IRB #: STU00207577-MOD0018 Approved by NU IRB for use on or after 7/8/2020 through 9/29/2020. NU Study Number: NU 18I01 A Phase 2 study of pembrolizumab in combination with pelareorep in patients with advanced pancreatic adenocarcinoma Principal Investigator: Devalingam Mahalingam MD, PhD Northwestern University Associate Professor, Division of Hematology and Oncology Developmental Therapeutics Institute (DTI) 233 East Superior Street, Ground Floor, Olson Pavilion Chicago, IL 60611 Phone: 312-695-6929 Fax: 312-472-0564 E-mail: [email protected] Sub-Investigator(s): Division of Hematology and Oncology Northwestern University Al Benson, MD Aparna Kalyan, MBBS, FRACP Sheetal Kircher, MD Mary Mulcahy, MD Biostatistician: Hui Zhang, PhD [email protected] Study Intervention(s): Pelareorep and Pembrolizumab IND Number: PS003760 IND Holder: Devalingam Mahalingam MD, PhD Funding Source: Oncolytics Biotech Inc: drug support (pelareorep) Merck: drug support (pembrolizumab) Version Date: 3.23.2020 Coordinating Center: Clinical Trials Office Robert H. Lurie Comprehensive Cancer Center Northwestern University 676 N. St. Clair, Suite 1200 Chicago, IL 60611 http://cancer.northwestern.edu/research/clinical-trials-office/ NU 18I01 Protocol Version Date:3.23.2020 i IRB #: STU00207577-MOD0018 Approved by NU IRB for use on or after 7/8/2020 through 9/29/2020. NU Study Number: NU 18I01 Table of Contents LIST OF ABBREVIATIONS..........................................................................................................................iv STUDY SCHEMA.........................................................................................................................................vi STUDY SUMMARY.....................................................................................................................................vii 1. INTRODUCTION - BACKGROUND AND RATIONALE.......................................................................9 1.1 Disease Background.....................................................................................................................9 1.2 Interventional Background & Overview.........................................................................................9 1.3 Pre-Clinical Experience...............................................................................................................11 1.4 Immune Checkpoint Inhibition in Cancer Treatment...................................................................14 1.5 Pelareorep and Checkpoint Inhibitors.........................................................................................16 1.6 Rationale for Current Study ........................................................................................................17 2. OBJECTIVES.....................................................................................................................................18 2.1 Primary Objectives......................................................................................................................18 2.2 Secondary Objectives.................................................................................................................18 2.3 Exploratory Objectives................................................................................................................18 3. PATIENT ELIGIBILITY.......................................................................................................................19 3.1 Inclusion Criteria .........................................................................................................................19 3.2 Exclusion Criteria........................................................................................................................21 4. TREATMENT PLAN...........................................................................................................................23 4.1 Overview.....................................................................................................................................23 4.2 Treatment Administration............................................................................................................23 4.3 Toxicity Management & Dose Delays/Modifications...................................................................25 4.4 Supportive Care with Pembrolizumab.........................................................................................27 4.5 Concomitant Medications/Treatments ........................................................................................30 4.6 Duration of Therapy ....................................................................................................................31 4.7 Duration of follow-up...................................................................................................................32 4.8 Subject Withdrawal/Discontinuation Criteria...............................................................................32 4.9 Patient Replacement...................................................................................................................33 4.10 Discontinuation of Study Therapy after CR.................................................................................33 5. STUDY PROCEDURES.....................................................................................................................34 6. ENDPOINTS and ASSESSMENTS ...................................................................................................37 6.1 Definitions ...................................................................................................................................37 6.2 Methods of Measurement ...........................................................................................................38 6.3 Baseline Documentation of Target and Non-Target Lesions......................................................38 6.4 Evaluation of Target Lesions ......................................................................................................39 6.5 Evaluation of Non-Target Lesions...............................................................................................40 6.6 Overall Response Evaluation......................................................................................................40 6.7 Immune-related response criteria [1] ..........................................................................................40 6.8 Primary Endpoint .......................................................................................................................42 NU 18I01 Protocol Version Date:3.23.2020 ii IRB #: STU00207577-MOD0018 Approved by NU IRB for use on or after 7/8/2020 through 9/29/2020. NU Study Number: NU 18I01 6.9 Secondary Endpoints..................................................................................................................42 6.10 Exploratory Endpoints.................................................................................................................43 6.11 Assessment of Antineoplastic Activity.........................................................................................43 7. ADVERSE EVENTS...........................................................................................................................43 7.1 Adverse Event Monitoring...........................................................................................................43 7.2 Definitions & Descriptions...........................................................................................................43 7.3 Adverse Event Reporting............................................................................................................45 7.4 Protocol-Specific Additional Reporting Requirements for Serious Adverse Event Reporting.....47 8. DRUG INFORMATION ......................................................................................................................49 8.1 Pembrolizumab...........................................................................................................................49 8.2 PELAREOREP............................................................................................................................52 9. CORRELATIVES/SPECIAL STUDIES...............................................................................................56 10. STATISTICAL METHODS .................................................................................................................57 11. STUDY MANAGEMENT ....................................................................................................................57 11.1 Institutional Review Board (IRB) Approval and Consent ............................................................57 11.2 Amendments...............................................................................................................................58 11.3 Registration Procedures .............................................................................................................58 11.4 Data Submission.........................................................................................................................58 11.5 Instructions for Participating Sites...............................................................................................59 11.6 Data Management and Monitoring/Auditing................................................................................59 11.7 Adherence to the Protocol ..........................................................................................................59