clinical protocol
untitled h2

Protocol No. M18-006 Title: YOSEMITE: A 3-Arm Phase 2 Double-Blind Randomized StudY of Gemcitabine, Abraxane® Plus PlacebO versuS GEMcitabIne, Abraxane® plus 1 or 2 TruncatEd Courses of Demcizumab in Subjects with 1st-Line Metastatic Pancreatic Ductal Adenocarcinoma  
| Version:        | 23 October 2014  Amendment 1: 24 November 2014  Amendment 2: 10 February 2015  Amendment 3: 28 May 2015  Amendment 4: 31 March 2016  Amendment 5: 19 December 2016   |
|-----------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| EudraCT Number: | 2014‐003355‐56                                                                                                                                                       |
| 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of OncoMed Pharmaceuticals, Inc. Acceptance of this document constitutes agreement by the recipient that no previously unpublished information contained herein will be published or disclosed without the prior written approval of OncoMed Pharmaceuticals, Inc. with the exception that this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.
investigator signature page
confidential

OncoMed Pharmaceuticals Protocol No. M18-006 Amendment 5: 19 December 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  
Telephone Number:  
| Printed Name:  Institution:  Address:   |
|-----------------------------------------|
sponsor signature page
confidential

OncoMed Pharmaceuticals, Inc.  
Protocol No. M18-006 Amendment 5: 19 December 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.  
Signature of Sponsor Representative Date Printed Name of Sponsor Representative
sponsor signature page
synopsis

Title of Study:
YOSEMITE: A 3-Arm Phase 2 Double-Blind Randomized Study of Gemcitabine, Abraxane® Plus Placebo versus Gemcitabine, Abraxane® plus 1 or 2 Truncated Courses of Demcizumab in Subjects with 1st-Line Metastatic Pancreatic Ductal Adenocarcinoma Study Period: Approximately 12–16 months **Development Phase:** Phase 2  
Objectives: Primary Objective:
To compare the efficacy of Arm 1 to the pooled decizumab arms (i.e., Arm 1 to Arms 2 and 3) (See Section 5.0 for description of Treatment Arms) in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.  
Secondary Objectives:
To compare the efficacy of Arm 1 to Arm 2 and Arm 1 to Arm 3 in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.  
To compare the safety of Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.  
To determine the rate of immunogenicity against demcizumab when combined with Abraxane® and gemcitabine in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.  
. To determine population pharmacokinetics of demcizumab in subjects receiving demcizumab and Abraxane® and gemcitabine in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.  
Exploratory Objectives:
To compare the safety and efficacy of Arm 2 to Arm 3 in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.  
To compare the exploratory biomarkers of Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.
sponsor signature page
study design

This is a randomized, double blind, 3 arm (1:1:1) study in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma. Prior to randomization, subjects will undergo screening to determine study eligibility. Two hundred and one evaluable subjects will be randomized via an IWRS system.  
Gemcitabine will be given by intravenous (IV) infusion at a dose of 1000 mg/m2 on Days 1, 8 and 15 of each 28-day treatment cycle (or until toxicity necessitates reducing or holding a dose). Abraxane® will be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8 and 15 of each 28-day treatment cycle. Demcizumab 3.5 mg/kg or placebo will be administered by IV infusion (prior to the administration of Abraxane® and gemcitabine) once every 2 weeks for either one (1st course through Study Day 70) or two (2nd course begun on Study Day 168 and continued through Study Day 238) 70 day courses. Randomized subjects will be treated in the following manner (See Appendix A):
Arm 1 - Abraxane® and gemcitabine plus placebo (3 cycles), Abraxane® and gemcitabine (3 cycles), Abraxane® and gemcitabine plus placebo (3 cycles) and then Abraxane® and gemcitabine until disease progression Arm 2 - Abraxane® and gemcitabine plus demcizumab (3 cycles), Abraxane® and gemcitabine (3 cycles),
Abraxane® and gemcitabine plus placebo (3 cycles) and then Abraxane® and gemcitabine until disease progression Arm 3 - Abraxane® and gemcitabine plus demcizumab (3 cycles), Abraxane® and gemcitabine (3 cycles),
Abraxane® and gemcitabine plus demcizumab (3 cycles) and then Abraxane® and gemcitabine until disease progression Dosing of gemcitabine, Abraxane® and demcizumab or placebo must be done within ± 2 days of the Study Day listed in the protocol. If a drug cannot be given within this 2 day window, then the dose of that drug is permanently missed. Subjects will only receive their second 70 day course of placebo or demcizumab if their Day 168 BNP is ≤100 pg/mL, peak tricuspid velocity is ≤ 3.0 m/s and LVEF is ≥50% and they did not develop pulmonary hypertension or heart failure while on study. Any subject who has two consecutive B-type natriuretic (BNP) values >100 pg/mL or one value >200 pg/mL will be unblinded by the Investigator through the IWRS system. If the subject is receiving demcizumab they will be started on an ACE inhibitor or carvedilol, unless the BNP elevation occurred more than 100 days after the discontinuation of demcizumab or there is a contraindication to administering these agents and if appropriate, referred to a cardiologist. If they are not receiving demcizumab they will be cared for according to standard medical practice. Subjects will be assessed for disease status every 8 weeks and for safety at every visit and through 30 days following the termination visit. In all three arms, subjects should remain on study until disease progression, Immunogenicity will be assessed at baseline, every 8 weeks while on study and at treatment termination. Biomarker assessment will be performed at Days 0, 21, 35, 49 and 63 and at treatment termination. Plasma sample for PK analysis to be obtained prior to the demcizumab infusion on Days 0, 14, 56, 70, 168, 182, 224 and 238, and at the end of the demcizumab infusion (prior to chemo infusion) on Days 0, 56, 70, 168, 224 and at treatment termination. If all of the study drugs are discontinued prior to disease progression, the subject should remain on study until disease progression or withdrawal of consent. Once discontinuation criteria for the study are met (disease progression, use of other anti-cancer therapy, subject or investigator decision or protocol non-compliance) 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 and other assessments as required per protocol. Study Population: Subjects must have histologically confirmed metastatic pancreatic ductal adenocarcinoma. In addition, subjects must measurable disease per RECIST 1.1. Diagnosis and Main Criteria for Eligibility (for Complete Eligibility Criteria, See Section 6.0):
Inclusion Criteria:
1. Subjects must have cytologically or histologically confirmed metastatic pancreatic ductal adenocarcinoma..  
Prior chemotherapy and/or radiotherapy either in the adjuvant or neoadjuvant setting or for metastatic disease is not allowed.  
2. Age >21 years 3. ECOG performance status 0 or 1 (see Appendix C) 4. Measurable disease per RECIST v1.1 (see Appendix D)
Exclusion Criteria:
1. Subjects with a neuroendocrine tumor of the pancreas, an acinar tumor of the pancreas or a pancreatic tumor with mixed histologies.  
2. Subjects receiving heparin, warfarin, factor Xa inhibitors or other similar anticoagulants. Note: Subjects may be receiving low-dose aspirin and/or non-steroidal anti-inflammatory agents.  
3. 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 E).  
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.  
History of heart failure or pulmonary hypertension Received a total cumulative dose of ≥400 mg/m2 doxorubicin Grade ≥2 ventricular arrhythmia
sponsor signature page
test product dose and mode

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 3.5 mg/kg or placebo) will be administered as an intravenous infusion over at least 30 minutes once every 2 weeks for 6 doses (e.g., the last dose given on Day 70). A second course of study drug
(demcizumab at 3.5 mg/kg or placebo) will be administered once every 2 weeks for 6 doses starting on Day 168
(e.g., the last dose given on Day 238) if the subject's Day 168 BNP is ≤100 pg/mL, peak tricuspid velocity is
<3.0 m/s and LVEF is ≥50%, and the subject did not develop pulmonary hypertension or heart failure while on study.
sponsor signature page
duration of treatment

Subjects should remain on study until they develop progressive disease per the Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1, develop unacceptable toxicity or withdrawal consent. Disease progression should be based on radiographic assessment rather than an elevation of CA 19-9. If disease progression is suspected due to an elevation in CA 19-9 an early radiographic assessment may be performed to determine if progression has occurred. If all of the study drugs are discontinued prior to disease progression, the subject should still remain on study until disease progression.
sponsor signature page
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 every 14 days, doppler echocardiogram, anti-demcizumab testing, and subject interview on an ongoing basis (as outlined in the Schedule of Assessments) from randomization through 30 days following the termination visit.
sponsor signature page
efficacy evaluation

Subjects will be assessed for response using RECIST criteria 1.1 at Study Day 56 and then every 8 weeks. In addition, CA 19-9 levels will be obtained at baseline and then every 8 weeks. Disease progression should be based on radiographic assessment rather than an elevation of CA 19-9. If disease progression is suspected due to an elevation in CA 19-9 an early radiographic assessment may be performed to determine if progression has occurred. Investigator-assessed response rates, duration of response, time to progression, and survival will be evaluated. In addition, an optional independent assessment of the radiographs may be performed. Immunogenicity: Subjects will be assessed at baseline and then every 8 weeks while the subject is on study. In addition, subjects will be assessed for immunogenicity at the time of treatment termination.
sponsor signature page
pharmacokinetics

Sparse PK sampling will be obtained on all subjects. Plasma sample for PK analysis to be obtained prior to the demcizumab infusion on Days 0, 14, 56, 70, 168, 182, 224 and 238, and at the end of the demcizumab infusion
(prior to chemo infusion) on Days 0, 56, 70, 168, 224 and at treatment termination.
sponsor signature page
biomarker evaluation

