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CLINICAL STUDY PROTOCOL A Phase 1/2, Open-Label Safety and Efficacy Evaluation of CRS-207 in Combination with Epacadostat in Adults with Platinum-Resistant Ovarian, Fallopian, or Peritoneal Cancer Investigational Products: CRS-207, epacadostat, and pembrolizumab Protocol Number: ADU-CL-11 Sponsor: Aduro Biotech, Inc. 740 Heinz Avenue Berkeley, CA 94710-2224 USA Telephone: +1 510-848-4400 Facsimile: +1 510-848-5614 Original Protocol: 28 October 2015 Amendment 1: 22 April 2016 Amendment 2: 15 November 2016 Amendment 3: 18 February 2017 IND: 16,702 Confidentiality Statement The information in this document is confidential and is not to be disclosed without the written consent of Aduro Biotech, Inc. except to the extent that disclosure would be required by law and for the purpose of evaluating and/or conducting a clinical study for Aduro Biotech, Inc. You are allowed to disclose the contents of this document only to your Institutional Review Board (IRB) or Independent Ethics Committee (IEC) and study personnel directly involved with conducting this protocol. Persons to whom the information is disclosed must be informed that the information is confidential and proprietary to Aduro Biotech, Inc. and that it may not be further disclosed to third parties. Aduro Biotech, Inc. Clinical Study Protocol ADU-CL-11 INVESTIGATOR AGREEMENT By signing below I agree that: I have read this amended protocol. I approve this document and I agree that it contains all necessary details for carrying out the study as described. I will conduct this study in accordance with the design and specific provision of this protocol and will make a reasonable effort to complete the study within the time designated. I will provide copies of this protocol and access to all information furnished by Aduro Biotech, Inc. to study personnel under my supervision. I will discuss this material with them to ensure they are fully informed about the study product and study procedures. I will let them know that this information is confidential and proprietary to Aduro Biotech, Inc. and that it may not be further disclosed to third parties. I understand that the study may be terminated or enrollment suspended at any time by Aduro Biotech, Inc., with or without cause. I have the right to suspend enrollment of subjects at my study site if necessary to protect the best interests of the study subjects. I agree to conduct this study in full accordance with Food and Drug Administration Regulations, Institutional Review Board/Ethic Committee Regulations and ICH Guidelines for Good Clinical Practices. ______________________________________________ ____________________ Investigator’s Signature Date ______________________________________________ Investigator’s Printed Name Confidential & Proprietary 3 Amendment 3, 18 Feb 2017 Aduro Biotech, Inc. Clinical Study Protocol ADU-CL-11 SYNOPSIS TITLE: A Phase 1/2, Open-Label Safety and Efficacy Evaluation of CRS-207 in Combination with Epacadostat in Adults with Platinum-Resistant Ovarian, Fallopian, or Peritoneal Cancer PROTOCOL NUMBER: ADU-CL-11 INVESTIGATIONAL PRODUCTS: CRS-207, epacadostat (IDO), and pembrolizumab (pembro) OBJECTIVES AND ENDPOINTS: The objectives and endpoints for this study are as follows: Phase 1: Dose Evaluation, Assigned Arms Objective(s) Endpoints Primary Primary • Determine the RP2D of epacadostat • Hematologic and non-hematologic DLTs; administered with CRS-207 in subjects • Adverse events by CTCAE grade; vital signs, physical with platinum-resistant ovarian, fallopian exam findings, changes in ECG readings and changes in or peritoneal cancer chemistry and hematology and coagulation parameters • Assess safety and tolerability of CRS-207 alone and CRS-207 in combination with epacadostat in subjects with platinum- resistant ovarian, fallopian or peritoneal cancer Secondary Secondary • Characterize the PK of epacadostat • Plasma concentration of epacadostat and derived PK • Evaluate the preliminary anti-tumor parameters; activity of each study drug regimen • ORR, defined as CR or PR as determined by mRECIST, • Characterize pharmacological effects on RECIST v1.1, and GCIG CA-125 criteria; immune biomarkers in peripheral blood • PFS, defined as the time from the date of first dose to PD and tumor tissue or death due to any cause. PFS is measured through the • Characterize shedding and clearance of last tumor assessment or commencement of a new CRS-207 when given alone or with systemic therapy. PD is determined by mRECIST, epacadostat RECIST v1.1 and GCIG CA-125 criteria; • Disease control rate, defined as CR+PR+SD as determined by mRECIST, RECIST v1.1, and GCIG CA-125 criteria; • Duration of response, defined as the time from first CR or PR until PD as determined by mRECIST, RECIST v1.1, and GCIG