Clinical trial NCT02259582
Conditions: Nonsquamous Nonsmall Cell Neoplasm of Lung
Keywords: Phase 2 histologically confirmed malignancy metastatic pemetrexed carboplatin carcinoma non small cell lung lung neoplasms lung diseases
Sponsor: OncoMed Pharmaceuticals, Inc.
Start date: 2015-02-01; Completion date: 2017-04-07
Enrollment: 82 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized, double-blind, 3-arm (1:1:1) study in subjects with first-line Stage IV non-squamous NSCLC. The purpose is to test the efficacy and safety of demcizumab, when given in combination with carboplatin and pemetrexed compared to placebo. The administration of carboplatin and pemetrexed is a standard treatment for patients with non-squamous non-small cell lung cancer.

Detailed description:
Patients will be enrolled at centers in North America, Western Europe, Australia and New Zealand. Up to 28 days (4 weeks) prior to treatment.

If enrolled in the study, you will receive intravenous (in the vein) infusions of demcizumab (or placebo), carboplatin, and pemetrexed administered on the same day, every 21 days for 4 cycles, or until it has been shown that your cancer has gotten worse. If your physician decides to delay treatment with one of the agents due to side effects, the other agents may still be administered as scheduled. After 4 cycles, if you have stable or improved disease, you will continue to receive pemetrexed once every 21 days as maintenance therapy. After 8 cycles, if you have stable or improved disease, you may receive demcizumab (or placebo), every 21 days for 4 more cycles.

You will undergo assessments every 6 weeks to determine the status of your disease.

Arms: arm 1: Pemetrexed (500 mg/m2),carboplatin (area under the concentration-time curve of 6 mg/mL x min) once every 21 days X 4 cycles, pemetrexed maintenance and placebo starting at Day 84 arm 2: Pemetrexed (500 mg/m2), carboplatin (area under the concentration-time curve of 6 mg/mL x min) x 4 cycles, one course of demcizumab 5mg/kg, maintenance pemetrexed + placebo starting on Day 84 arm 3: Pemetrexed (500 mg/m2), carboplatin (area under the concentration-time curve of 6 mg/mL x min) x 4 cycles, maintenance pemetrexed starting on Day 84. 2 courses of demcizumab 5 mg/kg
Interventions: intervention 1: Pemetrexed intervention 2: Carboplatin intervention 3: demcizumab
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
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Page 39 of 40


Page 40 of 40

Prot_ICF_001.pdf: 
 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 1 of 135 
29 November 2016  
CONFIDENTIAL 
CLINICAL PROTOCOL 
Protocol No. 
M18-007 
Title: 
A 3-Arm Phase 2 Double-Blind Randomized Study of Carboplatin, Pemetrexed Plus 
Placebo versus Carboplatin, Pemetrexed plus 1 or 2 Truncated Courses of Demcizumab 
in Subjects with Non-Squamous Non-Small Cell Lung Cancer 
 
DENALI: A 3-Arm Phase 2 Double-Blind RandomizEd Study of CarboplatiN, 
Pemetrexed Plus Placebo versus CarboplAtin, Pemetrexed pLus 1 or 2 Truncated 
Courses of Demcizumab In Subjects with Non-Squamous Non-Small Cell Lung Cancer
Version: 
12 September 2014 
 
Amendment 1:  8 October 2014 
Amendment 2:  4 March 2016 
Amendment 3: 29 November 2016 
 
 
 
 
 
 
 
 
EudraCT Number: 
2014-003356-30 
Sponsor: 
OncoMed Pharmaceuticals, Inc. 
800 Chesapeake Drive 
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. 
 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 2 of 135 
29 November 2016 
 
CONFIDENTIAL 
SPONSOR CONTACTS 
 
Medical Monitor: 
_________________ 
(Primary) 
 
 
 
 
 
Email: _______________________ 
 
 
 
Phone:  ______________________ 
Medical Monitor: 
__________________ 
(Secondary)  
___________________________ 
 
 
 
Email: _____________________ 
 
 
 
Phone: _____________________ 
Safety Reporting: 
Australia and Europe  
 
 
 
Phone: __________________  
 
 
 
Fax: ____________________ 
 
 
 
United States  
 
 
 
Phone: __________________ 
 
 
 
Fax: ____________________ 
 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 3 of 135 
29 November 2016 
 
CONFIDENTIAL 
INVESTIGATOR SIGNATURE PAGE 
OncoMed Pharmaceuticals 
Protocol No. M18-007, Amendment 3 
29 November 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: 
 
 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 4 of 135 
29 November 2016 
 
CONFIDENTIAL 
SPONSOR SIGNATURE PAGE 
 
OncoMed Pharmaceuticals, Inc. 
Protocol No. M18-007, Amendment 3 
29 November 2016 
 
This study protocol has been reviewed and approved by the undersigned person.  It is confirmed 
that the information and guidance given in this protocol complies with the scientific principles, 
the guideline of Good Clinical Practices, the Declaration of Helsinki in the latest relevant 
version, and the applicable legal and regulatory requirements.  
 
 
 
 
 
 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 5 of 135 
29 November 2016 
 
CONFIDENTIAL 
SYNOPSIS 
A 3-Arm Phase 2 Double-Blind Randomized Study of Carboplatin, Pemetrexed plus Placebo versus Carboplatin, 
Pemetrexed Plus 1 or 2 Truncated Courses of Demcizumab in Subjects with Non-Squamous Non-Small Cell Lung 
Cancer 
Study Period:  Approximately 30-36 months 
Development Phase:  Phase 2 
Objectives: 
All objectives apply to the study population of subjects with 1st-line stage IV non-squamous non-small cell lung cancer 
(NSCLC). 
Primary Objective: 
 
To compare the efficacy of Arm 1 to Arm 2 and Arm 3 combined 
Secondary Objectives: 
 
To compare the safety of Arm 1 to Arm 2 and Arm 1 to Arm 3 
 
To determine the rate of immunogenicity against demcizumab when combined with carboplatin and 
pemetrexed 
 
To determine population pharmacokinetics of demcizumab when combined with carboplatin and pemetrexed 
Exploratory Objective: 
 
To compare the exploratory pharmacodynamics (PD) and predictive biomarkers, such as DLL4 tumor 
expression, in Arm 1 to Arm 2 and Arm 3 combined 
Study Design: 
This is a randomized, double-blind, 3-arm (1:1:1) study in subjects with first-line Stage IV non-squamous NSCLC.  
Following determination of study eligibility, at least two-hundred and one subjects were to be randomized via an IWRS 
system to one of three arms. After randomization of 82 subjects, enrollment was discontinued due to significant 
difficulties in reaching the projected total subject number in a reasonable timeframe. 
 


 
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Study Design: (Cont’d) 
Demcizumab (5 mg/kg) or placebo will be administered once every 21 days for a total of 4 cycles (i.e., last 
administration on Day 63).  Subjects will only receive their second 4-cycle course (starting on Day 168) of 
demcizumab (5 mg/kg) or placebo if they meet the original cardiac-related eligibility criteria (see Exclusion 
Criterion 21 in Section 6.2), they did not develop pulmonary hypertension or heart failure while on study, and blood 
pressure is controlled to ≤140/90 mmHg. Subjects who do not meet the criteria to receive the second 4-cycle course of 
placebo or demcizumab will continue to receive maintenance pemetrexed per protocol without demcizumab or placebo.
Pemetrexed (500 mg/m2) and carboplatin (area under the concentration-time curve of 6 mg/mL x min) will be 
administered once every 21 days for a total of 4 cycles (or until toxicity necessitates reducing or holding a dose or 
terminating treatment).  The maintenance pemetrexed (500 mg/m2) will be given once every three weeks starting at 
Day 84.  On days of study drug administration, demcizumab or placebo, if applicable, will be administered first, 
followed by the administration of pemetrexed and then carboplatin (if applicable).  To reduce gastrointestinal and 
hematologic toxicity, subjects must receive oral folic acid ≥400 µg daily for at least 5 of the 7 days preceding the first 
dose of pemetrexed and continuing daily during the full course of therapy and for 21 days after the last dose of 
pemetrexed.  Subjects must also receive an intramuscular injection of vitamin B12 1000 µg during the week preceding 
the first dose of pemetrexed and then every 63 days while being treated with pemetrexed.  Unless contraindicated, 
subjects should also receive dexamethasone 4 mg orally twice daily on the day before, the day of, and the day after 
pemetrexed administration to reduce the risk of developing skin rash. 
In the absence of unacceptable toxicities or disease progression per RECIST v1.1, subjects should continue to receive 
study treatment. Regardless of discontinuation of one, two or all three study drugs, subjects should continue on study 
with assessments as outlined in Section 12.0 and Appendix A).  Once discontinuation criteria for the study are met 
(disease progression, use of other anti-cancer therapy, subject or investigator decision or protocol non-compliance, see 
Section 7.0), a termination visit should occur ≤14 days later. The termination visit may occur later after discussion with 
the OncoMed Medical Monitor for specific circumstances, such as prolonged hospitalization. After the termination 
visit, subjects should have regular follow-up for survival, subsequent anti-cancer therapies and other assessments as 
required per protocol (see Section 12.4).  Study procedures and assessments are further detailed in Appendix A. 
Diagnosis and Main Criteria for Eligibility (for complete eligibility criteria, see Section 6.0) 
Inclusion Criteria 
1. Signed Informed Consent Form 
2. Histologically or cytologically confirmed Stage IV non-squamous NSCLC   
3. If available, agreement to provide archival FFPE tumor tissue (obtained by core biopsy or surgical resection) for 
exploratory biomarker analyses 
4. Age >21 years 
5. ECOG performance status of 0 or 1 (see Appendix B) 
6. Disease that is measurable per RECIST v1.1 (Appendix C) 
7. Adequate organ and marrow function 
8. For women of childbearing potential and men with partners of childbearing potential, agreement to use two 
 
effective forms of contraception 


 
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Exclusion Criteria  
1. Histologically or cytologically documented, advanced, mixed non-small cell and small cell tumors or mixed 
adenosquamous carcinomas 
2. NSCLC with EGFR mutation or anaplastic lymphoma kinase (ALK) gene translocation (such as EML4-ALK) 
3. Prior or ongoing therapy (including chemotherapy, antibody therapy, tyrosine kinase inhibitors, radiotherapy, 
immunotherapy, hormonal therapy, or investigational therapy) for the treatment of Stage IV non-squamous 
NSCLC 
4. Evidence of tumor invading major blood vessels, cavitation of one or more pulmonary tumor mass(es) or tracheo-
esophageal fistula 
5. Brain metastases, leptomeningeal disease, uncontrolled seizure disorder, or active neurologic disease  
6. Metastases involving the lumen of the gastrointestinal tract 
7. Malignancies other than non-squamous NSCLC successfully treated within 3 years prior to randomization (with 
the exception of certain early-stage cancers) 
8. Prior radiation to the chest wall or mediastinum if the radiation field involved the heart 
9. History of a significant allergic reaction attributed to humanized or human monoclonal antibody therapy 
10. Significant intercurrent illness defined as an illness that may result in the subject’s death prior to their death from 
non-squamous NSCLC and/or significantly limit their ability to comply with the requirements of this study 
11. Recent hemoptysis >2.5 mL or serious bleeding from another site, known bleeding disorder or coagulopathy or 
therapeutic anti-coagulation 
12. History of cerebral vascular accident (CVA) or transient ischemic attacks (TIAs) within 6 months of randomization
13. Clinically significant arterial aneurysm 
14. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to randomization, or 
anticipation of need for major surgical procedure during the course of the study 
15. Blood pressure (BP) of >140/90 mmHgHistory, signs or symptoms indicative of an increased cardiac risk, 
including, but not limited to BNP value of >100 pg/mL, left ventricular ejection fraction (LVEF) <50%, peak 
tricuspid velocity >3.0 m/s on Doppler echocardiogram, history of or current cardiac ischemia or congestive heart 
failure 
16. History of interstitial lung disease or pneumonitis that required oral or intravenous corticosteroids 
Test Product, Dose, and Mode of Administration 
Demcizumab is an IgG2 humanized monoclonal antibody that is directed against the Delta-Like Ligand 4 (DLL4).  
Demcizumab is supplied at a concentration of 10 mg/mL in 25-mL single-use glass vials filled to 20 mL to deliver a 
total of 200 mg per vial.  Demcizumab vials must be stored at 2°–8°C.  DO NOT FREEZE.  DO NOT SHAKE.  
Placebo is a clear to slightly opalescent, colorless to slightly yellow liquid formulation of 50 mM Histidine, 100mM 
Sodium Chloride, 45mM Sucrose and 0.01% (v/v) Polysorbate-20, pH 6.0. Study drug (demcizumab at 5 mg/kg or 
placebo) will be administered as an intravenous infusion over 30 (+5) minutes once every 3 weeks for 4 cycles (i.e., 
last administration on Day 63).  A second course of study drug (demcizumab at 5 mg/kg or placebo) will be 
administered once every 3 weeks for 63 days starting at Day 168 if the criteria outlined in Study Design are met. 
Duration of Treatment: 
Subjects should be treated until they develop unacceptable toxicities or disease progression per the Response 
Evaluation Criteria in Solid Tumor (RECIST) version 1.1. 


 
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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 including assessment of BNP, Doppler 
echocardiogram, anti-demcizumab testing, and subject interview on an ongoing basis (as outlined in Appendix A) from 
randomization through 30 days following the discontinuation of treatment.  Subjects who have two consecutive BNP 
values >100 pg/mL or one value ≥200 pg/mL will have their treatment unblinded and, if they are receiving 
demcizumab, will be started on a cardioprotective agent, either an ACE inhibitor or carvedilol.  In addition, any subject 
who develops a BNP ≥300 pg/mL, a LVEF decline ≥10% from baseline and LVEF <50%, clinically significant 
pulmonary hypertension (i.e., peak tricuspid velocity >3.4 m/s on Doppler echocardiogram and diagnosed with 
clinically significant pulmonary hypertension that includes minimal dyspnea by a cardiologist or pulmonologist) and/or 
symptoms of heart failure must have their dose of demcizumab held. Demcizumab must be discontinued for BNP 
≥400 pg/mL, Grade ≥2 pulmonary hypertension, Grade ≥2 bronchopulmonary or gastrointestinal bleeding, 
hypertensive crisis or encephalopathy, blood pressure ≥200/120 mmHg despite maximum treatment and/or need for 
therapeutic anti-coagulation.  Administration of chemotherapy should be continued, unless contraindicated, when 
demcizumab/placebo is held or discontinued (see Section 8.1.6). 
Efficacy Evaluation: 
Subjects will be assessed for response using RECIST criteria v1.1 during screening, then every 6 weeks, and at the 
termination visit (unless performed within 14 days of the termination visit or at a prior response evaluation that 
documented progressive disease).  Investigator-assessed progression-free survival, response rates, duration of response, 
and survival will be evaluated. 
Immunogenicity: 
Serum samples for immunogenicity analysis will be obtained at Day 0, every 6 weeks during the study, and at the 
termination visit. 
Pharmacokinetics: 
Plasma samples for PK analysis will be obtained prior to the demcizumab (or placebo) infusion on Days 0, 42, 84, 126, 
168, 210, 252, 294 and 336, and at the end of the demcizumab (or placebo) infusion (prior to chemotherapy infusion, if 
applicable) on Days 0, 42, 168 and 210, and at the termination visit. 
Biomarker Evaluation: 
Whole blood will be obtained for biomarker evaluations on Study Days 0 and 28, and at the termination visit as 
outlined in Appendix A.  In addition, a pharmacogenomics sample will be collected at baseline from subjects who give 
informed consent.  If available, archival FFPE tumor tissue (from either the primary tumor, locoregional disease or a 
metastatic site) obtained by core biopsy or surgical resection will be collected.  Analysis of candidate genes and/or 
proteins relevant to the Notch pathway may be performed (e.g., DLL4, Notch1, Hey1, FBXW7). 


 
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CONFIDENTIAL 
1.0 
TABLE OF CONTENTS 
1.0 
TABLE OF CONTENTS ..................................................................................................9 
LIST OF TABLES .......................................................................................................................12 
LIST OF FIGURES .....................................................................................................................12 
LIST OF APPENDICES .............................................................................................................13 
2.0 
LIST OF ABBREVIATIONS .........................................................................................14 
3.0 
BACKGROUND ..............................................................................................................16 
3.1 
Investigational Medicinal Product .........................................................................16 
3.2 
Stage IV Non-Small Cell Lung Cancer .................................................................16 
3.3 
Nonclinical Background ........................................................................................17 
3.3.1 
Activity of Anti-DLL4 in Non-Small Cell Lung Cancer Xenografts ...17 
3.3.2 
Potential for Immune-Mediated Mechanism of Action for Anti-
DLL4 .....................................................................................................21 
3.4 
Clinical Background ..............................................................................................25 
3.4.1 
Phase 1a Study M18-001 ......................................................................25 
3.4.2 
Phase 1b Studies M18-002, M18-003, and M18-004 and Phase 1b/2 
Study M18-005 .....................................................................................26 
3.5 
Dose Rationale .......................................................................................................37 
3.6 
Study Conduct ........................................................................................................38 
4.0 
STUDY OBJECTIVES AND ENDPOINTS ..................................................................38 
4.1 
Study Objectives ....................................................................................................38 
4.2 
Endpoints ...............................................................................................................39 
5.0 
OVERALL STUDY DESIGN AND PLAN – DESCRIPTION....................................40 
6.0 
SELECTION OF STUDY POPULATION ...................................................................43 
6.1 
Inclusion Criteria ...................................................................................................43 
6.2 
Exclusion Criteria ..................................................................................................44 
7.0 
REMOVAL OF SUBJECTS FROM ON-STUDY PART OF PROTOCOL .............47 
8.0 
STUDY TREATMENTS .................................................................................................47 
8.1 
Study Drug (Demcizumab or Placebo) ..................................................................47 
8.1.1 
Administration ......................................................................................47 
8.1.2 
Description ............................................................................................49 
8.1.3 
Packaging ..............................................................................................49 
8.1.4 
Drug Ordering, Storage, and Accountability ........................................49 
8.1.5 
Drug Preparation ...................................................................................49 
8.1.6 
Treatment Modification and Termination Criteria for 
Demcizumab/Placebo ............................................................................50 
8.1.7 
Infusion Reaction Management ............................................................52 


 
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8.2 
Pemetrexed .............................................................................................................52 
8.2.1 
Administration ......................................................................................52 
8.2.2 
Description ............................................................................................52 
8.2.3 
Storage ..................................................................................................52 
8.2.4 
Packaging ..............................................................................................53 
8.2.5 
Vitamin Supplementation and Dexamethasone Administration ...........53 
8.2.6 
Renally Impaired Subjects ....................................................................53 
8.2.7 
Preparation and Administration Precautions .........................................53 
8.2.8 
Preparation for Intravenous Infusion Administration ...........................53 
8.3 
Carboplatin .............................................................................................................54 
8.3.1 
Administration ......................................................................................54 
8.3.2 
Description ............................................................................................55 
8.3.3 
Storage ..................................................................................................55 
8.3.4 
Packaging ..............................................................................................55 
8.4 
Pemetrexed and Carboplatin Dose Modification/Treatment Delay .......................55 
8.5 
Anti-Emetics and Hematologic Supportive Care ...................................................59 
8.6 
Concomitant and Prohibited Therapy ....................................................................59 
8.7 
Treatment Compliance ...........................................................................................60 
9.0 
SAFETY ASSESSMENTS ..............................................................................................60 
9.1 
Adverse Events Definitions and Reporting Procedures .........................................60 
9.1.1 
Definition of Adverse Event .................................................................60 
9.1.2 
Definition of Serious Adverse Event ....................................................61 
9.1.3 
Disease Progression and Death .............................................................62 
9.1.4 
Serious Adverse Event Reporting Procedures ......................................62 
9.2 
Clinical Laboratory Assessments ...........................................................................62 
9.2.1 
Hematology ...........................................................................................62 
9.2.2 
Serum Chemistry ...................................................................................63 
9.2.3 
BNP Assessment ...................................................................................63 
9.2.4 
Urinalysis ..............................................................................................63 
9.3 
Vital Signs and Other Physical Findings ...............................................................63 
9.4 
Cardiopulmonary Studies .......................................................................................64 
9.5 
Immunogenicity Assessments ................................................................................64 
9.6 
Pharmacokinetic Assessments ...............................................................................65 
10.0 
EFFICACY ASSESSMENTS .........................................................................................65 
11.0 
EXPLORATORY ASSESSMENTS ...............................................................................66 
12.0 
STUDY VISIT SCHEDULE AND ASSESSMENTS ....................................................67 


 
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12.1 
Screening................................................................................................................67 
12.2 
Assessments for On-study Part of Protocol (Day 0 up to Termination Visit) .......67 
12.3 
Termination Visit ...................................................................................................68 
12.4 
Follow-up after Termination Visit .........................................................................69 
13.0 
DATA QUALITY ASSURANCE ...................................................................................69 
14.0 
STATISTICAL PLAN .....................................................................................................70 
14.1 
Subject Populations for Analysis ...........................................................................75 
14.2 
Demographics and Baseline Characteristics ..........................................................75 
14.3 
Treatment Exposure ...............................................................................................75 
14.4 
Endpoints ...............................................................................................................76 
14.4.1 
Safety Endpoints ...................................................................................76 
14.4.2 
Immunogenicity Endpoints ...................................................................77 
14.4.3 
Pharmacokinetic Endpoints ...................................................................77 
14.4.4 
Efficacy Endpoints ................................................................................77 
14.4.5 
Continuous Variable Assessment of Tumor Length .............................79 
14.4.6 
Duration of Response ............................................................................80 
14.4.7 
Overall Survival ....................................................................................80 
14.4.8 
Landmark Survival ................................................................................81 
14.4.9 
Exploratory Endpoints ..........................................................................81 
14.5 
Termination Criteria...............................................................................................81 
14.6 
Deviation Reporting ...............................................................................................82 
15.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ................................82 
16.0 
ETHICAL CONSIDERATIONS ....................................................................................82 
17.0 
INVESTIGATOR REQUIREMENTS ..........................................................................82 
17.1 
Informed Consent...................................................................................................82 
17.2 
Institutional Review Board/Ethics Committee Approval ......................................82 
17.3 
Study Monitoring ...................................................................................................83 
17.4 
Auditing Procedures...............................................................................................83 
17.5 
Data Collection ......................................................................................................83 
17.6 
Investigational Medicinal Product Accountability ................................................84 
17.7 
Disclosure of Data and Publication ........................................................................84 
17.8 
Retention of Records ..............................................................................................84 
18.0 
REFERENCES .................................................................................................................85 
 


 
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LIST OF TABLES 
Table 1: 
Activity of Anti-DLL4 in NSCLC Tumor Xenografts ..............................18 
Table 2: 
Overall Response Assessment for Subjects Enrolled in Study M18-002 
(n=47) .........................................................................................................27 
Table 3: 
Overall Response Assessment for Subjects in Study M18-004 (n =40) ....30 
Table 4: 
Subsequent Anti-Cancer Therapies for Subjects after Discontinuation 
from Study M18-004..................................................................................35 
Table 5: 
Dose Reduction for Pemetrexed and Carboplatin - Hematologic 
Toxicities....................................................................................................58 
Table 6: 
Dose Reduction for Pemetrexed and Carboplatin – Nonhematologic 
Toxicities....................................................................................................58 
Table 7: 
Dose Reduction for Pemetrexed and Carboplatin – Motor or Sensory 
Neurotoxicity .............................................................................................59 
Table 8: 
Power to Detect an Increase in Response Rate ..........................................70 
Table 9: 
Power to Detect a Difference in the Overall Survial Kaplan Meier 
Curves Beyond 10 Months.........................................................................72 
Table 10: 
Probability Heart Failure Rate Will Exceed 15 Percent over Control .......74 
 
LIST OF FIGURES 
Figure 1: 
Activity of Anti-DLL4 in LU2 (left panel) and LU25 (right panel) 
NSCLC Tumors .........................................................................................19 
Figure 2: 
Activity of Anti-DLL4 in Combination with Paclitaxel in LU53 
NSCLC Tumors .........................................................................................19 
Figure 3: 
Activity of Anti-DLL4 in Combination with Pemetrexed in LU45 
NSCLC Tumors .........................................................................................20 
Figure 4: 
Reduction of Tumor Growth and Tumorigenic Cell Frequency by 
Anti-DLL4 in Combination with Carboplatin plus Pemetrexed ................21 
Figure 5: 
Inhibition of Tumor Growth by the Combination of Anti-DLL4 and 
Anti-PD1 ....................................................................................................22 
Figure 6: 
Effects of Anti-DLL4 and Anti-PD1 on Cytokine Production ..................23 
Figure 7: 
Anti-DLL4 Selectively Reduces the Frequency of Monocytic Myeloid-
Derived Suppressor Cells ...........................................................................24 
Figure 8: 
Percent Change in Tumor Target Lesion Size - Study M18-002 ...............28 
Figure 9: 
Percent Change in Tumor Target Lesion Size of the Nab-
paclitaxel/Gemcitabine/Demcizumab Subjects - Study M18-002 .............29 
Figure 10: 
Percent Change in Tumor Target Lesion Size - Study M18-004 ...............31 
Figure 11: 
Progression-free and Overall Survival for Subjects with Continuous 
Demcizumab Dosing - Study M18-004 .....................................................32 


 
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Figure 12: 
Progression-free and Overall Survival for Subjects with Truncated 
Demcizumab Dosing - Study M18-004 .....................................................32 
Figure 13: 
Exploratory Subset Analysis for Overall Survival - Study M18-004 ........33 
Figure 14: 
Overall Survival for Subjects with Continuous and Truncated 
Demcizumab (DEM) Dosing - Study M18-004 .........................................34 
Figure 15: 
Exploratory Overall Survival Analysis for Immune Biomarkers - Study 
M18-004 .....................................................................................................36 
Figure 16: 
Three-Arm Design of Study M18-007 .......................................................40 
Figure 17: 
Two Main Periods (On Study and Follow-up) of Study M18-007 ............42 
Figure 18: 
Approach to Demcizumab/Placebo Dosing ...............................................48 
Figure 19: 
Demcizumab-like Approach to Pemetrexed and Carboplatin Dosing .......56 
Figure 20: 
Standard Approach to Pemetrexed and Carboplatin Dosing .....................57 
 
LIST OF APPENDICES 
Appendix A: 
SCHEDULE OF ASSESSMENTS ............................................................88 
Appendix B: 
ECOG PERFORMANCE STATUS CRITERIA.......................................96 
Appendix C: 
RECIST CRITERIA VERSION 1.1 ..........................................................97 
Appendix D: 
NEW YORK HEART ASSOCIATION CLASSIFICATION .................103 
Appendix E: 
SAMPLE INFORMED CONSENT ........................................................104 
Appendix F: 
PHARMACOGENOMICS INFORMED CONSENT .............................124 
Appendix G: 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ..................129 
AMENDMENT 1: 
8 OCTOBER 2014 ...................................................................................129 
AMENDMENT 2: 
4 MARCH 2016 .......................................................................................130 
AMENDMENT 3: 
29 NOVEMBER 2016 .............................................................................134 
 


 
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2.0 
LIST OF ABBREVIATIONS 
Abbreviation or Term 
Definition/Explanation 
AE 
adverse event 
ALT (SGPT) 
alanine aminotransferase (serum glutamic pyruvic transaminase) 
ANC 
absolute neutrophil count 
aPTT 
Activated partial thrombplastin time 
AST (SGOT) 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase) 
BNP 
B-type natriuretic peptide 
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) 
dL 
deciliter(s) 
DLL 
Delta-like ligand (DLL1, 3, 4) 
DLT 
dose-limiting toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
FACS 
Fluorescent-activated cell sorting 
GI 
gastrointestinal 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IMP 
Independent Medicinal Product 
IEC 
Independent Ethics Committee 
IGS 
Invasiveness gene signature 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
intent-to-treat (population) 
IV 
intravenous 
IWRS 
Interactive web randomization system/Interactive  voice randomization system 
kg 
kilogram(s) 
LD 
longest diameter (of a lesion) 
LDH 
lactic dehydrogenase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram(s) 


 
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Abbreviation or Term 
Definition/Explanation 
mL 
milliliter(s) 
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
NE 
Not evaluable 
NOAEL 
no observed adverse effect level 
PD 
progressive disease 
POC 
point of care 
PR 
partial response 
RDC 
remote data capture 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease 
ULN 
upper limit of normal 
US 
ultrasound 
VEGF 
vascular endothelial growth factor 
 


 
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3.0 
BACKGROUND 
3.1 
Investigational Medicinal Product 
Demcizumab is an IgG2 humanized monoclonal antibody directed against Delta-Like Ligand 4 
(DLL4), which is one of the ligands that bind to the Notch 1, 2, 3, and 4 receptors. 
3.2 
Stage IV Non-Small Cell Lung Cancer 
Lung cancer is the leading cause of malignancy-related mortality worldwide.  Over 1,000,000 
new cases of lung cancer are diagnosed annually, and more than 900,000 people die of the 
disease every year (Ref 1, Ref 2).  Non-small cell lung cancer (NSCLC) accounts for 85% of all 
lung cancers, with the major histologic subtypes being adenocarcinoma, squamous-cell 
carcinoma, and large-cell carcinoma.  The prognosis for subjects with Stage IV NSCLC is 
particularly poor with only approximately 2% of these subjects alive 5 years after diagnosis 
(Ref 3). 
Platinum-based combination chemotherapy is the standard first-line treatment for subjects with 
Stage IV NSCLC.  For subjects with good performance status, platinum-based chemotherapy has 
demonstrated prolongation of survival and improvement in quality-of-life compared with best 
supportive care (Ref 4, Ref 5, and Ref 6). More recently, it was demonstrated that, 
in chemotherapy-naïve subjects with NSCLC, overall survival with a cisplatin + pemetrexed 
doublet was statistically non-inferior to that achieved with cisplatin + gemcitabine; additionally, 
in subjects with non-squamous histology, overall survival was superior with cisplatin + 
pemetrexed as compared to cisplatin + gemcitabine (Ref 7).  The combination of pemetrexed 
with a platinum, typically carboplatin, has emerged as a popular regimen for non-squamous 
NSCLC because of its efficacy and its superior toxicity profile (Ref 8). 
In subjects who achieve disease stabilization or an objective response, the use of maintenance 
therapy with continued administration of a single drug until disease progression has also resulted 
in improved survival (Ref 9). Pemetrexed is one of the drugs used in this setting (Ref 10). 
For a small subset of NSCLC subjects with specific genetic tumor alterations, these general 
treatment guidelines do no longer apply in their entirety.  Subjects whose tumor has an activating 
EGFR mutation should receive a tyrosine kinase inhibitor (TKI), either erlotinib or gefitinib.  
Subjects whose tumor has a rearrangement of the anaplastic lymphoma kinase (ALK) gene 
should receive the TKI crizotinib (Ref 11; and National Comprehensive Cancer Network Clinical 
Practice Guidelines in Oncology, Non-small cell lung cancer, Version 2.2013). 
More recently, immunomodulatory antibodies targeting the programmed death-1 pathway have 
emerged as an important treatment option for previously treated NSCLC subjects (Ref 12, 
Ref 13). 