Whole blood will be obtained for biomarker evaluations on Study Days 0, 21, 35, 49 and 63, and at treatment termination as outlined in the Schedule of Assessments. 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).  
| 1.0   | TABLE OF CONTENTS   |
|-------|---------------------|
| SPONSOR CONTACTS 2 INVESTIGATOR SIGNATURE PAGE 3 SPONSOR SIGNATURE PAGE 4 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 Disease Background 16 3.3 Nonclinical Background 16 3.3.1 Activity of Anti-DLL4 in Pancreatic Cancer Xenografts 17 3.3.2 Potential for Immune-Mediated Mechanism of Action for AntiDLL4 19 3.4 Clinical Background 22 3.4.1 Phase 1a Study M18-001 23 3.4.2 Phase 1b Studies M18-002, M18-003, and M18-004 and Phase 1b/2  Study M18-005 24 3.5 Risks/Benefits 31 3.6 Dose Rationale 33 3.7 Study Conduct 33 3.8 Subject Population 34 4.0 STUDY OBJECTIVES AND ENDPOINTS 34 4.1 Study Objectives 34 5.0 OVERALL STUDY DESIGN AND PLAN - DESCRIPTION 36 6.0 SELECTION OF STUDY POPULATION 37 6.1 Inclusion Criteria 37 6.2 Exclusion Criteria 39 7.0 REMOVAL OF SUBJECTS FROM STUDY 41 8.0 TREATMENT OF SUBJECTS 41 8.1 Study Drug (DEMCIZUMAB OR PLACEBO) 41 8.1.1 Administration 41 8.1.2 Description 42 8.1.3 Packaging 42       |                     |  
9.0  
| 8.1.4                                                                                                                                  | Drug Ordering, Storage, and Accountability ...........................................42                                                |
|----------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------|
| 8.1.5                                                                                                                                  | Study Drug Preparation                                                                                                                  |
| 8.1.6                                                                                                                                  | Treatment Modification and Termination Criteria..................................43                                                     |
| Infusion Reaction Management ....................................................................44                                    |                                                                                                                                         |
| 8.1.7                                                                                                                                  |                                                                                                                                         |
| 8.2                                                                                                                                    | Gemcitabine and Abraxane ®                                                                                                              |
| 8.2.1                                                                                                                                  | Abraxane® ........................................................................................................45                    |
| Gemcitabine .......................................................................................................45                  |                                                                                                                                         |
| 8.2.2                                                                                                                                  |                                                                                                                                         |
| 8.2.3                                                                                                                                  | Gemcitabine and Abraxane ® Dose Modification Guidelines...............46                                                                |
| 8.3                                                                                                                                    | Anti-Emetics and Hematopoietic Supportive Care                                                                                          |
| 8.4                                                                                                                                    | Concomitant and Prohibited Therapy ......................................................................................50             |
| Treatment Compliance                                                                                                                   |                                                                                                                                         |
| 8.5                                                                                                                                    |                                                                                                                                         |
| SAFETY ASSESSMENTS .                                                                                                                   |                                                                                                                                         |
| 9.1                                                                                                                                    | Adverse Events Definitions and Reporting Procedures ..................................................51                                |
| 9.1.1                                                                                                                                  | Definition of Adverse Event ..................................................................................52                        |
| Definition of Serious Adverse Event ...............................................................52                                  |                                                                                                                                         |
| 9.1.2                                                                                                                                  |                                                                                                                                         |
| 9.1.3                                                                                                                                  | Serious Adverse Event Reporting Procedures .............................................53                                              |
| 9.2                                                                                                                                    | Clinical Laboratory Assessments                                                                                                         |
| 9.2.1                                                                                                                                  | Hematology .                                                                                                                            |
| 9.2.2                                                                                                                                  | Serum Chemistry                                                                                                                         |
| 9.2.3                                                                                                                                  | BNP Assessment                                                                                                                          |
| 9.2.4                                                                                                                                  | Urinalysis .........................................................................................................................54  |
| 9.2.5                                                                                                                                  | Pregnancy Testing                                                                                                                       |
| Vital Signs and Other Physical Findings ...............................................................................54              |                                                                                                                                         |
| 9.3                                                                                                                                    |                                                                                                                                         |
| 9.4                                                                                                                                    | CC                                                                                                                                      |
| 9.5                                                                                                                                    | Immunogenicity Assessments                                                                                                              |
| 9.6                                                                                                                                    | Pharmacokinetic Assessments                                                                                                             |
| EFFICACY ASSESSMENTS .                                                                                                                 |                                                                                                                                         |
| EXPLORATORY ASSESSMENTS                                                                                                                |                                                                                                                                         |
| STUDY VISIT SCHEDULE AND ASSESSMENTS                                                                                                   |                                                                                                                                         |
| 12.1                                                                                                                                   | Screening                                                                                                                               |
| Study Day 0.                                                                                                                           |                                                                                                                                         |
| 12.2                                                                                                                                   |                                                                                                                                         |
| 12.3                                                                                                                                   | Study Days 7, 14, 21, 28, 35, 42, and 49 ..........................................................................60                   |
| 12.4                                                                                                                                   | Study Day 56.........................................................................................................................61 |
| 12.5                                                                                                                                   | Study Days 63, 70                                                                                                                       |
| Study Day 77........................................................................................................................62 |                                                                                                                                         |
| 12.6                                                                                                                                   |                                                                                                                                         |
| 12.7                                                                                                                                   | Study Days 84, 91, 98                                                                                                                   |  
10.0 1.0 12.0  
| 12.8                                                                                                                                                  | Study Day 105                                                                                                                                           |
|-------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------|
| 12.9                                                                                                                                                  | Termination Visit                                                                                                                                       |
| 12.10                                                                                                                                                 | Follow-up after Termination Visit ....................................................................................65                                |
| DATA QUALITY ASSURANCE ...................................................................................................65                          |                                                                                                                                                         |
| 13.0                                                                                                                                                  |                                                                                                                                                         |
| 14.0                                                                                                                                                  | STATISTICAL PLAN .............................................................................................................................66        |
| 14.1                                                                                                                                                  | Data Safety Monitoring Board                                                                                                                            |
| Study Stopping Rules                                                                                                                                  |                                                                                                                                                         |
| 14.2                                                                                                                                                  | Subject Populations for Analysis ...............................................................................................71                      |
| 14.3                                                                                                                                                  |                                                                                                                                                         |
| 14.4                                                                                                                                                  | Demographics and Baseline Characteristics                                                                                                               |
| 14.5                                                                                                                                                  | T Treatment Exposure                                                                                                                                    |
| Endpoints .........................................................................................................................................72 |                                                                                                                                                         |
| 14.6                                                                                                                                                  | Sety Endpoints .                                                                                                                                        |
| 14.6.1                                                                                                                                                |                                                                                                                                                         |
| 14.6.2                                                                                                                                                | Immunogenicity Endpoints ..................................................................................73                                           |
| 14.6.3                                                                                                                                                | Pharmacokinetic Endpoints                                                                                                                               |
| Efficacy Endpoints                                                                                                                                    |                                                                                                                                                         |
| 14.6.4                                                                                                                                                | Continuous Variable Assessment of Tumor Length ...................................75                                                                    |
| 14.6.5                                                                                                                                                |                                                                                                                                                         |
| 14.6.6                                                                                                                                                | Duration of Response                                                                                                                                    |
| 14.6.7                                                                                                                                                | OVERALL SURVIVAL                                                                                                                                        |
| Termination Criteria                                                                                                                                  |                                                                                                                                                         |
| 14.7                                                                                                                                                  | Deviation Reporting                                                                                                                                     |
| 14.8                                                                                                                                                  |                                                                                                                                                         |
| 15.0                                                                                                                                                  | DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION .................................77                                                                          |
| 16.0                                                                                                                                                  | ETHICAL CONSIDERATIONS                                                                                                                                  |
| INVESTIGATOR REQUIREMENTS .....................................................................................................77                     |                                                                                                                                                         |
| 17.0                                                                                                                                                  | Informed Consent                                                                                                                                        |
| 17.1                                                                                                                                                  |                                                                                                                                                         |
| 17.2                                                                                                                                                  | Institutional Review Board/Ethics Committee Approval .........................................78                                                        |
| 17.3                                                                                                                                                  | Study Monitoring ..............................................................................................................................78       |
| A Auditing Procedures                                                                                                                                 |                                                                                                                                                         |
| 17.4                                                                                                                                                  |                                                                                                                                                         |
| 17.5                                                                                                                                                  | DATA COLLECTION .....................................................................................................................................79 |
| 17.6                                                                                                                                                  | Investigational Medicinal Product Accountability .......................................................79                                              |
| 17.7                                                                                                                                                  | Disclosure of Data and Publication                                                                                                                      |
| Retention of Records                                                                                                                                  |                                                                                                                                                         |
| 17.8                                                                                                                                                  |                                                                                                                                                         |
| REFERENCES                                                                                                                                            |                                                                                                                                                         |
| 18.0                                                                                                                                                  |                                                                                                                                                         |  
| LIST OF TABLES   |                                                                                                                             |
|------------------|-----------------------------------------------------------------------------------------------------------------------------|
| Table 1:         | Summary of the Activity of Anti-DLL4 (Demcizumab + 21R30) in  Human Pancreatic Xenografts 18                                |
| Table 2:         | Overall Response Assessment for Subjects Enrolled in Study M18-002  (n=52) 25                                               |
| Table 3:         | Overall Response Assessment for Subjects in Study M18-004 (n =40) 28                                                        |
| Table 4:         | Dose Modifications 46                                                                                                       |
| Table 5:         | Dose Recommendation and Modifications for Neutropenia and/or  Thrombocytopenia at the Start of a Cycle or Within a Cycle 47 |
| Table 6:         | Dose Modifications for Other Adverse Drug Reactions 48                                                                      |
| Table 7:         | Power for a Two Arm Comparison 67                                                                                           |
| Table 8:         | Summary of Power and Type 1 Error 68                                                                                        |
| Table 9:         | Probability CHF Rate will Exceed 15 Percent over Control 70 LIST OF FIGURES                                                 |
| Figure 1:        | Inhibition of Pancreatic Tumor Growth by Anti-DLL4 as a Single  Agent and in Combination with Gemcitabine 18                |
| Figure 2:        | Reduction of Cancer Stem Cell Frequency after Treatment with  Anti-DLL4 19                                                  |
| Figure 3:        | Activity of Anti-DLL4 in Combination with Anti-PD1 in Reducing the  Growth of CT26wt Tumors in Immunocompetent Mice 20      |
| Figure 4:        | Increase in IL-2 Expression by Splenocytes after Treatment with AntiDLL4 in Combination with Anti-PD1 21                                                                                                                             |
| Figure 5:        | Anti-DLL4 Treatment Increases Memory T cells in Splenocytes of  Tumor-Bearing Mice 22                                       |
| Figure 6:        | Percent Change in Tumor Target Lesion Size - Study M18-002 26                                                               |
| Figure 7:        | Percent Change in Tumor Target Lesion Size of the  Abraxane®/Gemcitabine/Demcizumab Subjects - Study M18-002 27             |
| Figure 8:        | Percent Change in Tumor Target Lesion Size - Study M18-004 29                                                               |  
| LIST OF APPENDICES   |                                                                     |
|----------------------|---------------------------------------------------------------------|
| APPENDIX A:          | STUDY SCHEMA 83                                                     |
| APPENDIX B:          | SCHEDULE OF ASSESSMENTS 84                                          |
| APPENDIX C:          | ECOG PERFORMANCE STATUS CRITERIA 88                                 |
| APPENDIX D:          | RECIST CRITERIA 1.1 89                                              |
| APPENDIX E:          | NEW YORK HEART ASSOCIATION CLASSIFICATION 95                        |
| APPENDIX F:          | SAMPLE INFORMED CONSENT 96                                          |
| APPENDIX G:          | SAMPLE PHARMACOGENOMICS AND TUMOR DNA TESTING  INFORMED CONSENT 121 |
| APPENDIX H:          | PROTOCOL AMENDMENTS SUMMARY OF CHANGES 126                          |
| AMENDMENT 1:         | 24 NOVEMBER 2014 126                                                |
| AMENDMENT 2:         | 10 FEBRUARY 2015 127                                                |
| AMENDMENT 3:         | 28 MAY 2015 128                                                     |
| AMENDMENT 4:         | 31 MARCH 2016 129                                                   |
| AMENDMENT 5:         | 19 DECEMBER 2016 130                                                |  
| 2.0                           | LIST OF ABBREVIATIONS                                                   |
|-------------------------------|-------------------------------------------------------------------------|
| Abbreviation or Term          | Definition/Explanation                                                  |
| aPTT                          | activated partial thromboplastin time                                   |
| AE                            | adverse event                                                           |
| ALT (SGPT)                    | alanine aminotransferase (serum glutamic pyruvic transaminase)          |
| ANC                           | absolute neutrophil count                                               |
| AST (SGOT)                    | aspartate aminotransferase (serum glutamic oxaloacetic transaminase)    |
| 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             |
| IEC                           | Independent Ethics Committee                                            |
| IGS                           | Invasiveness gene signature                                             |
| IMP                           | Investigational Medicinal Product                                       |
| INR                           | International normalized ration                                         |
| IRB                           | Institutional Review Board                                              |
| ITT                           | intent-to-treat (population)                                            |
| IV                            | intravenous                                                             |
| IWRS                          | Interactive web randomization system                                    |
| kg                            | kilogram(s)                                                             |
| LD                            | longest diameter (of a lesion)                                          |
| LDH                           | lactic dehydrogenase                                                    |
| LVEF                          | left ventricular ejection fraction                                      |
| MedDRA                        | Medical Dictionary for Regulatory Activities                            |
| Protocol M18-006, Amendment 5 | Page 14 of 130                                                          |  
**Amendment 5 Page 14 of 130** CONFIDENTIAL 19 December 2016  
| Abbreviation or Term   | Definition/Explanation                       |
|------------------------|----------------------------------------------|
| mg                     | milligram(s)                                 |
| mL                     | milliliter(s)                                |
| MRI                    | magnetic resonance imaging                   |
| NCI                    | National Cancer Institute                    |
| NE                     | Not evaluable                                |
| NOAEL                  | no observed adverse effect level             |
| PD                     | progressive disease                          |
| PK                     | pharmacokinetic(s)                           |
| 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           |
sponsor signature page
3.0 background 3.1 investigational medicinal

Demcizumab (OMP-21M18) 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.
sponsor signature page
3.2 disease background

Pancreatic cancer is an aggressive malignancy that is usually unresectable at the time of diagnosis, 80%–85%. As complete resection offers the only hope of cure, 5-year survival rates are less than 10%. For patients diagnosed locally advanced or metastatic pancreatic ductal adenocarcinoma the median survival is 8–12 months. Single agent chemotherapy, including the commonly used agents gemcitabine, Abraxane®, oxaliplatin, irinotecan, leucovorin, fluorouracil, produce objective partial responses in 5-15% of subjects. More recently, gemcitabine and Abraxane® has resulted in somewhat higher response rate, time to progression and survival
(Ref 1). In addition, other combinations, such as FOLFIRINOX have reported encouraging activity. However, unresectable metastatic pancreatic ductal adenocarcinoma remains and incurable disease. Consequently, there is a significant need to develop novel approaches for the treatment of unresectable and metastatic pancreatic ductal adenocarcinoma.
sponsor signature page
3.3 nonclinical background

Many current cancer treatments, while producing an initial reduction in tumor burden and/or a prolongation of time to progression, have not resulted in meaningful long-term benefit. A possible explanation for this observation is the presence of cancer stem cells (CSC) (Ref 2, Ref 3), which represent a subset of the tumor, but are the most tumorigenic component driving growth and metastasis and are more resistant to traditional cytotoxic therapy, including both radiotherapy (Ref 4) and chemotherapy (Ref 5), than the remaining bulk of the tumor. Consequently, efforts have been made to isolate cancer stem cells and then identify active pathways in these cells, which could serve as targets for antibody treatment. Using this approach, the Notch pathway was identified as a potential target. There are four Notch receptors (1–4) and five ligands, including two Jagged (1 and 2) and three Delta-Like Ligands (DLLs) (1, 3, and 4). There appears to be differential binding of these ligands to specific members of the Notch family, with DLL4, for example, having a higher specificity for Notch 1 than DLL1 (Ref 6). Among the breast, colon, and lung cancers assessed at OncoMed by IHC, all but two lung cancers expressed both Notch 1 and the Notch ligand DLL4. In addition to its important role on cancer stem cells, Notch 1 is also important in the cell signaling process of the remaining nontumorigenic cancer cells. Finally, DLL4 and Notch 1 have also been shown to be essential for angiogenesis (Ref 7). Blockade of DLL4 results in tumor-associated endothelial cell hyperproliferation, coupled to a non-productive angiogenesis associated with poor tumor perfusion, regional hypoxia and an inhibition of tumor growth (Ref 8, Ref 9). Thus, inhibition of the Notch pathway could potentially produce an anti-tumor effect by 1) impacting the growth of the cancer stem cells, 2) impacting the growth of the remaining cancer cells, and 3) dysregulating tumor angiogenesis.  
Demcizumab is a humanized IgG2 monoclonal antibody directed against DLL4. Demcizumab is not anticipated to exhibit a high rate of immunogenicity. The antibody binds to DLL4 with high affinity, as measured by Biacore, the affinity of demcizumab for human DLL4 is 0.64 nM. The binding of demcizumab to DLL4 blocks its interactions with Notch receptors however, the Notch signaling pathway may still be activated by other ligands, as demcizumab is specific for DLL4. Nonclinical mouse xenograft studies have suggested that demcizumab possess anti-tumor activity via all three of the potential mechanisms described above. In mouse xenograft models, demcizumab and the murine antibody (m21M18) that was humanized to produce demcizumab have been demonstrated to have a direct effect on cancer stem cells, reducing the frequency of this population. In these same models, demcizumab and m21M18 have been shown to also have a direct effect on the nontumorigenic cancer cells. Finally, in these models, a phage-derived antibody against DLL4 that is capable of binding to murine DLL4, but not human DLL4, has been shown to have dys-angiogenic effects coupled to an inhibition of tumor growth.
sponsor signature page
3.3.1 activity of anti-dll4 in

