clinical protocol
untitled h2

Protocol No. M18-007  
Version: 12 September 2014  
EudraCT Number: 2014-003356-30  
| 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 Amendment 1: 8 October 2014  Amendment 2: 4 March 2016  Amendment 3: 29 November 2016   |
|----------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
Sponsor: OncoMed Pharmaceuticals, Inc.  
800 Chesapeake Drive Redwood City, CA 94063 Phone: 650-995-8200
clinical protocol
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of OncoMed Pharmaceuticals, Inc. Acceptance of this document constitutes agreement by the recipient that no previously unpublished information contained herein will be published or disclosed without the prior written approval of OncoMed Pharmaceuticals, Inc. with the exception that this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.
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confidential

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:
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confidential

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.
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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
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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
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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, s**ee Section 6.0)**
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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 tracheoesophageal 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).
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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.
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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).  
| OncoMed Pharmaceuticals, Inc.   | Demcizumab          |
|---------------------------------|---------------------|
| 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 AntiDLL4 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 52Protocol M18-007, Amendment 3 Page 9 of 135 29 November 2016                                 |                     |  
Protocol M18-007, Amendment 3 Page 9 of 135 29 November 2016 CONFIDENTIAL  
| OncoMed Pharmaceuticals, Inc.                                                                                                           | Demcizumab                                                                                                                                |                                                                                                              |
|-----------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------|
| 8.2                                                                                                                                     | Pemetrexed                                                                                                                                |                                                                                                              |
| 8.2.1                                                                                                                                   | Administration ................................................................................................................52         |                                                                                                              |
| Description                                                                                                                             |                                                                                                                                           |                                                                                                              |
| 8.2.2                                                                                                                                   | Storage                                                                                                                                   |                                                                                                              |
| 8.2.3                                                                                                                                   |                                                                                                                                           |                                                                                                              |
| 8.2.4                                                                                                                                   | Packaging                                                                                                                                 |                                                                                                              |
| 8.2.5                                                                                                                                   | Vitamin Supplementation and Dexamethasone Administration ...........53                                                                    |                                                                                                              |
| Renally Impaired Subjects ............................................................................................53                |                                                                                                                                           |                                                                                                              |
| 8.2.6                                                                                                                                   |                                                                                                                                           |                                                                                                              |
| 8.2.7                                                                                                                                   | Preparation and Administration Precautions                                                                                                |                                                                                                              |
| 8.2.8                                                                                                                                   | Preparation for Intravenous Infusion Administration ..............................53                                                      |                                                                                                              |
| 8.3                                                                                                                                     | Carboplatin                                                                                                                               |                                                                                                              |
| Administration ..............................................................................................................54         |                                                                                                                                           |                                                                                                              |
| 8.3.1                                                                                                                                   | Description                                                                                                                               |                                                                                                              |
| 8.3.2                                                                                                                                   |                                                                                                                                           |                                                                                                              |
| 8.3.3                                                                                                                                   | S STORAGE                                                                                                                                 |                                                                                                              |
| 8.3.4                                                                                                                                   | Packaging                                                                                                                                 |                                                                                                              |
| 8.4                                                                                                                                     | Pemetrexed and Carboplatin Dose Modification/Treatment Delay........................55                                                    |                                                                                                              |
| Anti-Emetics and Hematologic Supportive Care                                                                                            |                                                                                                                                           |                                                                                                              |
| 8.5                                                                                                                                     |                                                                                                                                           |                                                                                                              |
| 8.6                                                                                                                                     | Concomitant and Prohibited Therapy ....................................................................................................59 |                                                                                                              |
| 8.7                                                                                                                                     | Treatment Compliance                                                                                                                      |                                                                                                              |
| SAFETY ASSESSMENTS ..................................................................................................................60 |                                                                                                                                           |                                                                                                              |
| 9.0                                                                                                                                     | Adverse Events Definitions and Reporting Procedures .............................................60                                       |                                                                                                              |
| 9.1                                                                                                                                     | 9.1.1                                                                                                                                     | Definition of Adverse Event ..............................................................................60 |
| 9.1.2                                                                                                                                   | Definition of Serious Adverse Event .............................................................61                                       |                                                                                                              |
| Disease Progression and Death .......................................................................62                                 |                                                                                                                                           |                                                                                                              |
| 9.1.3                                                                                                                                   | Serious Adverse Event Reporting Procedures ...........................................62                                                  |                                                                                                              |
| 9.1.4                                                                                                                                   |                                                                                                                                           |                                                                                                              |
| 9.2                                                                                                                                     | Clinical Laboratory Assessments                                                                                                           |                                                                                                              |
| 9.2.1                                                                                                                                   | Hematology ....................................................................................................................62         |                                                                                                              |
| Serum Chemistry                                                                                                                         |                                                                                                                                           |                                                                                                              |
| 9.2.2                                                                                                                                   |                                                                                                                                           |                                                                                                              |
| 9.2.3                                                                                                                                   | BNP Assessment .                                                                                                                          |                                                                                                              |
| 9.2.4                                                                                                                                   | Urinalysis ................................................................................................................63             |                                                                                                              |
| 9.3                                                                                                                                     | Vital Signs and Other Physical Findings ......................................................................63                          |                                                                                                              |
