TITLE: A Phase 2 Study of GVAX Colon Vacci ne (with Cyclophosphamide) and Pembrolizumab in Patients with Mismat ch Repair-Proficient (MMR-p) Advanced Colorectal Cancer Johns Hopkins #: IRB00114053, J16154 Merck Protocol #: MK-3475-485 Principal Investigator: Nilofer Azad, MD 1650 Orleans Street, Room 4M10 Baltimore, Maryland 21287 Lead Associate Investigator: Mark Yarchoan, MD 1650 Orleans St. CRB1 4M Baltimore, MD 21287 Regulatory Specialist: Jennifer Durham, PhD Statistician: Chiung-Yu Huang, PhD Lead Study Coordinator: Christina Rodriguez Lead Research Nurse: Anna Ferguson, RN Merck Supplied Agent : Pembrolizumab (KEYTRUDA®, MK-3475) JHU Supplied Agent : GVAX Colon Vaccine (Allogeneic SW 837 and SW 620 cell lines admixed with GM-CSF Producing Bystander K562 cell line) Commercial Agent : Cyclophosphamide IND: BB IND 13520 IND Sponsor: Lei Zheng, MD, PhD 1650 Orleans St, Room 488 Baltimore, MD 21287 Phase 2 Study of GVAX (with CY) and pem brolizum ab in MMR-p advanced colorectal cancer J16154/Version 5 / January 17, 2018 2Protocol Type / Version # / Version Date: Original/ Version 1.0 / November 10, 2016 Original/ Version 1.1 / December 16, 2016 Amendment 1/ Version 2 / March 28, 2017 Amendment 2/ Version 3 / September 1, 2017 Amendment 3/ Version 4 / October 20, 2017 Amendment 4/ Version 5 / January 17, 2018 Phase 2 Study of GVAX (with CY) and pembrolizum ab in MMR-p advanced colorectal cancer J16154/Version 5 / January 17, 2018 3TRIAL DESIGN  This is an open-label phase 2 trial evaluating the GVAX Colon Vaccine with Cyclophosphamide and Pembrolizumab in Patients with Mismatch Repair-Proficient (MMR-p) Advanced Colorectal Cancer  Each treatment cycle = 21 days  Patients will receive pembrolizumab on day 1 of each cycle  Patients will also receive cyclosphophami de on day 1, and GVAX on day 2, for each of the first four cycles, and then every fourth cycle thereafter  For all patients, imaging scans will be perf ormed at baseline and at least every 12 weeks thereafter, irrespective of the treatment schedule. Phase 2 Study of GVAX (with CY) and pembrolizum ab in MMR-p advanced colorectal cancer J16154/Version 5 / January 17, 2018 4TABLE OF CONTENTS 1. OBJECTIVES .................................................................................................................... ..6 1.1 Primary Objectives ...................................................................................................6 1.2 Secondary Objectives ...............................................................................................6 1.3 Exploratory Objectives ............................................................................................6 1.4 Primary Endpoint .....................................................................................................6 1.5 Secondary Endpoints ...............................................................................................7 1.6 Exploratory endpoints ..............................................................................................7 1.7 Study Design ............................................................................................................7 2. BACKGROUND .................................................................................................................8 2.1 Disease Type ............................................................................................................9 2.2 Vaccine Therapy (GVAX) .......................................................................................9 2.3 Anti-PD-1 /PD-L1 therapy (Pembrolizumab (MK-3475 or Keytruda)) .................12 2.4 Preclinical and Clinical Trial Data .........................................................................14 2.5 Rationale ................................................................................................................14 3. PATIENT SELECTION ....................................................................................................15 3.1 Eligibility Criteria ..................................................................................................15 3.2 Exclusion Criteria ..................................................................................................17 3.3 Inclusion of Wome n and Minorities ......................................................................19 4. TREATMENT PLAN ........................................................................................................19 4.1 Agent Administration .............................................................................................19 4.2 General Concomitant Medication an d Supportive Care Guidelines ......................20 4.3 Prohibited and Restricted Therapies ......................................................................24 4.4 Dosing Criteria .......................................................................................................24 4.5 Definition of an Overdose for this Protocol ...........................................................24 4.6 Contraception, Use in Pregnancy, Use in Nursing ................................................25 4.7 Dose Limiting Toxicity ..........................................................................................26 4.8 Duration of Therapy ...............................................................................................29 4.9 Off Treatment Evaluation and Retreatment Criteria ..............................................30 4.10 Duration of Follow Up ...........................................................................................31 4.11 Criteria for Removal from Study Treatment ..........................................................31 5. DOSING DELAYS/DOSE MODIFICATIONS................................................................32 5.1 Dose Modifications ................................................................................................32 5.2 Dosing Delays ........................................................................................................32 6.