Pancreatic cancer remains a disease with a generally poor clinical prognosis and one of the most difficult malignancies to treat effectively (Ref 10). The Notch pathway has been implicated in playing a role in normal pancreatic development where active Notch signaling is required for maintaining cells in undifferentiated state (Ref 11). Activation of Notch signaling has been also been associated with drug resistance in pancreatic cancer (Ref 12). We have found that blockade of Notch signaling with anti-DLL4 is efficacious in a variety of pancreatic xenograft models (Table 1). Representative tumor growth data is shown for PN4 in Figure 1. Inhibition of DLL4-Notch signaling in the tumor stroma and vasculature was associated with hyperproliferation of endothelial cells as shown by immunofluorescence with an anti-CD31 (data not shown) as was previously shown in colon tumors. Activity in reducing cancer stem cells was observed in both the PN4 (Figure 2) as well as the PN8 and PN13 xenograft models.  
| Tumor                                                                                                     | Single Agent   | Combination   | Reduction in CSCs   |
|-----------------------------------------------------------------------------------------------------------|----------------|---------------|---------------------|
| PN4                                                                                                       | +              | +             | +                   |
| PN8                                                                                                       | +              | +             | +                   |
| PN9                                                                                                       | +              | +             |                     |
| PN13                                                                                                      | +              | +             | +                   |
| PN16                                                                                                      | +              | +             |                     |
| PN17                                                                                                      | +              | +             |                     |
| PN21                                                                                                      | +              | +             |                     |
| PN23                                                                                                      | +              | -             |                     |
| PN35                                                                                                      | +              | +             |                     |
| PN38                                                                                                      | -              |               |                     |
| PN40                                                                                                      | -              | +             |                     |
| PN42                                                                                                      | +              |               |                     |
| Anti-DLL4 were tested as a single agent and in combination with gemcitabine or gemcitabine + Abraxane® in |                |               |                     |  
Anti-DLL4 were tested as a single agent and in combination with gemcitabine or gemcitabine + Abraxane® in pancreatic tumors. The activity of anti-DLL4 treatment as a single agent or in combination with gemcitabine 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 the chemotherapeutic agent(s) plus control antibody (p < 0.05). For PN4, PN8 and PN13 tumors, anti-DLL4 treatment resulted in a reduction cancer stem cell frequency as shown by in vivo limiting dilution analyses.  
  
Figure 2: Reduction of Cancer Stem Cell Frequency after Treatment with  
  
  
Anti-DLL4 We determined that targeting DLL4-Notch signaling in both tumor and stromal/vasculature cells was required for anti-tumor efficacy (Ref 13). In addition to carrying combination studies with gemcitabine alone, we have tested anti-DLL4 in combination with gemcitabine plus Abraxane and observed combination activity in this setting as well. These data indicate that anti-DLL4 exhibits broad spectrum activity in pancreatic tumor models. Strikingly, synergy with gemcitabine or gemcitabine plus Abraxane was observed in the vast majority of the models (Table 1). The reduction in CSC frequency after anti-DLL4 treatment indicates that Notch signaling in the tumorigenic cells is required for CSC function.
sponsor signature page
3.3.2 potential for immune-mediated mechanism

Notch signaling is now known to play a key role in various aspects of the immune response (Ref 14). Notch signaling has been shown to upregulate PD1 expression during the immune response (Ref 15). Since PD1 functions to limit T-cell activation, inhibition of DLL4-Notch signaling might be expected to increase anti-tumor immune responses. Our previous studies were carried out using patient-derived xenografts that necessitated the use of immunocompromised mice and, thus, were not suitable for testing the effect of anti-DLL4 on the interaction of lymphocytes in the tumor microenvironment. To investigate the potential role of anti-DLL4 on the host immune response during tumor growth, we have carried out a series of experiments using murine tumors implanted in an isogenic murine host strain. An example combining anti-DLL4 and anti-PD1 is shown in Figure 5. This experiment utilized the CT26wt colon tumor model and was carried out in Balb/C mice. Anti-DLL4 reduced tumor growth as a single agent and showed additive activity in combination with anti-PD1 (Figure 3). Subsequent analyses indicated that the combination of anti-DLL4 and anti-PD1 increased the expression of IL-2 in tumor-specific splenocytes (Figure 4). Furthermore, anti-DLL4 administration increased the fraction of memory T cells in the spleens of tumor-bearing mice (Figure 5). In addition to these results, we have observed in other experiments an increase in the cytotoxic activity of CD8+ T cells in killing tumor cells using an ex vivo assay (data not shown). Collectively, our experiments in immunocompetent animals suggest that anti-DLL4 may increase the anti-tumor immune response. Thus, in addition, to its previously characterized mechanisms of action (targeting CSCs and disrupting tumor vasculature), promotion of anti-tumor immunity may contribute to the efficacy of demcizumab treatment. This immune-mediated mechanism may be particularly important for the long-term, durable responses that have been observed in the Phase 1b clinical testing of demcizumab. Figure 3: Activity of Anti-DLL4 in Combination with Anti-PD1 in Reducing the Growth of CT26wt Tumors in Immunocompetent Mice  
  
Figure 4: Increase in IL-2 Expression by Splenocytes after Treatment with Anti-DLL4 in Combination with Anti-PD1
figure 5 anti-dll4 treatment increases
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 Abraxane® plus demcizumab in subjects with locally advanced or metastatic pancreatic ductal adenocarcinoma. 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 5 anti-dll4 treatment increases
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 anti-hypertensives 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 5 anti-dll4 treatment increases
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 (M18-004), 17 Sept 2014 (M18-002) and 21 August 2014 (M18-005), 104 subjects have been treated in these trials. Study M18-002 is an ongoing open-label Phase 1b study of gemcitabine or gemcitabine and Abraxane® plus demcizumab in subjects with locally advanced or metastatic pancreatic ductal adenocarcinoma. 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 5 anti-dll4 treatment increases
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 Abraxane® in subjects with previously untreated adenocarcinoma of the pancreas. Thirty-eight of the 52 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. Ten of the 22 (45%) evaluable subjects treated with Abraxane®, gemcitabine and demcizumab had a partial response, and 9 (41%) 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)   | Cohort  7  Tr. Dem  3.5 mg/kg  q2w  (n=5)   | 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                                                                                      | -                                       | -                                           | -                                        | -                                         | -                                           | -       | -  | -  | -        |
| Response                                                                                                | 1                                       | 1                                           | 2                                        | 4 (25%)                                   | 4                                           | 3       | 3  | -  | 10 (45%) |
| Partial  Disease                                                                                        | 4                                       | 2                                           | 1                                        | 7 (44%)                                   | 1                                           | 4       | 4  | -  | 9 (41%)  |
| Stable                                                                                                  |                                         |                                             |                                          |                                           |                                             |         |    |    |          |
| Progressive  Disease                                                                                    | -                                       | 3                                           | 2                                        | 5 (31%)                                   | 1                                           | 1       | 1  | -  | 3 (14)%  |
| evaluable                                                                                               | 3                                       | 2                                           | 3                                        | 8                                         | -                                           | -       | 1  | 5  | 6        |
| Not                                                                                                     |                                         |                                             |                                          |                                           |                                             |         |    |    |          |
| Dem = demcizumab; Gem = gemcitabine; Nab = Abraxane®; q2w = every 2 weeks; q4w = every 4 weeks; Tr. Dem |                                         |                                             |                                          |                                           |                                             |         |    |    |          |  
Not  
evaluable 3 2 3 8 - - 1 5 6  
Dem = demcizumab; Gem = gemcitabine; Nab = Abraxane®; 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 Abraxane®, gemcitabine  
and demcizumab (truncated dosing regimen).  
Figure 6 and Figure 7 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 Abraxane®, respectively.
figure 6 percent change in
3.4.2.1 phase 1b efficacy data

Waterfall Plot  
  
Figure 6 provides the best % change in tumor target lesion size for all subjects (i.e., subjects treated with gemcitabine and demcizumab and subjects treated with Abraxane®, 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 7: Percent Change in Tumor Target Lesion Size of the Abraxane®/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 8 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 Tumor Target Lesion Size - Study M18-004  

Each bar represents an individual subject. All subjects were dosed once every 3 weeks.  
Five subjects with platinum-resistant ovarian cancer have been enrolled in study M18-005 and were treated with paclitaxel and demcizumab. Two of these subjects had stable disease, and 3 had progressive disease.
figure 6 percent change in
3.4.2.2 phase 1b safety data

The treatment-emergent adverse events (AEs) in the 104 subjects treated 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 (44.2%), nausea (41.3%), hypertension/blood pressure increased (30.8%), vomiting (25%), edema peripheral (22.1%), diarrhea (21.1%), appetite decreased (17.3%), increased BNP (17.3%), anemia (13.5%), thrombocytopenia (13,5%), neutropenia (13.5%), dyspnea (11.5%), headache (10.6%) and pulmonary hypertension (10.6%).  
The Grade 3-5 treatment-emergent AEs considered to be related to demcizumab that occurred in > 5% of subjects were hypertension/blood pressure increased (15.4%), neutropenia (7.7%) and thrombocytopenia (6.7%). 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 50 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 6 percent change in
3.5 risks/benefits