| Cardiopulmonary Studies                                                                                                                 |                                                                                                                                           |                                                                                                              |
| 9.4                                                                                                                                     |                                                                                                                                           |                                                                                                              |
| 9.5                                                                                                                                     | Immunogenicity Assessments                                                                                                                |                                                                                                              |
| 9.6                                                                                                                                     | Pharmacokinetic Assessments ............................................................................................65                |                                                                                                              |
| 10.0                                                                                                                                    | EFFICACY ASSESSMENTS .......................................................................................................65            |                                                                                                              |
| EXPLORATORY ASSESSMENTS                                                                                                                 |                                                                                                                                           |                                                                                                              |
| 1.0                                                                                                                                     | STUDY VISIT SCHEDULE AND ASSESSMENTS.........................................................67                                           |                                                                                                              |
| 12.0                                                                                                                                    |                                                                                                                                           |                                                                                                              |  
Protocol M18-007, Amendment 3  
| OncoMed Pharmaceuticals, Inc.                                                                                                          | Demcizumab                                                                                                                                               |                  |
|----------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------|------------------|
| 12.1                                                                                                                                   | Screening                                                                                                                                                |                  |
| 12.2                                                                                                                                   | Assessments for On-study Part of Protocol (Day 0 up to Termination Visit) ......67                                                                       |                  |
| Termination Visit                                                                                                                      |                                                                                                                                                          |                  |
| 12.3                                                                                                                                   | Follow-up after Termination Visit                                                                                                                        |                  |
| 12.4                                                                                                                                   |                                                                                                                                                          |                  |
| 13.0                                                                                                                                   | DATA QUALITY ASSURANCE ................................................................................................69                                |                  |
| 14.0                                                                                                                                   | STATISTICAL PLAN                                                                                                                                         |                  |
| Subject Populations for Analysis ...................................................................................................75 |                                                                                                                                                          |                  |
| 14.1                                                                                                                                   | Demographics and Baseline Characteristics                                                                                                                |                  |
| 14.2                                                                                                                                   |                                                                                                                                                          |                  |
| 14.3                                                                                                                                   | Treatment Exposure ...................................................................................................................................75 |                  |
| 14.4                                                                                                                                   | Endpoints                                                                                                                                                |                  |
| Sety Endpoints .                                                                                                                       |                                                                                                                                                          |                  |
| 14.4.1                                                                                                                                 | Immunogenicity Endpoints .....................................................................................77                                         |                  |
| 14.4.2                                                                                                                                 |                                                                                                                                                          |                  |
| 14.4.3                                                                                                                                 | Pharmacokinetic Endpoints                                                                                                                                |                  |
| 14.4.4                                                                                                                                 | Efficacy Endpoints ........................................................................................................77                            |                  |
| 14.4.5                                                                                                                                 | Continuous Variable Assessment of Tumor Length ..................................79                                                                      |                  |
| Duration of Response                                                                                                                   |                                                                                                                                                          |                  |
| 14.4.6                                                                                                                                 |                                                                                                                                                          |                  |
| 14.4.7                                                                                                                                 | OVERALL SURVIVAL ..........................................................................................................80                            |                  |
| 14.4.8                                                                                                                                 | LANDMARK SURVIVAL                                                                                                                                        |                  |
| Exploratory Endpoints .........................................................................................81                      |                                                                                                                                                          |                  |
| 14.4.9                                                                                                                                 |                                                                                                                                                          |                  |
| Termination Criteria                                                                                                                   |                                                                                                                                                          |                  |
| 14.5                                                                                                                                   |                                                                                                                                                          |                  |
| 14.6                                                                                                                                   | Deviation Reporting                                                                                                                                      |                  |
| 15.0                                                                                                                                   | DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION ..................................82                                                                          |                  |
| ETHICAL CONSIDERATIONS                                                                                                                 |                                                                                                                                                          |                  |
| 16.0                                                                                                                                   | INVESTIGATOR REQUIREMENTS .......................................................................................82                                      |                  |
| 17.0                                                                                                                                   | 17.1                                                                                                                                                     | Informed Consent |
| 17.2                                                                                                                                   | Institutional Review Board/Ethics Committee Approval ..........................................82                                                        |                  |
| Study Monitoring                                                                                                                       |                                                                                                                                                          |                  |
| 17.3                                                                                                                                   |                                                                                                                                                          |                  |
| 17.4                                                                                                                                   | A AUDITING Procedures                                                                                                                                    |                  |
| 17.5                                                                                                                                   | DATA COLLECTION ..............................................................................................................................83         |                  |
| 17.6                                                                                                                                   | Investigational Medicinal Product Accountability .....................................................84                                                 |                  |
| Disclosure of Data and Publication                                                                                                     |                                                                                                                                                          |                  |
| 17.7                                                                                                                                   |                                                                                                                                                          |                  |
| 17.8                                                                                                                                   | Retention of Records                                                                                                                                     |                  |
| 18.0                                                                                                                                   | REFERENCES                                                                                                                                               |                  |  
| 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 MyeloidDerived 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 Nabpaclitaxel/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                  |  
| 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                                                                                      |  
| 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)                                                                |                  |
| Protocol M18-007, Amendment 3 | Page 14 of 135                                                              | 29 November 2016 |  
Protocol M18-007, Amendment 3 Page 14 of 135 29 November 2016 CONFIDENTIAL  
| 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

