doses within 
18 days. 
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On days when study drug is given together with etoposide and cisplatin/carboplatin, study drug 
should be given prior to etoposide and cisplatin/carboplatin administration.  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. If tarextumab held or discontinued, subjects will 
continue to receive etoposide on days 1, 2, and 3, and platinum therapy on day 1 of each 21-day 
cycle for a total 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 prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study 
entry and are good candidates for PCI per the Investigators 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 Investigators, PCI can be initiated at the time that is determined 
appropriated per 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 (Appendix A).   
Subjects will discontinue study treatment if there is evidence of central nervous system (CNS) 
metastasis.   
The baseline weight should be used to calculate the total dose (mg) of the study drug, etoposide, 
and cisplatin throughout the study, unless the weight changes by >10%, in which case the current 
weight should be used to calculate the dose. 
In the absence of subjects meeting any of the withdrawal criteria (see Section 6.3), they may 
receive study treatment for up to 1 year at the discretion of the Investigator and beyond 1 year 
with the agreement of the Investigator and the Sponsor. 
7.1
Study Drug (tarextumab or Placebo) 
7.1.1
Study Drug Administration 
Please refer to the Pharmacy Manual for the details on tarextumab or Placebo preparation and 
administration.    
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CONFIDENTIAL 
There is no provision for intra-subject dose escalation of study drug.  Weight-based doses will 
not be recalculated unless there is a weight change 10%. Carboplatin dose needs to be 
recalculated in subjects who have  10% weight change from baseline. If a semipermanent 
peripheral or central line is used to administer the drug, the catheter should be flushed per 
institutional standard procedures prior to and at the end of each infusion and the line should NOT 
be used for blood draws when there is a post-dose PK sampling.  On days when study drug is 
given together with etoposide and platinum therapy, study drug should be given prior to 
etoposide and platinum therapy administration.   
7.1.2
Study Drug Description 
Tarextumab is an IgG2 fully human monoclonal antibody that is directed against the 
Notch2/3 receptors.   
Tarextumab is a clear to opalescent, colorless to slightly yellow liquid and is supplied at a 
concentration of 10 mg/mL in 25-mL single-use glass vial filled to 20 mL to deliver at total of 
200 mg per vial.   
Placebo is a clear to slightly opalescent, colorless to slightly yellow liquid formulation of 50mM 
Histidine, 100mM Sodium Chloride, 45mM Sucrose and 0.01% (v/v) Polysorbate-20, pH 6.0. 
7.1.3
Study Drug Packaging 
Labeling of the study drug vials and cartons will comply with all applicable regulations. 
7.1.4
Study Drug Ordering, Storage, and Accountability 
The instructions for drug ordering are provided in the Pharmacy Binder.  The study drug vials 
must be stored at 2°C–8°C.  DO NOT FREEZE.  DO NOT SHAKE.  An accurate study drug 
accountability log must be maintained and kept up to date at all times. 
7.1.5
Study Drug Preparation 
Please refer to the Pharmacy Manual for details on study drug preparation. 
Any unused portion left in a vial may not be used for another subject, as the product contains no 
preservative (i.e., they are single-use vials). 
7.2
Etoposide 
7.2.1
Administration 
Etoposide must be administered after the administration of the study drug, and prior to cisplatin 
on Day 1.  Etoposide should be administered by IV infusion at a dose of 100 mg/m2 over 30 to 
60 minutes on Days 1, 2, and 3 of every 21-day cycle.   
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OncoMed Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
7.2.2
Description 
Etoposide (also commonly known as VP-16) is a semisynthetic derivative of podophyllotoxin 
used in the treatment of certain neoplastic diseases. The chemical name for etoposide is 
4'-Demethylepipodophyllotoxin 9-[4,6-O-(R)-ethylidene-ȕ-D-glucopyranoside], 4'-(dihydrogen 
phosphate). 
7.2.3
Storage 
Etoposide should be stored in a controlled setting according to the instructions of the package 
insert.  
7.2.4
Packaging 
The labeling of etoposide will comply with all applicable regulations. 
7.3
Cisplatin 
7.3.1
Administration 
Cisplatin must be administered after the administration of the study drug and etoposide on Day 1.  
Cisplatin should be administered by IV infusion at a dose of 80 mg/m2 
over 30 minutes to 
2 hours on Day 1 of every 21-day cycle for Phase 1b and 75 mg/m2 for Phase 2 portion of the 
study.   
7.3.2
Description 
Cisplatin is a platinum containing anti-cancer drug used mainly in solid malignancies.  The 
chemical name for cisplatin is (SP-4-2)-diamminedichloridoplatinum. 
7.3.3
Storage 
Cisplatin must be stored at 15°C–25°C (59°F–77°F) in a controlled setting.  Do not refrigerate.  
Protect the contents from light.  
7.3.4
Packaging 
The labeling of cisplatin will comply with all applicable regulations. 
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6
Page 44 of 235 
22 April 2016 
 
CONFIDENTIAL 
7.4
Carboplatin 
7.4.1
Administration 
Carboplatin must be administered after the administration of the study drug and etoposide on 
Day 1.  Carboplatin should be administered by IV infusion at a dose of AUC of 5 mg/mL•min 
over 15 minutes or longer on Day 1 of every 21-day cycle per package insert. Using Calvert 
formula for carboplatin dosing, the total carboplatin is calculated in mg, total dose (mg) = target 
AUC of 5 x (GFR+25). 
7.4.2
Description 
Carboplatin is a platinum containing anti-cancer drug used mainly in solid malignancies. The 
chemical name for Carboplatin is platinum, diammine[1,1-cyclobutanedicarboxylato(2-)-O,O']-, 
(SP-4-2). 
7.4.3
Storage  
Carboplatin must be stored at 15°C–30°C (59°F–86°F) in a controlled setting.  Do not 
refrigerate.  Protect unopened vials from light. Solutions for infusion should be discarded 8 hours 
after preparation. 
7.4.4
Packaging 
The labeling of carboplatin will comply with all applicable regulations. 
7.5
Dose Modifications or Delay for Treatment-Related Toxicities 
The Investigator should try his/her best to assess whether an adverse event is possibly related to 
study drug only, etoposide only, cisplatin or carboplatin only, or a combination of the drugs, and 
treat the subject accordingly.  This section and Table 5 provides suggested guidelines for the 
management of various study drug related toxicities in subjects receiving study drug, etoposide, 
and cisplatin or carboplatin.   
Etoposide dosing should be withheld for  Grade 2 etoposide-related toxicities and resumed at 
the same dose or at a 25% dose reduction, which refers to a decrease of 25 mg/m2 depending on 
the timing of recovery and number of episodes occurred (see Table 5).  If etoposide dosing is 
delayed for > 21 consecutive days despite supportive treatment per standard clinical practice or 
more than 2 dose reductions of etoposide ( 50 mg/m2) is required, stop etoposide therapy or call 
the Sponsor’s Medical Monitor to discuss resuming etoposide treatment after more than 21 
consecutive days interruption or further dose reduction beyond 50 mg/m2 if clinically indicated.  
Study drug and platinum therapy may continue as scheduled in the event of delay or 
discontinuation of etoposide. 
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6
Page 45 of 235 
22 April 2016 
 
CONFIDENTIAL 
Cisplatin dosing should be withheld for Grade 2 cisplatin-related toxicities (except for 
peripheral neuropathy that cisplatin dosing should be held for  Grade 3), and resumed at the 
same dose or at a 25% dose reduction, depending on the timing of recovery and number of 
episodes occurred (see Table 5).  If cisplatin dosing is delayed for > 21 consecutive days despite 
supportive treatment per standard clinical practice or more than 2 dose reductions of cisplatin 
(< 35 mg/m2) is required, stop cisplatin therapy, or call the Sponsor’s Medical Monitor to discuss 
resuming cisplatin treatment after more than 21 consecutive days interruption or further dose 
reduction beyond 35 mg/m2 if clinically indicated.  Study drug and etoposide may continue as 
scheduled in the event of delay or discontinuation of cisplatin. 
Carboplatin dosing should be withheld for Grade 2 carboplatin-related toxicities, and resumed 
at the same dose or at reduced to AUC of 4 mg/mL•min, depending on the timing of recovery 
and number of episodes occurred (see Table 5).  If carboplatin dosing is delayed for >21 
consecutive days despite supportive treatment per standard clinical practice or 
carboplatin-related toxicities recurred after the dose has been reduced to AUC of 4 mg/mL•min, 
stop carboplatin therapy or call the Sponsor’s Medical Monitor to discuss resuming carboplatin 
treatment after more than 21 consecutive days interruption or further dose reduction beyond 
AUC of 4 mg/mL•min  if clinically indicated.  Study drug and etoposide may continue as 
scheduled in the event of delay or discontinuation of carboplatin. 
The Investigator should hold tarextumab/Placebo for treatment related toxicity according to 
suggested guideline in Table 5, along with his/her best judgment.  Subjects with a starting dose 
of 5 mg/kg study drug will have dose reduced to 2.5 mg/kg if dose reduction is required.  Study 
drug will be discontinued permanently if study drug dosing is delayed for >21 consecutive days 
due to treatment –related toxicity (this is not applicable when PCI is administered as study drug 
will be held for >21 consecutive days during PCI administration and will resume 14 days after 
the completion of PCI) despite supportive treatment, or if more than 2 dose reductions of study 
drug are required or dose reduction to <2.5 mg/kg is required or the Investigator should call the 
Sponsor’s Medical Monitor to discuss to resume study drug after > 21 days consecutive days 
interruption or further dose reduction if clinically indicated.  Subjects continuing EP after 
discontinuing study drug will continue to receive etoposide on days 1, 2, and 3, and platinum 
therapy on day 1 of each 21-day cycle for the completion of planned cycles.  Special attention 
should be paid to diarrhea as this is an expected adverse event of tarextumab and Section 7.5 
describes the recommended diarrhea management approach in this study. 
 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 46 of 235 
22 April 2016 
 
CONFIDENTIAL 
Table 5: 
Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay 
Adverse Event 
Study Drug Dose 
Reduction and/or Delay 
Etoposide Dose Reduction and/or 
Delay 
Cisplatin Dose Reduction and/or 
Delay 
Carboplatin Dose Reduction and/or 
Delay 
Absolute Neutrophil Count (ANC) 
1000/mm3  
No change.   
No change.  Continue supportive care 
according to institution’s standard 
No change.  Continue supportive care 
according to institution’s standard 
No change.  Continue supportive care 
according to institution’s standard 
500 -999/mm3 
without fever 
No change 
Hold etoposide till ANC  1000/ mm3. 
Resume etoposide based on timing of 
recovery and number of previous 
episodes 
¾
 3 consecutive weeks of 
interruption 
•
1st episode, no change.  Consider 
prophylactic myeloid growth 
factor according to institution’s 
standard 
•
2nd episode: reduce etoposide dose 
by 25% from starting dose for all 
subsequent administration 
•
3rd episode, reduce etoposide dose 
by 50% from starting dose for all 
subsequent administration 
•
4th episode, discontinue etoposide 
treatment or call the Sponsor’s 
Medical Monitor to discuss 
further dose reduction if clinically 
indicated 
¾
> 3 consecutive weeks of 
interruption, discontinue etoposide 
permanently or call the Sponsor’s 
Medical Monitor to discuss 
resuming the treatment of 
etoposide if clinically indicated 
Continue supportive care according to 
institution’s standard 
Hold cisplatin till ANC  1000/ mm3.  
Resume cisplatin based on timing of 
recovery and number of previous 
episodes 
¾
 3 consecutive weeks of 
interruption 
•
1st episode, no change.  Consider 
prophylactic myeloid growth 
factor according to institution’s 
standard  
•
2nd episode: reduce cisplatin dose 
by 25% for all subsequent 
administration 
•
3rd episode, reduce cisplatin dose 
by 50% from starting dose for all 
subsequent administration 
•
4th episode, discontinue cisplatin 
treatment or call the Sponsor’s 
Medical Monitor to discuss 
further dose reduction if 
clinically indicated 
¾
> 3 consecutive weeks of 
interruption, discontinue cisplatin 
permanently or call the Sponsor’s 
Medical Monitor to discuss 
resuming the treatment of 
cisplatin if clinically indicated  
Continue supportive care according to 
institution’s standard 
Hold carboplatin till ANC  1000/ 
mm3.  Resume carboplatin based on 
timing of recovery and number of 
previous episodes 
¾
 3 consecutive weeks of 
interruption 
•
1st episode, no change.  Consider 
prophylactic myeloid growth 
factor according to institution’s 
standard  
•
2nd episode: reduce carboplatin 
dose to AUC of 4 mg/mL•min for 
all subsequent administration 
•
3rd episode:  discontinue 
carboplatin treatment or call the 
Sponsor’s Medical Monitor to 
discuss further dose reduction if 
clinically indicated. 
¾
> 3 consecutive weeks of 
interruption, discontinue 
carboplatin or call the Sponsor’s 
Medical Monitor to discuss 
resuming the treatment of 
carboplatin  if clinically 
indicated 
Continue supportive care 
according to institution’s standard 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 47 of 235 
22 April 2016 
 
CONFIDENTIAL 
Table 5: 
Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont’d) 
Adverse Event 
Study Drug Dose 
Reduction and/or Delay 
Etoposide Dose Reduction 
and/or Delay 
Cisplatin Dose Reduction and/or 
Delay 
Carboplatin Dose Reduction and/or 
Delay 
Fever  38.30C 
(1010F) with either 
500 -999/mm3 or < 
500/mm3 
OR  
< 500/mm3 without 
fever 
No change.  
Hold etoposide till ANC  1000/ 
mm3 Resume etoposide based on 
timing of recovery and number of 
previous episodes 
¾
 3 consecutive weeks of 
interruption 
•
1st episode, reduce etoposide 
dose by 25% from starting 
dose for all subsequent 
administration 
•
2nd episode, reduce etoposide 
dose by 50% from starting 
dose for all subsequent 
administration 
•
3rd episode, discontinue 
etoposide treatment or call 
the Sponsor’s Medical 
Monitor to discuss further 
dose reduction if clinically 
indicated 
¾
> 3 consecutive weeks of 
interruption, discontinue 
etoposide permanently or call 
the Sponsor’s Medical 
Monitor to discuss resuming 
the treatment of etoposide if 
clinically indicated 
Continue supportive care 
according to institution’s standard 
Hold cisplatin till ANC  1000/ mm3.  
Resume cisplatin based on timing of 
recovery and number of previous 
episodes 
¾
 3 consecutive weeks of 
interruption 
•
1st episode, reduce cisplatin dose 
by 25% for all subsequent 
administration 
•
2nd episode, reduce cisplatin dose 
by 50% from starting dose for all 
subsequent administration 
•
3rd episode, discontinue cisplatin 
treatment or call the Sponsor’s 
Medical Monitor to discuss 
further dose reduction if 
clinically indicated 
¾
> 3 consecutive weeks of 
interruption, discontinue cisplatin 
permanently or call the Sponsor’s 
Medical Monitor to discuss 
resuming the treatment of 
cisplatin if clinically indicated  
Continue supportive care according to 
institution’s standard 
Hold carboplatin till ANC  1000/ 
mm3.  Resume carbplatin based on 
timing of recovery and number of 
previous episodes 
¾
 3 consecutive weeks of 
interruption 
•
1st episode, reduce carboplatin 
dose to be AUC of 4 mg/mL•min 
for all subsequent administration 
•
2nd episode, discontinue 
carboplatin treatment or call the 
Sponsor’s Medical Monitor to 
discuss further dose reduction if 
clinically indicated  
¾
>3 consecutive weeks of 
interruption, discontinue 
carboplatin permanently or call 
the Sponsor’s Medical Monitor 
to discuss resuming the treatment 
of carboplatin  if clinically 
indicated 
Continue supportive care according to 
institution’s standard 
Thrombocytopenia 
75,000/mm3 
No change.   
No change.   
No change.   
No change 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 48 of 235 
22 April 2016 
 
CONFIDENTIAL 
Table 5: 
Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd) 
Adverse Event 
Study Drug Dose 
Reduction and/or 
Delay 
Etoposide Dose Reduction and/or Delay 
Cisplatin Dose Reduction and/or 
Delay 
Carboplatin Dose Reduction 
and/or Delay 
Thrombocytopenia (Cont’d) 
50,000-
74,999/mm3, or 
25,000-49,999/mm3 
No change.   
Consider to hold etoposide till platelet 
count  75,000/ mm3 Resume etoposide 
based on timing of recovery and number of 
previous episodes 
¾
 3 consecutive weeks of interruption 
•
1st episode, no change to etoposide 
dose 
•
2nd episode, reduce etoposide dose by 
25% from starting dose for all 
subsequent administration 
•
3rd episode, reduce etoposide dose by 
50% from starting dose for all 
subsequent administration 
•
4th episode, discontinue etoposide 
treatment or call the Sponsor’s 
Medical Monitor to discuss further 
dose reduction if clinically indicated 
¾
> 3 Consecutive weeks of 
interruption, discontinue etoposide 
permanently or call the Sponsor’s 
Medical Monitor to discuss resuming 
the treatment of etoposide if clinically 
indicated 
Consider to hold cisplatin till platelet 
count  75,000/ mm3 Resume cisplatin 
based on timing of recovery and 
number of previous episodes 
¾
 3 consecutive weeks of 
interruption 
•
1st episode, no change to cisplatin 
dose 
•
2nd episode, reduce cisplatin dose 
by 25% from starting dose for all 
subsequent administration 
•
3rd episode, reduce cisplatin dose 
by 50% from starting dose for all 
subsequent administration 
•
4th episode, discontinue cisplatin 
treatment or call the Sponsor’s 
Medical Monitor to discuss further 
dose reduction if clinically 
indicated. 
¾
> 3 Consecutive weeks of 
interruption, discontinue cisplatin 
permanently or call the Sponsor’s 
Medical Monitor to discuss 
resuming the treatment of 
cisplatin if clinically indicated 
Consider to hold carboplatin till 
platelet count  75,000/ mm3 Resume 
carboplatin based on timing of 
recovery and number of previous 
episodes 
¾
 3 consecutive weeks of 
interruption 
•
1st episode, no change to 
carboplatin dose 
•
2nd episode, reduce carboplatin 
dose to AUC of 4 mg/mL•min 
for all subsequent administration 
•
3rd episode, discontinue 
carboplatin treatment or call the 
Sponsor’s Medical Monitor to 
discuss further dose reduction if 
clinically indicated. 
¾
> 3 Consecutive weeks of 
interruption, discontinue 
cisplatin permanently or call the 
Sponsor’s Medical Monitor to 
discuss resuming the treatment 
of carboplatin  if clinically 
indicated 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 49 of 235 
22 April 2016 
 
CONFIDENTIAL 
Table 5: 
Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd) 
Adverse Event 
Study Drug Dose 
Reduction and/or 
Delay 
Etoposide Dose Reduction and/or Delay 
Cisplatin Dose Reduction and/or 
Delay 
Carboplatin Dose Reduction 
and/or Delay 
Thrombocytopenia (Cont’d) 
<25,000/mm3  
No change 
Hold etoposide till platelet count  
 75,000/ mm3.  Resume etoposide based 
on timing of recovery and number of 
previous episodes 
¾
 3 consecutive weeks of interruption 
•
1st episode, reduce etoposide dose by 
25% from starting dose for all 
subsequent administration 
•
2nd episode, reduce etoposide  by 50% 
from the starting dose for all 
subsequent cycles 
•
3rd episode, discontinue etoposide 
treatment or call the Sponsor’s 
Medical Monitor to discuss further 
dose reduction if clinically indicated 
¾
> 3 Consecutive weeks of 
interruption, discontinue etoposide 
permanently or call the Sponsor’s 
Medical Monitor to discuss resuming 
the treatment of etoposide if clinically 
indicated 
Platelet transfusions should be 
administered prophylactically if platelets 
10,000/mm3 or as clinically indicated if 
there is bleeding. 
Hold cisplatin till platelet count  
75,000/ mm3. Resume cisplatin based 
on timing of recovery and number of 
previous episodes 
¾
 3 consecutive weeks of 
interruption 
•
1st episode, reduce cisplatin dose 
by 25% from starting dose for all 
subsequent administration 
•
2nd episode, reduce cisplatin dose 
by 50% from starting dose for all 
subsequent administration 
•
3rd episode, discontinue cisplatin 
treatment or call the Sponsor’s 
Medical Monitor to discuss further 
dose reduction if clinically 
indicated 
¾
> 3 Consecutive weeks of 
interruption, discontinue cisplatin 
permanently or call the Sponsor’s 
Medical Monitor to discuss 
resuming the treatment of cisplatin 
if clinically indicated 
Platelet transfusions should be 
administered prophylactically if 
platelets 10,000/mm3 or as clinically 
indicated if there is bleeding. 
Hold carboplatin till platelet count 
 75,000/ mm3 Resume carboplatin 
based on timing of recovery and 
number of previous episodes 
¾
 3 consecutive weeks of 
interruption 
•
1st episode, reduce carboplatin 
dose to AUC of 4 mg/mL•min 
for all subsequent administration 
•
2nd episode, discontinue 
carboplatin treatment or call the 
Sponsor’s Medical Monitor to 
discuss further dose reduction if 
clinically indicated 
¾
> 3 Consecutive weeks of 
interruption, discontinue 
carboplatin permanently or call 
the Sponsor’s Medical Monitor 
to discuss resuming the 
treatment of carboplatin if 
clinically indicated 
Platelet transfusions should be 
administered prophylactically if 
platelets 10,000/mm3 or as clinically 
indicated if there is bleeding. 
 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 50 of 235 
22 April 2016 
 
CONFIDENTIAL 
Table 5: 
Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd) 
Adverse Event 
Study Drug Dose Reduction 
and/or Delay 
Etoposide Dose Reduction 
and/or Delay 
Cisplatin Dose Reduction and/or 
Delay 
Carboplatin Dose Reduction 
and/or Delay 
Renal (creatinine) 
Grade 1 (> ULN-1.5x 
ULN or > 1-1.5 x 
baseline) 
No change 
No change 
Monitor renal function and consider 
IV hydration 
Monitor renal function and consider 
IV hydration 
Grade 2 (>1.5-3x ULN 
or >1.5-3.0 x baseline) 
No change.   
No change  
Consider to hold cisplatin until 
creatinine returns to Grade  1. 
Resume cisplatin based on timing 
of recovery and number of previous 
episodes 
¾  3 consecutive weeks of 
interruption 
• 1st episode, reduce cisplatin dose 
by 25% from starting dose for 
all subsequent administration 
• 2nd episode, reduce cisplatin 
dose by 50% from starting dose 
for all subsequent administration 
•
3rd episode, discontinue 
cisplatin administration 
¾ > 3 consecutive weeks of 
interruption, discontinue 
cisplatin permanently  
Consider increasing the duration of 
cisplatin infusion and other 
supportive cares 
Recalculate carboplatin dose with 
the creatinine and GFR to have the 
AUC of 5 mg/mL•min  
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 51 of 235 
22 April 2016 
 
CONFIDENTIAL 
Table 5: 
Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd) 
Adverse Event 
Study Drug Dose Reduction 
and/or Delay
Etoposide Dose Reduction 
and/or Delay
Cisplatin Dose Reduction and/or 
Delay
Carboplatin Dose Reduction 
and/or Delay
Renal (creatinine) Cont’d 
Grade  3 (>3-6x 
ULN/>3 baseline 
or >6 ULN) 
No change if creatinine returns 
to Grade  1 before the next 
study drug administration after 
withholding cisplatin or 
etoposide for one cycle.   
Hold study drug if creatinine 
does not return to Grade 1 
after holding cisplatin or 
etoposide for one cycle. 
Resume study drug if creatinine 
returns to Grade 1 within 3 
weeks. 
¾  3 consecutive weeks of 
interruption 
• Resume study drug at the 
next lower dose 
¾ > 3 Consecutive weeks of 
interruption, discontinue or 
call the Sponsor’s Medical 
Monitor to resume the 
treatment if clinically 
indicated 
No change if creatinine returns 
to Grade 1 before the next 
scheduled etoposide 
administration after withholding 
one dose of cisplatin or reduced 
carboplatin dose. 
Hold etoposide until creatinine 
returns to Grade 1.   Resume 
etoposide based on timing of 
recovery and number of previous 
episodes 
¾  3 consecutive weeks of 
interruption 
• 1st episode, reduce etoposide 
dose by 25% from starting 
dose for all subsequent 
administration 
• 2nd episode, reduce etoposide 
dose by 50% from starting 
dose for all subsequent 
administration 
• 3rd  episode, discontinue 
etoposide treatment  
¾ > 3 Consecutive weeks of 
interruption, discontinue 
etoposide permanently or call 
the Sponsor’s Medical 
Monitor to resume the 
treatment if clinically 
indicated 
Consider supportive care 
according to institution’s 
standard 
Hold cisplatin until creatinine 
returns to Grade  1. Resume 
cisplatin based on timing of 
recovery and number of previous 
episodes 
¾  3 consecutive weeks of 
interruption 
• 1st episode, reduce cisplatin dose 
by 25% from starting dose for 
all subsequent administration 
• 2rd episode, reduce cisplatin dose 
by 50% from starting dose for 
all subsequent administration 
• 3rd episode, discontinue cisplatin 
treatment 
¾ > 3 Consecutive weeks of 
interruption, discontinue 
cisplatin permanently  
Consider supportive care according 
to institution’s standard, and 
decrease the infusion rate 
Hold carboplatin until creatinine 
returns to Grade  1  Resume 
carboplatin based on timing of 
recovery and number of previous 
episodes 
¾
 3 consecutive weeks of 
interruption 
•
1st episode, reduce carboplatin 
dose to AUC of 4 mg/mL•min 
for all subsequent 
administration 
•
2nd episode, discontinue 
carboplatin treatment 
¾
> 3 Consecutive weeks of 
interruption, discontinue 
carboplatin permanently  
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
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Table 5: 
Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd) 
Adverse Event 
Study Drug Dose Reduction 
and/or Delay 
Etoposide Dose Reduction 
and/or Delay 
Cisplatin Dose Reduction and/or 
Delay 
Carboplatin Dose Reduction 
and/or Delay 
Diarrhea 
Grade 2 
No change.  Supportive care 
according to standard practice and 
diarrhea management described in 
the protocol (Section 7.5 below) 
No change.  Supportive care 
according to standard practice 
No change.  Supportive care 
according to standard practice 
No change.  Supportive care 
according to standard practice 
Grade 3 
Hold study drug, supportive care 
according to standard practice. 
Resume study drug according to 
the number of episodes that 
resolved to Grade 1 within 3 
weeks of treatment interruption: 
•
1st  episode: resume at the next 
lower dose (reduce by 2.5 
mg/kg or to discuss the 
increment of dose reduction 
with the Sponsor’s Medical 
Monitor) 
•
2rd episode: reduce by 5 mg/kg 
from starting dose or to 
discuss alternative increment 
of dose reduction with the 
Sponsor’s Medical Monitor 
•
3rd  episode: discontinue study 
drug permanently or call the 
Sponsor’s Medical Monitor to 
discuss further dose reduction 
if clinically indicated 
diarrhea management 
described in the protocol 
(Section 7.5 below) 
Hold etoposide if diarrhea does 
not improve to Grade 1 after 
withholding study drug for one 
cycle. 
Resume etoposide according to the 
number of episodes that resolved 
to Grade 1 within 3 weeks of 
study drug interruption: 
•
1st  episode: resume at the 
same dose  
•
2rd  episode: reduce etoposide 
dose by 25% from starting 
dose for all subsequent 
administration 
•
3rd episode: reduce etoposide 
dose by 50% from starting 
dose for all subsequent 
administration 
•
4th episode: discontinue 
etoposide permanently or call 
the Sponsor’s Medical 
Monitor to discuss further 
dose reduction if clinically 
indicated 
Hold cisplatin if diarrhea does not 
improve to Grade 1 after 
withholding study drug for three 
weeks. 
Resume cisplatin according to the 
number of episodes that resolved 
to Grade 1 within 3 weeks of 
study drug interruption: 
•
1st  episode: resume at the 
same dose  
•
2rd  episode: reduce cisplatin 
dose by 25% from starting 
dose for all subsequent 
administration 
•
3rd  episode: reduce cisplatin 
dose by 50% from starting 
dose for all subsequent 
administration 
•
4th episode: discontinue 
cisplatin permanently or call 
the Sponsor’s Medical 
Monitor to discuss further 
dose reduction if clinically 
indicated 
Hold carboplatin if diarrhea does 
not improve to Grade 1 after 
withholding study drug for three 
weeks. 
Resume carboplatin according to 
the number of episodes that 
resolved to Grade 1 within 3 
weeks of study drug interruption: 
•
1st  episode: resume at the 
same dose  
•
2rd  episode: reduce 
carboplatin dose to AUC of 4 
mg/mL•min  for all 
subsequent administration 
•
3rd  episode: discontinue 
carboplatin permanently or 
call the Sponsor’s Medical 
Monitor to discuss further 
dose reduction if clinically 
indicated 
 
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Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 53 of 235 
22 April 2016 
 
CONFIDENTIAL 
Table 5: 
Suggested Guidelines for Study Drug and Etoposide-Platinum Therapy Dose Modification and Delay (Cont'd) 
Adverse Event 
Study Drug Dose Reduction 
and/or Delay 
Etoposide Dose Reduction 
and/or Delay 
Cisplatin Dose Reduction and/or 
Delay 
Carboplatin Dose Reduction 
and/or Delay 
Peripheral Neuropathy 
Grade  2 
No change 
No change 
No change 
No change 
Grade   3 
No change 
No change 
Hold cisplatin for one cycle to see 
if peripheral neuropathy improves 
to Grade 2. 
Resume cisplatin according to the 
number of episodes that improved 
to Grade 2 within 3 weeks of 
study drug interruption: 
•
1st  episode: Reduce cisplatin 
dose by 25% from starting 
dose for all subsequent cycles 
•
2rd episode: reduce cisplatin 
dose by 50% from starting 
dose for all subsequent 
administration. 
•
3rd  episode: discontinue 
cisplatin permanently or call 
the Sponsor’s Medical 
Monitor to discuss further 
dose reduction if clinically 
indicated 
 
Call the Sponsor’s Medical 
Monitor to discuss resume 
cisplatin if the event does not 
recover to Grade  2 after one 
cycle of cisplatin interruption. 
Hold carboplatin for one cycle to 
see if peripheral neuropathy 
improves to Grade 2. 
Resume carboplatin according to 
the number of episodes that 
improved to Grade 2 within 3 
weeks of study drug interruption: 
•
1st  episode: Reduce 
carboplatin dose to AUC of 4 
mg/mL•min  for all 
subsequent cycles 
•
2rd episode: discontinue 
carboplatin permanently or 
call the Sponsor’s Medical 
Monitor to discuss further 
dose reduction if clinically 
indicated 
 
Call the Sponsor’s Medical 
Monitor to discuss resume 
carboplatin if the event does not 
recover to Grade  2 after one 
cycle of carboplatin interruption. 
 
 
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7.5.1
Infusion Reaction Management 
The administration of monoclonal antibodies may result in an infusion reaction that may consist 
of a symptom complex characterized by fever, chills, nausea, vomiting, headache, dizziness, 
bronchospasm, dyspnea, hypotension, and/or rash including urticaria.  If an infusion reaction 
occurs, the infusion should be stopped and any appropriate medical care should be administered.  
For subjects whose infusion-associated events were either Grade 1 or 2, and completely resolved 
on the day of the infusion, the infusion may be resumed at the discretion of the Investigator at a 
rate that is slower than the initial rate of infusion.  If a Grade 1 or 2 reaction occurs during the 
first cycle (also with complete resolution of symptoms), the infusion may be resumed at either a 
slower rate or at the initial rate of infusion (i.e. over 180 minutes).  Please refer to the Pharmacy 
Manual for details on study drug administration.  All subsequent infusions for that subject should 
then be administered at the reduced rate of infusion.   
Subjects experiencing a Grade 2 infusion reaction should be premedicated prior to subsequent 
infusions.  Premedications may include medications such as corticosteroids, diphenhydramine, 
and/or bronchodilators as indicated.  If the Grade 2 infusion reaction recurs during subsequent 
infusions despite the premedications, the subject should be removed from treatment.  In addition, 
permanently discontinue the study drug therapy in any subject who experiences a Grade 3 or 4 
infusion reaction or acute allergic reaction (e.g., symptomatic bronchospasm with or without 
urticaria, edema, angioedema, or hypotension).  Grade 3 or 4 acute allergic reactions should be 
medically managed as appropriate and treatment may include the administration of epinephrine, 
corticosteroids, diphenhydramine, bronchodilators, and/or oxygen as indicated. 
7.6
Anti-Emetics, Anti-diarrhea and Hematopoietic Supportive Care 
Antiemetic therapy and anti-diarrheal medications may be administered at the discretion of the 
Investigator.  However, since diarrhea is the main adverse event associated with tarextumab as a 
single agent it is recommended that the Investigator follow diarrhea management guidelines 
below. 
It is recommended that all subjects enrolled on the study are to be given a prescription for 
loperamide at study entry with instructions to take an initial 4 mg dose following the first loose 
stool, followed by 2 mg after every unformed stool with a maximum of 16 mg per day.  
Loperamide should be continued until the subject was diarrhea-free for 12 hours.  If Grade 3 
diarrhea develops, loperamide should be discontinued and the subject would be started on 
second-line therapy (i.e., Lomotil 2 tablets 4 times daily and/or octreotide 100-150 μg SC three 
times daily up to a maximum 500 μg 3 times daily).   
Hematopoietic growth factors, transfusion of blood and blood products should not be used 
prophylactically prior to the dosing of the study drug and EP on Day 1 of Cycle 1, but may be 
administered per standard clinical practice during the course of the study as needed.   
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Protocol 59R5-003, Amendment 6 
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7.7
Concomitant and Prohibited Therapy 
All concomitant medication administered within 28 days prior to the first administration of study 
drug through 30 days following the administration of the last dose of study drug will be recorded 
on the Concomitant Medication eCRF.  Investigational medicinal products, therapeutic warfarin 
(prophylactic low dose of warfarin, i.e., 1 mg daily is allowed for port catheter) and anticancer 
agents (e.g., cytotoxic agents and biologics with known activity against small cell lung cancer) 
may not be administered from enrollment through the first line therapy.   
Subjects planning to initiate intravenous bisphosphonate or denosumab therapy after study entry 
must begin within the first 30 days of the first administration of study drug.  Oral bisphosphonate 
may be initiated at any point in the study for the treatment of osteoporosis.  Subjects can switch 
intravenous bisphosphonate to denosumab or vice versa during the study, but the initiation of a 
new intravenous bisphosphonate or denosumab therapy beyond 30 days after the first 
administration of study drug is prohibited. 
After the completion of 6 cycles of EP, subjects who do not have disease progression and have 
not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study 
entry and are good candidates for PCI per the Investigators 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 Investigators, PCI can be initiated at the time that is determined 
appropriated per 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 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 (Appendix A).  Subjects will discontinue 
study treatment if there is evidence of central nervous system (CNS) metastasis. 
7.8
Treatment Compliance 
Tarextumab, Placebo, etoposide and cisplatin or carboplatin will be administered IV by study 
site personnel.  Thus, compliance with each infusion will be documented in the subject’s medical 
records and then recorded on the appropriate electronic data capture (EDC) screen.  In addition, 
drug accountability will be performed. 
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8.0
SAFETY ASSESSMENTS 
Safety will be assessed by adverse event monitoring (including attribution of AEs and SAEs), 
physical examination, vital signs, clinical laboratory testing, anti-tarextumab testing, and subject 
interview on an ongoing basis as outlined in the Schedule of Assessments (see Appendix B, and 
Appendix C). 
Samples that test positive for tarextumab antibodies will be assessed for neutralizing capability.  
The impact of positive samples on safety and biologic activity will be assessed. 
8.1
Adverse Events Definitions and Reporting Procedures 
All Adverse Events from the time of the first administration of study drug through 30 days after 
the last dose of study drug or EP whichever is discontinued last must be documented in the 
medical record and reported on the AE Case Report Form (CRF). 
Adverse events will be coded in accordance with the Medical Dictionary for Regulatory 
Activities (MedDRA).  The grading of the adverse events will be done using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.02 (see 
Study Reference Binder).   
8.1.1
Definition of Adverse Event 
An adverse event is 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.  Any medical 
condition or clinically significant laboratory abnormality with an onset date before the first 
administration of study drug is a pre-existing condition that must be listed on the Medical 
History CRF and should not be considered an adverse event unless the condition worsens in 
intensity or frequency after enrollment (e.g., Grade 2 nausea prior to the first administration of 
study drug becomes Grade 3 nausea after the first administration of study drug). 
8.1.2
Adverse Event -Causality rating 
The causality of each adverse event should be assessed and classified by the Investigator as 
“related” or “not related”.  An event is considered related if the administration of study drug and 
the occurrence of the AE are reasonably related in time AND the event could not be explained 
equally well by factors or causes other than exposure to study drug.  An event is considered 
unrelated if the administration of study drug and the occurrence of the AE are not reasonably 
related in time AND the event is likely to be related to an etiology other than the use of study 
drug; that is, there are facts, evidence or arguments to suggest a causal relationship to study drug. 
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8.1.3
Definition of Serious Adverse Event 
A serious adverse event is any event that results in the following: 
•
death 
•
life-threatening condition (places the subject at immediate risk of death) 
•
subject hospitalization or prolongation of existing hospitalization 
•
persistent or significant disability/incapacity 
•
congenital anomaly/birth defect, or any other adverse event that, based upon the Investigators 
medical judgment, may require medical or surgical intervention to prevent one of the 
outcomes listed above (examples of such events include allergic bronchospasm requiring 
intensive treatment in the emergency room or at home, blood dyscrasias or convulsions that 
do not result in subject hospitalization, or the development of drug dependency or drug 
abuse) 
8.1.3.1
Disease Progression and Death 
Disease progression (including progression of small cell lung cancer, and death due to 
disease progression) is generally recorded as part of the efficacy evaluation and should not be 
reported as an AE or SAE. When an AE resulting from disease progression meets the 
requirements to be considered serious, the SAE verbatim term should be reported as the 
sign/symptom that best describes the event rather than as disease progression.  For instance, a 
subject with pleural effusion presents with shortness of breath.  The cause of the shortness of 
breath is a pleural effusion resulting from disease progression.  The event term may be reported 
as “pleural effusion” instead of disease progression.  
Death should not be reported as a serious adverse event, but as a clinical outcome of a specific 
SAE. The cause of death, reported on a source document such as the Death Certificate or autopsy 
report, should be used as the event term for the SAE.  
8.1.4
Serious Adverse Event Reporting Procedures 
SAEs that occur during the study must be clearly documented in the medical record.  In addition, 
the SAE form must be completed for each event and promptly submitted to OncoMed designated 
fax number.  Details of SAE reporting procedures will be available in Study Reference Manual. 
The Investigator is encouraged to discuss with the Medical Monitor any AEs for which the issue 
of seriousness is unclear or questioned.  Contact information for the Medical Monitor is as 
follows: 
Primary:  
 
 
 
 
 
 
 
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Protocol 59R5-003, Amendment 6 
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Backup: 
 
 
 
 
 
 
OncoMed Pharmaceuticals, Inc. 
 