The toxicology and pharmacokinetics of demcizumab were studied in the cynomolgus monkey. The toxicology findings in the initial definitive 8 week cynomolgus monkey study were limited to minor clinical pathology alterations, minimal effects on body weight (seen in selected monkeys that received 200 mg/kg), minimal-to-slight congestion or hemorrhage in the gastrointestinal tract, and dose-related degeneration/necrosis of the physis-metaphysis of the distal femur. The body weight, clinical pathology and gastrointestinal effects were not considered to be adverse. Based on the severity, the degeneration/necrosis of the physismetaphysis of the distal femur noted at 50 and 200 mg/kg/week was considered adverse.  
Following recovery, degeneration/necrosis and loss of the physis-metaphysis of the distal femur was limited to one male that previously had been dosed at 200 mg/kg/week. Whether this finding was persistent or delayed in onset is uncertain. However, it should be noted that the monkeys that were treated in this study were adolescent monkeys with growth plates that were not yet fused. These finding would probably not have been observed if adult monkeys with fused growth plates had been studied. Similarly, as demcizumab will only be administered to patients who are at least 21 years of age in the human clinical trials this effect is unlikely to occur. Based upon the results of this study, demcizumab was generally well tolerated at doses up to 200 mg/kg/week. The maximum tolerated dose (MTD) of demcizumab was at least 200 mg/kg/week, corresponding to a mean Day 50 AUC of 497 mg.hr/mL. A subsequent cynomolgus monkey study was performed in which the animals received doses of demcizumab as a weekly infusion, 10, 30 or 100 mg/kg, for 26 weeks. In this study, long term administration of the two highest doses was not tolerated. Histopathologic findings present in the heart included hypertrophy, both of the cardiac myofibers and of the endothelial cells lining the small vessels within the myocardium, and myofiber degeneration and necrosis. In addition, test-article related changes in the liver included atrophy of centrilobular hepatocytes and dilation of the centrilobular sinusoids. Data from this study revealed that cardiotoxicity related to demcizumab occurred principally in monkeys that were treated with high doses (30 and 100 mg/kg) of demcizumab weekly, for prolonged periods of time. However, animals that received lower doses (10 mg/kg/week) of demcizumab did not manifest any clinical signs of cardiotoxicity with prolonged treatment (up to 6 months). This nonclinical study, in addition to emerging clinical data, was pivotal to the redesign of the clinical trials of demcizumab to incorporate lower dose administration of the drug to patients and to institute the cardiac risk mitigation plan on the ongoing Phase 1b trials, although subsequently the use of truncated dosing was also incorporated. These findings prompted changes to the clinical protocols to include more frequent ECG monitoring and to add echocardiography and BNP measurements. The emerging clinical data from the 5 demcizumab studies conducted to date suggest that the primary drug-related toxicities associated with demcizumab administration are hypertension, bleeding, pulmonary hypertension and heart failure. Newly diagnosed hypertension or exacerbation of pre-existing hypertension occurred in about one-third to one-half of the subjects on the demcizumab clinical trials. Thus, subjects receiving demcizumab should be closely monitored for the development of hypertension or the exacerbation of pre-existing hypertension, and patients with hypertension should be treated according to the standard treatment guidelines for managing hypertension (Ref 16). Serious bleeding, primarily from luminal tumors in the gastrointestinal tract occurred in 5 subjects in the Phase 1 dose escalation study. As a result, subjects having luminal tumors were subsequently excluded from the demcizumab clinical trials and, subsequently, there was only 1 case of possible serious tumor-associated bleeding in the gastrointestinal tract in the Phase 1b or Phase 1b/2 studies. Grade 3 or greater right- and/or leftsided heart failure with or without Grade 3 pulmonary hypertension has occurred in 8 of the subjects treated with continuous demcizumab between Days 112-184. As a result, several modifications to the risk mitigation strategy, monitoring and dosing of demcizumab were instituted. Subsequent to implementation of this updated risk mitigation procedure, none of the 50 subjects treated according to this approach have developed Grade 2 or greater pulmonary hypertension or heart failure; i.e., only 1 patient has developed Grade 1 pulmonary hypertension. Strict adherence to the risk mitigation, monitoring and demcizumab dosing guidelines (provided in Section 7 of the Investigator Brochure) is required to avoid pulmonary hypertension and/or heart failure. As the 5 clinical studies conducted to date have all been at the Phase 1 stage of development (with the exception of Phase 1b/2 study in patients with ovarian cancer, which at present has data reported on 5 subjects), the extent of efficacy data is limited. Nevertheless, there are observations of activity in the Phase 1b studies (see Section 6.4 of the Investigator's Brochure for a comprehensive overview). Most relevant for the upcoming Phase 2 study in pancreatic cancer is the ongoing Phase 1b study in subjects with 1st-line pancreatic cancer who were treated with demcizumab in combination with gemcitabine or gemcitabine plus Abraxane®
(protocol M18-002). Four of the sixteen (25%) evaluable subjects treated with gemcitabine and demcizumab had partial response and 7 (44%) had stable disease and nine of the twenty-two
(41%) evaluable subjects treated with Abraxane®, gemcitabine and demcizumab had a partial response and 10 (45%) had stable disease. In addition, twenty of the twenty-one evaluable subjects had a reduction in the size of their target lesions. In summary, OncoMed has gained critical safety experience from the cynolmolgus monkey studies and from Phase 1 clinical development in understanding the primary risks associated with demcizumab treatment. OncoMed instituted a risk mitigation procedure early on in the program, as a result of histopathologic findings from the second cynomolgus study. The risk mitigation plan was further refined during clinical development, and subsequent to implementation of the updated risk mitigation plan, no patients have developed greater than Grade 1 cardiotoxicity to date. This risk mitigation strategy has been incorporated into the proposed Phase 2 protocol and is reviewed extensively in the Investigator's Brochure (Section 7). There have been observations of clinical activity in the Phase 1b trials as reviewed in Section 6.4 of the Investigator's Brochure and as briefly described above. Thus, the current risk/benefit assessment of demcizumab supports the continued clinical development of this novel investigational anti-cancer therapeutic in a randomized, placebo-controlled Phase 2 trial, which will more rigorously assess the clinical potential of demcizumab in the treatment of1st line pancreatic cancer.
figure 6 percent change in
3.6 dose rationale

In the Phase 1b study of demcizumab and gemcitabine or demcizumab plus gemcitabine and Abraxane® (study M18-002), subjects in the 1st 3 dose cohorts received demcizumab doses of either 5 mg/kg once every 2 weeks or 2.5 or 5 mg/kg once every 4 weeks until disease progression. As 1 of the subjects in the 3rd dose cohort of this study and 2 additional patients in the ongoing non-small cell lung cancer Phase 1b study developed pulmonary hypertension and heart failure at approximately Day 168, the 38 subjects in the subsequent 4 cohorts received a truncated dosing regimen of 2.5, 3.5 or 5 mg/kg once every 2 weeks for 70 days (i.e., 6 doses over 70 days). No cases of Grade 2 pulmonary hypertension or heart failure were observed in any of these subjects. However, the data safety monitoring board (DSMB) for the study felt that the BNP and peak tricuspid velocity data of subjects in the.5 mg/kg cohort suggested that the dose may be too high and thus recommended that the truncated dosing regimen of 3.5 mg/kg once every 2 weeks be used for the Phase 2 study. Subjects in the 3rd arm of this study will receive 2 truncated courses of demcizumab at 3.5 mg/kg once every 2 weeks (one from Days 0-70 and one from Days 168-238). Only subjects who meet the original cardiac-related inclusion/exclusion criteria at Day 168 will receive the 2nd truncated course of demcizumab in this arm of the study. With a terminal half life of 16 days, the 3-month washout period will allow more than 99.5% of the drug to be eliminated before re-dosing. 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 and subjects have to meet stringent criteria for the second course of demcizumab. Furthermore, the DSMB for this study will be monitoring the emerging safety data very closely to ensure that this approach is safe for continued use in the trial.
figure 6 percent change in
3.7 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.
figure 6 percent change in
3.8 subject population

Subjects must be at least 21 years of age, have 1st line metastatic pancreatic ductal adenocarcinoma, have not received prior chemotherapy for their metastatic pancreatic ductal adenocarcinoma, have adequate organ and bone marrow function, have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and have a life expectancy of more than 3 months. In addition, subjects must have measurable disease per RECIST 1.1.
figure 6 percent change in
4.0 study objectives and endpoints

To compare the efficacy of Arm 1 to the pooled decizumab arms (i.e., Arm 1 to Arms 2 and 3) (See Section 5.0 for description of Treatment Arms) in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma
figure 6 percent change in
secondary objectives

To compare the efficacy of Arm 1 to Arm 2 and Arm 1 to Arm 3 in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma To compare the safety of Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.  
To determine the rate of immunogenicity against demcizumab when combined with Abraxane® and gemcitabine in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.  
To determine population pharmacokinetics of demcizumab in subjects receiving demcizumab and Abraxane® and gemcitabine in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.
figure 6 percent change in
exploratory objectives

To compare the safety and efficacy of Arm 2 to Arm 3 in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.  
To compare the exploratory biomarkers of Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.
figure 6 percent change in
primary endpoint

To compare the hazard of progression using the Investigator assessed progression-free survival time between subjects in Arm 1 and the pooled demcizumab arms (i.e., Arms 2 + 3)in 1st-line metastatic pancreatic ductal adenocarcinoma.
figure 6 percent change in
secondary endpoints

To compare the hazard of progression using the Investigator assessed progression-free survival time between subjects in Arm 1 and Arm 2 and Arm 1 and Arm 3 in 1st-line metastatic pancreatic ductal adenocarcinoma.  
To compare the Investigator-assessed RECIST response rate in Arm 1 to Arm 2 , Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1st-line metastatic pancreatic cancer.  
To compare the Investigator-assessed RECIST clinical benefit rate (i.e., the rate of complete response + partial response + stable disease) in Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.  
To compare the Investigator-assessed progression-free survival at 6 months in Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.  
To compare the Independent Review Facility (IRF)-assessed RECIST response rate and progression-free survival based solely on radiographs in Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled (Optional).  
To determine the half-life, volume of distribution and clearance of demcizumab when combined with Abraxane® and gemcitabine in with subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.
To compare the safety profile through adverse event monitoring (including attribution of adverse events and serious adverse events [SAEs]), physical examination, vital signs, and clinical laboratory testing as outlined in the Schedule of Assessments (see Appendix B)
between Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1stline metastatic pancreatic ductal adenocarcinoma. To compare the incidence of antidemcizumab antibody development and neutralizing antibody development in subjects with 1st-line locally advanced or metastatic pancreatic ductal adenocarcinoma being treated with Abraxane® and gemcitabine plus demcizumab in Arm 1 to Arm 2, Arm 1 to 3 and Arms 1 to Arms 2 and 3 pooled.  
To compare the median survival in Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma The compare the Kaplan Meier estimates of survival at 6, 12, 18 and 24 months in Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma.
figure 6 percent change in
exploratory endpoints

To compare the pharmacodynamic and predictive biomarkers for demcizumab and determine their correlation with response in Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled (see Section 11.0).  
To compare the CA-19-9 response rate (i.e., at least a 50% decline from baseline) between Arm 1 to Arm 2, Arm 1 to 3 and Arm 1 to Arms 2 and 3 pooled in subjects with 1stmetastatic pancreatic ductal adenocarcinoma.
figure 6 percent change in
5.0 overall study design and

This is a randomized, double blind, 3 arm (1:1:1) study in subjects with 1st-line metastatic pancreatic ductal adenocarcinoma. Prior to randomization, subjects will undergo screening to determine study eligibility. Two hundred and one evaluable subjects will be randomized via an IWRS system.  
Gemcitabine will be given by intravenous (IV) infusion at a dose of 1000 mg/m2 on Days 1, 8 and 15 of each 28-day treatment cycle (or until toxicity necessitates reducing or holding a dose).  
Abraxane® will be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8 and 15 of each 28-day treatment cycle. Demcizumab 3.5 mg/kg or placebo will be administered by IV infusion (prior to the administration of Abraxane® and gemcitabine) once every 2 weeks for either one (1st course through Study Day 70) or two (2nd course begun on Study Day 168 and continued through Study Day 238) 70 day courses (i.e., 6 doses per course). Randomized subjects will be treated in the following manner:
Arm 1 - Abraxane® and gemcitabine plus **placebo** (3 cycles), Abraxane® and gemcitabine (3 cycles), Abraxane® and gemcitabine plus **placebo** (3 cycles) and then Abraxane® and gemcitabine until disease progression Arm 2 - Abraxane® and gemcitabine plus **demcizumab** (3 cycles), Abraxane® and gemcitabine (3 cycles), Abraxane® and gemcitabine plus **placebo** (3 cycles) and then Abraxane® and gemcitabine until disease progression Arm 3 - Abraxane® and gemcitabine plus **demcizumab** (3 cycles), Abraxane® and gemcitabine (3 cycles), Abraxane® and gemcitabine plus **demcizumab** (3 cycles) and then Abraxane® and gemcitabine until disease progression Dosing of gemcitabine, Abraxane® and demcizumab or placebo must be done within ± 2 days of the Study Day listed in the protocol. If a drug cannot be given within this 2 day window, then the dose of that drug is permanently missed. Subjects will only receive their second 70 day course of placebo or demcizumab if their Day 168 BNP is ≤100 pg/mL, peak tricuspid velocity is ≤3.0 m/s and LVEF is ≥50% and they did not develop pulmonary hypertension or heart failure while on study. Any subject who has two consecutive B-type natriuretic (BNP) values ˃100 pg/mL or one value >200 pg/mL will be unblinded by the Investigator (these subjects will remain on study) through the IWRS system. If the subject is receiving demcizumab they will be started on an ACE inhibitor or carvedilol, unless the BNP elevation occurred more than 100 days after the discontinuation of demcizumab or there is a contraindication to administering these agents and if appropriate, referred to a cardiologist. If they are not receiving demcizumab they will be cared for according to standard medical practice. Subjects will be assessed for disease status every 8 weeks and for safety at every visit and through 30 days following the termination visit. In all three arms, subjects should remain on study until disease progression. Immunogenicity will be assessed at baseline, every 8 weeks while on study and at treatment termination. Biomarker assessment will be performed at Days 0, 21, 35, 49 and 63 and at treatment termination. Plasma sample for PK analysis to be obtained prior to the demcizumab infusion on Days 0, 14, 56, 70, 168, 182, 224 and 238, and at the end of the demcizumab infusion (prior to chemo infusion) on Days 0, 56, 70, 168, 224 and at treatment termination. If all of the study drugs are discontinued prior to disease progression, the subject should remain on study until disease progression or withdrawal of consent. Once discontinuation criteria for the study are met (disease progression, use of other anti-cancer therapy, subject or investigator decision or protocol non-compliance) 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 and other assessments as required per protocol.
figure 6 percent change in
6.0 selection of study population

Subjects must meet all of the following criteria to be eligible for the study: 1. Subjects must have cytologically or histologically confirmed metastatic pancreatic ductal adenocarcinoma. Prior chemotherapy and/or radiotherapy either in the adjuvant or neoadjuvant setting or for metastatic disease is not allowed.  
2. Age >21 years 3. ECOG performance status 0 or 1 (see Appendix C) 4. Measurable disease per RECIST v1.1 (Appendix D) 5. Adequate organ and marrow function as defined below:
Absolute neutrophil count >1.5 x 109/L
o Without granulocyte colony-stimulating factor support within 2 weeks prior to randomization Hemoglobin >100 g/L
o Without transfusion within 2 weeks prior to randomization Platelets >125 X 109/L
o Without transfusion within 2 weeks prior to randomization Total bilirubin <1 X institutional upper limit of normal (ULN)
Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT)
<5 X institutional ULN
Albumin > 3 g/dL International normalized ratio (INR) and activated partial thromboplastin time (aPTT)
within 1.5 X the institutional ULN
Creatinine <1.5 X institutional ULN
OR  
Calculated creatinine clearance >60 mL/min using the Cockcroft and Gault formula as follows:
Creatinine clearance (mL/min) = (140 - age) x ideal body weight [kg] 0.814 x serum creatinine [µmol/L]
o For women, multiply the value from the equation above by 0.85.  
o Where age is in years, weight is in kg, and serum creatinine is in µmol/L
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]
6. 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 (e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants) from study entry through at least 6 months after the termination visit.  
Alkaline phosphatase <5 X institutional ULN
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.  
7. Ability to understand and the willingness to sign a written informed consent document
figure 6 percent change in
6.2 exclusion criteria