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.
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3.2 stage iv non-small cell

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 overexpression 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.
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3.3.1 activity of anti-dll4 in

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).  
| Anti-DLL4                                                                                          | Anti-DLL4                 |                |                |
|----------------------------------------------------------------------------------------------------|---------------------------|----------------|----------------|
| Tumor                                                                                              | Path                      | Single Agent   | 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 |                           |                |                |  
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 antiDLL4 combination activity with either pemetrexed (Figure 2) or paclitaxel (Figure 3).
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figure 3 activity of anti-dll4

LU45 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.
figure 4 reduction of tumor
3.3.2 potential for immune-mediated mechanism

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). Figure 5: Inhibition of Tumor Growth by the Combination of Anti-DLL4 and  
  
Anti-PD1 Following the treatment phase of the experiment shown in Figure 5, splenocytes from tumorbearing 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 IL17 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.  
  
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).  
Figure 7: Anti-DLL4 Selectively Reduces the Frequency of Monocytic MyeloidDerived Suppressor Cells  
  
  
  
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.
figure 4 reduction of tumor
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.
figure 4 reduction of tumor
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. 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.
figure 4 reduction of tumor
3.4.2 phase 1b studies m18-002

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.
figure 4 reduction of tumor
3.4.2.1 phase 1b efficacy data

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.  
| Cohort 1                                                                                                                                                                                                            | Cohort 2                                 | Cohort 3                               | 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)                                                                                                                                                                                  |                                          |                                        |                                          |         |    |    |    |          |
| 5 mg/kg  q2w  (n=8)                                                                                                                                                                                                 | 2.5 mg/kg  q4w  (n=8)                    | 5 mg/kg  q4w  (n=8)                    |                                          |         |    |    |    |          |
| 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 |                                          |                                        |                                          |         |    |    |    |          |  
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.
figure 8 percent change in
3.4.2.1 phase 1b efficacy data

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.  
Figure 9: Percent Change in Tumor Target Lesion Size of the Nabpaclitaxel/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.  
| Cohort 1                                                                                                                     | Cohort 2                       | Cohort 3            | Cohort 4  (Expansion)   | Cohort 5   | Cohort 6   | Cohort 7  (Expansion)  Trunc Dem  5 mg/kg  q3w  (n=1)   | TOTAL  (evaluable:  n=33)   |          |
|------------------------------------------------------------------------------------------------------------------------------|--------------------------------|---------------------|-------------------------|------------|------------|---------------------------------------------------------|-----------------------------|----------|
| Trunc Dem 7.5 mg/kg q3w  (n=6)                                                                                               | Trunc Dem  5 mg/kg  q3w  (n=7) |                     |                         |            |            |                                                         |                             |          |
| 5 mg/kg  q3w  (n=6)                                                                                                          | 2.5 mg/kg  q3w  (n=6)          | 5 mg/kg  q3w  (n=8) | 5 mg/kg  q3w  (n=6)     |            |            |                                                         |                             |          |
| 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.
figure 8 percent change in
progression-free survival and overall survival