 
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3.3 
Nonclinical Background 
Notch signaling controls various cellular processes including stem cell self-renewal, cell fate 
specification, differentiation, proliferation and survival (Ref 14).  Evidence has accumulated that 
tumors are composed of heterogeneous cell types and that tumor growth is driven by a subset of 
cells termed cancer stem cells (CSCs) or tumor initiating cells (Ref 15).  DLL4 is an important 
component of Notch-mediated stem cell self-renewal and vascular development.  DLL4 over-
expression is found in tumor vasculature and tumor cells and has been shown to activate Notch 
signaling in CSCs.  Inhibition of DLL4 in epithelial tumors resulted in an anti-tumor effect 
through an increase of vasculature sprouting resulting in dysfunctional vasculature (Ref 16, 
Ref 17).  We have shown anti-tumor activity in a variety of epithelial tumors including breast, 
colon, and pancreatic cancers (Ref 18, Ref 19, Ref 20).  These experiments demonstrated that 
anti-DLL4 reduces tumor growth through at least two mechanisms of action – disrupting tumor 
angiogenesis and reducing tumorigenic cell frequency. 
3.3.1 
Activity of Anti-DLL4 in Non-Small Cell Lung Cancer Xenografts 
Notch signaling has been implicated in cancer stem cell function and disease progression in 
NSCLC (Ref 21, Ref 22).  In order to evaluate the potential of demcizumab for the treatment of 
NSCLC, we have tested anti-DLL4 in a variety of patient-derived NSCLC tumor xenografts and 
found that this treatment is efficacious as a single agent and in combination with various 
chemotherapeutic regimens including pemetrexed, carboplatin plus pemetrexed, or paclitaxel 
(Table 1). 


 
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Table 1: 
Activity of Anti-DLL4 in NSCLC Tumor Xenografts 
Tumor 
Path 
Anti-DLL4  
Single Agent  
Anti-DLL4 
Combination  
LU2 
Large cell (met to colon) 
+ 
+ (paclitaxel) 
LU11 
Squamous 
(Primary) 
+ 
+ (paclitaxel) 
LU24 
Squamous 
(primary) 
+ 
- (pemetrexed) 
LU25 
Squamous 
(primary) 
+ 
- (paclitaxel) 
LU45 
Adeno  
(primary) 
- 
+ (pemetrexed) 
LU53 
Squamous 
(primary) 
+ 
+ (paclitaxel) 
LU56 
Squamous 
(primary) 
+ 
+ (carbo/pem) 
Anti-DLL4 (OMP-21M18 + 21R30) was tested as a single agent and in combination in NSCLC tumors.  The 
activity of anti-DLL4 treatment as a single agent or in combination with either paclitaxel or pemetrexed is 
indicated.  A “+” for the single agent activity indicates that tumor volume was less than the control antibody 
treated group, while “+” in the combination activity column indicates the effect on tumor volume relative to 
combination agent group (p < 0.05). 
 
Examples of the single-agent activities of anti-DLL4 are shown in Figure 1.  Established LU2 or 
LU25 NSCLC tumor xenografts were treated with the combination of anti-human DLL4 
(OMP-21M18) and anti-mouse (21R30) DLL4.  Blockade of DLL4-Notch signaling significantly 
delayed tumor growth in both models (Figure 1).  In addition, we have seen evidence of anti-
DLL4 combination activity with either pemetrexed (Figure 2) or paclitaxel (Figure 3). 


 
OncoMed Pharmaceuticals, Inc. 
 
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29 November 2016 
 
CONFIDENTIAL 
Figure 1: 
Activity of Anti-DLL4 in LU2 (left panel) and LU25 (right panel) NSCLC 
Tumors 
 
 
 
LU2 (left panel) or LU25 (right panel) patient-derived xenograft NSCLC tumors were treated with control antibody 
(Ab) or anti-DLL4 (OMP-21M18 + 21R30).  
 
Figure 2: 
Activity of Anti-DLL4 in Combination with Paclitaxel in LU53 NSCLC 
Tumors 
 
LU53 patient-derived xenograft NSCLC tumors were treated with control antibody (Ab), anti-DLL4 (OMP-21M18 
+ 21R30), paclitaxel (Taxol) alone, or the combination of anti-DLL4 plus paclitaxel (Taxol).  The antibodies 
and paclitaxel (Taxol) were administered at 10 mg/kg weekly. 
 
0
5
10
15
20
25
30
0
400
800
1200
1600
Control Ab
Anti-DLL4
Days Post Treatment
tumor volume  mm3
LU2
 
 
 
 
 
 
 
 
 
0
7
14
21
28
35
42
49
0
500
1000
1500
2000
Control Ab
anti-DLL4
Taxol
Anti-DLL4+Taxol
Days Post-Treatment
Tumor Volume, mm3
 
0
5
10
15
20
0
250
500
750
1000
1250
Control Ab
Anti-DLL4
Days Post Treatment
tumor volume (mm3)
LU25


 
OncoMed Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
Figure 3: 
Activity of Anti-DLL4 in Combination with Pemetrexed in LU45 NSCLC 
Tumors 
 
LU45 patient-derived xenograft NSCLC tumors were treated with control antibody (Ab), anti-DLL4 (OMP-21M18 
+ 21R30), pemetrexed alone, or the combination of anti-DLL4 plus pemetrexed.  The antibodies were 
administered at 10 mg/kg weekly, and pemetrexed was dosed at 150 mg/kg five times per week. 
 
The activity of anti-DLL4 in combination with carboplatin plus pemetrexed was also tested.  
Anti-DLL4 was effective in reducing both tumor volume and tumorigenic cell frequency (Figure 
4).  The reduction in tumorigenic cell frequency was determined by a serial transplantation 
experiment.  These data indicate that, as in other tumor types, anti-DLL4 treatment results in a 
long-term effect on NSCLC cells that limits their proliferative capacity and ability to propagate 
tumor growth. 
0
5
10
15
0
200
400
600
800
1000
1200
Control Ab
pemetrexed
Anti-DLL4
pemetrexed +Anti-DLL4
LU45
Days Post Treatment
Tumor Volume, mm3


 
OncoMed Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
Figure 4: 
Reduction of Tumor Growth and Tumorigenic Cell Frequency by 
Anti-DLL4 in Combination with Carboplatin plus Pemetrexed 
 
LU56 patient-derived xenograft NSCLC tumors were treated with control antibody (Ab), anti-DLL4 (OMP-21M18 
+ 21R30), carboplatin plus pemetrexed, or the triple combination of anti-DLL4, carboplatin (carbo) and 
pemetrexed (pem). The antibodies were administered at 10 mg/kg weekly, carboplatin at 25 mg/kg weekly, and 
pemetrexed at 100 mg/kg three times per week. Tumor volumes are shown in the left panel. Following 
treatment, human tumor cells were isolated from the control antibody, carboplatin/pemetrexed and anti-DLL4 
plus carboplatin/pemetrexed groups. Fifty tumor cells were injected into 10 mice each and allowed to grow for 
54 days without further treatment (right panel). Tumor cells from animals previously treated with anti-DLL4 + 
carboplatin/pemetrexed had a reduced rate of tumor growth compared to controls, indicating a reduction in 
tumor initiating cell frequency.  
 
3.3.2 
Potential for Immune-Mediated Mechanism of Action for Anti-DLL4 
Evidence has accumulated that Notch signaling plays a significant role in various aspects of the 
immune response, including the generation of IL-17 producing T cells (Ref 23, Ref 24).  Based 
on the emerging understanding of the activity of DLL4-Notch signaling in immune function, we 
wanted to determine if inhibition of DLL4-Notch signaling might augment anti-tumor immune 
response.  To address this question, we have carried out pre-clinical experiments with murine 
tumors in immunocompetent mice.  Initial experiments showed that anti-DLL4 increased 
cytotoxic T cell activity in tumors comparable to IL-2 treatment (data not shown).  Subsequently, 
we tested anti-DLL4 in combination with anti-PD1 and found that both anti-DLL4 and anti-PD1 
treatments reduced tumor growth, and the combination produced an additive effect (Figure 5).   
 
0
10
20
30
0
500
1000
1500
Control mAb
anti-DLL4
Anti-DLL4 + Carbo/pem
Carboplatin + pemetrexed
Days Post Treatment
Tumor Volume, mm3
Tumor Volume Day 54
Control mAb
Carbo/pem
Anti-DLL4+Carbo/pem
0
500
1000
1500
2000
Tumor Volume, mm3


 
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CONFIDENTIAL 
Figure 5: 
Inhibition of Tumor Growth by the Combination of Anti-DLL4 and 
Anti-PD1 
 
CT26 murine tumors were grown in Balb/c mice and treated with either control Ab, anti-PD1, anti-DLL4 (OMP-
21R30), or the combination of anti-DLL4 and anti-PD1 (n = 10/group). Antibodies were administered at 20 
mg/kg, IP, twice per week. Mean tumor volumes (+SEM) are shown on the indicated days. 
 
Following the treatment phase of the experiment shown in Figure 5, splenocytes from tumor-
bearing mice were tested for their ability to produce various cytokines in response to an antigenic 
peptide derived from the CT26 tumor.  Anti-PD1 increased IFN-γ production, as expected, 
whereas anti-DLL4 treatment had no effect (data not shown).  The combination of anti-DLL4 
and anti-PD1 increased IL-2 production and, of most interest, anti-DLL4 treatment reduced IL-
17 production, either as a single agent or in combination with anti-PD1 (Figure 6).  Higher levels 
of IL-17 production in tumors have been shown to be associated with poor clinical outcome in 
cancer patients (Ref 25); therefore inhibiting IL-17 is expected to be beneficial. 


 
OncoMed Pharmaceuticals, Inc. 
 
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29 November 2016 
 
CONFIDENTIAL 
Figure 6: 
Effects of Anti-DLL4 and Anti-PD1 on Cytokine Production 
 
Cytokine production in splenoctyes was measured by ELISPOT assay. Spleen cells from each group were cultured 
with and without tumor-specific peptide (AH1) for 2 days, and AH1-specific cytokine was determined. IL-2 
production was increased by the combination of anti-DLL4 and anti-PD1 (left panel). IL-17 production was 
decreased by single-agent anti-DLL4 and combination treatment (right panel).  
 
IL-17 has been identified as a key factor inducing myeloid-derived suppressor cells (MDSCs), 
and these cells are critical in promoting an immunosuppressive environment in tumors (Ref 26).  
Anti-DLL4 treatment was found to significantly reduce MDSCs, specifically the monocytic 
MDSCs, in tumor-bearing mice as shown by flow cytometry (Figure 7). 
 
 
 
 
 
 
 
 
 
 
 
Control
Anti-DLL4
Anti-PD1
Combination
0
25
50
75
100
*
No. of spots (IL2)
IL-2
Control
Anti-DLL4
Anti-PD1
Combination
0
100000
200000
300000
IL-17
*
*
Total Area (IL17)


 
OncoMed Pharmaceuticals, Inc. 
 
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CONFIDENTIAL 
Figure 7: 
Anti-DLL4 Selectively Reduces the Frequency of Monocytic Myeloid-
Derived Suppressor Cells 
 
The frequency of sub-classes of myeloid-derived suppressor cells (MDSCs) was investigated by flow cytometry. 
CD11b positive cells were analyzed for Ly6G and Ly6C expression. The percentage of monocytic MDSCs (M-
MDSC), but not granulocytic MDSCs (G-MDSC), was reduced by anti-DLL4 treatment. The results are 
quantified in the graphs on the right. 
 
These data show that anti-DLL4 may inhibit tumor growth by promoting anti-tumor immunity.  
Our data indicate that anti-DLL4 operates through distinct mechanisms in the immune system 
compared with immune checkpoint blockers such as anti-PD1.  Inhibition of DLL4 signaling 
reduces IL-17 production and the prevalence of monocytic MDSCs.  Thus, in addition to its well 
established activities in maintaining functional tumor vasculture and self-renewal of cancer stem 
cells, DLL4 appears to play a key role in regulating the immune response in the tumor 
microenvironment. 


 
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CONFIDENTIAL 
3.4 
Clinical Background 
Five clinical studies (M18-001, M18-002, M18-003, M18-004 and M18-005) have been or are 
being conducted with demcizumab.  M18-001 was a Phase 1a single-agent dose escalation trial 
of demcizumab in subjects with previously treated advanced solid tumors.  Study M18-002 is an 
ongoing open-label Phase 1b study of gemcitabine or gemcitabine and nab-paclitaxel plus 
demcizumab in subjects with locally advanced or metastatic pancreatic cancer.  Study M18-003 
was an open-label Phase 1b study of 5-fluorouracil, folinic acid and irinotecan (FOLFIRI ) plus 
demcizumab in subjects with metastatic colorectal cancer that was closed after seven subjects 
were treated on the trial due to changing corporate priorities.  Study M18-004 is an ongoing 
open-label Phase 1b study of carboplatin and pemetrexed plus demcizumab in subjects with 
unresectable locally advanced, recurrent, or metastatic non-squamous NSCLC.  Finally, study 
M18-005 is an ongoing Phase 1b/2 study of paclitaxel plus demcizumab in subjects with 
platinum-resistant ovarian cancer.  
3.4.1 
Phase 1a Study M18-001 
M18-001 was a Phase 1a single-agent dose escalation trial of demcizumab in subjects with 
previously treated advanced solid tumors.  This trial was conducted to determine the maximum 
tolerated dose (MTD), safety, pharmacokinetics, immunogenicity, and preliminary efficacy of 
demcizumab.  A total of 61 subjects were enrolled in the trial, and 55 subjects received 
treatment.  In the dose-escalation phase of the study, 39 subjects received treatment at 0.5 (n=3), 
1.0 (n=3), 2.5 (n=6), and 5.0 (n=3) mg/kg once weekly for the first 56 days and then once every 
other week, and 2.5 (n=6), 5 (n=6) and 10 (n =12) mg/kg once every other week until disease 
progression.  In the expansion phase of the study, an additional 15 subjects were treated with 
10 mg/kg once every other week.  Finally, one subject was treated with 10 mg/kg weekly on 
Day 0, 7, and 14 (as a loading dose) and then 10 mg/kg once every other week.   
The MTD as assessed by DLTs observed over the first 28 days was not reached at 10 mg/kg once 
every other week.  Hypertension or blood pressure increased that was managed with oral 
antihypertensives was the most frequent related event occurring in 55% of subjects.  Other 
common related events included fatigue, anemia, headache, hypoalbuminemia, and dyspnea.  
A decline in hemoglobin of >2 g/dL was also observed in 17 of the 55 (31%) treated subjects. 
During the conduct of the study, cardiotoxicity was identified as a potential toxicity in the 
ongoing 6-month cynomolgus monkey study.  As a result, the protocol was amended to include 
monitoring with brain natriuretic peptide (BNP) and echocardiograms.  Increases in BNP to 
>400 pg/mL (or NT-pro-BNP >800 pg/mL) considered to be possibly related to study drug were 
observed in 6 subjects who received 10 mg/kg once every other week.  This toxicity is 
considered dose-, schedule- and duration-related.  High doses of demcizumab administered 
frequently for prolonged periods of time can result in the emergence of cardiotoxicity as was 
seen on study M18-001 in the subjects treated at 10mg/kg dosed every other week for a 
prolonged period of time (>100 days).  Three of the subjects who had a screening left ventricular 
ejection fraction of at least 50% subsequently had a value that was <40% after receiving therapy 
for >100 days.  


 
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CONFIDENTIAL 
Four subjects who received 10 mg/kg once every other week developed congestive heart failure 
(3 Grade 3 and 1 Grade 4).  A rise in BNP above 250 pg/mL occurred prior to the development 
of congestive heart failure in 3 of these 4 subjects.  In addition, 1 subject who received 2.5 mg/kg 
once every week developed Grade 3 right ventricular failure.  In all 5 subjects, demcizumab 
therapy was discontinued, and the subjects were started on medication to treat their heart failure 
when the event occurred.  The symptoms of heart failure subsequently diminished in all 
5 subjects.  In addition, 2 subjects developed pulmonary hypertension.  One of these subjects 
received 2.5 mg/kg once every week and developed Grade 1 pulmonary hypertension.  
Enrollment in the study was stopped early due to an unacceptably high rate of congestive heart 
failure in subjects treated at 10 mg/kg once every other week for longer than 100 days.  The data 
from this trial suggest that high (i.e., 10 mg/kg) doses of demcizumab administered for a 
prolonged period of time (i.e., >100 days) results in an increased incidence of heart failure. 
One unconfirmed partial response as per RECIST version 1.1 (v1.1) was observed in a refractory 
pancreatic cancer subject treated at 10 mg/kg once every other week.  In addition, a number of 
subjects with a variety of solid tumors including NSCLC, renal cell carcinoma, colorectal cancer, 
and pancreatic cancer, had a reduction in the size of their target lesions of <30%.  A high 
percentage of subjects (59%; 16 of 27) treated at 10 mg/kg once every other week had stable 
disease (n=15) or a partial response (n=1).  One subject at 10 mg/kg once every other week with 
a refractory ovarian cancer (granulosa cell) who had progressed through 12 prior treatment 
regimens remained on therapy with disease control for 518 days.  
3.4.2 
Phase 1b Studies M18-002, M18-003, and M18-004 and Phase 1b/2 Study 
M18-005 
Three Phase 1b studies (M18-002, M18-003, and M18-004) and one Phase 1b/2 study 
(M18-005) of demcizumab plus chemotherapy have been or are being conducted.  As of the 
cut-off dates of 23 July 2013 (M18-003), 25 July 2014 (M18-002 and M18-004), and 
21 August 2014 (M18-005), 99 subjects have been treated in these trials.  Study M18-002 is an 
ongoing open-label Phase 1b study of gemcitabine or gemcitabine and nab-paclitaxel plus 
demcizumab in subjects with locally advanced or metastatic pancreatic cancer.  Study M18-003 
was an open-label Phase 1b study of 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus 
demcizumab in subjects with metastatic colorectal cancer that was closed after seven subjects 
were treated on the trial due to changing corporate priorities.  Study M18-004 is an ongoing 
open-label Phase 1b study of carboplatin and pemetrexed plus demcizumab in subjects with 
unresectable locally advanced, recurrent, or metastatic non-squamous NSCLC.  Finally, study 
M18-005 is an ongoing Phase 1b/2 study of paclitaxel plus demcizumab in subjects with 
platinum-resistant ovarian cancer.  


 
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CONFIDENTIAL 
3.4.2.1 
Phase 1b Efficacy Data 
Response Data for All Three Phase 1b Studies 
Study M18-002 is an ongoing Phase 1b trial of demcizumab in combination with gemcitabine or 
gemcitabine and nab-paclitaxel in subjects with previously untreated adenocarcinoma of the 
pancreas.  Thirty-eight of the 47 subjects were evaluable for response.  Four of the 16 (25%) 
evaluable subjects treated with gemcitabine and demcizumab had a partial response, and 7 (44%) 
had stable disease.  Nine of the 22 (41%) evaluable subjects treated with nab-paclitaxel, 
gemcitabine and demcizumab had a partial response, and 10 (45%) had stable disease. 
Table 2 summarizes the RECIST v1.1 response data for this study.  
Table 2: 
Overall Response Assessment for Subjects Enrolled in Study M18-002 
(n=47) 
 
Cohort 1 
 
5 mg/kg 
q2w 
(n=8) 
Cohort 2 
 
2.5 mg/kg 
q4w 
(n=8) 
Cohort 3 
 
5 mg/kg 
q4w 
(n=8) 
TOTAL 
Gem + 
Dem 
(evaluable: 
n=16) 
Cohort 4 
Tr. Dem 
2.5 mg/kg 
q2w 
(n=6) 
Cohort 5 
Tr. Dem 
5 mg/kg 
q2w 
(n=8) 
Cohort 6 
Tr. Dem 
3.5 mg/kg 
q2w 
(n=9) 
TOTAL 
Nab/Gem + 
Dem 
(evaluable: 
n=22) 
Complete 
Response 
- 
- 
- 
- 
- 
- 
- 
- 
Partial 
Response 
1 
1 
2 
4 (25%) 
4 
3 
2 
9 (41%) 
Stable 
Disease 
4 
2 
1 
7 (44%) 
1 
4 
5 
10 (45%) 
Progressive 
Disease 
- 
3 
2 
5 (31%) 
1 
1 
1 
3 (14)% 
Not 
evaluable 
3 
2 
3 
8 
- 
- 
1 
1 
Dem = demcizumab; Gem = gemcitabine; Nab = nab-paclitaxel; q2w = every 2 weeks; q4w = every 4 weeks; Tr. 
Dem = truncated demcizumab dosing regimen (last demcizumab dose on Day 70; see Section 3.4.2.2). Subjects 
in Cohorts 1-3 received gemcitabine plus demcizumab. Subjects in Cohorts 4-6 received nab-paclitaxel, 
gemcitabine and demcizumab (truncated dosing regimen). 
 
Figure 8 and Figure 9 are the waterfall plots showing the best % reduction in target lesion size 
for all of the subjects on the study and those who received demcizumab, gemcitabine and 
nab-paclitaxel, respectively.  


 
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CONFIDENTIAL 
Figure 8: 
Percent Change in Tumor Target Lesion Size - Study M18-002 
 
Figure 8 provides the best % change in tumor target lesion size for all subjects (i.e., subjects treated with 
gemcitabine and demcizumab and subjects treated with nab-paclitaxel, gemcitabine and demcizumab) enrolled 
in study M18-002.  Thirty-one of the 38 evaluable subjects had a reduction in the size of their target lesions, and 
7 subjects had an increase in the size of their target lesions.  Each bar represents an individual subject.  Subjects 
were dosed either once every 2 weeks or every 4 weeks. 
 


 
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CONFIDENTIAL 
Figure 9: 
Percent Change in Tumor Target Lesion Size of the Nab-
paclitaxel/Gemcitabine/Demcizumab Subjects - Study M18-002 
 
 
Only 7 1st- or 2nd-line colorectal cancer subjects were enrolled in study M18-003, and their 
treatment was stopped early.  Thus, response data are not displayed. 
Table 3 summarizes the RECIST v1.1 response data for study M18-004 that is an ongoing 
Phase 1b study in subjects with 1st-line NSCLC who were treated with demcizumab in 
combination with pemetrexed and carboplatin.  Thirty-three of the 40 subjects were evaluable for 
response.  Sixteen of the 33 (48%) evaluable subjects had a response, and 13 (39%) subjects had 
stable disease. 
‐100
‐90
‐80
‐70
‐60
‐50
‐40
‐30
‐20
‐10
0
10
% Change in Tumor Size 


 
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CONFIDENTIAL 
Table 3: 
Overall Response Assessment for Subjects in Study M18-004 (n =40) 
 
Cohort 1 
 
 
5 mg/kg 
q3w 
(n=6) 
Cohort 2 
 
 
2.5 mg/kg 
q3w 
(n=6) 
Cohort 3
 
 
5 mg/kg 
q3w 
(n=8) 
Cohort 4 
(Expansion)
 
5 mg/kg 
q3w 
(n=6) 
Cohort 5 
 
Trunc Dem
7.5 mg/kg
q3w 
(n=6) 
Cohort 6 
 
Trunc Dem 
5 mg/kg 
q3w 
(n=7) 
Cohort 7 
(Expansion) 
Trunc Dem 
5 mg/kg 
q3w 
(n=1) 
TOTAL 
(evaluable: 
n=33) 
Best Overall Response, n (%) 
Complete 
Response 
- 
- 
- 
1 
- 
- 
- 
1 (3%) 
Partial 
Response 
2 
4 
2 
- 
4 
3 
- 
15 (45%) 
Stable 
Disease 
2 
2 
4 
2 
1 
2 
- 
13 (39%) 
Progressive 
Disease 
- 
- 
1 
2 
1 
- 
- 
4 (12%) 
Not 
evaluable  
2 
- 
1 
1 
- 
2 
1 
7 
q3w = every 3 weeks; Trunc Dem = truncated demcizumab dosing regimen (last demcizumab dose on Day 63, 
see Section 3.4.2.2). 
 