CA-125 criteria; • OS, defined as the time from first dose until date of death due to any cause; • Ratio of tumor infiltrating lymphocytes CD8/Treg (FoxP3); • Plasma kynurenine/tryptophan ratio; • Other immunological and tumor biomarker endpoints: o Cytokine/chemokine responses o Antibody responses o Modulation of immune cell populations and functions in PBMCs and tumor, and o CA-125, mesothelin, IDO-1, PD-L1 and additional tumor biomarkers; and • Detection of CRS-207 in urine, saliva, feces, and blood Confidential & Proprietary 4 Amendment 3, 18 Feb 2017 Aduro Biotech, Inc. Clinical Study Protocol ADU-CL-11 CA-125 = cancer antigen-125; CR = complete response; CTCAE = Common Terminology Criteria for Adverse Events; DLT = dose-limiting toxicity; GCIG = Gynecologic Cancer Intergroup; IDO = epacadostat; mRECIST = modified Response Evaluation Criteria in Solid Tumors; ORR = objective response rate; OS = overall survival; PBMC = peripheral blood mononuclear cells; PD = disease progression; PD-L1 = programmed death receptor ligand 1; pembro = pembrolizumab; PFS = progression-free survival; PK = pharmacokinetics; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; RP2D = recommended Phase 2 dose; SD = stable disease; Treg = regulatory T cells. Phase 2: Randomized, 2-stage Objective(s) Endpoints Primary Primary • Assess safety of CRS-207/pembrolizumab • Adverse events, vital signs, physical exam findings, administered with or without epacadostat changes in ECG readings, and changes in chemistry, • Assess tumor response and PFS hematology, and coagulation parameters • ORR, defined as CR or PR as determined by mRECIST • PFS, defined as the time from the date of first dose to PD or death due to any cause. PFS is measured through the last tumor assessment or commencement of a new systemic therapy. PD is determined by mRECIST. Secondary Secondary • Assess disease control rate and duration • Disease control rate, defined as CR+PR+SD as determined of response by mRECIST, RECIST v1.1, and GCIG CA-125 criteria • Assess OS • Duration of response, defined as the time from first CR or PR until PD as determined by mRECIST, RECIST v1.1, and GCIG CA-125 criteria • ORR as determined by RECIST v1.1 and GCIG CA-125 criteria • OS, defined as the time from first dose until date of death due to any cause • PFS where PD is determined by RECIST v1.1 and GCIG CA-125 criteria Additional Additional • Assess the association of clinical efficacy Immunological and tumor biomarker endpoints: (ORR, PFS, and OS) with immunologic • Cytokine/chemokine and antibody responses and tumor biomarkers • Modulation of immune cell populations and functions in • Characterize the PK of epacadostat PBMCs and tumor • Characterize shedding and clearance of • Mesothelin, IDO-1 and PD-L1 expression CRS-207/pembrolizumab administered • CA-125 and additional candidate tumor biomarkers with or without epacadostat Pharmacokinetic endpoints: • Plasma concentration of epacadostat and derived PK parameters • Detection of CRS-207 in urine, saliva, feces, and blood STUDY DESIGN: The study is designed to assess the safety and efficacy of the following investigational treatment regimens in adult females with epithelial ovarian, fallopian, or primary peritoneal cancer that is platinum-resistant (i.e. has progressed within 6 months after completing platinum-based chemotherapy): • CRS-207/epacadostat/pembrolizumab (CRS-207/IDO/pembro) • CRS-207/pembrolizumab (CRS-207/pembro) Confidential & Proprietary 5 Amendment 3, 18 Feb 2017 Aduro Biotech, Inc. Clinical Study Protocol ADU-CL-11 The study will be conducted in 2 phases as depicted in the study schematic. Phase 1 seeks to evaluate safety and tolerability and is aimed at determining the recommended Phase 2 dose (RP2D) of epacadostat administered with CRS-207 for further evaluation in Phase 2. The randomized Phase 2 portion of the study will begin with a safety-run in to evaluate the addition of pembrolizumab, followed by a 2-stage design to evaluate safety and efficacy in subjects who have received no more than 3 prior chemotherapy regimens for locally advanced or metastatic disease. Study Schematic The Schedules of Events for Phases 1 and 2 are provided in Appendix F and Table 1, respectively. The study consists of a 28-day screening period, followed by administration of study drug(s) in 3-week cycles. Treatment will continue for as long as there is adequate safety and potential for clinical benefit with the exception that pembrolizumab may be given for up to 24 months to subjects without disease progression. After 6 cycles, CRS-207 will be administered every 6 weeks (Q6W); all other assigned treatments remain the same. Archived tumor tissue and paired tumor biopsies (collected at Screening and Cycle 2 Day 15) will
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