Subjects who meet any of the following criteria will not be eligible for participation in the study: 1. Subjects with a neuroendocrine tumor of the pancreas, an acinar tumor of the pancreas or a pancreatic tumor with mixed histologies.  
2. Subjects receiving any other investigational medicinal products or anti-cancer therapy. 3. Subjects with brain metastases (subjects must have a CT scan or MRI of the head within 28 days prior to randomization to rule out brain metastases), uncontrolled seizure disorder, or active neurologic disease 4. Subjects with leptomeningeal disease 5. Subjects with > Grade 2 peripheral neuropathy 6. History of interstitial pulmonary disease or pneumonitis 7. Malignancies other than pancreatic cancer successfully treated within 3 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, treated superficial bladder cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent 8. Prior radiation to the chest wall or mediastinum if the radiation field involves the heart 9. History of a significant allergic reaction attributed to humanized or human monoclonal antibody therapy 10. Significant intercurrent illness that will limit the patient's ability to participate in the study or may result in their death over the next 18 months.  
11. Pregnant women or nursing women 12. Subjects with known HIV infection 13. Known bleeding disorder or coagulopathy 14. Subjects receiving therapeutic doses of heparin, warfarin, factor Xa inhibitors or other similar anticoagulants. Note: Subjects may be receiving prophylactic doses of heparin, warfarin, factor Xa inhibitors or other similar anticoagulants, low-dose aspirin and/or non-steroidal anti-inflammatory agents.  
15. Subjects with known clinically significant gastrointestinal disease including, but not limited to, inflammatory bowel disease 16. Subjects with a blood pressure of >140/90 mmHg. The BP should be taken using the method described in Section 9.3. Subjects taking antihypertensive medications must be taking ≤2 medications to obtain this level of BP control.  
17. Subjects with tumors that are currently involving the lumen of the gastrointestinal tract 18. History of cerebral vascular accident (CVA) or transient ischemic attacks (TIAs) within 6 months prior to randomization, 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.  
19. Subjects with an active infection requiring antibiotics 20. Subjects with an uncontrolled seizure disorder or active neurologic disease 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 E)
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.  
History of heart failure or pulmonary hypertension Received a total cumulative dose of ≥400 mg/m2 doxorubicin Grade ≥2 ventricular arrhythmia Inability to comply with study and follow-up procedures
figure 6 percent change in
7.0 removal of subjects from

Subjects must be withdrawn from the study 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 (as assessed by the Sponsor)
Subjects who meet one of the above criteria will undergo the termination evaluations for the study (see Section 12.9). After the termination visit, subjects will have regular follow-up for survival and other assessments as required per protocol (see Section 12.10). If a subject has permanently discontinued one, two or all three of the study drugs due to toxicities or any other reasons, the subject should remain on study until one of the above criteria is met. Subjects who have discontinued all study drugs and continue on study should have assessments performed as outlined in Section 12.0.
figure 6 percent change in
8.0 treatment of subjects

Dosing of gemcitabine, Abraxane® and demcizumab or placebo must be done within ± 2 days of the Study Day listed in the protocol. If a drug cannot be given within this 2 day window, then the dose of that drug is permanently missed. If one or more of these drugs needs to be temporarily or permanently discontinued the subject should continue to receive the other drug(s) and remain on study until disease progression.
figure 6 percent change in
8.1 study drug (demcizumab or

Study drug (demcizumab at 3.5 mg/kg or placebo) will be administered once every 2 weeks for 6 doses (i.e., the last dose is given on Day 70). A second course of study drug (demcizumab at 3.5 mg/kg or placebo) will be administered once every 2 weeks for 6 doses starting at Day 168 if the subject's Day 168 BNP is ≤100 pg/mL, peak tricuspid velocity is <3.0 m/s and LVEF is ≥50%, and the subject did not develop pulmonary hypertension or heart failure while on study. No dose reductions of demcizumab/placebo are allowed 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 minutes as an infusion prior to the administration of Abraxane® and gemcitabine, 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 (+/- 2days) (See Section 12.0) , 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 6 percent change in
8.1.2 description

Demcizumab is an IgG2 humanized monoclonal antibody that is directed against the DeltaLike 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, 100mM Sodium Chloride, 45mM 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.
figure 6 percent change in
8.1.3 packaging

Labeling of demcizumab or placebo vials and cartons will comply with all applicable regulations.
figure 6 percent change in
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 study drug accountability log must be maintained and kept up to date at all times. Blinded study drug perforated labels must be kept for drug accountability.
figure 6 percent change in
8.1.5 study 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 3.5 mg/kg, then the subject's dose would be 245 mg. Because the vials contain a concentration of 10 mg/mL, a total of 24.5 mL containing 245 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.
figure 6 percent change in
8.1.6 treatment modification and termination

Any subject who has two consecutive BNP values ˃100 pg/mL or one value >200 pg/mL will be unblinded by the Investigator through the IWRS system. If the subject is receiving demcizumab they will started on a cardioprotective agent such as an ACE inhibitor or 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 and if appropriate referred to a cardiologist. If they are not on demcizumab they should be cared for according to standard medical practice. 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 17). If there is a contraindication to administering both of these agents, the patient's treatment should be discussed with the OncoMed Medical Monitor. In addition, any subject who develops a BNP of ≥300 pg/mL, a LVEF decline of ≥10% from baseline and a LVEF value that is <50%, clinically significant pulmonary hypertension (i.e., the subject has a peak tricuspid velocity >3.4 m/s on doppler echocardiogram and has been seen by a cardiologist and diagnosed with clinically significant pulmonary hypertension) and/or symptoms of heart failure must have their dose of demcizumab held, but administration of their chemotherapy may be continued. Dosing of demcizumab must continue to be held until the subjects BNP is <300 pg/mL, the decline in LVEF is <10% and a LVEF value that is >50%, their clinically significant pulmonary hypertension has resolved and symptoms of heart failure has resolved. Any subject who has a BNP of >300 pg/mL that is considered to be related to demcizumab, ≥10% decline in left ventricular ejection fraction and a LVEF value that is <50%, signs and symptoms of heart failure or clinically significant pulmonary hypertension (i.e., the subject has a peak tricuspid velocity >3.4 m/s on doppler echocardiogram and has been seen by a cardiologist and diagnosed with clinical significant pulmonary hypertension) that persists beyond Day 70 or occurs beyond Day 70 must have their demcizumab permanently discontinued. Demcizumab/placebo must also be discontinued for any of the following:
BNP of ≥400 pg/mL
≥Grade 2 pulmonary hypertension Evidence of Grade >2 bleeding (except for readily manageable local bleeding, such as hemorrhoidal bleeding)
Hypertensive crisis Hypertensive encephalopathy Blood pressure of  200/120 mmHg Need for therapeutic anti-coagulation o If therapeutic anti-coagulation is no longer required, the subject may receive any remaining demcizumab/placebo administrations.  
If the demcizumab/placebo need to be held or discontinued, the administration of the chemotherapy should continue until disease progression, unless contraindicated.
figure 6 percent change in
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 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, permanently discontinue demcizumab therapy 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.
figure 6 percent change in
8.2 gemcitabine and abraxane

The dose of gemcitabine and Abraxane® should be modified according to the criteria in Section 8.2.3. All dose modifications are permanent. Dosing of gemcitabine and Abraxane®
must be done within ± 2 days of the Study Day listed in the protocol. If a gemcitabine or Abraxane® cannot be given within this 2 day window, then the dose of that drug is permanently missed. The administration of the chemotherapy should not be held if the demcizumab/placebo needs to be held or discontinued.
figure 6 percent change in
8.2.1 abraxane 8.2.1.1 administration

Abraxane® must be administered after the demcizumab, but before gemcitabine administration on days when three drugs are given. Abraxane® should be administered by IV infusion at a dose of 125 mg/m2 over 30 minutes on Days 1, 8 and 15 of every 28-day cycle. The Study Day 0 weight should be used to calculate the body surface area that is used to calculate the total dose
(mg) of Abraxane® throughout the study, unless the weight changes by >5%, in which case the current weight should be used to calculate the body surface area.  
Subjects do not require premedication prior to Abraxane® administration, as hypersensitivity reactions are not expected. If a hypersensitivity reaction occurs, the infusion should be stopped and not restarted. If felt to be in the subject's best interest, at the investigator's discretion, treatment may continue on subsequent cycles using the premedication regimen the institution typically uses for solvent-based paclitaxel.
figure 6 percent change in
8.2.1.2 description

Abraxane®, a microtubule inhibitor, is an albumin bound form of paclitaxel with a mean particle size of approximately 130 nanometers. The active agent in Abraxane® is paclitaxel. The chemical name for paclitaxel is 5, 20-Epoxy-1, 2, 4, 7, 10, 13-hexahydroxytax-11-en-9one 4, 10-diacetate 2-benzoate, 13 ester with (2R, 3S) –N-benzoyl-3-phenylisoserine.
figure 6 percent change in
8.2.2 gemcitabine 8.2.2.1 administration

Gemcitabine must be administered after the administration of demcizumab and Abraxane®. Gemcitabine should be administered by IV infusion at a dose of 1000 mg/m2 over 30 minutes once weekly (Days 1, 8 and 15 of each 28 day cycle) for 3 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest every 28 days. The Day 0 weight should be used to calculate the total dose (mg) of gemcitabine throughout the study, unless the weight changes by >5%, in which case the current weight should be used to calculate the dose. Clearance in women and the elderly is reduced and women are somewhat less able to receive subsequent cycles.
figure 6 percent change in
8.2.2.2 description

Gemcitibine is a nucleoside metabolic inhibitor that exhibits antitumor activity. Gemcitabine HCl is 2´-deoxy-2´, 2´-difluorocytidine monohydrochloride (-isomer).
figure 6 percent change in
8.2.2.3 storage

Gemcitibine must be stored as recommended on the label. The labeling of gemcitabine will comply with all applicable regulations.
figure 6 percent change in
8.2.3 gemcitabine and abraxane dose

Dose reductions/modifications of gemcitabine and Abraxane® are permanent, except in some circumstances when the dose reduction was a result of neutropenia (see Section 8.2.3.1). Doses of gemcitabine and Abraxane® must be given within +/- 2 days of the Study Day specified in the protocol. If a dose is not given in the window it is permanently missed. Doses will be reduced for hematologic and other toxicities. Dose adjustments are to be made according to the system showing the greatest degree of toxicity. Toxicities will be graded using the NCI CTCAE Version 4.03. Two levels of dose modifications are permitted according to the criteria below. If a toxicity requiring dose modification occurs following the second dose reduction of either drug, further treatment with Abraxane® and gemcitabine should be discontinued, although demcizumab and/or placebo therapy should be continued.
figure 6 percent change in
table 4 dose modifications

Dose Level Abraxane® Dose (mg/m2)  
i. **Gemcitabine (mg/m2**)  
Study Dose 125 1000  
-1 100 800  
-2ii. 75 600  
i.Dose reductions may or may not be concomitant, refer to Table 5. If the dose is withheld due to hematologic  
toxicity on Day 15, resume at the next lower dose level when the subject has adequate ANC and platelet counts to begin Day 1 of the next cycle. Refer to Table 5 for specific recommendations regarding dose modifications for Day 1.  
ii.A maximum of 2 dose level reductions are allowed.  
Subjects who have had two dose level reductions as outlined in Table 4 and are still unable to tolerate the gemcitabine/Abraxane regimen may receive the -2 dose levels on Days 1 and 15 (i.e., omit Day 8) of each 28 day cycle.
figure 6 percent change in
8.2.3.1 dose modifications