 
800 Chesapeake Drive 
 
 
Redwood City, CA  94063 
The reporting period for SAEs is the period from the first administration of the study drug 
through 30 days after the last administration of study drug or EP whichever is discontinued last.  
SAEs reported to the Investigator outside of this reporting period will be reported to OncoMed or 
its designee if in the judgment of the Investigator there is “a reasonable possibility” that the event 
may have been caused by the product.   
All SAEs will continue to be followed until the end of the Study or until such events have 
resolved or the Investigator, in conjunction with the Sponsor, deems them to be chronic or stable. 
8.2
Clinical Laboratory Assessments 
8.2.1
Hematology 
Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and 
platelet count.  Coagulation test of PT/INR and aPTT will be obtained on Day 1 of each 
treatment cycle. The results need to be reviewed by the Investigator prior to each study drug 
administration.   
8.2.2
Chemistry 
For Phase 1b, Serum Chemistry includes sodium, potassium, chloride, bicarbonate, blood urea 
nitrogen (BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, direct 
bilirubin, lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphorus, and 
magnesium.  The results for BUN, bicarbonate, creatinine, glucose, chloride, potassium, and 
sodium need to be reviewed by the Investigator prior to each study drug administration.   
For Phase 2, Chemistry (Serum or Plasma) includes sodium, potassium, chloride, bicarbonate, 
blood urea nitrogen (BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, 
direct bilirubin, lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphorus, and 
magnesium.  The results for BUN, bicarbonate, creatinine, glucose, chloride, potassium, and 
sodium need to be reviewed by the Investigator prior to each study drug administration.   
8.2.3
Urinalysis 
For Phase 1b, Urinalysis (dip stick is sufficient) includes color, appearance, pH, ketones, specific 
gravity, bilirubin, protein, blood, glucose and urobilinogen.  
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Protocol 59R5-003, Amendment 6 
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CONFIDENTIAL 
For Phase 2, Urinalysis (dip stick is sufficient) includes pH, ketones, specific gravity, bilirubin, 
protein, blood and glucose.  
8.3
Vital Signs and Other Physical Findings 
A full physical examination will be done at screening, clinically indicated during the study and 
treatment termination.  Targeted physical examinations will be done at all other times, with areas 
of the body to be examined at the Investigator’s discretion. 
Vitals signs (blood pressure, pulse, respiratory rate, and temperature) will be done at screening 
and during study visits as specified in the Schedule of Assessments (Appendix B and 
Appendix C).   
8.4
Cardiac Studies 
Twelve-lead electrocardiograms (ECGs) with assessment of PR interval, QRS duration, and QTc 
interval will be obtained at Screening and during study visits as specified in the Schedule of 
Assessments (APPENDIX B and APPENDIX C).   
8.5
Immunogenicity Assessments 
During Phase 1b, serum samples will be obtained for immunogenicity assessment (Anti-
tarextumab) prior to study drug administration on Day 1 of Cycle 1, every three cycles thereafter 
(Day 1 of Cycle 4, 7, 10, etc.), at other times as clinically indicated such as when significant 
toxicities occur and at the time of treatment termination for all subjects enrolled in Phase 1b. 
Samples that test positive will be assessed for neutralizing capability.  
During Phase 2, serum samples will be obtained for immunogenicity assessment 
(Anti-tarextumab) prior to study drug administration on Day 1 of Cycle 1, every other cycle 
thereafter (Day 1 of Cycle 3, 5, 7, etc.), at other times as clinically indicated such as when 
significant toxicities occur and at the time of treatment termination for all subjects enrolled in 
Phase 2. Samples that test positive will be assessed for neutralizing capability. 
Instructions for sample collection, handling, storage, and shipping can be found in the Study 
Reference Binder. 
8.6
Pharmacokinetic Assessments 
For subjects enrolled in Phase 1b portion only:  Plasma samples from all subjects enrolled in 
Phase 1b portion will be obtained for pharmacokinetic analysis of tarextumab at pre-dose and 
5 minutes post tarextumab infusion on Day1 of Cycles 1 and 3, on Days 3 and 8 of Cycles 1 and 
3, at other times as clinically indicated such as when significant toxicities occur as well as at the 
time of treatment termination, as outlined in the Schedule of Assessments (Appendix B).   
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Protocol 59R5-003, Amendment 6 
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CONFIDENTIAL 
For subjects enrolled in Phase 2 portion only:  Plasma samples from all subjects enrolled in 
Phase 2 portion will be obtained for pharmacokinetic analysis of tarextumab on Day 1 of Cycles 
1 and 3, at  pre-dose and 5 minutes post tarextumab infusion Day 3 of Cycle 1 and Cycle 3 prior 
to etoposide administration; Day 8 of Cycle 1 and Cycle 3 when blood sample is taken for 
biomarker evaluation;  Day 1 of every other cycle staring from Cycle 5 prior to study drug 
infusion and, at other times as clinically indicated such as when significant toxicities occur as 
well as at the time of treatment termination, as outlined in the Schedule of Assessments (
Appendix C). 
Pharmacokinetic parameters (i.e. area under the curve [AUC], clearance, volume of distribution 
and apparent half life) of tarextumab will be assessed for each evaluable subject.  Instructions for 
sample collection, handling, storage, and shipping can be found in the Study Reference Binder. 
9.0
EFFICACY ASSESSMENTS 
Subjects will be assessed for response using Response Evaluation Criteria in Solid Tumors 
(RECIST) criteria 1.1.  The first response assessment will occur approximately 6 weeks/42 days 
(± 5 days) after the first dose of the study drug.  Subsequent response assessments will occur 
every 6 weeks/42 days (± 5 days).  Subjects who discontinue study treatment for any reason 
other than disease progression will be followed with tumor assessment every 6 weeks/42 days 
(±5 days) during Follow-up until documented disease progression or initiation of new anti-cancer 
therapy, whichever is sooner. 
10.0
BIOMARKERS AND EXPLORATORY ASSESSMENTS 
Instructions for biomarker sample collection, handling, labeling, and shipping are provided in the 
Study Reference Binder. 
Notch Expression:  Notch3, Hes1, Hey2, Hey1 and Hes6 expression levels will be assessed in 
FFPE tumor specimens, either archived or fresh core needle biopsied at study entry (two fresh 
cores preferred whenever possible).  FFPE samples must be obtained during screening for 
Notch3, Hes1, Hey2, Hey1 and Hes6 levels to be measured by immunohistochemistry and/or 
gene expression assays.  Notch 2 and other Notch-related genes and proteins may also be 
measured.   
In addition, DNA testing may be performed on the FFPE tumor specimens for subjects who sign 
the optional FFPE Informed Consent for DNA testing.  Exploratory analysis of these tumors may 
help to identify biomarkers that could be used in the future to predict which subjects are more 
likely to respond to tarextumab treatment.  Analysis of candidate genes relevant to the Notch 
pathway may be performed (e.g. Notch2, Notch3, etc.). 
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Blood Biomarkers:  A pre-dose sample of a total of 19 mL of blood will be drawn during study 
visits according to Schedule of Assessments (Appendix B and Appendix C) to evaluate changes 
in plasma proteins by immunochemistry (e.g., EGFR, PLGF, ENA-78, etc.), circulating tumor 
cells(CTCs), and Notch-related gene expression of mRNA, e.g., Affymetrix microarrays, 
quantitative PCR.  Plasma microRNAs may also be evaluated by microRNA expression 
profiling.  A sample will also be obtained at the time of treatment termination unless one has 
been obtained during the prior 14 days. A pre-dose blood sample will also be obtained on Day 1 
of Cycles 4 and 5 to explore effects of treatment on CTCs. 
CTCs will be enumerated in blood and correlation with response to EP plus tarextumab will be 
assessed.  Biomarker proteins and mRNA expression in the CTCs (e.g., Notch3, Notch2, CD44, 
ALDH1, etc.) may also be evaluated.  Circulating endothelial cells may also be evaluated. 
Hair Follicle mRNA Expression for subjects in Phase 1b only:  Predose hair samples (6 hairs) 
will be collected during study visits according to Schedule of Assessments (Appendix B) for 
gene expression RT-PCR analysis of Notch-pathway related mRNA expression, e.g., heyl, hey2, 
etc.  RNA extracted from hair samples may be analyzed on microarrays, e.g., Affymetrix 
platform to measure tarextumab–affected gene expression changes in samples. 
Pharmacogenomics:  A blood sample (10 mL) will be collected on Day 1 of Cycle 1.  
Pharmacogenomic analysis of candidate genes relevant to tarextumab may influence safety, 
tolerability, or pharmacodynamic effects of tarextumab for the treatment of extensive stage small 
cell lung cancer.  Analysis of genes relevant to Notch/DLL4 target or pathway genes or disease 
genes may be performed (e.g., Notch 2, Notch3, FBW7 and PTEN).  Pharmacogenomic samples 
will be destroyed after 10 years. 
Optional Tumor Biomarkers:  Optional tumor specimens will be collected during study visits and 
at the time of treatment termination, if feasible according to Schedule of Assessments  
(Appendix B and Appendix C) from subjects who are consented and who have tumor lesions that 
are amenable to core biopsies.  Tumor samples will be analyzed for treatment-induced changes 
in Notch-related gene expression (i.e., mRNA) and/or protein markers and cancer stem cell–
related gene expression. 
11.0
STUDY VISIT SCHEDULE AND ASSESSMENTS 
Subjects must sign and date the Informed Consent Form that has been approved by the IEC/IRB 
prior to undergoing any study-related procedures.   
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The enrollment and cohort assignment will be centrally managed by OncoMed and its designee.  
When a treatment cohort is open for enrollment during Phase 1b portion, the site will fax in a 
Subject Registration Form along with subject eligibility supporting documents for each potential 
subject to OncoMed and its designee after the subject’s screening process has been completed.  
OncoMed and its designee will assign a subject number and treatment cohort for each subject 
that is accepted into the study.  Sites cannot enroll or start dosing a subject without receiving the 
assigned subject number and treatment cohort from OncoMed or its designee during Phase 1b 
portion.  During Phase 2 portion, the Investigator/study coordinator will use a randomization 
method that is detailed in the Study Reference Manual to enroll the subject after OncoMed or its 
representative has signed and approved the enrollment form.  Study drug must be administered 
within 4 days from the date of enrollment/randomization.  The following study evaluations must 
be performed at the indicated timepoints. 
11.1
Screening 
The following evaluations and procedures will be performed within 28 days prior to the first 
study drug administration (Cycle 1 Day 1):  
•
Informed Consent (must be obtained before any study specific procedures are 
performed) 
•
Medical and oncology history including demographics  
•
Radiographic evaluation:  CT with contrast, or MRI of the chest, abdomen, pelvis, and brain, 
and bone scan performed as outlined by the RECIST criteria 1.1 (see Appendix E).  Note:  
PET/CT can be used in lieu of bone scan to identify and follow up bone lesions.  The same 
method (CT or MRI, bone scan or PET/CT for bone lesions) must be used consistently 
throughout the study to follow the same anatomical location.   
•
FFPE tumor tissues, either archived or fresh core needle biopsied available for Notch3, Hes1, 
Hey1, Hey2, and Hes6 analysis (two fresh cores preferred whenever possible).  In addition, 
DNA testing may be performed on the FFPE tumor specimens for subjects who sign the 
optional Pharmacogenomics/DNA Testing Informed Consent form.  Details of the 
requirement of tissue specimen will be provided in the Study Reference Manual 
•
Tumor core biopsy (Optional and only if subject has signed the optional tumor core 
biopsy consent) 
•
Concomitant medications  
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 63 of 235 
22 April 2016 
 
CONFIDENTIAL 
The following evaluations and procedures will be performed within 14 days prior to the first 
administration of study drug (Cycle 1 Day 1): 
•
Physical examination 
•
Vital signs 
•
Height 
•
Weight 
•
ECOG performance status 
•
Hematology 
•
Chemistry 
•
Coagulation 
•
Serum pregnancy test for all females of childbearing potential (a negative result must be 
obtained prior to enrollment)  
•
Urinalysis (dip stick is sufficient) 
•
Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc 
interval 
•
Concomitant medications 
11.2
Treatment Visits – Phase 1b 
If the subject meets all inclusion/exclusion criteria after the screening visit(s), the site will 
complete an enrollment form and submit it to OncoMed along with supporting source documents 
for approval.  Once OncoMed or its representative has approved the enrollment form, the 
Investigator/study coordinator will receive a subject number and dose cohort assignment from 
OncoMed and its designees to enroll a subject into Phase 1b portion of the study.   
The subject will start treatment of study drug on Day 1 in combination with etoposide 100 mg/m2 
on Days 1, 2, and 3, and cisplatin 80 mg/m2 for Phase 1b or carboplatin at AUC of 5 mg/mL•min 
on Day 1 of every 21-day cycle.  On days when study drug is given together with etoposide and 
platinum therapy, study drug should be given prior to etoposide and platinum therapy 
administration.  Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and 
sodium lab results must be available and reviewed by the Investigator prior to each study drug 
dosing.  For subjects who have study drug held or discontinued for tolerability reasons, EP 
chemotherapy should continue to the completion of 6 cycles. 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 64 of 235 
22 April 2016 
 
CONFIDENTIAL 
After the completion of 6 cycles of EP, subjects who do not have disease progression and have 
not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study 
entry and are good candidates for PCI per the Investigators 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 Investigators, PCI can be initiated at the time that is determined 
appropriated per 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 administration (tarextumab or Placebo) should continue at every 21-day (± 1 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 (tarextumab or Placebo)  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. 
11.2.1 
Cycle 1 
11.2.1.1
Cycle 1 Day 1 
The following assessments will be completed prior to study drug infusion.  These assessments 
will be repeated if they were done more than 7 days prior to Cycle 1 Day 1. 
•
Physical examination 
•
ECOG performance status 
•
Hematology 
•
Serum chemistry 
•
Coagulation 
•
Urinalysis (dip stick is sufficient) 
•
Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc 
interval 
The following assessments will be done prior to study drug infusion on Cycle 1 Day 1: 
•
Weight 
•
Serum sample for anti-tarextumab antibody on all subjects  
•
Blood sample for biomarker 
•
Plasma sample for tarextumab PK from all subjects 
•
Hair follicle samples (6 hairs)  
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 65 of 235 
22 April 2016 
 
CONFIDENTIAL 
•
Blood sample for pharmaco-genomics (Optional and only if subject has signed the 
separate pharmacogenomics Informed Consent Form)  
•
Concomitant medications 
•
Vital Signs 
Administration of study drug, etoposide, and cisplatin or carboplatin: 
Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results 
must be reviewed by the Investigator prior to study drug dosing.  Study drug will be 
administered first, followed by etoposide infusion, and then cisplatin or carboplatin infusion.   
The following procedures will be completed after administration of study drug: 
•
Plasma samples for tarextumab PK only from all subjects:  5 (±2) minutes after the end of 
tarextumab infusion, but prior to EP administration. 
•
Adverse event recording 
11.2.1.2
Cycle 1 Day 2  
The following assessments will be completed prior to etoposide infusion: 
•
Vital signs 
•
Weight 
•
Concomitant medications 
•
Adverse event recording 
Administration of etoposide: 
Etoposide dosing will be given. 
11.2.1.3
Cycle 1 Day 3  
The following assessments will be completed prior to etoposide infusion: 
•
Vital signs 
•
Weight 
•
Plasma sample for tarextumab PK from all subjects enrolled 
•
Concomitant medications 
•
Adverse event reporting 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 66 of 235 
22 April 2016 
 
CONFIDENTIAL 
Administration of etoposide: 
Etoposide dosing will be given.  
•
Adverse event recording 
11.2.1.4
Cycle 1 Day 8 
•
Blood sample for biomarker 
•
Plasma sample for tarextumab PK from all subjects  
•
Hematology 
•
Concomitant medications 
•
Adverse event recording 
11.2.2
Cycles 2-6  
11.2.2.1
Day 1 (± 1 day) of Cycles 2-6  
The following assessments will be completed prior to study drug infusion (laboratory 
assessments can be performed up to 3 days prior to Day 1 of Cycles 2-6): 
•
Targeted physical examination at the Investigator’s discretion 
•
Vital signs 
•
Weight 
•
ECOG performance status 
•
Hematology 
•
Serum chemistry 
•
Coagulation 
•
Urinalysis (dip stick is sufficient) 
•
Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc 
interval 
•
Concomitant medications 
•
Serum sample for anti-tarextumab antibody on all subjects (Collect at Cycle 4, only) 
•
Blood sample for CTCs (collect at Cycles 4 and 5 only) 
•
Plasma sample for tarextumab PK from all subjects enrolled Collect at Cycle 3 only 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 67 of 235 
22 April 2016 
 
CONFIDENTIAL 
•
Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, and pelvis will 
be done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 3 and every 6 
weeks+5 days thereafter).  The same method should be used throughout the study to follow 
the same anatomical location.  Bone scan will be only performed at the investigator’s 
discretion if clinically indicated 
Administration of study drug, etoposide, and cisplatin or carboplatin: 
Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results 
must be reviewed by the Investigator prior to study drug dosing.  Study drug will be 
administered first, followed by etoposide infusion, and then cisplatin or carboplatin infusion.   
•
Adverse event recording 
The following procedures will be completed after administration of study drug at Cycle 3 only 
for all subjects and for subjects enrolled in Phase 2 portion: 
•
Plasma samples for tarextumab PK at Cycle 3 only:  5 (±2) minutes after the end of 
tarextumab infusion, but prior to EP administration. 
11.2.2.2
Day 2 of Cycles 2-6  
The following assessments will be completed prior to etoposide infusion: 
•
Vital signs 
•
Weight 
•
Blood sample for biomarker (Collect at Cycles 2 and 3 only) 
•
Concomitant medications 
•
Adverse event recording 
Administration of etoposide: 
Etoposide dosing will be given. 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 68 of 235 
22 April 2016 
 
CONFIDENTIAL 
11.2.2.3
Day 3 of Cycles 2-6  
The following assessments will be completed prior to etoposide infusion: 
•
Vital signs 
•
Weight 
•
Plasma sample for tarextumab PK at Cycle 3 only 
•
Concomitant medications 
•
Adverse event reporting 
Administration of etoposide: 
Etoposide dosing will be given. 
11.2.2.4
Day 8 of Cycles 2 and 3 Only  
•
Plasma sample for tarextumab PK from all subjects (Collect at Cycle 3 only) 
•
Blood sample for biomarker  
•
Hematology 
•
Hair follicle samples (6 hairs) (Collect at Cycle 2 only.) 
•
Tumor core biopsy (Optional and only if subject has signed the optional tumor core 
biopsy consent; collect at Cycle 2 only). The site can call the Sponsor’s medical monitor to 
discuss an alternative timepoint if it is not feasible to collect the optional tumor biopsy on 
Day 8 (±2) of Cycle 2. 
•
Concomitant medications 
•
Adverse event recording 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 69 of 235 
22 April 2016 
 
CONFIDENTIAL 
11.2.3
After Cycle 6 of etoposide and cisplatin/carboplatin with tarextumab 
After the completion of 6 cycles of EP, subjects who do not have disease progression and have 
not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study 
entry and are good candidates for PCI per the Investigators 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 Investigators, PCI can be initiated at the time that is determined 
appropriated per 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.  
tarextumab 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 (Appendix A Study Schema).  Subjects will 
discontinue study treatment if there is evidence of central nervous system (CNS) metastasis.   
11.2.4
Cycle 7 and every cycle thereafter 
11.2.4.1
Day 1 (± 1 day) of Cycle 7 and every cycle thereafter 
After the subject completes 6 cycles of EP, only tarextumab will be given on Day 1 of 
subsequent cycles.   
The first dose of tarextumab after the completion of prophylactic cranial irradiation (PCI) should 
be given > 14 days after the last dose of radiation. 
The following assessments will be completed prior to study drug infusion (laboratory 
assessments can be done up to 3 days prior to Day 1 of each cycle): 
•
Targeted physical examination at the Investigator’s discretion 
•
Vital signs 
•
Weight 
•
ECOG performance status 
•
Hematology 
•
Serum chemistry 
•
Coagulation 
•
Urinalysis (dip stick is sufficient) 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 70 of 235 
22 April 2016 
 
CONFIDENTIAL 
•
Concomitant medications 
•
Serum sample for anti-tarextumab antibody on all subjects (Phase 1b Subjects: collect at 
Cycle 7, 10 and every 3rd cycle thereafter, only) 
•
Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, pelvis, will be 
done every 6 weeks +5 days after Day 1 of Cycle 1 (Day 1 of Cycle 7 and every 6 weeks 
+5 days thereafter).  The same method should be used throughout the study to follow the 
same anatomical location. Bone scan will be only performed at the investigator’s discretion if 
clinically indicated 
Administration of study drug: 
Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results 
must be reviewed by the Investigator prior to study drug dosing.  Only study drug will be given 
on day 1 of each cycle beginning at Cycle 7. 
•
Adverse event recording 
11.3
Treatment Visits – Phase 2 
If the subject meets all inclusion/exclusion criteria after the screening visit(s), the site will 
complete an enrollment form and submit it to OncoMed along with supporting source documents 
for approval.  Once OncoMed or its representative has approved the enrollment form, OncoMed 
will use a randomization system to enroll a subject into Phase 2 portion of the study.   
The subject will start treatment of study drug on Day 1 in combination with etoposide 100 mg/m2 
on Days 1, 2, and 3, and cisplatin 75 mg/m2 or carboplatin at AUC of 5 mg/mL•min on Day 1 of 
every 21-day cycle.  On days when study drug is given together with etoposide and platinum 
therapy, study drug should be given prior to etoposide and platinum therapy administration.  
Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results 
must be available and reviewed by the Investigator prior to each study drug dosing.  For subjects 
who have study drug held or discontinued for tolerability reasons, EP chemotherapy should 
continue to the completion of 6 cycles. 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 71 of 235 
22 April 2016 
 
CONFIDENTIAL 
After the completion of 6 cycles of EP, subjects who do not have disease progression and have 
not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to study 
entry and are good candidates for PCI per the Investigators 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 Investigators, PCI can be initiated at the time that is determined 
appropriated per 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 administration (tarextumab or Placebo) should continue at every 21-day (± 1 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 (tarextumab or Placebo)  14 days after 
completion of PCI, until disease progression or unacceptable treatment-related toxicities or 
withdrawal of consent (Appendix A Study Schema).   Subjects will discontinue study treatment 
if there is evidence of central nervous system (CNS) metastasis. 
11.3.1 
Cycle 1 
11.3.1.1
Cycle 1 Day 1 
The following assessments will be completed prior to study drug infusion.  These assessments 
will be repeated if they were done more than 7 days prior to Cycle 1 Day 1. 
•
Physical examination 
•
ECOG performance status 
•
Hematology 
•
Chemistry 
•
Coagulation 
•
Urinalysis (dip stick is sufficient) 
•
Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc 
interval 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 72 of 235 
22 April 2016 
 
CONFIDENTIAL 
The following assessments will be done prior to study drug infusion on Cycle 1 Day 1: 
•
Weight 
•
Serum sample for anti-tarextumab antibody on all subjects  
•
Blood sample for biomarker 
•
Plasma sample for tarextumab PK  
•
Blood sample for pharmaco-genomics (Optional and only if subject has signed the 
separate pharmacogenomics Informed Consent Form)  
•
Concomitant medications 
•
Vital Signs 
Administration of study drug, etoposide, and cisplatin or carboplatin: 
Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results 
must be reviewed by the Investigator prior to study drug dosing.  Study drug will be 
administered first, followed by etoposide infusion, and then cisplatin or carboplatin infusion.   
The following procedures will be completed after administration of study drug: 
•
Plasma samples for tarextumab PK:  5 (±2) minutes after the end of study drug infusion, but 
prior to EP administration. 
•
Adverse event recording 
11.3.1.2
Cycle 1 Day 2  
The following assessments will be completed prior to etoposide infusion: 
•
Vital signs 
•
Weight 
•
Concomitant medications 
•
Adverse event recording 
Administration of etoposide: 
Etoposide dosing will be given. 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 73 of 235 
22 April 2016 
 
CONFIDENTIAL 
11.3.1.3
Cycle 1 Day 3  
The following assessments will be completed prior to etoposide infusion: 
•
Vital signs 
•
Weight 
•
Plasma sample for tarextumab PK  
•
Concomitant medications 
•
Adverse event reporting 
Administration of etoposide: 
Etoposide dosing will be given.  
•
Adverse event recording 
11.3.1.4
Cycle 1 Day 8 
•
Blood sample for biomarker 
•
Plasma sample for tarextumab PK  
•
Hematology 
•
Concomitant medications 
•
Adverse event recording 
11.3.2
Cycles 2-6  
11.3.2.1
Day 1 (± 1 day) of Cycles 2-6  
The following assessments will be completed prior to study drug infusion (laboratory 
assessments can be performed up to 3 days prior to Day 1 of Cycles 2-6): 
•
Targeted physical examination with areas of the body to be examined at the Investigator’s 
discretion 
•
Vital signs 
•
Weight 
•
ECOG performance status 
•
Hematology 
•
Chemistry 
•
Coagulation 
•
Urinalysis (dip stick is sufficient) 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 74 of 235 
22 April 2016 
 
CONFIDENTIAL 
•
Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc 
interval 
•
Concomitant medications 
•
Serum sample for anti-tarextumab antibody on all subjects (Collect at Cycles 3 and 5 only) 
•
Blood sample for CTCs (Collect at Cycles 4 and 5 only) 
•
Plasma sample for tarextumab PK (Collect at Cycles 3 and 5 only) 
•
Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, and pelvis will 
be done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 3 and every 6 
weeks+5 days thereafter).  The same method should be used throughout the study to follow 
the same anatomical location.  Bone scan will be only performed at the investigator’s 
discretion if clinically indicated 
Administration of study drug, etoposide, and cisplatin or carboplatin: 
Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results 
must be reviewed by the Investigator prior to study drug dosing.  Study drug will be 
administered first, followed by etoposide infusion, and then cisplatin or carboplatin infusion.   
•
Adverse event recording 
The following procedures will be completed after administration of study drug at Cycle 3 only: 
•
Plasma samples for tarextumab PK:  5 (±2) minutes after the end of study drug infusion, but 
prior to EP administration. 
11.3.2.2
Day 2 of Cycles 2-6 
The following assessments will be completed prior to etoposide infusion: 
•
Vital signs 
•
Weight 
•
Blood sample for biomarker (Collect at Cycles 2 and 3 only) 
•
Concomitant medications 
•
Adverse event recording 
Administration of etoposide: 
Etoposide dosing will be given. 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 75 of 235 
22 April 2016 
 
CONFIDENTIAL 
11.3.2.3
Day 3 of Cycles 2-6  
The following assessments will be completed prior to etoposide infusion: 
•
Vital signs 
•
Weight 
•
Plasma sample for tarextumab PK at Cycles 3 and 5 
•
Concomitant medications 
•
Adverse event reporting 
Administration of etoposide: 
Etoposide dosing will be given. 
11.3.2.4
Day 8 of Cycles 2 and 3 Only  
•
Plasma sample for tarextumab PK (Collect at Cycle 3 only) 
•
Blood sample for biomarker  
•
Hematology 
•
Tumor core biopsy (Optional and only if subject has signed the optional tumor core 
biopsy consent; collect at Cycle 2 only).  The site can call the Sponsor’s medical monitor to 
discuss an alternative timepoint if it is not feasible to collect the optional tumor biopsy on 
Day 8 (±2) of Cycle 2. 
•
Concomitant medications 
•
Adverse event recording 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 76 of 235 
22 April 2016 
 
CONFIDENTIAL 
11.3.3
After Cycle 6 - Planned EP Treatment cycles   
After the completion of 6 planned cycles of EP, subjects who do not have disease progression 
and have not had prophylactic cranial irradiation (PCI) or whole brain radiation (WBRT) prior to 
study entry and are good candidates for PCI per the Investigators 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 Investigators, PCI can be initiated at the time that is determined 
appropriated per 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  
(Appendix A).  Subjects will discontinue study treatment if there is evidence of central nervous 
system (CNS) metastasis.   
11.3.4
Subsequent Cycles After Cycle 6  
11.3.4.1
Day 1 (± 1 day) of Subsequent Cycles After Completion of Planned EP Cycles 
After the subject completes the 6 planned cycles of EP, only study drug will be given on Day 1 
of subsequent cycles.   
The first dose of study drug after the completion of prophylactic cranial irradiation (PCI) should 
be given > 14 days after the last dose of radiation. 
The following assessments will be completed prior to study drug infusion (laboratory 
assessments can be done up to 3 days prior to Day 1 of each cycle): 
•
Targeted physical examination at the Investigator’s discretion 
•
Vital signs 
•
Weight 
•
ECOG performance status 
•
Hematology 
•
Chemistry 
•
Coagulation 
•
Urinalysis (dip stick is sufficient) 
•
Concomitant medications 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 77 of 235 
22 April 2016 
 
CONFIDENTIAL 
•
Serum sample for anti-tarextumab antibody on all subjects (Collect at Cycle 7, 9 and every 
other cycle thereafter, only) 
•
Plasma sample for tarextumab PK (collect at Cycle 7, 9 and every other cycle thereafter 
only) 
•
Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, pelvis, will be 
done every 6 weeks +5 days after Day 1 of Cycle 1 (Day 1 of Cycle 7 and every 6 weeks 
+5 days thereafter).  The same method should be used throughout the study to follow the 
same anatomical location. Bone scan will be only performed at the investigator’s discretion if 
clinically indicated 
Administration of study drug: 
Hematology, BUN, bicarbonate, creatinine, glucose, chloride, potassium, and sodium lab results 
must be reviewed by the Investigator prior to study drug dosing.  Only study drug will be given 
on day 1 of each cycle after Cycle 4. 
•
Adverse event recording 
11.4
Treatment Termination 
Subjects who have agreed to the optional tumor core biopsy in the Informed Consent and have 
pre and post-treatment optional tumor biopsy collected, will have tumor core biopsy at the time 
of treatment termination visit, if feasible.  
The following assessments must be performed approximately 4 weeks after the last dose of study 
drug, etoposide, or cisplatin or carboplatin, whichever is discontinued last, but prior to the 
initiation of a new anti-cancer therapy: 
•
Physical examination 
•
Vital signs 
•
Weight 
•
ECOG performance status 
•
Hematology 
•
Chemistry 
•
Coagulation 
•
Urinalysis (dip stick is sufficient) 
•
Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc 
interval 
,19(67,*$7,21$/1(:'58*
5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 78 of 235 
22 April 2016 
 
CONFIDENTIAL 
•
Serum sample for anti-tarextumab antibody on all subjects 
•
Blood sample for biomarker (unless done within the last 14 days)  
•
Plasma sample for tarextumab PK from all subjects enrolled. 
•
Tumor assessment with CT (with contract) or MRI scan of chest, abdomen, and pelvis for 
subjects who have not previously demonstrated disease progression within the previous 4 
weeks.  
•
Concomitant medications 
•
Adverse event recording  
11.5
Follow up 
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 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.  
Additionally, subjects who discontinue study treatment for any reason other than disease 
progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) and bone 
scan every 12 weeks (+/- 5 days) during the Follow-up Period until documented disease 
progression or initiation of new anti-cancer therapy, whichever is sooner. 
12.0
DATA QUALITY ASSURANCE 
Accurate, consistent, and reliable data will be ensured through the use of standard practices and 
procedures.  Site initiation visits will be conducted separately at each clinical site.  Clinical 
Research Associates (CRAs) will monitor the study and verify that the data are accurate.  
OncoMed Pharmaceuticals, Inc. has contracted with a contract research organization (CRO) to 
perform the data management of this trial.  The data will be captured using a validated EDC 
system.  The medical monitors, CRAs, and site personnel will be trained in the use of the EDC 
system.  The clinical data and the site-specific laboratory data will be entered by site personal 
into the EDC system.  System backups for data stored at OncoMed Pharmaceuticals, Inc. and at 
all CROs, and records retention for the study data will be consistent with the standard procedures 
for these organizations. 
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13.0
STATISTICAL PLAN  
13.1
Power and Sample Size 
13.1.1
Phase 1b 
The Phase 1b portion of the trial is a 3+3 dose escalation design.  Table 6 shows the probability 
of declaring a dose as exceeding the MTD for a variety of underlying toxicity rates.  For example 
there is an 83 percent probability to declare a dose with an incidence of dose limiting toxicity of 
50 percent as exceeding the MTD.  This compares with a probability of 29 percent for a dose 
with an incidence of dose limiting toxicity of 20 percent. 
Table 6: 
Power to Declare a Dose as Exceeding the MTD for Various Incidence 
Rates 
Incidence of Toxicity 
Probability of more than 
1 out of 3 subjects with 
Toxicity in first group of 
three 
Probability of 1 subject 
with Toxicity in first 
group of  3 then at least 
1 subject with toxicity in 
second group of 3 
Probability of Stopping 
Dose Escalation 
0.05 
0.007 
0.019 
0.027 
0.10 
0.028 
0.066 
0.094 
0.15 
0.061 
0.125 
0.186 
0.20 
0.104 
0.187 
0.291 
0.25 
0.156 
0.244 
0.400 
0.30 
0.216 
0.290 
0.506 
0.35 
0.282 
0.322 
0.604 
0.40 
0.352 
0.339 
0.691 
0.45 
0.425 
0.340 
0.766 
0.50 
0.500 
0.328 
0.828 
 
13.1.2
Sample Size Justification – Phase 2 
At the final analysis we will evaluate the effect of tarextumab on PFS in subjects in the intention 
to treat population. The final analysis will take place when 91 progression events have been 
observed or 10 months after the completion of enrollment whichever occurs first.  
Lets denote the treatment effect in terms of the log of the hazard ratio by 
1θ : 
We can write the null hypotheses for this test in the ITT group of subjects as. 
1
1
:
0
H
θ =
 
and the alternative as 
1
:
0
A
H
θ <
 
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The power and type 1 error for the log rank test of this hypothesis is presented in Table 7. . 
Table 7: 
PFS: Power for H1 
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 
0.069 
0.14 
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 
0.809 
 
HR=0.65 
0.0687 
0.3365 
0.846 
 
HR=0.60 
0.1204 
0.4709 
0.9194 
 
HR=0.50 
0.3223 
0.7647 
0.9884 
Cumulative Prob of Stopping for Harm 
 
 
 
 
Alt 
4e-04 
8e-04 
0.0018 
 
Null 
0.0381 
0.0762 
0.1501 
 
HR=1/0.75=1.33 
0.258 
0.4246 
0.6275 
 
HR=1/0.67=1.49 
0.4172 
0.617 
0.8052 
 
HR=1/0.50=2.0 
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 percent power with 0.15 type 1 error to detect a 
hazard ratio of 0.67.  There is a 7.6 percent chance of stopping early for Harm under the null, 
42.5 percent chance of stopping early for Harm if the hazard ratio is 1/.75 = 1.33, 61.7 percent 
chance of stopping early for harm if the hazard ratio is 1/.67 = 1.49, and a 94.1 percent chance 
of stopping early for harm if the hr = 1/.5 = 2.0.  
Analyses 1 and 2 will take place at the last two quarterly safety review meeting of the DSMB.  
The estimated number of events at those times are presented in Table 7.  If the number of events 
differs from what is presented in the table, the efficacy and safety boundaries will be 
recalculated using the spending functions which are footnoted in Table 7. 
Survival is a secondary endpoint in this study.  An analysis of overall survival 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.  
Further the final analysis of survival will take place when there are 98 events or 6 months after 
the final analysis for PFS whichever occurs first.  Figure 10 and Table 10 present enrollment, 
PFS events and Deaths over time. The calculations in Figure 9 and Table 10 take into account 
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non constant hazard as described in Table 8 and 9.  The basis for the estimates of non constant 
hazard are presented in Figure 6- 9 which are Kaplan -Meier (KM) curves for PFS and Survival 
in (Ref 10, and Ref 14).  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 10 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 percent of the rate at which events accrue in 
the control arm and 60 percent of the rate at which events accrue in the tarextumab arm.  When 
79 PFS event accrued in the study, we observed 39 censors for a censoring rate of 
39/(39+79)=33 percent. This information was used to recalibrate the total number of events at 
the final analysis, the type 1 error and the power.  
Table 8: 
Hazards for Piece-Wise Exponential Model of Progression Free 
Survival 
Period 
0-5 months 
5-7 months 
7-8 months 
>8 months 
Percent 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)  
from 8 to 18 
months (Noda) 
 
0.50 
(0.125 to 0.0625) 
from 8 to 11 
months (Hanna) 
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 
 
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Table 9: 
Hazards for Piece-wise Exponential Model of Survival 
Period 
0-9 months 
9-15 months 
15-18 months 
>18 months 
Percent 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 
(.15 to 0.080 from 18 to 
24 months Hanna) 
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 
 
Figure 6: 
PFS in Subjects Treated with Etoposide plus Cisplatin. from 
Noda et al 
 
 
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Figure 7: 
PFS in Subjects Treated with Etoposide plus Cisplatin - Hanna 
 
 
Figure 8: 
Survival in Subjects Treated with Etoposide plus Cisplatin(from Noda 
et al.) 
 
 
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Figure 9: 
Survival in Subjects Treated with Etoposide plus Cisplatin (from 
Hanna et al.) 
 
 
Figure 10: 
Enrollment, Progressions and Deaths over Time – Control Hazard of 
Progression of 0.1386 Beyond 9 months 
 
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Table 10: 
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 
21 
22 
23 
24 
25 
26 
27 
28 
29 
30 
Cum Enrollment 
22 
77 
85 
89 
91 
105 
119 
133 
134 
134 
134 
134 
134 
134 
134 
134 
134 
134 
134 
134 
Total PFS Events 
5 
31 
38 
43 
49 
55 
62 
69 
75 
80 
85 
90 
94 
96 
97 
98 
99 
99 
100 
100 
Total PFS Events2 
6 
35 
42 
48 
54 
61 
68 
76 
82 
87 
92 
98 
101 
103 
104 
104 
105 
105 
105 
106 
Total Deaths 
3 
19 
23 
27 
32 
37 
42 
49 
55 
61 
66 
72 
77 
81 
86 
91 
95 
99 
102 
105 
Total Deaths2 
4 
22 
27 
32 
37 
42 
49 
56 
63 
69 
75 
81 
86 
91 
96 
100 
104 
108 
111 
114 
PFS Censor(Trt) 
1 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
15 
16 
16 
16 
16 
16 
16 
17 
PFS Censor(Ctl) 
1 
4 
5 
6 
7 
8 
9 
9 
10 
11 
12 
12 
13 
13 
13 
13 
13 
13 
13 
13 
Total PFS Events 2 and Total Deaths 2 refer to the number of progressions and deaths observed when tarextumab does not prolong 
progression nor death. 
 
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We see from Table 10 that approximately 70 percent of the 98 deaths required for the final 
analysis of survival will be observed at the time of the final analysis for PFS.  Table 11 presents 
the power to detect a survival benefit for several hazard ratios assuming that type 1 error is 
controlled at the 0.15 level and additional analyses take place at approximately 50, 67, 83 
percent 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 11. 
  