Figure 10 provides the best percent change in tumor target lesion size for study M18-004.  
Twenty-seven of the 31 evaluable subjects had a reduction the size of their target lesions. 


 
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Figure 10: 
Percent Change in Tumor Target Lesion Size - Study M18-004 
 
Each bar represents an individual subject.  All subjects were dosed once every 3 weeks.Five subjects with platinum-
resistant ovarian cancer have been enrolled in study M18-005 and were treated with paclitaxel and demcizumab.  
Two of these subjects had stable disease, and 3 had progressive disease. 
 
Progression-free Survival and Overall Survival Data for M18-004 (NSCLC Phase 1b) 
The Phase 1b study for NSCLC subjects (M18-004) was analyzed for progression-free survival 
and overall survival using on- and off-study data.  Figure 11 shows the results for the first group 
of 23 subjects who received continuous demcizumab dosing. 


 
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Figure 11: 
Progression-free and Overall Survival for Subjects with Continuous 
Demcizumab Dosing - Study M18-004 
 
Data as of 17 June 2015. 23 subjects who received 6 cycles of demcizumab, carboplatin and pemetrexed followed 
by demcizumab maintenance.  Excludes 3 patients from Cohort 4. 
 
 
Figure 12 shows the results for the second group of 23 subjects who received truncated 
demcizumab dosing. 
Figure 12: 
Progression-free and Overall Survival for Subjects with Truncated 
Demcizumab Dosing - Study M18-004 
 
Data as of 17 June 2015. 23 subjects who received 4 cycles of demcizumab, carboplatin and pemetrexed followed 
by pemetrexed maintenance. Includes 3 patients from Cohort 4. 
 


 
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In a combined analysis for all 46 subjects, subject demographics and laboratory parameters were 
assessed to determine which factors were associated with the prolonged survival tail on the 
Kaplan-Meier curves.  Across all these subject variables the survival tail on the Kaplan-Meier 
curves remained evident (Figure 13). 
Figure 13: 
Exploratory Subset Analysis for Overall Survival - Study M18-004 
 
(Ref 27) 
 
Figure 14 shows the results for overall survival with additional follow-up for both groups of 
subjects. 


 
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Figure 14: 
Overall Survival for Subjects with Continuous and Truncated 
Demcizumab (DEM) Dosing - Study M18-004 
 
Data as of 8 December 2016 
 
Subjects were assessed for subsequent therapies after participation in M18-004.  Comparison of 
subjects who lived or did not live beyond 10 months did not reveal significant differences 
(Table 4). 


 
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Table 4: 
Subsequent Anti-Cancer Therapies for Subjects after Discontinuation 
from Study M18-004 
 
Continuous Demcizumab 
Truncated Demcizumab 
Alive <10 
mths 
(n=13) 
Alive ≥10 
mths 
(n=10) 
Alive <10 
mths 
(n=11) 
Alive ≥10 
mths 
(n=12) 
Ongoing 
0 
0 
0 
3 
No 2
nd-line treatment 
5 
5 
10 
6 
2
nd-line treatment unknown 
7 
1 
1 
0 
2
nd-line chemotherapy 
0 
3 
0 
3 
2
nd-line checkpoint inhibitor 
0 
0 
0 
0 
2
nd-line ALK inhibitor 
0 
0 
0 
0 
2
nd-line EGFR inhibitor 
1 
1 
0 
0 
3
rd line EGFR inhibitor 
0 
1 
0 
0 
3
rd- line chemotherapy 
0 
2 
0 
0 
4
th-line checkpoint inhibitor 
0 
1 
0 
0 
 
Twelve of the 23 subjects receiving truncated demcizumab had tumor tissue available for further 
analyses.  Figure 15 shows the exploratory overall survival analysis for several immune 
biomarkers. 


 
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Figure 15: 
Exploratory Overall Survival Analysis for Immune Biomarkers - 
Study M18-004 
 
TILs = tumor-infiltrating lymphocytes. FFPE tumors from truncated patients were evaluated for % immune 
cells/tumor area, % TILs/tumor area, % PDL-1 positivity (membrane plus cytoplasm) on infiltrating immune 
cells and % PDL-1 positivity on tumor cells (Ref 28). 
 
In summary, two separate cohorts of M18-004 subjects (continuous versus truncated 
demcizumab dosing) showed prolonged survival tails on the Kaplan-Meier curves, and these tails 
persisted regardless of associated demographic or laboratory parameters.  The exploratory 
analysis of available tumor tissue demonstrated that a high number of tumor-infiltrating 
lymphocytes was associated with long-term survival, suggesting that immunomodulatory 
mechanisms may contribute to the observed subject benefit. 
3.4.2.2 
Phase 1b Safety Data 
The treatment-emergent adverse events (AEs) in the 3 Phase 1b studies and the 1 Phase 1b/2 
study considered to be related or possibly related to demcizumab by the Investigators and that 
occurred in >10 % of subjects were fatigue (45.5%), nausea (41.4%), hypertension/blood 
pressure increased (32.3%), vomiting (26.3%), edema peripheral (21.2%), diarrhea (22.2%), 
appetite decreased (18.2%), increased BNP (17.2%),  anemia (15.2%), thrombocytopenia 
(15.2%), neutropenia (14.1%), dyspnea (12.1%), headache (11,1%), pulmonary hypertension 
(11.1%), constipation (10.1%), and rash (10.1%). 


 
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The Grade 3-5 treatment-emergent AEs considered to be related to demcizumab that occurred in 
>5% of subjects were neutropenia (27.2%), hypertension/blood pressure increased (16.2%) and 
thrombocytopenia (7.1%). 
While subjects were being dosed in the first cohorts of the Phase 1b studies (M18-002, M18-003 
and M18-004), some subjects in the Phase 1a single-agent study (M18-001) developed 
congestive heart failure, and, thus, the enrollment and treatment of subjects in the first dose 
cohort of the Phase 1b trials was stopped while the data for the subjects with congestive heart 
failure were analyzed.  A decision was made to close study M18-003, but, subsequently, 
enrollment was resumed in studies M18-002 and M18-004 after the protocols were amended to 
include the following changes: 1) modified demcizumab dosing approach to include less frequent 
and lower doses; 2) standard bed-side Alere Triage BNP testing, 3) exclusion of subjects with a 
screening BNP of >100 pg/mL, 4) exclusion of subjects with a left ventricular ejection fraction 
(LVEF) of <50% or with pulmonary hypertension defined as a peak tricuspid velocity >3.4 m/s 
on Doppler echocardiogram, and 5) implementation of a dosing risk mitigation strategy 
including the administration of a cardioprotective agent (ACE inhibitor or carvedilol) to subjects 
with one BNP value >200 pg/mL or two values >100 pg/mL.  As 3 subjects in the 2 ongoing 
Phase 1b studies (M18-002 and M18-004) subsequently developed pulmonary hypertension 
and/or heart failure between Days 168-184, further modifications were made including the 
utilization of truncated dosing with the last dose of demcizumab being administered on Day 63 
in the NSCLC trial and on Day 70 in the pancreatic cancer trial.  The use of truncated dosing 
allowed for washout of the drug prior to the timeframe when cardiopulmonary events had been 
observed.  The utilization of truncated demcizumab dosing and further modifications of the risk 
mitigation strategy have resulted in none of the subsequent 51 subjects developing Grade >2 
pulmonary hypertension or heart failure; i.e., only 1 subject has developed Grade 1 
asymptomatic pulmonary hypertension, and none have developed heart failure. 
These data demonstrate that the risk mitigation strategy that was employed in the Phase 1b 
studies was successful in preventing any clinically significant cases of pulmonary hypertension 
or heart failure.   
3.5 
Dose Rationale 
In the Phase 1b study of demcizumab, pemetrexed and carboplatin in 1st-line non-squamous 
NSCLC subjects (study M18-004), subjects in the 1st 4 dose cohorts received demcizumab doses 
of either 2.5 or 5 mg/kg once every 3 weeks until disease progression.  As 2 of these subjects 
developed Grade 3 pulmonary hypertension and heart failure at approximately Day 168, the 
20 subjects in the subsequent 3 cohorts received a truncated dosing regimen (i.e., 4 doses over 
63 days) of either 5 or 7.5 mg/kg once every 3 weeks.  Whereas no cases of Grade 2 pulmonary 
hypertension or heart failure were observed in any of these subjects, the data safety monitoring 
board (DSMB) for the study felt that the BNP and peak tricuspid velocity data of subjects in the 
7.5 mg/kg cohort suggested that the dose may be too high and thus recommended that the 
truncated dosing regimen of 5 mg/kg once every 3 weeks be used for the Phase 2 study.  Subjects 
in the 3rd arm of this study will receive 2 truncated courses of demcizumab at 5 mg/kg once 


 
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every 3 weeks (one from Days 0-63 and one from Days 168-231).  Only subjects who, on 
Day 168,  meet the original cardiac-related eligibility criteria (Exclusion Criterion 21 in 
Section 6.2), who did not develop pulmonary hypertension or heart failure while on study, and 
for whom blood pressure is controlled to ≤140/90 mmHg will receive the 2nd truncated course of 
demcizumab in this arm of the study.  This arm was included in the study to determine if a 
second truncated course of demcizumab can enhance efficacy compared to a single truncated 
course of demcizumab.  Whereas the demcizumab regimen of the 3rd arm was not directly tested 
in the supporting Phase 1b program, the risk/benefit ratio for subjects in this arm is deemed 
acceptable, since the truncated dosing regimen has demonstrated an excellent safety profile, 
cardiac-related demcizumab toxicity appears reversible, subjects have to meet stringent criteria 
for the second course of demcizumab, and investigators, in addition, will be able to make an 
overall risk assessment based on how a subject fared during the first course of 
demcizumab/placebo.  Furthermore, the DSMB for this study (see Section 14.0) will be 
monitoring the emerging safety data very closely to ensure that this approach is safe for 
continued use in the trial. 
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. 
4.0 
STUDY OBJECTIVES AND ENDPOINTS 
4.1 
Study Objectives 
All objectives apply to the study population of subjects with 1st-line stage IV non-squamous non-
small cell lung cancer (NSCLC). 
Primary Objective: 
 To compare the efficacy of Arm 1 to Arm 2 and Arm 3 combined 
Secondary Objectives: 
 To compare the safety of Arm 1 to Arm 2 and Arm 1 to Arm 3  
 To determine the rate of immunogenicity against demcizumab when combined with 
carboplatin and pemetrexed  
 To determine population pharmacokinetics of demcizumab when combined with carboplatin 
and pemetrexed  


 
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Exploratory Objective: 
 To compare the exploratory pharamacodynamics (PD) and predictive biomarkers, such as 
DLL4 tumor expression, in Arm 1 to Arm 2 and Arm 3 combined 
4.2 
Endpoints 
All endpoints apply to the study population of subjects with 1st-line stage IV non-squamous non-
small cell lung cancer (NSCLC). 
Primary Endpoint 
 To compare the Investigator-assessed RECIST v1.1 response rate (unconfirmed) in Arm 1 to 
Arm 2 and Arm 3 combined 
Secondary Endpoints 
 To compare the Investigator-assessed RECIST v1.1 clinical benefit rate (i.e., the rate of 
complete response + partial response + stable disease, all unconfirmed) in Arm 1 to Arm 2 
and Arm 3 combined 
 To compare the hazard of progression using the Investigator-assessed progression-free 
survival time as assessed by RECIST v1.1 in Arm 1 to Arm 2 and Arm 3 combined 
 To compare the Investigator-assessed progression-free survival at 6 months in Arm 1 to Arm 
2 and Arm 3 combined 
 To compare the median survival in Arm 1 to Arm 2 and Arm 3 combined 
 To compare the Independent-Review-Facility-assessed RECIST v1.1 response rate and 
progression-free survival based solely on radiographs in Arm 1 to Arm 2 and Arm 3 
combined (optional) 
 To determine the half-life, volume of distribution and clearance of demcizumab when 
combined with carboplatin and pemetrexed 
 To compare the safety profile through adverse event (AE) monitoring (including attribution 
of AEs and serious adverse events [SAEs]), physical examination, vital signs, and clinical 
laboratory testing as outlined in the Schedule of Assessments (see Appendix A) between 
Arm 1 to Arm 2 and Arm 1 to Arm 3  
 To determine the incidence of anti-demcizumab antibody development and neutralizing 
antibody development in Arms 2 and 3 
Exploratory Endpoints 
 To compare the pharmacodynamics (PD) and predictive biomarkers for demcizumab and 
determine their correlation with response in Arm 1 to Arm 2 and Arm 3 combined (see 
Section 11.0). 


 
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5.0 
OVERALL STUDY DESIGN AND PLAN – DESCRIPTION 
This is a randomized, double-blind, 3-arm (1:1:1) study in subjects with first-line Stage IV non-
squamous NSCLC.  Following determination of study eligibility, at least two-hundred and one 
subjects were to be randomized via an IWRS system to one of three arms (Figure 16).  Subjects 
will be stratified according to smoking status (current versus former or never) and region 
(Australia/Europe versus North America).  After randomization of 82 subjects, enrollment was 
discontinued due to significant difficulties in reaching the projected total subject number in a 
reasonable timeframe. 
Figure 16: 
Three-Arm Design of Study M18-007 
 
 
Demcizumab (5 mg/kg) or placebo will be administered once every 21 days for a total of 
4 cycles (i.e., last administration on Day 63).  Subjects will only receive their second 4-cycle 
course (starting on Day 168) of demcizumab (5 mg/kg) or placebo if they meet the original 
cardiac-related eligibility criteria (see Exclusion Criterion 21 in Section 6.2), they did not 
develop pulmonary hypertension or heart failure while on study, and blood pressure is controlled 
to ≤140/90 mmHg. Subjects who do not meet the criteria to receive the second 4-cycle course of 
placebo or demcizumab will continue to receive maintenance pemetrexed per protocol without 
demcizumab or placebo. 


 
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Pemetrexed (500 mg/m2) and carboplatin (area under the concentration-time curve of 6 mg/mL 
x min) will be administered once every 21 days for a total of 4 cycles (or until toxicity 
necessitates reducing or holding a dose or terminating treatment).  The maintenance pemetrexed 
(500 mg/m2) will be given once every three weeks starting at Day 84. 
On days of study drug administration, demcizumab or placebo, if applicable, will be 
administered first, followed by the administration of pemetrexed and then carboplatin (if 
applicable).  To reduce gastrointestinal and hematologic toxicity, subjects must receive oral folic 
acid of ≥400 µg daily for at least 5 of the 7 days preceding the first dose of pemetrexed and 
continuing daily during the full course of therapy and for 21 days after the last dose of 
pemetrexed.  Subjects must also receive an intramuscular injection of vitamin B12 1000 µg 
during the week preceding the first dose of pemetrexed and then every 63 days while being 
treated with pemetrexed.  Unless contraindicated, subjects should also receive dexamethasone 
4 mg orally twice daily on the day before, the day of, and the day after pemetrexed 
administration to reduce the risk of developing skin rash. 
Subjects will be assessed for AEs as outlined in Section 9.1 at every visit and through 30 days 
following the termination visit.  AEs will be graded according to NCI CTCAE, version 
4.03 (v4.03).    
Plasma samples for PK analysis will be obtained prior to the demcizumab (or placebo) infusion 
on Days 0, 42, 84, 126, 168, 210, 252, 294 and 336, and at the end of the demcizumab (or 
placebo) infusion (prior to pemetrexed infusion, if applicable) on Days 0, 42, 168 and 210, and at 
the termination visit.  Immunogenicity will be assessed at baseline, every 6 weeks during the 
study, and at the termination visit.  Blood biomarker assessment will be performed at Study Days 
0 and 28, and at the termination visit. 
Disease status will be assessed using RECIST v1.1, and subjects will undergo tumor assessments 
during screening, every 6 weeks while on study and at the termination visit (unless performed 
within 14 days of termination or at a prior response evaluation that documented progressive 
disease).   
In the absence of unacceptable toxicities or disease progression per RECIST v1.1, subjects 
should continue to receive study treatment.  Regardless of discontinuation of one, two or all 
three study drugs, subjects should continue on study with assessments as outlined in 
Section 12 and Appendix A.  Once discontinuation criteria for the study are met (disease 
progression, use of other anti-cancer therapy, subject or investigator decision or protocol non-
compliance, see Section 7.0), a termination visit should occur ≤14 days later.  The termination 
visit may occur later after discussion with the OncoMed Medical Monitor for specific 
circumstances, such as prolonged hospitalization. After the termination visit, subjects should 
have regular follow-up for survival, subsequent anti-cancer therapies and other assessments as 
required per protocol (see Section 12.4).  Figure 17 illustrates the two main periods of the study 
(on study and follow-up), before and after the termination visit. 


 
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Figure 17: 
Two Main Periods (On Study and Follow-up) of Study M18-007 
 
Note: A subject who has discontinued all three study drugs (example at left bottom, discontinued study drugs 
indicated by ‘Ø’) should continue with the on-study part of the protocol with assessments as outlined in 
Section 12.0 and Appendix A. 
 
Study procedures and assessments are further detailed in Appendix A. 


 
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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. Signed Informed Consent Form 
2. Histologically or cytologically confirmed Stage IV non-squamous NSCLC 
 Stage IV as defined by the International Association for the Study of Lung Cancer 
International Staging Committee (Ref 29) and adopted by the American Joint 
Committee on Cancer (AJCC) and the Union Internationale Contre le Cancer (UICC) in 
the 7th edition of the lung cancer TMN classification and staging system (Ref 30, Ref 31)   
3. If available, agreement to provide archival FFPE tumor tissue (obtained by core biopsy or 
surgical resection) for exploratory biomarker analyses 
 FFPE tumor tissue may originate from either the primary tumor, locoregional disease or 
a metastatic site 
 Availability of FFPE tumor tissue is not mandatory for participation in this study 
4. Age >21 years 
5. ECOG performance status of 0 or 1 (see Appendix B) 
6. Disease that is measurable per RECIST v1.1 (Appendix C) 
7. Adequate organ and marrow function as defined below: 
 Absolute neutrophil count >1.5 x 109/L (without granulocyte colony-stimulating factor 
support within 2 weeks prior to randomization) 
 Hemoglobin >100 g/L (without transfusion within 2 weeks prior to randomization) 
 Platelets >125 x 109/L (without transfusion within 2 weeks prior to randomization) 
 Total bilirubin <2 x  institutional upper limit of normal (ULN) 
 Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) 
<5 x institutional ULN 
 Alkaline phosphatase < 5 x institutional ULN 
 International normalized ratio (INR) <1.5 and activated partial thromboplastin time 
(aPTT) within 1.5 x institutional ULN 
 Albumin  3 g/dL 


 
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 Calculated creatinine clearance ≥60 mL/min using the Cockcroft and Gault formula as 
follows: 
Creatinine clearance (mL/min) = (140 – age [years]) x actual body weight [kg] 
 
 
 
 
 
         0.814 x serum creatinine [µmol/L] 
For women, multiply the value from the equation above by 0.85. 
8. For women of childbearing potential and men with partners of childbearing potential, 
agreement (by subject and/or partner) to use two effective forms of contraception from study 
entry through at least 6 months after the termination visit.  
 Women of childbearing potential are those women who have not been permanently 
sterilized or are not postmenopausal.  Postmenopausal is defined as 12 months with no 
menses without an alternative medical cause. 
 Highly effective methods of birth control include those that result in a low failure rate 
(i.e., less than 1% per year) when used consistently and correctly, such as implants, 
injectables, combined oral contraceptives, levonorgestrel-releasing intrauterine system, 
intra-uterine devices (IUDs), vasectomized partner, and true sexual abstinence. 
6.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will not be eligible for participation in the study: 
1. Histologically or cytologically documented, advanced, mixed non-small cell and small cell 
tumors or mixed adenosquamous carcinomas 
2. NSCLC with EGFR mutation or anaplastic lymphoma kinase (ALK) gene translocation (such 
as EML4-ALK) 
 Negative results for these genetic aberrations, as determined by local assessments, must 
be documented in order for a subject to be eligible. 
3. Prior or ongoing therapy (including chemotherapy, antibody therapy, tyrosine kinase 
inhibitors, radiotherapy, immunotherapy, hormonal therapy, or investigational therapy) for 
the treatment of Stage IV non-squamous NSCLC 
 Subjects who received prior adjuvant chemotherapy or radiotherapy for non-squamous 
NSCLC are allowed if the time interval from completion of adjuvant therapy until 
evidence of metastatic disease is 12 months. 
 Subjects who underwent NSCLC resection with curative intent and were subsequently 
diagnosed with metastatic disease are allowed regardless of time interval between 
resection and metastatic disease. 
 Subjects with locally recurrent disease only are not allowed.  


 
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 Subjects who received prior palliative radiotherapy for metastatic or lobar lesions (not 
including target lesions) are not excluded (if >2 weeks prior to randomization). 
 Chronic use of bisphosphonate or denosumab therapy is allowed. 
4. Evidence of tumor invading major blood vessels on imaging 
 The investigator or the local radiologist must exclude evidence of tumor that is fully 
contiguous with, surrounding, or extending into the lumen of a major blood vessel 
(e.g., pulmonary artery or superior vena cava). 
5. Evidence of cavitation of one or more pulmonary tumor mass(es) 
6. Evidence of a tracheo-esophageal fistula 
7. Brain metastases (subjects must have an MRI of the brain, or CT scan with IV contrast, on or 
after Study Day -28 and prior to randomization, to rule out brain metastases) 
8. Uncontrolled seizure disorder or active neurologic disease 
9. Leptomeningeal disease 
10. Metastases involving the lumen of the gastrointestinal tract 
 Colonoscopy and/or upper gastrointestinal endoscopy must be performed in subjects with 
symptoms suggestive of possible gastrointestinal involvement to rule out gastrointestinal 
involvement. 
11. Malignancies, other than non-squamous NSCLC, successfully treated within 3 years prior to 
randomization, except for adequately treated carcinoma in situ of the cervix, basal or 
squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, 
adequately treated low-stage bladder cancer and ductal carcinoma in situ treated surgically 
with curative intent 
12. Prior radiation to the chest wall or mediastinum if the radiation field involved the heart 
13. History of a significant allergic reaction attributed to humanized or human monoclonal 
antibody therapy 
14. Recent (within the last 8 weeks prior to randomization) hemoptysis >2.5 mL or serious 
bleeding from another site within this timeframe 
15. Known bleeding disorder or coagulopathy 
16. Therapeutic anti-coagulation with heparin, warfarin, or other anticoagulants 
 Low-dose aspirin and/or non-steroidal anti-inflammatory agents are allowed. 


 
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 Use of thrombolytics to establish patency of indwelling venous catheters is allowed. 
 Prophylactic anticoagulation for venous access devices is allowed as long as INR is 
1.5 and aPTT 1.5  institutional ULN. 
17. History of cerebral vascular accident (CVA) or transient ischemic attacks (TIAs) within 6 
months of randomization 
18. Clinically significant arterial aneurysm 
19. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to 
randomization, or anticipation of need for major surgical procedure during the course of the 
study 
 Placement of vascular access device will not be considered major surgery. 
20. Blood pressure (BP) of >140/90 mmHg.  The BP should be taken using the methods 
described in Section 9.3.  Subjects taking antihypertensive medications must be taking 
≤2 medications to obtain this level of BP control. 
21. Any of the following cardiac-related criteria: 
 B-type natriuretic peptide (BNP) value of >100 pg/mL 
 Left ventricular ejection fraction (LVEF) <50% 
 Peak tricuspid velocity >3.0 m/s on Doppler echocardiogram 
 Receiving any medications for cardiac ischemia 
 Current evidence of cardiac ischemia 
 History of acute myocardial infarction within 6 months prior to randomization 
 New York Heart Association Classification II, III, or IV (See Appendix D) 
o For subjects to meet class II criteria with mild shortness of breath and/or angina, as 
defined by the NYHA guidelines, the cardiac etiology of the symptoms should be 
confirmed by a cardiologist taking 12-lead electrocardiogram, transthoracic Doppler 
echocardiogram and other studies into consideration, as appropriate. 
 Heart failure within the last 6 months prior to randomization 
 Received a total cumulative dose of ≥400 mg/m2 doxorubicin 
 Grade ≥2 ventricular arrhythmia 
22. History of interstitial lung disease or pneumonitis that required oral or intravenous 
corticosteroids 
23. Active infection requiring antibiotics 


 
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24. Known HIV infection 
25. Pregnancy or nursing 
26. Significant intercurrent illness defined as an illness that may result in the subject’s death 
prior to death from non-squamous NSCLC and/or significantly limit the ability to comply 
with the requirements of this study 
27. Inability to comply with study and follow-up procedures 
7.0 
REMOVAL OF SUBJECTS FROM ON-STUDY PART OF PROTOCOL 
Subjects must be withdrawn from the on-study part of the protocol (see Section 12.2 and 
Appendix A) for the following reasons: 
– Disease progression according to RECIST v1.1 
– Use of other anti-cancer therapy 
– Subject decision 
– Investigator decision based on subject’s best interest 
– Significant protocol non-compliance by subject 
Subjects who meet one of the above criteria will undergo the termination evaluations for the 
study (see Section 12.3).  After the termination visit, subjects will have regular follow-up for 
survival and other assessments as required per protocol (see Section 12.4). 
If a subject has permanently discontinued one, two or all study drugs due to toxicities or any 
other reasons, the subject should continue with the on-study part of the protocol until one of the 
above criteria is met. Subjects who have discontinued one, two or all study drugs and continue 
with the on-study part should have assessments performed as outlined in Section 12.2  and 
Appendix A. 
8.0 
STUDY TREATMENTS 
8.1 
Study Drug (Demcizumab or Placebo) 
8.1.1 
Administration 
Study drug (demcizumab at 5 mg/kg or placebo) will be administered once every 3 weeks for 
4 cycles (i.e., last administration on Day 63).  A second course of study drug (demcizumab at 
5 mg/kg or placebo) will be administered once every 3 weeks for 63 days starting at Day 168 
only if the criteria outlined in Section 5.0 are met.  No dose reductions of demcizumab/placebo 
are allowed (see Section 8.1.6 for required modifications of demcizumab/placebo dosing). 
The demcizumab or placebo dose should be based on the Day 0 weight throughout the study, 
unless the weight changes by >10%.  Study drug must be delivered as an intravenous infusion 
over 30 (+5) minutes prior to the administration of pemetrexed and carboplatin, if applicable.  


 
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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. 
If an infusion reaction occurs, the infusion must be stopped and any appropriate medical care 
administered (see Section 8.1.7).  Once the infusion reaction has resolved, and at the discretion 
of the Investigator, the infusion may be resumed 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.   
Study drug should not be held for chemotherapy-induced toxicity, such as hematologic toxicity.  
The Investigator should contact the OncoMed Medical Monitor if he/she wishes to hold 
demcizumab or placebo therapy for what is believed to be chemotherapy-induced toxicity.  
If demcizumab/placebo cannot be administered within the specified time window of ±2 days (see 
Appendix A) for demcizumab/placebo-related (see Section 8.1.6) or other reasons, the missed 
dose cannot be administered at a later time point. Instead, no demcizumab/placebo is to be 
administered until the next scheduled dose (Figure 18). 
Figure 18: 
Approach to Demcizumab/Placebo Dosing 
 
D/P = demcizumab/placebo; Ø = demcizumab/placebo dose that was missed for demcizumab/placebo-related or 
other reasons and that is not to be administered at a later time point. 
A) shows the schedule of demcizumab/placebo administrations without any missed doses. The time window for 
demcizumab/placebo dosing is ±2 days. 
B) provides an example for a missed demcizumab/placebo administration during the first course of 
demcizumab/placebo. 
C) illustrates a missed demcizumab/placebo administration during the second course of demcizumab/placebo.  