In the event dose modifications are required at the start of a cycle or within a cycle due to hematologic toxicities of neutropenia and/or thrombocytopenia, doses of Abraxane® and gemcitabine may be adjusted as detailed in Table 5. WBC growth factor may be given according to institutional guidelines for the treatment of neutropenic fever or infections associated with neutropenia and for the prevention of febrile neutropenia in subjects with an ANC
<500 cells/mm3. Subject's not experiencing resolution of neutropenia within 21 days, despite uninterrupted WBC growth factor treatment, will discontinue gemcitabine and Abraxane®. In addition, WBC growth factors may be administered as supportive therapy to recover ANC adequately such that dosing levels may be maintained. If a dose reduction was required due to neutropenia, a dose re-escalation may be considered with continued growth factor support. If a dose reduction is required for a reason other than neutropenia, no dose re-escalation will be permitted for the duration of the study. If hematologic toxicity is restricted to platelet counts alone, dose modification of only gemcitabine could be considered after discussion with the sponsor.  
| Cycle                                                   | ANC   | Platelet count  (cells/mm3 )   | Abraxane® Dose                                                                                 | Gemcitabine Dose                                                                         |
|---------------------------------------------------------|-------|--------------------------------|------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------|
| (cells/mm3 )                                            |       |                                |                                                                                                |                                                                                          |
| Day  Day 1                                              | ≥1500 | AND                            | ≥100,000                                                                                       | Treat on time at current dose levels                                                     |
| <1500                                                   | OR    | <100,000                       | Delay doses until recovery                                                                     |                                                                                          |
| Day 8                                                   | ≥1000 | AND                            | ≥ 5,000                                                                                        | Treat on time at current dose levels                                                     |
| ≥500 but <1000                                          | OR    | ≥50,000 but <75,000            | Reduce doses 1 dose level                                                                      |                                                                                          |
| <500                                                    | OR    | < 50,000                       | Withhold doses                                                                                 |                                                                                          |
| Day 15: IF Day 8 doses were given without modification: |       |                                |                                                                                                |                                                                                          |
| Day 15                                                  | ≥1000 | AND                            | ≥75,000                                                                                        | Treat on time at current dose levels                                                     |
| ≥500 but <1000                                          | OR    | ≥50,000 but <75,000            | Reduce doses 1 dose level from Day 8; consider  following with WBC growth factors for support* |                                                                                          |
| <500                                                    | OR    | <50,000                        | Withhold doses                                                                                 |                                                                                          |
| Day 15: IF Day 8 doses were reduced:                    |       |                                |                                                                                                |                                                                                          |
| Day 15                                                  | ≥1000 | AND                            | ≥75,000                                                                                        | Treat with same doses as Day 8; consider following  with WBC growth factors for support* |
| ≥500 but <1000                                          | OR    | ≥50,000 but <75,000            | Reduce doses 1 dose level from Day 8; consider  following with WBC growth factors for support* |                                                                                          |
|                                                         | <500  | OR                             | <50,000                                                                                        | Withhold doses                                                                           |  
| Day 15:                                                                                                       | IF Day 8 doses were withheld:  Option A: Maintain dose level from Day 1 and  follow with WBC growth factors for support*  OR  Option B: Reduce doses 1 dose levels from Day 1   |         |                |                                                                                               |
|---------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------|----------------|-----------------------------------------------------------------------------------------------|
| Day 15                                                                                                        | ≥000                                                                                                                                                                            | AND     | ≥75,000        | Option A: Reduce 1 dose level from Day 1 and  follow with WBC growth factors for support*  OR |
| Option B: Reduce doses 2 dose levels from Day 1                                                               |                                                                                                                                                                                 |         |                |                                                                                               |
| <500                                                                                                          | OR                                                                                                                                                                              | <50,000 | Withhold doses |                                                                                               |
| Abbreviations: ANC = absolute neutrophil count; WBC = white blood cell  ≥500 but <1000 OR ≥50,000 but <75,000 |                                                                                                                                                                                 |         |                |                                                                                               |  
Table 5: Dose Recommendation and Modifications for Neutropenia and/or Thrombocytopenia at the Start of a Cycle or Within a Cycle (Cont'd)
Dose modifications for other adverse drug reactions are provided in Table 6.
figure 6 percent change in
table 6 dose modifications for

| Adverse Drug Reaction                                                                                             | Abraxane® Dose                                                                          | Gemcitabine Dose                              |                      |
|-------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------|-----------------------------------------------|----------------------|
| Febrile Neutropenia:                                                                                              | Withhold doses until fever resolves and ANC is ≥1500; resume at  next lower dose levelb |                                               |                      |
|                                                                                                                   | Grade 3 or 4                                                                            | Withhold dose until improvement  to ≤Grade 1; | Treat with same dose |
| resume at next lower dose level                                                                                   |                                                                                         |                                               |                      |
| Peripheral Neuropathy:   Grade 3 or 4  Cutaneous Toxicity:                                                        | Reduce doses to next lower dose level;                                                  |                                               |                      |
|                                                                                                                   | Grade 2 or 3                                                                            | discontinue treatment if ADR persists         |                      |
| For all other nonhematologic  toxicities (except nausea,  vomiting, alopecia and pulmonary  embolism) of >Grade 3 | Withhold doses until improvement to ≤Grade 1;  resume at next lower dose leveli.        |                                               |                      |
| Abbreviations: ADR, adverse drug reaction; ANC = absolute neutrophil count                                        |                                                                                         |                                               |                      |  
Abbreviations: ADR, adverse drug reaction; ANC = absolute neutrophil count i.White blood cell growth factor may be given according to institutional guidelines for the treatment of neutropenic fever or infections associated with neutropenia and for the prevention of febrile neutropenia in subjects with an ANC of <500 cells/mm3 b See Table 5 for dose level reductions.
figure 6 percent change in
8.2.3.1.1 administration of abraxane and

Abraxane® and gemcitabine should only be administered if hepatic function is within the parameters established in the eligibility criteria. Hepatic toxicity may occur but it is uncommon. Therefore, hepatic dysfunction that occurs while the subject is on study should prompt an evaluation to determine the cause, including the possibility of metastatic disease and hepatotoxicity from concurrent medications, alcohol use, or other factors.
figure 6 percent change in
8.2.3.1.2 interstitial pneumonitis

While participating in this study, subjects should be carefully monitored to prevent or minimize the occurrence of interstitial pneumonitis. Careful pre-study screening with continuous on-study monitoring for signs and symptoms is required. Should a subject develop symptoms of pneumonitis during this study, the timely initiation of appropriate management is required. Recommended guidelines are as follows: 1. Before randomization, evaluate candidate subjects for familial, environmental, or occupational exposure to opportunistic pathogens, and do not enroll those with a history of slowly progressive dyspnea and unproductive cough, or of conditions such as sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis, or multiple allergies.  
2. During study treatment, provide close attention to episodes of transient or repeated dyspnea with unproductive persistent cough or fever. Radiographic evaluation with chest x-rays and CT scans (normal or high resolution) may be indicated to evaluate for infiltrates, ground-glass opacities, or honeycombing patterns. Pulse oximetry and pulmonary function tests can show respiratory and ventilation compromise.  
3. Infections should be ruled out with routine immunological/ microbiological methods.  
Transbronchial lung biopsy is not recommended, given its limited value and risk of pneumothorax and hemorrhage, and should be reserved for cases with unclear etiology.  
4. Administration of Abraxane® and gemcitabine must be permanently discontinued from upon the diagnosis of interstitial pneumonitis. However, the administration of the demcizumab or placebo should be continued, unless contraindicated. After ruling out an infectious etiology, intravenous high-dose corticosteroid therapy should be instituted without delay, with appropriate premedication and secondary pathogen coverage. Subjects with an added immunological agent may also require immune modulation with azathioprine or cyclophosphamide. Appropriate ventilation and oxygen support should be used when required.
figure 6 percent change in
8.2.3.1.3 prophylaxis against sepsis

In the MPACT metastatic pancreatic ductal adenocarcinoma Phase 3 study, an increase in cases of non-neutropenic sepsis was observed with the combination of Abraxane® and gemcitabine.  
An exploratory analysis suggested that the presence of biliary stents may have increased the risk of sepsis in that population. Investigators were to provide oral broad spectrum antibiotics to subjects who were then to initiate these antibiotics at the first occurrence of fever. Subjects enrolled in this clinical trial may not have the same risk of sepsis as metastatic pancreatic ductal adenocarcinoma patients. Subjects should be advised that there could be an increased risk of serious infection and they should contact their physician for evaluation when they develop a fever. Fever or similar symptoms should be fully evaluated as an early sign of a serious infection. Broad spectrum antibiotics such as fluoroquinolones may be provided to subjects to treat or as prophylaxis for infection at the discretion of the treating physician.
figure 6 percent change in
8.2.3.1.4 hypersensitivity reactions

Hypersensitivity reactions are infrequent with Abraxane®. If they do occur, minor symptoms such as flushing, skin reactions, dyspnea, hypotension, or tachycardia may require temporary interruption of the infusion. However, severe reactions, such as hypotension requiring treatment, dyspnea requiring bronchodilators, angioedema, or generalized urticaria require immediate discontinuation of IP administration and aggressive symptomatic therapy.  
Subjects who develop a severe hypersensitivity reaction to Abraxane® should not be rechallenged.
figure 6 percent change in
8.3 anti-emetics and hematopoietic supportive

Antiemetic therapy and/or hematopoietic growth factors and/or red blood cell/platelet transfusions may be administered at the discretion of the Investigator.
figure 6 percent change in
8.4 concomitant and prohibited therapy

All concomitant medication administered from randomization through 30 days following treatment termination 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 subjects' specific tumor type) may not be administered from randomization through treatment termination. 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 after consultation with the OncoMed medical monitor. 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. 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, and the subject should continue on study with continued gemcitabine plus Abraxane® administrations and regular assessments to ensure close follow-up. Once the therapeutic anti-coagulation is discontinued, subjects may receive any remaining scheduled demcizumab/placebo infusion.
figure 6 percent change in
8.5 treatment compliance

Demcizumab, gemcitabine and Abraxane® 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 eCRF in Medidata. In addition, drug accountability will be performed.
figure 6 percent change in
9.0 safety assessments

Safety will be assessed by adverse event monitoring (including attribution of AEs and SAEs), physical examination, vital signs, clinical laboratory testing, anti-demcizumab testing, and subject interview on an ongoing basis as outlined in the Schedule of Assessments (see Appendix B - Schedule of Assessments) 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.
figure 6 percent change in
9.1 adverse events definitions and

All Adverse Events from the time of randomization through 30 days after discontinuation from the study (i.e., 30 days from the date of the treatment termination visit) **must** be documented in the medical record and reported on the AE Case Report Form (CRF). Adverse events will be coded in accordance with the Medical Dictionary for Regulatory Activities (MedDRA). The grading of the adverse events will be done using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. In addition, for each adverse event the Investigator must indicate the attribution of AE to study drug (i.e., related or unrelated) and the attribution of the AE to the malignancy. The principal investigator is responsible for assessing whether an adverse event is **related** (or possibly related) to participation in the research. In general, adverse events are considered **related to participation in the research** if there is not a clear alternative explanation. Adverse events 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.
figure 6 percent change in
9.1.1 definition of adverse event

An adverse event is any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease temporally associated with the subject's participation in the research, whether or not considered related to the subject's participation in the research. Any medical condition or clinically significant laboratory abnormality with an onset date before randomization is a pre-existing condition that must be listed on the Medical History CRF and should not be considered an adverse event unless the condition worsens in intensity or frequency after randomization (e.g., Grade 2 nausea prior to randomization becomes Grade 3 nausea after randomization). 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 9.1.3). Monitoring of the subject should continue through outcome of the birth, or longer if any fetal abnormality is present.
figure 6 percent change in
9.1.2 definition of serious adverse

A **serious adverse event** is any event that results in the following:
death life-threatening condition (places the subject at immediate risk of death) subject hospitalization or prolongation of existing hospitalization persistent or significant disability/incapacity congenital anomaly/birth defect any other adverse event that, based upon the Investigators medical judgment, may require medical or surgical intervention to prevent one of the outcomes listed above (examples of such events include allergic bronchospasm requiring intensive treatment in the emergency room or at home, blood dyscrasias or convulsions that do not result in subject hospitalization, or the development of drug dependency or drug abuse)
figure 6 percent change in
9.1.2.1 disease progression and death

Disease progression (including progression of pancreatic cancer, and death due to disease progression) is generally recorded as part of the efficacy evaluation and should not be reported as an AE or SAE. When an AE resulting from disease progression meets the requirements to be considered serious, the SAE verbatim term should be reported as the sign/ symptom that best describes the event rather than as disease progression. For instance, a subject with pleural effusion presents with shortness of breath. The cause of the shortness of breath is a pleural effusion resulting from disease progression. The event term may be reported as "pleural effusion" instead of disease progression. Death should not be reported as a serious adverse event, but as a clinical outcome of a specific SAE. The cause of death, reported on a source document such as the Death Certificate or autopsy report, should be used as the event term for the SAE.
figure 6 percent change in
9.1.3 serious adverse event reporting

SAEs that occur during the study must be clearly documented in the medical record. SAEs should be reported by completing the AE page in Medidata within 24 hours of the Investigator's knowledge of the event. By completing the 'serious' information, this will generate an autonotification to PVG. Only in the event of a system outage, a manual SAE form must be completed and faxed or emailed to PPD PVG (also within 24 hours of the Investigator's knowledge of the event). The following is the contact information for PPD Drug Safety. 9.1.3.1 **Pharmacovigilance telephone contacts:**  
EMEA/APAC: ___________________  
 United States: ___________________
9.1.3.2 **Pharmacovigilance fax contacts:**  
  
EMEA/APAC: ___________________
United States: ___________________
figure 6 percent change in
9.1.3.3 pharmacovigilance email contact (all

EMEAAsiaSafetyCentral.SM@ppdi.com 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.
figure 6 percent change in
9.2 clinical laboratory assessments 9.2.1

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 at baseline.
figure 6 percent change in
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.
figure 6 percent change in
9.2.3 bnp assessment