Table 11: 
Power for OS 
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 
0.002  
0.0226  
0.1499  
0.6511 
 
HR=0.682 
0.0054  
0.053  
0.2711  
0.8047 
 
HR=0.60 
0.0178  
0.1365  
0.4869  
0.9324 
 
HR=0.65 
0.0086  
0.0777  
0.3471  
0.8637 
 
HR=0.50  
0.0717  
0.361  
0.7846  
0.9918 
 
 
 
 
 
Cumulative Probability of Stopping 
for Harm 
 
 
 
 
 
Alt  
3e-04  
5e-04  
9e-04  
0.0019 
 
Null  
0.0179  
0.0381  
0.0744  
0.1501 
 
HR=1/0.75 = 1.33 
0.1372  
0.266  
0.4332  
0.647 
 
HR=1/0.682=1.47 
0.2235  
0.4037  
0.6007  
0.80 
 
HR=1/0.50 =2.00 
0.6278  
0.8426  
0.9496  
0.9911 
1The boundary for rejecting the null hypothesis  for efficacy is obtained  from the gamma(-16)  alpha spending 
function 
2The 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 percent power with 0.15 type 1 error to detect a 
hazard ratio of 0.682. There is a 7.4 percent chance of stopping early for Harm under the null, 
43.3 percent chance of stopping early for Harm if the hazard ratio is 1/.75 = 1.33, 60.1 percent 
chance of stopping early for harm if the hazard ratio is 1/.682 = 1.47, and a 95.0 percent chance 
of stopping early for harm if the hr = 1/.5 = 2.0. 
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13.1.3
Randomization and Blinding 
For the purpose of randomizing subjects to treatment, each subject’s platinum based therapy as 
well as the the prior use of whole brain radiation or PCI will be collected at screening.  A 
dynamic randomization system will assign subjects to treatment in a way that balances the 
assignments to tarextumab + Chemo versus Chemo + placebo alone among all subjects in the 
trial, among all subjects receiving the same platinum based therapy (Carboplatin or Cisplatin), 
and among subjects who received as well as those who did not receive prior whole brain 
radiation or PCI. 
Investigators, site personnel, subjects, and the sponsor will remain blinded to treatment 
assignment for the duration of the study until the final analysis of overall survival is completed. 
13.1.4
Procedures for Unblinding 
All requests for urgent safety unblinding require the approval of the Medical Monitor and may 
be made by calling either the Medical Monitor directly during business hours or the 24-hour 
randomization support staff after business hours (contact information will be provided in the 
Study Reference Manual).  The randomization support staff will forward the request to the 
Medical Monitor.  Upon OncoMed’s approval, the randomization system will provide the site 
with the study treatment assignment.  No treatment cross-over will be permitted in the study. 
13.2
Phase 1b 
All reported adverse events will be mapped to standard coding terms using the Medical 
Dictionary for Regulatory Activities (MedDRA), grouped by system organ class and preferred 
terms and tabulated by dose groups.  The incidence of adverse events at each dose will be 
tabulated by grade and relationship to study drug.  Vital signs and Laboratory markers will also 
be summarized by dose of study drug using mean changes from baseline.  Shift tables for lab 
markers will be provided for each dose of study drug. 
Tumor response will be presented in a subject listing sorted by dose group.  Information included 
in the listing will be Best tumor response, time to progression or death, best percent decrease in 
sum of longest diameter (SLD) from baseline, and duration of response. 
Tumor response in the expansion cohort will also be summarized.  Time to Progression or Death 
and duration of response will be summarized with a Kaplan Meier Curve and related statistics.  
Best tumor response will be summarized with simple descriptive statistics.  The largest percent 
decrease in SLD will be summarized with a waterfall plot and simple descriptive statistics. 
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13.3
Phase 2 
13.3.1
Subject Populations for Analysis 
The Intent-to-Treat (ITT) Population is comprised of all randomized subjects.  All baseline 
characteristics, demographic and efficacy data will be analyzed using the ITT Population. 
The Per Protocol Population (PP) is comprised of all randomized subjects who received at least 
one dose of study drug and had at least one post baseline tumor assessment.  All efficacy data 
will be analyzed using the PP population as well as the ITT Population. 
The Safety Population is comprised of all subjects who receive 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).  All safety endpoints will be summarized using the Safety Population. 
The Pharmacokinetic Population is comprised of all subjects who had at least one follow-up 
tarextumab blood sample obtained. 
The Immunogenicity Population is comprised of all subjects who had a baseline and at least one 
follow-up anti-tarextumab sample obtained. 
13.3.2
Analysis Set 
The Analysis set for the Phase 2 portion of the study will include all subjects who were 
randomized in the Phase 2 portion of the trial to receive either tarextumab or control. The 
Analysis set will not include data from subjects who were enrolled in the Phase 1b portion of the 
trial.  The data cut for the formal final analysis of the study will take place at the point where 91 
progression events have occurred or 10 months after the completion of enrollment, whichever 
occurs first.  Note that the analysis time may be extended beyond 10 months for reasons 
concerning study conduct (e.g. subjects who are randomized and not treated). This will ensure 
that the study will have 81 percent power to detect a hazard ratio of 0.67 (improvement in 
median PFS from 4.8 months to 7.2 months) with an associated total one sided type 1 error of  
0.15.  The data cut for the final analysis of survival will be 6 months after the data cut for the 
formal final analysis of the study or when 98 deaths have been observed, whichever occurs first. 
Once again, the time for the final analysis may be extended beyond 6 months for reasons of 
study conduct. 
13.4
Endpoints 
13.4.1
Efficacy Endpoints 
Efficacy endpoints will include Investigator-assessed progression-free survival, continuous 
variable assessment of tumor length, best response, response rate defined as rate of confirmed 
complete response (CR) + rate of confirmed partial response (PR), duration of response, sites of 
progression, Land mark survival at 6, 12, 18 and 24 months and overall survival.  Efficacy 
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endpoints will be analyzed using the ITT Population and are described in more detail in the 
Statistical Methods (Section 13.6).  
13.4.2
Safety Endpoints 
Safety endpoints will include AEs, SAEs, clinical laboratory assessments, and anti-tarextumab 
antibody testing.  Safety endpoints will be analyzed using the Safety Population for both 
treatment groups.  The purpose of these analyses will be to provide a thorough evaluation of 
potential safety issues. 
Adverse Events 
All reported adverse events will be mapped to standard coding terms using the Medical 
Dictionary for Regulatory Activities (MedDRA), grouped by system organ class and preferred 
terms and tabulated by treatment groups.  The incidence of adverse events in each treatment 
group will be tabulated by NCI-CTCAE v 4.0.2 grade and relationship to study drug.  Adverse 
events that led to withdrawal and adverse events that were considered serious will be tabulated 
separately. 
Clinical Laboratory Assessments and Vital Signs 
Clinical laboratory data (hematology, chemistry, and urinalysis) and vital signs will be 
summarized by treatment group using descriptive statistics of the reported values and changes 
from baseline at the point of each subject’s minimum value/change, maximum value /change and 
the last value/change.  In addition, the frequency counts and percentages of subjects shifting 
from “low,” or “normal,” at baseline to “high” post baseline or “high” or “normal” at baseline to 
“low” post baseline for each treatment group will also be provided at the same time points.   The 
high and low post baseline categories will be further classified by NCI-CTCAE grading if 
available.   All laboratory and vital sign data will be presented in listings and special attention 
will be given to any unexpected abnormal results. 
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ECOG 
ECOG performance status at baseline and follow-up will be listed by subject for each treatment 
group.  Changes in ECOG performance status scores from baseline will be summarized by 
treatment group at selected scheduled timepoints using shift tables. 
13.4.3
Immunogenicity Endpoints 
Immunogenicity endpoints will be analyzed using the Immunogenicity Population.  The 
incidence of anti-tarextumab antibody development in each treatment group will be compared 
with simple proportions.  For subjects with a positive result for anti-tarextumab antibody, the 
incidence of neutralizing capability development will further be summarized by standard 
quantitative methods.  In addition, the impact on safety and efficacy of detectable 
anti-tarextumab antibodies and neutralizing anti-tarextumab antibodies will be assessed by 
summarizing PFS and Response rate in the subgroups of subjects with and without these anti 
tarextumab antibodies. These analyses may not be carried out if the number of subjects with anti-
59R5 antibodies does not permit a reasonable estimate of PFS and Response rate. 
13.4.4
Pharmacokinetic Endpoints 
For subjects enrolled in the Phase 1b portion of the trial, AUC, clearance, volume of distribution 
and apparent half life) of tarextumab will be summarized by dose group with descriptive 
statistics including the mean, variance, median and range.  
Pharmacokinetic data obtained from the Phase 1b and Phase 2 portions of the study will be 
pooled with data from the Phase 1a study (Study 59R5-001) to conduct population PK analysis.  
Population mean and inter-individual variability of the PK parameters will be reported.  
Individual PK parameter and exposure will be reported.  
13.4.5
Exploratory Endpoints 
Changes from baseline in exploratory pharmacodynamic biomarkers, including Notch pathway 
related genes and proteins and circulating tumor cells following tarextumab treatment will be 
summarized with simple descriptive statistics. Tests to compare the changes in these variables 
between the 59R5 arm and the control arm may be undertaken as well on an informal descriptive 
basis. Surrogacy of changes in these exploratory biomarkers will be evaluated in models for time 
to progression and response that include these exploratory variables and the randomized 
treatment assignment. These models may also account for the level of Notch 3 expression. 
13.5
Statistical Methods 
Other than for the primary efficacy endpoint of PFS, and overall survival, no adjustment will be 
made for multiplicity. The methods of analyses listed below are described for the intention to 
treat group of subjects. 
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13.5.1
Progression-Free Survival 
The primary endpoint PFS, based on the Investigator-assessments of tumor response, is defined 
as the number of days from randomization until death or disease progression as defined by 
RECIST criteria for the ITT Population.  The Kaplan-Meier method will be used to estimate the 
proportion of subjects without progression or death overtime and the median progression-free 
survival time.  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.  The stratification factors will be platinum choice (cisplatin versus 
carboplatin) and the prior use of whole brain radiation or PCI. . Subjects who have not 
experienced death or progression by their last contact will be censored at the time of their last 
radiographic response assessment and the number and percentage of these subjects will be 
displayed.  In addition subjects who receive non protocol anti-cancer therapy will be censored at 
the time they start this treatment. Surgical resection of tumor, palliative radiation (prophylactic 
cranial irradiation, according to standard of care, is permitted for subjects who are without 
progression following 6 cycles of EP treatment, subjects may have prophylactic cranial 
irradiation (PCI) or whole brain radiation (WBRT) prior to study entry) and/or a new systemic 
anti-cancer therapy will be considered non protocol therapy. Initiation of a new intravenous 
bisphosphonate or denosumab more than 30 days after the first administration of study drug will 
be also considered non protocol therapy.  
Formal testing for determining whether tarextumab has an impact of PFS will be carried out as 
described in Table 7.  If there is a disparity in discontinuation rates between treatment arms or in 
the types of censoring or in the use of non protocol therapy, sensitivity analyses will be 
performed to assess the impact.  
In addition, for subjects who died or progressed after an extended lost-to-follow-up period 
(greater than 17 weeks from the previous assessment), PFS will be right censored at the date of 
the last adequate assessment prior to the lost to follow-up period.  Subjects who do not have any 
tumor assessments will be treated as censored at Day 1. 
PFS will also be summarized for the subset of subjects who received cisplatin and separately for 
the subset of subjects who received carboplatin.  
Continuous Variable Assessment of Tumor Length 
The tumor length will be calculated as the sum of the longest diameters for the target lesions (as 
defined by RECIST 1.1 criteria).  The data will be displayed graphically with waterfall plots.  
Summary statistics including mean, standard deviation, median, minimum, and maximum for 
tumor length will be presented for baseline, 6 weeks post-baseline, and 12 weeks post-baseline.  
These summary statistics will also be presented for differences from baseline at 6 and 12 weeks 
post-baseline for each arm of the study.  Along with the summary statistics, the 95% confidence 
intervals of the mean tumor length for each treatment arm at each of the three timepoints will 
also be displayed.  An ANCOVA model will be used to test the hypothesis that there is no 
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difference between treatment arms with regard to changes from baseline tumor length at 
scheduled tumor assessments.  Choice of platinum therapy (cisplatin versus carboplatin) and 
prior use of WBRT or PCI will be factors in the model and baseline tumor length will be used as 
a covariate.  Missing values will not be imputed. 
In the event that the parametric assumptions are not met, the p-value will be generated using a 
nonparametric test utilizing ranks.  This nonparametric test will be performed at scheduled tumor 
assessments, using the log of (tumor length at week t divided by tumor length at baseline) as the 
endpoint.  In the case of complete response when the outcome variable is undefined, the best 
possible rank will be assigned.  In the case of death or withdrawal due to adverse event, the worst 
possible rank will be assigned. 
The rate of change in tumor volume at progression (SLD at progression – SLD at nadir)/SLD at 
nadir will be compared between the two arms of the study. The rate of change in tumor burden 
has been shown to be predictive of survival (Ref 15, and Ref 16).  In addition the rate of change 
in tumor volume from baseline to the first tumor assessment (SLD first scheduled post baseline 
tumor assessment – SLD baseline)/(SLD baseline) will be compared between the two arms of the 
study. The comparison will be made to test the difference in the growth rate in the tarextumab 
arm versus control arm. 
13.5.2
Response Rate (Best Overall Response) 
The best overall response is defined as the best Investigator-assessed response recorded from the 
start of the treatment until disease progression in the following order of importance: 
•
Complete Response (CR) 
•
Partial Response (PR) 
•
Stable Disease (SD) 
•
Progressive Disease (PD) 
•
Not Evaluable (NE) 
The number and proportion of subjects achieving each of these categories of response will be 
summarized for each dose group.  The best overall response rate is the number of subjects whose 
best response is either a CR or PR divided by the number of subjects randomized to the 
respective arms.  The confirmed response rate is the number of subjects per treatment arm who 
have either a confirmed CR or confirmed PR (according to RECIST criteria) divided by the 
number of subjects randomized to the respective arms.  These proportions and their 95% 
confidence intervals will be displayed.  The p-value for equality between treatment arms will be 
calculated for the two groups using a logistic regression model with treatment, type of platinum 
based therapy, and prior use of WBRT or PCI as factors in the model.  Subjects without any 
tumor assessments will be counted as a non responder.  
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13.5.3
Duration of Response 
The Investigator-assessed duration of response is defined as the time from the first partial or 
complete response to the time of death or disease progression for subjects with a confirmed 
response.  The Kaplan-Meier method will be used to estimate the duration of response.  The 95% 
confidence intervals for duration of response will also be calculated for each treatment arm.  The 
p-value for treatment effect will be generated using a Cox proportional hazards model.  Subjects 
who have not experienced death or progression by their last contact will be censored at the time 
of their last radiographic response assessment. If the number of responses is not sufficient to 
produce interpretable KM curves, the analysis of duration of response may not be undertaken. 
Sites of Progression 
The sites of progression will be classified according to organ type and compared between the 
two arms using a chi-square test. If a subject has a new site of disease, that site will be used as 
the organ site. If a subject has no new site of disease, then the organ site will be classified as 
existing tumor. Two chi-square tests will be performed, one using the classification existing 
organ site versus other and the second using the full classification described above. 
13.5.4
Overall Survival 
A comparison of the overall survival for the two groups will be performed.  Overall survival is 
defined as the number of days from randomization until death occurs.  No treatment cross-over is 
permitted in the study.  The Kaplan-Meier method will be used to estimate both the survival 
curves and the median survival time.  The 95% confidence intervals for median survival times 
will also be calculated.  A p-value for treatment effect will also be generated using a stratified 
Cox proportional hazards model.  The stratification factors will be type of platinum based 
therapy and the prior use of whole brain radiation or PCI.  Subjects who have not experienced 
death by their last contact date will be censored at that time and the number and percentage of 
these subjects will be displayed.  Subjects will not be censored for OS if they start non-protocol 
therapy. If there is a disparity in discontinuation rates between treatment arms, a sensitivity 
analysis will be performed to assess the impact. 
Survival will also be summarized for the subset of subjects who received cisplatin and separately 
for the subset of subjects who received carboplatin.  
13.5.5
Landmark Survival 
The Kaplan Meier estimates of survival at 6, 12, 18 and 24 months will be compared between the 
two arms using a simple Z test. 
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13.5.6
Correlation of Biomarkers with Efficacy Endpoints 
The impact of the biomarkers Notch3, Hes1, Hey2, Hey1 and Hes6 on the treatment effect as 
measured by PFS and OS will be evaluated with a Cox Proportional Hazards regression model 
with treatment, biomarker and treatment by biomarker interaction included in the model as 
independent variables.  The impact of these biomarkers will also be assessed on the treatment 
effect for 12 month OS and ORR using a logistic regression model with treatment, biomarker and 
treatment by biomarker interaction included in the model. 
13.6
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be analyzed using the Intent-to-Treat Population 
for both treatment arms.  Quantitative and/or categorical summaries will be presented for 
demographics and other baseline characteristics.  For continuous variables, data will be 
summarized by sample size, mean, standard deviation, median, minimum, and maximum.  
Categorical data will be summarized as frequency counts and percentages.   
13.7
Treatment Exposure 
Treatment exposure will be summarized as duration on treatment and extent of exposure to 
Cisplatin, Carboplatin, Etoposide, tarextumab, and Placebo by treatment arm.  Duration on 
treatment will be summarized quantitatively by number of doses and duration in days using 
mean, standard deviation, median, minimum, and maximum. 
Measures of extent of exposure include the cumulative dose per subject, dose intensity and 
compliance.  Dose intensity is defined as the total dose the subject actually received divided by 
the total dose the subject would have received had there been no dose delays and no dose 
reductions. Compliance will be summarized as the number of subjects who had dose(s) withheld 
or delayed.  A table summarizing the number of subjects with 0%, 20%, 40%, 60%, 80%, and 
100% compliance will also be presented.  The reasons for dose(s) withheld or delayed will also 
be summarized. 
13.8
Termination Criteria 
Enrollment will terminate when approximately 135 subjects have been randomized.  All ongoing 
subjects will continue to be dosed until disease progression, unacceptable toxicity, subject 
withdrawal, or the Investigator withdraws subjects from the study. 
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13.9
Deviation Reporting 
The following protocol deviations will be recorded and summarized by treatment arm in the final 
report: 
1. enrollment violations 
2. dosing violations 
3. concomitant therapy violations 
4. continuation of therapy when treatment should have been discontinued 
13.10 Data Safety Monitory Board 
A Data Safety Monitoring Board (DSMB) will review data on an ongoing basis in Phase 2 
portion of the study to ensure subject safety.  Specifically, they will review partially blinded 
demographic, dosing and safety data at the following timepoints:  1) after 10 subjects have been 
randomized and all subjects have received at least 2 doses of tarextumab or Placebo, 2) after 25 
subjects have been randomized and all subjects have received 2 doses of tarextumab or Placebo, 
and 3) quarterly thereafter.  The DSMB will consist of at least two Oncologists and a statistician 
who are not otherwise participating in the conduct of the trial.  A separate unblinded and 
independent statistician designated by OncoMed will prepare summary tables and listings 
summarizing results for all subjects..  The rules/details of presentations to the DSMB will be 
summarized in the DSMB Charter. 
13.11 Analysis of PFS and OS Prior to the Final Analysis 
Two analyses for PFS are planned beyond the DSMB Safety Reviews detailed in Section 13.10. 
These analyses will take place at the quarterly meetings of the DSMB and be initiated in 
May 2016.  As noted above in Table 7 and Table 11, 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 the assessment of harm arising from the 
multiple analysis over time of PFS and overall survival.  The final analysis for pfs will occur 
when 91 progression events have occurred while the final analysis for OS will occur when 98 
deaths have been observed 
13.12 DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
By participating in this trial, the Investigator(s)/institution(s) agree to permit trial-related 
monitoring, audits, IRB/IEC(s) review by OncoMed and its representative and regulatory 
inspection(s) by providing direct access to all primary source documents, such as medical 
records, CT scans, etc. 
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14.0
ETHICAL CONSIDERATIONS 
This study will be conducted according to international standards of Good Clinical Practice 
(ICH guidance E6), all federal, state, and local regulations as well as with the requirements of the 
appropriate Institutional Review Board or Ethics Committee and any other institutional 
requirements. 
15.0
INVESTIGATOR REQUIREMENTS 
15.1
Informed Consent 
A sample informed consent form will be provided.  OncoMed must review any proposed 
deviations from the sample informed consent form prior to submission to the IRB/IEC.  The final 
IRB/IEC-approved document must be provided to OncoMed for regulatory purposes. 
The informed consent document must be signed and dated by the subject or the subject’s legally 
authorized representative before his/her participation in the study.  Documentation is required in 
each subject’s record that informed consent was obtained prior to participation in the study.  A 
copy of the informed consent document must be provided to the subject or the subject’s legally 
authorized representative. 
Signed consent forms must be kept in each subject’s study file and must be available for 
review/verification by study monitors at any time. 
15.2
Institutional Review Board/Ethics Committee Approval 
This protocol, the informed consent documents, and relevant supporting information must be 
submitted to the IRB or IEC for review and must be approved before the study is initiated.  The 
study will be conducted in accordance with all regulatory requirements and the IRB or IEC 
requirements. 
The Principal Investigator is responsible for keeping the IRB or IEC apprised of the progress of 
the study and of any changes made to the protocol as deemed appropriate.  The IRB or IEC must 
be updated at least once a year or in accordance with local requirements.  The Principal 
Investigator must also inform the IRB or IEC of any significant adverse events. 
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Investigators are required to follow their respective IRB or IEC requirements for the reporting of 
Serious Adverse Events and written safety reports to the IRB or IEC.  Investigators must 
immediately forward to their IRBs or IECs any updates provided by OncoMed (e.g., Investigator 
Brochure, safety amendment, etc.) 
15.3
Study Monitoring 
Site visits will be conducted on a regular basis by an authorized OncoMed representative (e.g., 
Clinical Research Associate [CRA]) to inspect study data, subjects’ medical records, and remote 
data capture (RDC) fields in accordance with current GCPs.  During the site visit, the OncoMed 
CRA or representative will review the following: 
–
Completeness of subject records 
–
Accuracy of entries in the RDC fields 
–
Adherence to the protocol and to GCP 
–
Adherence to specifications for study drug storage, dispensing, and accountability 
The OncoMed CRA or representative will be responsible for reviewing completed RDC fields 
and clarifying and resolving any data queries. 
The CRA will also review regulatory study documents during site visits.  The Investigator and 
key study personnel must be available to assist the OncoMed monitor or representative during 
these visits. 
The Principal Investigator will permit authorized representatives of OncoMed and any regulatory 
authority to inspect facilities and records relevant to this study. 
15.4
Auditing Procedures 
A representative of OncoMed may conduct an audit of the clinical research activities to ensure 
accordance with internal standard operating procedures (SOPs) and to evaluate compliance with 
the principles of GCP.  Any regulatory authority may also conduct an inspection during the study 
or after its completion.  If an inspection is requested by a regulatory authority, the Investigator 
must inform OncoMed of this immediately. 
15.5
Data Collection 
The data will be reported by the site via an internet-based remote data entry capture (RDC).  The 
RDC screens should be completed in accordance with instructions from OncoMed. 
The RDC screens should be completed by examining personnel, the study coordinator, or 
designee.  The RDC screens must be reviewed by the Investigator.  The Investigator will ensure 
that all data is completely and accurately recorded on the RDC screens. 
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15.6
Investigational Medicinal Product Accountability 
The tarextumab and Placebo required for completion of this study will be provided by OncoMed 
or its agent.  The recipient will acknowledge receipt of this IMP by completing the Drug 
Request/ Acknowledgment of Receipt Form and faxing it to OncoMed or its representative in 
Phase 1b portion of the study and by completing the corresponding information in Interactive 
Web-based randomization system (IWRS) in Phase 2 portion of the study.  Damaged supplies 
will be replaced. 
Accurate records of all IMP dispensed from and returned to the pharmacy should be documented 
by completing the Drug Accountability Log. 
Sites will destroy all used and/or partially used vials.  If the site does not have the capacity to 
destroy IMP, the used/partially used vials should be returned to the drug distribution center for 
destruction along with a completed Drug Return Form. 
Sites will destroy all unopened, unused, and expired vials per the site’s institutional guidelines 
after approval by OncoMed or designee.  Site may also return the remaining IMP to the drug 
distribution center along with a completed Drug Return Form. 
All IMP Accountability Forms will be provided by OncoMed.  Upon agreement by OncoMed, 
the site may use its own IMP Accountability Log if it contains all of the information required on 
OncoMed’s log. 
15.7
Disclosure of Data and Publication 
Subject medical information obtained by this study is confidential, and disclosure to third parties 
other than those noted below is prohibited. 
Upon the subject’s permission, medical information may be given to his or her personal 
physician or other appropriate medical personnel responsible for his/her welfare. 
Data generated by this study must be available for inspection upon request by representatives of 
any regulatory authority, auditors, OncoMed representatives, and the local IRB or IEC for each 
study site. 
OncoMed commits to publish the study results.  The manuscript will include all subjects from all 
sites.  The Investigators will participate in writing and reviewing the manuscript.  OncoMed will 
make the final decision on all presentations of study results and submissions of abstracts and 
manuscripts working in good faith with the Investigators. 
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15.8
Retention of Records 
Regulations require that records and documents pertaining to the conduct of this study and the 
distribution of investigational drug, including consent forms, laboratory test results, study 
medication inventory records, and regulatory documents, must be retained by the Principal 
Investigator for 2 years after marketing application approval.  If no application is filed, these 
records must be kept for 2 years after the study is discontinued and the applicable regulatory 
authorities are notified.  OncoMed will notify the Principal Investigator of these events. 
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16.0
REFERENCES  
1.
D’Angelo SP, Pietanza MC. The molecular pathogenesis of small cell lung cancer. 
Cancer Biology & Therapy 2010;10 (1):1-10. 
2.
Puglisi M, Dolly S, Faria A, Myerson JS, Popat S, O’Brien MER. Treatment options for 
small cell lung cancer – do we have more choice? British Journal of Cancer 
2010;102:629-638. 
3.
Clarke MF, Fuller M. Stem Cells and Cancer: Two Faces of Eve. Cell 2006;124:1111-
1115. 
4.
Wicha MS, Liu S, Dontu G. Cancer Stem Cells: An Old Idea – A Paradigm Shift. Cancer 
Research 2006;66:1883-1890. 
5.
Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells 
promote radioresistance by preferential activation of the DNA damage response. Nature 
2006; 444:756-760. 
6.
Dylla SJ, Beviglia L, Park IK, Chartier C, Raval J, Ngan L, et al. Colorectal Cancer Stem 
Cells Are Enriched in Xenogeneic Tumors Following Chemotherapy. PloS ONE 
2008;3(6):1-13. 
7.
Rosen JM, Jordan CT. The Increasing Complexity of the Cancer Stem Cell Paradigm. 
Science 2009;324:1670-1673.  
8.
Takebe N, Harris PJ, Warren RQ, Ivy SP. Targeting cancer stem cells by inhibiting Wnt, 
Notch, and Hedgehog pathways. Nature Clinical Oncology 2011; 8:97-106. 
9.
Daniel VC, Marchionni L, Hierman JS, Rhodes JT, Devereux WL, Rudin CM, et al.A 
Primary Xenograft Model of Small_Cell Lung Cancer Reveals Irreversible Changes in 
Gene Expression Imposed by Culture In vitro. Cancer Research 2009;69(8):3364-3373. 
10.
Noda K, Nishiwaki Y, Kawahara M, Negoro S, Sugiura T, et al. Irinotecan plus cisplatin 
compared with etoposide plus cisplatin for extensive small-cell lung cancer. New 
England Journal of Medicine 2002;346(2): 85-91. 
11.
Foster N, Mandrekar S, Schild S, Nelson G, Rowland K, et al. Prognostic Factors Differ 
by Tumor Stage for Small Cell Lung Cancer. Cancer 2009;115:2721-31. 
12.
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 1982;5:649-655. 
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13.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New 
response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). 
Eur J Cancer 2009:45:228–47. 
14.
Hanna N, Bunn PA Jr., Langer C, Einhorn L, Guthrie T Jr., Beck T, 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):2038-43. 
15.
Claret L, Girard P, Hoff PM, Van Cutsem E, Zuideveld KP, Jorga K, et al. Model-Based 
Prediction of Phase III Overall Survival in Colorectal Cancer on the Basis of Phase II 
Tumor Dynamics. J. Clin. Oncol. 27:4103-8 2009. 
16.
Claret L, Gupta M, Han K, Joshi A, Sarapa N, He J, et al. Evaluation of Tumor-Size 
Response Metrics to Predict Overall Survival in Western and Chinese Patients With First-
Line Metastatic Colorectal Cancer. J. Clin. Oncol. 31:2110-14, 2013 
 
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APPENDIX A: 
STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
MTD w/etoposide 
+cisplatin 
Phase 1b dose finding
tarextumab in combination with EP 
Blinded Treatment Phase 
Choice of platinum therapy (cisplatin or carboplatin) will 
be declared at the investigator’s discretion prior to 
randomization.  
Follow-up
(subsequent anti-cancer 
therapy and survival 
status follow-up every 3 
months) 
Arm A
EP + 
tarextumab  
for 6 cycles  
Phase 2, multicenter, randomized, placebo controlled 
Arm B
EP + placebo  
for 6 cycles  
Treatment assignment will be blinded until the final analysis is completed for overall 
survival. No cross-over will be allowed. 
*PCI given to subjects who have not received PCI or WBRT prior study entry per Investigator 
Alteration to the choice of platinum therapy is not permitted after the randomization 
tarextum
ab alone 
till PD 
Placebo
alone till 
PD 
MTD w/etoposide 
+carboplatin 
*PCI
(SD,
PR,
CR) 
*PCI
(SD,
PR,
CR) 
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APPENDIX B: 
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 1B 
Procedure 
Screening 
Treatment Period 
Follow-Upb 
Cycles 1-6 (every 21 days) 
 
> Cycles 7 
(every 21 days) 
Treatment 
Terminationa 
 
Day -28 
to -1 
Day-14 
to -1 
Day 1 
(±1 
day) 
Day 2 
Day 3 
 
 
Every 3 
months 
Day 8 
(Cycles 1-3 
only) 
Post Cycle 
6 
Day 1(± 1 day) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical and oncology 
history 
X 
 
 
 
 
 
 
 
 
 
Physical examinationc 
 
X 
Xd
 
 
 
 
X 
X 
 
Weight, vital signs, 
heighte 
 
X 
X 
X 
X 
 
 
X 
X 
 
ECOG performance 
status 
 
X 
Xd 
 
 
 
 
X 
X 
 
Electrocardiogram 
 
X 
Xd 
 
 
 
 
 
X 
 
Hematologyf 
 
X 
Xd 
 
 
X 
 
X 
X 
 
Serum chemistryg 
 
X 
Xd 
 
 
 
 
X 
X 
 
Coagulation (PT/INR, 
aPTT) 
 
X 
Xd 
 
 
 
 
X 
X 
 
Urinalysis (dip stick 
sufficient) 
 
X 
Xd 
 
 
 
 
X 
X 
 
Serum pregnancy test 
(childbearing potential 
only) 
 
X 
 
 
 
 
 
 
 
 
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APPENDIX B: 
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 1B (CONT'D) 
Procedure 
Screening 
Treatment Period 
Follow-Upb 
Cycles 1-6 (every 21 days) 
Post Cycle 
6 
> Cycles 7 
(every 21 days) 
Treatment 
Terminationa 
 
Day -28 
to -1 
Day-
14 to -
1 
Day 1 
(±1 day) 
Day 
2 
Day 3 
 
Every 3 
months 
Day 8 
(Cycles 1-3 
only) 
Day 1(± 1 day) 
Pharmacokineticsh 
 
 
Xh
(C1/C3) 
 
Xh
(C1/C3) 
Xh
(C1/C3) 
 
 
Xh 
 
Anti-tarextumabi 
 
 
Xi
(C1/C4) 
 
 
 
 
Xi 
Xi 
 
Blood for biomarkersj 
 
 
Xj
(C1) 
Xj
(C2/C3) 
 
Xj
(C1/C2/C3) 
 
 
Xj 
 
Hair for biomarkers k 
 
 
Xk 
 
 
Xk
(C2) 
 
 
 
 
Blood for pharmaco-
genomics  
 
 
Xl 
 
 
 
 
 
 
 
FFPE  tissuem 
X 
 
 
 
 
 
 
 
 
 
Optional tumor biopsyn 
X 
 
 
 
 
Xn
(C2) 
 
 
Xn 
 
Contrast CT, or MRI 
(chest, abdomen, and 
pelvis), brain MRI/CT 
with contrasto 
X 
 
Xo 
(C3/C5) 
 
 
 
 
Xo 
Xo 
Every 6 
weeksp 
Bone Scan 
X 
 
As clinically indicated 
 
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Protocol 59R5-003, Amendment 6 
Page 105 of 235 
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CONFIDENTIAL 
APPENDIX B: 
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 1B (CONT’D) 
Procedure 
Screening 
Treatment Period 
Follow-Upb 
Cycles 1-6 (every 21 days) 
Post Cycle 
6 
> Cycles 7 
(every 21 days) 
Treatment 
Terminationa 
 
Day -28 
to -1 
Day-
14 to -
1 
Day 1 
(±1 day) 
Day 
2 
Day 3 
 
Every 3 
months 
Day 8 
(Cycles 1-3 
only) 
Day 1(± 1 day) 
Concomitant medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Adverse events 
 
 
X 
X 
X 
X 
 
X 
X 
 
Survival Follow-up 
 
 
 
 
 
 
 
 
 
X 
Subsequent anti-cancer 
therapies 
 
 
 
 
 
 
 
 
 
X 
Etoposide administration 
 
 
X 
X 
X 
 
 
 
 
 
Platinum therapy 
administration 
 
 
X 
 
 
 
 
 
 
 
tarextumab Infusion 
 
 
X 
 
 
 
 
X 
 
 
Prophylactic cranial 
irradiation (PCI)  
 
 
 
 
 
 
Xq 
 
 
 
 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 106 of 235 
22 April 2016 
 
CONFIDENTIAL 
NOTES TO APPENDIX B: 
a.
Approximately 4 weeks after the last study drug, or etoposide or platinum therapy, whichever is discontinued last, but before the initiation of a new anti-
cancer therapy 
b.
All Subjects will be followed for survival and subsequent anti-cancer therapy information after the treatment termination unless a subject requests to be 
withdrawn from study survival follow-up.  Survival follow-up and subsequent anti-cancer therapy information will be collected during telephone calls, 
through subjects’ medical records, and/or at clinic visit every 3 months until death, loss to follow-up or study termination by the sponsor. 
c.
Full physical examination at screening and treatment termination only. At all other times, targeted physical examination will be done at the Investigator’s 
discretion. 
d.
The assessment does not need to be repeated if it was done within 7 days prior to the first dose 
e.
Height required at screening only. Vital signs and weight: screening, day 1 of each cycle prior to the start of study drug dosing, days 2 and 3 prior to 
etoposide administration during Cycles 1 through 6 and treatment termination.  
f.
Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and platelet count.  The results need to be reviewed by the 
Investigator prior to each study drug and EP administration.  Hematology on Day 1 of each cycle starting from Cycle 2 can be performed up to 3 days prior 
to Day 1 dosing. 
g.
Full chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total 
bilirubin, direct bilirubin, lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphorus, and magnesium.  Chemistry on Day 1 of each cycle 
starting from Cycle 2 can be performed up to 3 days prior to Day 1 dosing. 
h.
Plasma samples will be obtained for tarextumab pharmacokinetic analysis at pre-dose and 5 minutes (±2 minutes) after the end of tarextumab infusion and 
prior to the EP administration on Day 1 of Cycle 1 and Cycle 3, and on Days 3 (pre-dose) and 8 of Cycles 1 and 3, at other times as clinically indicated such 
as when significant toxicities occur, as well as at treatment termination. On days when tarextumab and etoposide and/or platinum therapy are given together, 
the plasma sample should be obtained 5 minutes (±2 minutes) after the completion of the infusion of tarextumab, but prior to EP administration. 
i.
Serum samples will be obtained for anti-tarextumab pre-dose on Day 1 of every three cycles starting from Cycle 1, at other times as clinically indicated such 
as when significant toxicities occur, and at the Treatment Termination visit. 
j.
A pre-dose sample of a total of 19 mL of blood will be drawn on Day 1 of Cycle 1(pre-dose), on Day 2 of Cycles 2 and 3, and on Day 8 of Cycles 1-3 for 
subjects continuing on tarextumab to evaluate changes in plasma proteins (4 mL) (e.g., EGFR, PLGF, ENA-78, etc.), CTCs (10 mL), and Notch-related gene 
expression of mRNA (5 mL) as described in Section 10.0.  A sample will also be obtained at the time of treatment termination, unless one has been obtained 
during the prior 14 days. A pre-dose sample of blood will be drawn on Day 1 of Cycle 4 and 5 to explore effects of treatment on CTCs. Instructions for the 
collection, handling, storage, and shipment are provided in the Study Reference Binder. 
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 107 of 235 
22 April 2016 
 
CONFIDENTIAL 
NOTES TO APPENDIX B:  (Cont’d) 
k.
Hair follicle mRNA expression:  Predose hair samples (6 hairs) will be collected at Day 1 of Cycle 1 (pre-dose) and on Day 8 of Cycle 2 only for gene 
expression analysis of Notch pathway–related gene expression as described in Section 11.0.  Instructions for the collection, handling, storage, and shipment 
of these samples are provided in the Study Reference Binder. 
l.
Only on Day 1 of Cycle 1 prior to tarextumab infusion from subjects who have signed separate pharmacogenomics Informed Consent Form. 
m. FFPE tumor specimens obtained will be collected.  Notch3 expression levels will be assessed in FFPE tumor specimens, either archived or fresh core needle 
biopsied at study entry (two FFPE cores preferred whenever possible).  FFPE samples must be obtained during screening.  Notch3 levels will be measured 
by immunohistochemistry and/or a quantitative PCR gene expression assay. Notch 2 and other Notch-related genes and proteins may also be measured.  In 
addition, DNA testing may be performed on the FFPE tumor specimens for subjects who sign the optional FFPE Informed Consent for DNA testing.  
Instructions for the collection, handling, storage, and shipment of these samples are provided in the Study Reference Binder. 
n.
Optional tumor biopsy will be done at screening, on Day 8 of Cycle 2, and at the time of treatment termination, if feasible.  The site can call the Sponsor’s 
medical monitor to discuss an alternative timepoint if it is not feasible to collect the optional tumor biopsy on Day 8 (±2) of Cycle 2. 
o.
Contrast CT of chest, abdomen and pelvis, and brain MRI/CT with contrast will be performed at screening.  Contrast CT of chest, abdomen and pelvis will 
be performed every 6 weeks (±5 days) after initial study drug dosing (prior to the start of Cycle 3 and every 6 weeks±5 days thereafter).  MRI can be used in 
lieu of contrast-enhanced CT for subjects who are allergic to contrast.  The same methodology should be used throughout the study to follow the same 
lesion.   
p.
Subjects who have not demonstrated disease progression will have contrast CT of chest, pelvis and abdomen (or MRI for subjects who are allergic to 
contrast), conducted every 6 weeks (± 5 days) after initial study drug dosing until disease progression or initiation of new anti-cancer therapy.  The same 
methodology should be used throughout the study.   
q.
After the completion of 6 cycles of EP, subjects who do not have disease progression and have not had prophylactic cranial irradiation (PCI) or whole brain 
radiation (WBRT) prior to study entry and are good candidates for PCI per the Investigators should receive PCI within 8 weeks after the last dose of 
chemotherapy at a total dose of 25 Gy in 10 fractions.  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.  tarextumab 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 tarextumab alone  14 days after completion of PCI, until disease progression or unacceptable treatment-related 
toxicities or withdrawal of consent (APPENDIX A).  Subjects will discontinue study treatment if there is evidence of central nervous system (CNS) 
metastasis. 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 108 of 235 
22 April 2016 
 
CONFIDENTIAL 
APPENDIX C  
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 2 
Procedure 
Screening 
Treatment Period 
Follow-Upb 
Cycles 1-6 (every 21 days) 
 
> Cycles 7 
(every 21 
days) 
Treatment 
Terminationa 
Day -
28 to -
1 
Day-14 
to -1 
Day 1  
(± 1 day) 
Day 2 
Day 3 
 
 
Every 3 
months 
Day 8 
(Cycles 1-3 
only) 
Post Cycle 6 
Day 1(± 1 
day) 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical and oncology 
history 
X 
 
 
 
 
 
 
 
 
 
Physical examinationc 
 
X 
Xd
 
 
 
 
X 
X 
 
Weight, vital signs, 
heighte 
 
X 
X 
X 
X 
 
 
X 
X 
 
ECOG performance 
status 
 
X 
Xd 
 
 
 
 
X 
X 
 
Electrocardiogram 
 
X 
Xd 
 
 
 
 
 
X 
 
Hematologyf 
 
X 
Xd 
 
 
X 
 
X 
X 
 
Chemistryg 
 
X 
Xd 
 
 
 
 
X 
X 
 
Coagulation (PT/INR, 
aPTT) 
 
X 
Xd 
 
 
 
 
X 
X 
 
Urinalysis (dip stick 
sufficient) 
 
X 
Xd 
 
 
 
 
X 
X 
 
Serum pregnancy test 
(childbearing potential 
only) 
 
X 
 
 
 
 
 
 
 
 
Anti-tarextumabh 
 
 
Xh
(C1/C3/C5) 
 
 
 
 
Xh 
Xh 
 
 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 109 of 235 
22 April 2016 
 
CONFIDENTIAL 
APPENDIX C  
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 2 (CONT'D) 
Procedure 
Screening 
Treatment Period 
Follow-Upb 
Cycles 1-6 (every 21 days) 
Post Cycle 6 
> Cycles 7 
(every 21 
days) 
Treatment 
Terminationa 
Day -
28 to -
1 
Day-14 
to -1 
Day 1 
(± 1 
day) 
Day 2 
Day 3 
Day 8 
(Cycles 1-3 
only) 
Every 3 
months 
Day 1 (± 1 
day) 
Pharmacokineticsl 
 
 
Xl
(C1/C3/C5) 
 
Xl
(C1/C3/C5) 
Xl
(C1/C3) 
 
Xl
 
Xl
 
 
Blood for biomarkersi 
 
 
Xi
(C1) 
Xi
(C2/C3) 
 
Xi
(C1/C2/C3) 
 
 
X 
 
Blood for pharmaco-
genomics  
 
 
Xj 
 
 
 
 
 
 
 
FFPE tissuek 
X 
 
 
 
 
 
 
 
 
 
Tumor biomarker testing 
X 
 
 
 
 
 
 
 
 
 
Optional tumor biopsym 
X 
 
 
 
 
Xm
(C2) 
 
 
X 
 
Contrast CT or MRI 
(chest, abdomen, and 
pelvis), brain MRI/CT 
with contrastn 
X 
 
Xn 
(C3/C5) 
 
 
 
 
Xn 
Xn 
Every 6 
weekso 
Bone Scan 
X 
 
as clinically indicated 
Concomitant medications 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
Adverse events 
 
 
X 
X 
X 
X 
 
X 
X 
 
Survival Follow-up 
 
 
 
 
 
 
 
 
 
X 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 110 of 235 
22 April 2016 
 
CONFIDENTIAL 
APPENDIX C  
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 2 (CONT’D) 
Procedure 
Screening 
Treatment Period 
Follow-Upb 
Cycles 1-6 (every 21 days) 
Post Cycle 
6 
> Cycles 7
(every 21 days) 
Treatment 
Terminationa 
Day -
28 to -
1 
Day-14 
to -1 
Day 1 
(± 1 day) 
Day 
2 
Day 3 
Day 8 
(Cycles 1-3 
only) 
Every 3 
months 
Day 1 (± 1 
day) 
Subsequent anti-cancer 
therapies 
 
 
 
 
 
 
 
 
 
X 
Etoposide administration 
 
 
X 
X 
X 
 
 
 
 
 
Platinum therapy 
administration 
 
 
X 
 
 
 
 
 
 
 
Study Drug Infusion 
(tarextumab or Placebo) 
 
 
X 
 
 
 
 
X 
 
 
Prophylactic cranial 
irradiation (PCI) p 
 
 
 
 
 
 
Xp 
 
 
 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 111 of 235 
22 April 2016 
 
CONFIDENTIAL 
NOTES TO APPENDIX C: 
a.
Approximately 4 weeks after the last study drug, or etoposide or platinum therapy, whichever is discontinued last, but before the initiation of a new anti-
cancer therapy 
b.
All Subjects will be followed for survival and subsequent anti-cancer therapy information after the treatment termination unless a subject requests to be 
withdrawn from study survival follow-up.  Survival follow-up and subsequent anti-cancer therapy information will be collected during telephone calls, 
through subjects’ medical records, and/or at clinic visit every 3 months until death, loss to follow-up or study termination by the sponsor. 
c.
Full physical examination at screening and treatment termination only. At all other times, targeted physical examination, at the Investigator’s discretion. 
d.
The assessment does not need to be repeated if it was done within 7 days prior to the first dose. 
e.
Height required at screening only. Vital signs and weight: screening, day 1 of each cycle prior to the start of the treatment, days 2 and 3 prior to etoposide 
administration from Cycles 1 thru 6, and treatment termination. 
f.
Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and platelet count.  The results need to be reviewed by the 
Investigator prior to each study drug administration. Hematology on day 1 of each cycle starting from Cycle 2 can be performed up to 3 days prior to Day 1 
dosing. 
g.
Full chemistry (serum or plasma) includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen (BUN), creatinine, glucose, ALT, AST, alkaline 
phosphatase, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphorus, and magnesium.  Chemistry on Day 
1 of each cycle starting from Cycle 2 can be performed up to 3 days prior to Day 1 dosing. 
h.
Serum samples will be obtained for anti-tarextumab pre-dose on Day 1 of every other cycle starting from Cycle 1, at other times as clinically indicated such 
as when significant toxicities occur and at the Treatment Termination visit. 
i.
A pre-dose sample of a total of 19 mL of blood will be drawn on Day 1 of Cycle 1 (pre-dose), on Day 2 of Cycles 2 and 3, and on Day 8 of Cycles 1-3 for 
subjects continuing on tarextumab to evaluate changes in plasma proteins (4 mL) (e.g., EGFR, PLGF, ENA-78, etc.), CTCs (10 mL), and Notch-related gene 
expression of mRNA (5 mL) as described in Section 10.0.  A sample will also be obtained at the time of treatment termination, unless one has been obtained 
during the prior 14 days.  A pre-dose sample of blood will be drawn on Day 1 of Cycle 4 and 5 to explore effects of treatment on CTCs.  Instructions for the 
collection, handling, storage, and shipment are provided in the Study Reference Binder. 
j.
Only on Day 1 of Cycle 1 prior to tarextumab infusion from subjects who have signed separate pharmacogenomics Informed Consent Form. 
k.
FFPE tumor specimens obtained will be collected.  Notch3, Hes1, Hey1, Hey2, and Hes6 expression levels will be assessed in FFPE tumor specimens, either 
archived or fresh core needle biopsied at study entry (two FFPE cores preferred whenever possible).  FFPE samples must be obtained during 
screening.  Notch3, Hes1, Hey1, Hey2, and Hes6 levels will be measured by immunohistochemistry and/or a gene expression assays. Notch 2 and other 
Notch-related genes and proteins may also be measured.  In addition, DNA testing may be performed on the FFPE tumor specimens for subjects who sign 
the optional FFPE Informed Consent for DNA testing.  Instructions for the collection, handling, storage, and shipment of these samples are provided in the 
Study Reference Binder. 
l. 
Plasma samples will be obtained for tarextumab pharmacokinetic analysis at on Day 1 of Cycles 1 and 3, at  pre-dose and 5 minutes (±2 
minutes) post tarextumab infusion;  Day 3 of Cycle 1 and Cycle 3 prior to etoposide administration; Day 8 of Cycle 1 and Cycle 3 when blood 
sample is taken for biomarker evaluation;  Day 1 of every other cycle starting from Cycle 5 prior to study drug infusion and, at other times as 
clinically indicated such as when significant toxicities occur as well as at the time of treatment termination.  On days when tarextumab and 
etoposide and/or platinum therapy are given together, the plasma sample should be obtained 5 minutes (±2 minutes) after the completion of the 
infusion of tarextumab, but prior to EP administration. 
 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 112 of 235 
22 April 2016 
 
CONFIDENTIAL 
NOTES TO APPENDIX C: (Cont’d) 
m. Optional tumor biopsy will be done at screening, on Day 8 of Cycle 2, and at the time of treatment termination, if feasible.  The site can call the Sponsor’s 
medical monitor to discuss an alternative timepoint if it is not feasible to collect the optional tumor biopsy on Day 8 (±2) of Cycle 2. 
n.
Contrast CT of chest, abdomen and pelvis, and MRI of brain will be performed at screening.  During the study, contrast CT of chest, abdomen and pelvis 
will be performed every 6 week s ± 5 days) after initial study drug dosing (prior to the start of Cycle 3 and every two cycles thereafter).  MRI can be used in 
lieu of contrast-enhanced CT for subjects who are allergic to contrast.  The same methodology should be used throughout the study to follow the same 
lesion.   
o.
Subjects who have not demonstrated disease progression will have contrast CT of chest, abdomen and pelvis (or MRI for subjects who are allergic to 
contrast), conducted every 6 weeks (±5 days) after initial study drug dosing until disease progression or initiation of new anti-cancer therapy.  The same 
methodology should be used throughout the study.   
p.
After the completion of 6 cycles of EP, subjects who do not have disease progression and have not had prophylactic cranial irradiation (PCI) or whole brain 
radiation (WBRT) prior to study entry and are good candidates for PCI per the Investigators 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 Investigators, PCI can be initiated at the time that is determined appropriated per 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 administration 
(tarextumab or Placebo) 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 
(tarextumab or Placebo)  14 days after completion of PCI, until disease progression or unacceptable treatment-related toxicities or withdrawal of consent (
APPENDIX A Study Schema).   Subjects will discontinue study treatment if there is evidence of central nervous system (CNS) metastasis. 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 113 of 235 
22 April 2016
 
CONFIDENTIAL 
APPENDIX D: 
ECOG PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale (Ref 12) 
Grade 
Descriptions 
0 
Fully active, able to carry on all pre-disease performance without restriction. 
1 
Restricted in physically strenuous activity, but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light housework, office work). 
2 
Ambulatory and capable of all self-care, but unable to carry out any work activities.  Up 
and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead 
 
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 114 of 235 
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CONFIDENTIAL 
APPENDIX E: 
RECIST CRITERIA 1.1 
Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference 
ELIGIBILITY 
Subjects must have measurable disease at baseline to be eligible for the Phase 2 portion of the 
study. 
Measurable Disease – the presence of at least one measurable lesion.  If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
Measurable Lesions – lesions that can be accurately measured in at least one dimension 
with the minimum size of: 
•
10 mm by CT scan or MRI (no less than double the slice thickness and a 
minimum of 10 mm). 
•
10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measureable). 
•
15 mm for nodal disease in short axis 
•
20 mm by chest X-ray (if clearly defined and surrounded by aerated lung) 
•
Malignant lymph node: 15 mm in short axis when assessed by CT scan (CT scan 
slice thickness no greater than 5 mm).  At baseline and in follow-up only the short 
axis is to be followed. 
Non-Measurable Lesions – all other lesions, including small lesions (longest diameter 
<10 mm or pathological lymph nodes with >10 to <15 mm short axis)  as well as truly 
non-measurable lesions.  Lesions considered truly non-measurable include 
leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, 
lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly 
identified by physical examination that is not measurable by reproducible imaging 
techniques, and nodal disease that is 10 to <15 mm in short axis. 
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OncoMed Pharmaceuticals, Inc. 
 