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. Figure 11: Progression-free and Overall Survival for Subjects with Continuous  
  
Demcizumab Dosing - Study M18-004 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 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 14 shows the results for overall survival with additional follow-up for both groups of subjects.  
Figure 14:
Overall Survival for Subjects with Continuous and Truncated Demcizumab (DEM) Dosing - Study M18-004  
  
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).  
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  |
| nd -line treatment              | 5                       | 5                       | 10                      | 6  |
| No 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  |
| 2 rd  line EGFR inhibitor       | 0                       | 1                       | 0                       | 0  |
| 3 rd - line chemotherapy        | 0                       | 2                       | 0                       | 0  |
| 3 th -line checkpoint inhibitor | 0                       | 1                       | 0                       | 0  |
| 4                               |                         |                         |                         |    |  
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.  
Figure 15: Exploratory Overall Survival Analysis for Immune Biomarkers -  
  
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.
figure 8 percent change in
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%).  
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.
figure 8 percent change in
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 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.
figure 8 percent change in
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.
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4.0 study objectives and endpoints

All objectives apply to the study population of subjects with 1st-line stage IV non-squamous nonsmall cell lung cancer (NSCLC).
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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*
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4.2 endpoints

All endpoints apply to the study population of subjects with 1st-line stage IV non-squamous nonsmall cell lung cancer (NSCLC).
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primary endpoint

To compare the Investigator-assessed RECIST v1.1 response rate (unconfirmed) in Arm 1 to Arm 2 and Arm 3 combined
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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
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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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overall study design and plan

This is a randomized, double-blind, 3-arm (1:1:1) study in subjects with first-line Stage IV nonsquamous 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.  
  
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 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 noncompliance, 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.  
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

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
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.
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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.  
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.  
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 1.5institutional 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 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
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7.0 removal of subjects from

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.
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8.0 study treatments 8.1 study

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.  
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).
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figure 18 approach to demcizumab/placebo

B  
  
  
ن  
  
  
  
  
  
  
  
105  
  
  
  
  
  
  
  
   
  
   
$$\overline{{{\;\;294\;\;\;\;\;\;\;\;\;\;\;\;\;315\;\;\;\;\;\;\;\;\;}}}$$  
DP = 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.  
  
$$294$$  
294
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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.
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8.1.3 packaging

Labeling of demcizumab or placebo vials and cartons will comply with all applicable regulations.
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8.1.4 drug ordering storage and

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.
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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

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. Subjects with any of the following findings must have their dose of demcizumab or placebo held, regardless of relationship to demcizumab or placebo:
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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.
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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.
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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.
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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[2,3d]pyrimidin-5-yl)ethyl]benzoyl]-, disodium salt, heptahydrate.
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8.2.5 vitamin supplementation and dexamethasone

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.
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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.
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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.
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8.2.8 preparation for intravenous infusion

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. 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.
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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.  
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.
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8.3.2 description

Carboplatin produces predominantly interstrand DNA cross-links rather than DNA-protein crosslinks. This effect is apparently cell-cycle nonspecific.
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8.4 pemetrexed and carboplatin dose

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 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).
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a

C  
  
  
  
P
147 P
147  
  
  
  
D/P  
  
| D/P   | D/P   | D/P   |
|-------|-------|-------|
| PIC   | P/C   | P/C   |
| 0     | 21    | 42    |  
  
  
273  
| D/P   |    |
|-------|----|
| P/C   | P  |
| 63    | 84 |  
273
P
315  
  
DP = 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.  
| P   | P   | p   | P   |
|-----|-----|-----|-----|
| 252 | 273 | 294 | 315 |  
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  
| D/P   |
|-------|
| P     |
| 231   |  
('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  
| D/P   | D/P   | D/P   |     |     |     |
|-------|-------|-------|-----|-----|-----|
| o     |       |       |     |     |     |
| P     | P     | P     | P   | p   |     |
| 105   | 126   | 147   | 168 | 189 | 210 |  
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.
Alternatively, the standard approach to chemotherapy administration may be used.  If pemetrexed and/or carboplatin cannot be administered within the specified time window for  
| D/P   |
|-------|
| P/C   |
| 21    |  
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  
| D/P   |
|-------|
| P/C   |  
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.
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figure 20 standard approach to

| D/P   |
|-------|
| P/C   |
| 42    |  
  
| e   |
|-----|
| 147 |  
  
PIC  
  
  
  