 
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8.1.2 
Description 
Demcizumab is an IgG2 humanized monoclonal antibody that is directed against the Delta-Like 
Ligand 4 (DLL4). 
Demcizumab is supplied at a concentration of 10 mg/mL in a 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 50 mM 
Histidine, 100 mM Sodium Chloride, 45 mM Sucrose and 0.01% (v/v) Polysorbate-20, pH 6.0. 
All investigational products should be kept in a secure area inaccessible to unauthorized 
individuals.   
8.1.3 
Packaging 
Labeling of demcizumab or placebo vials and cartons will comply with all applicable 
regulations. 
8.1.4 
Drug Ordering, Storage, and Accountability 
The instructions for drug ordering via the IWRS are provided in the Pharmacy Binder.  
Demcizumab or placebo vials must be refrigerated at 2°C–8°C.  Demcizumab or placebo must 
not be shaken or frozen.  An accurate demcizumab or placebo accountability log must be 
maintained and kept up to date at all times. Perforated labels on blinded study drug vials must be 
retained for review for drug accountability purposes. 
8.1.5 
Drug Preparation 
Demcizumab or placebo should be diluted for infusion using aseptic technique.  Withdraw the 
necessary amount of demcizumab or placebo 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 demcizumab or placebo solutions may be stored at room temperature (19°C–25°C) 
for up to 4 hours.   


 
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8.1.6 
Treatment Modification and Termination Criteria for Demcizumab/Placebo 
Results for B-type natriuretic peptide (BNP) are one of the important monitoring tools, and they 
are used to decide on the following: 
 Unblind a subject 
 Hold demcizumab/placebo 
 Discontinue demcizumab/placebo 
Results for peak tricuspid velocity (PTV) obtained by Doppler echocardiogram are a second 
important monitoring tool, and they are used to decide on the following: 
 Initiate work-up for clinically significant pulmonary hypertension 
Subjects with any of the following findings will have their treatment unblinded by the 
Investigator through the IWRS system: 
 Two BNP values >100 pg/mL at consecutive scheduled BNP assessments (i.e. 21 days apart) 
 One BNP value ≥200 pg/mL (e.g. 287, 315 or 459) 
The unblinding information should be limited to the smallest number of site team members 
feasible, ideally to the principal investigator or treating physician only.  Assuming criteria for 
continued demcizumab/placebo dosing are met, dosing for both demicuzmab and placebo should 
continue as scheduled.  Any BNP value >100 pg/ml does not trigger more frequent BNP 
assessments. BNP assessments should continue to be obtained as scheduled. 
If the subject is receiving demcizumab, the subject will be started on a cardioprotective agent, 
either an ACE inhibitor or the β-blocker carvedilol, unless the BNP elevation occurred more than 
100 days after the discontinuation of demcizumab or there is a contraindication to the use of 
these agents.  If deemed necessary and appropriate, the subject should also be evaluated by a 
cardiologist.  The selection and dose of the ACE inhibitor to be administered or the dose of 
carvedilol to be administered should be based on the recommendations in standard guidelines for 
treating heart failure (Ref 32).  Carvedilol is the only option for the drug class of β-blockers.  If 
there are contraindications for both ACE inhibitors and carvedilol, the subject’s treatment should 
be discussed with the OncoMed Medical Monitor. 
If the subject is not on demcizumab, the subject should be cared for according to standard 
medical practice. 
For BNP values <300 pg/mL, demcizumab/placebo should be continued as per protocol. 
Chemotherapy should be continued as well, unless contraindicated. 


 
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Subjects with any of the following findings must have their dose of demcizumab or placebo held, 
regardless of relationship to demcizumab or placebo: 
 BNP ≥300 pg/mL  
 LVEF decline ≥10% from baseline and LVEF <50% (for example from 55% to 45%) 
 Clinically significant pulmonary hypertension (i.e.,  peak tricuspid velocity >3.4 m/s on 
Doppler echocardiogram and diagnosed with clinically significant pulmonary hypertension 
that includes minimal dyspnea by a cardiologist or pulmonologist) 
 Signs and symptoms of heart failure 
Chemotherapy should be continued while demcizumab or placebo is being held, unless 
contraindicated. 
Dosing of demcizumab or placebo must continue to be held until the subject has: 
 BNP <300 pg/mL 
 LVEF decline <10% from baseline and LVEF ≥50% 
 No clinically significant pulmonary hypertension, and 
 No signs or symptoms of heart failure  
Subjects with any of the following findings must have demcizumab or placebo permanently 
discontinued, regardless of relationship to demcizumab or placebo: 
 BNP ≥300 pg/mL, LVEF decline ≥10% and LVEF <50%, signs or symptoms of heart failure 
or clinically significant pulmonary hypertension (i.e., peak tricuspid velocity >3.4 m/s on 
Doppler echocardiogram and diagnosed with clinically significant pulmonary hypertension 
that includes minimal dyspnea by a cardiologist or pulmonologist) that persists for 9 weeks 
 BNP ≥400 pg/mL 
 Grade ≥2 pulmonary hypertension 
 Grade ≥2 bronchopulmonary or gastrointestinal bleeding (except for readily manageable 
local bleeding, such as hemorrhoidal bleeding) 
 Hypertensive crisis 
 Hypertensive encephalopathy 
 Blood pressure 200/120 mmHg (i.e.both systolic and diastolic criteria are met), despite 
maximum treatment with at least three anti-hypertensive drugs 
 Need for therapeutic anti-coagulation 
o If therapeutic anti-coagulation is no longer required, the subject may receive the 
remaining demcizumab/placebo administrations, if any. 
Chemotherapy should be continued until disease progression, unless contraindicated. 


 
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8.1.7 
Infusion Reaction Management 
The administration of monoclonal antibodies may result in an infusion reaction that may consist 
of a symptom complex characterized by symptoms such as fever, chills, nausea, vomiting, 
headache, dizziness, bronchospasm, dyspnea, hypotension, and/or rash including urticaria.  
Subjects experiencing a Grade 2 infusion reaction of dyspnea (asymptomatic bronchospasm) or 
generalized urticaria should be premedicated prior to subsequent demcizumab or placebo 
infusions.  Premedications may include medications such as corticosteroids, diphenhydramine, 
and/or bronchodialators as indicated.  If the Grade 2 allergic reaction recurs during subsequent 
infusions despite the premedications, the subject should be removed from treatment.  In addition, 
demcizumab or placebo therapy should be permanently discontinued in any subject who 
experiences a Grade 3 or 4 acute allergic reaction (e.g., symptomatic bronchospasm with or 
without urticaria, edema, angioedema, or hypotension).  Grade 3/4 acute allergic reactions should 
be medically managed as appropriate and treatment may include the administration of 
epinephrine, corticosteroids, diphenhydramine, bronchodialators, and/or oxygen as indicated. 
8.2 
Pemetrexed 
Subjects taking NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days 
following pemetrexed administration.  If concomitant administration of an NSAID is necessary, 
subjects should be monitored closely for toxicity, especially myelosuppression and renal and 
gastrointestinal toxicity. 
8.2.1 
Administration 
Pemetrexed at 500 mg/m2 should be administered as an intravenous infusion over ≥10 minutes 
once every 21 days.  Adjustments of dosing due to weight changes of the subject should be made 
according to local standards or guidelines. Pemetrexed must be administered after the 
administration of demcizumab/placebo, if applicable.  Pemetrexed will be administered for the 
first 4 cycles with carboplatin (or less than 4 full cycles if disease progression or toxicity 
warrants treatment interruption or termination).  Starting with Cycle 5, subjects should continue 
to receive pemetrexed without carboplatin once every 21 days until disease progression.  The 
administration of pemetrexed should not be held if demcizumab/placebo needs to be held or 
discontinued.   
8.2.2 
Description 
Pemetrexed is a multitargeted anti-folate agent. Pemetrexed disodium heptahydrate has the 
chemical name L-Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-
d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate. 
8.2.3 
Storage 
Pemetrexed must be stored at controlled room temperature at 25°C. 


 
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8.2.4 
Packaging 
The labeling of pemetrexed will comply with all applicable regulations. 
8.2.5 
Vitamin Supplementation and Dexamethasone Administration 
To reduce gastrointestinal and hematologic toxicity, subjects must receive oral folic acid of 
≥400 µg daily for at least 5 of the 7 days preceding the first dose of pemetrexed and continuing 
daily during the full course of therapy and for 21 days after the last dose of pemetrexed.  
Subjects must also receive an intramuscular injection of vitamin B12 1000 µg during the week 
preceding the first dose of pemetrexed and then every 63 days while being treated with 
pemetrexed. 
Unless contraindicated, subjects should also receive dexamethasone 4 mg orally twice daily on 
the day before, the day of, and the day after pemetrexed administration to reduce skin rash. 
8.2.6 
Renally Impaired Subjects 
Pemetrexed cannot be administered concurrently with nonsteroidal anti-inflammatory drugs 
(NSAIDs) to subjects whose calculated creatinine clearance is <80 mL/min.  Pemetrexed must be 
discontinued if a subject’s calculated creatinine clearance is <45 mL/min using the standard 
Cockcroft and Gault formula (see below) or GFR measured by Tc99m-DPTA serum clearance 
method: 
Creatinine clearance (mL/min) =  
(140 - age [years]) x actual body weight [kg] 
 
 
 
 
 
 
0.814 x serum creatinine [µmol/L] 
For women, multiply the value from the equation above by 0.85. 
8.2.7 
Preparation and Administration Precautions 
As with other potentially toxic anticancer agents, care should be exercised in the handling and 
preparation of infusion solutions of pemetrexed.  The use of gloves is recommended.  If a 
solution of pemetrexed contacts the skin, wash the skin immediately and thoroughly with soap 
and water.  If pemetrexed contacts the mucous membranes, flush thoroughly with water.  Several 
published guidelines for the handling and disposal of anticancer agents are available. 
Pemetrexed is not a vesicant.  There is no specific antidote for extravasation of pemetrexed.  
To date, there have been few reported cases of pemetrexed extravasation, none of which were 
assessed as serious by the investigator.  Pemetrexed extravasation should be managed with local 
standard practice for extravasation as with other non-vesicants. 
8.2.8 
Preparation for Intravenous Infusion Administration 
Pemetrexed for injection is a white to either light-yellow or green-yellow lyophilized powder 
available in sterile single-use vials containing 100 mg or 500 mg pemetrexed. 


 
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Reconstitute each 100-mg vial with 4.2 mL of 0.9% Sodium Chloride Injection (preservative 
free).  Reconstitute each 500-mg vial with 20 mL of 0.9% Sodium Chloride Injection 
(preservative free).  Reconstitution of either size vial gives a solution containing 25 mg/mL 
pemetrexed.  Gently swirl each vial until the powder is completely dissolved.  The resulting 
solution is clear and ranges in color from colorless to yellow or green-yellow without adversely 
affecting product quality. 
The appropriate quantity of the reconstituted pemetrexed solution must be further diluted into a 
solution of 0.9% Sodium Chloride Injection (preservative free), so that the total volume of 
solution is 100 mL.  Pemetrexed is administered as an IV infusion over 10 minutes. 
Stability of reconstituted and infusion solutions of pemetrexed were demonstrated for up to 
24 hours following initial reconstitution, when stored at refrigerated or ambient room 
temperature and lighting.  Discard any unused portion. 
Pemetrexed is physically incompatible with diluents containing calcium, including Lactated 
Ringer’s Injection, USP, and Ringer’s Injection, USP, and therefore, these diluents should not be 
used. 
Please refer to the approved prescribing information for additional information on the 
preparation for pemetrexed. 
8.3 
Carboplatin 
8.3.1 
Administration 
Carboplatin at 6 mg/mL x min should be administered as an intravenous infusion over 15 to 
60 minutes once every 21 days for 4 cycles (or less than 4 full cycles if disease progression or 
toxicity warrants treatment interruption or termination).  Calculation of the carboplatin dose of 
6 mg/mL x min may be done according to local standards or guidelines, or as outlined below.  
Adjustments of dosing due to weight changes of the subject should be made according to local 
standards or guidelines.  The administration of the carboplatin should not be held if 
demcizumab/placebo needs to be held or discontinued.   
Demcizumab or placebo must be administered first, followed by pemetrexed and then 
immediately afterwards carboplatin.  The dose of carboplatin in mg should be calculated by 
using the following formula: 
Carboplatin Dose (mg) = 6 mg/mL x min x [CrCl (mL/min) +25) 
Note:  carboplatin dose calculated using the formula above is in mg not mg/m2
. 


 
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The calculated creatinine clearance (CrCl) should be determined by using the Cockcroft and 
Gault formula as follows: 
Creatinine clearance (mL/min) =  
(140 - age [years]) x ideal body weight [kg] 
 
 
 
 
 
       0.814 x serum creatinine [µmol/L] 
For women, multiply the value from the equation above by 0.85. 
The ideal body weight for use in the Cockcroft and Gault formula should be determined 
as follows: 
– Men:  50 + [(Height [cm] -154) x 0.9]  
– Women:  45.5 + [(Height [cm] -154) x 0.9] 
Carboplatin is a premixed aqueous solution of 10 mg/mL carboplatin.  Carboplatin aqueous 
solution can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water 
(D5W) or 0.9% Sodium Chloride Injection, USP.  When prepared as directed, carboplatin 
aqueous solutions are stable for 8 hours at room temperature (25°C).  Since no antibacterial 
preservative is contained in the formulation, it is recommended that carboplatin aqueous 
solutions be discarded 8 hours after dilution. 
NOTE:  Aluminum reacts with carboplatin causing precipitate formation and loss of 
potency; therefore, needles or intravenous sets containing aluminum parts that may come 
in contact with the drug must not be used for the preparation or administration of 
carboplatin. 
Please refer to the approved prescribing information for additional information on the 
preparation for carboplatin. 
8.3.2 
Description 
Carboplatin produces predominantly interstrand DNA cross-links rather than DNA-protein cross-
links.  This effect is apparently cell-cycle nonspecific. 
8.3.3 
Storage 
Carboplatin must be stored at controlled room temperature at 25°C.  
8.3.4 
Packaging 
The labeling of carboplatin will comply with all applicable regulations. 
8.4 
Pemetrexed and Carboplatin Dose Modification/Treatment Delay 
As outlined in Section 8.1.6, demcizumab/placebo must be administered on a fixed schedule, and 
missed doses cannot be made up at a later timepoint.  In order to keep chemotherapy 
administrations synchronized with demcizumab/placebo, a similar approach may therefore be 
applied to chemotherapy with the difference that all four cycles of pemetrexed with carboplatin 


 
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should be administered.  Consequently, if pemetrexed and/or carboplatin cannot be administered 
within the specified time window for demcizumab/placebo of ±2 days (see Appendix A) for 
chemotherapy-related or other reasons, the missed dose(s) would then not be administered until 
the next scheduled administration of chemotherapy with or without demcizumab/placebo 
(Figure 19). 
Figure 19: 
Demcizumab-like Approach to Pemetrexed and Carboplatin Dosing 
 
D/P = demcizumab/placebo; P/C = pemetrexed plus carboplatin; P = pemetrexed; Ø = pemetrexed plus carboplatin 
or pemetrexed dose that was missed for chemotherapy-related or other reasons. 
A) shows the schedule of demcizumab/placebo, pemetrexed and carboplatin administrations without any missed 
doses.  
B) provides an example for a missed pemetrexed plus carboplatin administration during the first course of 
demcizumab/placebo. The missed doses of pemetrexed plus carboplatin should be administered on Day 84 
(‘P/C’ in bold) to ensure that the subject receives a total of four cycles of pemetrexed/carboplatin combination 
therapy. 
C) illustrates a missed pemetrexed administration during the second course of demcizumab/placebo. This missed 
dose is not made up at a later time point because of the general principle that chemotherapy should always be 
given on the same day as demcizumab/placebo. 
 


 
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Alternatively, the standard approach to chemotherapy administration may be used.  If 
pemetrexed and/or carboplatin cannot be administered within the specified time window for 
demcizumab/placebo of ±2 days (see Appendix A) for chemotherapy-related or other reasons, 
the missed dose(s) would then be administered when it is appropriate.  As a consequence, any 
subsequent demcizumab/placebo administrations will continue to be asynchronous with 
chemotherapy administrations (Figure 20).  After completion of demcizumab/placebo dosing on 
Day 63, pemetrexed cycles may then be extended to up to 4 weeks in order to synchronize 
pemetrexed administration with assessments with a fixed time window, such as tumor 
assessments. 
Figure 20: 
Standard Approach to Pemetrexed and Carboplatin Dosing 
 
D/P = demcizumab/placebo; P/C = pemetrexed plus carboplatin; P = pemetrexed 
A) shows the schedule of demcizumab/placebo, pemetrexed and carboplatin administrations without any missed 
doses.  
B) provides an example for a missed pemetrexed plus carboplatin administration during the first course of 
demcizumab/placebo. In the example, all missed doses of pemetrexed plus carboplatin are then administered 7 
days after demcizumab/placebo that continues to be administered during the protocol-specified time window. 
C) illustrates a missed pemetrexed administration during the second course of demcizumab/placebo. 
Examples B and C also show how 4-week chemotherapy cycles can be used to align chemotherapy administrations 
with other assessments. 
 


 
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The following are suggested guidelines for the management of specific toxicities expected to be 
related to pemetrexed and/or carboplatin.  These general guidelines may be modified at the 
discretion of the investigator based on local clinical practice and best clinical judgement at that 
time.  Any toxicities related to pemetrexed and/or carboplatin should be managed according to 
standard medical practice.  Dose reductions of carboplatin and pemetrexed are permanent.  Dose 
adjustments at the start of a cycle should be based on nadir hematologic counts (for 2nd and 3rd 
cycles of pemetrexed with carboplatin) or other nonhematologic toxicity from the preceding 
cycle of therapy.  Additional non-protocol-specified laboratory assessments should be obtained 
as guided by toxicities observed in prior cycles and per standard of care.  Treatment may be 
delayed to allow sufficient time for recovery.  Upon recovery, retreatment should be scheduled 
as outlined above (Figure 19 and Figure 20) using the criteria in Table 5, Table 6 and Table 7. 
Table 5: 
Dose Reduction for Pemetrexed and Carboplatin - Hematologic Toxicities 
Nadir ANC <500/mm3 and nadir platelets 
≥50,000/mm3 
75% of previous dose (pemetrexed and 
carboplatin) 
Nadir platelets <50,000/mm3 without bleeding 
regardless of nadir ANC 
75% of previous dose (pemetrexed and 
carboplatin) 
Nadir platelets <50,000/mm3 with Grade ≥2 bleeding 
from any site, regardless of nadir ANC 
50% of previous dose (pemetrexed and 
carboplatin) 
Nadir ANC <1,000/mm3 and fever ANC <°C 
(101°F), regardless of nadir platelets 
75% of previous dose (pemetrexed and 
carboplatin) 
 
If subjects develop Grade 3 or 4 nonhematologic toxicities, treatment should be delayed until 
resolution to less than or equal to the subject’s pre-therapy value.  Treatment should be resumed 
according to criteria in Table 6 and Table 7. 
Table 6: 
Dose Reduction for Pemetrexed and Carboplatin – Nonhematologic Toxicities 
 
Dose of Pemetrexed 
(mg/m2) 
Dose of Carboplatin 
(mg/m2) 
Any diarrhea requiring hospitalization 
(irrespective of Grade) or Grade 3 or 4 diarrhea 
75% of previous dose 
100% of previous dose 
Grade 3 or 4 mucositis 
50% of previous dose 
100% of previous dose 
Grade 3 or 4 nausea or vomiting 
100% of previous dose 
100% of previous dose 
Grade 3 transaminase elevation 
75% of previous dose 
75% of previous dose 
Grade 4 transaminase elevation 
Discontinue pemetrexed 
Discontinue carboplatin 
Any other Grade 3 or 4 toxicity (if deemed 
appropriate by the treating physician) 
75% of previous dose 
75% of previous dose 
 


 
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In the event of neurotoxicity, the recommended dose adjustments for pemetrexed and carboplatin 
are described in Table 7. 
Table 7: 
Dose Reduction for Pemetrexed and Carboplatin – Motor or Sensory 
Neurotoxicity 
CTCAE Grade 
Dose of Pemetrexed (mg/m2) 
Dose of Carboplatin (mg/m2) 
1 or 2 
100% of previous dose 
100% of previous dose 
3 or 4 
75% of previous dose 
75% of previous dose 
 
Any subject with 2 prior dose reductions who experiences a toxicity that would cause a third 
dose reduction should be discontinued from the chemotherapy agent assessed as the cause of the 
toxicity.  
8.5 
Anti-Emetics and Hematologic Supportive Care 
Antiemetic therapy and/or hematopoietic growth factors and/or red blood cell/platelet 
transfusions may be administered at the discretion of the Investigator. 
8.6 
Concomitant and Prohibited Therapy 
All concomitant medication administered from randomization through 30 days following the 
termination visit will be recorded on the Concomitant Medication remote data capture (RDC) 
screen.  
Investigational medicinal products and anticancer agents (e.g., cytotoxic agents, biologics, and 
hormonal agents with known activity against the subject’s specific tumor type) may not be 
administered from randomization through the termination visit.  However, subjects may have 
radiation or non-invasive surgical resection of a solitary non-target lesion for relief of significant 
signs or symptoms, such as pain or bleeding, in the absence of disease progression.  Such 
subjects will remain fully evaluable.  In addition, subjects who are receiving adjuvant hormonal 
therapy, such as tamoxifen for a history of breast cancer, may continue to receive this treatment.  
Previously initiated chronic bisphosphonate or denosumab therapy may be continued during 
study participation. Initiation of bisphosphonate or denosumab therapy during study treatment is 
not allowed. 
DVT prophylaxis during a hospitalization according to institutional standards is permitted.  
Should a medical condition require therapeutic anti-coagulation, demcizumab/placebo must be 
discontinued while therapeutic anti-coagulation is administered (see Section 8.1.6), and the 
subject should continue on study with continued pemetrexed/carboplatin administrations and 
regular assessments to ensure close follow-up.  


 
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Subjects treated for erectile dysfunction with a daily low dose of a phosphodiesterase type 5 
inhibitor may continue to receive this treatment as long as special attention is paid to the possible 
effects of phosphodiesterase type 5 inhibition on the cardiovascular system.  
8.7 
Treatment Compliance 
Demcizumab, placebo, carboplatin and pemetrexed 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 RDC screen.  In addition, drug accountability will 
be performed. 
9.0 
SAFETY ASSESSMENTS 
Safety will be assessed by adverse event (AE) monitoring (including attribution of AEs and 
SAEs), physical examination, vital signs, clinical laboratory testing, anti-demcizumab testing, 
and subject interview on an ongoing basis as outlined in the Schedule of Assessments 
(see Appendix A). 
Samples that test positive for demcizumab antibodies will be assessed for neutralizing capability.  
The impact of positive samples on safety and biologic activity will be assessed. 
9.1 
Adverse Events Definitions and Reporting Procedures 
All AEs from the time of randomization through 30 days after the termination visit must be 
documented in the medical record and reported on the AE Case Report Form (CRF). 
AEs will be coded in accordance with the Medical Dictionary for Regulatory Activities 
(MedDRA).  The grading of the AEs will be done using the National Cancer Institute (NCI) 
Common Terminology Criteria for AE (CTCAE), version 4.03 (see Investigator Reference 
Manual).  In addition, for each AE the Investigator must indicate the attribution of AE to 
demcizumab or placebo (i.e., related or unrelated) and the attribution of the AE to the 
malignancy. 
The principal investigator is responsible for assessing the causality of an AE (related or 
unrelated) to participation in the research.   
In general, AEs are considered related to participation in the research if there is not a clear 
alternative explanation.  AEs are considered unrelated to participation in the research if they 
are solely caused by the subject’s disease or condition or by other circumstances unrelated to 
either the research or to the subject’s condition. 
9.1.1 
Definition of Adverse Event 
An AE 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 


 
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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 randomization is a pre-existing 
condition that must be listed on the Medical History CRF and should not be considered an AE 
unless the condition worsens in intensity or frequency after first study drug infusion (e.g., 
Grade 2 nausea prior to the initial study drug infusion becomes Grade 3 nausea after initial study 
drug infusion). 
Laboratory abnormalities should only be reported as AEs if they are associated with clinical 
symptoms and/or require treatment. 
Pregnancy should not be reported as an AE. Should a subject enrolled in the study become 
pregnant or suspect she is pregnant while participating in this study or within 6 months after 
discontinuation of study drug(s), the Medical Monitor should be informed within the same 
timeframe as required for SAEs (see Section 9.1.4).  Monitoring of the subject should continue 
through outcome of the birth, or longer if any fetal abnormality is present. 
9.1.2 
Definition of Serious Adverse Event 
A serious adverse event (SAE) 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 
The following events involving hospitalization do not require reporting as an SAE as long as 
there is no occurrence of an AE: 
o Efficacy measurement for the study 
o Diagnostic or elective surgical procedure 
o Administration of scheduled therapy for this study 
 Persistent or significant disability/incapacity 
 Congenital anomaly/birth defect 
 Any other AE that, based upon the Investigator’s 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) 


 
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9.1.3 
Disease Progression and Death 
Disease progression (including progression of NSCLC, 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 an SAE, 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.  
9.1.4 
Serious Adverse Event Reporting Procedures 
SAEs that occur during the study must be clearly documented in the medical record.  An SAE 
form must be completed for each event and submitted with 24 hours of the Investigator’s 
knowledge of the event.  Please see the Investigator Manual for details regarding SAE reporting.  
The following is the contact information for PPD Drug Safety. 
Pharmacovigilance telephone contacts: 
 Australia and Europe: _______________ 
 United States: __________________ 
Pharmacovigilance fax contacts: 
 Australia and Europe: _________________ 
 United States: _________________ 
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. 
9.2 
Clinical Laboratory Assessments 
All clinical laboratory assessments will be performed using the site’s local laboratory (see 
Section 9.2.3 for details about BNP assessments). 
9.2.1 
Hematology 
A complete blood count (CBC) with differential and platelet count will be obtained at each 
protocol-specified visit and an INR and aPTT will be obtained during screening. 