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Page 115 of 235 
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CONFIDENTIAL 
Special Considerations Regarding Lesion Measurability:  Bone lesions, cystic lesions, and 
lesions previously treated with local therapy require particular comment: 
Bone lesions: 
Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions.  However, these techniques can be used to confirm the presence or disappearance 
of bone lesions. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
Blastic bone lesions are non-measurable. 
Cystic lesions: 
Lesions that meet the criteria for radiographically defined simple cysts should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are, by definition, 
simple cysts. 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, 
if they meet the definition of measurability described above.  However, if noncystic lesions are 
present in the same subject, these are preferred for selection as target lesions. 
Lesions with prior local treatment: 
Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion.  Study protocols should detail the conditions under which such lesions 
would be considered measurable. 
Measurement of Lesions 
All measurements should be taken and recorded in metric notation, using calipers if clinically 
assessed.  All baseline evaluations should be performed as closely as possible to the beginning of 
treatment and never more than 28 days before the beginning of the treatment. 
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 116 of 235 
22 April 2016
 
CONFIDENTIAL 
Methods of Measurement 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and at each subsequent response assessment.  Imaging 
based evaluation should always be done rather than clinical examination unless the lesion(s) 
being followed cannot be imaged but are assessable by clinical examination. 
For the case of skin lesions, documentation by color photography, including a ruler to estimate 
the size of the lesion, is recommended. 
•
CT is currently the best currently available and reproducible method to measure target 
lesions selected for response assessment.  The CT scan slice thickness should be 5 mm or 
less.  When the CT scans have a slice thickness that is greater than 5 mm, the minimum size 
for a measurable lesion should be twice the slice thickness.  MRI is also acceptable.  Please 
see Ref 13 for more details concerning the use of CT scan and MRI. 
•
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined 
and surrounded by aerated lung.  However, CT is preferable. 
•
Ultrasound (US) should not be used to measure tumor lesions.  The utilization of endoscopy 
and laparoscopy for objective tumor evaluations not advised. 
•
FDG-PET can be used to determine a new lesion if the lesion was absent at baseline on 
FDG-PET 
•
Tumor markers alone cannot be used to assess response.  If markers are initially above the 
upper normal limit, they must normalize for a subject to be considered in complete  response 
when all lesions have disappeared. 
•
Cytology and histology can be used to differentiate between PR and CR in rare cases (e.g., 
after treatment to differentiate between residual benign lesions and residual malignant lesions 
in tumor types such as germ cell tumors). 
Baseline Documentation of “Target” and “Non-Target” Lesions 
•
All measurable lesions up to a maximum of two lesions per organ and 5 lesions in total, 
representative of all involved organs should be identified as target lesions and recorded and 
measured at baseline. 
•
Target lesions should be selected on the basis of their size (lesions with the longest diameter) 
and be representative of all involved organs, but in addition should lend themselves accurate 
repeated measurements. 
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
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Page 117 of 235 
22 April 2016
 
CONFIDENTIAL 
•
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum diameters.  The baseline sum diameters will be used as reference by which 
to characterize the objective tumor.  If lymph nodes are to be included in the sum, then as 
noted above, only the short axis is added to the sum. 
•
If a target lesion becomes too small to measure, a default value of 5 mm is assigned.  If the 
lesion disappears, the measurement is recorded at 0 mm. 
•
If extranodal target lesions fragment, the LDs of the fragmented portion are added in the 
sum.  If targets lesions coalesce and cannot be distinguished, the LD of the coalesced lesion 
is added to the sum. 
•
For a patient with SD or PR, a lesion which disappears and then reappears will continue to be 
measured and added to the sum.  Response will depend upon the status of the other lesions.  
For a patient with CR, reappearance of a lesion is considered PD. 
•
New lesions should be unequivocal and not attributable to differences in scanning technique 
or findings which may not be tumor.  If a new lesion is equivocal, repeat scans are needed to 
confirm.  If confirmed, PD is assessed from the date of the first scan. 
•
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline.  Measurements of these lesions are not required, but the 
presence or absence of each or in rare case unequivocal progression should be noted at each 
subsequent response assessment. 
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RESPONSE CRITERIA 
Evaluation of Target Lesions 
*Complete Response (CR): 
Disappearance of all target lesions.  Any pathological lymph node (whether 
target or non-target) must have reduction in short axis to <10 mm 
*Partial Response (PR): 
At least a 30% decrease in the sum of the diameters of target lesions, taking as 
reference the baseline sum diameters 
*Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must 
also demonstrate an absolute increase of at least 5 mm.  The appearance of one 
or more new lesions is also considered progression. 
*Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
 
Evaluation of Non-Target Lesions 
*Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor marker level. 
All lymph nodes must be non-pathological in size (i.e., <10 mm short axis) 
*Non-CR/Non-PD 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits 
*Progressive Disease (PD): 
Unequivocal progression of the existing non-target lesions.  The appearance of 
one or more new lesions is also considered progressive disease. 
(1) Although a clear progression of “non-target” lesions only is exceptional, in such circumstances, the opinion 
of the Investigator should prevail. 
 
Evaluation of Overall Response 
The overall response is assessed according to the following table. 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD  
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
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•
Subjects with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as having 
“symptomatic deterioration”.  Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
•
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete 
response status.  If described in the clinical protocol, FDG-PET may be used to upgrade a 
response to a CR in a manner similar to a biopsy in cases where a residual radiographic 
abnormality is thought to represent fibrosis or scarring. 
Confirmation 
Confirmation of response is not required in this randomized study since the control arm serves as 
an appropriate means to interpret the data. 
REPORTING OF RESULTS 
All subjects included in the study must be assessed for response to treatment, even if there are 
major protocol treatment deviations or if they are ineligible.  Each subject will be assigned one 
of the following categories:  1) complete response, 2) partial response, 3) stable disease, 
4) progressive disease, 5) inevaluable for response:  specify reason such as early death from 
malignant disease, early death from toxicity, tumor assessments not repeated/incomplete, or 
other (specify). 
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APPENDIX F: 
SAMPLE INFORMED CONSENT – PHASE 1B
PROTOCOL 59R5-003:  A Phase 1b/2 Study of Taretumab (OMP-59R5) in Combination with 
Etoposide and Platinum Therapy in Subjects with Untreated Extensive Stage Small Cell Lung 
Cancer 
 
Principal Investigator:  _____________________________________________ 
Before you decide whether or not to take part in this research study, it is important for you to 
understand the purpose of the study, what risks may be involved, and what is expected of you 
during the study.  Your participation in this study is entirely voluntary.  If you have any 
questions that are not answered or if there are words that you do not understand in this consent 
form, your study doctor will give you more information.  Once you understand the purpose of 
this study, and if you decide to volunteer to participate in the study, you will be asked to sign this 
consent form.  Once you sign the consent form, you will be referred to as a “subject”. 
PURPOSE AND BACKGROUND 
Many current cancer therapies often produce an initial reduction in tumor size but may not have 
long-term benefits.  One possible explanation for this is the presence of a specific type of cancer 
cell known as a cancer stem cell.  Cancer stem cells make up a small part of the tumor but are 
believed to be responsible for much of the growth and spread of the cancer.  Cancer stem cells 
may also be more resistant to traditional types of therapy, such as chemotherapy and radiation 
therapy. 
The study drug, tarextumab (OMP-59R5), used in this study is experimental.  That means the 
United States Food and Drug Administration (FDA) has not approved it for use by the general 
public.  Tarextumab is a humanized monoclonal antibody and was developed to target cancer 
stem cells. Tarextumab may block the growth of cancer stem cells, the remaining tumor cells.  
The sponsor for this study is OncoMed Pharmaceuticals. 
The research study consists of two portions and you will participate in the first portion.  The 
purpose of the first portion is to test the safety and to determine the highest tolerable dose of 
tarextumab, when given in combination with etoposide and cisplatin or carboplatin.  Cisplatin 
and carboplatin both contain platinum (called platinum therapy).  Cisplatin and carboplatin have 
similar anti-tumor activities, but with slightly different side effects.  Etoposide and platinum 
therapy (either cisplatin or carboplatin) are a standard treatment for extensive small cell lung 
cancer.  The purpose of the second portion is to test if tarextumab, when given in combination 
with etoposide and platinum therapy (cisplatin or carboplatin), is able to slow tumor growth in 
subjects with extensive small cell lung cancer or shrink tumors in subjects with extensive small 
cell lung cancer. 
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You have been asked to participate in this research study because you have small cell lung 
cancer that has spread to other parts of your body and you have not been treated for this disease, 
and your doctor feels that etoposide and platinum therapy (cisplatin or carboplatin) in 
combination with tarextumab, may be a treatment option for you. 
Although tarextumab has been given to cancer patients, it has not been given in combination 
with etoposide and platinum therapy (cisplatin or carboplatin). It is not known if it will provide 
any benefit to you and may cause harmful side effects. 
PROCEDURES 
The first portion of the study will include approximately 40 subjects at about 12 centers in the 
United States.  
During the first portion of the study, initially all subjects will receive tarextumab intravenously 
(through vein) on Day 1, etoposide 100mg/m2 on Days 1, 2 and 3, and cisplatin 80 mg/m2 on 
Day 1 of every 21-day cycle for 6 cycles.  After 6 cycles, subjects will continue on tarextumab 
only on Day 1 of every 21-day cycle.  A group of 3 to 6 subjects will be treated at each 
tarextumab dose with etoposide and cisplatin, until the highest tolerable dose of tarextumab is 
reached.  Once the highest tolerable dose is determined for tarextumab in combination with 
etoposide and cisplatin, a group of 6 subjects will be entered into the study to receive the highest 
tolerable dose of tarextumab in combination with etoposide and carboplatin to confirm the 
tolerability of the highest tolerable dose in combination with etoposide and carboplatin.  
When the first portion is completed, the study will then proceed to the second portion.  The study 
participation consists of the following periods: 
•
Screening 
•
Treatment: If you participate in the first portion of the study before the highest tolerable 
dose is determined, you will receive tarextumab with etoposide and cisplatin for 6 cycles 
followed by treatment with tarextumab alone. If you are entered into the first portion of 
the study after the highest tolerable dose is determined, you will receive tarextumab with 
etoposide and carboplatin. If you participate in the second portion of the study, you may 
receive either tarextumab with etoposide and cisplatin or carboplatin, or Placebo with 
etoposide and cisplatin or carboplatin for 6 cycles followed by treatment with tarextumab 
alone.  This period may last until you experience severe side effects or your tumor has 
grown or spread or you have decided to stop the treatment. 
•
Treatment termination: This visit will occur approximately 4 weeks after your last dose 
of study drug, etoposide, or cisplatin/carboplatin, whichever you discontinue the last, but 
prior to the start of new anti-cancer therapy that your doctor has chosen for you. 
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•
Follow-up: You will be followed about every three months to check on your health status 
and the new type of cancer therapy you are receiving.  This may be done by phone or a 
clinic visit. 
SCREENING 
If you decide to be in this study and you sign this informed consent form, you will be asked to 
complete the procedures listed below at a screening visit within 28 days before your first dose of 
study drug to make sure that you are a suitable candidate.   
Informed Consent:  You will read, confirm understanding, and sign this informed consent.  No 
study-related tests will be performed prior to signing this informed consent form.   
Medical History:  Your doctor and/or nurse will ask you questions about your past and current 
health and medication use. 
Physical Examination:  Your doctor will examine you. Your blood pressure, temperature, heart 
rate, rate of breathing, height, and weight will also be measured.   
Electrocardiogram (ECG):  You will have an ECG.  An ECG traces the electrical activity of 
the heart.  It is a non-invasive test and requires no needles. 
Blood and Urine Sample Collection:  Blood will be taken from a vein in your arm using a 
needle.  The blood (about 1 tablespoon) and a urine sample will be used to check your general 
health and, if you are a female who is able to get pregnant, to make sure that you are not 
pregnant. 
Tumor tissues:  If you had your tumor tissue biopsied previously and your doctor still has some 
of that tissue available, you will be asked to allow your doctor to send some of that tissue for 
testing for this study.  If you don’t have previously collected tumor tissues available, your doctor 
will perform a biopsy at one of your tumor sites.  This is a required procedure in order for you to 
be able to participate in the study.  This will help your doctor understand the nature of your 
cancer and other people’s small cell lung cancer and why certain people may be more likely to 
respond to certain treatment.  If you are participating in the second portion of the study, you 
might not be eligible for the study if your cancer does not contain certain level of gene as 
determined by a OncoMed appointed laboratory. 
Optional tumor biopsy:  You will sign a separate consent page if you agree to this procedure.  
If you sign this separate consent, you will be asked to get a tumor biopsy within 28 days of your 
first study drug administration.  This will help to see certain genes and/or proteins that are 
involved in your cancer development have changed with the study treatment.  This procedure is 
optional. 
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Tumor assessments: An examination of your tumor(s) by CT (computerized tomography test, 
like an x-ray that produces a picture of your body including tumors using radiation), or MRI 
(magnetic resonance imaging - use of a magnetic field to produce an image of your body 
including tumors) or PET/CT (positron emission tomography- measures metabolic activity 
within the body.  When combined with CT, PET/CT will determine abnormal metabolic activity 
at a specific anatomic location) or bone scan (an X-ray to look at your bone).  Your study doctor 
will determine which type of test (CT or MRI, or PET/CT or bone scan) is best to assess your 
cancer.  This is part of your routine cancer care.   
TREATMENT PHASE 
If you are found to be eligible to participate, you will be enrolled in the study.  
You will be assigned to a pre-determined dose level of tarextumab.  The dose levels of 
tarextumab that will be tested in this study will start at 5mg/kg and increase in 2.5 mg/kg 
increments not to exceed 15 mg/kg(if the lower doses are tolerable) administered through the 
vein. You will be given the following drugs every 21 days: tarextumab on Day1, etoposide 
100 mg/m2 on Days 1, 2, and 3, and cisplatin 80 mg/m2 on Day 1 or carboplatin (if you are 
entered into the first portion of the study after the highest tolerable dose is determined) at AUC 
of 5 mg/mL•min – a target drug concentration in your blood that is calculated based on your 
gender, age, weight and kidney function. 
The study drug is tarextumab and will be given in “cycles.”  Each cycle is 3 weeks long for a 
total of 21 days.  The first day of the first cycle will be called “Cycle 1 Day 1”, followed by 
“Cycle 1 Day 2”, and so on.  
Your study drug (tarextumab) will be given through the vein for 30 minutes or longer depending 
on the dose you are assigned, your weight and if you have experienced any allergic reaction to 
study drug.  Your study staff will let you know how long your treatment with study drug will be.  
Etoposide will be given through the vein for 30 to 60 minutes.   
You will be treated with platinum therapy, cisplatin or carboplatin as determined by the 
Investigator prior to randomization.  Cisplatin will be given through the vein for 30 minutes to 
2 hours.  Carboplatin will be given through the vein for 15 minutes or longer depending on your 
kidney function.  On days when the study drug, etoposide and platinum therapy are given 
together, the study drug will be given first, followed by etoposide, and then cisplatin.  You will 
receive study drug, etoposide, and platinum therapy for 6 cycles.  After that, you will receive 
study drug only on Day 1 of each following cycle.   
You will receive this combination of drugs until you have experienced severe side effects, or 
your tumor has grown or spread or you have decided to stop your treatment.  If you experience 
side effects that are related to one of the three drugs, you may continue the other drugs if your 
tumor has not grown or spread. 
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Protocol 59R5-003, Amendment 6 
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If your disease is at least stable or have responded to therapy at the end of cycle 6 and you doctor 
think it is appropriate, you will also receive radiation to your brain to help prevent tumors 
recurring within 8 weeks after the last administration of chemotherapy.  You will continue study 
drug treatment between the completion of 6 cycles of chemotherapy and the start of the brain 
radiation.  The study drug will not be given within 2 weeks of the start and completion of the 
brain radiation and will not be given during the brain radiation. 
Your doctor and/or nurse will review tests and complete pre-dose procedures once you are at the 
clinic.  If he/she feels that you are in a good health, you will be receiving study drug, etoposide 
and platinum therapy. 
During each visit, your doctor will also review any changes in the medications you have been 
taking or any changes in your health since the previous visit.   
The following procedures will take place at each of the following visits. 
Additional blood samples (approximately 1 to 2 teaspoons for each blood sample) might be 
taken to check the level of study drug (tarextumab) and/or proteins against tarextumab in 
your body: 
Cycle 1 Day 1 
This is the first day of study treatment (Cycle 1 Day 1).You will receive study drug, etoposide, 
and platinum therapy on this day. You will have the following procedures done during this visit:  
•
Physical Examination before dosing (if this was done more than 7 days ago) 
•
Electrocardiogram (ECG) before dosing (if this was done more than 7 days ago)  
•
Urine Sample Collection before dosing (if this was done more than 7 days ago) 
•
Blood Sample Collection before dosing – about 1 tablespoon of blood for your health 
condition (if this was done more than 7 days ago)  
•
Weight before dosing 
•
Hair follicles: Six hairs will be plucked from your head for additional marker testing  
•
Additional Blood Sample Collection before dosing – about 2 tablespoons of blood to assess 
the level of certain markers and proteins that might be against tarextumab  
•
1 teaspoon of blood taken before starting study drug dosing to check the level of tarextumab 
in the blood 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will be asked about any changes in your health status after taking your initial dose of the 
study drug, etoposide, and platinum therapy. 
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You will have your blood drawn 1 more time about 5 minutes after completing study drug dosing 
but before the start of etoposide and platinum therapy treatment.  About 1 teaspoon of blood will 
be collected to measure the amount of tarextumab in your blood. 
Cycle 1 Day 2 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 1 Day 3 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will also have 1 teaspoon of blood taken before starting etoposide to measure the amount 
of tarextumab in your blood.   
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 1 Day 8 
•
About 3 tablespoons of blood sample will be taken to check the level of certain markers, the 
level of tarextumab in the blood and your health status 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 2 Day 1 
You will receive study drug, etoposide, and platinum therapy on this day. The following 
procedures will be done prior to study drug dosing: 
•
Physical Examination: only if you report changes in your health or how you feel  
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured. 
•
About 1 tablespoon of blood will be taken to review your health condition. 
•
Urine Sample Collection. 
•
Electrocardiogram (ECG). 
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•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 2 Day 2 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
About 2 tablespoons of blood will be taken to assess the level of certain markers. 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 2 Day 3 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 2 Day 8 
•
About 3 tablespoons of blood will be taken to check the level of certain markers and your 
health status.  
•
Hair follicles: Six hairs will be plucked from your head for additional marker testing. You 
will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
•
Optional Tumor Biopsy, if you agree to this procedure. If your doctor feels this is not a good 
time to have the biopsy, your biopsy might be taken later instead 
End of Cycle 2 (about every 6 weeks): 
Tumor assessment: A CT scan or MRI or PET/CT will be done approximately every 6 weeks 
after your initial study drug dosing (Day 1 of Cycle 3 and every 6 weeks thereafter).  If a bone 
scan is used, bone scan may be repeated as indicated by your doctor  
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Cycle 3 Day 1 
You will receive study drug, etoposide, and platinum therapy on this day. The following 
procedures will be done prior to study drug dosing: 
•
Physical Examination: only if you report changes in your health or how you feel  
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured. 
•
Blood Sample Collection (about 2 tablespoons to check your health condition and to measure 
the level of tarextumab in your blood and proteins that might be against tarextumab. 
•
Urine Sample Collection before dosing 
•
Electrocardiogram (ECG) before dosing 
•
You will also have your blood drawn 1 more time about 5 minutes after completing study 
drug dosing but before the start of etoposide and platinum therapy.  About 1 teaspoon of 
blood will be collected to measure the amount of tarextumab in your blood. 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 3 Day 2 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
About 2 tablespoons of blood will be taken to assess the level of certain markers.  
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 3 Day 3 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured. 
•
You will also have 1 teaspoon of blood drawn before starting etoposide to measure the 
amount of tarextumab in your blood. 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
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Cycle 3 Day 8 
•
About 3 tablespoon of blood to check the level of certain markers and your health status.   
•
You will also have 1 teaspoon of blood drawn before starting etoposide to measure the 
amount of tarextumab in your blood. 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycles 4-6: Day 1 
You will receive study drug, etoposide, and platinum therapy on this day. The following 
procedures will be done prior to study drug dosing: 
•
Physical Examination: only if you report changes in your health or how you feel  
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
Blood Sample Collection (about 1 tablespoon) to check your health condition. 
•
About 1 tablespoon of blood sample will be taken to check the level of certain markers at 
Cycles 4 and 5 only 
•
About 1 tablespoon of blood will also be taken to check proteins that might be against 
tarextumab and to measure the level of tarextumab in the blood.  This sample will be 
collected at Cycle 4 only if you are participating in the first portion of the study and at Cycle 
3 and 5 if you are participating in the second portion of the study 
•
Urine Sample Collection  
•
Electrocardiogram (ECG) before dosing 
•
You will also have your blood drawn 1 more time about 5 minutes after completing study 
drug dosing but before the start of etoposide and cisplatin or carboplatin treatment at Cycle 3. 
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Tumor assessment: A CT scan or MRI or PET/CT will be done approximately every 6 weeks 
after your initial study drug dosing (Day 1 of Cycle 3 and every 6 weeks thereafter).  If a bone 
scan is used, bone scan may be repeated as indicated by your doctor. 
Cycles 4-6: Day 2 
You will receive etoposide treatment only on Day 2.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
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Cycles 4-6: Day 3 
You will receive etoposide treatment only on Day 3.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
•
You will have 1 teaspoon of blood drawn to measure the amount of tarextumab in your blood 
at Cycle 3.   
End of Cycle 6 
•
Tumor assessment: A CT scan or MRI or PET/CT will be done approximately every 6 weeks 
after your initial study drug dosing. A bone scan may be repeated as indicated by your doctor 
•
At the end of cycle 6, if your disease is at least stable or have responded to therapy, you 
doctor may decide that you will receive radiation to your brain to help prevent tumors before 
continuing with study drug treatment.   
Cycle 7 and beyond 
Starting at cycle 7, you will receive study drug on Day 1 of each cycle only.  The following 
procedures will be performed on Day 1 of Cycle 7 and every cycle thereafter.  
•
Physical Examination before dosing: only if you report changes in your health or how you 
feel  
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
Blood Sample Collection before dosing (about 1 tablespoon) to check your health condition. 
•
Blood sample collection before dosing (about 1 teaspoon) to check proteins that might be 
against tarextumab.  This sample will be collected at Cycle 7 and every 3rd cycle thereafter 
(e.g. Cycle 10, Cycle 13, etc). 
•
Urine Sample Collection before dosing 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
•
Tumor assessment: A CT scan or MRI or PET/CT will be done approximately every 6 weeks 
after your initial study drug dosing.  If a bone scan is used, bone scan will be done at every 
other tumor assessment (approximately every 12 weeks after initial study drug dosing). 
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TREATMENT TERMINATION 
You will be asked to return to complete the procedures listed below at the termination visit if you 
will no longer be continuing on study drug, etoposide, or cisplatin/carboplatin. This visit will be 
done about 4 weeks after your last dose of study, etoposide, or cisplatin/carboplatin whichever is 
discontinued last. 
•
Physical Examination  
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
Electrocardiogram (ECG)  
•
Urine Sample Collection  
•
Blood Sample Collection – about 3 tablespoons of blood to check your health condition and 
to check the level of certain markers, proteins that might be against tarextumab, and the level 
of OMP59R5 in the blood 
•
Tumor assessment: either by CT or MRI or PET/CT, or bone scan, if these procedures were 
not done within the last 4 weeks and if the last tumor assessment did not show that your 
tumor has grown or spread 
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Optional Tumor Biopsy:  An optional tumor biopsy will be done only if you agree. 
FOLLOW UP  
After you stopped study drug and your tumor has not grown, a tumor assessment (CT or MRI 
approximately every 6 weeks and bone scan approximately every 12 weeks) will be done until 
your tumor has grown.   
After you have stopped receiving study drug, the study staff will call you about every 3 months 
after your last clinic visit to follow your health status.  If necessary, your doctor may be 
contacted by OncoMed or OncoMed’s designee to obtain this information. 
If you withdraw from the study treatment but not from study follow-up, the study staff will still 
contact you about every 3 months after your last visit to check on your health status, or the study 
staff may use a public information (like county records) to obtain information about your 
survival status only, which will be reported to OncoMed as part of the data for the study. 
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POSSIBLE RISKS AND DISCOMFORTS 
Tarextumab: 
As of November 17, 2015, tarextumab or placebo has been tested in 356 subjects who have 
cancer;  
The following side effects have been noted in subjects receiving tarextumab or placebo and were 
considered possibly related to tarextumab or placebo treatment: 
Common one (occurred in >10% of the subjects who used the drug):  
•
Diarrhea    
•
Fatigue-tiredness 
•
Nausea  
•
Decreased appetite 
•
Vomiting 
•
Low red blood counts that might make you feel tired, 
•
Low blood counts that might make you easy to be bruised 
•
Low blood count that might make you easier to get infection 
Less Common (occurring in 5% to 10% of subjects who used the drug): 
•
Hands/feet swollen 
•
Low potassium level 
•
Hair loss 
•
Nose bleeding 
•
Redness of skin and/or rashes/hives 
•
Dehydration 
•
Change in taste 
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Most of the above-mentioned side effects were mild and moderate.  Diarrhea was the most 
common side effect and can be severe if it is not treated immediately.  You will be given some 
medications after your first dose of tarextumab to take home to treat diarrhea.  In addition, you 
will be advised to drink enough fluid and eat a balanced diet to avoid the dehydration and 
imbalanced electrolytes.  
Tarextumab will be given as an intravenous infusion.  There may be minor discomfort from the 
needle in your arm.  Bruising, swelling, and, in rare instances, infection and blood clot may 
occur at the infusion site. 
Tarextumab is a monoclonal antibody.  There is the possibility of a reaction to the monoclonal 
antibody as it is being infused (given) through your vein; these are called infusion reactions.  
Symptoms can include fever, chills, rash, and/or hives, changes in blood pressure, temperature 
and heart rate.  As of November 17, 2015, twelve of 356 subjects who have been given 
tarextumab or placebo have experienced infusion reactions; all of these infusion reactions were 
mild or moderate.  You will be watched carefully during the infusion and after the completion of 
the infusion.  If you do have a reaction to the study drug, your study doctor may need to give the 
study drug at a slower rate (over a longer period of time) and /or give you some medications to 
prevent the reaction.  If after slowing the rate of infusion and giving you some medications to 
prevent the infusion reaction, you continue to have infusion reactions, you may need to stop 
taking tarextumab.  
During the course of this study, your blood will be drawn for laboratory tests (1-3 tablespoons 
will be collected at each blood draw).  The risks of drawing blood include some discomfort from 
the needle in your arm, bruising, swelling at the needle site and, in rare instances, infection or 
fainting. 
You should discuss the risk and side effects with your study doctor.  There may be other side 
effects that we cannot predict.  You will be informed of any new significant side effects that 
develop during the course of this research study, or others regarding the use of tarextumab. 
There may be side effects that we cannot predict and in some cases they may be serious, long-
lasting, or fatal.   
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ETOPOSIDE: 
The following side effects have been noted in subjects receiving etoposide: 
Common one (occurred in > 10% of the subjects who used this drug) 
•
Low blood counts: Your white and red blood cells and platelets may temporarily 
decrease. This may put you at an increased risk for infection, anemia, and/or bleeding  
•
Nausea 
•
Vomiting 
•
Feeling weak and low energy 
•
Chills 
•
Fever 
•
Hair loss 
•
Poor appetite 
•
Sores, ulcers, or white spots on the lips or in the mouth 
Less common (occurred in 5 to 10% of the subjects who used this drug) 
•
Diarrhea 
•
Constipation 
•
Taste alteration 
•
Abdominal pain 
•
Dizziness 
•
Injection site inflammation or vein inflammation 
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Rarely (occurred in < 5% of the subjects who used this drug) 
•
Increased or decreased blood pressure 
•
Allergic reaction: This medicine may cause a serious type of allergic reaction called 
anaphylaxis that is presented with symptoms such as chills, fever, fast heartbeat, sudden 
constriction of airway, shortness of breath, excessive sweating, itchiness of the skin or 
rash, change in blood pressure, and loss of consciousness, etc . Anaphylaxis can be life-
threatening and requires immediate medical attention.  Tell your doctor or nurse right 
away if you have chills; fever; lightheadedness, dizziness, or fainting; fast, pounding 
heartbeat; swelling of the face, tongue, and throat; or trouble with breathing after you 
receive the medicine 
Other side effects may occur following the administration of etoposide.  Your doctor will further 
explain the side effects of etoposide. 
CISPLATIN: 
The following side effects have been noted in subjects receiving cisplatin: 
Common one (occurred in > 10% of the subjects who used this drug) 
•
Low blood counts: Your white and red blood cells and platelets may temporarily 
decrease. This may put you at an increased risk for infection, anemia, and/or bleeding  
•
Nausea 
•
Vomiting 
•
Ringing in the ears or Hearing loss 
•
Impairment of kidney function and damages to kidney  
•
Changes in how food tastes 
•
Diarrhea 
•
Damages to nerve that causes pain, numbness, tingling of hands and feet, and sometimes 
even have the difficulty in motion 
•
Hair loss 
•
Imbalance of electrolyte 
•
Extreme fatigue 
•
Mild elevation of liver enzymes 
Less common or rare (occurred in  10% of the subjects who used this drug) 
•
Change in vision or inflammation of optic nerve and blindness 
•
Injection site inflammation or vein inflammation 
•
Change in blood vessels that trigger heart attack and heart problem, stroke or brain injury 
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•
Allergic reaction: This medicine may cause a serious type of allergic reaction called 
anaphylaxis that is presented with symptoms such as chills, fever, fast heartbeat, sudden 
constriction of airway, shortness of breath, excessive sweating, itchiness of the skin or 
rash, change in blood pressure, and loss of consciousness, etc . Anaphylaxis can be life-
threatening and requires immediate medical attention.  Tell your doctor or nurse right 
away if you have chills; fever; lightheadedness, dizziness, or fainting; fast, pounding 
heartbeat; swelling of the face, tongue, and throat; or trouble with breathing after you 
receive the medicine 
Other side effects may occur following the administration of cisplatin.  The side effects are 
generally reversible and gradually disappears when treatment ends.  However, some side effects 
might take a long time to disappear.  Your doctor will further explain the side effects of cisplatin. 
CARBOPLATIN: 
The following side effects have been noted in subjects receiving carboplatin: 
Common ones (occurred in >10% of the subjects who used this drug) 
•
Low blood counts: Your white and red blood cells and platelets may temporarily 
decrease. This may put you at an increased risk for infection, anemia, and/or bleeding  
•
Nausea 
•
Vomiting 
•
Damages to nerve that causes pain, numbness, tingling of hands and feet, and sometimes 
even have the difficulty in motion 
•
Ringing in the ears or hearing loss 
•
Hair loss 
•
Imbalance of electrolytes 
•
Extreme fatigue 
•
Elevation of liver enzymes 
•
Pain 
•
Allergic reaction 
•
Muscle weakness 
Less common or rare (occurred in 10% of the subjects who used this drug) 
•
Sores, ulcers, or white spots on the lips or in the mouth 
•
Loss of vision for light or color 
•
Impairment of kidney function and damages to kidney.  Your carboplatin dose will be 
modified if you have impairment of kidney function  
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Other side effects may occur following the administration of carboplatin.  The side effects are 
generally reversible and gradually disappears when treatment ends.  However, some side effects 
might take a long time to disappear.  Your doctor will further explain the side effects of 
carboplatin 
PREGNANCY 
There is a very high risk that tarextumab may be harmful to an unborn baby (embryo or fetus) or 
newborn child. 
Therefore, women who are pregnant or breastfeeding may not participate in this study.  Women 
must have a negative pregnancy test before beginning the study.  It is important that both men 
and women take steps to prevent pregnancy during this study through the use of adequate 
contraception (for example, a barrier or hormone method or abstinence) 30 days prior to first 
study drug administration and for the duration of the study until 30 days after the last dose of 
study drug or etoposide or cisplatin whichever is discontinued last. 
If you become pregnant or suspect that you are pregnant, or if your partner becomes pregnant or 
suspects that she is pregnant during the study or within 30 days after the last dose of study drug 
or etoposide or cisplatin whichever is discontinued last, you must notify the study Investigator 
immediately.  If you become pregnant, you will be taken off of treatment and will undergo 
assessments listed under the Treatment Termination Section of this document, except for the 
radiographic studies, which will not be performed.  If your partner becomes pregnant, you will 
remain on the study.  If either you or your partner becomes pregnant during the study or within 
30 days after the last dose of study drug or etoposide or cisplatin whichever is discontinued last, 
you and/or your partner will be followed through outcome of the birth. 
POTENTIAL BENEFITS 
There is no guarantee that there will be any direct benefit to you if you take part in this research 
study.  The treatments you receive may be harmful.  It is possible that the information learned 
from this study may be helpful in the future to other people with cancer. 
SIGNIFICANT NEW FINDINGS 
Any significant new findings regarding tarextumab that become known during the course of this 
research study, which might reasonably affect your willingness to participate in this study, will 
be provided to you. 
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ALTERNATIVE TREATMENTS AND PROCEDURES 
If you decide not to participate in this study, you will continue to receive medical care to which 
you were entitled prior to your participation in this study.  Your doctor will discuss other options 
available to you.  Your choice not to participate in this study will not affect your medical care in 
any way. 
TERMINATION OF SUBJECT PARTICIPATION 
Your participation in this research study may be terminated at any time for medical reasons or 
because the sponsor finds it necessary to limit or terminate this clinical trial.  Some reasons for 
termination include progression of your disease, any other illness that prevents further 
administration of study drug, unacceptable adverse events, general or specific changes in your 
condition that make further treatment unacceptable in the opinion of your doctor, and protocol 
non-compliance. 
Your doctor may decide to hold or stop the study drug infusions at any time during the study for 
safety reasons. 
If your doctor or the sponsor decides to withdraw you from the study, you will undergo the same 
assessments listed under Treatment Termination. 
COSTS AND COMPENSATION 
The cost of all “standard of care” assessments related to your participation in this study and your 
medical care will be billed to you and/or your insurance company.  These are tests that would 
normally be performed in subjects to evaluate their cancer.  Due to the investigational nature of 
this research study, insurance companies or government health care programs may limit their 
obligation to pay for experimental treatments and their consequences.  You may want to discuss 
this with your insurance company before agreeing to participate.  The cost of all non-standard of 
care assessments will be paid for by OncoMed. 
You will not be paid for participation in this study. 
COMPENSATION FOR RESEARCH-RELATED INJURY 
If you are physically injured as a direct result of study drug or study procedure properly 
performed under the plan for this study and it is not due to a pre-existing medical condition or 
underlying disease, OncoMed will reimburse you for the reasonable medical expenses for the 
treatment of that injury which are not covered by another payer, your own insurance or health 
care program.  No other compensation is available from OncoMed if any injury occurs.  
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CONFIDENTIALITY 
Every effort will be made to keep your medical information confidential (secret).  You will be 
identified by a code and no information that identifies you will be released without your written 
permission, except as required by law.  To the extent permitted by law and by signing the 
consent form, you allow access by representatives of the Food and Drug Administration (FDA), 
other regulatory bodies, Institutional Review Boards, Independent Ethics Committees, and 
OncoMed monitors/representatives and collaborators to inspect your research and medical 
records without removal of identifying information, such as your name, initials, date of birth, 
sex, race, and location of the research study.  If information from this study is presented publicly 
or published in a medical journal, you will not be identified by name, picture, or by any other 
personally identifying information. 
You will be asked to review and sign a HIPAA (Health Insurance Portability and Accountability 
Act) Research Authorization Form requesting your authorization to collect, use, and disclose 
your medical information, 
OR IF SITE DOES NOT HAVE OWN HIPAA FORM: 
AUTHORIZATION TO USE AND DISCLOSE MY HEALTH INFORMATION 
I authorize (give permission to) insert name of study site to use and disclose (share) my health 
information solely for the purposes of this research study and research directly related to the use 
of tarextumab.  I understand that my health information that I am authorizing to be used and 
disclosed (Authorized Health Information) includes all health information about me that has been 
and will be created or received by (SITE) and that is in my medical records maintained by  
(SITE). 
I understand that I am free at any time to restrict the (Site’s) use and disclosure of my Authorized 
Health Information, without penalty or other consequences.  However, I also understand that I 
may be denied participation in, or continued participation in, this research study if at any time I 
choose to restrict the (Site’s) use and disclosure of Authorized Health Information that is 
necessary for the completion of this research study. 
AUTHORIZED PERSONS AND RECIPIENTS 
I authorize the following person(s) and groups of persons to request, receive, and use my 
Authorized Health Information: representatives of the FDA, other regulatory authorities, the 
Institutional Review Board/Independent Ethics Committee, OncoMed representatives and 
monitors, and OncoMed collaborators and licensees.  I authorize (SITE) to disclose my 
Authorized Health Information to these persons and groups or persons. 
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RE-DISCLOSURES TO THIRD PARTIES 
I understand that once (Site) discloses my Authorized Health Information to the recipient(s) 
identified in the previous section Authorized Persons and Recipients, (Site) cannot guarantee that 
the recipient(s) will not re-disclose my Authorized Health Information to other persons who may 
not be bound by this informed consent form. 
EXPIRATION DATE 
My authorization (permission) to use and disclose my Authorized Health Information will 
continue indefinitely, but that use and sharing will only be for the purposes described in the 
informed consent form. 
EFFECT OF MY REVOCATION OF AUTHORIZATION TO USE AND DISCLOSE 
AUTHORIZED HEALTH INFORMATION 
I understand that my authorization for (site) to use and disclose my Authorized Health 
Information will remain in effect until I withdraw my permission by sending my written notice 
of revocation (withdrawal of permission) to the Privacy Office listed in the Questions section of 
the following page.  My written revocation will be effective immediately upon (Site’s) receipt of 
my written notice, except that the revocation will not have any effect on any actions taken by 
(SITE) in relying on this authorization before it received my written notice of withdrawal of 
permission. 
QUESTIONS 
If you have any question about the study and/or its procedure or safety, you may contact Dr. 
(Name of Investigator) at (telephone number).  In the event of any injury, you may contact Dr. 
(name) at (telephone number).  You may also call (Name) at (telephone number) for information 
on experimental subjects’ rights. 
If at any time during this research study you feel that you have not been adequately informed of 
your rights with respect to the privacy of your health information, or you feel that the privacy of 
your health information has not been adequately protected, you may contact or visit (Site’s) 
privacy office during normal working hours at (Privacy Office name) at (telephone number and 
address). 
VOLUNTARY PARTICIPATION AND DOCUMENTATION OF CONSENT 
Your decision to participate in this study is entirely voluntary.  You may refuse to participate in 
or withdraw from the study at any time without prejudice or loss of benefits to which you are 
otherwise entitled.  A signed copy of this consent form will be given to you for your records and 
a copy will be retained by the Investigator for his or her files 
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By signing the form below, you have read the above information about this research study, and 
have had a chance to ask questions to help you understand your participation in this study and 
how your information will be used. 
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CONSENT FOR OPTIONAL TUMOR BIOPSY 
 _______ _________If you give your consent for a punch biopsy of your tumor  
Initials 
Date 
lesion, please check the box and write your initials and the date in  
 
 
the space provided. 
 _______ _________If you do not give your consent for a punch biopsy of your  
Initials 
Date 
tumor lesion, please check the box and write your initials and the  
 
 
date in the space provided. 
 
