Protocol name: Phase II Neoadjuvant trial of Nivolumab in Combination with HF10 Oncolytic Viral Therapy in Resectable Stage IIIB, IIIc, IVM1a Melanoma (Neo-NivoHF10) Version Date: 22JUL2019 Principal Investigator: John Hyngtrom, MD Phase II Neoadjuvant trial of Nivolumab in Combination with HF10 Oncolytic Viral Therapy in Resectable Stage IIIB, IIIC, IVM1a Melanoma (Neo-NivoHF10) Trial ID: HCI102346/ IRB#102346 Drug Manufacturer protocol # CA209-9F3 NCT03259425 Principal Investigator John Hyngstrom, MD Huntsman Cancer Institute/University of Utah 2000 Circle of Hope Drive Salt Lake City, UT 84112 801-585-0255 [email protected] Sub-investigator(s) Brittany Thomas, PA-C Huntsman Cancer Institute/University of Utah [email protected] Elizabeth Flores, PA Huntsman Cancer Institute/University of Utah [email protected] Carolyn Luckett, APRN Huntsman Cancer Institute/University of Utah [email protected] Siwen Hu-Lieskovan, MD Huntsman Cancer Institute/University of Utah [email protected] Protocol name: Phase II Neoadjuvant trial of Nivolumab in Combination with HF10 Oncolytic Viral Therapy in Resectable Stage IIIB, IIIc, IVM1a Melanoma (Neo-NivoHF10) Version Date: 22JUL2019 Principal Investigator: John Hyngtrom, MD Kenneth Grossmann, MD Huntsman Cancer Institute/University of Utah [email protected] Statistician Kenneth Boucher, PhD Huntsman Cancer Institute/University of Utah [email protected] Drug Manufacturer Takara Bio Inc. Nojihigashi 7-4-38, Kusatsu Shiga 525-0058, Japan +81-77-565-6976 Bristol-Myers Squibb PO Box 5100 Wallingford, CT 06492-7660 203-677-6000 Investigational agent HF10 Nivolumab (OPDIVO) IND Number 17693 Page 2 of 61 Protocol name: Phase II Neoadjuvant trial of Nivolumab in Combination with HF10 Oncolytic Viral Therapy in Resectable Stage IIIB, IIIc, IVM1a Melanoma (Neo-NivoHF10) Version Date: 22JUL2019 Principal Investigator: John Hyngtrom, MD Historical Protocol Versions Version 1: 25SEP2017 Version 2: 08AUG2018 Version 3: 06JUN2019 Version 4: 22JUL2019 Page 3 of 61 Protocol name: Phase II Neoadjuvant trial of Nivolumab in Combination with HF10 Oncolytic Viral Therapy in Resectable Stage IIIB, IIIc, IVM1a Melanoma (Neo-NivoHF10) Version Date: 22JUL2019 Principal Investigator: John Hyngtrom, MD TABLE OF CONTENTS Page PROTOCOL SIGNATURE PAGE……………………………….....................................9 STUDY SUMMARY …………………………………………………………………...10 1 OBJECTIVES ........................................................................................................... 16 Primary Objectives and Endpoint ...................................................................... 16 Secondary Objectives and Endpoint .................................................................. 16 Exploratory Objective and Endpoint .................................................................. 16 2 BACKGROUND ...................................................................................................... 18 Introduction ........................................................................................................ 18 The Investigational Product ............................................................................... 18 Nonclinical and Preclinical Studies.................................................................... 20 Clinical Studies with HF10 ................................................................................ 24 3 Potential risks and benefits ....................................................................................... 27 HF10 ................................................................................................................... 27 Nivolumab .......................................................................................................... 28 4 STUDY DESIGN...................................................................................................... 29 Description ......................................................................................................... 29 Number of Patients ............................................................................................. 29 Number of Study Centers ................................................................................... 29 Study Duration ................................................................................................... 29 5 ELIGIBILITY CRITERIA........................................................................................ 30 Inclusion Criteria ................................................................................................ 30 Exclusion Criteria ............................................................................................... 31 6 TREATMENT PLAN ............................................................................................... 33 Administration Schedule .................................................................................... 33 Nivolumab .......................................................................................................... 34 HF10 ................................................................................................................... 35 Prohibited Concomitant Medications ................................................................. 35 Page 4 of 61 Protocol name: Phase II Neoadjuvant trial of Nivolumab in Combination with HF10 Oncolytic Viral Therapy in Resectable Stage IIIB, IIIc, IVM1a Melanoma (Neo-NivoHF10) Version Date: 22JUL2019 Principal Investigator: John Hyngtrom, MD Duration of Therapy ........................................................................................... 36 7 TOXICITIES AND DOSEAGE MODIFICATION ................................................. 36 Dose Modifications ............................................................................................ 36 Subject Compliance............................................................................................ 39 Patient Precautions for Minimizing Virus Exposure to Others .......................... 39 Healthcare Provider Precautions ........................................................................ 39 Supportive Care .................................................................................................. 40 8 STUDY CALENDAR .............................................................................................. 41 9 CRITERIA FOR EVALUATION AND ENDPOINT .............................................. 43 Pathological response ......................................................................................... 43 Safety .................................................................................................................. 43 Recurrence Free Survival ................................................................................... 43 Neo-Adjuvant Therapy Tumor Response .......................................................... 44 irRC and RECIST 1.1 Concordance .................................................................. 45 Overall Survival ................................................................................................. 47 Correlative Biomarker Analysis ......................................................................... 47 Complete Surgical Resection ............................................................................. 47 Pathology ............................................................................................................ 47 Stopping Rules ................................................................................................ 47 10 STATISTICAL CONSIDERATIONS...................................................................... 47 11 REGISTRATION GUIDELINES ............................................................................. 48 12 DATA SUBMISSION SCHEDULE ........................................................................ 48 13 SPECIAL INSTRUCTIONS – CORRELATIVE STUDIES ................................... 49 Tissue Samples ............................................................................................... 49 Blood Samples ................................................................................................ 49 14 ETHICAL AND REGULATORY CONSIDERATIONS ........................................ 50 Informed consent ............................................................................................ 50 Institutional Review ........................................................................................ 50 Data and Safety Monitoring Plan ................................................................... 50 Adverse Events / Serious Adverse Events ...................................................... 50 SAE Reporting Requirements ........................................................................ 52 Reporting of Pregnancy .................................................................................. 54 Page 5 of 61 Protocol name: Phase II Neoadjuvant trial of Nivolumab in Combination with HF10 Oncolytic Viral Therapy in Resectable Stage IIIB, IIIc, IVM1a Melanoma (Neo-NivoHF10) Version Date: 22JUL2019 Principal Investigator: John Hyngtrom, MD Protocol Amendments .................................................................................... 54 Protocol Deviations ........................................................................................ 55 FDA Annual Reporting .................................................................................