 
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9.2.2 
Serum Chemistry 
Serum chemistries (including albumin, alkaline phosphatase, total bilirubin, bicarbonate, blood 
urea nitrogen [BUN], calcium, chloride, creatinine, glucose, lactic dehydrogenase [LDH], 
phosphorus, potassium, total protein, AST [SGOT], ALT [SGPT], sodium) will be obtained at 
each protocol-specified visit. 
9.2.3 
BNP Assessment 
BNP will be assessed during screening, then every 21 days, and at the termination visit.  After 
discontinuation of demcizumab or placebo (either as scheduled per protocol or unscheduled for 
other reasons), BNP assessments are continued every 21 days for another 105 days 
(5 assessments total).  For example, if the last scheduled demcizumab or placebo dose is given 
on Day 231, a total of 5 more BNP assessments will occur on Days 252, 273, 294, 315 and 336.  
However, should the BNP result not meet eligibility criteria at the last assessment 105 days after 
the last demcizumab or placebo dose, BNP assessments have to be continued every 21 days until 
two consecutive assessments meet eligibility criteria or the termination visit has occurred. 
BNP will be measured using any Alere Triage POC device (or the site’s laboratory, if approved 
by OncoMed).  BNP must be assessed on the same day prior to each dose of 
demcizumab/placebo, and elevations will be managed per Section 8.1.6.   
9.2.4 
Urinalysis 
Urinalysis (with microscopic analysis) will be obtained during screening and at the termination 
visit. 
9.3 
Vital Signs and Other Physical Findings 
A full physical examination will be done at screening.  Subsequently, an abbreviated physical 
examination will performed at Day 0, every 3 weeks during the on-study part of the protocol and 
at the termination visit.  The abbreviated physical examination must include respiratory rate, 
auscultatory examination of the heart and lungs, abdominal examination, and assessment for the 
presence or absence of edema and/or ascites.  A more complete physical examination should be 
conducted when clinically indicated. 
Vitals signs will be done as outlined in Appendix A.  On days of demcizumab or placebo dosing, 
vital signs will be obtained before infusion (-1 hour), 15 (±5) minutes after start of infusion, end 
of infusion (+5 minutes), and 15 (±5) minutes after end of infusion of demcizumab or placebo.  
Blood pressure (BP) may be measured with an automated BP monitor or manually.  For the 
measurement, the subject should be in the same position at each study visit.  The same cuff 
method should be used to measure BP throughout the study.  For manual measurements, diastolic 
BP will be measured by the disappearance of Kortokoff sounds, phase V.  If possible, 
measurements will be taken by the same staff member at each visit. 


 
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For subjects presenting with hypertension, their BP must be adequately controlled to 
≤140/90 mmHg prior to randomization.  This may be achieved by adjusting the existing anti-
hypertensive medications or adding new ones for a maximum of 2 medications following 
guidelines for the management of high BP in adults (Ref 33).  Any subject with hypertension 
(i.e., >150/90 mmHg) that is considered to be related to demcizumab or placebo at the time of 
the termination visit will continue to have BPs monitored once every 2 weeks until the BP is 
≤150/90 mmHg over a 4-week period with every-2-week BP measurements. 
9.4 
Cardiopulmonary Studies 
A twelve-lead electrocardiogram (ECG; with assessment of PR interval, QRS duration, and QTc 
interval) and a transthoracic Doppler echocardiogram (with assessment of left ventricular 
ejection fraction, right ventricular systolic pressure and peak tricuspid velocity) will be obtained 
at screening, then every 28 days, and at the termination visit.  After discontinuation of 
demcizumab or placebo (either as scheduled per protocol or unscheduled for other reasons), ECG 
and Doppler echocardiogram assessments are continued every 28 days for ≥105 days.  For 
example, if the last scheduled demcizumab or placebo dose is given on Day 231, a total of 
4 more ECG and Doppler echocardiogram assessments will occur on Days 252, 280, 308 and 
336.  However, should results of the Doppler echocardiogram not meet eligibility criteria at the 
last assessment ≥105 days (depending on timing of assessments) after the last demcizumab or 
placebo dose, assessments have to be continued every 28 days until two consecutive Doppler 
echocardiograms meet eligibility criteria or the termination visit has occurred.  The Doppler 
echocardiograms may also be sent to an Independent Cardiologist of the Sponsor’s choice for 
central review.  Clinically significant ECG abnormalities should be addressed according to 
standard of care. 
A CT pulmonary angiogram (CTPA) should be performed if clinically significant pulmonary 
hypertension is diagnosed (i.e., peak tricuspid velocity >3.4 m/s on Doppler echocardiogram and 
diagnosed with clinically significant pulmonary hypertension that includes minimal dyspnea by a 
cardiologist or pulmonologist) to determine if pulmonary embolism might be the cause of the 
pulmonary hypertension.  An MR angiogram or VQ scan may be performed instead per local or 
country standards or if the subject has a contrast allergy. 
9.5 
Immunogenicity Assessments 
Serum samples for immunogenicity will be obtained at baseline, every 6 weeks (prior to the 
demcizumab or placebo infusion, if applicable) during the study, and at the termination visit.  
Samples that test positive will be assessed for neutralizing capability.  In addition, the impact of 
positive samples on safety and biologic activity will be assessed.  Instructions for sample 
collection, handling, storage and shipping can be found in the Study Reference Binder. 


 
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9.6 
Pharmacokinetic Assessments 
Plasma samples for PK analysis will be obtained prior to the demcizumab (or placebo) infusion, 
if applicable, on Days 0, 42, 84, 126, 168, 210, 252, 294 and 336, and at the end of the 
demcizumab (or placebo) infusion (prior to the chemotherapy infusion, if applicable) on Days 0, 
42, 168 and 210, and at the termination visit.  The PK samples must be drawn from a location 
that is different from the site of demcizumab or placebo administration.  If demcizumab or 
placebo is administered via a vein in the arm, the PK samples must be drawn from a vein in the 
contralateral arm.  Instructions for sample collection, handling, storage, and shipping can be 
found in the Study Reference Binder. 
10.0 
EFFICACY ASSESSMENTS 
Tumor assessments will be performed at screening and then every 6 weeks.  The schedule of 
every 6 weeks is to be maintained throughout the study and will not be shifted if there are dose 
holds (see Appendix A).  Any measurable disease must be documented at screening and 
reassessed at each subsequent tumor evaluation.  Progression-free survival, response, and 
duration of response will be assessed using the RECIST criteria v1.1 (see Appendix C) (Ref 34). 
The primary response outcomes will be based on the Investigator’s assessement.  However, the 
radiographs will be collected centrally (by VirtualScopics), and an optional independent read of 
the radiographs may be performed.  Please refer to the Investigator Manual for instructions of 
submission of the radiographs to VirtualScopics. 
Assessments of the tumor marker CEA (if elevated at baseline) will be performed on the same 
schedule as imaging studies.  Response assessment should be based solely on the radiographic 
assessment and not based on changes in CEA. 
Overall survival will be assessed by collecting survival data including the date and cause of 
death. 
The same imaging method used at screening must be used throughout the study.  A documented 
standard-of-care tumor assessment performed on or after Study Day -28 may be used for the 
screening assessment provided it meets the below requirements. 
At baseline, tumor assessments should include the following: 
 
Diagnostic-quality, contrast-enhanced CT scans of chest, abdomen, and pelvis 
To be suitable for RECIST v1.1 assessments, CT scans should have a maximum 
thickness of 5 mm and no gaps.   
CT scan is the preferred imaging modality for tumor assessments of chest, abdomen, and 
pelvis. 


 
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In subjects for whom the preferred CT scans are contraindicated because of, for example, a 
CT IV contrast allergy, a CT of the chest without contrast and MRI of the abdomen and 
pelvis with contrast are recommended. 
MRI scans may be performed in lieu of CT scans.  At screening, tumor assessments should 
include a diagnostic-quality, contrast-enhanced MRI scan of the chest, abdomen, and pelvis.  
To be suitable for RECIST v1.1 assessments, MRI scans should ideally have a maximum 
thickness of 5 mm and minimal gaps. 
 
MRI of the brain 
MRI is the preferred imaging modality for tumor assessments of the brain. 
In subjects for whom MRI of the brain is not available, a CT scan of the brain with IV 
contrast may be performed. 
 
CT scan of the neck or bone scan should be included if clinically indicated.  
MRI scan of the neck may be substituted for CT scan of the neck. 
Subsequent tumor assessments should include the following: 
 
Diagnostic-quality, contrast-enhanced CT scans of chest and abdomen 
If another imaging method was used at baseline, the same imaging method must be used 
for subsequent tumor assessments. 
 
Imaging of all other known sites of disease 
The same imaging method as at baseline must be used. 
In addition to the scheduled on-protocol tumor assessments, CT scans or other imaging studies 
may be performed at the investigator’s discretion at any time as clinically indicated.  
11.0 
EXPLORATORY ASSESSMENTS 
Instructions for biomarker sample collection, handling, labeling, and shipping are provided in the 
Study Reference Binder. 
FFPE tumor tissue and predictive biomarkers: If available, archival FFPE tumor tissue (from 
either the primary tumor, locoregional disease or a metastatic site) obtained by core biopsy or 
surgical resection will be collected for protein and gene expression biomarker 
analysis.  Exploratory predictive biomarkers such as DLL4 will be measured in FFPE tumor 
specimens.  Gene expression biomarker analysis including Notch pathway-related genes may 
also be measured by RT-PCR and/or microarrays.  Tumor-derived DNA may be used to test for 
mutations in candidate genes relevant to the Notch pathway (e.g., Notch1, DLL4, FBXW7).  
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 demcizumab, pemetrexed and 
carboplatin treatment.  


 
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Blood Biomarkers:  A sample of 9 mL of blood will be drawn on Study Days 0 and 28, and at the 
termination visit to evaluate changes in plasma proteins by immunochemistry (e.g., VEGF, β
FGF, SDF1, PLGF, TNF, MCP1, etc.), and Notch-related gene expression of mRNA using 
microarrays, e.g., Affymetrix platform.  Plasma microRNAs may also be evaluated by 
microRNA expression profiling.  A termination visit sample will not be obtained if one is 
available from the prior 14 days. 
Optional Pharmacogenomics:  For subjects who sign the optional Pharmacogenomics Informed 
Consent (Appendix F), a blood sample (10 mL) will be collected pre-dose at Study Day 0 (where 
local regulations permit).  Pharmacogenomic analysis of candidate genes relevant to 
demcizumab or placebo may influence safety, tolerability, or pharmacodynamic effects of 
demcizumab or placebo for the treatment of solid tumors.  Analysis of genes relevant to 
Notch/DLL4 target or pathway genes or disease genes may be performed (e.g., FBW7 and 
PTEN).  Analysis of genes related to carboplatin and pemetrexed metabolism may also be 
performed (e.g., ABCB1). 
12.0 
STUDY VISIT SCHEDULE AND ASSESSMENTS 
Subjects must sign and date the Informed Consent Form (Appendix E) that has been approved by 
the IEC/IRB prior to undergoing any study-related procedures.  Once the screening process has 
been completed, the Investigator must complete a randomization request form and submit it for 
approval.  Once OncoMed or its representative has approved randomization in the IWRS system, 
the investigator/study coordinator will use the IWRS system to randomize the subject.  Subjects 
who are randomized will not be replaced.  The IWRS system will then assign a subject number, 
and the subject will be officially enrolled in the study. This unique subject number will be on all 
electronic case report form (eCRF) pages.  Study drug must be administered within 4 days from 
the date of randomization. Study Day 0 will be the first day of study drug administration.  
12.1 
Screening 
All screening tests must be performed within 28 days preceding Day 0 (defined as the day of first 
study drug administration), unless otherwise indicated.  Results of standard-of-care tests or 
examinations performed prior to obtaining informed consent and within the screening window 
may be used and do not have to be repeated as long as they meet protocol specifications. 
Subjects must receive pemetrexed premedication prior to Day 0 as outlined in Section 8.2.5. 
Please see the Study Flowchart provided in Appendix A for details of screening assessments. 
12.2 
Assessments for On-study Part of Protocol (Day 0 up to Termination Visit) 
Unless otherwise indicated, all assessments must be performed prior to dosing for all study visits 
when dosing occurs. BNP must be assessed on the same day prior to each dose of 
demcizumab/placebo.  


 
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All on-study evaluations (i.e., from Day 0 up to Termination visit) must be done within the 
following timeframes: 
 Dosing of demcizumab or placebo within ± 2 days of the Study Day listed in Appendix A 
 Laboratory evaluations within ± 3 days of the Study Day listed in Appendix A 
 Tumor assessment, tumor marker CEA (if applicable), ECG, and transthoracic Doppler 
echocardiogram within ± 7 days of the Study Day listed in Appendix A 
For subjects who only receive pemetrexed maintenance after discontinuation of carboplatin and 
demcizumab/placebo, every-three-week visits can be rescheduled accordingly if pemetrexed 
administration and associated assessments (i.e., physical examination, weight, vital signs, ECOG 
performance status, CBC, and chemistry) were delayed for adverse or other unforeseen events.  
In addition, if the timing of a protocol-mandated study visit coincides with a holiday or weekend 
that precludes the visit, the visit should be scheduled on the nearest following feasible date, with 
subsequent visits rescheduled accordingly.  Pemetrexed cycles may be extended from 3 to up to 
4 weeks to realign assessments. 
Subjects who have discontinued all study drugs and have no clinically significant ongoing 
related adverse events that require close follow-up have to undergo the following assessments 
only every 42 days (ideally synchronized with tumor assessments and tumor marker CEA, if 
applicable): physical examination, weight, vital signs, ECOG performance status, CBC, and 
chemistry. 
However, the schedule for BNP assessments (every 21 days; for more details see Section 9.2.3), 
for ECG and transthoracic Doppler echocardiogram (every 28 days; for more details see 
Section 9.4), and for tumor assessment and tumor marker CEA, if applicable (every 42 days), 
must be maintained.  
Please see the Study Flowchart provided in Appendix A for detailed schedule of treatments and 
assessments. 
12.3 
Termination Visit 
The termination visit should be done as soon as possible, but no later than 14 days, after one of 
the discontinuation criteria for the study are met (see Section 7.0).  The termination visit may 
occur later after discussion with the OncoMed Medical Monitor for specific circumstances, such 
as prolonged hospitalization.  The visit at which a tumor assessment shows progressive disease 
may be used as the treatment termination visit provided that all required assessments were 
performed as outlined in Appendix A. 
Tumor assessments do not have to be repeated if they were performed within 14 days of the 
termination visit or at a prior response evaluation that documented progressive disease.  ECG 


 
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and Doppler echocardiogram do not have to be repeated if they were performed within 14 days 
of the termination visit. 
12.4 
Follow-up after Termination Visit 
The subject’s treatment assignment will be blinded until the final analysis for overall survival is 
completed in the study. 
If the BP was >150/90 mmHg at the termination visit, the subject needs to be followed as 
outlined in Section 9.3. 
SURVIVAL DATA:  Once a subject has completed the termination visit, overall survival follow 
up will be performed every three months ±1 week for up to 5 years to determine the subject’s 
status and ultimately the date and cause of death. Follow-up may be conducted through 
telephone calls, review of medical records, and/or clinic visits.  In addition, the site may check 
public data sources to get this information, if needed (e.g., obituaries). 
SUBSEQUENT ANTI-CANCER THERAPIES:  Subsequent anti-cancer therapies, including 
systemic therapies, surgery (resection of metastatic disease), and radiation therapy will be 
collected through telephone calls, review of medical records, and/or clinic visits on the same 
schedule as for survival data. 
RESPONSE ASSESSMENT DATA:  Response assessment data (i.e., progressive disease or no 
progression of disease) will continue to be collected (based on standard-of-care radiographs) on 
subjects who have not progressed at the time of the termination visit.  For these subjects, copies 
of the standard-of-care radiographs may be provided to the Sponsor in a de-identified manner.  
These data and radiographs will continue to be collected until the subject starts alternative anti-
cancer treatment or develops progressive disease, whichever occurs first. 
BNP AND DOPPLER ECHOCARDIOGRAM:  If a subject has a BNP of ≥400 pg/mL and/or 
a diagnosis of pulmonary hypertension or heart failure at the time of the termination visit, all 
subsequent standard-of-care BNP data until the value is <200 pg/mL and all subsequent 
standard-of-care LVEF and PTV values until they normalize, if collected or available, will be 
entered into the database. 
13.0 
DATA QUALITY ASSURANCE 
Accurate, consistent and reliable data will be ensured through the use of standard practices and 
procedures.  Clinical Research Associates (CRAs) from PPD will monitor the study and verify 
that the data are accurate.  OncoMed Pharmaceuticals, Inc. has contracted with PPD to perform 
the data management of this trial.  The data will be captured using a validated remote data 
capture (RDC) system.  The medical monitors, CRAs, and site personnel will be trained in the 
use of Medidata RAVE.  The clinical data and the site-specific laboratory data will be entered by 
site personal into Medidata.  Analysis of samples for antibodies to demcizumab will be 
performed by ICON.  Analysis of biomarker samples and pharmacogenomics samples will be 


 
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CONFIDENTIAL 
performed at OncoMed Pharmaceuticals, Inc.  Drug Safety Reporting will be the responsibility 
of PPD.  System backups for data stored at OncoMed Pharmaceuticals, Inc. and at all contract 
research organizations (CROs) and records retention for the study data will be consistent with the 
standard procedures for these organizations. 
14.0 
STATISTICAL PLAN 
The KEYNOTE-021 Cohort G trial reported a confirmed response rate in the chemotherapy 
alone arm of 29% (Ref 35).  Here, we will assume that the unconfirmed response rate for 
chemotherapy alone is 40 percent.  Table 8 presents the power to detect an increase in the 
unconfimed tumor response rate in the pooled demcizumab arms (Arm 2 and Arm 3) compared 
to control.  With the type 1 error controlled at 0.10 1-sided, there is greater than 80 percent 
power to detect an increase in the response rate from 0.40 in the control arm to 0.65 in the pooled 
demcizumab arms.  With the type 1 error controlled at 0.40 1-sided, there is greater than 
80 percent power to detect an increase in the response rate from 0.40 in the control arm to 0.55 in 
the pooled demcizumab arms, which is still a clinical important improvement in the response 
rate. 
Table 8: 
Power to Detect an Increase in Response Rate 
Subjects Randomized 
Response Rate 
Type 1 
Error 1-
sided 
Power 
Total 
Control 
Demcizumab 
Control 
Demcizumab 
82 
27 
55 
0.4 
0.45 
0.100 
0.20 
82 
27 
55 
0.4 
0.50 
0.100 
0.34 
82 
27 
55 
0.4 
0.55 
0.100 
0.51 
82 
27 
55 
0.4 
0.60 
0.100 
0.68 
82 
27 
55 
0.4 
0.65 
0.100 
0.82 
82 
27 
55 
0.4 
0.70 
0.100 
0.92 
82 
27 
55 
0.4 
0.45 
0.400 
0.57 
82 
27 
55 
0.4 
0.50 
0.400 
0.73 
82 
27 
55 
0.4 
0.55 
0.400 
0.85 
82 
27 
55 
0.4 
0.60 
0.400 
0.93 
82 
27 
55 
0.4 
0.65 
0.400 
0.97 
82 
27 
55 
0.4 
0.70 
0.400 
0.99 
82 
27 
55 
0.4 
0.45 
0.500 
0.67 
82 
27 
55 
0.4 
0.50 
0.500 
0.81 
82 
27 
55 
0.4 
0.55 
0.500 
0.90 
82 
27 
55 
0.4 
0.60 
0.500 
0.96 
82 
27 
55 
0.4 
0.65 
0.500 
0.99 
82 
27 
55 
0.4 
0.70 
0.500 
1.00 
 


 
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CONFIDENTIAL 
In the Phase 1b trial M18-004, a tail was observed in the OS survival curve suggesting that the 
hazard of death is greatly reduced beyond 10 months in first-line NSCLC subjects treated with 
demcizumab.  Table 9 presents the power to detect a difference in the hazard between the pooled 
demcizumab arms and control beyond 10 months.  The median OS is assumed to be 10 months 
prior to 10 months and 12 months post 10 months to account for treatment with checkpoint 
inhibitors, such as nivolumab.  With a total study duration of 30 months, we expect to see 
5 deaths in the control arm beyond 10 months.  If the hazard ratio beyond 10 months is 0.25, 
there will be 81 percent power to detect a difference in hazards between the control arm and the 
pooled demcizumab arms of the trial beyond 10 months. 
 


 
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Table 9: 
Power to Detect a Difference in the Overall Survial Kaplan Meier Curves Beyond 10 Months 
Hazard of Death 
End of 
Study Month 
Events 
Events >10 months 
Power 
>10 months 
0-10 
months 
>10 months 
  
DEM 
Control 
DEM 
Control 
  
1 
1.00 
25 (Feb 2017) 
31.09 
15.55 
6.35 
3.18 
0.1000 
1 
0.50 
25 
28.29 
15.55 
4.11 
3.18 
0.3616 
1 
0.25 
25 
26.58 
15.55 
2.77 
3.18 
0.6571 
1 
0.10 
25 
25.43 
15.55 
1.89 
3.18 
0.8897 
1 
1.00 
30 (Jul 2017) 
36.31 
18.16 
10.63 
5.32 
0.1000 
1 
0.50 
30 
31.95 
18.16 
6.93 
5.32 
0.4683 
1 
0.25 
30 
29.10 
18.16 
4.56 
5.32 
0.8135 
1 
0.10 
30 
27.12 
18.16 
2.94 
5.32 
0.9705 
1 
1.00 
36 (Jan 2018) 
40.71 
20.36 
15.59 
7.79 
0.1000 
1 
0.50 
36 
35.03 
20.36 
10.24 
7.79 
0.5700 
1 
0.25 
36 
30.94 
20.36 
6.52 
7.79 
0.9083 
1 
0.10 
36 
27.94 
20.36 
3.85 
7.79 
0.9920 


 
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Cardiac Safety Monitoring 
If two or more of the first 10 subjects treated with demcizumab experience Grade 3-5 (per NCI 
CTCAE v. 4.03) heart failure and/or pulmonary hypertension, that is deemed at least possibly 
related to demcizumab, the study will be stopped.  
If after 10 subjects have been treated with demcizumab,  subjects experience greater than or 
equal to 15% above the rate in the control arm of Grade 3-5 (per NCI CTCAE v4.03) heart 
failure and/or pulmonary hypertension, that is deemed at least possibly related to demcizumab, 
the study will be stopped.   
During the trial, the proportion of subjects developing Grade ≥3 heart failure or pulmonary 
hypertension will be closely monitored by the DSMB on an ongoing basis.  In addition to the 
ongoing review of safety data by the DSMB, one formal joint interim safety analysis of the 
Grade >3 heart failure and Grade >3 pulmonary hypertension data from this trial and the ongoing 
companion trial in 1st line pancreatic cancer will occur after 60 demcizumab-treated subjects 
between the two studies have completed a minimum of 2 treatment cycles and the last of these 
60 demcizumab subjects has been followed for 100 days.  Following review of these data, the 
DSMB will inform OncoMed in writing whether the incidence of Grade ≥3 heart failure and the 
incidence of Grade ≥3 pulmonary hypertension in the demcizumab-treated subjects is less than 
or greater than or equal to 15% above the incidence in the control arm.   
Table 10 presents the probability of exceeding the 15-percent threshold at the interim analysis 
and final analysis in the trial.  It is assumed the single course demcizumab  arms are combined in 
Yosemite and Denali and that each study contributes 33-34 subjects to the demcizumab arm and 
the control arm at the interim analysis (50% enrollment) and 67 subjects at the final analysis 
(100% enrollment).  The actual number of subjects available for the analysis at the interim and 
final will likely be different from those assumed in the table so the calculation using the 
appropriate number of subjects will have to be undertaken at the time of the analysis. 
 


 
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Table 10: 
Probability Heart Failure Rate Will Exceed 15 Percent over Control 
Control 
Rate 
Dem 
Rate 
Probabilty of Exceeding 
15% at Interim (67 subjects 
enrolled in demcizumab 
treated arm, 67 subjects in 
the control arm) 
Probabilty of Exceeding 
15% at Final (134 
subjects with 
demcizumab, 134 
subjects with control) 
Probabilty of Not Exceeding 
15% at Final  
Total Probability of 
Exceeding 15%  
Total 
Probability 
0.03 
0.03 
0.00016 
0.00000 
0.99984 
0.00016 
1.00000 
0.03 
0.06 
0.00877 
0.00016 
0.99108 
0.00893 
1.00001 
0.03 
0.09 
0.05897 
0.00502 
0.93603 
0.06399 
1.00002 
0.03 
0.12 
0.17202 
0.03042 
0.79758 
0.20244 
1.00002 
0.03 
0.15 
0.33041 
0.07915 
0.59047 
0.40956 
1.00003 
0.03 
0.18 
0.50000 
0.12501 
0.37501 
0.62501 
1.00002 
0.03 
0.21 
0.65292 
0.14233 
0.20478 
0.79525 
1.00003 
0.03 
0.24 
0.77491 
0.12838 
0.09673 
0.90329 
1.00002 
0.03 
0.27 
0.86330 
0.09702 
0.03969 
0.96032 
1.00001 
0.03 
0.30 
0.92226 
0.06359 
0.01416 
0.98585 
1.00001 
0.03 
0.33 
0.95869 
0.03694 
0.00438 
0.99563 
1.00001 
0.03 
0.36 
0.97958 
0.01926 
0.00116 
0.99884 
1.00000 
0.03 
0.39 
0.99067 
0.00907 
0.00026 
0.99974 
1.00000 
0.03 
0.42 
0.99609 
0.00386 
0.00005 
0.99995 
1.00000 
0.03 
0.45 
0.99852 
0.00147 
0.00001 
0.99999 
1.00000 
0.03 
0.48 
0.99950 
0.00050 
0.00000 
1.00000 
1.00000 
Note: The sum of the probabilities in columns 3 to 6 adds up to 1.00. 
 