_______________________________________________________ 
Printed Name of Subject or Subject’s Authorized Representative 
________________________________________________________ 
 
___________ 
Signature of Subject or Subject’s Authorized Representative 
 
 
Date 
_________________________________________________________ 
Printed Name of Person Obtaining Informed Consent 
__________________________________________________________  
____________ 
Signature of Person Obtaining Informed Consent 
 
 
 
Date 
__________________________________________________________ 
Printed Name of Witness* 
_______________________________________________ 
__________ 
 
___________ 
Signature of Witness* 
 
 
 
 
 
 
 
Date 
*If the Principal Investigator or Institutional Review Board deems a witness signature is necessary 
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VOLUNTARY PARTICIPATION AND DOCUMENTATION OF CONSENT 
Your decision to participate in this study is entirely voluntary.  You may refuse to participate in 
or withdraw from the study at any time without prejudice or loss of benefits to which you are 
otherwise entitled.  A signed copy of this consent form will be given to you for your records and 
a copy will be retained by the Investigator for his or her files. 
By signing the form below, you acknowledge that you have read the above information about 
this research study, and have had a chance to ask questions to help you understand your 
participation in this study and how your information will be used. 
 
________________________________________________________ 
 
___________ 
Signature of Subject or Subject’s Authorized Representative  
 
Date 
_________________________________________________________ 
Printed Name of Person Obtaining Informed Consent 
__________________________________________________________  
____________ 
Signature of Person Obtaining Informed Consent 
 
 
 
Date 
__________________________________________________________ 
Printed Name of Witness* 
__________________________________________________________  
____________ 
Signature of Witness*  
 
 
 
 
 
 
Date 
*If the Principal Investigator or Institutional Review Board deems a witness signature is necessary. 
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APPENDIX G: 
SAMPLE INFORMED CONSENT – PHASE 2 
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 
 
Principal Investigator:  _____________________________________________ 
Before you decide whether or not to take part in this research study, it is important for you to 
understand the purpose of the study, what risks may be involved, and what is expected of you 
during the study.  Your participation in this study is entirely voluntary.  If you have any 
questions that are not answered or if there are words that you do not understand in this consent 
form, your study doctor will give you more information.  Once you understand the purpose of 
this study, and if you decide to volunteer to participate in the study, you will be asked to sign this 
consent form.  Once you sign the consent form, you will be referred to as a “subject”. 
PURPOSE AND BACKGROUND 
Many current cancer therapies often produce an initial reduction in tumor size but may not have 
long-term benefits.  One possible explanation for this is the presence of a specific type of cancer 
cell known as a cancer stem cell.  Cancer stem cells make up a small part of the tumor but are 
believed to be responsible for much of the growth and spread of the cancer.  Cancer stem cells 
may also be more resistant to traditional types of therapy, such as chemotherapy and radiation 
therapy. 
The study drug, tarextumab, used in this study is experimental.  That means the United States 
Food and Drug Administration (FDA) has not approved it for use by the general public.   
tarextumab is a humanized monoclonal antibody and was developed to target cancer stem cells. 
tarextumab may block the growth of cancer stem cells, the remaining tumor cells.  The sponsor 
for this study is OncoMed Pharmaceuticals. 
The research study consists of two portions and you will participate in the second portion.  The 
purpose of the first portion is to test the safety and to determine the highest tolerable dose of 
tarextumab, when given in combination with etoposide and cisplatin or carboplatin. The purpose 
of the second portion is to test if tarextumab, when given in combination with etoposide and 
platinum therapy (cisplatin or carboplatin), is able to slow tumor growth in subjects with 
extensive small cell lung cancer or shrink tumors in subjects with extensive small cell lung 
cancer. 
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You have been asked to participate in this research study because you have small cell lung 
cancer that has spread to other parts of your body and you have not been treated for this disease, 
and your doctor feels that etoposide and platinum therapy (cisplatin or carboplatin) in 
combination with tarextumab may be a treatment option for you. 
Although tarextumab has been given to cancer patients, it has not been given in combination 
with etoposide and platinum therapy (cisplatin or carboplatin). It is not known if it will provide 
any benefit to you and may cause harmful side effects.  
In one other study with tarextumab in subjects with cancer of the pancreas (also known as the 
ALPINE study), a group of independent physicians and statisticians called a “Data Safety 
Monitoring Board” or DSMB who are responsible for monitoring the safety and efficacy of 
clinical studies, reviewed the data and made recommendations to OncoMed, the Sponsor of the 
study, about the pancreatic cancer study. While they did not see unexpected safety findings (side-
effects) between the patients on the study who received tarextumab and placebo, they reported 
that on average patients treated with tarextumab had a lower chance of their tumors shrinking 
than those treated with placebo. Also, patients who received tarextumab had their cancer under 
control for a shorter period of time. Patients treated with tarextumab on the pancreatic cancer 
study may not seem to be living as long as those treated with placebo. The cancer type that you 
have is called small cell lung cancer and it is very different from pancreatic cancer. Also, the 
chemotherapy that you are receiving is very different from the chemotherapy used in the 
pancreatic cancer study. The PINNACLE study also has a DSMB that has been meeting since the 
start of this study, consisting of 3 lung cancer doctors and one statistician. This group reviews 
the data from the clinical study at least 4 times a year. If the DSMB informs OncoMed of any 
new information regarding the safety of tarextumab on the PINNACLE you and your doctor will 
be informed immediately.   
PROCEDURES 
The second portion of the study will include approximately 135 subjects at about 50 centers in 
the United States.   
Your study doctor will determine the type of platinum therapy (cisplatin or carboplatin) you will 
receive.  You will then be randomly assigned (by chance) to one of two treatment arms: Subjects 
in one arm will receive etoposide and platinum therapy (cisplatin or carboplatin) plus 
tarextumab.  Subjects in the other arm will receive etoposide and platinum therapy (cisplatin or 
carboplatin) plus Placebo (an inactive substance that looks like tarextumab).  The choice of 
platinum therapy (cisplatin or carboplatin) you will receive will not change during the study once 
it is selected by your doctor.  After 6cycles of treatment, you will continue on tarextumab or 
Placebo on Day 1 of every 21-day cycle.  If you discontinue etoposide and  platinum therapy 
prior to 6 cycles because of side effects, you will still be allowed to stay on the study and receive 
tarextumab or Placebo. Your chance of being randomized to one of the treatment arms is 50%.  
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Neither you nor your doctor will know whether you are receiving tarextumab or Placebo.  Both 
tarextumab and Placebo are considered “study drug”. 
The study participation consists of the following periods: 
•
Screening 
•
Treatment: You may receive either tarextumab with etoposide and platinum therapy 
(cisplatin or carboplatin), or Placebo with etoposide and platinum therapy (cisplatin or 
carboplatin) for6 cycles followed by treatment with tarextumab or Placebo alone.  This 
treatment period may last until you experience severe side effects or your tumor has 
grown or spread or you have decided to stop the treatment. 
•
Treatment termination: This visit will occur approximately 4 weeks after your last dose 
of study drug, etoposide, or platinum therapy (cisplatin or carboplatin), whichever you 
discontinue the last, but prior to the start of new anti-cancer therapy that your doctor has 
chosen for you. 
•
Follow-up: You will be followed about every three months to check on your health status 
and the new type of cancer therapy you are receiving.  This may be done by phone or a 
clinic visit. 
SCREENING 
If you decide to be in this study and you sign this informed consent form, you will be asked to 
complete the procedures listed below at a screening visit within 28 days before your first dose of 
study drug to make sure that you are a suitable candidate.   
Informed Consent:  You will read, confirm understanding, and sign this informed consent.  No 
study-related tests will be performed prior to signing this informed consent form.   
Medical History:  Your doctor and/or nurse will ask you questions about your past and current 
health and medication use. 
Physical Examination:  Your doctor will examine you. Your blood pressure, temperature, heart 
rate, rate of breathing, height, and weight will also be measured.   
Electrocardiogram (ECG):  You will have an ECG.  An ECG traces the electrical activity of the 
heart.  It is a non-invasive test and requires no needles. 
Blood and Urine Sample Collection:  Blood will be taken from a vein in your arm using a 
needle.  The blood (about 1 tablespoon) and a urine sample will be used to check your general 
health and, if you are a female who is able to get pregnant, to make sure that you are not 
pregnant. 
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Tumor tissues:  If you had your tumor tissue biopsied previously and your doctor still has some 
of that tissue available, you will be asked to allow your doctor to send some of that tissue for 
testing for this study.  If you don’t have previously collected tumor tissues available, your doctor 
will perform a biopsy at one of your tumor sites.  This is a required procedure in order for you to 
be able to participate in the study.  This will help your doctor understand the nature of your 
cancer and other people’s small cell lung cancer and why certain people may be more likely to 
respond to certain treatment.   
Optional tumor biopsy:  You will be asked to sign a separate consent page if you agree to this 
procedure.  If you sign this separate consent, you will be asked to get a tumor biopsy within 28 
days of your first study drug administration.  This will help to see certain genes and/or proteins 
that are involved in your cancer development have changed with the study treatment.  This 
procedure is optional. 
Tumor assessments: An examination of your tumor(s) by CT (computerized tomography test, 
like an x-ray that produces a picture of your body including tumors using radiation), or MRI 
(magnetic resonance imaging - use of a magnetic field to produce an image of your body 
including tumors), or PET/CT (positron emission tomography- measures metabolic activity 
within the body.  When combined with CT, PET/CT will determine abnormal metabolic activity 
at a specific anatomic location), or bone scan (an X-ray to look at your bone).  Your study doctor 
will determine which type of test (CT or MRI, or PET/CT or bone scan) is best to assess your 
cancer.  This is part of your routine cancer care. 
TREATMENT PHASE 
If you are found to be eligible to participate, you will be enrolled in the study.  
You will be randomly (by chance) assigned to one of the two treatment arms, where you will 
either receive etoposide and platinum therapy (cisplatin or carboplatin)  plus tarextumab or 
etoposide and platinum therapy (cisplatin or carboplatin) plus Placebo (an inactive substance that 
looks like tarextumab).  Your study doctor will determine the type of platinum therapy (cisplatin 
or carboplatin) you will receive.  Then you will be randomized to receive either tarextumab or 
Placebo.  Your chance of being randomized to each of the treatment arm is 50%.  Neither you 
nor your doctor will know whether you are receiving tarextumab or Placebo.   The choice of 
platinum therapy (cisplatin or carboplatin) you will receive will not change during the study once 
it is selected by your study doctor.   
The study drug is either tarextumab or Placebo (an inactive substance that looks like tarextumab) 
and will be given in “cycles.”  Each cycle is 3 weeks long for a total of 21 days.  The first day of 
the first cycle will be called “Cycle 1 Day 1”, followed by “Cycle 1 Day 2”, and so on.  
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Your study drug (tarextumab or Placebo) will be given through the vein for 90 minutes or longer 
depending on the dose you are assigned, your weight and if you have experienced any allergic 
reaction to study drug.  Your study staff will let you know how long your treatment with study 
drug will be.  Etoposide will be given through the vein for 30 to 60 minutes.   
You will be treated with platinum therapy (cisplatin or carboplatin) as determined by your study 
doctor prior to randomization.  Cisplatin will be given through the vein for 30 minutes to 2 
hours.  Carboplatin will be given through the vein for 15 minutes or longer depending on your 
kidney function.  On days when the study drug, etoposide and platinum therapy (cisplatin or 
carboplatin) are given together, the study drug will be given first, followed by etoposide, and 
then cisplatin.  You will receive study drug, etoposide, and platinum therapy (cisplatin or 
carboplatin) for 6 cycles.  After that, you will receive study drug only on Day 1 of each 
following cycle.  If you discontinue platinum therapy prior to 6 cycles because of side effects, 
you will still be allowed to stay on the study and receive study drug. 
You will receive this combination of drugs until you have experienced severe side effects, or 
your tumor has grown or spread or you have decided to stop your treatment.  If you experience 
side effects that are related to one of the three drugs, you may continue the other drugs if your 
tumor has not grown or spread. 
If your disease is at least stable or has responded to therapy at the end of cycle 6 and your doctor 
thinks it is appropriate, you will also receive radiation to your brain to help prevent tumors 
recurring within 8 weeks after the last administration of chemotherapy.  You will continue study 
drug treatment between the completion of 4 cycles of chemotherapy and the start of the brain 
radiation.  The study drug will not be given within 2 weeks of the start and completion of the 
brain radiation and will not be given during the brain radiation. 
Your doctor and/or nurse will review tests and complete pre-dose procedures once you are at the 
clinic.  If he/she feels that you are in a good health, you will be receiving study drug, etoposide 
and platinum therapy (cisplatin or carboplatin). 
During each visit, your doctor will also review any changes in the medications you have been 
taking or any changes in your health since the previous visit.   
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Cycle 1 Day 1 
This is the first day of study treatment (Cycle 1 Day 1).You will receive study drug, etoposide, 
and platinum therapy (cisplatin or carboplatin) on this day. You will have the following 
procedures done during this visit:  
•
Physical Examination before dosing (if this was done more than 7 days ago) 
•
Electrocardiogram (ECG) before dosing (if this was done more than 7 days ago)  
•
Urine Sample Collection before dosing (if this was done more than 7 days ago) 
•
Blood Sample Collection before dosing – about 1 tablespoon of blood to check your health 
condition (if this was done more than 7 days ago)  
•
Weight before dosing 
•
Additional Blood Sample Collection before dosing – about 2 tablespoons of blood to assess 
the level of certain markers and proteins that might be against tarextumab  
•
You will also have about 1 teaspoon of blood taken before starting study drug dosing to 
check the level of tarextumab in the blood 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will be asked about any changes in your health status after taking your initial dose of the 
study drug, etoposide, and platinum therapy (cisplatin or carboplatin). 
•
You will have your blood drawn 1 more time about 5 minutes after completing study drug 
dosing but before the start of etoposide and platinum therapy (cisplatin or carboplatin) 
treatment.  About 1 teaspoon of blood will be collected to measure the amount of tarextumab 
in your blood. 
Cycle 1 Day 2 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 1 Day 3 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will also have 1 teaspoon of blood taken before starting etoposide to measure the 
amount of tarextumab in your blood.   
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•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 1 Day 8 
•
About 3 tablespoons of blood sample will be taken to check the level of certain markers, the 
level of tarextumab in the blood and your health status 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 2 Day 1 
You will receive study drug, etoposide, and platinum therapy (cisplatin or carboplatin) on this 
day. The following procedures will be done prior to study drug dosing: 
•
Physical Examination: only if you report changes in your health or how you feel  
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured. 
•
About 1 tablespoon of blood will be taken to review your health condition. 
•
Urine Sample Collection. 
•
Electrocardiogram (ECG). 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 2 Day 2 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
About 2 tablespoons of blood will be taken to assess the level of certain markers. 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 2 Day 3 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
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Cycle 2 Day 8 
•
About 3 tablespoons of blood will be taken to check the level of certain markers and your 
health status.  
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
•
Optional Tumor Biopsy, if you agree to this procedure. If your doctor feels this is not a good 
time to have the biopsy, your biopsy might be taken later instead 
End of Cycle 2 (about every 6 weeks): 
Tumor assessment: A CT scan or MRI or PET/CT will be done approximately every 6 weeks 
after your initial study drug dosing (Day 1 of Cycle 3 and every 6 weeks thereafter).  If a bone 
scan is used, bone scan may be repeated as indicated by your doctorCycle 3 Day 1 
You will receive study drug, etoposide, and platinum therapy (cisplatin or carboplatin) on this 
day. The following procedures will be done prior to study drug dosing: 
•
Physical Examination: only if you report changes in your health or how you feel  
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured. 
•
Blood Sample Collection (about 2 tablespoons to check your health condition and to measure 
the level of tarextumab in your blood and proteins that might be against tarextumab). 
•
Urine Sample Collection before dosing 
•
Electrocardiogram (ECG) before dosing 
•
You will also have your blood drawn 1 more time about 5 minutes after completing study 
drug dosing but before the start of etoposide and platinum therapy (cisplatin or carboplatin).  
About 1 teaspoon of blood will be collected to measure the amount of tarextumab in your 
blood. 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 3 Day 2 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
About 2 tablespoons of blood will be taken to assess the level of certain markers.  
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
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Cycle 3 Day 3 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured. 
•
You will also have 1 teaspoon of blood drawn before starting etoposide to measure the 
amount of tarextumab in your blood. 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycle 3 Day 8 
•
About 3 tablespoon of blood to check the level of certain markers and your health status.   
•
You will also have 1 teaspoon of blood drawn before starting etoposide to measure the 
amount of tarextumab in your blood. 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycles 4-6: Day 1 
You will receive study drug, etoposide, and platinum therapy (cisplatin or carboplatin) on this 
day. The following procedures will be done prior to study drug dosing: 
•
Physical Examination: only if you report changes in your health or how you feel  
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
Blood Sample Collection (about 1 tablespoon) to check your health condition. 
•
About 1 tablespoon of blood sample will be taken to check the level of certain markers at 
Cycles 4 and 5 only.  
•
About 1 tablespoon of blood will also be taken to check proteins that might be against 
tarextumab and to measure the level of tarextumab in the blood.  This sample will be 
collected at Cycle 3 and 5  
•
Urine Sample Collection  
•
Electrocardiogram (ECG) before dosing 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
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Cycles 4-6: Day 2 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Cycles 4-6: Day 3 
You will receive etoposide treatment only on this day.  Before your etoposide treatment, the 
following procedures will be done: 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
•
You will have 1 teaspoon of blood drawn to measure the amount of tarextumab in your blood 
at Cycle 5 
End of Cycles  4 and 6 
•
Tumor assessment: A CT scan or MRI or PET/CT will be done approximately every 6 weeks 
after your initial study drug dosing. A bone scan may be repeated as indicated by your doctor 
After the completion of 6 planned cycles etoposide and platinum therapy 
•
 If your disease is at least stable or have responded to therapy, you doctor may decide that 
you will receive radiation to your brain to help prevent tumors before continuing with study 
drug treatment.   
Cycle 7 and beyond 
Starting at Cycle 7, you will receive study drug on Day 1 of each cycle only.  The following 
procedures will be performed on Day 1 of Cycle 7 and every cycle thereafter.  
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•
Physical Examination before dosing: only if you report changes in your health or how you 
feel  
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
Blood Sample Collection before dosing (about 1 tablespoon) to check your health condition. 
•
Blood sample collection before dosing (about 1 teaspoon) to check proteins that might be 
against tarextumab and the level of study drug in the blood.  These samples will be collected 
at Cycle 7 and every other cycle (i.e., Cycle 7, Cycle 9, Cycle 11, etc.) 
•
Urine Sample Collection before dosing 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
•
Tumor assessment: A CT scan or MRI or PET/CT will be done approximately every 6 weeks 
after your initial study drug dosing.  If a bone scan is used, bone scan may be repeated as 
indicated by your doctor. 
TREATMENT TERMINATION 
You will be asked to return to complete the procedures listed below at the termination visit if you 
will no longer be continuing on study drug, etoposide, or platinum therapy (cisplatin or 
carboplatin). This visit will be done about 4 weeks after your last dose of study, etoposide, or 
platinum therapy (cisplatin or carboplatin) whichever is discontinued last. 
•
Physical Examination  
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
Electrocardiogram (ECG)  
•
Urine Sample Collection  
•
Blood Sample Collection – about 3 tablespoons of blood to check your health condition, to 
check the level of certain markers, to check for proteins that might be against tarextumab, 
and to check the level of OMP59R5 in the blood 
•
Tumor assessment: either by CT or MRI or PET/CT, or bone scan, if these procedures were 
not done within the last 4 weeks and if the last tumor assessment did not show that your 
tumor has grown or spread 
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
Optional Tumor Biopsy:  An optional tumor biopsy will be done only if you agree. 
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FOLLOW UP  
After you have stopped receiving study drug and your tumor has not grown, a tumor assessment 
(CT scan or MRI or PET/CT will be done approximately every 6 weeks after your initial study 
drug dosing.  If a bone scan is used, bone scan may be repeated as indicated by your doctor) will 
be done until your tumor has grown.   
After you have stopped receiving study drug, the study staff will call you about every 3 months 
after your last clinic visit to follow your health status.  If necessary, your doctor may be 
contacted by OncoMed or OncoMed’s designee to obtain this information. 
If you withdraw from the study treatment but not from study follow-up, the study staff will still 
contact you about every 3 months after your last visit to check on your health status, or the study 
staff may use public information (like county records) to obtain information about your survival 
status only, which will be reported to OncoMed as part of the data for the study. 
POSSIBLE RISKS AND DISCOMFORTS 
tarextumab: 
As of November 17, 2015, tarextumab or placebo has been tested in 356 subjects who have 
cancer;  
The following side effects have been noted in subjects receiving tarextumab and were considered 
possibly related to tarextumab treatment: 
Common (occurred in >10% of the subjects who used the drug):  
•
Low red blood counts that might make you feel tired, easier to get infections or 
bruised/bleeding 
•
Diarrhea    
•
Fatigue-tiredness 
•
Nausea  
•
Decreased appetite 
•
Vomiting 
 
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Less Common (occurring in 5% to 10% of subjects who used the drug): 
•
Low potassium level 
•
Infusion related or allergic reactions 
•
Weight loss 
•
Redness of skin and/or rashes/hives 
Most of the above-mentioned side effects were mild and moderate, with the exception of one 
subject who experienced fatal cardiac arrest, considered to be related to study drug.  Diarrhea 
was the most common side effect and can be severe if it is not treated immediately.  You will be 
given some medications after your first dose of tarextumab to take home to treat diarrhea.  In 
addition, you will be advised to drink enough fluid and eat a balanced diet to avoid the 
dehydration and imbalanced electrolytes.  
Tarextumab will be given as an intravenous infusion.  There may be minor discomfort from the 
needle in your arm.  Bruising, swelling, and, in rare instances, infection and blood clots may 
occur at the infusion site. 
Tarextumab is a monoclonal antibody.  There is the possibility of a reaction to the monoclonal 
antibody as it is being infused (given) through your vein; these are called infusion reactions.  
Symptoms can include fever, chills, rash and/or hives, changes in blood pressure, temperature 
and heart rate.  As of November 17, 2015, eighteen of 356 subjects who have been given 
tarextumab or placebo have experienced infusion or hypersensitivity reactions; most of these 
infusion reactions were mild or moderate.  You will be watched carefully during the infusion and 
after the completion of the infusion.  If you do have a reaction to the study drug, your study 
doctor may need to give the study drug at a slower rate (over a longer period of time) and /or 
give you some medications to prevent the reaction.  If after slowing the rate of infusion and 
giving you some medications to prevent the infusion reaction, you continue to have infusion 
reactions, you may need to stop taking tarextumab.  
During the course of this study, your blood will be drawn for laboratory tests (1-3 tablespoons 
will be collected at each blood draw).  The risks of drawing blood include some discomfort from 
the needle in your arm, bruising, swelling at the needle site and, in rare instances, infection or 
fainting. 
You should discuss the risk and side effects with your study doctor.  There may be other side 
effects that we cannot predict.  You will be informed of any new significant side effects that 
develop during the course of this research study regarding the use of tarextumab. 
There may be side effects that we cannot predict and in some cases they may be serious, long-
lasting, or fatal.   
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ETOPOSIDE: 
The following side effects have been noted in subjects receiving etoposide: 
Common (occurred in > 10% of the subjects who used this drug) 
•
Low blood counts: Your white and red blood cells and platelets may temporarily 
decrease. This may put you at an increased risk for infection, anemia, and/or bleeding  
•
Nausea 
•
Vomiting 
•
Feeling weak and low energy 
•
Chills 
•
Fever 
•
Hair loss 
•
Poor appetite 
•
Sores, ulcers, or white spots on the lips or in the mouth 
Less common (occurred in 5 to 10% of the subjects who used this drug) 
•
Diarrhea 
•
Constipation 
•
Taste alteration 
•
Abdominal pain 
•
Dizziness 
•
Injection site inflammation or vein inflammation 
Rarely (occurred in < 5% of the subjects who used this drug) 
•
Increased or decreased blood pressure 
•
Allergic reaction: This medicine may cause a serious type of allergic reaction called 
anaphylaxis that is presented with symptoms such as chills, fever, fast heartbeat, sudden 
constriction of airway, shortness of breath, excessive sweating, itchiness of the skin or 
rash, change in blood pressure, and loss of consciousness, etc.  Anaphylaxis can be life-
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threatening and requires immediate medical attention.  Tell your doctor or nurse right 
away if you have chills; fever; lightheadedness, dizziness, or fainting; fast, pounding 
heartbeat; swelling of the face, tongue, and throat; or trouble with breathing after you 
receive the medicine 
Other side effects may occur following the administration of etoposide.  Your doctor will further 
explain the side effects of etoposide. 
CISPLATIN: 
The following side effects have been noted in subjects receiving cisplatin: 
Common (occurred in > 10% of the subjects who used this drug) 
•
Low blood counts: Your white and red blood cells and platelets may temporarily 
decrease. This may put you at an increased risk for infection, anemia, and/or bleeding  
•
Nausea 
•
Vomiting 
•
Ringing in the ears or hearing loss 
•
Impairment of kidney function and damages to kidney  
•
Changes in how food tastes 
•
Diarrhea 
•
Damages to nerve that causes pain, numbness, tingling of hands and feet, and sometimes 
even have the difficulty in motion 
•
Hair loss 
•
Imbalance of electrolyte 
•
Extreme fatigue 
•
Mild elevation of liver enzymes 
Less common or rare (occurred in  10% of the subjects who used this drug) 
•
Change in vision or inflammation of optic nerve and blindness 
•
Injection site inflammation or vein inflammation 
•
Change in blood vessels that trigger heart attack and heart problem, stroke or brain injury 
•
Allergic reaction: This medicine may cause a serious type of allergic reaction called 
anaphylaxis that is presented with symptoms such as chills, fever, fast heartbeat, sudden 
constriction of airway, shortness of breath, excessive sweating, itchiness of the skin or 
rash, change in blood pressure, and loss of consciousness, etc.  Anaphylaxis can be 
life-threatening and requires immediate medical attention.  Tell your doctor or nurse right 
away if you have chills; fever; lightheadedness, dizziness, or fainting; fast, pounding 
heartbeat; swelling of the face, tongue, and throat; or trouble with breathing after you 
receive the medicine 
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Other side effects may occur following the administration of cisplatin.  The side effects are 
generally reversible and gradually disappear when treatment ends.  However, some side effects 
might take a long time to disappear.  Your doctor will further explain the side effects of cisplatin. 
CARBOPLATIN: 
The following side effects have been noted in subjects receiving carboplatin: 
Common (occurred in >10% of the subjects who used this drug) 
•
Low blood counts: Your white and red blood cells and platelets may temporarily 
decrease. This may put you at an increased risk for infection, anemia, and/or bleeding  
•
Nausea 
•
Vomiting 
•
Damages to nerve that causes pain, numbness, tingling of hands and feet, and sometimes 
even have the difficulty in motion 
•
Ringing in the ears or hearing loss 
•
Hair loss 
•
Imbalance of electrolytes 
•
Extreme fatigue 
•
Elevation of liver enzymes 
•
Pain 
•
Allergic reaction 
•
Muscle weakness 
Less common or rare (occurred in 10% of the subjects who used this drug) 
•
Sores, ulcers, or white spots on the lips or in the mouth 
•
Loss of vision for light or color 
•
Impairment of kidney function and damages to kidney.  Your carboplatin dose will be 
modified if you have impairment of kidney function  
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Other side effects may occur following the administration of carboplatin.  The side effects are 
generally reversible and gradually disappear when treatment ends.  However, some side effects 
might take a long time to disappear.  Your doctor will further explain the side effects of 
carboplatin 
PREGNANCY 
There is a very high risk that tarextumab may be harmful to an unborn baby (embryo or fetus) or 
newborn child. 
Therefore, women who are pregnant or breastfeeding may not participate in this study.  Women 
must have a negative pregnancy test before beginning the study.  It is important that both men 
and women take steps to prevent pregnancy during this study through the use of adequate 
contraception (for example, a barrier or hormone method or abstinence) 30 days prior to first 
study drug administration and for the duration of the study until 30 days after the last dose of 
study drug or etoposide or platinum therapy (cisplatin or carboplatin) whichever is discontinued 
last. 
If you become pregnant or suspect that you are pregnant, or if your partner becomes pregnant or 
suspects that she is pregnant during the study or within 30 days after the last dose of study drug, 
etoposide, or platinum therapy (cisplatin or carboplatin) whichever is discontinued last, you must 
notify the study doctor immediately.  If you become pregnant, you will be taken off of treatment 
and will undergo assessments listed under the Treatment Termination Section of this document, 
except for the radiographic studies, which will not be performed.  If your partner becomes 
pregnant, you will remain on the study.  If either you or your partner becomes pregnant during 
the study or within 30 days after the last dose of study drug, etoposide, or platinum therapy 
(cisplatin or carboplatin) whichever is discontinued last, you and/or your partner will be followed 
through outcome of the birth. 
POTENTIAL BENEFITS 
There is no guarantee that there will be any direct benefit to you if you take part in this research 
study.  The treatments you receive may be harmful.  It is possible that the information learned 
from this study may be helpful in the future to other people with cancer. 
SIGNIFICANT NEW FINDINGS 
Any significant new findings regarding tarextumab that become known during the course of this 
research study, which might reasonably affect your willingness to participate in this study, will 
be provided to you. 
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ALTERNATIVE TREATMENTS AND PROCEDURES 
If you decide not to participate in this study, you will continue to receive medical care to which 
you were entitled prior to your participation in this study.  Your doctor will discuss other options 
available to you.  Your choice not to participate in this study will not affect your medical care in 
any way. 
TERMINATION OF SUBJECT PARTICIPATION 
Your participation in this research study may be terminated at any time for medical reasons or 
because the sponsor finds it necessary to limit or terminate this clinical trial.  Some reasons for 
termination include progression of your disease, any other illness that prevents further 
administration of study drug, unacceptable adverse events, general or specific changes in your 
condition that make further treatment unacceptable in the opinion of your doctor, and protocol 
non-compliance. 
Your doctor may decide to hold or stop the study drug infusions at any time during the study for 
safety reasons. 
If your doctor or the sponsor decides to withdraw you from the study, you will undergo the same 
assessments listed under Treatment Termination. 
COSTS AND COMPENSATION 
The cost of all “standard of care” assessments related to your participation in this study and your 
medical care will be billed to you and/or your insurance company.  These are tests that would 
normally be performed in subjects to evaluate their cancer.  Due to the investigational nature of 
this research study, insurance companies or government health care programs may limit their 
obligation to pay for experimental treatments and their consequences.  You may want to discuss 
this with your insurance company before agreeing to participate.  The cost of all non-standard of 
care assessments will be paid for by OncoMed. 
You will not be paid for participation in this study. 
COMPENSATION FOR RESEARCH-RELATED INJURY 
If you are physically injured as a direct result of study drug or study procedure properly 
performed under the plan for this study and it is not due to a pre-existing medical condition or 
underlying disease, OncoMed will reimburse you for the reasonable medical expenses for the 
treatment of that injury which are not covered by another payer, your own insurance or health 
care program.  No other compensation is available from OncoMed if any injury occurs.  
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CONFIDENTIALITY 
Every effort will be made to keep your medical information confidential (secret).  You will be 
identified by a code and no information that identifies you will be released without your written 
permission, except as required by law.  To the extent permitted by law and by signing the 
consent form, you allow access by representatives of the Food and Drug Administration (FDA), 
other regulatory bodies, Institutional Review Boards, Independent Ethics Committees, and 
OncoMed monitors/representatives and collaborators to inspect your research and medical 
records without removal of identifying information, such as your name, initials, date of birth, 
sex, race, and location of the research study.  If information from this study is presented publicly 
or published in a medical journal, you will not be identified by name, picture, or by any other 
personally identifying information. 
The description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  The website will not include information that can identify you.  At most, 
the website will include a summary of the results. You can search this website at any time 
You will be asked to review and sign a HIPAA (Health Insurance Portability and Accountability 
Act) Research Authorization Form requesting your authorization to collect, use, and disclose 
your medical information, 
OR IF SITE DOES NOT HAVE OWN HIPAA FORM: 
AUTHORIZATION TO USE AND DISCLOSE MY HEALTH INFORMATION 
I authorize (give permission to) insert name of study site to use and disclose (share) my health 
information solely for the purposes of this research study and research directly related to the use 
of tarextumab.  I understand that my health information that I am authorizing to be used and 
disclosed (Authorized Health Information) includes all health information about me that has been 
and will be created or received by (SITE) and that is in my medical records maintained by  
(SITE). 
I understand that I am free at any time to restrict the (Site’s) use and disclosure of my Authorized 
Health Information, without penalty or other consequences.  However, I also understand that I 
may be denied participation in, or continued participation in, this research study if at any time I 
choose to restrict the (Site’s) use and disclosure of Authorized Health Information that is 
necessary for the completion of this research study. 
AUTHORIZED PERSONS AND RECIPIENTS 
I authorize the following person(s) and groups of persons to request, receive, and use my 
Authorized Health Information: representatives of the FDA, other regulatory authorities, the 
Institutional Review Board/Independent Ethics Committee, OncoMed representatives and 
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monitors, and OncoMed collaborators and licensees.  I authorize (SITE) to disclose my 
Authorized Health Information to these persons and groups or persons. 
RE-DISCLOSURES TO THIRD PARTIES 
I understand that once (Site) discloses my Authorized Health Information to the recipient(s) 
identified in the previous section Authorized Persons and Recipients, (Site) cannot guarantee that 
the recipient(s) will not re-disclose my Authorized Health Information to other persons who may 
not be bound by this informed consent form. 
EXPIRATION DATE 
My authorization (permission) to use and disclose my Authorized Health Information will 
continue indefinitely, but that use and sharing will only be for the purposes described in the 
informed consent form. 
EFFECT OF MY REVOCATION OF AUTHORIZATION TO USE AND DISCLOSE 
AUTHORIZED HEALTH INFORMATION 
I understand that my authorization for (site) to use and disclose my Authorized Health 
Information will remain in effect until I withdraw my permission by sending my written notice 
of revocation (withdrawal of permission) to the Privacy Office listed in the Questions section of 
the following page.  My written revocation will be effective immediately upon (Site’s) receipt of 
my written notice, except that the revocation will not have any effect on any actions taken by 
(SITE) in relying on this authorization before it received my written notice of withdrawal of 
permission. 
QUESTIONS 
If you have any question about the study and/or its procedure or safety, you may contact Dr. 
(Name of Investigator) at (telephone number).  In the event of any injury, you may contact Dr. 
(name) at (telephone number).  You may also call (Name) at (telephone number) for information 
on experimental subjects’ rights. 
If at any time during this research study you feel that you have not been adequately informed of 
your rights with respect to the privacy of your health information, or you feel that the privacy of 
your health information has not been adequately protected, you may contact or visit (Site’s) 
privacy office during normal working hours at (Privacy Office name) at (telephone number and 
address). 
VOLUNTARY PARTICIPATION AND DOCUMENTATION OF CONSENT 
Your decision to participate in this study is entirely voluntary.  You may refuse to participate in 
or withdraw from the study at any time without prejudice or loss of benefits to which you are 
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otherwise entitled.  A signed copy of this consent form will be given to you for your records and 
a copy will be retained by the study doctor for his or her files. 
By signing the form below, you have read the above information about this research study, and 
have had a chance to ask questions to help you understand your participation in this study and 
how your information will be used. 
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CONSENT FOR OPTIONAL TUMOR BIOPSY 
 _______ _________If you give your consent for a core biopsy of your tumor  
Initials 
Date 
lesion, please check the box and write your initials and the date in  
 
 
the space provided. 
 _______ _________If you do not give your consent for a core biopsy of your  
Initials 
Date 
tumor lesion, please check the box and write your initials and the  
 
 
date in the space provided. 
 
_______________________________________________________ 
Printed Name of Subject or Subject’s Authorized Representative 
________________________________________________________ 
 
___________ 
Signature of Subject or Subject’s Authorized Representative 
 
 
Date 
_________________________________________________________ 
Printed Name of Person Obtaining Informed Consent 
__________________________________________________________  
____________ 
Signature of Person Obtaining Informed Consent 
 
 
 
 
Date 
__________________________________________________________ 
Printed Name of Witness* 
_______________________________________________ 
__________ 
 
___________ 
Signature of Witness* 
 
 
 
 
 
 
 
Date 
*If the Principal Investigator or Institutional Review Board deems a witness signature is necessary 
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VOLUNTARY PARTICIPATION AND DOCUMENTATION OF CONSENT 
Your decision to participate in this study is entirely voluntary.  You may refuse to participate in 
or withdraw from the study at any time without prejudice or loss of benefits to which you are 
otherwise entitled.  A signed copy of this consent form will be given to you for your records and 
a copy will be retained by the study doctor for his or her files. 
By signing the form below, you acknowledge that you have read the above information about 
this research study, and have had a chance to ask questions to help you understand your 
participation in this study and how your information will be used. 
 