BNP will be assessed during Screening and then every 14 days while on treatment, and at the time of treatment termination. BNP will be measured using any Alere Triage POC device (or if approved by OncoMed the site's laboratory). BNP must be drawn on the day of dosing and assessed prior to dosing (or if approved by OncoMed it may be drawn the day before dosing and assessed prior to dosing) and elevations will be managed per Section 8.1.6.
figure 6 percent change in
9.2.4 urinalysis

Urinalysis (with microscopic analysis) will be obtained during screening, at Study Days 28, 56, and every 56 days thereafter, and at the time of treatment termination.
figure 6 percent change in
9.2.5 pregnancy testing

For women of childbearing potential, a serum pregnancy test is required during Screening, every 56 days while on study, at the termination visit and 56 and 112 days following the treatment termination visit.
figure 6 percent change in
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 other week while on treatment and at treatment termination. 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 Schedule A. Blood pressure should be measured with the subject in the same position. The same cuff method should be used to measure blood pressure throughout the study. 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 anti-hypertensive medications or adding new ones by following the guidelines for the management of high blood pressure in adults (Ref 16). 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 it is ≤150/90 mmHg over a 4-week period with every-2-week BP measurements.
figure 6 percent change in
9.4 cardiac studies

Twelve-lead electrocardiograms (ECGs) with assessment of PR interval, QRS duration, and QTc interval will be obtained at Screening, every 28 days, and at the termination visit. A transthoracic Doppler echocardiogram with left ventricular ejection fraction, right ventricular systolic pressure and peak tricuspid velocity determination will be obtained at Screening and then every 28 days. The Day 168 Doppler echocardiogram must be performed prior to the Day 168 visit, so that the peak tricuspid velocity and left ventricular ejection fraction values are available at the time of the Day 168 visit. The Doppler echocardiograms may also be sent to an Independent Cardiologist of the Sponsor's choice for central review. A CT pulmonary angiogram (CTPA) should be performed if pulmonary hypertension is diagnosed (i.e., the subject has a peak tricuspid velocity >3.4 m/s on Doppler echocardiogram, has been seen by a cardiologist and was diagnosed with clinically significant pulmonary hypertension) 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.
figure 6 percent change in
9.5 immunogenicity assessments

Subjects will be assessed during screening and then every 8 weeks while the subject is on study. In addition, subjects will be assessed for immunogenicity at the time of treatment termination. 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.
figure 6 percent change in
9.6 pharmacokinetic assessments

Sparse PK sampling will be done in all subjects on the study. Plasma samples for PK analysis will be obtained prior to the demcizumab infusion on Days 0, 14, 56, 70, 168, 182, 224 and 238, and at the end of the demcizumab infusion (prior to chemo infusion) on Days 0, 56, 70, 168, 224 and at treatment termination. The PK samples must be drawn from a location that is different from the site of study drug administration. If the study drug is administered via a vein in the arm, *post-dose* 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.
figure 6 percent change in
10.0 efficacy assessments

Tumor assessments will be performed at screening and then every 8 weeks. The schedule of every 8 weeks is to be maintained throughout the study and will not be shifted if there are dose holds (see Appendix B). Any measurable disease must be documented at screening and reassessed at each subsequent tumor evaluation. Response, progression-free survival and duration of response will be assessed using the RECIST criteria v1.1 (see Appendix D) (Ref 18). The primary response outcomes will be based on the Investigator's assessment. 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 CA 19-9 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 CA 19-9. Overall survival will be assessed by collecting survival data including the date and cause of death. Once a patient has completed the treatment termination visit, overall survival follow up will be performed every three months for up to 5 years. Follow up may be conducted by telephone interview or chart review. The same imaging method used at screening must be used throughout the study. A documented standard-of-care tumor assessment performed within Study Days -28 to 0 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  
o To be suitable for RECIST v1.1 assessments, CT scans should have a maximum thickness of 5 mm and no gaps.
MRI of the brain o MRI is the preferred imaging modality for tumor assessments of the brain.  
o 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.  
o CT scan is the preferred imaging modality for tumor assessments of chest, abdomen, and pelvis.  
o 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.  
o 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.
Subsequent tumor assessments should include the following:
Diagnostic-quality, contrast-enhanced CT scans of chest and abdomen  
o 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 o The same imaging method as at baseline must be used.
figure 6 percent change in
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 specimens obtained at the time of surgical resection or from a core biopsy will be collected for protein and gene expression biomarker analysis. Exploratory predictive biomarkers such as tumor endothelial cell DLL4 expression will be measured in FFPE tumor specimens. Gene expression biomarker analysis including Notch pathway-related predictive biomarker 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, Abraxane® and gemcitabine treatment. Blood Biomarkers: A predose sample of 9 mL of blood will be drawn on Study Days 0, 21, 35, 49 and 63 and at treatment termination to evaluate changes in plasma proteins by immunochemistry (e.g., VEGF, βFGF, SDF1, PLGF, SCF, 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 sample will also be obtained at the time of treatment termination unless one has been obtained during the prior 14 days. Optional Pharmacogenomics: For subjects who sign the optional Pharmacogenomics Informed Consent (Appendix G), 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 may influence safety, tolerability, or pharmacodynamic effects of demcizumab 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 gemcitabine metabolism may also be performed (e.g., CMPK and DCK).
figure 6 percent change in
12.0 study visit schedule and

Subjects must sign and date the Informed Consent Form (Appendix F) 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 form in the PPD IWRS system and submit it electronically for approval. Once OncoMed or its representative has approved the randomization form, the investigator/study coordinator will use the IWRS system to randomize the subject. The IWRS system will then assign a subject number and the subject will be officially enrolled in the study. 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. All on-study evaluations (i.e., those done from Day 0 and beyond) must be done within the following timeframe:  
Dosing of gemcitabine, Abraxane® and demcizumab or placebo must be done within
± 2 days of the Study Day listed in the protocol. If a drug cannot be given within this 2 day window, then the dose of that drug is permanently missed.  
Laboratory evaluations within ± 3 days of the Study Day listed in the protocol, except for BNP which must be done on the day of demcizumab/placebo dosing and must be done prior to the demcizumab/placebo dose.  
Imaging studies (e.g., CT scans, MRI), ECG, and transthoracic Doppler echocardiogram within ± 7 days for the Study Day listed in the protocol.
Unless otherwise indicated, all assessments must be performed prior to dosing for all study visits when dosing occurs. **BNP must be drawn on the day of dosing and assessed prior to dosing** (or if approved by OncoMed it may be drawn the day before dosing and assessed prior to dosing). For subjects who have discontinued demcizumab/placebo, all assessments as outlined in Appendix B should continue.
figure 6 percent change in
12.1 screening

All screening tests must be performed within Study Days -28 to 0, unless otherwise indicated.  
Informed Consent (must be obtained before any study specific procedures are performed)  
Past medical history
Physical examination Peripheral neuropathy assessment  
Vital signs
Height Weight ECOG performance status CBC with differential and platelet count Serum chemistry INR/aPTT B-type natriuretic peptide (BNP) measured using an Alere Triage POC device (or if approved by OncoMed the site's laboratory)
Urinalysis with microscopic analysis Electrocardiogram (ECG) including PR interval, QRS duration, and QTc interval Transthoracic doppler echocardiogram with LVEF, and peak tricuspid velocity determination Tumor marker: CA 19-9 Serum pregnancy test for all females of childbearing potential (a negative result must be obtained prior to randomization) (must be done within 7 days prior to randomization).  
Tumor assessment: Diagnostic-quality, contrast-enhanced CT scans of chest, abdomen, and pelvis (MRI scans may be performed in lieu of CT scans; see Section 10.0) performed as outlined by the RECIST criteria v1.1 (see Appendix D). Note: The same radiographic technique of each region must be used consistently throughout the study.  
MRI of the brain, or CT scan of the brain with IV contrast (see Section 10.0) Colonoscopy and/or upper gastrointestinal endoscopy to rule out gastrointestinal involvement in subjects having symptoms suggestive of possible gastrointestinal involvement.  
FFPE (if tissue blocks are available; i.e., FNA is not adequate). Note: FFPE may be shipped any time after enrollment.
figure 6 percent change in
12.2 study day 0

Demcizumab or placebo Abraxane®
Gemcitabine Abbreviated physical examination Vital signs (prior to demcizumab or placebo infusion, 15 minutes after start of infusion, end of infusion, and 15 minutes post infusion).  
Weight ECOG performance status CBC with differential and platelets **(unless previously obtained on Study Days -3 to -1)** Serum chemistry **(unless previously obtained on Study Days -3 to -1)** Serum for anti-demcizumab antibody collected prior to demcizumab or placebo infusion Concomitant medications  
Adverse event recording
Peripheral neuropathy assessment Blood for biomarkers **(must be obtained prior to dosing)** Blood for pharmacogenomics (Optional and only if subject has signed the separate pharmacogenomics Informed Consent Form)
Plasma for pharmacokinetics prior to the demcizumab or placebo infusion and at the end of the infusion (i.e., within 30 minutes prior to and post infusion, but prior to chemotherapy)
figure 6 percent change in
12.3 study days 7 14

Demcizumab or placebo - Days 14, 28 and 42 Abraxane® - Study Days 7, 14, 28, 35, and 42)
Gemcitabine - - Study Days 7, 14, 28, 35, and 42 ) Abbreviated physical examination (Study Days 14, 28, and 42 only) Vital signs (prior to demcizumab or placebo infusion, 15 minutes after start of infusion, end of infusion, and 15 minutes post infusion) (Study Days 14, 28 and 42 only)
Vital signs obtained once: Study Days 7, 21, 35 and 49 only) Weight ECOG performance status CBC with differential and platelet count Serum chemistry BNP measured using an Alere Triage POC device (or if approved by OncoMed the site's laboratory) **(Study Days 14, 28, and 42)**
Urinalysis with microscopic analysis **(Study Day 28 only)** ECG including PR interval, QRS duration, and QTc interval **(Study Day 28** only) Transthoracic doppler echocardiogram with LVEF and peak tricuspid velocity determination
(Study Day 28 only)
Concomitant medication Adverse event recording Peripheral neuropathy assessment **(Study Day 28 only)** Blood for biomarkers **(Study Days 21, 35 and 49 only)** Plasma for pharmacokinetics prior to the infusion (i.e., with 30 minutes pre- infusion) (Study Day 14 only)
figure 6 percent change in
12.4 study day 56

Demcizumab or placebo Abraxane®
Gemcitabine Abbreviated physical examination Vital Signs (prior to demcizumab or placebo infusion, 15 minutes after start of infusion, end of infusion, and 15 minutes post infusion)
Weight ECOG performance status CBC with differential and platelet count Serum chemistry BNP measured using any Alere Triage POC device (or if approved by OncoMed the site's laboratory)
Urinalysis with microscopic analysis ECG including PR interval, QRS duration, and QTc interval Transthoracic doppler echocardiogram with LVEF and peak tricuspid velocity determination Tumor marker: CA 19-9 (if elevated at baseline) Serum pregnancy test for all females of childbearing potential Tumor assessment: Diagnostic-quality, contrast-enhanced CT scans of chest and abdomen, as well as imaging of all other known sites of disease, performed as outlined by the RECIST criteria v1.1 (see Appendix D). Note: If another imaging method was used at baseline, the same imaging method must be used consistently throughout the study.  
Serum for anti-demcizumab antibody (prior to demcizumab or placebo infusion) Concomitant medication Adverse event recording Peripheral neuropathy assessment Plasma for pharmacokinetics prior to the demcizumab or placebo infusion and at the end of the infusion (i.e., within 30 minutes prior to and post infusion, but prior to chemotherapy)
figure 6 percent change in
12.5 study days 63 70

Demcizumab or placebo - **(Study Day 70 only)**
Abraxane®
Gemcitabine Abbreviated physical examination **(Study Day 70 only)** Vital signs (prior to demcizumab or placebo infusion, 15 minutes after start of infusion, end of infusion, and 15 minutes post infusion) **(Study Day 70 only)**
Vital signs obtained once **(Study Day 63 only)** Weight ECOG performance status CBC with differential and platelet count Serum chemistry BNP measured using an Alere Triage POC device (or if approved by OncoMed the site's laboratory) **(Study Day 70 only)**
Concomitant medication Adverse event recording Blood for biomarkers **(Study Day 63 only)** Plasma for pharmacokinetics prior to the infusion and at the end of infusion (i.e., with 30 minutes pre- and post infusion) (**Study Day 70 only**)
figure 6 percent change in
12.6 study day 77

Vital signs measured once Weight ECOG performance status CBC with differential and platelet count Serum chemistry Concomitant medication Adverse event recording
figure 6 percent change in
12.7 study days 84 91

Abraxane®
Gemcitabine Abbreviated physical examination (Study Days 84 and 98 only)
Vital signs obtained once Weight ECOG performance status CBC with differential and platelet count Serum chemistry BNP measured using an Alere Triage POC device (or if approved by OncoMed the site's laboratory) **(Study Days 84 and 98 only)**
ECG including PR interval, QRS duration, and QTc interval **(Study Day 84 only)** Transthoracic doppler echocardiogram with LVEF and peak tricuspid velocity determination
(Study Day 84 only)
Concomitant medication Adverse event recording Peripheral neuropathy assessment (Study Day 84 only)
figure 6 percent change in
12.8 study day 105