 
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For continuous variables, descriptive statistics will include the number of non-missing values, 
mean, standard deviation, median, minimum, maximum, and possibly geometric mean and 
geometric standard error if applicable to biomarker data.  For categorical variables, descriptive 
statistics will include counts and percentages per category.  Statistics for time-to-event variables 
will be estimated by the Kaplan-Meier method. 
14.1 
Subject Populations for Analysis 
Eighty two (82)  subjects were randomized in the trial.  
The Intent-to-Treat (ITT) Population comprises all subjects who are randomized.  Subjects will 
be analysed as they were randomized.  All baseline characteristics and demographic, efficacy, 
immunogenicity, and biomarker data will be analyzed using the ITT Population. 
The Per-Protocol (PP) Population comprises all subjects who receive at least one dose of study 
drug and who have at least one postbaseline tumor assessment.  Subjects will be analysed as they 
were treated.  Efficacy, immunogenicity and biomarker data will be analysed using the per-
protocol population as well as the ITT population. 
The Safety Population comprises all subjects who receive at least one partial or complete dose of 
demcizumab or placebo and who have at least one post-dosing safety evaluation.  Subjects will 
be analysed as they were treated.  All safety endpoints will be summarized using the Safety 
Population. 
The Pharmacokinetic (PK) Population comprises all subjects who receive at least one partial or 
complete dose of demcizumab or placebo and who provide adequate PK samples, as defined by 
the PK specialist, to calculate the PK parameters.  Subjects will be analysed as they were treated.  
Subjects with protocol violations will be assessed on a subject-by-subject basis for inclusion in 
the PK Population.  PK analysis will be conducted using the Pharmacokinetic Population. 
Missing values will not be imputed. 
14.2 
Demographics and Baseline Characteristics 
Demographic and baseline characteristics will be analyzed using the Intent-to-Treat Population.  
Quantitative and/or categorical summaries will be presented for demographics, medical history, 
and other baseline characteristics.  For continuous variables, data will be summarized by sample 
size, mean, standard deviation, median, minimum, and maximum.  For categorical variables, data 
will be summarized as frequency counts and percentages.  Medical history will also be displayed 
by subject in listing formats. 
14.3 
Treatment Exposure 
Treatment exposure will be summarized as duration of treatment and extent of exposure to 
demcizumab/placebo, pemetrexed and carboplatin.  Duration of exposure will be summarized 


 
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quantitatively in days using sample size, mean, standard deviation, median, minimum, and 
maximum. 
Measures of extent of exposure include the total number of doses per subject, cumulative dose 
per subject, dose intensity and compliance.  Compliance will be summarized as the number of 
subjects who had dose(s) withheld or delayed.  The reasons for dose(s) withheld or delayed will 
also be summarized. 
14.4 
Endpoints 
14.4.1 
Safety Endpoints 
Safety endpoints include AEs; SAEs; vital signs; clinical laboratory testing including assessment 
of BNP every 21 days; electrocardiograms with assessment of PR interval, QRS duration, and 
QTc interval; transthoracic Doppler echocardiograms with left ventricular ejection fraction and 
peak tricuspid velocity determination, if measurable; and anti-demcizumab antibody testing.  
Safety endpoints will be analyzed by treatment arm using the Safety Population. 
Adverse Events 
All reported AEs will be mapped to standard Medical Dictionary for Regulatory Activities 
(MedDRA) coding terms, grouped by system organ class and preferred terms and tabulated by 
treatment arm.  The incidence of AEs in each treatment arm will be tabulated by seriousness, 
severity, and relationship to study drug. 
Clinical Laboratory Assessments and Vital Signs 
Clinical laboratory data (hematology, serum chemistry, and urinalysis) and vital signs will be 
summarized by treatment arm using descriptive statistics of the reported values and change from 
baseline values 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 CTC grade if available.  
All laboratory and vital sign data will be presented in listings and special attention will be given 
to any unexpected abnormal results. 
BNP Assessment 
The proportion of subjects with at least two consecutive BNP assessments >100 pg/mL or at 
least one BNP assessment ≥200 pg/mL, the proportion of subjects who had their treatment held 
due to a BNP ≥300 pg/mL and the proportion of subjects who have a BNP ≥400 pg/mL will be 
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Among the subjects in the demcizumab groups with two BNP measurements >100 pg/mL or one 
≥200 pg/mL, the use of ACE inhibitors and carvedilol will be described with simple descriptive 
statistics and the proportion of subjects with an elevation ≥400 pg/mL will also be summarized 
along with the total amount of follow-up time both preceding and following the initiation of 
ACE inhibitors or carvedilol. 
ECOG and Physical Examination 
ECOG performance status at baseline and follow-up and physical examination data at baseline 
will be listed by subject for each treatment arm.  Changes in ECOG performance status scores 
from baseline will be summarized by treatment group at selected scheduled time points using 
shift tables. 
ECG and Doppler Echocardiogram 
An electrocardiogram with assessment of PR interval, QRS duration, and QTc interval will be 
obtained every 28 days, and a transthoracic Doppler echocardiogram with left ventricular 
ejection fraction and peak tricuspid velocity determination, if measurable, will be obtained every 
28 days.  The maximum change in PR interval (increase), QRS duration (increase) and QTc 
interval (increase) will be summarized by treatment arm. 
14.4.2 
Immunogenicity Endpoints 
Immunogenicity endpoints will be analyzed using the ITT Population.  The incidence of anti-
demcizumab antibody development in subjects receiving carboplatin, pemetrexed and 
demcizumab will be summarized by frequency counts and percentages.  For subjects with a 
positive result for an anti-demcizumab antibody, the incidence of neutralizing capability 
development will be further summarized by standard quantitative methods for each treatment 
arm.  In addition, the impact of positive results on safety and biologic activity will be assessed. 
14.4.3 
Pharmacokinetic Endpoints  
Peak and trough concentrations will be summarized with simple descriptive statistics.  
Demcizumab concentration data from this study will be also included in a population 
pharmacokinetic analysis encompasses all studies in which pharmacokinetic sampling was 
conducted, to estimate the individual PK parameters (i.e., half life, volume of distribution, 
clearance etc.) and to analyze the inter-subject variability and factors that may contribute to the 
inter-subject variability of the PK of demcizumab. 
14.4.4 
Efficacy Endpoints 
Efficacy endpoints include best overall response, confirmed response, time to progression, 
duration of response and survival.  Efficacy endpoints will be analyzed using the ITT Population. 
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The primary endpoint of response rate will be based on Investigator-assessed best overall 
response, and is defined as the best unconfirmed response determined by RECIST v1.1 recorded 
from the start of the treatment until disease progression (see detailed definition in Appendix C) 
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 their best overall response will be summarized 
for each dose group. 
Response rate based on the IRF (optional) assessment of tumor response will be similarly 
defined.  The optional IRF assessment will be performed if the Investigator-assessed best overall 
data show a sufficiently positive trend in favor of the combined demcizumab arms. 
The confimed response rate will be assessed as well and is the number of subjects per treatment 
arm who have either a confirmed CR or a confirmed PR (according to RECIST v1.1 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 a 
demcizumab treatment arm and control will be calculated for the two groups using a logistic 
regression model with treatment, performance status and region as factors in the model.   
Progression-Free Survival and Duration of Response 
The secondary endpoint of PFS based on the Investigator assessment of tumor response, is 
defined as the number of days from randomization until death or disease progression as defined 
by the RECIST v1.1 criteria for the ITT Population.  Deaths that occur more than 49 days 
(1 tumor assessment + 7 days) after the last tumor assessment will not be accounted as PFS 
events.  The Kaplan-Meier method will be used to estimate the proportion of subjects without 
progression or death over time 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-values for the demcizumab treatment effects will be generated using a 
stratified log rank test.  A stratified Cox proportional hazards regression model will be used to 
estimate the hazard.  The stratification factors will be smoking status (current versus former or 
never) and region (Australia/Europe versus North America).  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 therapy will be censored at the point they start this 
treatment.  Radiotherapy and surgery directed at a disease site will be considered non-protocol 


 
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therapy.  Bisphosphonates and hormones will not be considered non-protocol therapy.  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 0. 
PFS based on the IRF (optional) assessment of tumor response will be similarly defined with 
performance status and prior history of smoking being the stratification factors.  The optional 
IRF assessment will be performed if the Investigator-assessed efficacy data show a sufficiently 
positive trend in favor of the combined demcizumab arms. 
In addition to the log rank test, the wilcoxon test will also be used as a sensitivity analysis to 
evaluate the impact of treatment on progression free survival. 
To evaluate the impact of the second course of demcizumab therapy, a cox regression analysis 
will be used with a time dependnent covariate to capture the affect of the second course of 
demcizumab.  The two demcizumab arms will be pooled and compared with control.  A time-
dependent variable to capture the effect of the second course of demziumab will be used.  The 
variabe will be zero unless a subject has started a second course of demcizumab which case the 
variable will assume the value of 1.  A standard variable will also be included in the model to 
capture the randomized assignment of subjects to control or demcizumab (pooled). 
14.4.5 
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 v1.1 criteria and determined by both the Investigator and the IRF 
[optional]).  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, as well as 6, 12 and 18 weeks post baseline.  These summary statistics 
will also be presented for differences from baseline at 6, 12 and 18 weeks post baseline.  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 presented.  An ANCOVA model will 
be used to test the hypothesis that there is no difference between treatment arms with regard to 
changes from baseline tumor length at scheduled tumor assessments.  Treatment and ECOG PS 
and region 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 X divided by tumor length at baseline) as the 
endpoint.  In the case of complete response when the outcome variable is undefined, the best 


 
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possible rank will be assigned.  In the case of death or withdrawal due to AE, the worst possible 
rank will be assigned. 
In addition, the rate of change in tumor volume at progression (sum of the longest diameters 
(SLD) at progression – SLD at nadir)/SLD at nadir as determined by both the Investigator and 
the IRF (optional) will be compared between the two arms of the study.  The rate of change in 
tumor burden at progression has been associated with survival (references) 
14.4.6 
Duration of Response 
The Investigator-assessed and IRF-assessed (optional) duration of response are 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.  Subjects who have not experienced death or progression by 
their last contact will be censored at the time of their last radiographic response assessment.  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.   
Sites of Progression 
The sites of progression as determined by the Investigator and by the IRF (optional) will be 
classified according to organ type and compared between the two arms of the study 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. 
14.4.7 
Overall Survival 
A comparison of the overall survival for the combined demcizumab arms with control will be 
performed.  Overall survival is defined as the number of days from randomization until death 
occurs.  Subjects who have not experienced death by their last contact date will be censored at 
that time.  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 
interval for the median survival time will be calculated.  A p-value for treatment effect will also 
be generated using a stratified Cox proportional hazards model.  The stratification factors will be 
smoking status (current versus former or never) and region (Australia/New Zealand versus 
Europe versus North America).  The number and percentage of these subjects who are treated as 
an event and as a censor will be displayed.  If there is a disparity in discontinuation rates between 
treatment arms, a sensitivity analysis will be performed to assess the impact. 
Two analyses of survival will be undertaken, one at the time of the final analysis for PFS and the 
second 9 months after the time of the PFS analysis.  A number of secondary analyses for OS will 
be undertaken.  First, the log rank test and the hazard ratio estimate will be determined using 


 
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only patients who survived beyond 10 months.  Next, a robust test procedure which adaptively 
weights which time points receive the greatest weights in the construction of the test will be 
applied (Ref 36).  This test is based on weighted KM curve differences, and the weighting is 
data-dependent.  To supplement the model-based hazard ratio estimate, we will calculate the 
difference in the area under the KM curves between the control arm and the pooled demcizumab 
arms restricted up to the time point T, which is the minimum of the two largest observed death 
times from the two arms combined.  Finally we will compare the hazard of death in the pooled 
demcizumab arms of the trial between those subjects who lived past 10 months and those 
subjects who did not.  The estimate of the hazard will be simply the number of events observed 
divided by the amount of follow-up time.  Testing will be based on a Z test using 1/number of 
events as the variance for the log(hazard). 
In addition to the analyses described above, OS analyses will be undertaken to identify a 
subgroup of subjects who may derive a large benefit from the experimental treatment.  First we 
will evaluate OS between the control arm and the pooled demcizumab arms of the trial in those 
subjects whose baseline albumin level is greater than 0.7*LLN + 0.3*ULN.  Then we will cast a 
wider net by applying the method of Li et al (Ref 37) to the following list of baseline covariates:  
baseline albumin, LDH, alkaline phosphatase, ECOG PS, and smoking status (others may be 
added). 
14.4.8 
Landmark Survival 
The Kaplan Meier estimates of survival at 6, 12, 18 and 24 months will be compared between the 
demcizumab arms and control using a simple Z test.  Greenwood’s formula for the variance of 
the survival estimate will be used to construct the Z-test.  
14.4.9 
Exploratory Endpoints 
Exploratory endpoints include blood markers (see Section 11.0).  These endpoints will be 
analyzed using the Intent-to-Treat Population.  The correlation of changes in these endpoints 
with tumor response (best response and PFS) and extended survival past 10 months will be 
explored. 
14.5 
Termination Criteria 
Randomization was terminated after 82 subjects had been randomized.  All ongoing subjects will 
continue to be dosed until disease progression, subject withdrawal, or the Investigator withdraws 
subjects from the study. 


 
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14.6 
Deviation Reporting 
The following protocol deviations will be recorded and summarized for the Intent-to-Treat 
population in the final report: 1) randomization violations, 2) dosing violations, 3) concomitant 
therapy violations, and 4) continuation of therapy when treatment should have been 
discontinued. 
15.0 
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. 
16.0 
ETHICAL CONSIDERATIONS 
This study will be conducted according to international standards of Good Clinical Practice 
(ICH guidance E6). 
17.0 
INVESTIGATOR REQUIREMENTS 
17.1 
Informed Consent 
A sample informed consent form will be provided.  OncoMed or PPD 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. 
17.2 
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 regulatory requirements and 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 


 
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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 AEs. 
Investigators are required to follow their respective IRB or IEC requirements for the reporting of 
SAEs and written safety reports to the IRB or IEC.  Investigators must immediately forward to 
their IRBs or IECs any written safety report or update provided by OncoMed (e.g., Investigator 
Brochure, safety amendment, etc.) 
17.3 
Study Monitoring 
Site visits will be conducted on a regular basis by an authorized OncoMed representative 
(e.g., CRA) to inspect study data, subjects’ medical records, and remote data capture (RDC) 
fields in accordance with current U.S. 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 demcizumab 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. 
17.4 
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. 
17.5 
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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17.6 
Investigational Medicinal Product Accountability 
All IMP required for completion of this study will be provided by OncoMed or its agent.  The 
recipient will acknowledge receipt of this IMP by confirming receipt in the IWRS system.  
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 and document destruction on the Investigational Medicinal Product Return or 
Destruction Form, or return all unopened, unused, and expired vials to the drug distribution 
center along with a completed Investigational Drug Product Return or Destruction Form.  Sites 
must have appropriate processes or SOPs and capabilities, in order to destroy study drug. 
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. 
17.7 
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. 
17.8 
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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37. 
Li J, Zhao L, Tian L, et al. A Predictive Enrichment Procedure to Identify Potential 
Responders to a New Therapy for Randomized, Comparative Controlled Clinical Studies. 
Biometrics 72, 877–887 September 2016 
 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 88 of 135 
29 November 2016 
 
CONFIDENTIAL 
APPENDIX A: 
SCHEDULE OF ASSESSMENTS 
 
Screeninga 
On Study 
(pemetrexed, carboplatin + demcizumab/placebo) 
On Study 
(pemetrexed maintenance) 
Termination
Visit 
Follow-
up 
Period 
Day(s) 
-28 to -1 
0 
7 
14 
21 
28 
35 
42 
56 
63 
84 
105 
112 
126 
140 
147 
168b 
Informed 
consenta 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Folic acidc 
  
X……………………..………………………………………………………………………………………………………………..
…………Xc 
 
 
Vitamin 
B12d 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X d 
 
 
 
 
 
Dexa- 
methasonee 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
 
 
Pemetrexedf,g 
 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
X
X 
 
 
Demcizumab 
or placebof,g 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
Xf 
 
 
Carboplatinf,g 
 
X 
 
 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
Past medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 89 of 135 
29 November 2016 
 
CONFIDENTIAL 
APPENDIX A: 
SCHEDULE OF ASSESSMENTS (CONT’D) 
 
Screeninga 
On Study 
(pemetrexed, carboplatin + demcizumab/placebo) 
On Study 
(pemetrexed maintenance) 
Termination
Visit 
Follow-
up 
Period 
Day(s) 
-28 to -1 
0 
7 
14 
21 
28 
35 
42 
56 
63 
84 
105 
112 
126 
140 
147 
168b 
 
 
Physical 
examinationh 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
X  
X 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X  
Xj
ECOG 
performance 
status 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
CBC with 
differential 
and platelet 
count 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 
Chemistryk 
X 
X 
 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 90 of 135 
29 November 2016 
 
CONFIDENTIAL 
APPENDIX A: 
SCHEDULE OF ASSESSMENTS (CONT’D) 
 Screeninga 
On Study 
(pemetrexed, carboplatin + demcizumab/placebo)
On Study 
(pemetrexed maintenance) 
Termination
Visit 
Follow
-up 
Period
Day(s) 
-28 to -1 
0 
7 
14 
21
28
35
42
56
63
84
105
112 
126
140 
147
168b 
 
 
INR/aPTT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum 
pregnancy 
testl 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
with micro 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
MRI or CT 
of brainm 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Tumor 
assessmentm 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Tumor 
marker CEA 
X 
 
 
 
 
 
 
Xn 
 
 
Xn 
 
 
Xn 
 
 
Xn 
Xn 
 
BNPo 
X 
 
 
 
X 
 
 
X 
 
X 
X 
X 
 
X 
 
X 
Xb 
X 
 
 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 91 of 135 
29 November 2016 
 
CONFIDENTIAL 
APPENDIX A: 
SCHEDULE OF ASSESSMENTS (CONT’D) 
 
Screeninga 
On Study 
(pemetrexed, carboplatin + demcizumab/placebo)
On Study 
(pemetrexed maintenance) 
Termination
Visit 
Follow-
up 
Period 
Day(s) 
-28 to -1 
0 
7 
14 
21 
28 
35 
42 
56 
63 
84 
105 
112 
126 
140 
147 
168b 
 
 
ECGp 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Xb 
X 
 
Transthoracic 
Doppler 
echocardiogramq 
X 
 
 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Xb 
X 
 
CT pulmonary 
angiogram  
(if applicable)r 
 
If clinically significant pulmonary hypertension is diagnosed, 
 perform CT pulmonary angiogram (or other appropriate study) to rule out pulmonary embolism 
 
Concomitant 
medications 
 
X………………………………………….…………………………………………………………………………………….……………X 
 
Adverse event 
evaluations 
 
X………………………………………….………..………………………………………………………………………………………..…………..Xs 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 92 of 135 
29 November 2016 
 
CONFIDENTIAL 
APPENDIX A: 
SCHEDULE OF ASSESSMENTS (CONT’D) 
 Screeninga
On Study 
(pemetrexed, carboplatin + demcizumab/placebo)
On Study 
(pemetrexed maintenance) 
Termination
Visit 
Follow-
up 
Period 
Day(s) 
-28 to -1 
0 
7 
14 
21
28
35
42
56
63
84
105
112 
126
140 
147
168b 
 
 
Pharmaco- 
kineticst 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Xt 
X 
 
Anti-
demcizumab 
antibodyu 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
Xu 
X 
 
Blood for 
biomarkersv 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Optional 
Pharmaco- 
Genomicsw 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Colonoscopy 
and/or upper GI 
endoscopy (if 
applicable)x 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FFPEy 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survival data 
(with  date and 
cause of death)z 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xz 
Subsequent 
anti-cancer 
therapiesaa 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xaa 
Response 
assessment databb 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xbb 
BNP and 
Doppler 
echocardio- 
gramcc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xcc 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 93 of 135 
29 November 2016 
 
CONFIDENTIAL 
 
NOTES TO APPENDIX A 
Unless otherwise indicated, all assessments must be performed prior to dosing for all study visits when dosing occurs.  
All on-study evaluations (i.e., from Day 0 up to Termination visit) must be done within the following timeframes: 
 
Dosing of demcizumab or placebo within ± 2 days of the Study Day 
 
Laboratory evaluations within ± 3 days of the Study Day 
 
Tumor assessment, tumor marker CEA (if applicable), ECG, and transthoracic Doppler echocardiogram within ± 7 days of the Study Day 
For subjects who only receive pemetrexed maintenance after discontinuation of carboplatin and demcizumab/placebo, every-three-week visits can be rescheduled accordingly if 
pemetrexed administration and associated assessments (i.e. physical examination, weight, vital signs, ECOG performance status, CBC, and chemistry) were delayed for adverse or 
other unforeseen events. In addition, if the timing of a protocol-mandated study visit coincides with a holiday or weekend that precludes the visit, the visit should be scheduled on 
the nearest following feasible date, with subsequent visits rescheduled accordingly. Pemetrexed cycles may be extended from 3 to up to 4 weeks to realign assessments. 
Subjects who have discontinued all study drugs and have no clinically significant ongoing related adverse events that require close follow-up have to undergo the following 
assessments only every 42 days (ideally synchronized with tumor assessments and tumor marker CEA, if applicable): physical examination, weight, vital signs, ECOG performance 
status, CBC, and chemistry. 
However, the schedule for BNP assessments (every 21 days; see footnote o. for more details), for ECG and transthoracic Doppler echocardiogram (every 28 days; see footnotes p. 
and q. for more details), and for tumor assessment and tumor marker CEA, if applicable (every 42 days), is to be maintained.  
a. 
Subjects must sign and date the Informed Consent Form (Appendix E) that has been approved by the IEC/IRB prior to undergoing any study-related procedures. Once the 
screening process has been completed, the Investigator must complete a randomization request form and submit it for approval. Once OncoMed or its representative has 
approved randomization, the investigator/study coordinator will use the IWRS system to randomize the subject. Subjects who are randomized will not be replaced. The IWRS 
system will then assign a subject number, and the subject will be officially enrolled in the study. This unique subject number will be on all electronic case report form (eCRF) 
pages. Study drug must be administered within 4 days from the date of randomization. Study Day 0 will be the first day of study drug administration. 
b. 
The frequency of assessments from Days 168 to 252 (then Days 252 to 336, and so on) is the same as shown for the 84-day time window from Days 84 to 168.   
Four types of assessments are exceptions to this general rule as they are eventually discontinued. 
 
BNP: see footnote o. 
 
ECG: see footnote p. 
 
Doppler echocardiogram: see footnote q. 
 
Pharmacokinetics: see footnote t. 
c. 
Subjects must receive oral folic acid ≥400 μg daily for at least 5 days of the 7 days preceding the first dose of pemetrexed and continue folic acid at this dose level during the 
full course of therapy and for 21 days after the last dose of pemetrexed. 
d. 
Subjects must receive an IM injection of vitamin B12 1000 μg during the week preceding the first dose of pemetrexed and then every 63 days while receiving pemetrexed. 
e. 
Unless contraindicated, subjects should also receive dexamethasone 4 mg orally twice daily on the day before, the day of, and the day after pemetrexed administration to reduce 
the risk of developing skin rash. 
f. 
Arm 1 - carboplatin, pemetrexed plus placebo every 3 weeks for 4 cycles (i.e., last administration on Day 63), then maintenance pemetrexed once every 3 weeks beginning on 
Day 84 and a second course of placebo once every 3 weeks for 63 days beginning at Study Day 168  
 
Arm 2 - carboplatin, pemetrexed plus demcizumab every 3 weeks for 4 cycles (i.e., last administration on Day 63), then maintenance pemetrexed once every 3 weeks beginning 
on Day 84 and a course of placebo once every 3 weeks for 63 days beginning at Study Day 168 
 
Arm 3 - carboplatin, pemetrexed plus demcizumab every 3 weeks for 4 cycles (i.e., last administration on Day 63), then maintenance pemetrexed once every 3 weeks beginning 
on Day 84 and a second course of demcizumab once every 3 weeks for 63 days beginning at Study Day 168 
 
Subjects will only receive their second 4-cycle course (starting on Day 168) of demcizumab (5 mg/kg) or placebo if they meet the original cardiac-related eligibility criteria (see 
Exclusion Criterion 21 in Section 6.2), they did not develop pulmonary hypertension or heart failure while on study, and blood pressure is controlled to ≤140/90 mmHg. 
Subjects who do not meet the 
 
criteria to receive the second 4-cycle course of placebo or demcizumab will continue to receive maintenance pemetrexed per protocol without demcizumab or placebo. 
 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 94 of 135 
29 November 2016 
 
CONFIDENTIAL 
 
NOTES TO APPENDIX A: CONT’D 
g. 
Demcizumab or placebo, pemetrexed and carboplatin must be dosed as described in Section 8.0. Demcizumab or placebo is to be administered first, followed by pemetrexed 
and then carboplatin. 
h. 
A full physical examination will be done at screening.  Subsequently, an abbreviated physical examination will be performed at Day 0, every 3 weeks during the on-study part 
of the protocol and at the termination visit.  The abbreviated physical examination must include respiratory rate, auscultatory examination of the heart and lungs, abdominal 
examination, and assessment for the presence or absence of edema and/or ascites.  A more complete physical examination should be conducted when clinically indicated. 
i. 
On days of demcizumab or placebo dosing, vital signs will be obtained before infusion (- 1 hour), 15 (±5) minutes after start of infusion, end of infusion (+ 5 minutes), and 
15 (±5) minutes  
after end of infusion of demcizumab or placebo. 
 
Vitals will be obtained once at the visits where demcizumab or placebo is not administered, prior to pemetrexed (and/or carboplatin) infusion, if applicable. 
j. 
Any subject with hypertension (i.e., >150/90 mmHg) that is considered to be related to demcizumab or placebo at the time of the termination visit will continue to have BPs 
monitored once every 2 weeks until the BP is ≤150/90 mmHg over a 4-week period with every-2-week BP measurements. 
k. 
Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, phosphorus, potassium, total protein, AST (SGOT), 
ALT (SGPT), sodium 
l. 
Serum pregnancy test (women of childbearing potential only) must be obtained within 7 days prior to randomization. 
m. Perform tumor assessment at screening (Study Days -28 to -1), every 6 weeks thereafter until disease progression, and at the termination visit (unless performed within 14 days 
of termination or at a prior response evaluation that documented progressive disease). The schedule of every 6 weeks is to be maintained throughout the study and will not be 
shifted if there are dose holds. 
 
