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Clinical Protocol OncoMed Pharmaceuticals, Inc. Demcizumab CLINICAL PROTOCOL 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 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of OncoMed Pharmaceuticals, Inc. Acceptance of this document constitutes agreement by the recipient that no previously unpublished information contained herein will be published or disclosed without the prior written approval of OncoMed Pharmaceuticals, Inc. with the exception that this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. Protocol M18-006, Amendment 5 Page 1 of 130 CONFIDENTIAL 19 December 2016 OncoMed Pharmaceuticals, Inc. Demcizumab SPONSOR CONTACTS Medical Monitor: ___________________ (Primary) ___________________________ Email: ___________________ Phone: ____________________ Medical Monitor: ___________________ (Secondary) ___________________ Email: ___________________ Phone: ___________________ Safety Reporting: Europe, Australia Phone: ___________________ Fax: ___________________ United States Phone: ___________________ Fax: ___________________ Protocol M18-006, Amendment 5 Page 2 of 130 CONFIDENTIAL 19 December 2016 OncoMed Pharmaceuticals, Inc. Demcizumab INVESTIGATOR SIGNATURE PAGE 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 Printed Name: Institution: Address: Telephone Number: Protocol M18-006, Amendment 5 Page 3 of 130 CONFIDENTIAL 19 December 2016 OncoMed Pharmaceuticals, Inc. Demcizumab SPONSOR SIGNATURE PAGE 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 Protocol M18-006, Amendment 5 Page 4 of 130 CONFIDENTIAL 19 December 2016 OncoMed Pharmaceuticals, Inc. Demcizumab 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. Protocol M18-006, Amendment 5 Page 5 of 130 CONFIDENTIAL 19 December 2016 OncoMed Pharmaceuticals, Inc. Demcizumab 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. Protocol M18-006, Amendment 5
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