________________________________________________________ 
 
___________ 
Signature of Subject or Subject’s Authorized Representative  
 
Date 
_________________________________________________________ 
Printed Name of Person Obtaining Informed Consent 
__________________________________________________________  
____________ 
Signature of Person Obtaining Informed Consent 
 
 
 
Date 
__________________________________________________________ 
Printed Name of Witness* 
__________________________________________________________  
____________ 
Signature of Witness*  
 
 
 
 
 
 
Date 
*If the Principal Investigator or Institutional Review Board/Ethics Committee deems a witness signature is 
necessary. 
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APPENDIX H: 
SAMPLE PHARMACOGENOMICS/DNA INFORMED CONSENT 
WHAT IS THE PURPOSE OF THIS PART OF THE STUDY? 
The cells of your body contain deoxyribonucleic acid, or DNA for short.  DNA is passed down 
from your parents.  Genes carry the DNA that determine your physical appearance such as the 
color of your eyes and hair.  Differences in our genes help explain why we all look different.  
Differences in our genes may also help explain why some drugs work and are safe in some 
people, but not in others.  Differences in our genes also help explain why some people get certain 
diseases, but others do not. 
The sponsor would like to study the differences in people's DNA to learn more about diseases 
and response to drugs.  This information will be used to try to develop safer and better drugs.  
To do this, the Sponsor would like to do DNA tests related to tarextumab and the diseases for 
which this drug is developed.  The DNA tests are only for research.  The tests are not for your 
medical care.  All volunteers taking part in the main study are also being invited to take part in 
DNA research (where possible). 
WHAT AM I BEING ASKED TO DO? 
You are being asked to give one small blood sample (10 mL, about 2 teaspoons) on Day 1 of 
Cycle 1 prior to the administration of study drug.  Blood will be drawn from a vein using a 
needle.  DNA will be extracted from your blood sample.  Additionally, you are being asked to 
allow the Sponsor to perform the DNA testing on the mandatory tumor tissues you have 
provided for the study entry.  If you had agreed to have optional tumor biopsies performed, you 
are also being asked to allow the Sponsor to perform DNA testing on these tissues.  
Your DNA may be tested for specific genes relevant to tarextumab (the study drug), the 
Notch/DLL4 pathways (the targets of the tarextumab) and/or other genes related to your cancer.  
Only DNA research related to tarextumab or to the diseases for which this drug is developed will 
be performed.  The Sponsor will store the tissue samples until there is no DNA left.  The Sponsor 
will also destroy the blood sample used for DNA testing after 10 years. 
You can also decide not to take part at all in DNA research.  No blood sample for DNA research 
will be taken from you unless you sign and date this Informed Consent Form, and No DNA 
testing will be performed on the tumor tissues collected from you.  Your decision to give, or not 
to give, a DNA sample will not affect the medical care that you receive from your study doctor 
or his/her staff.  Your participation is voluntary. 
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HOW WILL MY IDENTITY AND RESULTS BE KEPT CONFIDENTIAL? 
The Sponsor has taken several steps to keep your identity and results confidential.  These are 
described below. 
a)  Coding of your DNA Sample 
Your DNA sample will not have your name or address on it.  Your DNA sample will be coded 
with your Subject number from the main study.  After the study is officially over, the Subject 
number will be removed from your DNA sample.  Your DNA sample and results will be labeled 
with a new number. 
b)  Restricted Access to Your DNA Sample 
The Sponsor will control your DNA sample.  Your DNA sample will be stored in a secure room 
at a facility in Redwood City, CA, or other site designated by the sponsor.  Only authorized staff 
are allowed to enter the room.  Your DNA sample may be transferred to other research partners 
working with the Sponsor.  DNA samples transferred to research partners will not contain your 
Subject number.  Your DNA sample will not be sold, loaned, or given to any other independent 
groups for their own use.  Research partners working with the Sponsor are not allowed to share 
DNA samples with anyone else. 
c)  Restricted Access to Results 
Your DNA results will be stored by the Sponsor both on paper and in computer records.  You will 
not be identified by name in these records.  Your results will only be labeled with a code number.  
This is to protect your privacy.  Your results will be kept as long as necessary.  The following 
people may see your test results: 
•
The Sponsor 
•
Research partners working with the Sponsor 
•
Independent Ethics Committees/Institutional Review Boards 
•
Regulatory authorities, like the Food and Drug Administration (FDA) or the European 
Medicines Evaluation Agency (EMEA) 
Unless the law requires it, your individual results will not be given to anyone who is not listed 
above.  For example, your results will not be given to employers, insurance companies or family 
members.  Research partners working with the Sponsor may not use or share your results without 
permission from the Sponsor. 
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DNA results from the study may be published or added to public databases.  They also may be 
presented in public meetings.  No publication or presentation will identify you by your code 
number or name. 
d)  Separate Storage of DNA Forms 
Your study doctor will keep your signed DNA informed consent form, and any other DNA 
forms, separate from your other medical files.  People who have access to your medical files 
(such as insurance companies) would not know that you took part in a DNA research study by 
looking at your medical files.  You will be given a copy of your signed DNA consent form. 
WHAT IF I CHANGE MY MIND LATER? 
If you change your mind and decide later that you no longer want to take part in DNA research, 
you may ask for your DNA sample to be destroyed as long as the study is not officially over.  
You can stay in the main study even if you change your mind about taking part in DNA research. 
WILL I GET MY DNA TEST RESULTS? 
The tests will be performed in a research laboratory.  Results from a research laboratory may not 
always be exact.  They cannot be used to make a diagnosis about your health.  Also, research 
laboratories cannot give advice on health or health risks.  For these reasons, the results of your 
DNA tests will not be given to you or your study doctor (or his/her staff). 
WHAT ARE THE BENEFITS? 
You will not directly benefit from taking part in this DNA research.  This research could provide 
information about tarextumab or the diseases for which this drug is developed.  This information 
could help others in the future. 
WHAT ARE THE RISKS? 
There may be some pain or bruising from the needle stick used to draw the blood.  Some people 
may faint when their blood is drawn.  Very rarely, there may be an infection at the place where 
the needle went into the skin.  Any problem that you have from drawing blood will be handled 
the same way as in the main study.  Your research results cannot be used to make a diagnosis 
about your health. 
WILL I BE PAID FOR TAKING PART OR FOR THE USE OF MY RESULTS? 
You will not be paid for taking part in the DNA research part of the study.  You will not be paid 
for any use of your DNA sample or results or for any inventions that are made from them.  If you 
take part, you are providing your DNA sample for use by the Sponsor.  The Sponsor intends to 
own any use of the results, treatments, or inventions that can be made from the research. 
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QUESTIONS 
If you have any question about the study and/or its procedure or safety, you may contact Dr.  
(Name of Investigator) at (telephone number).  In the event of any injury, you may contact Dr.  
(name) at (telephone number).  You may also call (Name) at (telephone number) for information 
on experimental subjects’ rights. 
If at any time during this research study you feel that you have not been adequately informed of 
your rights with respect to the privacy of your health information, or you feel that the privacy of 
your health information has not been adequately protected, you may contact or visit (Site’s) 
privacy office during normal working hours at (Privacy Office name) at (telephone number and 
address). 
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VOLUNTARY PARTICIPATION AND DOCUMENTATION OF CONSENT 
Your decision to participate in this part of the study is entirely voluntary and. you may choose 
not to participate in this part of the study without prejudice or loss of benefits to which you are 
otherwise entitled in the remainder of the study.  A signed copy of this consent form will be 
given to you for your records and a copy will be retained by the Investigator for his or her files. 
By signing the form below, you acknowledge that you have read the above information about 
this research study, and have had a chance to ask questions to help you understand your 
participation in this study and how your information will be used. 
_____   _______ 
If you give your consent for a small blood sample for DNA research, 
please check the box and write your initials and the date in the space 
provided. 
Initials  
Date 
_____   _______ 
If you do not give your consent for a small blood sample for DNA 
research, please check the box and write your initials and the date in the 
space provided. 
Initials  
Date 
_____   _______ 
If you give your consent to allow DNA testing on the tumor tissue 
collected from you, please check the box and write your initials and the 
date in the space provided. 
Initials  
Date 
_____   _______ 
If you do not give your consent to allow DNA testing on the tumor tissue 
collected from you, please check the box and write your initials and the 
date in the space provided. 
Initials  
Date 
Printed Name of Subject or Subject’s Authorized Representative 
________________________________________________________ 
___________ 
Signature of Subject or Subject’s Authorized Representative  
Date 
_________________________________________________________ 
Printed Name of Person Obtaining Informed Consent 
__________________________________________________________ ____________ 
Signature of Person Obtaining Informed Consent 
 
 
Date 
__________________________________________________________ 
Printed Name of Witness* 
_________________________________________________________ ___________ 
Signature of Witness*  
 
 
 
 
 
Date 
*If the Principal Investigator or Ethic’s Committee deems a witness signature is necessary 
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APPENDIX I: 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
AMENDMENT 1: 
09 MAY 2013 
The following changes were made to the protocol.  Italics in the text indicate new text.   
RATIONALE 
The protocol has been amended to allow the enrollment of current smokers, to exclude 
concurrent use of therapeutic warfarin, and to allow enrollment of a subject with treated brain 
metastasis provided that the subject has stable neurologic condition for at least 2 weeks after the 
completion of the radiation and is not receiving corticosteroid of > 40 mg prednisone daily 
equivalent dose to control the symptoms, to clarify the definition of DLT for Grade 4 
neutropenia,  and to clarify study drug preparation and administration.  Additional minor changes 
have been made to improve clarity and consistency. 
SUMMARY OF CHANGES: 
SYNOPSIS 
Diagnosis and Main Criteria for Eligibility: (Cont’d) 
Inclusion Criteria: 
Previously Read: 
d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated 
partial thromboplastin time (aPTT) 1.5 × ULN unless the subject is on heparin or 
warfarin or other similar anti-coagulants. 
Now Reads: 
d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated 
partial thromboplastin time (aPTT) 1.5 × ULN. 
Additionally, for individuals eligible to participate in Phase 2 portion of the study: 
Previously Read: 
2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed extensive 
stage small cell lung cancer. Exceptions to this exclusion criterion include: 1) prophylactic 
cranial irradiation or whole brain radiation (WBRT) prior to the first administration of study 
drug provided that the subject has stable neurologic condition for at least 2 weeks after the 
completion of the radiation, 2) focused radiation for symptomatic relief for isolated bone 
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metastases; 3) bisphosphonate or denosumab therapy for bone metastasis initiated prior to 
study entry. 
3. Symptomatic brain metastases requiring whole brain irradiation within 4 weeks prior to first 
study drug administration or requiring daily doses of >40mg of oral prednisone, or require 
use of anti-epileptic drugs. 
4. Presence of uncontrolled Grade  1 diarrhea within 4 weeks prior to the first study drug 
administration. 
5. Current smoker. 
6. Presence of any serious or uncontrolled illness including, but not limited to:  ongoing or 
active infection, symptomatic congestive heart failure unstable angina pectoris, cardiac 
arrhythmia, arterial thrombosis, symptomatic pulmonary embolism, and psychiatric illness 
that would limit compliance with study requirement. 
7. History of myocardial infarction, acute coronary syndromes (including unstable angina), 
coronary angioplasty and/or stenting within 6 months prior to the first administration of study 
drug. 
8. A history of malignancy with the exception of: 
a.
Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ 
cervical cancer 
b. Adequately treated stage I cancer from which the subject is currently in remission, or  
c.
Any other cancer from which the subject has been disease-free for  3 years 
9. Known human immunodeficiency virus (HIV) infection. 
10. Females who are pregnant or breastfeeding. 
Now Reads: 
2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed extensive 
stage small cell lung cancer.  Exceptions to this exclusion criterion include: 1) prophylactic 
cranial irradiation or whole brain radiation (WBRT) prior to the first administration of study 
drug provided that the subject has stable neurologic condition for at least 2 weeks after the 
completion of the radiation and is not receiving corticosteroid of > 40 mg prednisone daily 
equivalent dose to control the symptoms, 2) focused radiation for symptomatic relief for 
isolated bone metastases; 3) bisphosphonate or denosumab therapy for bone metastasis 
initiated prior to study entry. 
3. Presence of uncontrolled Grade  1 diarrhea within 4 weeks prior to the first study drug 
administration. 
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4. Presence of any serious or uncontrolled illness including, but not limited to:  ongoing or 
active infection, symptomatic congestive heart failure unstable angina pectoris, uncontrolled 
cardiac arrhythmia, uncontrolled arterial thrombosis, symptomatic pulmonary embolism, and 
psychiatric illness that would limit compliance with study requirement. 
5. History of myocardial infarction, acute coronary syndromes (including unstable angina), 
coronary angioplasty and/or stenting within 6 months prior to the first administration of study 
drug. 
6. A history of malignancy with the exception of: 
a.
Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ 
cervical cancer 
b. Adequately treated stage I cancer from which the subject is currently in remission, or  
c.
Any other cancer from which the subject has been disease-free for  3 years 
7. Known human immunodeficiency virus (HIV) infection. 
8. Females who are pregnant or breastfeeding. 
9. Concurrent use of therapeutic warfarin (prophylactic low dose of warfarin, i.e., 1 mg daily 
for port catheter is allowed). 
Test Product, Dose, and Mode of Administration 
Previously Read: 
OMP-59R5 must be delivered through either polyvinyl chloride (PVC) or non-PVC tubing that 
contains a 0.22-micron filter and should be infused over 30 minutes as an IV infusion.  
Placebo is a formulation of 50mM Histidine, 100mM Sodium Chloride, 45mM Sucrose and 
0.01% (v/v) Polysorbate-20, pH 6.0.  Placebo will be administered in the same manner as 
OMP-59R5; i.e., withdraw the necessary amount of Placebo and dilute with 5% Dextrose in 
Water (D5W) to a total volume of 250 mL and infuse over 30 minutes. 
Now Reads: 
OMP-59R5 must be delivered through either polyvinyl chloride (PVC) or non-PVC tubing 
containing a Baxter 0.22-micron high pressure extended life filter (part number 2H5660) which 
will be provided by OncoMed and should be infused over 30 minutes (+/- 5 minutes) as an IV 
infusion.  
Placebo is a formulation of 50mM Histidine, 100mM Sodium Chloride, 45mM Sucrose and 
0.01% (v/v) Polysorbate-20, pH 6.0.  Placebo will be administered in the same manner as 
OMP-59R5; i.e., withdraw the necessary amount of Placebo and dilute with either half normal 
saline (NS) (0.45% Sodium Chloride (NaCl) or 5% Dextrose and 0.45% NaCl (D5W ½ NS) to a 
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total volume of 250 mL and infuse over 30 minutes (+/- 5 minutes).  The diluted study drug 
should be administered within 4 hours of preparation. 
3.4 
Clinical Background 
Previously Read: 
As of November 5, 2012, a total of thirty-nine subjects have been treated in Study 59R5-001: 
three at 0.5 mg/kg weekly, three at 1 mg/kg weekly, six at 2.5 mg/kg weekly, nine at 5 mg/kg 
weekly, six at 5 mg/kg every other week, three at 7.5mg/kg every other week, three at 10 mg/kg 
every other week, and six at 7.5mg/kg every three weeks.   
The initial dose levels of OMP-59R5 in this study were 0.5, 1, 2.5, and 5 mg/kg administered IV 
once weekly.  There were no DLTs observed at the 0.5 mg/kg (n=3), 1 mg/kg (n=3) or 2.5 mg/kg 
(n=3) dose levels.  Two of the six subjects treated at 5 mg/kg once weekly experienced DLTs: 
one had Grade 3 hypokalemia secondary to diarrhea and the other had Grade 3 diarrhea.  As a 
result, 5mg/kg once weekly exceeded the MTD and an additional three subjects were treated at 
2.5 mg/kg once weekly.  These three additional subjects tolerated treatment without a DLT thus 
defining an MTD as 2.5mg/kg once weekly for OMP-59R5.  
Once the initial MTD was defined as described above, the protocol was amended to use a 
standard treatment algorithm to treat diarrhea and the DLT criteria was revised to define Grade 3 
and above diarrhea that does not respond to standard medical treatment within 48 hours as a 
DLT.  An additional three subjects were treated at the dose level of 5 mg/kg weekly with 
concomitant use of anti-diarrheal medications: all subjects were given a prescription for 
loperamide at study entry with instructions to take an initial 4 mg dose following the first loose 
stool, followed by 2 mg after every unformed stool with a maximum of 16 mg per day.  
Loperamide was continued until the subject was diarrhea-free for 12 hours.  If Grade 3 diarrhea 
develops, loperamide would be discontinued and the subject would be started on second-line 
therapy (i.e., Lomotil 2 tablets 4 times daily and/or octreotide 100-150 ȝg subcutaneously [sc] 
three times daily and up to a maximum 500ȝg 3 times daily).  One subject with prostate cancer 
developed Grade 2 anorexia and Grade 1 diarrhea.  The second subject at 5mg/kg weekly, with 
colorectal cancer, developed Grade 2 diarrhea, Grade 2 dehydration, and Cycle 3 of OMP-59R5 
was held at the discretion of the treating physician.  The third subject at this dose level with non-
small cell lung cancer developed Grade 1 diarrhea and Grade 1 abdominal pain.  Due to poor 
tolerability of the 5 mg/kg weekly dose, despite the concomitant use of anti-diarrheal medication, 
a revised dosing schedule was implemented to define a new MTD with dosing of OMP-59R5 
every other week.  
Three subjects were treated at 5 mg/kg every other week and only Grade 1 diarrhea was noted 
from each of these three subjects.  Dose escalation proceeded to 10 mg/kg every other week and 
two out of three subjects experienced DLT with Grade 3 diarrhea.  Thus, 10 mg/kg every other 
week was defined as a dose above the MTD and the 5 mg/kg every other week dose level was 
expanded to enroll three additional subjects.  A total of six subjects have been treated at 5 mg/kg 
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every other week and no DLT was noted. The dosing schedule was revised to explore an 
intermediary dose of 7.5mg/kg of OMP-59R5 every three weeks. Six subjects were treated at 
dose of 7.5mg/kg every three weeks with no DLTs noted, establishing the MTD of every three 
weeks schedule of 7.5 mg/kg.  In addition, an intermediary dose of 7.5mg/kg every other week is 
also being explored.  As of November 5, 2012, three subjects have been treated at 7.5mg/kg 
every other week and no DLT were noted.  Exploration of 7.5 mg/kg every other week is 
ongoing with enrolling 3 additional subjects. 
Diarrhea has been the most common adverse event, occurring in 58% (21 of 36) of subjects 
treated on the study regardless of schedule, which was expected based on the observance of 
diarrhea in the cynomolgus monkey toxicology study.  Diarrhea was observed at 2.5 mg/kg 
weekly and above dose cohorts, and was dose dependent.  Table 2 below tabulates the incidence 
and severity of diarrhea among dose levels according NCI-CTCAE criteria v4.02.   
Table 2: 
Study 59R5-001: Treatment Related Diarrhea (N=21/36) 
Diarrhea 
Grade 
0.5 mg/kg  
QW  
(n=0/3) 
1 mg/kg  
QW  
(n=0/3) 
2.5 mg/kg 
QW  
(n=4/6) 
5 mg/kg  
QW  
(n=8/9) 
5 mg/kg  
QoW  
(n=2/3) 
10 mg/kg 
Q0W 
 (n=3/3) 
7.5 mg/kg 
Q3W 
 (n=4/6) 
1 
- 
- 
2 
4 
2 
- 
2 
2 
- 
- 
2 
2 
- 
- 
2 
3 
- 
- 
- 
2 
- 
3 
- 
 
Additional common treatment-related adverse events included fatigue (28%), nausea (22%), 
decreased appetite (14%), vomiting (11%), dizziness (8%), increased alanine transaminase 
(ALT) (8%), dehydration (8%), hypokalemia (8%), abdominal pain (8%), anemia (8%), and 
thrombocytopenia (8%). 
Table 2 and Table 3 summarize all treatment related CTC Grade 3 adverse events that occurred 
in Study 59R5-001 by body system; there were no Grade 4 or 5 events on study. 
Table 3: 
Study 59R5-001: Grade 3 Treatment Related Adverse Events by Body 
System (N=36) 
Body System  
Preferred Term 
Number of Subjects 
Gastrointestinal Disorders 
Diarrhea 
5 
Blood and Lymphatic System Disorders 
Anemia 
2 
Investigations 
Alanine Aminotransferase 
Increased (Grade 3) 
1 
Metabolism and Nutrition Disorders 
Hypokalaemia 
1 
General Disorders and Administration Site 
Conditions 
Fatigue 
1 
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No RECIST complete or partial responses have been noted on this Phase 1 study.  However, six 
subjects have had RECIST stable disease (SD) lasting greater than 56 days (ranging from 61 
days to 165 days, all of them have come off the study).   
Treatment with etoposide and cisplatin is the standard of care for subjects with untreated 
extended stage small cell lung cancer.  The most common AE of OMP-59R5 is diarrhea, whereas 
cytopenia is the most common adverse event with EP administration.  Therefore, the most 
common AEs of OMP-59R5 and EP do not overlap, providing the justification for investigating 
this combination in the study.  Subjects enrolled in this study will receive a starting dose of 
5 mg/kg of OMP-59R5 once every three weeks, which is one dose below the MTD of 7.5 mg/kg 
every three weeks in Study 59R5-001.  Phase 1b lead-in portion of the study will provide 
preliminary safety and tolerability profile of this combination before the initiation of Phase 2 
portion of the study.  OMP-59R5 has an estimated apparent half time of 2 to 3 days at 7.5 mg/kg 
in Study 59R5-001, subjects will not receive PCI or WBRT within 2 weeks of study drug 
administration and will not receive OMP-59R5 during the radiation to alleviate any potential 
interaction between the study drug and the radiation.  Therefore, risks and potential benefits of 
participation have been appropriately mitigated for this patient population. 
Now Reads: 
As of April 25, 2013, a total of forty-two subjects have been treated in Study 59R5-001: three at 
0.5 mg/kg weekly, three at 1 mg/kg weekly, six at 2.5 mg/kg weekly, nine at 5 mg/kg weekly, six 
at 5 mg/kg every other week, six at 7.5mg/kg every other week, three at 10 mg/kg every other 
week, and six at 7.5mg/kg every three weeks.   
Two DLTs occurred in two of nine subjects treated at 5 mg/kg weekly: one Grade 3 hypokalemia 
secondary to Grade 3 diarrhea in one subject and one Grade 3 diarrhea in another subject, 
which led to the MTD for weekly dosing schedule to be 2.5 mg/kg.  No DLTs occurred in 6 
subjects treated at 7.5 mg/kg every three weeks that led to the MTD for every three week 
schedule to be 7.5 mg/kg.  Two DLTs both Grade 3 diarrhea, occurred in two of three subjects 
treated with a single dose of OMP-59R5 at 10 mg/kg every other week and no DLTs occurred in 
6 subjects treated at 7.5 mg/kg every other week, which led to the MTD for every other week 
schedule to be 7.5 mg/kg every other week. 
Toxicities observed to date have been mostly Grades 1 and 2, and were manageable with 
supportive care and/or interruption or dose reduction of OMP-59R5.  There were no AEs of a 
Grade 4 severity reported.  AEs with a severity of Grade 3 were uncommon and have been 
primarily diarrhea.  
Diarrhea has been the most common adverse event, occurring in 81% (34 of 42) of subjects 
treated on the study regardless of schedule, which was expected based on the observance of 
diarrhea in the cynomolgus monkey toxicology study.  Diarrhea was observed at 2.5 mg/kg 
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weekly and above dose cohorts, and was dose dependent.  Table 2 below tabulates the incidence 
and worse severity of diarrhea occurred while receiving OMP-59R5 among dose levels 
according NCI-CTCAE criteria v4.02.   
Table 2: 
Study 59R5-001: Worse Grade Treatment Related Diarrhea (N=34/42) 
Diarrhea 
Grade 
0.5 mg/kg  
QW  
(n=2/3) 
1 mg/kg  
QW  
(n=0/3) 
2.5 mg/kg 
QW  
(n=6/6) 
5 mg/kg 
QW  
(n=8/9) 
5 mg/kg 
QoW  
(n=4/6) 
10 mg/kg 
QoW 
 (n=3/3) 
7.5 mg/kg 
Q3W 
 (n=5/6) 
7.5 mg/kg 
QoW 
(n=6/6) 
1 
1 
- 
3 
4 
3 
- 
4 
3 
2 
1 
- 
3 
2 
- 
- 
1 
3 
3 
- 
- 
- 
2 
1 
3 
- 
 
 
Additional common treatment-related adverse events included (as of November 17, 2012 data 
cutoff with 39 subjects treated) fatigue (30.8%), nausea (28.2%), decreased appetite (17.9%), 
vomiting (15.4%), increased alanine transaminase (ALT) (10.3%), hypokalemia (15.4 and 
dizziness (10.3%). 
Table 2 and Table 3 summarize all treatment related CTC Grade 3 adverse events that occurred 
in Study 59R5-001 by body system as of November 17, 2012; there were no Grade 4 or 5 events 
on study. 
Table 3: 
Study 59R5-001: Grade 3 Treatment Related Adverse Events by Body 
System (N=39) 
Body System  
Preferred Term 
Number of Subjects 
Gastrointestinal Disorders 
Diarrhea 
6 (15.4%) 
Blood and Lymphatic System Disorders 
Anemia 
2 (5.1%) 
Investigations 
Alanine Aminotransferase 
Increased  
Aspartate Aminotransferase 
Increase 
1 (2.6%) 
1 (2.6%) 
Metabolism and Nutrition Disorders 
Hypokalaemia 
2 (5.1%) 
General Disorders and Administration Site 
Conditions 
Fatigue 
1 (2.6%) 
 