Vital signs obtained once Weight ECOG performance status CBC with differential and platelet count Serum chemistry Concomitant medication Adverse event recording As long as the subject has stable disease or a response, the subject should continue to be treated and beginning weekly at Day 112 will undergo the tests designated for Study Days 84, 91, 98, and 105. In addition, the following will be done every 8 weeks beginning at Day 112:
a CT, spiral CT, or MRI of the chest, abdomen, and pelvis performed as outlined by the RECIST criteria 1.1 (see Appendix D),
a CA 19-9 level obtained (if elevated at baseline), Serum pregnancy test for all females of childbearing potential a urinalysis with microscopic analysis a serum sample for anti-demcizumab antibody Finally, a second course of demcizumab or placebo once every 2 weeks for 70 days will be given starting on Day 168 (see Section 8.1.1) and plasma for pharmacokinetics will be obtained prior to demcizumab or placebo infusion on Day 168, 182, 224 and 238, and at the end of demcizumab or placebo infusion on Day 168 and 224.
figure 6 percent change in
12.9 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. The following assessments must be performed on the day of study drug termination:
Abbreviated physical examination Vital signs measured once Weight ECOG performance status CBC with differential and platelet count Serum chemistry BNP measured using an Alere Triage POC device (or if approved by OncoMed the site's laboratory) (unless performed within the last 28 days)
Serum for anti-demcizumab antibody Plasma for pharmacokinetics Urinalysis with microscopic analysis **(unless performed within the last 28 days)** ECG including PR interval, QRS duration, and QTc interval Transthoracic doppler echocardiogram with LVEF and peak tricuspid velocity determination
(unless done within the last 28 days)
Tumor marker: CA 19-9 (if elevated at baseline) Serum pregnancy test for all females of childbearing potential Tumor assessment: unless performed within 7 days of termination or at a prior response evaluation that documented progressive disease: Diagnostic-quality, contrast-enhanced CT scans of chest and abdomen, as well as imaging of all other known sites of disease, performed as outlined by the RECIST criteria v1.1 (see Appendix D). Note: If another imaging method was used at baseline, the same imaging method must be used consistently throughout the study.  
Concomitant medication **(through 30 days following treatment termination)**
Adverse event recording at the time of treatment termination and through 30 days following treatment termination Peripheral neuropathy assessment Blood for biomarkers (unless performed within the last 14 days)
figure 6 percent change in
12.10 follow-up after termination visit

If the BP was >150/90 mmHg at the termination visit, the subject needs to be followed as outlined in Section 9.3. Serum pregnancy test for all females of childbearing potential 56 and 112 days following the treatment termination visit. 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 patients who have not progressed at the time of treatment termination until they receive subsequent treatment. For these subjects, copies of the standard of care radiographs may be provided to the Sponsor in a de-identified manner. These data and radiographs will continue to be collected until the subject starts alternative anti-cancer treatment or develops progressive disease, whichever occurs first. BNP AND DOPPLER ECHOCARDIOGRAM: If a subject has a BNP of ≥400 pg/mL and/ or a diagnosis of pulmonary hypertension or heart failure at the time of termination, all subsequent standard of care BNP data until the value is <200 pg/mL and all subsequent standard of care LVEF and PTV values until they normalize will be collected and entered into the database. SURVIVAL DATA: Once a patient has completed the treatment termination visit, overall survival follow up will be performed every three months +/- 1 week or more frequently at the request of the Sponsor for up to 5 years. Follow up may be conducted by telephone interview or chart review
figure 6 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) 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 the RDC system. The clinical data and the site-specific laboratory data will be entered by site personal into the RDC system. Analysis of samples for antibodies to demcizumab will be performed by ICON Development Solutions. 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 CROs, and records retention for the study data will be consistent with the standard procedures for these organizations.
figure 6 percent change in
14.0 statistical plan

Table 7 presents the power to detect the difference between the control arm and the pooled demcizumab arms in the trial for the primary endpoint of PFS. Type 1 error is controlled at the 0.10 one sided level. Two hundred and one subjects followed until 125 PFS events have been observed will provide 80 percent power to detect a hazard ratio of 0.67 which corresponds to an increase in median PFS from 5.5 months to 8.2 months.  
| End of  Study   |                 |                   |                 |                   |               |                |                 |              |       |       |        |
|-----------------|-----------------|-------------------|-----------------|-------------------|---------------|----------------|-----------------|--------------|-------|-------|--------|
| Total           |                 |                   |                 |                   |               |                |                 |              |       |       |        |
| #Subjects       | Median  Control | Median  Treatment | Hazard  Control | Hazard  Treatment | Hazard  Ratio | Total  #Events | Events  Control | Event  Treat | Type1 | Power |        |
| Error           |                 |                   |                 |                   |               |                |                 |              |       |       |        |
| (months)        |                 |                   |                 |                   |               |                |                 |              |       |       |        |
| 201             | 5.5             | 5.5               | 0.126027        | 0.126027          | 1.000000      | 23             | 123.6           | 42.6         | 81.0  | 0.1   | 0.1000 |
| 201             | 5.5             | 6.0               | 0.126027        | 0.115525          | 0.916669      | 24             | 124.9           | 43.7         | 81.1  | 0.1   | 0.2068 |
| 201             | 5.5             | 6.5               | 0.126027        | 0.106638          | 0.846152      | 24             | 123.1           | 43.7         | 79.4  | 0.1   | 0.3466 |
| 201             | 5.5             | 7.0               | 0.126027        | 0.099021          | 0.785713      | 25             | 124.2           | 44.7         | 79.6  | 0.1   | 0.5033 |
| 201             | 5.5             | 7.5               | 0.126027        | 0.092420          | 0.733335      | 26             | 125.2           | 45.4         | 79.7  | 0.1   | 0.6507 |
| 201             | 5.5             | 8.0               | 0.126027        | 0.086643          | 0.687496      | 26             | 123.6           | 45.4         | 78.2  | 0.1   | 0.7664 |
| 201             | 5.5             | 8.2               | 0.126027        | 0.084530          | 0.670729      | 26             | 123.0           | 45.4         | 77.6  | 0.1   | 0.8041 |
| 201             | 5.5             | 8.5               | 0.126027        | 0.081547          | 0.647060      | 27             | 124.5           | 46.1         | 78.4  | 0.1   | 0.8563 |  
In addition to PFS, subjects will also be followed for the overall survival endpoint. At the time of the PFS final analysis, which is anticipated to occur when approximately 87 deaths have been observed, an interim analysis for OS will take place. After this final analysis for PFS, there will be two more planned analyses for OS, one based on all deaths as of June 1 2017 and the final analysis based on all deaths as of November 1 2017. Table 8 presents the interim analysis plan for OS along with the power to detect a hazard ratio of 0.675 with type 1 error of 0.10. The efficacy boundary is determined from the O'Brien Fleming spending function while the futility boundary simply allows the study to continue while the estimated hazard ratio is less than 1 in favor of a survival benefit for demcizumab. The rejection boun dary for OS may have to be adjusted using the O'Brien Fleming spending function for the number of deaths actually observed at times of the interim analyses (100% information = 131 deaths).
figure 6 percent change in
table 8 summary of power

| Interim 1                                       |                |       |       |
|-------------------------------------------------|----------------|-------|-------|
| PFS Final Analysis                              | Interim 2      |       |       |
| Deaths as of June 1 2017                        | Final Analysis |       |       |
| Deaths as of Nov 1 2017                         |                |       |       |
| Z-Statistic (reject the null)                   | 1.72           | 1.52  | 1.42  |
| Z-Statistic (reject the alt)                    | 0              | 0     | 1.42  |
| Events Total                                    | 87             | 112   | 131   |
| Events Control                                  | 34             | 43    | 49    |
| Events Treatment                                | 53             | 69    | 82    |
| Cumulative Power (HR=0.675)                     | 0.531          | 0.713 | 0.8   |
| Cumulative Type 1 Error (1-sided)               | 0.043          | 0.076 | 0.1   |
| Cumulative Prob. of Stopping for Futility (Alt) | 0.036          | 0.042 | 0.201 |
| Cumulative Pro. of Stopping for Futility (Null) | 0.5            | 0.577 | 0.9   |  
The study will have 80 percent power to detect a hazard ratio of 0.675 with a type 1 error of 0.10 one-sided. The study followup for overall survival will stop for futility at either the OS analysis done at the time of the PFS analysis or the subsequent interim analysis for OS if the hazard ratio is greater than 1 suggesting that treatment with demcizumab may shorten survival. The first analysis for OS
will be based on all subjects who have died as of the data cutoff date for PFS.The final two analyses for OS will be based on all deaths on or prior to June 1 and November 1 2017. The probability of stopping for futility at the first interim when there is no treatment benefit is 0.5. The probability of stopping for futility at the first interim when demcizumab has an overall suvival benefit described by a hazard ratio of 0.675 is 0.036.
figure 6 percent change in
14.1 data safety monitoring board

A data safety monitoring board consisting of a Chairman, at least 2 medical oncologists and a statistician will meet quarterly to review the emerging data from the trial. In addition to the planned Data Review meetings, the sponsor and/or DSMB may convene ad hoc meetings, should they be deemed necessary. Specifically, the DSMB will review all adverse events (i.e., all Grades regardless of attribution to study drug) and safety data by treatment arm.
figure 6 percent change in
14.2 study stopping rules

These stopping rules apply to all subjects randomized on the study. 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 v. 4.03) 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 non-small cell lung 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 9 presents the probability of exceeding the 15 percent threshold either at the formal interim or the final analyses of the trial.  
| Prob of exceeding 15 pct at  Interim  (67 subjects enrolled in  demcizumab treated arm,  67 subjects in the control  arm)   | Prob of exceeding 15 pct  at final   |                         |         |         |         |         |
|-----------------------------------------------------------------------------------------------------------------------------|--------------------------------------|-------------------------|---------|---------|---------|---------|
| Control                                                                                                                     | Dem                                  | Total Prob of exceeding | Total   |         |         |         |
| exceeding 15 pct at final                                                                                                   | 15 pct                               | Probability             |         |         |         |         |
| Prob of Not                                                                                                                 |                                      |                         |         |         |         |         |
| (134 subjects with  demcizumab, 134  subjects with control)                                                                 |                                      |                         |         |         |         |         |
| 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.
figure 6 percent change in
14.3 subject populations for analysis

As noted above, 201 evaluable subjects will be enrolled in the trial. The Intent-to-Treat (ITT) Population comprises all subjects who receive at least one partial or complete dose of demcizumab or placebo. All baseline characteristics and demographic, efficacy, immunogenicity, and biomarker data will be analyzed using the ITT Population.  
The Per Protocol Population (PP) is comprised of all randomized subjects who received at least one dose of study drug and had at least one post baseline tumor assessment. All efficacy data will be analyzed using the PP population as well as the ITT Population. The Safety Population 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. 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 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.
figure 6 percent change in
14.4 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.
figure 6 percent change in
14.5 treatment exposure

Treatment exposure will be summarized as duration on treatment and extent of exposure to demcizumab in Arms 2 and 3. 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.
figure 6 percent change in
14.6 endpoints 14.6.1 safety endpoints

Safety endpoints include AEs; SAEs; physical examination; vital signs; clinical laboratory testing including assessment of BNP every 14 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; and anti-demcizumab testing. Safety endpoints will be analyzed by treatment arm using the Safety Population.
figure 6 percent change in
14.6.1.1 adverse events

All reported adverse events 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 adverse events in each treatment arm will be tabulated by seriousness, severity, and relationship to study drug.
figure 6 percent change in
14.6.1.2 clinical laboratory assessments and

Clinical laboratory data (hematology, serum chemistry, and urinalysis with microscopic analysis) 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.
figure 6 percent change in
14.6.1.3 bnp assessment

The proportion of subjects with at least two consecutive BNP assessments above 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 elevation ≥400 pg/mL will be summarized by treatment group. Among the subjects in the demcizumab groups with two BNP measurements above 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 to ≥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.
figure 6 percent change in
14.6.1.4 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.
figure 6 percent change in
14.6.1.5 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 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.
figure 6 percent change in
14.6.2 immunogenicity endpoints

Immunogenicity endpoints will be analyzed using the ITT Population. The incidence of antidemcizumab antibody development in each treatment arm 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.
figure 6 percent change in
14.6.3 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 6 percent change in
14.6.4 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 6 percent change in
14.6.4.1 best overall response

The best overall response is defined as the best response recorded from the start of the treatment until disease progression (see detailed definition in Appendix D) 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 and for the pooled demcizumab arms. The confirmed response rate is the number of subjects per treatment arm who have either a confirmed CR or a confirmed PR (according to RECIST criteria) divided by the number of subjects randomized to the respective arms. These proportions and their 95% confidence intervals will be displayed for each treatment arm as well as for the pooled demcizumab arms. The p-value for equality between the pooled demcizumab treatment arms and control will be calculated using a logistic regression model with treatment performance status and region as factors in the model. A similar comparison will be made between each individual demcizumab arm and control
figure 6 percent change in
14.6.4.2 clinical benefit rate

The Investigator-assessed RECIST clinical benefit rate (i.e., the rate of complete response + partial response + stable disease) will be calculated for the pooled demcizumab arms and will be compared with control. In addition, the rates in each individual demcizumab arm will also be compared with control.