Screening assessments should include CT scans of the chest, abdomen, and pelvis, as well as MRI of the brain.  CT scan of the neck or bone scan should be performed if 
clinically indicated.  A documented standard-of-care tumor assessment performed on or after Study Day -28 may be used for the screening assessment provided it meets 
protocol requirements.  Alternative imaging modalities may be used as outlined in Section 10.0. Subsequent tumor assessments must include imaging of chest and abdomen, as 
well as all other known sites of disease.  The same imaging methods used at screening must be used throughout the study.  Response assessments will be performed by the 
investigator according to RECIST v1.1 (Appendix C). 
n. 
If elevated at baseline 
o. 
BNP must be assessed on the same day prior to each dose of demcizumab/placebo, and elevations will be managed per Section 8.1.6. After discontinuation of demcizumab 
or placebo (either as scheduled per protocol or unscheduled for other reasons), BNP assessments are continued every 21 days for another 105 days (5 assessments total). For 
example, if the last scheduled demcizumab or placebo dose is given on Day 231, a total of 5 more BNP assessments will occur on Days 252, 273, 294, 315 and 336. However, 
should the BNP result not meet eligibility criteria at the last assessment 105 days after the last demcizumab or placebo dose, BNP assessments have to be continued every 21 
days until two consecutive assessments meet eligibility criteria or the termination visit has occurred. 
p. 
A 12-lead ECG must include assessment of the PR interval, QRS duration, and QTc interval and must be done every 28 days. After discontinuation of demcizumab or placebo 
(either as scheduled per protocol or unscheduled for other reasons), ECG assessments are continued every 28 days for ≥105 days. For example, if the last scheduled 
demcizumab or placebo dose is given on Day 231, a total of 4 more ECG assessments will occur on Days 252, 280, 308 and 336. Clinically significant ECG abnormalities at 
the last assessment ≥105 days (depending on timing of assessments) after the last demcizumab or placebo dose should be addressed according to standard of care. ECG does not 
have to be repeated at the termination visit if it was performed within 14 days of the termination visit. 
q. 
A Doppler echocardiogram with left ventricular ejection fraction and peak tricuspid velocity determination, if measurable, must be done every 28 days. After discontinuation of 
demcizumab or placebo (either as scheduled per protocol or unscheduled for other reasons), Doppler echocardiogram assessments are continued every 28 days for ≥105 days. 
For example, if the last scheduled demcizumab or placebo dose is given on Day 231, a total of 4 more ECG and Doppler echocardiogram assessments will occur on Days 252, 
280, 308 and 336. However, should results of the Doppler echocardiogram not meet eligibility criteria at the last assessment ≥105 days (depending on timing of assessments) 
after the last demcizumab or placebo dose, assessments have to be continued every 28 days until two consecutive Doppler echocardiograms meet eligibility criteria or the 
termination visit has occurred. Doppler echocardiogram does not have to be repeated at the termination visit if it was performed within 14 days of the termination visit. 
r. 
A CT pulmonary angiogram (CTPA) should be performed if clinically significant pulmonary hypertension is diagnosed (i.e, peak tricuspid velocity >3.4 m/s on Doppler 
echocardiogram and diagnosed with clinically significant pulmonary hypertension that includes minimal dyspnea by a cardiologist or pulmonologist) to determine if pulmonary 
embolism might be the cause of the pulmonary hypertension. An MR angiogram or VQ scan may be performed instead per local or country standards or if the subject has a 
contrast allergy. 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 95 of 135 
29 November 2016 
 
CONFIDENTIAL 
 
NOTES TO APPENDIX A: CONT’D 
s. 
To be collected from randomization until 30 days after the termination visit. 
t. 
Plasma samples for PK analysis will be obtained prior to the demcizumab/placebo infusion, if applicable, on Days 0, 42, 84, 126, 168, 210, 252, 294 and 336, and at the end of 
the demcizumab/placebo infusion (prior to the chemotherapy infusion, if applicable) on Days 0, 42, 168 and 210, and at the termination visit.  Instructions for the collection 
handling, storage, and shipment of these samples are provided in the Study Reference Binder. 
u. 
Serum samples for immunogenicity will be obtained at baseline, every 6 weeks (prior to the demcizumab or placebo infusion, if applicable) during the study, and at the 
termination visit.  Instructions for the collection, handling, storage, and shipment are provided in the Study Reference Binder. 
v. 
A total of 9 mL of blood will be drawn for biomarkers on Days 0 and 28, and at the termination visit, unless one has been obtained during the prior 14 days for subjects 
continuing on demcizumab/placebo to evaluate changes in plasma proteins (4 mL; e.g., VEGF, βFGF, SDF1, PLGF, TNFα, MCP1, etc.), and Notch-related gene expression of 
mRNA (5 mL) as described in Section 11.0.   Instructions for the collection, handling, storage, and shipment are provided in the Study Reference Binder. 
w. For subjects who sign the optional Pharmacogenomics Informed Consent only, a blood sample (10 mL) will be collected at Day 0 (where local regulations permit).  Analysis of 
genes relevant to Notch/DLL4 target or pathway genes may be performed (e.g., FBW7 and PTEN).  Instructions for the collection, handling, storage, and shipment of these 
samples are provided in the Study Reference Binder 
x. 
Colonoscopy and/or upper gastrointestinal endoscopy must be performed in subjects with symptoms suggestive of possible gastrointestinal involvement to rule out 
gastrointestinal involvement. 
y. 
If available, archival FFPE tumor tissue (from either the primary tumor, locoregional disease or a metastatic site) obtained by core biopsy or surgical resection will be collected. 
Analysis of candidate genes and/or proteins relevant to the Notch pathway may be performed (e.g., DLL4, Notch1, Hey 1, FBW7, etc.).  Archived FFPE specimens may be 
obtained during screening or post-screening, as long as the trial is active. Instructions for the collection, handling, storage, and shipment of these samples are provided in the 
Study Reference Binder.  
z. 
Once a subject has completed the termination visit, overall survival follow-up will be performed every three months ± 1 week for up to 5 years to determine the subject’s status 
and ultimately the date and cause of death. Follow-up may be conducted through telephone calls, review of medical records, and/or clinic visits.  In addition, the site may check 
public data sources to get this information, if needed (e.g., obituaries). 
aa. Subsequent anti-cancer therapies, including systemic therapies, surgery (resection of metastatic disease), and radiation therapy will be collected through telephone calls, review 
of medical records, and/or clinic visits on the same schedule as for survival data (see note z.). 
bb. Response assessment data (i.e., progressive disease or no progression of disease) will continue to be collected (based on standard-of-care radiographs) on subjects who have not 
progressed at the time of the termination visit. For these subjects, copies of the standard-of-care radiographs may be provided to the Sponsor in a de-identified manner.  These 
data and radiographs will continue to be collected until the subject starts new anti-cancer treatment or develops progressive disease, whichever occurs first. 
cc. If a subject has a BNP of ≥400 pg/mL and/or a diagnosis of pulmonary hypertension or heart failure at the time of the termination visit, all subsequent standard-of-care BNP 
data until the value is <200 pg/mL and all subsequent standard-of-care LVEF and PTV values until they normalize will be collected and entered into the database. 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 96 of 135 
29 November 2016 
 
CONFIDENTIAL 
APPENDIX B: 
ECOG PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  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 
In bed <50% of the time.  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 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead 
 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 97 of 135 
29 November 2016 
 
CONFIDENTIAL 
APPENDIX C: 
RECIST CRITERIA VERSION 1.1 
Response Evaluation Criteria in Solid Tumors (RECIST) Quick Reference 
ELIGIBILITY 
Only subjects with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint. 
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. 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
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Page 98 of 135 
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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. 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 99 of 135 
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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 Appendix II 
(Ref 34) 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. 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 100 of 135 
29 November 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 portions 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 subjectwith 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 subjectwith 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. 
RESPONSE CRITERIA 
Evaluation of Target Lesions 
Complete Response (CR): Disappearance of all target lesions.  Any pathological lymph node (whether 
target or nontarget) 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. 
 


 
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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 
 
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.  Symptomatic deterioration is not a 
descriptor of an objective response: it is a reason for stopping study therapy.  The objective 
response status of such patients is to be determined by evaluation of target and non-target disease 


 
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 
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 D: 
NEW YORK HEART ASSOCIATION CLASSIFICATION 
NYHA 
Class 
Symptoms 
I 
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, e.g. no 
shortness of breath when walking, climbing stairs etc. 
II 
Mild symptoms (mild shortness of breath and/or angina) and slight limitation during 
ordinary activity. 
III 
Marked limitation in activity due to symptoms, even during less-than-ordinary activity, e.g., 
walking short distances (20-100 m).  Comfortable only at rest. 
IV 
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound subjects. 
 


 
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APPENDIX E: 
SAMPLE INFORMED CONSENT 
PROTOCOL M18-007:  A 3-Arm Phase 2 Double-Blind Randomized  Study of Carboplatin, 
Pemetrexed Plus Placebo versus Carboplatin, Pemetrexed plus 1 or 2 Truncated Courses of 
Demcizumab in Subjects with Non-Squamous Non-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.  If you have any questions that are not answered or if there are words that you 
do not understand in this consent form, a member of the research team will give you further 
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. 
You are being asked to participate in this research study because you have been diagnosed with 
advanced non-squamous non-small cell lung cancer that is no longer operable. 
PURPOSE AND BACKGROUND 
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 represent 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 purpose of this study is to test the efficacy and safety of a new experimental drug, 
demcizumab, when given in combination with carboplatin and pemetrexed. To evaluate the 
efficacy of demcizumab, demcizumab will be compared to placebo (looks like demcizumab, but 
does not contain any medication). The administration of carboplatin and pemetrexed is a 
standard treatment for patients with non-squamous non-small cell lung cancer.  You will also be 
given 2 vitamins (folic acid and vitamin B12) and 1 corticosteroid (dexamethasone) to reduce the 
adverse effects of pemetrexed. 
Demcizumab is a humanized monoclonal antibody and was developed to target cancer stem 
cells.  Demcizumab may block the growth of cancer stem cells and the remaining cancer cells, 
and it may also prevent the growth of new blood vessels that tumors need to grow and spread. 
Demcizumab, used in this study, is experimental. That means that the United States Food and 
Drug Admininstration (FDA) has not approved it for use by the general public. This study is 
sponsored by OncoMed Pharmaceuticals, which is referred to as OncoMed or the Sponsor in this 
consent form.   


 
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WHAT IS EXPECTED FROM YOU? 
When deciding whether to participate, consider whether you are able and willing: 
 To follow the study rules 
 To commit the time required to keep appointments 
 To tell the study doctor truthfully about your complete medical history 
 To report any new problems, illnesses, or changes in medication during the study 
 PROCEDURES 
At least 201 patients will be enrolled at up to approximately 60 to 90 centers in North America, 
Western Europe and Australia.  Up to 28 days (4 weeks) prior to treatment you will undergo 
testing to determine your eligibility to take part in this study, and then, if enrolled in the study, 
you will receive intravenous (in the vein) infusions of demcizumab (or placebo), carboplatin, and 
pemetrexed administered on the same day, every 21 days for 4 cycles, or until it has been shown 
that your cancer has gotten worse.  If your physician decides to delay treatment with one of the 
agents due to side effects, the other agents may still be administered as scheduled.  After 
4 cycles, if you have stable or improved disease, you will continue to receive pemetrexed once 
every 21 days as maintenance therapy.  After 8 cycles, if you have stable or improved disease, 
you will receive demcizumab (or placebo), every 21 days for 4 more cycles.  You will undergo 
assessments every 6 weeks to determine the status of your disease.  
In addition to routine testing of blood and urine (for complete blood counts with differential and 
platelets; coagulation studies to determine how quickly your blood is clotting; serum chemistries; 
B-type natriuretic peptide [BNP], which indicate how well your heart is working; creatinine 
clearance to measure your kidney function; and urinalysis), special tests will be performed 
during the study at specific time points listed below.  The special tests include the following: 
 Tumor markers:  These are substances that can be detected in higher than normal 
amounts in blood, urine, or body tissues for certain types of cancer.  The tumor marker 
level may indicate the extent of the cancer in your body and may show how you are 
responding to treatment.  For this study, only blood samples will be taken to check for 
tumor markers.  The tumor marker for non-small cell lung cancer is CEA.  If your 
baseline CEA tumor marker is not elevated, the test will not be repeated during the study.  
If your baseline CEA is elevated at baseline, the test will be repeated every 6 weeks. 
 Antibodies to demcizumab:  Antibodies are proteins produced by your body's immune 
system in response to a foreign substance.  In some cases, the development of antibodies 
to a treatment will not have any impact on the effectiveness of the treatment.  In other 
cases, the development of antibodies to a treatment can cause the treatment to be 
ineffective.  Blood will be drawn every 6 weeks while you are receiving study drugs 
(demcizumab or placebo, or carboplatin or pemetrexed) and at the termination visit to 
determine if you are developing antibodies to demcizumab.  Additional testing may also 


 
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be done to provide information on the response seen in the demcizumab test.  Various 
experiments would be performed on the samples taken from you for antibodies to 
demcizumab testing.  These experiments will determine the identity and obtain more 
detailed information on the anti-drug antibody response. 
 Pharmacokinetic Analysis:  Blood samples will be obtained prior to your demcizumab (or 
placebo) infusion on Study Days 0, 42, 84, 126, 168, 210, 252, 294 and 336, and at the 
end of infusion on Study Days 0, 42, 168 and 210, and at your termination visit, to 
determine how the demcizumab is distributed and eliminated from your body. 
 Biomarkers:  On Study Days 0 and 28, and at your termination visit, blood samples will 
be obtained to assess whether the demcizumab is producing desired changes to the genes 
and proteins related to your cancer.  In addition, archival tumor tissue sections (formalin-
fixed paraffin-embedded, FFPE) will be collected any time after enrollment, if available, 
for gene and protein testing of biomarkers related to your cancer.  No additional 
procedures or surgery will be performed to obtain these archival tumor tissue sections.  If 
you agree to have DNA testing on your FFPE tissue, you will sign a separate consent.  
DNA testing of your tumor may help to identify biomarkers that could be used in the 
future to predict which patients are more likely to respond to demcizumab, carboplatin 
and pemetrexed treatment. 
In addition, you will have an electrocardiogram (ECG) and Doppler echocardiogram performed 
during screening, then every 28 days on study (up to Study Day 336, assuming you receive all 
doses of demcizumab/placebo) and at your termination visit.  Your Doppler echocardiograms 
may be sent to a cardiologist at another hospital who may perform a central read on some of the 
Doppler echocardiograms in this study.  Finally, you will have imaging of your brain (magnetic 
resonance imaging [MRI] or computerized tomography [CT]) at baseline, and CT scans and/or 
other radiographs performed at baseline, then every 6 weeks, and at your termination visit, to 
assess the status of your tumor. A CT pulmonary angiogram (CTPA; or MR angiogram or VQ 
scan) may be performed if you are diagnosed with pulmonary hypertension to see if you have a 
pulmonary embolism. 
SCREENING 
If you volunteer to be in this study and you sign this informed consent form, you will be 
screened within 28 days before study entry to make sure that you are a suitable candidate.  No 
study-related tests will be performed prior to signing this informed consent form.  Your doctor 
will conduct a review of your physical health and medical history, including other cancer 
treatments that you have had and a review of any medications you are or have been taking.  In 
addition, a physical examination including height and weight will be performed, and vital signs 
including your pulse, blood pressure, breathing rate and temperature will be measured.  Blood 
and urine samples will be collected for routine testing, including BNP.  Blood will also be drawn 
for testing of the tumor marker CEA.  Approximately 3 tablespoons of blood will be taken at this 


 
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visit.  You will also have an ECG, Doppler echocardiogram, and either a CT scan or MRI of 
your chest, abdomen, pelvis, and head.  Finally, if your tumor involves your esophagus, stomach, 
or intestinal tract or if you have symptoms that suggest that your tumor may involve these areas, 
you will also have a colonoscopy and/or upper gastrointestinal endoscopy to ensure that your 
tumor does not currently involve your gastrointestinal tract.  If you are a female of childbearing 
potential, you will have a serum pregnancy test within 7 days prior to randomization (time when 
you are assigned a treatment arm), to ensure that you are not pregnant at the start of the study. 
TREATMENT PHASE 
Demcizumab (or Placebo) 
Once your doctor has evaluated the results of your screening tests to ensure that you meet the 
criteria for the study and are eligible to participate, you will be randomized in the study and 
assigned to a treatment arm. 
You will receive 5 mg/kg demcizumab or placebo as shown in the treatment arms, below.  A 
placebo looks like the demcizumab, but does not contain any medication.  The demcizumab or 
placebo will be administered intravenously (in the vein) over 30 minutes, every 3 weeks for 
63 days, starting on Day 0 and again starting on Day 168.  With each infusion, your vital signs 
will be obtained at least four times:  before the infusion; 15 minutes after the start of the infusion, 
at the end of the infusion, and 15 minutes after the end of the infusion. 
You will be randomly (by chance) assigned to one of the three treatment arms: 
Arm 1: 
 to receive carboplatin, pemetrexed plus placebo every 3 weeks for 4 cycles (last dose on 
Day 63) 
 then, starting on Day 84, to receive pemetrexed alone every 3 weeks for 4 cycles (last 
dose on Day 147) 
 then, starting on Day 168, to receive pemetrexed plus placebo every 3 weeks for 4 cycles 
(last dose on Day 231) 
 then, continue to receive pemetrexed every 3 weeks 
Arm 2: 
 to receive carboplatin, pemetrexed plus demcizumab every 3 weeks for 4 cycles (last 
dose on Day 63) 
 then, starting on Day 84, to receive pemetrexed alone every 3 weeks for 4 cycles (last 
dose on Day 147) 
 then, starting on Day 168, to receive pemetrexed plus placebo every 3 weeks for 4 cycles 
(last dose on Day 231) 
 then, continue to receive pemetrexed every 3 weeks 


 
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Arm 3: 
 to receive carboplatin, pemetrexed plus demcizumab every 3 weeks for 4 cycles (last 
dose on Day 63) 
 then, starting on Day 84, to receive pemetrexed alone every 3 weeks for 4 cycles (last 
dose on Day 147) 
 then, starting on Day 168, to receive pemetrexed plus demcizumab every 3 weeks for 4 
cycles (last dose on Day 231) 
 then, continue to receive pemetrexed every 3 weeks 
You will have an equal chance of being assigned to Arm 1, Arm 2 or Arm 3.  Neither you nor 
your doctor will know which treatment arm you have been assigned to or whether you are 
receiving demcizumab or placebo.   
Pemetrexed 
Pemetrexed will be administered at a dose of 500 mg/m2 as an intravenous infusion over 
≥10 minutes on the first day of every 21-day cycle for 4 cycles, after the administration of 
demcizumab or placebo.  Pemetrexed may be given for 4 cycles unless you have side effects or 
disease progression that necessitates stopping the drug.  After 4 cycles, if you have stable or 
improved disease, you will continue to receive pemetrexed once every 21 days as maintenance 
therapy until your tumor progresses. 
In order to reduce gastrointestinal and hematologic side effects, you will take folic acid of 
≥400 µg daily for at least 5 of the 7 days before the first dose of pemetrexed is administered and 
you will continue to take ≥400 µg of daily folic acid throughout the treatment period and for the 
first 21 days after the last dose of pemetrexed.  You will also receive an intramuscular injection 
of vitamin B12 at a dose of 1000 μg during the week before the first dose of pemetrexed and 
every 63 days while you are being treated with pemetrexed  (on Days 63, 126, 189, etc.). 
In order to reduce the occurrence of skin rashes, you will receive dexamethasone, 4 mg orally 
twice a day on the day before, the day of, and the day after pemetrexed administration, unless 
your physician determines that this is not right for you. 
Carboplatin 
Carboplatin will be administered as an intravenous infusion over 15–60 minutes on Day 1 of 
every 21-day cycle for 4 cycles, after the administration of demcizumab and pemetrexed.  The 
dose will depend on several factors including your kidney function as determined by the 
creatinine clearance test and your serum creatinine level.  Carboplatin may be given for 4 cycles 
unless you have side effects or disease progression that necessitates stopping the drug.  Your 
physician may prescribe medication to prevent nausea and vomiting from the administration of 
pemetrexed and carboplatin therapy. 


 
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If you develop side effects during this time period, your physician may decide to hold or reduce 
the carboplatin and/or pemetrexed.  If this occurs, the demcizumab or placebo may still be 
administered as scheduled. 
Study Day 0:  The following assessments will be done prior to the infusion of demcizumab or 
placebo, carboplatin, and pemetrexed:  abbreviated physical examination including weight; 
review of medications you are taking, including any changes in medication since the screening 
visit; changes in your medical status; and vital signs.  Approximately 4 tablespoons of blood will 
be drawn for routine tests, antibody testing, pharmacokinetic testing (before and after your 
infusion) and biomarkers. 
If you agree to the optional pharmacogenomics testing, you will sign the optional 
Pharmacogenomics Informed Consent, and a blood sample will be collected. 
Study drug will be administered and you will be monitored for at least 15 minutes after the 
demcizumab (or placebo) has been stopped.  Pemetrexed will then be administered, followed by 
carboplatin. 
Study Days 7, 14, 21, 28, 35, and 42:  Demcizumab or placebo, carboplatin, and pemetrexed 
will be given on Study Days 21and 42 only.  The following assessments will be obtained weekly: 
weight; review of the medications you are taking and any changes in medication since the 
previous visit; changes in your medical status or new health problems since the previous study 
visit; and vital signs.  An abbreviated physical examination will be performed on the days that 
you receive demcizumab or placebo. 
Blood will be taken weekly for routine testing (including BNP on Day 21 and Day 42).  At Day 
42 only, blood will also be obtained to test for pharmacokinetic testing and antibodies to 
demcizumab, and blood will be taken for testing tumor markers (if your CEA was elevated at 
your screening visit).  On Day 28, blood will also be obtained for biomarkers.  Approximately 
3 tablespoons of blood will be drawn on Study Days 7, 14, 21, 28, 35, and 42. 
On Day 28, an ECG and Doppler echocardiogram will be done. 
In addition, on Day 42, you will undergo a CT scan or MRI of the chest, abdomen, and other 
parts of your body, if your cancer has spread there, to assess whether your cancer has improved, 
progressed, or is stable.  If the CT scan or MRI shows that you have stable or improved disease, 
you may continue to receive demcizumab/placebo, carboplatin and pemetrexed. 
If the CT scan or MRI shows disease progression, you will be taken off the study and will 
undergo assessments listed under Termination Visit. 
Study Day 56:  The following assessments will be obtained: changes in your medical status or 
new health problems since the previous study visit. 
An ECG and Doppler echocardiogram will be done. 


 
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Study Day 63:  Demcizumab or placebo, carboplatin, and pemetrexed will be given.  The 
following assessments will be obtained prior to the infusion of drug: weight; review of the 
medications you are taking and any changes in medication since the previous visit; changes in 
your medical status or new health problems since the previous study visit; and vital signs.  An 
abbreviated physical examination will be performed. 
Blood, approximately 3 tablespoons, will be taken for routine testing (including BNP).   
Study Day 84:  Pemetrexed will be given.  The following assessments will be obtained:  weight; 
review of the medications you are taking and any changes in medication since the previous visit; 
changes in your medical status or new health problems since the previous study visit; and vital 
signs.  An abbreviated physical examination will be performed on the day that you receive 
pemetrexed. 
Blood will be taken for routine testing (including BNP).  Blood will also be obtained for testing 
for antibody formation to demcizumab and for pharmacokinetic testing, and blood will be taken 
for testing tumor markers (if your CEA was elevated at your screening visit).  Approximately 
3 tablespoons of blood will be drawn. 
An ECG and Doppler echocardiogram will be done. 
You will undergo a CT scan or MRI of the chest, abdomen, and other parts of your body, if your 
cancer has spread there, to assess whether your cancer has improved, progressed, or is stable.  If 
the CT scan or MRI shows that you have stable or improved disease, you may continue to 
receive demcizumab/placebo, carboplatin and pemetrexed. 
If the CT scan or MRI shows disease progression, you will be taken off the study and will 
undergo assessments listed under Termination Visit. 
Study Day 105:  The following assessments will be obtained prior to the infusion of 
pemetrexed:  abbreviated physical examination including weight; review of the medications you 
are taking and any changes in medication since the previous visit; changes in your medical status 
or new health problems since the previous study visit; and vital signs. 
Approximately 3 tablespoons of blood will be taken for routine testing, including BNP. 
As long as your disease is stable or shows a response, you may continue to receive pemetrexed 
every 3 weeks.  You will undergo the tests listed for Study Day 105 during each of these 3-week 
cycles.  You will receive intramuscular injection of vitamin B12 at a dose of 1000 μg every 
63 days while receiving pemetrexed.  In addition, every 6 weeks you will undergo a CT scan or 
MRI of the chest, abdomen and other parts of your body, if your cancer has spread there, to 
assess whether your cancer has improved, progressed, or is stable. 


 
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Every 6 weeks blood will be taken for antibodies to demcizumab, and blood will be obtained for 
tumor markers, if applicable.  You will also have an ECG and a Doppler echocardiogram every 
4 weeks. 
Starting on Day 168, you will receive demcizumab or placebo every 3 weeks for four 21-day 
cycles.  On Day 168 (before and after your infusion), Day 210 (before and after your infusion) 
and Days 252, 294 and 336 (before infusion) only, blood samples will be taken for 
pharmacokinetic testing. 
TERMINATION VISIT 
When you have discontinued receiving study drugs (demcizumab or placebo, carboplatin, and 
pemetrexed, or pemetrexed alone), and you are no longer being followed with study assessments, 
including CT scans or MRIs every 6 weeks to assess whether your cancer has improved, 
progressed, or is stable, the following assessments will be performed:  abbreviated physical exam 
with weight; review of  medications you are taking and any changes in medication since the 
previous visit; changes in your medical status or new health problems since the previous study 
visit; and vital signs. 
Blood samples will be obtained for routine testing (including BNP), antibody formation to 
demcizumab, and pharmacokinetic testing.  Blood will also be obtained for biomarkers unless 
obtained within the previous 14 days.  Blood will also be obtained for tumor marker testing if 
applicable and for BNP unless obtained within the previous 28 days.  A urine specimen will be 
obtained.  An ECG and a Doppler echocardiogram will be performed.  A repeat CT scan or MRI 
of the chest, abdomen, and other parts of your body, if your cancer has spread there, will be 
obtained unless performed within 14 days of Termination visit. 
Approximately 3 tablespoons of blood will be drawn during this visit. 
FOLLOW-UP AFTER TERMINATION VISIT 
If your blood pressure was too high at the Terminiation visit (greater than 150/90 mmHg), your 
blood pressure will be determined every 2 weeks until your blood pressure is less or equal to 
150/90 mmHg for a 4-week period. 
You will be contacted every 3 months for up to 5 years by the clinic study staff to check on your 
condition. This contact may be by telephone or medical record review.  Information regarding 
any anti-cancer therapies that you receive will also be collected through telephone calls, review 
of medical records, and/or clinic visits. 
In addition, if your tumor has not progressed at the time of your Termination visit, your tumor 
response outcome will continue to be followed until you begin receiving alternative anti-cancer 
treatment or your tumor progresses, whichever occurs first, and a copy of the corresponding 
radiographs (e.g., CT scans and/or MRIs) may be provided to OncoMed, the Sponsor of the trial.  
If you have a BNP ≥400 pg/mL and/or a diagnosis of pulmonary hypertension or heart failure at 


 
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the time of termination, all subsequent standard of care BNP data will be collected until the value 
is <200 pg/mL and all subsequent standard of care left ventricular ejection fraction (LVEF) and 
peak tricuspid velocity (PTV) values will be collected until they normalize.  LVEF and PTV are 
tests that provide information on how your heart is functioning. 
POSSIBLE RISKS AND DISCOMFORTS 
Demcizumab 
The following are the side effects that were observed in >10% (common) and 5-10% (less 
common) of the 55 patients treated in the initial single-agent study of demcizumab and were 
considered to be possibly related to demcizumab. 
Common (occurred in >10% of patients who received demcizumab) 
Hypertension, fatigue, anemia, diarrhea, headache, nausea, decreased protein in the blood and 
shortness of breath 
Less Common (occurred in 5-10% of patients who received demcizumab) 
Low sodium in blood, dizziness, weight loss, heart failure, shortness of breath with activity, 
laboratory values indicating a decrease in liver or kidney function, decreased white blood count 
in the blood, abdominal pain, chills, fever, insomnia and cough 
The following are the side effects that were observed in >10% (common) and 5-10% (less 
common) of the 99 patients treated in the 4 studies of demcizumab plus chemotherapy and 
were considered to be possibly related to demcizumab. 
Common (occurred in >10% of patients who received demcizumab and chemotherapy) 
Fatigue, nausea, hypertension, swelling of tissue due to increased fluid, diarrhea, appetite 
decreased, increased BNP (suggesting possible early damage to the heart), anemia, decreased 
platelet count in the blood, decreased white blood count in the blood, shortness of breath, 
headache, increased pressure in the lungs, constipation and rash. 
Less Common (occurred in 5-10% of patients who received demcizumab and 
chemotherapy) 
Change in taste, hair loss and laboratory values indicating a decrease in liver function 
The majority of the side effects observed in these studies were mild to moderate.  The most 
common adverse event across these studies that was clearly related to demcizumab was 
hypertension which occurred in 14-60% of the patients. Thus, if you participate in this study, 
your blood pressure will be checked frequently and, if necessary, you will be treated with 
medication(s) to lower your blood pressure.  If your increased blood pressure is not controlled by 
medications, administration of demcizumab will be discontinued. 