No RECIST complete or partial responses have been noted on this Phase 1 study.  However, six 
subjects have had RECIST stable disease (SD) lasting greater than 56 days (ranging from 61 
days to 165 days, all of them have come off the study).  
OMP-59R5 is also being studied in a phase 1b/2 study in combination with nab-paclitaxel and 
gemcitabine in subjects with previously untreated stage IV pancreatic cancer (Study OMP-59R5-
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Protocol 59R5-003, Amendment 6 
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002).  The study was initially conducted in combination with gemcitabine alone and was 
amended to incorporate nab-paclitaxel into the chemotherapy backbone in response to the 
changes in standard of care in this disease population.  As of April 26, 2013, thirteen subjects 
have been treated in Study OMP-59R5-002:  five at 2.5 mg/kg every other week in combination 
with gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle, four at 5 mg/kg every 
other week in combination with gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day 
cycle, four at 5 mg/kg every other week in combination with nab-paclitaxel at 125 mg/m2 and 
gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle,  No DLTs have been 
reported, and Grade 1 diarrhea was noted in one subject each treated with OMP-59R5 at 5 
mg/kg with gemcitabine, and with nab-paclitaxel and gemcitabine.Treatment with etoposide and 
cisplatin is the standard of care for subjects with untreated extended stage small cell lung cancer.  
The most common AE of OMP-59R5 is diarrhea, whereas cytopenia is the most common 
adverse event with EP administration.  Therefore, the most common AEs of OMP-59R5 and EP 
do not overlap, providing the justification for investigating this combination in the study.  
Subjects enrolled in this study will receive a starting dose of 5 mg/kg of OMP-59R5 once every 
three weeks, which is one dose below the MTD of 7.5 mg/kg every three weeks in Study 59R5-
001.  Phase 1b lead-in portion of the study will provide preliminary safety and tolerability profile 
of this combination before the initiation of Phase 2 portion of the study.  OMP-59R5 has an 
estimated apparent half time of 2 to 3 days at 7.5 mg/kg in Study 59R5-001, subjects will not 
receive PCI or WBRT within 2 weeks of study drug administration and will not receive OMP-
59R5 during the radiation to alleviate any potential interaction between the study drug and the 
radiation.  Therefore, risks and potential benefits of participation have been appropriately 
mitigated for this patient population. 
5.2 
Dose Limiting Toxicity 
Previously Read: 
Adverse events will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 4.03 (see Study Reference Binder).  
Dose-limiting toxicity (DLT) is defined as either of the following OMP-59R5 treatment-related 
toxicities occurring within the first 21 days (Cycle 1): 
•
Grade 4 neutropenia lasting >7 days in the absence of growth factor support 
Now Reads: 
Adverse events will be graded according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) version 4.02 (see Study Reference Binder).  
Dose-limiting toxicity (DLT) is defined as either of the following OMP-59R5 treatment-related 
toxicities occurring within the first 21 days (Cycle 1): 
•
Grade 4 neutropenia lasting >7 days  
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6.0 
SELECTION OF STUDY POPULATION 
6.1 
Inclusion Criteria 
Previously Read: 
d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated partial 
thromboplastin time (aPTT) 1.5 × ULN unless the subject is on heparin or warfarin or other 
similar anti-coagulants. 
Now Reads: 
d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated partial 
thromboplastin time (aPTT) 1.5 × ULN. 
6.2 
Exclusion Criteria 
Previously Read: 
2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed extensive 
stage small cell lung cancer. Exceptions to this exclusion criterion include: 1) prophylactic 
cranial irradiation or whole brain radiation (WBRT) prior to the first administration of study 
drug provided that the subject has stable neurologic condition for at least 2 weeks after the 
completion of the radiation, 2) focused radiation for symptomatic relief for isolated bone 
metastases; 3) bisphosphonate or denosumab therapy for bone metastasis initiated prior to 
study entry. 
3. Symptomatic brain metastases requiring whole brain irradiation within 4 weeks prior to first 
study drug administration or requiring daily doses of >40mg of oral prednisone, or require 
use of anti-epileptic drugs. 
4. Presence of uncontrolled Grade  1 diarrhea within 4 weeks prior to the first study drug 
administration. 
5. Current smoker. 
6. Presence of any serious or uncontrolled illness including, but not limited to:  ongoing or 
active infection, symptomatic congestive heart failure unstable angina pectoris, cardiac 
arrhythmia, arterial thrombosis, symptomatic pulmonary embolism, and psychiatric illness 
that would limit compliance with study requirement. 
7. History of myocardial infarction, acute coronary syndromes (including unstable angina), 
coronary angioplasty and/or stenting within 6 months prior to the first administration of study 
drug. 
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8. A history of malignancy with the exception of: 
a.
Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ 
cervical cancer 
b. Adequately treated stage I cancer from which the subject is currently in remission, or  
c.
Any other cancer from which the subject has been disease-free for  3 years 
9. Known human immunodeficiency virus (HIV) infection. 
10. Females who are pregnant or breastfeeding. 
Now Reads: 
2. Prior therapy including radiation, chemotherapy or surgery for newly diagnosed extensive 
stage small cell lung cancer.  Exceptions to this exclusion criterion include: 1) prophylactic 
cranial irradiation or whole brain radiation (WBRT) prior to the first administration of study 
drug provided that the subject has stable neurologic condition for at least 2 weeks after the 
completion of the radiation and is not receiving corticosteroid of > 40 mg prednisone daily 
equivalent dose to control the symptoms, 2) focused radiation for symptomatic relief for 
isolated bone metastases; 3) bisphosphonate or denosumab therapy for bone metastasis 
initiated prior to study entry. 
3. Presence of uncontrolled Grade  1 diarrhea within 4 weeks prior to the first study drug 
administration. 
4. Presence of any serious or uncontrolled illness including, but not limited to:  ongoing or 
active infection, symptomatic congestive heart failure unstable angina pectoris, uncontrolled 
cardiac arrhythmia, uncontrolled arterial thrombosis, symptomatic pulmonary embolism, and 
psychiatric illness that would limit compliance with study requirement. 
5. History of myocardial infarction, acute coronary syndromes (including unstable angina), 
coronary angioplasty and/or stenting within 6 months prior to the first administration of study 
drug. 
6. A history of malignancy with the exception of: 
a.
Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ 
cervical cancer 
b. Adequately treated stage I cancer from which the subject is currently in remission, or  
c.
Any other cancer from which the subject has been disease-free for  3 years 
7. Known human immunodeficiency virus (HIV) infection. 
8. Females who are pregnant or breastfeeding. 
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9. Concurrent use of therapeutic warfarin (prophylactic low dose of warfarin, i.e., 1 mg daily 
for port catheter is allowed). 
7.0 
TREATMENT OF SUBJECTS 
Previously Read: 
Study drug will be OMP-59R5 in the Phase 1b portion, and either OMP-59R5 or Placebo in the 
Phase 2 portion.  Study drug will be administered by IV infusion over 30 minutes on Day 1 of 
every 21-day cycle.  The subject should not take two consecutive doses of study drug within 
18 days.  
Now Reads: 
Study drug will be OMP-59R5 in the Phase 1b portion, and either OMP-59R5 or Placebo in the 
Phase 2 portion.  Study drug will be administered by IV infusion over 30 minutes (+/- 5 minutes) 
on Day 1 of every 21-day cycle.  The subject should not take two consecutive doses of study 
drug within 18 days.  
7.1 
Study Drug (OMP-59R5 or Placebo) 
7.1.1 Study Drug Administration 
Previously Read: 
During Phase 1b and 2, OMP-59R5 must be delivered through tubing that contains a 0.22-micron 
filter and should be infused over 30 minutes as an IV infusion.    
During Phase 2, Placebo will be administered in exactly the same manner as OMP-59R5; i.e., 
withdraw the necessary amount of Placebo and dilute with 5% Dextrose in Water (D5W) to a 
total volume of 250 mL and infuse over 30 minutes. 
Now Reads: 
During Phase 1b and 2, OMP-59R5 must be delivered through tubing containing a Baxter 0.22-
micron high pressure extended life filter (part number 2H5660) which will be provided by 
OncoMed and should be infused over 30 minutes (+/- 5 minutes) as an IV infusion.    
During Phase 2, Placebo will be administered in exactly the same manner as OMP-59R5; i.e., 
withdraw the necessary amount of Placebo and dilute with either half normal saline (NS) (0.45% 
Sodium Chloride (NaCl) or5% Dextrose and 0.45% NaCl (D5W ½ NS)to a total volume of 250 
mL and infuse over 30 minutes (+/- 5 minutes).  The diluted study drug should be administered 
within 4 hours of preparation. 
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7.1.5 Study Drug Preparation 
Previously Read: 
The study drug should be diluted for infusion using aseptic technique.  Withdraw the necessary 
amount of the study drug to obtain the required dose and dilute with 5% dextrose in water, USP, 
to a total volume of 250 mL.  For example, if a 70-kg subject is to be dosed at 5 mg/kg, then the 
subject’s dose would be 350 mg.  Because the vials contain a concentration of 10 mg/mL, a total 
of 35 mL containing 350 mg should be withdrawn from the vial and diluted with 5% dextrose in 
water, USP, to a total volume of 250 mL. 
Any unused portion left in a vial may not be used for another subject, as the product contains no 
preservative (i.e., they are single-use vials). 
The diluted study drug solutions may be stored at room temperature (19°C–25°C) for up to 
24 hours. 
Now Reads: 
The study drug should be diluted for infusion using aseptic technique.  Withdraw the necessary 
amount of the study drug to obtain the required dose and dilute with either half normal saline 
(NS) (0.45% Sodium Chloride (NaCl) or 5% Dextrose and 0.45% NaCl (D5 ½ NS), to a total 
volume of 250 mL.  For example, if a 70-kg subject is to be dosed at 5 mg/kg, then the subject’s 
dose would be 350 mg.  Because the vials contain a concentration of 10 mg/mL, a total of 35 mL 
containing 350 mg should be withdrawn from the vial and diluted with either 0.45% NaCl or 5% 
Dextrose and 0.45% NaCl (D5W ½ NS), to a total volume of 250 mL. 
Any unused portion left in a vial may not be used for another subject, as the product contains no 
preservative (i.e., they are single-use vials). 
The diluted study drug solutions may be stored at room temperature (19°C–25°C) for up to 
4 hours. 
7.4 
Dose Modifications or Delay for Treatment-Related Toxicities 
Previously Read: 
The investigator should hold OMP-59R5/placebo for treatment related toxicity according to 
Table 5, along with his/her best judgment.  Subjects with a starting dose of 5 mg/kg study drug 
will have dose reduced to 2.5 mg/kg if dose reduction is required.  Study drug will be 
discontinued permanently if study drug dosing is delayed for > 21 consecutive days despite 
supportive treatment, or if more than 2 dose reductions of study drug are required or dose 
reduction to < 2.5 mg/kg is required.  Subjects continuing EP after discontinuing study drug will 
continue to receive etoposide on days 1, 2, and 3, and cisplatin on day 1 of each 21-day cycle for 
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a total of 6 cycles.  Special attention should be paid to diarrhea as this is an expected adverse 
event of OMP-59R5 and Section 1.3 describes the recommended diarrhea management approach 
in this study. 
Now Reads: 
The investigator should hold OMP-59R5/placebo for treatment related toxicity according to 
Table 5, along with his/her best judgment.  Subjects with a starting dose of 5 mg/kg study drug 
will have dose reduced to 2.5 mg/kg if dose reduction is required.  Study drug will be 
discontinued permanently if study drug dosing is delayed for > 21 consecutive days due to 
treatment –related toxicity (this is not applicable when PCI is administered as study drug will be 
held for > 21 consecutive days during PCI administration and will resume  14 days after the 
completion of PCI) despite supportive treatment, or if more than 2 dose reductions of study drug 
are required or dose reduction to < 2.5 mg/kg is required.  Subjects continuing EP after 
discontinuing study drug will continue to receive etoposide on days 1, 2, and 3, and cisplatin on 
day 1 of each 21-day cycle for a total of 6 cycles.  Special attention should be paid to diarrhea as 
this is an expected adverse event of OMP-59R5 and Section 1.3 describes the recommended 
diarrhea management approach in this study. 
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Table 5: 
Suggested Guidelines for Study Drug and Etoposide-Cisplatin Dose Modification and Delay 
Added:
Adverse Event 
Study Drug Dose Reduction 
and/or Delay 
Etoposide Dose Reduction and/or Delay 
Cisplatin Dose Reduction and/or Delay 
Absolute Neutrophil Count (ANC) 
500 -999/mm3 without 
fever 
No change 
Hold etoposide till ANC  1000/ mm3. 
Resume etoposide based on timing of 
recovery and number of previous episodes 
¾
 3 consecutive weeks of 
interruption 
•
1st episode, no change.  
Consider prophylactic myeloid 
growth factor according to 
institution’s standard 
•
2nd episode: reduce etoposide 
dose by 25% from starting 
dose for all subsequent 
administration 
•
3rd episode, reduce etoposide 
dose by 50% from starting 
dose for all subsequent 
administration 
•
4th episode, discontinue 
etoposide treatment 
¾
> 3 consecutive weeks of 
interruption, discontinue etoposide 
permanently  
Continue supportive care according to 
institution’s standard 
Hold cisplatin till ANC  1000/ mm3.  Resume 
cisplatin based on timing of recovery and 
number of previous episodes 
¾
 3 consecutive weeks of interruption 
•
1st episode, no change.  Consider 
prophylactic myeloid growth factor 
according to institution’s standard  
•
2nd episode: reduce cisplatin dose 
by 25% for all subsequent 
administration 
•
3rd episode, reduce cisplatin dose 
by 50% from starting dose for all 
subsequent administration 
•
4th episode, discontinue cisplatin 
treatment. 
¾
> 3 consecutive weeks of interruption, 
discontinue cisplatin permanently  
Continue supportive care according to 
institution’s standard 
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7.5 
Anti-Emetics, Anti-diarrhea and Hematopoietic Supportive Care 
Previously Read: 
Hematopoietic growth factors, transfusion of blood and blood products should not be used in 
Cycle 1 of the dose escalation phase unless absolutely clinically necessary and after discussion 
with the OncoMed Medical Monitor.  However, hematopoietic growth factors, transfusion of 
blood and blood products may be administered after Cycle 1 in the dose escalation phase or 
anytime during phase 2 portion as needed.
Now Read: 
Hematopoietic growth factors, transfusion of blood and blood products should not be used 
prophylactically prior to the dosing of the study drug and EP on Day 1 of Cycle 1, but may be 
administered per standard clinical practice during the course of the study as needed. 
7.6 
Concomitant and Prohibited Therapy 
Previously Read: 
All concomitant medication administered within 28 days prior to the first administration of study 
drug through 30 days following the administration of the last dose of study drug will be recorded 
on the Concomitant Medication eCRF.  Investigational medicinal products and anticancer agents 
(e.g., cytotoxic agents and biologics with known activity against small cell lung cancer) may not 
be administered from enrollment through the first line therapy.   
Now Read: 
All concomitant medication administered within 28 days prior to the first administration of study 
drug through 30 days following the administration of the last dose of study drug will be recorded 
on the Concomitant Medication eCRF.  Investigational medicinal products, therapeutic warfarin 
(prophylactic low dose of warfarin, i.e., 1 mg daily is allowed for port catheter) and anticancer 
agents (e.g., cytotoxic agents and biologics with known activity against small cell lung cancer) 
may not be administered from enrollment through the first line therapy.   
8.1 
Adverse Events Definitions and Reporting Procedures 
Previously Read: 
Adverse events will be coded in accordance with the Medical Dictionary for Regulatory 
Activities (MedDRA).  The grading of the adverse events will be done using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03 (see 
Study Reference Binder). 
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Now Read: 
Adverse events will be coded in accordance with the Medical Dictionary for Regulatory 
Activities (MedDRA).  The grading of the adverse events will be done using the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.02 (see 
Study Reference Binder).   
10.0 
BIOMARKERS AND EXPLORATORY ASSESSMENTS 
Previously Read: 
Optional Tumor Biomarkers:  Optional tumor specimens will be collected during study visits and 
at the time of progression if feasible according to Schedule of Assessments (Appendix B and C) 
from subjects who are consented and who have tumor lesions that are amenable to core biopsies.  
Tumor samples will be analyzed for treatment-induced changes in Notch-related gene expression 
(i.e., mRNA) and/or protein markers and cancer stem cell–related gene expression. 
Now Read: 
Optional Tumor Biomarkers:  Optional tumor specimens will be collected during study visits and 
at the time of treatment termination, if feasible according to Schedule of Assessments 
(APPENDIX B and APPENDIX C) from subjects who are consented and who have tumor 
lesions that are amenable to core biopsies.  Tumor samples will be analyzed for treatment-
induced changes in Notch-related gene expression (i.e., mRNA) and/or protein markers and 
cancer stem cell–related gene expression. 
11.1 
Screening 
Deleted: 
•
Hair follicle samples (6 hairs) collected from subjects enrolled in Phase 1b portion only 
11.2 
Treatment Visits 
Previously Read: 
…Study drug administration (OMP-59R5 or placebo) should continue at every 21-day cycle 
between the completion of chemotherapy and the initiation of PCI. 
Now Read: 
…Study drug administration (OMP-59R5 or placebo) should continue at every 21-day (± 1 day) 
cycle between the completion of chemotherapy and the initiation of PCI. 
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11.2.1 Cycle 1 
11.2.1.1 
Cycle 1 Day 1 
Previously Read: 
The following assessments will be completed prior to study drug infusion.  These assessments 
will be repeated if they were done more than 3 days prior to Cycle 1 Day 1. 
•
Physical examination 
•
Weight 
•
ECOG performance status 
•
Hematology 
•
Serum chemistry 
•
Coagulation 
•
Urinalysis (dip stick is sufficient) 
•
Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc 
interval 
The following assessments will be done prior to study drug infusion on Cycle 1 Day 1: 
•
Serum sample for anti-OMP-59R5 antibody on all subjects  
•
Blood sample for biomarker 
•
Plasma sample for OMP-59R5 PK from subjects enrolled in Phase 1b portion only  
•
Blood sample for pharmaco-genomics (Optional and only if subject has signed the 
separate pharmacogenomics Informed Consent Form)  
•
Concomitant medications 
•
Vital Signs 
Now Reads: 
The following assessments will be completed prior to study drug infusion.  These assessments 
will be repeated if they were done more than 7 days prior to Cycle 1 Day 1. 
•
Physical examination 
•
ECOG performance status 
•
Hematology 
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•
Serum chemistry 
•
Coagulation 
•
Urinalysis (dip stick is sufficient) 
•
Electrocardiogram (ECG) including PR interval, RR interval, QRS duration, and QTc 
interval 
The following assessments will be done prior to study drug infusion on Cycle 1 Day 1: 
•
Weight 
•
Serum sample for anti-OMP-59R5 antibody on all subjects  
•
Blood sample for biomarker 
•
Plasma sample for OMP-59R5 PK from subjects enrolled in Phase 1b portion only  
•
Hair follicle samples (6 hairs) collected from subjects enrolled in Phase 1b portion only 
•
Blood sample for pharmaco-genomics (Optional and only if subject has signed the 
separate pharmacogenomics Informed Consent Form)  
•
Concomitant medications 
•
Vital Signs 
Previously Read: 
11.2.2.1 
Day 1 of Cycles 2-6  
Now Reads: 
11.2.2.1 
Day 1 (± 1 day) of Cycles 2-6  
Previously Read: 
11.2.4.1 
Day 1 of Cycle 7 and every cycle thereafter 
Now Reads: 
11.2.4.1 
Day 1 (± 1 day) of Cycle 7 and every cycle thereafter 
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11.3 
Treatment Termination 
Previously Read: 
Subjects who have agreed to the optional tumor core biopsy in the Informed Consent and have 
pre and post-treatment optional tumor biopsy collected, will have tumor core biopsy at the time 
of progression if feasible.  
Now Reads: 
Subjects who have agreed to the optional tumor core biopsy in the Informed Consent and have 
pre and post-treatment optional tumor biopsy collected, will have tumor core biopsy at the time 
of treatment termination visit, if feasible.  
11.4 
Follow up 
Previously Read: 
…
Additionally, subjects who discontinue study treatment for any reason other than disease 
progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during the 
Follow-up Period according to standard of care until documented disease progression or 
initiation of new anti-cancer therapy, whichever is sooner. 
Now Reads: 
…
Additionally, subjects who discontinue study treatment for any reason other than disease 
progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) and bone 
scan every 12 weeks (+/- 5 days) during the Follow-up Period according to standard of care until 
documented disease progression or initiation of new anti-cancer therapy, whichever is sooner. 
13.5.2 Safety Endpoints 
Adverse Events 
Previously Read: 
…The incidence of adverse events in each treatment group will be tabulated by NCI-CTCAE v 
4.03 grade and relationship to study drug.
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Protocol 59R5-003, Amendment 6 
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Now Reads: 
…The incidence of adverse events in each treatment group will be tabulated by NCI-CTCAE v 
4.02 grade and relationship to study drug. 
NOTES TO APPENDIX B and APPENDIX C: 
Additional tests were added and the Schedule of Assessments Tables were revised to reflect 
changes made in the protocol.  Footnotes were revised accordingly. 
APPENDIX B: 
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 1B
Previously Read: 
d. The assessment (except for vital sign that needs to be obtained prior to the infusion) does not 
need to be repeated if it was done within 3 days prior to the first dose 
e. Height required at screening only. Vital signs: screening, day 1 of each cycle prior to the start 
of study drug dosing, days 2 and 3 prior to etoposide administration during Cycles 1 through 
6 and treatment termination.  
f. Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and 
platelet count.  The results need to be reviewed by the investigator prior to each study drug 
and EP administration.  Hematology on Day 1 of each cycle can be performed up to 3 days 
prior to Day 1 dosing. 
g. Full chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, 
lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphate, and magnesium.  
Chemistry on Day 1 of each cycle can be performed up to 3 days prior to Day 1 dosing. 
h. Plasma samples will be obtained for OMP-59R5 pharmacokinetic analysis at pre-dose and 5 
minutes (±2 minutes) after the end of OMP-59R5 infusion on Day 1 of Cycle 1 and Cycle 3, 
and on Days 3 (pre-dose) and 8 of Cycles 1 and 3, as well as at treatment termination. On 
days when OMP-59R5 and etoposide and/or cisplatin are given together, the plasma sample 
should be obtained 5 minutes (±2 minutes) after the completion of the infusion of OMP-
59R5, but prior to EP administration. 
k. Hair follicle mRNA expression:  Predose hair samples (6 hairs) will be collected at screening 
and on Day 8 of Cycle 2 only for gene expression analysis of Notch pathway–related gene 
expression as described in Section 11.0.  Instructions for the collection, handling, storage, 
and shipment of these samples are provided in the Study Reference Binder. 
l. Only on Day 1 of Cycle 1 prior to OMP-59R5 infusion. 
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m. FFPE tumor specimens obtained will be collected.  Notch3 expression levels will be assessed 
in FFPE tumor specimens, either archived or fresh core needle biopsied at study entry (two 
FFPE cores preferred whenever possible).  FFPE samples must be obtained during 
screening.  Notch3 levels will be measured by immunohistochemistry and/or a quantitative 
PCR gene expression assay. Notch 2 and other Notch-related genes and proteins may also be 
measured.  In addition, DNA testing may be performed on the FFPE tumor specimens for 
subjects who sign the optional FFPE Informed Consent for DNA testing.  Instructions for the 
collection, handling, storage, and shipment of these samples are provided in the Study 
Reference Binder. 
n. Optional tumor biopsy will be done at screening, on Day 8 of Cycle 2, and at the time of 
progression if feasible.  The site can call the Sponsor’s medical monitor to discuss an 
alternative timepoint if it is not feasible to collect the optional tumor biopsy on Day 8 (±2) of 
Cycle 2. 
o. Contrast CT of chest, abdomen and pelvis, and brain MRI/CT with contrast will be 
performed every 6 weeks (±5 days) after initial study drug dosing (prior to the start of Cycle 
3 and every 6 weeks±5 days thereafter).  MRI can be used in lieu of contrast-enhanced CT 
for subjects who are allergic to contrast.  The same methodology should be used throughout 
the study to follow the same lesion.   
p. Subjects who have not demonstrated disease progression will have contrast CT of chest and 
abdomen (or MRI for subjects who are allergic to contrast), MRI/CT of brain conducted 
every 6 weeks (± 5 days) after initial study drug dosing until disease progression or initiation 
of new anti-cancer therapy.  The same methodology should be used throughout the study.   
Now Reads: 
d. The assessment does not need to be repeated if it was done within 7 days prior to the first 
dose 
e. Height required at screening only. Vital signs and weight: screening, day 1 of each cycle 
prior to the start of study drug dosing, days 2 and 3 prior to etoposide administration during 
Cycles 1 through 6 and treatment termination.  
f. Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and 
platelet count.  The results need to be reviewed by the investigator prior to each study drug 
and EP administration.  Hematology on Day 1 of each cycle starting from Cycle 2 can be 
performed up to 3 days prior to Day 1 dosing. 
g. Full chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, 
lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphate, and magnesium.  
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Chemistry on Day 1 of each cycle starting from Cycle 2 can be performed up to 3 days prior 
to Day 1 dosing. 
h. Plasma samples will be obtained for OMP-59R5 pharmacokinetic analysis at pre-dose and 5 
minutes (±2 minutes) after the end of OMP-59R5 infusion and prior to the EP administration 
on Day 1 of Cycle 1 and Cycle 3, and on Days 3 (pre-dose) and 8 of Cycles 1 and 3, as well 
as at treatment termination. On days when OMP-59R5 and etoposide and/or cisplatin are 
given together, the plasma sample should be obtained 5 minutes (±2 minutes) after the 
completion of the infusion of OMP-59R5, but prior to EP administration. 
k. Hair follicle mRNA expression:  Predose hair samples (6 hairs) will be collected at Day 1 of 
Cycle 1 (pre-dose) and on Day 8 of Cycle 2 only for gene expression analysis of Notch 
pathway-related gene expression as described in Section 11.0.  Instructions for the collection, 
handling, storage, and shipment of these samples are provided in the Study Reference Binder. 
l. Only on Day 1 of Cycle 1 prior to OMP-59R5 infusion from subjects who have signed 
separate pharmacogenomics Informed Consent Form. 
m. FFPE tumor specimens obtained will be collected.  Notch3 expression levels will be assessed 
in FFPE tumor specimens, either archived or fresh core needle biopsied at study entry (two 
FFPE cores preferred whenever possible).  FFPE samples must be obtained during 
screening.  Notch3 levels will be measured by immunohistochemistry and/or a quantitative 
PCR gene expression assay. Notch 2 and other Notch-related genes and proteins may also be 
measured.  In addition, DNA testing may be performed on the FFPE tumor specimens for 
subjects who sign the optional FFPE Informed Consent for DNA testing.  Instructions for the 
collection, handling, storage, and shipment of these samples are provided in the Study 
Reference Binder. 
n. Optional tumor biopsy will be done at screening, on Day 8 of Cycle 2, and at the time of 
treatment termination, if feasible.  The site can call the Sponsor’s medical monitor to discuss 
an alternative timepoint if it is not feasible to collect the optional tumor biopsy on Day 8 (±2) 
of Cycle 2. 
o. Contrast CT of chest, abdomen and pelvis, and brain MRI/CT with contrast will be 
performed at screening.  Contrast CT of chest, abdomen and pelvis will be performed every 
6 weeks (±5 days) after initial study drug dosing (prior to the start of Cycle 3 and every 6 
weeks±5 days thereafter).  MRI can be used in lieu of contrast-enhanced CT for subjects who 
are allergic to contrast.  The same methodology should be used throughout the study to 
follow the same lesion.   
p. Subjects who have not demonstrated disease progression will have contrast CT of chest, 
pelvis and abdomen (or MRI for subjects who are allergic to contrast), conducted every 6 
weeks (± 5 days) after initial study drug dosing until disease progression or initiation of new 
anti-cancer therapy.  The same methodology should be used throughout the study.   
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APPENDIX C  
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 2 
Previously Read: 
d. The assessment (except for vital sign that needs to be obtained prior to the infusion) does not 
need to be repeated if it was done within 3 days prior to the first dose. 
e.
Height required at screening only. Vital signs: screening, day 1 of each cycle prior to the start 
of the treatment, days 2 and 3 prior to etoposide administration from Cycles 1 thru 6, and 
treatment termination. 
f.
Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and 
platelet count.  The results need to be reviewed by the investigator prior to each study drug 
administration. Hematology on day 1 of each cycle can be performed up to 3 days prior to 
Day 1 dosing. 
g. Full chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, 
lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphate, and magnesium.  
Chemistry on Day 1 of each cycle can be performed up to 3 days prior to Day 1 dosing. 
j. Only on Day 1 of Cycle 1 prior to OMP-59R5 infusion. 
m. Optional tumor biopsy will be done at screening, on Day 8 of Cycle 2, and at the time of 
progression if feasible. The site can call the Sponsor’s medical monitor to discuss an 
alternative timepoint if it is not feasible to collect the optional tumor biopsy on Day 8 (±2) of 
Cycle 2. 
n. Contrast CT of chest, abdomen and pelvis, and MRI of brain will be performed every 6 week 
s ± 5 days) after initial study drug dosing (prior to the start of Cycle 3 and every two cycles 
thereafter).  MRI can be used in lieu of contrast-enhanced CT for subjects who are allergic to 
contrast.  The same methodology should be used throughout the study to follow the same 
lesion.   
o. Subjects who have not demonstrated disease progression will have contrast CT of chest, 
abdomen and pelvis (or MRI for subjects who are allergic to contrast), and MRI/CT of brain 
conducted every 6 weeks (±5 days) after initial study drug dosing until disease progression or 
initiation of new anti-cancer therapy.  The same methodology should be used throughout the 
study.   
Now Reads: 
d. The assessment does not need to be repeated if it was done within 7 days prior to the first 
dose. 
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e. Height required at screening only.  Vital signs and weight: screening, day 1 of each cycle 
prior to the start of the treatment, days 2 and 3 prior to etoposide administration from Cycles 
1 thru 6, and treatment termination. 
f. Hematology includes complete blood count (CBC) with differential, hemoglobin (Hgb), and 
platelet count.  The results need to be reviewed by the investigator prior to each study drug 
administration. Hematology on day 1 of each cycle starting from Cycle 2 can be performed 
up to 3 days prior to Day 1 dosing. 
g. Full chemistry includes sodium, potassium, chloride, bicarbonate, blood urea nitrogen 
(BUN), creatinine, glucose, ALT, AST, alkaline phosphatase, total bilirubin, direct bilirubin, 
lactate dehydrogenase (LDH), total protein, albumin, calcium, phosphate, and magnesium.  
Chemistry on Day 1 of each cycle starting from Cycle 2 can be performed up to 3 days prior 
to Day 1 dosing. 
j. Only on Day 1 of Cycle 1 prior to OMP-59R5 infusion from subjects who have signed 
separate pharmacogenomics Informed Consent Form. 
m. Optional tumor biopsy will be done at screening, on Day 8 of Cycle 2, and at the time of 
treatment termination, if feasible. The site can call the Sponsor’s medical monitor to discuss 
an alternative timepoint if it is not feasible to collect the optional tumor biopsy on Day 8 (±2) 
of Cycle 2. 
n. Contrast CT of chest, abdomen and pelvis, and MRI of brain will be performed at screening.  
Contrast CT of chest, abdomen and pelvis will be performed every 6 week s ± 5 days) after 
initial study drug dosing (prior to the start of Cycle 3 and every two cycles thereafter).  MRI 
can be used in lieu of contrast-enhanced CT for subjects who are allergic to contrast.  The 
same methodology should be used throughout the study to follow the same lesion.   
o. Subjects who have not demonstrated disease progression will have contrast CT of chest, 
abdomen and pelvis (or MRI for subjects who are allergic to contrast), conducted every 6 
weeks (±5 days) after initial study drug dosing until disease progression or initiation of new 
anti-cancer therapy.  The same methodology should be used throughout the study. 
APPENDIX F: 
SAMPLE INFORMED CONSENT 
SCREENING 
Blood and Urine Sample Collection: 
Deleted: 
Hair Follicles: Six hairs will be plucked from your head for additional marker testing if you are 
participating in the first portion of the study 
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Previously Read: 
Tumor assessments: An examination of your tumor(s) by CT (computerized tomography test, 
like an x-ray that produces a picture of your body including tumors using radiation), or MRI 
(magnetic resonance imaging - use of a magnetic field to produce an image of your body 
including tumors) or bone scan (an X-ray to look at your bone).  Your study doctor will 
determine which type of test (either CT or MRI) is best to assess your cancer.  A bone scan will 
also be done to find out if tumors have spread to your bones.  This is part of your routine cancer 
care.   
Now Reads: 
Tumor assessments: An examination of your tumor(s) by CT (computerized tomography test, 
like an x-ray that produces a picture of your body including tumors using radiation), or MRI 
(magnetic resonance imaging - use of a magnetic field to produce an image of your body 
including tumors) and bone scan (an X-ray to look at your bone).  Your study doctor will 
determine which type of test (either CT or MRI) is best to assess your cancer.  A bone scan will 
also be done to find out if tumors have spread to your bones.  This is part of your routine cancer 
care.   
Cycle 1 Day 1 
Previously Read: 
This is the first day of study treatment (Cycle 1 Day 1).You will receive study drug, etoposide, 
and cisplatin on this day. You will have the following procedures done during this visit:  
•
Physical Examination and weight before dosing (if this was done more than 3 days ago) 
•
Electrocardiogram (ECG) before dosing (if this was done more than 3 days ago)  
•
Urine Sample Collection before dosing (if this was done more than 3 days ago) 
•
Blood Sample Collection before dosing – about 1 tablespoon of blood for your health 
condition (if this was done more than 3 days ago)  
•
Additional Blood Sample Collection before dosing – about 2 tablespoons of blood to assess 
the level of certain markers and proteins that might be against OMP-59R5  
•
If you are participating in the first portion of the study, you will also have 1 teaspoon of 
blood taken before starting study drug dosing tocheck the level of OMP59R5 in the blood 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will be asked about any changes in your health status after taking your initial dose of the 
study drug, etoposide, and cisplatin. 
Now Reads: 
This is the first day of study treatment (Cycle 1 Day 1).You will receive study drug, etoposide, 
and cisplatin on this day. You will have the following procedures done during this visit:  
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•
Physical Examination before dosing (if this was done more than 7 days ago) 
•
Electrocardiogram (ECG) before dosing (if this was done more than 7 days ago)  
•
Urine Sample Collection before dosing (if this was done more than 7 days ago) 
•
Blood Sample Collection before dosing – about 1 tablespoon of blood for your health 
condition (if this was done more than 7 days ago)  
•
Weight before dosing 
•
Hair follicles: Six hairs will be plucked from your head for additional marker testing if you 
are participating in the first portion of the study 
•
Additional Blood Sample Collection before dosing – about 2 tablespoons of blood to assess 
the level of certain markers and proteins that might be against OMP-59R5  
•
If you are participating in the first portion of the study, you will also have 1 teaspoon of 
blood taken before starting study drug dosing tocheck the level of OMP59R5 in the blood 
•
Your blood pressure, temperature, heart rate, rate of breathing, and weight will be measured 
•
You will be asked about any changes in your health status after taking your initial dose of the 
study drug, etoposide, and cisplatin. 
TREATMENT TERMINATION 
Previously Read: 
Optional Tumor Biopsy:  If your tumor has grown or spread, an optional tumor biopsy will be 
done only if you agree. 
Now Reads: 
Optional Tumor Biopsy:  An optional tumor biopsy will be done only if you agree. 
PREGNANCY 
Previously Read: 
… If either you or your partner becomes pregnant during the study or within 30 days after the 
last dose of study drug or etoposide or cisplatin whichever is discontinued last, you and/or 
your partner will be followed through the first well-baby visit or longer if any abnormality is 
present.
Now Reads: 
…If either you or your partner becomes pregnant during the study or within 30 days after the last 
dose of study drug or etoposide or cisplatin whichever is discontinued last, you and/or your 
partner will be followed through outcome of the birth. 
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AMENDMENT 2: 
19 AUGUST 2013 
The following changes were made to the protocol.  Italics in the text indicate new text.   
RATIONALE 
The protocol has been amended to allow the dose escalation beyond 7.5 mg/kg if the MTD is not 
reached.  Additionally, the protocol clarifies that PET/CT scan can be used in lieu of bone scan 
to follow bone lesions throughout the study.  Day 2 and Day 3 blood draws for hematology have 
been eliminated as they are not part of standard of care.  Blood sample for hematology was 
added to Day 8 of Cycles 1 through 3 only when blood samples are taken for biomarkers and PK. 
SUMMARY OF CHANGES: 
Study Design (Cont’d): 
Previously Read: 
Additionally, subjects who discontinue study treatment for any reason other than disease 
progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during 
Follow-up according to standard of care until documented disease progression or initiation of 
new anti-cancer therapy, whichever is sooner. 
Now Reads: 
Additionally, subjects who discontinue study treatment for any reason other than disease 
progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) during 
Follow-up until documented disease progression or initiation of new anti-cancer therapy, 
whichever is sooner. 
Exclusion Criteria: 
Added:
b. 
Superficial bladder cancer 
Efficacy Evaluation: 
Previously Read:  
…Subjects who discontinue study treatment for any reason other than disease progression will be 
followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up according to 
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standard of care until documented disease progression or initiation of new anti-cancer therapy, 
whichever is sooner.  
Now Reads: 
… Subjects who discontinue study treatment for any reason other than disease progression will 
be followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up until 
documented disease progression or initiation of new anti-cancer therapy, whichever is sooner. 
3.4 
Clinical Background 
Previously Read:  
…As of April 26, 2013, thirteen subjects have been treated in Study OMP-59R5-002:  five at 2.5 
mg/kg every other week in combination with gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of 
every 28 day cycle, four at 5 mg/kg every other week in combination with gemcitabine at 1000 
mg/m2 on Days 1, 8 and 15 of every 28 day cycle, four at 5 mg/kg every other week in 
combination with nab-paclitaxel at 125 mg/m2 and gemcitabine at 1000 mg/m2 on Days 1, 8 and 
15 of every 28 day cycle,  No DLTs have been reported, and Grade 1 diarrhea was noted in one 
subject each treated with OMP-59R5 at 5 mg/kg with gemcitabine, and with nab-paclitaxel and 
gemcitabine. 
Now Reads: 
…As of August 19, 2013, twenty four subjects have been treated in Study OMP-59R5-002:  five 
and four at 2.5 mg/kg and 5.0 mg/kg respectively every other week in combination with 
gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day cycle, four, six and four at 
5 mg/kg, 7.5 mg/kg and 10 mg/kg respectively every other week in combination with nab-
paclitaxel at 125 mg/m2 and gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day 
cycle.  No DLTs have been reported, and the most common reported OMP-59R5 treatment-
related event is diarrhea, fatigue and nausea that are mostly grade 1 or 2, managed with 
supportive care. One Grade 3 diarrhea was noted in one of four subjects treated with 10 mg/kg 
OMP-59R5 with Nab-P+Gem, lasted less than 48 hours and resolved to Grade 1 diarrhea after 
concurrent use of lomotil.   
5.3 
Dose Escalation Plan 
Previously Read:  
… 
The starting dose of OMP-59R5 is 5 mg/kg on Day 1 of each 21-day cycle.  The subsequent dose 
level will be 7.5 mg/kg on Day 1 of each 21-day cycle.  Dose escalation will proceed if no DLT 
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is observed in a cohort of 3 subjects after discussion and agreement between the participating 
Investigators and Sponsor’s Medical Monitor.   
Now Reads: 
… 
The starting dose of OMP-59R5 is 5 mg/kg on Day 1 of each 21-day cycle.  The subsequent dose 
level will be increased in 2.5 mg/kg increments (i.e., 7.5 mg/kg, 10 mg/kg, etc) until the MTD is 
reached.  Dose escalation will only proceed if no DLT is observed in a cohort of at least 3 
subjects after discussion and agreement between the participating Investigators and Sponsor’s 
Medical Monitor.   
5.4.1 Follow-Up 
Previously Read:  
Subjects who discontinue study treatment for any reason other than disease progression will be 
followed with tumor assessment every 6 weeks/42 days (±5 days) during follow-up according to 
standard of care until documented disease progression or initiation of new anti-cancer therapy, 
whichever is sooner. 
Now Reads: 
Subjects who discontinue study treatment for any reason other than disease progression will be 
followed with tumor assessment every 6 weeks/42 days (±5 days) during follow-up until 
documented disease progression or initiation of new anti-cancer therapy, whichever is sooner.   
5.5.2 Follow-up 
Previously Read:  
Subjects who discontinue study treatment for any reason other than disease progression will be 
followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up according to 
standard of care until documented disease progression or initiation of new anti-cancer therapy, 
whichever is sooner. 
Now Reads: 
Subjects who discontinue study treatment for any reason other than disease progression will be 
followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up until 
documented disease progression or initiation of new anti-cancer therapy, whichever is sooner. 
6.2 
Exclusion Criteria 
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Previously Read:  
6. 
A history of malignancy with the exception of: 
a. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in 
situ cervical cancer 
b. Adequately treated stage I cancer from which the subject is currently in remission, or 
Now Reads: 
6. 
A history of malignancy with the exception of: 
a. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in 
situ cervical cancer 
b. Superficial bladder cancer 
7.5 
Anti-Emetics, Anti-diarrhea and Hematopoietic Supportive Care 
Previously Read:  
Antiemetic therapy and anti-diarrheal may be administered at the discretion of the Investigator. 
Now Reads: 
Antiemetic therapy and anti-diarrheal medications may be administered at the discretion of the 
Investigator. 
9.0 
EFFICACY ASSESSMENTS 
Previously Read:  
Subjects who discontinue study treatment for any reason other than disease progression will be 
followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up according to 
standard of care until documented disease progression or initiation of new anti-cancer therapy, 
whichever is sooner. 
Now Reads: 
Subjects who discontinue study treatment for any reason other than disease progression will be 
followed with tumor assessment every 6 weeks/42 days (±5 days) during Follow-up until 
documented disease progression or initiation of new anti-cancer therapy, whichever is sooner. 
11.1 
Screening 
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Previously Read:  
•
Radiographic evaluation:   CT with contrast, or MRI of the chest, abdomen, pelvis, and brain, 
and bone scan performed as outlined by the RECIST criteria 1.1 (see APPENDIX E).  Note:  
The same method (CT or MRI) must be used consistently throughout the study to follow the 
same anatomical location.   
Now Reads: 
•
Radiographic evaluation:   CT with contrast, or MRI of the chest, abdomen, pelvis, and brain, 
and bone scan performed as outlined by the RECIST criteria 1.1 (see APPENDIX E).  Note:  
PET/CT can be used in lieu of bone scan to identify and follow up bone lesions.  The same 
method (CT or MRI, bone scan or PET/CT for bone lesions) must be used consistently 
throughout the study to follow the same anatomical location.   
11.2.1.2 
Cycle 1 Day 2 
The following assessments will be completed prior to etoposide infusion: 
Deleted: 
•
Hematology 
Administration of etoposide: 
Previously Read: 
Hematology results must be reviewed by the investigator prior to etoposide dosing. 
Now Reads: 
•
Etoposide dosing will be given. 
11.2.1.3 
Cycle 1 Day 3 
The following assessments will be completed prior to etoposide infusion: 
Deleted: 
•
Hematology 
Added:
•
Adverse event reporting 
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Administration of etoposide: 
Previously Read: 
Hematology results must be reviewed by the investigator prior to etoposide dosing. 
Now Reads: 
•
Etoposide dosing will be given. 
11.2.1.4 
Cycle 1 Day 8 
Added:
•
Hematology 
11.2.2.1 
Day 1 (± 1 day) of Cycles 2-6 
Previously Read:  
•
Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, and pelvis will 
be done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 3 and every 6 
weeks+5 days thereafter).  The same method should be used throughout the study to follow 
the same anatomical location.  Bone scan will be completed every other tumor assessment 
(Day 1 of Cycle 5 and every 12 weeks/+5 days).  
Now Reads: 
Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, and pelvis will be 
done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 3 and every 6 weeks+5 days 
thereafter).  The same method should be used throughout the study to follow the same 
anatomical location.  If bone scan is used to follow bone lesions, bone scan will be completed 
every other tumor assessment (Day 1 of Cycle 5 and every 12 weeks/+5 days).  If PET/CT is 
used to follow bone lesions, PET/CT will be done at the same schedule as the assessments for 
other lesions (every 6 weeks +5 days thereafter). 
11.2.2.2 
Day 2 of Cycles 2-6 
The following assessments will be completed prior to etoposide infusion: 
Added:
•
Adverse event recording 
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Now Reads: 
•
Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, and pelvis will 
be done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 3 and every 6 
weeks+5 days thereafter).  The same method should be used throughout the study to follow 
the same anatomical location.  If bone scan is used to follow bone lesions, bone scan will be 
completed every other tumor assessment (Day 1 of Cycle 5 and every 12 weeks/+5 days).  If 
PET/CT is used to follow bone lesions, PET/CT will be done at the same schedule as the 
assessments for other lesions (every 6 weeks +5 days thereafter). 
11.2.2.2 
Day 2 of Cycles 2-6 
The following assessments will be completed prior to etoposide infusion: 
Deleted: 
•
Hematology 
Added:
•
Adverse event recording 
Administration of etoposide: 
Deleted: 
•
Adverse event recording 
Previously Read: 
Hematology results must be reviewed by the investigator prior to etoposide dosing. 
Now Reads: 
•
Etoposide dosing will be given. 
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11.2.2.3 
Day 3 of Cycles 2-6 
The following assessments will be completed prior to etoposide infusion: 
Deleted: 
•
Hematology 
Added:
•
Adverse event recording 
Administration of etoposide: 
Deleted: 
•
Adverse event recording 
Previously Read: 
Hematology results must be reviewed by the investigator prior to etoposide dosing. 
Now Reads: 
•
Etoposide dosing will be given. 
11.2.2.4. 
Day 8 of Cycles 2 and 3 Only 
The following assessments will be completed prior to etoposide infusion: 
Deleted: 
•
Hematology 
Added:
•
Adverse event reporting 
Administration of etoposide: 
Previously Read: 
Hematology results must be reviewed by the investigator prior to etoposide dosing. 
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Now Reads: 
•
Etoposide dosing will be given. 
Deleted: 
•
Adverse event reporting 
Day 3 of Cycles 2-6 
The following assessments will be completed prior to etoposide infusion: 
Deleted: 
•
Hematology 
Added:
•
Adverse event reporting 
Administration of etoposide: 
Previously Read: 
Hematology results must be reviewed by the investigator prior to etoposide dosing. 
Now Reads: 
•
Etoposide dosing will be given. 
Deleted: 
•
Adverse event reporting 
11.2.2.4 
Day 8 of Cycles 2 and 3 Only 
Added:
•
Hematology 
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11.2.4.1 
Day 1 (± 1 day) of Cycle 7 and every cycle thereafter 
Previously Read: 
•
Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, pelvis, will be 
done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 7 and every 
6 weeks+5 days thereafter).  The same method should be used throughout the study to follow 
the same anatomical location.  Bone scan will be completed every other tumor assessment 
(Day 1 of Cycle 9, and every 12 weeks/+5 days thereafter). 
Now Reads: 
•
Tumor assessment with CT (with contrast), or MRI scan of chest, abdomen, pelvis, will be 
done every 6 weeks+5 days after Day 1 of Cycle 1 (Day 1 of Cycle 7 and every 6 weeks+5 
days thereafter).  The same method should be used throughout the study to follow the same 
anatomical location.  If bone scan is used to follow bone lesions, bone scan will be completed 
every other tumor assessment (Day 1 of Cycle 9, and every 12 weeks/+5 days thereafter).  If 
PET/CT is used to follow bone lesions, PET/CT will be done at the same schedule as the 
assessments for other lesions (every 6 weeks +5 days thereafter). 
11.4 
Follow up 
Previously Read: 
… 
Additionally, subjects who discontinue study treatment for any reason other than disease 
progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) and bone 
scan every 12 weeks (+/- 5 days) during the Follow-up Period according to standard of care until 
documented disease progression or initiation of new anti-cancer therapy, whichever is sooner. 
Now Reads: 
…
Additionally, subjects who discontinue study treatment for any reason other than disease 
progression will be followed with tumor assessment every 6 weeks/42 days (±5 days) and bone 
scan every 12 weeks (+/- 5 days) during the Follow-up Period until documented disease 
progression or initiation of new anti-cancer therapy, whichever is sooner. 
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13.1 
Power and Sample Size 
Previously Read: 
The Phase 1b portion of the trial is a 3+3 dose escalation design.  Table 6 shows the probability 
of declaring a dose as the MTD for a variety of underlying toxicity rates.  For example there is an 
83 percent probability to declare a dose with an incidence of dose limiting toxicity of 50 percent 
as the MTD.  This compares with a probability of 29 percent for a dose with an incidence of dose 
limiting toxicity of 20 percent. 
Table 6: 
Power to Declare a Dose as the MTD for Various Incidence Rates 
Now Reads: 
The Phase 1b portion of the trial is a 3+3 dose escalation design.  Table 6 shows the probability 
of declaring a dose as exceeding the MTD for a variety of underlying toxicity rates.  For example 
there is an 83 percent probability to declare a dose with an incidence of dose limiting toxicity of 
50 percent as exceeding the MTD.  This compares with a probability of 29 percent for a dose 
with an incidence of dose limiting toxicity of 20 percent. 
Table 6: 
Power to Declare a Dose as Exceeding the MTD for Various Incidence Rates 
 
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APPENDIX B: 
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 1B 
Previously Read: 
Procedure 
Screening 
Treatment Period 
Follow-Upb 
Cycles 1-6 (every 21 days) 
 
> Cycles 7 
(every 21 days) 
Treatment 
Terminationa 
 
Day -28 
to -1 
Day-14 
to -1 
Day 1 
(±1 
day) 
Day 2 
Day 3 
 
 
Every 3 
months 
Day 8 
(Cycles 1-3 
only) 
Post Cycle 
6 
Day 1(± 1 day) 
Hematologyf 
 
X 
Xd 
X 
X 
 
 
X 
X 
 
Now Reads: 
Procedure 
Screening 
Treatment Period 
Follow-Upb 
Cycles 1-6 (every 21 days) 
 
> Cycles 7 
(every 21 days) 
Treatment 
Terminationa 
 
Day -28 
to -1 
Day-14 
to -1 
Day 1 
(±1 
day) 
Day 2 
Day 3 
 
 
Every 3 
months 
Day 8 
(Cycles 1-3 
only) 
Post Cycle 
6 
Day 1(± 1 day) 
Hematologyf 
 
X 
Xd 
 
 
X 
 
X 
X 
 
NOTES TO APPENDIX B:  (Cont’d) 
Previously Read: 
q. Bone scan will be done at screening and every other tumor assessment (every 12 weeks ±5 days) until disease progression or 
initiation or new anti-cancer therapy.  
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Now Reads: 
q. If bone scan is used to follow bone lesions, bone scan will be done at screening and every other tumor assessment (every 12 weeks 
±5 days) until disease progression or initiation or new anti-cancer therapy. If PET/CT is used to follow bone lesions, PET/CT will 
be completed at the same schedule as the assessments for other lesions (every 6 weeks ±5 days).  The same method (bone scan or 
PET/CT) should be used throughout the study to follow bone lesions. 
APPENDIX C  
SCHEDULE OF ASSESSMENTS FOR SUBJECTS IN PHASE 2 
Previously Read: 
Procedure 
Screening 
Treatment Period 
Follow-Upb 
Cycles 1-6 (every 21 days) 
 
> Cycles 7 
(every 21 days) 
Treatment 
Terminationa 
 
Day -28 
to -1 
Day-14 
to -1 
Day 1 
(±1 
day) 
Day 2 
Day 3 
 
 
Every 3 
months 
Day 8 
(Cycles 1-3 
only) 
Post Cycle 
6 
Day 1(± 1 day) 
Hematologyf 
 
X 
Xd 
X 
X 
 
 
X 
X 
 
Now Reads: 
Procedure 
Screening 
Treatment Period 
Follow-Upb 
Cycles 1-6 (every 21 days) 
 
> Cycles 7 
(every 21 days) 
Treatment 
Terminationa 
Day -28 
to -1 
Day-14 
to -1 
Day 1 
(±1 
day) 
Day 2 
Day 3 
 
 
Every 3 
months 
Day 8 
(Cycles 1-3 
only) 
Post Cycle 
6 
Day 1(± 1 day) 
Hematologyf 
 
X 
Xd 
 
 
X 
 
X 
X 
 
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NOTES TO APPENDIX C:  (Cont’d) 
Previously Read: 
p. Bone scan will be done at screening and every other tumor assessment (every 12 weeks ±5 days) until disease progression or 
initiation or new anti-cancer therapy.
Now Reads: 
p. If bone scan is used to follow bone lesions, bone scan will be done at screening and every other tumor assessment (every 12 weeks 
±5 days) until disease progression or initiation or new anti-cancer therapy.  If PET/CT is used to follow bone lesions, PET/CT will 
be completed at the same schedule as the assessments for other lesions (every 6 weeks ±5 days) The same method (bone scan or 
PET/CT) should be used throughout the study to follow bone lesions. 
 
 
 
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APPENDIX F: 
SAMPLE INFORMED CONSENT 
Previously Read: 
PROCEDURES 
The first portion of the study will include approximately 16 patients at about 5 centers in the 
United States and Europe.  The second portion of the study will include approximately 
80 patients at about 35 centers in the United States and Europe.   
Now Reads: 
The first portion of the study will include approximately 16 patients at about 7 centers in the 
United States.  The second portion of the study will include approximately 80 patients at about 
35 centers in the United States and Europe.   
Previously Read: 
Tumor assessments: An examination of your tumor(s) by CT (computerized tomography test, 
like an x-ray that produces a picture of your body including tumors using radiation), or MRI 
(magnetic resonance imaging - use of a magnetic field to produce an image of your body 
including tumors) and bone scan (an X-ray to look at your bone).  Your study doctor will 
determine which type of test (either CT or MRI) is best to assess your cancer.  A bone scan will 
also be done to find out if tumors have spread to your bones.  This is part of your routine cancer 
care.
Now Reads: 
Tumor assessments: An examination of your tumor(s) by CT (computerized tomography test, 
like an x-ray that produces a picture of your body including tumors using radiation), or MRI 
(magnetic resonance imaging - use of a magnetic field to produce an image of your body 
including tumors) or PET/CT (positron emission tomography- measures metabolic activity 
within the body.  When combined with CT, PET/CT will determine abnormal metabolic activity 
at a specific anatomic location) or bone scan (an X-ray to look at your bone).  Your study doctor 
will determine which type of test (CT or MRI, or PET/CT or bone scan) is best to assess your 
cancer.  This is part of your routine cancer care.   
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TREATMENT PHASE 
Previously Read: 
If you are found to be eligible to participate, you will be enrolled in the study.  
If you are in the first portion of the study, you will be assigned to a pre-determined dose level of 
OMP-59R5.  The initial dose levels of OMP-59R5 that will be tested in this study are 5mg/kg 
and 7.5 mg/kg (if the lower doses are tolerable) administered through the vein. You will be given 
the following drugs every 21 days: OMP-59R5 on Day1, etoposide 100 mg/m2 on Days 1, 2, and 
3, and cisplatin 80 mg/m2 on Day 1. 
… If your disease is at least stable or have responded to therapy at the end of cycle 6 and you 
doctor think it is appropriate, you will also receive radiation to your brain to help prevent tumors 
recurring around 8 weeks after the last administration of chemotherapy. 
Now Reads: 
If you are found to be eligible to participate, you will be enrolled in the study.  
If you are in the first portion of the study, you will be assigned to a pre-determined dose level of 
OMP-59R5.  The dose levels of OMP-59R5 that will be tested in this study are 5 mg/kg, 
7.5 mg/kg and at 2.5 mg/kg per increment (if the lower doses are tolerable) administered through 
the vein. You will be given the following drugs every 21 days: OMP-59R5 on Day1, etoposide 
100 mg/m2 on Days 1, 2, and 3, and cisplatin 80 mg/m2 on Day 1. 
… 
If your disease is at least stable or have responded to therapy at the end of cycle 6 and you doctor 
think it is appropriate, you will also receive radiation to your brain to help prevent tumors 
recurring within 8 weeks after the last administration of chemotherapy. 
Cycle 1 Day 2 
Deleted: 
•
About 1 tablespoon of blood sample will be taken to review your health condition. 
Cycle 1 Day 3 
•
About 1 tablespoon of blood sample will be taken to review your health condition. 
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OncoMed Pharmaceuticals, Inc. 
 