  
P/C P/C  
| D/P   | D   |
|-------|-----|
| 210   |     |  
  
4 weeks  
  
  
  
  
  
  
  
  
  
| D/P   | D/P   |
|-------|-------|
| P     | P     |
| 168   | 189   |  
| D/P   |
|-------|
| P     |
| 210   |  
| D/P   | D/P   |
|-------|-------|
| P     | P     |
| 168   | 189   |  
  
| 294   | 315   |
|-------|-------|  
P  
  
315  
  
| D/P   |
|-------|
| P     |
| 210   |  
  
  
| D/P   |     |     |
|-------|-----|-----|
| P     | P   | P   |
| 231   | 252 | 273 |  
P  
  
315 L  
  
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.  
| e   |
|-----|
| 126 |  
| D/P   |
|-------|
| P/C   |
| 0     |  
  
| D/P   |    |     |
|-------|----|-----|
| P/C   | P  | P   |
| 63    | 84 | 105 |  
| D/P   | D/P   |
|-------|-------|
| P     | L     |
| 168   | 189   |  
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.  
| Nadir ANC <500/mm3  and nadir platelets                                                                                                                                                                                                                                              | 75% of previous dose (pemetrexed and   |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------|
| ≥50,000/mm3                                                                                                                                                                                                                                                                          | carboplatin)                           |
| Nadir platelets <50,000/mm3  without bleeding                                                                                                                                                                                                                                        | 75% of previous dose (pemetrexed and   |
| regardless of nadir ANC                                                                                                                                                                                                                                                              | carboplatin)                           |
| Nadir platelets <50,000/mm3  with Grade ≥2 bleeding  50% of previous dose (pemetrexed and  from any site, regardless of nadir ANC  carboplatin)  Nadir ANC <1,000/mm3  and fever ANC <°C  75% of previous dose (pemetrexed and  (101°F), regardless of nadir platelets  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                                                                       | Dose of Carboplatin    |                         |
|------------------------------------------------------------------------------------------|------------------------|-------------------------|
| (mg/m2 )                                                                                 | (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    |  
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.
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8.5 anti-emetics and hematologic supportive

Antiemetic therapy and/or hematopoietic growth factors and/or red blood cell/platelet transfusions may be administered at the discretion of the Investigator.
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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. 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.
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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.
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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.
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9.1 adverse events definitions and

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.
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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 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.
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9.1.2 definition of serious adverse

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.
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9.1.4 serious adverse event reporting

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.
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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.
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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).
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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.
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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.
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9.2.4 urinalysis

Urinalysis (with microscopic analysis) will be obtained during screening and at the termination visit.
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9.3 vital signs and other

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. 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 antihypertensive 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.
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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.
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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.
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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. 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.
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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.
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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. 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).
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12.0 study visit schedule and

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.
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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.
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12.2 assessments for on-study part

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. 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.
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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 and Doppler echocardiogram do not have to be repeated if they were performed within 14 days of the termination visit.
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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 anticancer 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.
figure 8 percent change in
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 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.
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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.  
| Subjects Randomized   | Response Rate   | Type 1  Error 1-   | Power   |            |       |      |
|-----------------------|-----------------|--------------------|---------|------------|-------|------|
| sided                 |                 |                    |         |            |       |      |
| 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 |  
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.  
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.  
| 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)   |                                           |                      |         |         |         |
|-------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------|-------------------------------------------|----------------------|---------|---------|---------|
| Control                                                                                                                       | Dem                                                                                                  | Probabilty of Not Exceeding  15% at Final | Total Probability of | Total   |         |         |
| Exceeding 15%                                                                                                                 | Probability                                                                                          |                                           |                      |         |         |         |
| Rate                                                                                                                          | Rate                                                                                                 |                                           |                      |         |         |         |
| 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.                                                         |                                                                                                      |                                           |                      |         |         |         |  
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.
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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 perprotocol 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.
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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.
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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 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.
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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.
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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.
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clinical laboratory assessments and vital

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.
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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 summarized by treatment group. 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.
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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.
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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.
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14.4.2 immunogenicity endpoints

Immunogenicity endpoints will be analyzed using the ITT Population. The incidence of antidemcizumab 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.
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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.
figure 8 percent change in
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.
figure 8 percent change in
best overall response

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.