 
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In addition, in these studies, 7 patients developed serious bleeding in the gastrointestinal tract.  
Two patients died as a result of this bleeding.  Because of that, you will not be treated in this 
study if you have tumor in one or more locations that carries an increased risk for bleeding.  
If you participate in the study, your hemoglobin (a measurement of the amount of red blood 
cells) will be tested regularly.  If your hemoglobin decreases, your physician will look carefully 
for the reason.  If you develop active significant bleeding, administration of demcizumab will be 
discontinued. 
One patient in the single-agent study died as a result of complications relating to a tumor within 
the brain.  As a result, if you choose to participate in this study, prior to treatment you will have a 
scan of the brain to ensure that there is no tumor within the brain.  Patients who have a tumor 
within the brain will not be able to participate in the study. 
Finally, approximately 40% of patients treated in these trials developed rises in a laboratory test 
(BNP) suggesting possible early damage to their heart.  In addition, approximately 5-10% of the 
patients had symptoms of heart failure (such as shortness of breath and/or extra fluid in their 
legs).  These patients typically improved after discontinuation of demcizumab and treatment with 
medications to reduce their symptoms.  In addtition, the heart failure typically developed in 
patients who received demcizumab for at least 3 months.  Also, an increase in the blood pressure 
in the lungs which can also result in heart failure has been observed in some patients that were 
typically treated for more than than 3 months.  As a result, demcizumab will not be given on an 
ongoing basis in this study.  Instead, a shortened regimen of 4 doses over 63 days will be 
administered either once or twice during your time on study.  Approximately 50 patients have 
received this type of shortened treatment schedule, and none have developed serious heart failure 
or increased blood pressure in the lungs.  However, it is anticipated that heart failure and /or 
increased blood pressure in the lungs will likely still occur in some patients receiving this 
shortened duration of treatment with demcizumab.  Finally, no patients have been previously 
treated with a 2nd 63-day course of demcizumab that some patients will be receiving in this 
study, so the risks of this approach are unknown. 
You will not be treated in this study if you have an elevated BNP value, evidence of heart failure 
or evidence of disease in the vessels in your heart, or have a significant decrease in the amount of 
blood your heart is pumping on Doppler echocardiogram.  Your heart and lung function will be 
watched closely while you are on study using blood tests and echocardiograms. If these side 
effects are noted, you will be referred to a heart specialist who may be able to treat the side 
effects with drugs.  If further increases in your BNP occur or the amount of blood your heart is 
pumping declines further, your demcizumab therapy will be discontinued.   
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 demcizumab.  Rarely, a severe or serious 
allergic reaction can occur during or following the administration of an antibody. 
Not enough patients have yet been treated with demcizumab to fully understand the side effects 
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The following side effects have been observed in other drugs that have an anti-angiogenic effect 
(drugs that prevent the growth of new blood vessels that tumors need to grow and spread) and in 
other drugs that may inhibit the growth of cancer stem cells.  It is not known if the administration 
of demcizumab will result in any of these findings: 
· 
Gastrointestinal perforation sometimes associated with intra-abdominal abscess 
· 
Diarrhea, weight loss, constipation, vomiting, abdominal pain, nausea, and fever 
· 
Wound healing complications 
· 
Hemorrhage including minor bleeding events such as nose bleeds or more serious, 
sometimes fatal bleeding events 
· 
Arterial or venous thromboembolic events, including cerebral (brain) infarction, transient 
ischemic attacks (TIAs), myocardial infarction (MI), angina, and other sometimes fatal 
events 
· 
Hypertension including episodes of severe increased blood pressure 
· 
Neutropenia and/or infection 
· 
Proteinuria (loss of protein through your kidneys) 
· 
Congestive heart failure 
· 
Diarrhea 
· 
Rashes 
· 
Somnolence (sleepiness) 
· 
Fatigue 
· 
Prolonged QT interval (irregular heart rhythm) 
Pemetrexed:  The following side effects have been reported in >10% of patients receiving 
pemetrexed: 
· 
Low blood counts.  Your white and red blood cells, neutrophils and platelets may 
decrease.  This may put you at an increased risk for infection, anemia, and/or bleeding 
· 
Decreased kidney function 
· 
Fatigue 
· 
Nausea 
· 
Sensory neuropathy.  Neuropathy (nerve damage).  You may feel weakness, pain, 
numbness, and/or a tingling sensation especially in your fingers and toes 
· 
Taste disturbance 
· 
Rash, peeling of the skin, hives 
· 
Increases in liver enzymes 


 
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Carboplatin:  The following side effects have been reported in >10% of patients receiving 
carboplatin: 
· 
Low blood counts.  Your white and red blood cells, neutrophils, and platelets may 
decrease.  This may put you at an increased risk for infection, anemia, and/or bleeding. 
· 
Infection 
· 
Bleeding 
· 
Nausea 
· 
Vomiting 
· 
Peripheral neuropathy 
· 
Hearing loss 
· 
Central neurologic toxicity 
· 
Decreased kidney function 
· 
Elevation of liver function tests 
· 
Electrolyte imbalances 
· 
Pain 
· 
Weakness 
· 
Cardiovascular abnormalities 
· 
Respiratory problems 
· 
Mouth and lip sores and sore throat 
· 
Allergic reaction such as hives, redness and itching  
· 
Serious allergic reactions such as anaphylaxis 
· 
Hair loss 
Other less frequent adverse events occur following the administration of carboplatin and 
pemetrexed. 
Infusions 
Demcizumab or placebo, carboplatin and pemetrexed will be given as intravenous infusions.  
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. 
Blood Draws 
During the course of this study, your blood will be drawn for laboratory tests (3-4 tablespoons 
will be collected at each blood draw).  The risks of drawing blood include some discomfort from 


 
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the needle in your arm, bruising, swelling at the needle site and, in rare instances, infection or 
fainting. 
You will also be informed of any new significant side effects that develop during the course of 
this research study, or others regarding the use of demcizumab. 
Radiation exposure 
Risk relevant to the radiation exposure due to the following procedures: Radiographic 
evaluation:  Conventional CT, Spiral CT, or MRI of the chest, abdomen, and pelvis performed in 
screening, the same radiographic technique of each region must be used consistently throughout 
the study.  Radiographic evaluation:  Conventional CT, Spiral CT, or MRI of the head performed 
in screening. 
PREGNANCY 
There is a very high risk that demcizumab 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) prior to study entry and 
for the duration of the study until 6 months after the last dose of demcizumab. 
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 6 months after the last dose of 
demcizumab, 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 Termination Visit 
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 3 months after the last dose of demcizumab, you 
and/or your partner will be followed through the first well-baby visit or longer if any abnormality 
is present. 
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. 


 
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SIGNIFICANT NEW FINDINGS 
Any significant new findings regarding demcizumab that become known during the course of 
this research study that might reasonably affect your willingness to participate in this study, will 
be provided to you in a timely manner. 
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 PATIENT 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 demcizumab, unacceptable adverse events, unacceptable BNP  and/or LVEF 
values, 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 demcizumab or placebo injections 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 Termination Visit.  In addition, your doctor will discuss with you 
alternate therapies for your disease. 
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 patients 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. 
You may be reimbursed for any reasonable travel expenses (bus/train/taxi fares) incurred as a 
result of taking part in this study on production of a receipt. 


 
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COMPENSATION FOR RESEARCH-RELATED INJURY 
If you are physically injured as a direct result of demcizumab or a study procedure properly 
performed under the plan for this study and it is not due to a pre-existing medical condition or 
underlying disease, or your failure to follow the instructions provided by your doctor or another 
member of the study team, OncoMed will reimburse you for the reasonable medical expenses for 
medically necessary treatment of that injury which are not covered by another payor, your own 
insurance or health care program.  No other compensation is available from OncoMed if any 
injury occurs. 
CONFIDENTIALITY 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law.  This 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 anytime. 
HOW WILL YOUR CONFIDENTIALITY BE RESPECTED AND THE PRIVACY OF 
YOUR PERSONAL INFORMATION MAINTAINED? 
You have the right to control the use and disclosure of your personal information.  Basic 
personal information will be recorded including your name, contact details, gender, height, 
weight and racial origin, as well as information on your medical history, and clinical data 
collected about your participation in the study.  All this information will be used for research and 
clinical purposes only, including without limitation the pharmacokinetic and optional DNA 
research described in this consent form. 
The following people may also have access to these records: representatives of the FDA, other 
regulatory authorities, the Institutional Review Board/Independent Ethics Committee, OncoMed 
representatives and monitors, and OncoMed collaborators and licensees.  All personnel accessing 
your records are required to respect your confidentiality at all times. 
To ensure privacy, your name and other identifying information will not be attached to records or 
samples released for research purposes.  Instead, you will only be identified by a code.  Only the 
study doctor and authorized personnel will be able to connect this code to your name, by a list 
that will be kept securely by the study site for "[insert retention period]" years.  Your date of 
birth (Amend the sentence to account for any country-specific rules) may also be recorded to 
help identify your study record. Your coded data will be forwarded to OncoMed and its service 
providers for activities related to the study e.g., laboratory analysis.  It will be transferred into a 
computer database and processed to allow the results of this study to be analyzed and reported or 
published.  If the results of the study are published, your identity will remain confidential, you 
will not be identified by name, picture, or by any other personally identifying information.  A list 
of companies to whom your coded information is transferred is available from OncoMed via 
your study doctor.  


 
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EMEA: Under data protection law [identification of national law] your study site and OncoMed 
Pharmaceuticals shall be jointly responsible as ‘controllers’ for ensuring that your information is 
safeguarded.  OncoMed has appointed [PPD local company name] as its ‘representative’ in your 
country to fulfill its obligations under this law.  
The information that we collect from you may be transferred to, and stored at, a destination 
outside the European Economic Area ("EEA").  It may also be processed by staff operating 
outside the EEA who work for us or for our representative. By participating in the research 
study, you agree to this transfer, storing or processing outside of the EEA.  When transferring 
such information to destinations outside of the EEA, we will also make sure that your 
information will be treated with an adequate level of protection as required under your local data 
protection laws. 
APAC: Under data protection law [identification of national law] your study site shall be 
responsible for ensuring that your named personal information is safeguarded. 
USA: Because of the research goals of this study, however, your study records cannot be kept 
completely confidential.  The sponsor of this study is OncoMed Pharmaceuticals.  
The study data may be transferred to other countries for processing, including countries not 
covered by data protection legislation similar in scope to the data protection legislation of your 
country, or at all.  The laws of your state may provide further protection. 
CANADA: Under federal data protection law, The Personal Information Protection and 
Electronic Documents Act (PIPEDA) and regional specific regulations, your study site shall be 
responsible for ensuring that your information is safeguarded. 
You have the right to access, through your study doctor, all the information collected about you 
and, if applicable, ask for corrections.  But, in order to protect the scientific integrity of the study, 
the treatment you received in this study needs to remain unknown (i.e., blinded) until the study 
data is analyzed.  Recipients of your information may be in countries that do not have data 
protection safeguards and rights.  In such case, OncoMed and its authorized representatives, and 
regulatory authorities, shall anyway seek to maintain confidentiality within the limits of local 
laws in these countries and comply with the data export requirements of your country, including 
any requirements to ensure an adequate level of protection. 
If you should withdraw from the study, data collected prior to your withdrawal may still be 
processed along with other data collected as part of the study.  Normally no new information will 
be collected for the study database unless you specifically consent to such collection.  However, 
the law does require that any side effects you may suffer are documented and reported.  To 
complete the study findings, your long term health status may also be recorded (unless you 
object).  You have the right to require that any previously retained samples are destroyed.   


 
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WHAT WILL HAPPEN TO YOUR DATA? 
This clinical study may only be performed by collecting and using your medical information.  
Data protection laws give you the right to control the use of your personal information.  
Therefore, by signing this form you specifically authorize your information to be checked, 
transferred and processed as follows: 
 The authorized representatives of Oncomed, the Ethics Committee and regulatory 
authorities’ inspectors may review your medical information by direct access to your medical 
records. 
 Study data, including your coded medical information, may be used and shared for legitimate 
study and scientific purposes, including if you do not object, for future use in medical or 
pharmaceutical research. 
 
I agree to the use of my coded medical information for future research purposes. 
Signature:  _______________________________ 
 
 
I don´t agree to the use of my coded medical information for future research purposes.   
Signature:  _______________________________ 
 
 Study data may be transferred to other countries for processing, including countries not 
covered by data protection legislation similar in scope to the data protection legislation of 
your country, or at all. 
 
HAS THE STUDY RECEIVED MEDICAL OR ETHICAL APPROVAL? 
The Ethics Committee has given this study a positive opinion. 
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 demcizumab.  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 


 
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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 of 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 this 
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.  
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 take by (SITE) in relying on 
this authorization before it received my written notice of withdrawal of permission. 


 
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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 patients’ 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 
PROTOCOL M18-007:  A Three Arm Phase 2 Double-Blind Randomized  Study of Carboplatin, 
Pemetrexed Plus Placebo versus Carboplatin, Pemetrexed plus 1 or 2 Truncated Courses of 
Demcizumab in Subjects with Non-Squamous Non-Small Cell Lung Cancer 
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 Patient or Patient’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 F: 
PHARMACOGENOMICS INFORMED CONSENT 
PROTOCOL M18-007:  A Three Arm Phase 2 Double-Blind Randomized  Study of Carboplatin, 
Pemetrexed Plus Placebo versus Carboplatin, Pemetrexed plus 1 or 2 Truncated Courses of 
Demcizumab in Subjects with Non-Squamous Non-Small Cell Lung Cancer 
This Informed Consent Form is linked to the main ICF for the trial Master ICF version 1.0. This 
Informed Consent Form is only valid in addition to the main ICF described above.  
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 demcizumab 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) at Study Day 0.  
Blood will be drawn from a vein using a needle.  DNA will be extracted from your blood sample. 
Your DNA may be tested for specific genes relevant to demcizumab, carboplatin and/or 
pemetrexed (the study drugs), the Notch/DLL4 pathways (the targets of demcizumab) and/or 
other genes related to your cancer.  Only DNA research related to demcizumab, carboplatin, or 
pemetrexed or to the diseases for which these drugs are developed will be performed.  No blood 
sample for DNA research will be taken from you unless you sign and date this Informed Consent 
Form.   
In addition, if a piece of your tumor was previously collected as part of your diagnosis, you are 
being asked to have DNA testing performed on your tumor.  DNA will be extracted to help to 
identify biomarkers that could be used in the future to predict which patients are more likely to 
respond to demcizumab, carboplatin and pemetrexed treatment.  Analysis of candidate genes 
and/or proteins relevant to the Notch pathway may be performed (e.g., Notch1, Hey L, FBW7, 
etc.). No DNA research will be performed on your tumor unless you sign and date this Informed 
Consent Form.  


 
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The Sponsor will store the samples until there is no DNA left. 
The sampes will be retained at OncoMed Pharmaceuticals, 800 Chesapeake Dr., Redwood City, 
California, U.S.A, 94063.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.  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. 
HOW WILL MY IDENTITY AND RESULTS BE KEPT CONFIDENTIAL? 
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes 
it illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information.   
This law generally will protect you in the following ways:  
 Health insurance companies and group health plans may not request your genetic 
information that we get from this research. 
 Health insurance companies and group health plans may not use your genetic information 
when making decisions regarding your eligibility or premiums.  
 Employers with 15 or more employees may not use your genetic information that we get 
from this research when making a decision to hire, promote, or fire you or when setting 
the terms of your employment.  
Be aware that this Federal law does not protect you or your family against genetic discrimination 
by companies that sell life insurance, disability insurance, or long-term care insurance.  Also, 
GINA does not prohibit discrimination of individuals with a genetic disorder that has been 
diagnosed.   
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 Patient number from the main study.  After the study is officially over, the Patient 
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 


 
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Patient 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 Australian Health Authority or EMA 
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. 
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). 


 
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WHAT ARE THE BENEFITS? 
You will not directly benefit from taking part in this DNA research.  This research could provide 
information about demcizumab 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. 
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 patients’ 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). 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 128 of 135 
29 November 2016 
 
CONFIDENTIAL 
VOLUNTARY PARTICIPATION AND DOCUMENTATION OF CONSENT 
PROTOCOL M18-007:  A Three Arm Phase 2 Double-Blind Randomized  Study of Carboplatin, 
Pemetrexed Plus Placebo versus Carboplatin, Pemetrexed plus 1 or 2 Truncated Courses of 
Demcizumab in Subjects with Non-Squamous Non-Small Cell Lung Cancer 
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. 
I consent to the processing of my personal data, including any sensitive personal data, as set out 
above and to the transfer of such data to countries outside of the European Economic Area 
 
 Yes  
 
 No 
I consent to provide the Optional Pharmacogenomics Specimen 
 
 Yes  
 
 No 
I consent to allow my tumor specimen to be analyzed for DNA 
 
 Yes  
 
 No 
 
_______________________________________________________ 
Printed Name of Patient or Patient’s Authorized Representative 
________________________________________________________ 
 
___________ 
Signature of Patient or Patient’s Authorized Representative Personally  
Date 
_________________________________________________________ 
Printed Name of Person Obtaining Informed Consent 
__________________________________________________________  
____________ 
Signature of Person Obtaining Informed Consent Personally   
 
Date 
__________________________________________________________ 
Printed Name of Witness* 
_________________________________________________________ 
 
___________ 
Signature of Witness* Personally   
 
 
 
 
 
Date 
 
*If the Principal Investigator or Institutional Review Board deems a witness signature is 
necessary. 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 129 of 135 
29 November 2016 
 
CONFIDENTIAL 
APPENDIX G: 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
AMENDMENT 1: 
8 OCTOBER 2014 
RATIONALE 
The changes in the protocol described below are being made to comply with the request made by 
the FDA.  Italics below and in the protocol indicate new text.  Strike-through indicates text that 
has been removed.  Additional changes were made to improve clarity. 
SUMMARY OF CHANGES: 
Synopsis 
Previously Read: 
2. NSCLC with known EGFR mutation or anaplastic lymphoma kinase (ALK) gene 
translocation (such as EML4-ALK) 
Now Reads: 
2. NSCLC with EGFR mutation or anaplastic lymphoma kinase (ALK) gene translocation (such 
as EML4-ALK) 
 
The following change in Section 4.1, Study Objectives (Endpoints, Primary Endpoint) was made 
to improve clarity. 
 
Section 6.2, Exclusion Criteria 
Previously Read: 
2. NSCLC with known EGFR mutation or anaplastic lymphoma kinase (ALK) gene 
translocation (such as EML4-ALK). Note: testing for these mutations is not a prerequisite to 
study entry. 
Now Reads: 
2. NSCLC with EGFR mutation or anaplastic lymphoma kinase (ALK) gene translocation (such 
as EML4-ALK) 
 Negative results for these genetic aberrations must be documented in order for a subject 
to be eligible. 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 130 of 135 
29 November 2016 
 
CONFIDENTIAL 
AMENDMENT 2: 
4 MARCH 2016 
SUMMARY OF CHANGES AND RATIONALE 
Study M18-007 has been amended for the following reasons. 
1. To provide more specific information regarding the criteria that need to be met for further 
treatment with demcizumab/placebo starting on Day 168 (Section 3.5, Section 5.0 and 
Section 8.1.1). 
2. To remove the requirement for mandatory FFPE tumor tissue in order to make the study 
available to more NSCLC subjects (Section 6.0 and Section 11.0). 
  FFPE tumor tissue, if available, must be provided for exploratory biomarker analyses. 
3. To clarify that subjects with metastatic disease after initial NSCLC resection with curative 
intent and no adjuvant therapy are allowed to enter the study regardless of time from NSCLC 
resection, as metastatic disease must have been present at time of initial diagnosis but was 
not detected (Section 6.0). 
4. To add additional eligibility criteria for albumin, prior radiation to chest wall or 
mediastinum, arterial aneurysms, interstitial lung disease and pneumonitis (Section 6.0). 
 Ongoing feedback from investigators of this study indicated that these additions may 
further enhance the safety of subject participants. 
5. To base creatinine clearance calculations as it pertains to pemetrexed-related safety on the 
Cockcroft and Gault formula using actual body weight, as was done for pemetrexed safety 
data summarized in the pemetrexed prescribing information (Section 6.0 and 8.2.6). 
6. To clarify the terms of ‘women of childbearing potential’ and ‘effective forms of 
contraception (Section 6.0). 
7. To clarify and correct some aspects of demcizumab-related treatment modification and 
termination criteria (Section 8.1.6). 
8. To specify a second approach to pemetrexed and carboplatin dose modification in which 
chemotherapy is delivered 3 or more days after the fixed day of demcizumab/placebo 
administration for chemotherapy-related or other reasons (Section 8.4 with Figure 20). This 
enables dose modification for chemotherapy that is more in line with what is typically done 
in daily practice. 
9. To stop BNP, ECG and Doppler echocardiogram assessments after ≥105 days of regularly 
scheduled assessments after the last dose of demcizumab/placebo (depending on when 
discontinuation occurred), unless results for BNP and Doppler echocardiogram do not meet 
eligibility criteria (Sections 9.2.3 and 9.4, Appendix A). 
 It was deemed acceptable for subject safety to stop the outlined assessments at a time 
point when more than six half-lives of demcizumab have passed. 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 131 of 135 
29 November 2016 
 
CONFIDENTIAL 
10. To simplify PK assessments for demcizumab and stop them after Day 336 (Section 9.6 and 
Appendix A). 
11. To reduce the number of assessments for blood biomarkers to one on-study assessment seven 
days after demcizumab/placebo administration (Day 28) and remove assessments for 
circulating tumor cells (Section 11.0 and Appendix A). 
 This reduces the amount of blood drawn from subjects and will provide adequate 
information regarding blood-based pharmacodynamics biomarkers, considering that >50 
subjects will have undergone more extensive blood biomarker assessments by the time 
this amendment is active. 
12. To simplify protocol text for study visit schedule and assessments and make Appendix A the 
primary reference (Section 12.0). 
13. To provide additional flexibility in the timing of pemetrexed administrations and associated 
assessments after discontinuation of carboplatin and demcizumab/placebo (Section 12.2). 
14. To clarify which assessments are required in case of discontinuation of all study drugs 
(Section 12.2). 
15. To reduce the frequency of chemistry assessments to every three weeks and of hematology 
assessments to every three weeks starting with Day 42 (Cycle 3 of carboplatin and paclitaxel, 
assuming no dosing delays; Appendix A). 
 This reduces the amount of blood drawn from subjects, is more in line with standard of 
care and poses no safety risk to subjects given the large clinical safety experience with 
pemetrexed and carboplatin. 
16. To clarify and revise tables for protocol assessments to make them consistent with protocol 
changes (Appendix A). 
17. To clarify and revise the informed consent form to make it consistent with protocol changes 
(Appendix E). 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 132 of 135 
29 November 2016 
 
CONFIDENTIAL 
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 3.2 
Stage IV Non-Small Cell Lung Cancer 
Section 3.3.2 
Potential for Immune-Mediated Mechanism of Action for Anti-DLL4 
Section 3.4.2.1 
Phase 1b Efficacy Data 
Section 3.4.2.2 
Phase 1b Safety Data 
Section 3.5 
Dose Rationale 
Section 4.1 
Study Objectives 
Section 4.2 
Endpoints 
Section 5.0 
OVERALL STUDY DESIGN AND PLAN – DESCRIPTION 
Section 6.1 
Inclusion Criteria 
Section 6.2 
Exclusion Criteria 
Section 7.0 
REMOVAL OF SUBJECTS FROM ON-STUDY PART OF PROTOCOL 
Section 8.1.1 
Administration 
Section 8.1.4 
Drug Ordering, Storage, and Accountability 
Section 8.1.6 
Treatment Modification and Termination Criteria 
Section 8.2.5 
Vitamin Supplementation and Dexamethasone Administration 
Section 8.2.6 
Renally Impaired Subjects 
Section 8.3.1 
Administration 
Section 8.4 
Pemetrexed and Carboplatin Dose Modification/Treatment Delay 
Section 9.1.2 
Definition of Serious Adverse Event 
Section 9.1.4 
Serious Adverse Event Reporting Procedures 
Section 9.2 
Clinical Laboratory Assessments 
Section 9.2.1 
Hematology 
Section 9.2.3 
BNP Assessment 
Section 9.3 
Vital Signs and Other Physical Findings 
Section 9.4 
Cardiopulmonary Studies 
Section 9.5 
Immunogenicity Assessments 
Section 9.6 
Pharmacokinetic Assessments 
Section 10.0 
EFFICACY ASSESSMENTS 
Section 11.0 
EXPLORATORY ASSESSMENTS 
Section 12.0 
STUDY VISIT SCHEDULE AND ASSESSMENTS 
Section 12.1 
Screening 
Section 12.2 
Assessments for On-study Part of Protocol (Day 0 up to Termination Visit) 
Section 12.3 
Termination Visit 
Section 12.4 
Follow-up after Termination Visit 
Section 14.0 
STATISTICAL PLAN 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 133 of 135 
29 November 2016 
 
CONFIDENTIAL 
Section 14.3 
Treatment Exposure 
Section 14.4.1 
Safety Endpoints 
Section 14.4.2 
Immunogenicity Endpoints 
Section 14.4.4 
Efficacy Endpoints 
Section 14.4.9 
Exploratory Endpoints 
Section 17.6 
Investigational Medicinal Product Accountability 
Section 18.0 
REFERENCES 
Appendix A 
SCHEDULE OF ASSESSMENTS 
Notes to Appendix A 
Appendix E: 
SAMPLE INFORMED CONSENT 
Appendix F: 
PHARMACOGENOMICS INFORMED CONSENT 
 


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 134 of 135 
29 November 2016 
 
CONFIDENTIAL 
AMENDMENT 3: 
29 NOVEMBER 2016 
SUMMARY OF CHANGES AND RATIONALE 
The M18-007 protocol has been amended in order to update the primary and secondary 
endpoints of the study, as well as, the statistical plan.  The reason for this amendment is that 
enrollment of the full 201 subject trial is not feasible given major competition for enrollment, 
and the study should test an efficacy hypothesis with a smaller sample size. 
Due to significant enrollment competition in the first-line metastatic non-small cell lung cancer 
(NSCLC) treatment setting it has become apparent that enrollment of the planned 201 subjects 
would take a very long time and be very cost prohibitive.  The M18-007 study achieved first-
patient-in in February 2015 and was planned to complete enrollment of 201 subjects by March 
2016, however, as of October 2016 the study had enrolled 82 subjects.  Over the course of the 
last 6 months the M18-007 study has enrolled between 1 and 6 subjects per month (on average 
2.5 patients per month) across 40 open study sites--thus,  completion of the planned enrollment 
of 201 subjects would take several more years.  The challenge to enrollment is driven by many 
competing clinical trials of novel immune-oncology agents that have been initiated recently in 
the first-line NSCLC treatment space.  This includes over 7 global Phase 3 trials with many 
thousands of subjects to be enrolled.  These studies are directly competing with the M18-007 
trial due to the overlapping eligibility criteria and the significant enthusiasm that exists for 
immune-oncology agents (particularly anti-PD1 and anti-PDL1 therapy) in NSCLC. 
Due to the above, the sponsor (OncoMed) and our corporate partner (Celegene) have made the 
decision to discontinue enrollment on the M18-007 study.  However, 82 subjects have been 
enrolled on this double-blinded Phase 2 M18-007 study.  It is the feeling of OncoMed and the 
participating investigators that there are informative data that can be derived from this clinical 
trial.  In this amendment, OncoMed will continue to treat and follow subjects enrolled (as per 
protocol) and will change the primary endpoint of the study to be more suitable for a double 
blinded 82 subject Phase 2 experiment.  OncoMed will pool the two demcizumab experimental 
arms (arms 2 and 3 in the study) to compare the outcome of these subjects to the outcome of the 
control arm (arm 1).  The primary endpoint will be changed from progression free survival to 
response rate.  The Phase 1b data for demcizumab with carboplatin and pemetrexed 
chemotherapy in NSCLC suggested that the addition of demcizumab augmented response rate in 
these subjects.  As such OncoMed feels that response rate is an acceptable and scientifically 
based efficacy endpoint for the M18-007 study.  The statistical plan has been amended for this 
primary endpoint of response rate and to accommodate the smaller sample size of 82 
subjects.  The progression free survival endpoint has been changed from a primary to a 
secondary efficacy endpoint.  


 
OncoMed Pharmaceuticals, Inc. 
 
Demcizumab 
Protocol M18-007, Amendment 3 
Page 135 of 135 
29 November 2016 
 
CONFIDENTIAL 
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. 
Sponsor Contacts 
 
Synopsis 
 
Section 4.1 
Study Objectives 
Section 4.2 
Endpoints 
Section 5.0 
OVERALL STUDY DESIGN AND PLAN – DESCRIPTION 
Section 14.0 
STATISTICAL PLAN 
Section 14.1 
Subject Populations for Analysis 
Section 14.4.4 
Efficacy Endpoints 
Section 14.4.4.7 
Overall Survival 
Section 14.5 
Termination Criteria 
Section 18.0 
REFERENCES