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Protocol 59R5-003, Amendment 6 
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Cycle 1 Day 8 
Previously Read: 
•
About 2 tablespoons of blood sample will be taken to check the level of certain markers and 
the level of OMP-59R5 in the blood  
Now Reads: 
•
About 3 tablespoons of blood sample will be taken to check the level of certain markers, the 
level of OMP-59R5 in the blood and your health status 
Cycle 2 Day 2 
Previously Read: 
•
About 3 tablespoons of blood will be taken to review your health condition and to assess the 
level of certain markers. 
Now Reads: 
•
About 2 tablespoons of blood will be taken to assess the level of certain markers. 
Cycle 2 Day 3 
Previously Read: 
•
About 1 tablespoon of blood will be taken to review your health condition. You will be asked 
about changes in your medical status or any new health issues and any medications you are 
taking since the previous study visit. 
Now Reads: 
•
You will be asked about changes in your medical status or any new health issues and any 
medications you are taking since the previous study visit. 
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 214 of 235 
22 April 2016
 
CONFIDENTIAL 
Cycle 2 Day 8 
Previously Read: 
•
About 2 tablespoons of blood will be taken to check the level of certain markers.  
Now Reads: 
•
About 3 tablespoons of blood will be taken to check the level of certain markers and your 
health status.  
Cycle 3 Day 1 
Previously Read: 
Tumor assessment: A CT scan or MRI will be done approximately every 6 weeks after your 
initial study drug dosing (Day 1 of Cycle 3 and every 6 weeks thereafter). A bone scan will be 
done at every other tumor assessment (approximately every 12 weeks after initial study drug 
dosing). 
Now Reads: 
Tumor assessment: A CT scan or MRI or PET/CT will be done approximately every 6 weeks 
after your initial study drug dosing (Day 1 of Cycle 3 and every 6 weeks thereafter). If a bone 
scan is used, bone scan will be done at every other tumor assessment (approximately every 12 
weeks after initial study drug dosing). 
Cycle 3 Day 2 
Previously Read: 
•
About 3 tablespoons of blood will be taken to review your health condition and to assess the 
level of certain markers.  
Now Reads: 
•
About 2 tablespoons of blood will be taken to assess the level of certain markers.  
Cycle 3 Day 3 
Deleted: 
•
About 1 tablespoon of blood will be taken to review your health condition.   
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 215 of 235 
22 April 2016
 
CONFIDENTIAL 
Cycle 3 Day 8 
Previously Read: 
•
About 2 tablespoon of blood to check the level of certain markers.   
Now Reads: 
•
About 3 tablespoon of blood to check the level of certain markers and your health status.   
Cycles 4-6:  Day 1 
Previously Read: 
•
Tumor assessment: A CT scan or MRI will be done approximately every 6 weeks after your 
initial study drug dosing. A bone scan will be done at every other tumor assessment 
(approximately every 12 weeks after initial study drug dosing). 
Now Reads: 
•
Tumor assessment: A CT scan or MRI or PET/CT will be done approximately every 6 weeks 
after your initial study drug dosing. A bone scan will be done at every other tumor 
assessment (approximately every 12 weeks after initial study drug dosing) if a bone scan is 
used. 
Cycles 4-6: Day 2 
Deleted: 
•
About 1 tablespoon of blood will be taken to review your health condition. 
End of Cycle 6 
Previously Read: 
•
At the end of cycle 6, if your disease is at least stable or have responded to therapy, you will 
receive radiation to your brain to help prevent tumors before continuing with study drug 
treatment.   
Now Reads: 
•
At the end of cycle 6, if your disease is at least stable or have responded to therapy, you 
doctor may decide that you will receive radiation to your brain to help prevent tumors before 
continuing with study drug treatment.   
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 216 of 235 
22 April 2016
 
CONFIDENTIAL 
Cycle 7 and beyond 
Previously Read: 
•
Tumor assessment: A CT scan or MRI will be done approximately every 6 weeks after your 
initial study drug dosing. A bone scan will be done at every other tumor assessment 
(approximately every 12 weeks after initial study drug dosing). 
Now Reads: 
•
Tumor assessment: A CT scan or MRI or PET/CT will be done approximately every 6 weeks 
after your initial study drug dosing. If a bone scan is used, bone scan will be done at every 
other tumor assessment (approximately every 12 weeks after initial study drug dosing). 
TREATMENT TERMINATION 
Previously Read: 
•
Tumor assessment:  either by CT or MRI, and bone scan, if these procedures were not done 
within the last 4 weeks and if the last tumor assessment did not show that your tumor has 
grown or spread 
Now Reads: 
•
Tumor assessment:  either by CT or MRI or PET/CT, or bone scan, if these procedures were 
not done within the last 4 weeks and if the last tumor assessment did not show that your 
tumor has grown or spread 
POSSIBLE RISKS AND DISCOMFORTS 
OMP-59R5: 
Previously Read: 
OMP-59R5 is being testing in small number of patients who have cancer; diarrhea is the most 
common side effect and all three patients who were treated at 5 mg/kg every other week had 
mild diarrhea.  You will be given some medications to take home to treat diarrhea.  Other 
comment side effects reported are: fatigue-tiredness (30%), nausea (22%), decreased appetite 
(15%), increased liver function (ALT) (11%), dehydration (11%), low potassium level (11%), 
vomiting (11%), low blood counts that might make you feel tired or easy to bruise (11%).
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 217 of 235 
22 April 2016
 
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Now Reads: 
OMP-59R5 is being testing in small number of patients who have cancer; diarrhea is the most 
common side effect in the first in man study and all three patients who were treated at 5 mg/kg 
every other week had mild diarrhea.  You will be given some medications to take home to treat 
diarrhea.  Other comment side effects reported are: fatigue-tiredness (30%), nausea (22%), 
decreased appetite (15%), increased liver function (ALT) (11%), dehydration (11%), low 
potassium level (11%), vomiting (11%), low blood counts that might make you feel tired or easy 
to bruise (11%). 
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 218 of 235 
22 April 2016
 
CONFIDENTIAL 
AMENDMENT 3: 
23 OCTOBER 2013 
The following changes were made to the protocol.  Italics in the text indicate new text.   
RATIONALE 
The protocol has been amended to refer the details on study drug (OMP-59R5/Placebo) 
preparation and administration in the Pharmacy Manual, to collect additional blood sample for 
PK and/or anti-OMP-59R5 antibody analysis at other protocol-specified times as clinically 
indicated such as when significant toxicities develop, to modify inclusion criterion 5c to allow 
medical judgment of adequate hepatic function when the lab values are outside of the 
corresponding cutoff.  Sample Informed Consent template has been updated to reflect the 
changes on infusion duration, possible additional blood samples for PK and/or anti-OMP-59R5 
antibody analysis when significant toxicities develop, incidences of infusion reactions in 71 
patients treated with OMP-59R5 and the management of the infusion reaction. 
Additionally, Table 7 has been updated to reflect the probability of 4 or more subjects 
developing DLTs in a total of 10 subjects in the expansion to be more in line with  33% 
incidence of DLTs in a standard 3+3 dose escalation study.  
SUMMARY OF CHANGES: 
SYNOPSIS 
Diagnosis and Main Criteria for Eligibility: 
Inclusion Criteria: 
Previously Read: 
5. Adequate organ function: 
a. Adequate hematologic function (absolute neutrophil count [ANC]  1,500 cells/ȝL; 
hemoglobin  9 g/dL, platelets  100,000/ȝL). 
b. Adequate renal function (serum creatinine  1.5 mg/dL or calculated creatinine clearance  
60 mL/min using Cockroft Gault formula). Adequate hepatic function (alanine 
aminotransferase [ALT]  3 x upper limit of normal [ULN], aspartate  
c. aminotransferase [AST]  3 x ULN); ALT and AST may be  5 x ULN if due to liver 
metastases but cannot be associated with concurrent elevated bilirubin >1.5xULN). 
d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated partial 
thromboplastin time (aPTT) 1.5 × ULN. 
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Protocol 59R5-003, Amendment 6 
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Now Reads: 
5. Adequate organ function: 
a. Adequate hematologic function (absolute neutrophil count [ANC]  1,500 cells/ȝL; 
hemoglobin  9 g/dL, platelets  100,000/ȝL). 
b. Adequate renal function (serum creatinine  1.5 mg/dL or calculated creatinine clearance  
60 mL/min using Cockroft Gault formula).  
c. Adequate hepatic function (alanine aminotransferase [ALT]  3 x upper limit of normal 
[ULN], ALT may be  5 x ULN if due to liver metastases but cannot be associated with 
concurrent elevated bilirubin >1.5xULN unless it is approved by the Sponsor’s Medical 
Monitor). 
d. Prothrombin Time (PT)/International Normalized Ration (INR) 1.5 × ULN, activated partial 
thromboplastin time (aPTT) 1.5 × ULN. 
Test Product, Dose, and Mode of Administration 
Previously Read: 
OMP-59R5 is an IgG2 fully human monoclonal antibody that is directed against the Notch2/3 
receptors.  OMP-59R5 is supplied at a concentration of 10 mg/mL in 25mL single-use glass vial 
filled to 20 mL to deliver at total of 200 mg per vial.  OMP-59R5 vials must be stored at 2°C–
8°C.  DO NOT FREEZE.  DO NOT SHAKE. 
OMP-59R5 must be delivered through either polyvinyl chloride (PVC) or non-PVC tubing 
containing a Baxter 0.22-micron high pressure extended life filter (part number 2H5660) 
which will be provided by OncoMed and should be infused over 30 minutes (+/- 5 minutes) as an 
IV infusion. Placebo is a formulation of 50mM Histidine, 100mM Sodium Chloride, 45mM 
Sucrose and 0.01% (v/v) Polysorbate-20, pH 6.0.  Placebo will be administered in the same 
manner as OMP-59R5; i.e., withdraw the necessary amount of placebo and dilute with either half 
normal saline (NS) (0.45% Sodium Chloride (NaCl) or 5% Dextrose and 0.45% NaCl (D5W ½ 
NS)to a total volume of 250 mL and infuse over 30 minutes (+/- 5 minutes).  The diluted study 
drug should be administered within 4 hours of preparation. 
Now Reads: 
OMP-59R5 is an IgG2 fully human monoclonal antibody that is directed against the Notch2/3 
receptors.  OMP-59R5 is supplied at a concentration of 10 mg/mL in 25mL single-use glass vial 
filled to 20 mL to deliver at total of 200 mg per vial.  OMP-59R5 vials must be stored at 
2°C-8°C.  DO NOT FREEZE.  DO NOT SHAKE. 
Please refer to the Pharmacy Manual for the details on OMP-59R5 preparation and 
administration. Placebo is a formulation of 50mM Histidine, 100mM Sodium Chloride, 45mM 
Sucrose and 0.01% (v/v) Polysorbate-20, pH 6.0.  Placebo will be administered in the same 
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OncoMed Pharmaceuticals, Inc. 
 
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Protocol 59R5-003, Amendment 6 
Page 220 of 235 
22 April 2016
 
CONFIDENTIAL 
manner as OMP-59R5. Please refer to the Pharmacy Manual for details regarding Placebo 
preparation and administration. 
Immunogenicity: 
Previously Read: 
Serum samples will be obtained for immunogenicity assessment prior to study drug 
administration on Day 1 of Cycle 1, every three cycles thereafter (Day 1 of Cycle 4, 7, 10, etc.) 
and at the time of treatment termination for all subjects enrolled in Phase 1b and Phase 2 
portions.  Samples that test positive will be assessed for neutralizing capability. 
Now Reads: 
Serum samples will be obtained for immunogenicity assessment prior to study drug 
administration on Day 1 of Cycle 1, every three cycles thereafter (Day 1 of Cycle 4, 7, 10, etc.), 
at other times as clinically indicated such as when significant toxicities occur and at the time of 
treatment termination for all subjects enrolled in Phase 1b and Phase 2 portions.  Samples that 
test positive will be assessed for neutralizing capability. 
Pharmacokinetic Evaluation: 
Previously Read: 
For subjects enrolled in Phase 1b portion only:  Plasma samples from all subjects enrolled in 
Phase 1b portion will be obtained for pharmacokinetic analysis of OMP-59R5 at pre-dose and 5 
minutes post infusion on Day 1 of Cycles 1 and 3, on Days 3 and 8 of Cycles 1 and 3, as well as 
at the time of treatment termination, as outlined in the Schedule of Assessments (APPENDIX B).  
Pharmacokinetic parameters (i.e. area under the curve [AUC], clearance, volume of distribution 
and apparent half life) of OMP-59R5 will be assessed for each evaluable subject. 
Now Reads: 
For subjects enrolled in Phase 1b portion only:  Plasma samples from all subjects enrolled in 
Phase 1b portion will be obtained for pharmacokinetic analysis of OMP-59R5 at pre-dose and 5 
minutes post infusion on Day 1 of Cycles 1 and 3, on Days 3 and 8 of Cycles 1 and 3, at other 
times as clinically indicated such as when significant toxicities occur as well as at the time of 
treatment termination, as outlined in the Schedule of Assessments (APPENDIX B).  
Pharmacokinetic parameters (i.e. area under the curve [AUC], clearance, volume of distribution 
and apparent half life) of OMP-59R5 will be assessed for each evaluable subject. 
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Protocol 59R5-003, Amendment 6 
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CONFIDENTIAL 
3.4 
Clinical Background 
Previously Read: 
…
No RECIST complete or partial responses have been noted on this Phase 1 study.  However, six 
subjects have had RECIST stable disease (SD) lasting greater than 56 days (ranging from 
61 days to 165 days, all of them have come off the study).  
OMP-59R5 is also being studied in a phase 1b/2 study in combination with nab-paclitaxel and 
gemcitabine in subjects with previously untreated stage IV pancreatic cancer (Study 59R5-002).  
The study was initially conducted in combination with gemcitabine alone and was amended to 
incorporate nab-paclitaxel into the chemotherapy backbone in response to the changes in 
standard of care in this disease population.  As of August 19, 2013, twenty four subjects have 
been treated in Study 59R5-002:  five and four at 2.5 mg/kg and 5.0 mg/kg respectively every 
other week in combination with gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day 
cycle, four, six and four at 5 mg/kg, 7.5 mg/kg and 10 mg/kg respectively every other week in 
combination with nab-paclitaxel at 125 mg/m2 and gemcitabine at 1000 mg/m2 on Days 1, 8 and 
15 of every 28 day cycle.  No DLTs have been reported, and the most common reported OMP-
59R5 treatment-related event is diarrhea, fatigue and nausea that are mostly grade 1 or 2, 
managed with supportive care.  One Grade 3 diarrhea was noted in one of four subjects treated 
with 10 mg/kg OMP-59R5 with Nab-P+Gem, lasted less than 48 hours and resolved to Grade 1 
diarrhea after concurrent use of lomotil.  Treatment with etoposide and cisplatin is the standard 
of care for subjects with untreated extended stage small cell lung cancer.  The most common AE 
of OMP-59R5 is diarrhea, whereas cytopenia is the most common adverse event with EP 
administration.  Therefore, the most common AEs of OMP-59R5 and EP do not overlap, 
providing the justification for investigating this combination in the study.  Subjects enrolled in 
this study will receive a starting dose of 5 mg/kg of OMP-59R5 once every three weeks, which is 
one dose below the MTD of 7.5 mg/kg every three weeks in Study 59R5-001.  Phase 1b lead-in 
portion of the study will provide preliminary safety and tolerability profile of this combination 
before the initiation of Phase 2 portion of the study.  OMP-59R5 has an estimated apparent half 
time of 2 to 3 days at 7.5 mg/kg in Study 59R5-001, subjects will not receive PCI or WBRT 
within 2 weeks of study drug administration and will not receive OMP-59R5 during the radiation 
to alleviate any potential interaction between the study drug and the radiation.  Therefore, risks 
and potential benefits of participation have been appropriately mitigated for this patient 
population. 
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Protocol 59R5-003, Amendment 6 
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CONFIDENTIAL 
Now Reads: 
… 
No RECIST complete or partial responses have been noted on this Phase 1 study.  However, six 
subjects have had RECIST stable disease (SD) lasting greater than 56 days (ranging from 
61 days to 165 days, all of them have come off the study).  
As of October 22, 2013, three subjects have been treated in the current study (Study 59R5-003) 
at 5 mg/kg dose cohort with EP; two of which have completed 6 cycles of chemotherapy and are 
continuing OMP-59R5 alone, and the other one is currently in Cycle 5.  No significant OMP-
59R5 treatment-related toxicities were reported.  
OMP-59R5 is also being studied in a phase 1b/2 study in combination with nab-paclitaxel and 
gemcitabine in subjects with previously untreated stage IV pancreatic cancer (Study 59R5-002).  
The study was initially conducted in combination with gemcitabine alone and was amended to 
incorporate nab-paclitaxel into the chemotherapy backbone in response to the changes in 
standard of care in this disease population.  As of October 22, 2013, twenty six subjects have 
been treated in Study 59R5-002:  five and four at 2.5 mg/kg and 5.0 mg/kg respectively every 
other week in combination with gemcitabine at 1000 mg/m2 on Days 1, 8 and 15 of every 28 day 
cycle, four, six, six and one at 5 mg/kg, 7.5 mg/kg, 10 mg/kg and 12.5 mg/kg respectively every 
other week in combination with nab-paclitaxel at 125 mg/m2 and gemcitabine at 1000 mg/m2 on 
Days 1, 8 and 15 of every 28 day cycle.  No DLTs have been reported, and the most common 
reported OMP-59R5 treatment-related event is diarrhea, fatigue and nausea that are mostly grade 
1 or 2, managed with supportive care.  One Grade 3 diarrhea was noted in one of six subjects 
treated with 10 mg/kg OMP-59R5 with Nab-P+Gem, lasted less than 48 hours and resolved to 
Grade 1 diarrhea after concurrent use of lomotil.  Three subjects have experienced grade 2 
infusion-related reactions: one at 5mg/kg OMP-59R5 dose cohort with Nab-P+Gem at Cycle 4 
Day 1(the baseline weight was 87kg), two at 10 mg/kg OMP-59R5 dose cohort with Nab-P+Gem 
at Cycle 1 Day 15 and Cycle 2 Day 1 respectively(the baseline weight was 106 kg and 84 kg 
respectively). Infusion reaction was also reported from two of forty two subjects treated in Study 
59R5-001: one at 1.0 mg/kg weekly and the other at 5.0 mg/kg weekly dose cohorts (the baseline 
weight was 54.7 kg and 104 kg respectively), both occurred with the first OMP-59R5 infusion 
and were Grade 1 or Grade 2; Four of these five subjects have responded to use of 
antihistamines and/or steroids, and the subsequent doses were administered at a slower infusion 
rate in addition to premedication.  However, one subject from the 10 mg/kg dose cohort in the 
ALPINE study experienced a recurrent infusion reaction even with premedication and slower 
infusion rate. Thus far, no infusion reactions have been reported in three subjects treated with 
OMP-59R5 in the PINNACLE study (59R5-003).  However, in response to the incidence of 
infusion reactions reported at higher OMP-59R5 doses in the ALPINE study, and in heavier 
subjects, the details on preparation and administration of OMP-59R5 have been provided in the 
Pharmacy Manual.  
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 223 of 235 
22 April 2016
 
CONFIDENTIAL 
Treatment with etoposide and cisplatin is the standard of care for subjects with untreated 
extended stage small cell lung cancer.  The most common AE of OMP-59R5 is diarrhea, whereas 
cytopenia is the most common adverse event with EP administration.  Therefore, the most 
common AEs of OMP-59R5 and EP do not overlap, providing the justification for investigating 
this combination in the study.  Subjects enrolled in this study will receive a starting dose of 
5 mg/kg of OMP-59R5 once every three weeks, which is one dose below the MTD of 7.5 mg/kg 
every three weeks in Study 59R5-001.  Phase 1b lead-in portion of the study will provide 
preliminary safety and tolerability profile of this combination before the initiation of Phase 2 
portion of the study.  OMP-59R5 has an estimated apparent half time of 2 to 3 days at 7.5 mg/kg 
in Study 59R5-001, subjects will not receive PCI or WBRT within 2 weeks of study drug 
administration and will not receive OMP-59R5 during the radiation to alleviate any potential 
interaction between the study drug and the radiation.  Therefore, risks and potential benefits of 
participation have been appropriately mitigated for this patient population. 
6.1 
Inclusion Criteria 
Previously Read: 
… 
c. Adequate hepatic function (alanine aminotransferase [ALT]  3 x upper limit of normal 
[ULN], aspartate aminotransferase [AST]  3 x ULN); ALT and AST may be  5 x ULN if 
due to liver metastases but cannot be associated with concurrent elevated bilirubin 
> 1.5xULN). 
Now Reads: 
… 
c. Adequate hepatic function (alanine aminotransferase [ALT]  3 x upper limit of normal 
[ULN], ALT may be  5 x ULN if due to liver metastases but cannot be associated with 
concurrent elevated bilirubin > 1.5xULN unless it is approved by the Sponsor’s Medical 
Monitor). 
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OncoMed Pharmaceuticals, Inc. 
 
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Protocol 59R5-003, Amendment 6 
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CONFIDENTIAL 
7.0 
TREATMENT OF SUBJECTS 
Previously Read: 
… 
Study drug will be OMP-59R5 in the Phase 1b portion, and either OMP-59R5 or placebo in the 
Phase 2 portion.  Study drug will be administered by IV infusion over 30 minutes (+/- 5 minutes) 
on Day 1 of every 21-day cycle.  The subject should not take two consecutive doses of study 
drug within 18 days.  
Now Reads: 
… 
Study drug will be OMP-59R5 in the Phase 1b portion, and either OMP-59R5 or placebo in the 
Phase 2 portion.  Study drug will be administered by IV infusion on Day 1 of every 21-day cycle.  
The subject should not take two consecutive doses of study drug within 18 days.  
7.1.1 Study Drug Administration 
Previously Read: 
During Phase 1b and 2, OMP-59R5 must be delivered through tubing containing a 
Baxter 0.22-micron high pressure extended life filter (part number 2H5660) which will be 
provided by OncoMed and should be infused over 30 minutes (+/- 5 minutes) as an IV infusion.    
During Phase 2, Placebo will be administered in exactly the same manner as OMP-59R5; i.e., 
withdraw the necessary amount of placebo and dilute with either half normal saline (NS) (0.45% 
Sodium Chloride (NaCl) or5% Dextrose and 0.45% NaCl (D5W ½ NS) to a total volume of 
250 mL and infuse over 30 minutes (+/- 5 minutes).  The diluted study drug should be 
administered within 4 hours of preparation. 
There is no provision for intra-subject dose escalation of study drug.  Weight-based doses will 
not be recalculated unless there is a weight change 10%.  
Now Reads: 
Please refer to the Pharmacy Manual for the details on OMP-59R5 or Placebo preparation and 
administration.    
\There is no provision for intra-subject dose escalation of study drug.  Weight-based doses will 
not be recalculated unless there is a weight change 10%.  
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Protocol 59R5-003, Amendment 6 
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7.1.5 Study Drug Preparation 
Previously Read: 
The study drug should be diluted for infusion using aseptic technique.  Withdraw the necessary 
amount of the study drug to obtain the required dose and dilute with either half normal saline 
(NS) (0.45% Sodium Chloride (NaCl) or 5% Dextrose and 0.45% NaCl (D5 ½ NS), to a total 
volume of 250 mL.  For example, if a 70-kg subject is to be dosed at 5 mg/kg, then the subject’s 
dose would be 350 mg.  Because the vials contain a concentration of 10 mg/mL, a total of 35 mL 
containing 350 mg should be withdrawn from the vial and diluted with either 0.45% NaCl or 5% 
Dextrose and 0.45% NaCl (D5W ½ NS), to a total volume of 250 mL. 
Any unused portion left in a vial may not be used for another subject, as the product contains no 
preservative (i.e., they are single-use vials). 
The diluted study drug solutions may be stored at room temperature (19°C–25°C) for up to 
4 hours. 
Now Reads: 
Please refer to the Pharmacy Manual for details on study drug preparation. 
Any unused portion left in a vial may not be used for another subject, as the product contains no 
preservative (i.e., they are single-use vials). 
7.4.1 Infusion Reaction Management 
Previously Read: 
… For subjects whose infusion-associated events were either Grade 1 or 2, and completely 
resolved on the day of the infusion, the infusion may be resumed at the discretion of the 
Investigator at one-half of the initial rate of infusion.  All subsequent infusions for that subject 
should then be administered at the reduced rate of infusion.   
Now Reads: 
… For subjects whose infusion-associated events were either Grade 1 or 2, and completely 
resolved on the day of the infusion, the infusion may be resumed at the discretion of the 
Investigator at a rate that is slower than the initial rate of infusion.  Please refer to the Pharmacy 
Manual for details on study drug administration.  All subsequent infusions for that subject 
should then be administered at the reduced rate of infusion.   
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8.5 
Immunogenicity Assessments 
Previously Read: 
(Anti-OMP-59R5) prior to study drug administration on Day 1 of Cycle 1, every three cycles 
thereafter (Day 1 of Cycle 4, 7, 10, etc.) and at the time of treatment termination for all subjects 
enrolled in Phase 1b and Phase 2 portions.  Samples that test positive will be assessed for 
neutralizing capability. Instructions for sample collection, handling, storage, and shipping can be 
found in the Study Reference Binder. 
Now Reads: 
Serum samples will be obtained for immunogenicity assessment (Anti-OMP-59R5) prior to study 
drug administration on Day 1 of Cycle 1, every three cycles thereafter (Day 1 of Cycle 4, 7, 10, 
etc.), at other times as clinically indicated such as when significant toxicities occur and at the 
time of treatment termination for all subjects enrolled in Phase 1b and Phase 2 portions.  Samples 
that test positive will be assessed for neutralizing capability. Instructions for sample collection, 
handling, storage, and shipping can be found in the Study Reference Binder. 
8.6 
Pharmacokinetic Assessments 
Previously Read: 
For subjects enrolled in Phase 1b portion only:  Plasma samples from all subjects enrolled in 
Phase 1b portion will be obtained for pharmacokinetic analysis of OMP-59R5 at pre-dose and 5 
minutes post OMP-59R5 infusion on Day1 of Cycles 1 and 3, on Days 3 and 8 of Cycles 1 and 3, 
as well as at the time of treatment termination, as outlined in the Schedule of Assessments 
(APPENDIX B and APPENDIX C).  Pharmacokinetic parameters (i.e. area under the curve 
[AUC], clearance, volume of distribution and apparent half life) of OMP-59R5 will be assessed 
for each evaluable subject.  Instructions for sample collection, handling, storage, and shipping 
can be found in the Study Reference Binder. 
Now Reads: 
For subjects enrolled in Phase 1b portion only:  Plasma samples from all subjects enrolled in 
Phase 1b portion will be obtained for pharmacokinetic analysis of OMP-59R5 at pre-dose and 5 
minutes post OMP-59R5 infusion on Day1 of Cycles 1 and 3, on Days 3 and 8 of Cycles 1 and 3, 
at other times as clinically indicated such as when significant toxicities occur as well as at the 
time of treatment termination, as outlined in the Schedule of Assessments (APPENDIX B and 
APPENDIX C).  Pharmacokinetic parameters (i.e. area under the curve [AUC], clearance, 
volume of distribution and apparent half life) of OMP-59R5 will be assessed for each evaluable 
subject.  Instructions for sample collection, handling, storage, and shipping can be found in the 
Study Reference Binder. 
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
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13.1 
Power and Sample Size 
Previously Read: 
Table 7 presents the probability that more than 3 subjects will experience a DLT in the expansion 
cohort of 10 subjects. The probability of seeing 3 or more subjects with a dose limiting toxicity 
when the true incidence is 40 percent is 83.3 percent compared with 69 percent with the 
3+3 design. 
Table 7: 
Probability of that 3 or more Subjects will have a Dose Limiting Toxicity 
Probability of Toxicity 
 3/10 Not Tolerable 
0.05 
0.0115 
0.10 
0.0702 
0.15 
0.1798 
0.20 
0.3222 
0.25 
0.4744 
0.30 
0.6172 
0.35 
0.7384 
0.40 
0.8327 
0.45 
0.9004 
0.50 
0.9453 
Now Reads: 
Table 7 presents the probability that more than 4 subjects will experience a DLT in the expansion 
cohort of 10 subjects. The probability of seeing 4 or more subjects with a dose limiting toxicity 
when the true incidence is 40 percent is 3.5 percent compared with 69 percent with the 
3+3 design. 
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 228 of 235 
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Table 7: 
Probability of that 4 or more Subjects will have a Dose Limiting Toxicity 
Probability of 4 or more DLT’s in 10 Subjects 
Probability of Dose 
Limiting Toxicity 
Given 0 DLT out of the 
first 6 subjects 
Given 1 DLT out of the 
first 6 subjects 
Given 0 or 1 DLT’s out 
of the first 6 subjects 
0.05 
0.000 
0.000 
0.000 
0.10 
0.000 
0.001 
0.001 
0.15 
0.000 
0.005 
0.005 
0.20 
0.000 
0.011 
0.011 
0.25 
0.001 
0.018 
0.019 
0.30 
0.001 
0.025 
0.026 
0.35 
0.001 
0.031 
0.032 
0.40 
0.001 
0.033 
0.035 
0.45 
0.001 
0.033 
0.034 
0.50 
0.001 
0.029 
0.030 
NOTES TO APPENDIX B: 
Previously Read: 
h. Plasma samples will be obtained for OMP-59R5 pharmacokinetic analysis at pre-dose and 5 
minutes (±2 minutes) after the end of OMP-59R5 infusion and prior to the EP administration 
on Day 1 of Cycle 1 and Cycle 3, and on Days 3 (pre-dose) and 8 of Cycles 1 and 3, as well 
as at treatment termination. On days when OMP-59R5 and etoposide and/or cisplatin are 
given together, the plasma sample should be obtained 5 minutes (±2 minutes) after the 
completion of the infusion of OMP-59R5, but prior to EP administration. 
i. Serum samples will be obtained for anti-OMP-59R5 pre-dose on Day 1 of every three cycles 
starting from Cycle 1, and at the Treatment Termination visit. 
Now Reads: 
h. Plasma samples will be obtained for OMP-59R5 pharmacokinetic analysis at pre-dose and 5 
minutes (±2 minutes) after the end of OMP-59R5 infusion and prior to the EP administration 
on Day 1 of Cycle 1 and Cycle 3, and on Days 3 (pre-dose) and 8 of Cycles 1 and 3, at other 
times as clinically indicated such as when significant toxicities occur, as well as at treatment 
termination. On days when OMP-59R5 and etoposide and/or cisplatin are given together, the 
plasma sample should be obtained 5 minutes (±2 minutes) after the completion of the 
infusion of OMP-59R5, but prior to EP administration. 
i. Serum samples will be obtained for anti-OMP-59R5 pre-dose on Day 1 of every three cycles 
starting from Cycle 1, at other times as clinically indicated such as when significant 
toxicities occur, and at the Treatment Termination visit. 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 229 of 235 
22 April 2016
 
CONFIDENTIAL 
NOTES TO APPENDIX C: 
Previously Read: 
h. Serum samples will be obtained for anti-OMP-59R5 pre-dose on Day 1 of every third cycle 
starting from Cycle 1, and at the Treatment Termination visit. 
Now Reads: 
h. Serum samples will be obtained for anti-OMP-59R5 pre-dose on Day 1 of every third cycle 
starting from Cycle 1, at other times as clinically indicated such as when significant 
toxicities occur and at the Treatment Termination visit. 
APPENDIX F: 
SAMPLE INFORMED CONSENT 
TREATMENT PHASE 
Previously Read: 
… 
Your study drug (OMP59R5 or placebo) will be given through the vein for 30 minutes.  
Etoposide will be given through the vein for 30 to 60 minutes.  Cisplatin will be given through 
the vein for 30 minutes to 2 hours.  On days when the study drug, etoposide and cisplatin are 
given together, the study drug will be given first, followed by etoposide, and then cisplatin.  You 
will receive study drug, etoposide, and cisplatin up to 6 cycles.  After that, you will receive study 
drug only on Day 1 of each following cycle. 
… 
The following procedures will take place at each of the following visits.
Now Reads: 
… 
Your study drug (OMP-59R5 or placebo) will be given through the vein for 30 minutes or longer 
depending on the dose you are assigned, your weight and if you have experienced any allergic 
reaction to study drug.  Your study staff will let you know how long your treatment with study 
drug will be.  Etoposide will be given through the vein for 30 to 60 minutes.  Cisplatin will be 
given through the vein for 30 minutes to 2 hours.  On days when the study drug, etoposide and 
cisplatin are given together, the study drug will be given first, followed by etoposide, and then 
cisplatin.  You will receive study drug, etoposide, and cisplatin up to 6 cycles.  After that, you 
will receive study drug only on Day 1 of each following cycle. 
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 230 of 235 
22 April 2016
 
CONFIDENTIAL 
… 
The following procedures will take place at each of the following visits.
Additional blood samples (approximately 1 to 2 teaspoons for each blood sample) might be 
taken to check the level of study drug (OMP-59R5) and/or proteins against OMP-59R5 in your 
body:
POSSIBLE RISKS AND DISCOMFORTS 
OMP-59R5: 
Previously Read: 
OMP-59R5 is being testing in small number of patients who have cancer; diarrhea is the most 
common side effect in the first in man study and all three patients who were treated at 5 mg/kg 
every other week had mild diarrhea.  You will be given some medications to take home to treat 
diarrhea.  Other comment side effects reported are: fatigue-tiredness (30%), nausea (22%), 
decreased appetite (15%), increased liver function (ALT) (11%), dehydration (11%), low 
potassium level (11%), vomiting (11%), low blood counts that might make you feel tired or easy 
to bruise (11%).  In addition, as with all antibody treatments, there is the possibility of an allergic 
reaction, such as fever, chills, rash, and/or hives associated with the infusion of OMP-59R5.  
Rarely, a severe or serious allergic reaction can occur during or following the administration of 
an antibody.   
Now Reads: 
OMP-59R5 is being testing in small number of patients who have cancer; diarrhea is the most 
common side effect in the first in man study and all three patients who were treated at 5 mg/kg 
every other week had mild diarrhea.  You will be given some medications to take home to treat 
diarrhea.  Other common side effects reported are: fatigue-tiredness (30%), nausea (22%), 
decreased appetite (15%), increased liver function (ALT) (11%), dehydration (11%), low 
potassium level (11%), vomiting (11%), low blood counts that might make you feel tired or easy 
to bruise (11%).  There may be side effects that we cannot predict and in some cases they may be 
serious, long-lasting, or fatal. In addition, as with all antibody treatments, there is the possibility 
of an allergic reaction, such as fever, chills, rash, hives, changes in blood pressure, temperature 
and heart rate associated with the infusion of OMP-59R5.  Rarely, a severe or serious allergic 
reaction can occur during or following the administration of an antibody.  As of October 22, 
2013, five of 71 patients who have been given OMP-59R5 have experienced allergic reactions; 
all of these allergic reactions were mild or moderate.  If you do have a reaction to OMP-59R5, 
your study doctor may need to give OMP-59R5 at a slower rate (over a longer period of time) 
and may give you additional medications to prevent a reaction. If after slowing the rate of 
infusion and giving you additional medications you continue to have the allergic reactions, you 
may need to stop taking OMP-59R5. 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 231 of 235 
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CONFIDENTIAL 
AMENDMENT 4: 
17 APRIL 2014 
The following changes were made to the protocol.  Italics in the text indicate new text. 
RATIONALE 
The protocol has been amended to add a cohort of 6 subjects to be treated with etoposide and 
carboplatin after the highest tolerable dose is determined with OMP-59R5 in combination with 
etoposide and cisplatin, the non-clinical section has been updated to include an experiment using 
carboplatin, to specify 15 mg/kg of OMP-59R5 as the highest dose to be tested in Phase 1b 
portion of the study if the MTD has not been determined after 15 mg/kg of tarextumab has been 
tested, in phase 2 portion of the study, the randomization will be balanced on the choice of 
platinum therapy (cisplatin versus carboplatin) regions (US vs Europe) and the prior use of 
whole brain radiation or prophylactic cranial irradiation.  Choice of platinum therapy won’t be 
changed once the subject is randomized. Additional blood samples have been added for PK and 
immunogenicity assessment. Inclusion criterion of Notch 3 selection has been eliminated and 
statistical section has been updated to include analysis on all treated subjects and Notch 3 high 
subjects. Subjects are required to have radiation-related adverse events recovered to be  Grade 1 
in order to be eligible for the study. 
SUMMARY OF CHANGES: 
As a result, all the corresponding sections of the protocol have been updated to reflect the 
changes outlined above, (i.e., Synopsis, Section 2.0 List of Abbreviations, 
Section 3.3 Nonclinical Data, Section 3.4 Clinical Background, Section 3.5 Dose Rationale, 
Section 3.7 Subject Population, Section 4.1 Study Objectives, Section 5.0 Overall Study Design 
and Plan - Description, Section 5.1 Phase 1b Portion, Section 5.3 Dose Escalation Plan, 
Section 5.4 Maximum Tolerated Dose, Section 5.5 Phase 2 Portion, Section 5.5.1 Blinded 
Treatment Phase, Section 6.1 Inclusion Criteria, Section 6.2 Exclusion Criteria, 
Section 6.3 Removal of Subjects from Study Treatment, Section 6.4 Subject Identification and 
Replacement of Subjects, Section 7.0 Treatment of Subjects, Section 7.1.1 Study Drug 
Administration, Section 7.4.1 Administration, Section 7.4.2 Description, Section 7.4.3 Storage,  
Section 7.4.4 Packaging, Section 7.5 Dose Modifications or Delay for Treatment-Related 
Toxicities, Section 7.6 Anti-Emetics, Anti-diarrhea and Hematopoietic Supportive Care, 
Section 7.8 Treatment Compliance, Section 6.1 Inclusion Criteria, Section 8.1.4 Serious Adverse 
Event Reporting Procedure, Section 8.2.1 Hematology, Section 8.2.2 Serum Chemistry, 
Section 8.2.3 Urinalysis, Section 8.3 Vital Signs and Other Physical Findings, 
Section 8.4 Cardiac Studies, Section 8.5 Immunogenicity Assessments, 
Section 8.6 Pharmacokinetic Assessments, Section 11.0 Study Visit Schedule and Assessments, 
Section 11.2 Treatment Visits, Section 11.2.1.1 Cycle 1 Day 1, Section 11.2.1.2 Cycle 1 Day 2, 
Section 11.2.1.3 Cycle 1 Day 3, Section 11.2.2.1 Day 1 (± 1 day) of Cycles 2-6, 
Section 11.2.2.2 Day 2 of Cycles 2-6, Section 11.2.2.3 Day 3 of Cycles 2-6, 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 232 of 235 
22 April 2016
 
CONFIDENTIAL 
Section 11.2.2.4 Day8 of Cycles 2 and 3 Only, Section 11.2.3 After Cycle 6 of Etoposide and 
Cisplatin/Carboplatin with Study Drug, Section 11.2.4.1 Day 1 (± 1 day) of Cycle 7 and Every 
Cycle Thereafter, Section 11.2.4.2 Anytime between Day 3 thru Day 14 of Cycle 7 and Cycle 9, 
Section 11.2 Treatment Termination, Section 13.1.1 Phase 1b, Section 13.1.2 Sample Size 
Justification – Phase 2, Section 13.2 Randomization and Blinding, Section 13.4.1 Subject 
Populations for Analysis, Section 13.4.2 Analysis Sets, Section 13.5.1 Efficacy Endpoints, 
Section 13.5.3 Immunogenicity Endpoint, Section 13.5.4 Pharmacokinetic Endpoints, Section 
13.5.5 Exploratory Endpoints, Section 13.6 Statistical Method, Section 13.6.1 Progression Free 
Survival, Section 13.6.2 Response Rate (Best Overall Response), Section 13.6.3 Duration of 
Response, Section 13.6.4 Overall Survival, Section 13.6.5 Landmark Survival, Section 13.7 
Demographics and Baseline Characteristics, Section 13.8 Treatment Exposure, Section 13.9 
Termination Criteria, Section 13.11 Data Safety Monitory Board, Section 14.0 Direct Access to 
Source Data/Documentation, Section 16.3 Study Monitoring, Section 16.5 Data collection, 
Section 17.0 References, Appendix A Study Schema, Appendix B Schedule of Assessments for 
Subjects in Phase 1B, Notes to Appendix B, Appendix C Schedule of Assessments for Subjects 
in Phase 2, Notes to Appendix C, Appendix F Sample Informed Consent, Appendix G Sample 
Pharmacogenomics Informed Consent for Phase 1B, and Appendix H Technical Details 
Supporting Calculation of Power and Type 1 Error. 
Additional minor changes have been made to improve clarity and consistency.  Substantive new 
information appears in italics.  This amendment represents cumulative changes to the previous 
amendments. 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 233 of 235 
22 April 2016
 
CONFIDENTIAL 
AMENDMENT 5: 
10 SEPTEMBER 2014 
The following changes were made to the protocol.  Italics in the text indicate new text. 
RATIONALE 
The protocol has been amended to decrease the cisplatin dose to 75 mg/m2 in the Phase 2 portion 
of the study.  Pharmacokinetic (PK) sampling in the Phase 2 portion has been modified. The 
amendment also provides additional flexibility on treatment modification as clinically indicated 
after discussion with the Sponsor’s Medical Monitor. The frequency of bone scan after treatment 
on study in Phase 2 has been changed to be done as clinically indicated.  Subjects who have 
relapsed after treatment for limited disease will be excluded for Phase 2 portion of the study.  
Additionally, the amendment also modified the statistical calculation for the Phase 2 portion of 
the study. The timing of the first two DSMB meetings has been modified. 
SUMMARY OF CHANGES: 
As a result, all the corresponding sections in the table below have been updated to reflect the 
changes outlined above.  Additional minor changes have been made to improve clarity and 
consistency.  Substantive new information appears in italics.  This amendment represents 
cumulative changes to the previous amendments. 
Synopsis 
 
Section 2.0 
List of Abbreviations 
Section 3.4 
Clinical Background 
Section 3.5 
Dose Rationale 
Section 5.0 
Overall Study Design and Plan Description 
Section 5.1 
Phase 1b Portion 
Section 5.5 
Phase 2 Portion 
Section 5.5.1 
Blinded Treatment Phase 
Section 6.2 
Exclusion Criteria 
Section 6.4 
Subject Identification and Replacement of Subjects 
Section 7.0 
Treatment of Subjects 
Section 7.1.1 
Study Drug Administration 
Section 7.3.1 
Administration 
Section 7.5 
Dose Modifications or Delay for Treatment-Related Toxicities 
Section 7.6 
Anti-Emetics, Anti-diarrhea and Hematopoietic Supportive Care 
Section 7.7 
Concomitant and Prohibited Therapy 
Section 8.2.2 
Chemistry 
Section 8.6 
Pharmacokinetic Assessments 
Section 11.1 
Screening 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
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OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 234 of 235 
22 April 2016
 
CONFIDENTIAL 
Section 11.2 
Treatment Visits 
Section 11.2.2 
Cycles 2-6 for Phase 1b and Cycles 2-4 for Phase 2 
Section 11.2.2.1 
Day 1 (± 1 day) of Cycles 2-6 for Phase 1b and Cycles 2 -4 for Phase 2 
Section 11.2.2.2 
D ay 2 of Cycles 2-6 for Phase 1b and  Cycles 2 -4 for Phase 2 
Section 11.2.2.3 
Day 3 of Cycles 2-6 for Phase 1b and  Cycles 2 -4 for Phase 2 
Section 11.2.3 
After Planned EP Treatment cycles 
Section 11.2.4 
Subsequent Cycles After Completion of Planned EP Cycles 
Section 11.2.4.1 
Day 1 (± 1 day) of Subsequent Cycles After Completion of Planned EP Cycles 
Section 11.2.4.2 
Anytime between Day 3 thru Day 14 of Cycle 5 and Cycle 7 
Section 11.3 
Treatment Visits – Phase 2 
Section 13.1.2 
Sample Size Justification – Phase 2 
Section 13.2 
Randomization and Blinding 
Section 13.4.2 
Analysis Set 
Section 13.6.1 
Progression Free Survival 
Section 13.6.2 
Response Rate (Best Overall Response) 
Section 13.6.4 
Overall Survival 
Section 13.9 
Termination Criteria 
Section 13.11 
Data Safety Monitory Board 
Section 13.12 
Interim Analysis 
Section 16.6 
Investigational Medicinal Product Accountability 
Appendix A 
Study Schema 
Appendix B 
Schedule of Assessments for Subjects in Phase 1B 
Notes to Appendix B 
 
Appendix C 
Schedule of Assessments for Subjects in Phase 2 
Notes to Appendix C 
 
Appendix F 
Sample Informed Consent – Phase 1b 
Appendix G 
Sample Informed Consent – Phase 2 
 
 
 
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037


OncoMed Pharmaceuticals, Inc. 
 
Tarextumab (OMP-59R5) 
Protocol 59R5-003, Amendment 6 
Page 235 of 235 
22 April 2016
 
CONFIDENTIAL 
AMENDMENT 6: 
22 APRIL 2016 
The following changes were made to the protocol.  Italics in the text indicate new text. 
RATIONALE 
The protocol has been amended to de-prioritize the co-primary endpoint of determining PFS 
benefit by adding tarextumab to EP in first-line extensive stage small cell lung cancer patients 
with Notch 3 expression level into secondary endpoint.  In addition to assessing the treatment 
effect by adding tarextumab to EP in first line extensive stage small cell lung cancer patients 
with Notch 3 expression, the treatment effect will be also explored in subjects with Hes1, Hey2, 
Hey1 and Hes6 expression.  The required PFS events for the different analyses have been 
updated and other statistical sections have been updated accordingly.  Clinical background 
section has been updated with emerging safety information and corresponding risk section of the 
consent has been updated. In addition, the USAN name of tarextumab has been added throughout 
the protocol as appropriate. 
SUMMARY OF CHANGES: 
As a result, all the corresponding sections in the table below have been updated to reflect the 
changes outlined above.  Additional minor changes have been made to improve clarity and 
consistency.  Substantive new information appears in italics.  This amendment represents 
cumulative changes to the previous amendments. 
Synopsis 
 
Section 3.4 
Clinical Background 
Section 4.1 
Study Objectives 
Section 13.1.2 
Sample Size Justification – Phase 2 
Section 13.3.2 
Analysis Set 
Section 13.5 
Statistical Methods 
Section 13.5.1 
Progression-Free Survival 
Section 13.5.4 
Overall Survival 
Section 13.5.6 
Correlation of biomarkers with Efficacy Endpoints 
Section 13.11 
Analysis of PFS and OS Prior to the Final Analysis 
  
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5.3.4.2 Protocol No. 59R5-003 - Amendment 6 - 22 April 2016
IND No. 106826, Serial 0037