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PHASE II STUDY OF EPACADOSTAT (INCB024360) WITH PEMBROLIZUMAB  
  
(MK-3475) IN METASTATIC OR UNRESECTABLE GASTROESOPHAGEAL
JUNCTION AND GASTRIC ADENOCARCINOMA REQUIRING PAIRED BIOPSIES
Coordinating Center Stanford Cancer Institute 875 Blake Wilbur Drive Stanford, CA 94305 Protocol Director George A. Fisher, Jr., MD, PhD
Stanford University School of Medicine 875 Blake Wilbur Drive Stanford, CA 94305-6562  
  
Biostatistician Alex McMillan, PhD
Stanford University School of Medicine Biomedical Data Science -- Biostatistics Redwood Building, Study Coordinator Julia Krupa Cancer Clinical Trials Office 800 Welch Road Stanford, CA 94305.  
  
Merck Protocol \#: 3475-370 Version \# 3.1 / Version Date: September 10, 2018 Version \# 3.0 / Version Date: March 1, 2018 Version \# 2.0 / Version Date: June 20, 2017 Version \# 1.1 / Version Date: April 25, 2017  
Stanford University Medical Center  
  
  
  
NATIONAL CANCER INSTITUTE-DESIGNATED CANCER CENTER  
  
| TABLE OF CONTENTS                                                                                                                             |                                                                                                                                                  |
|-----------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------|
| SUMMARY OF CHANGES                                                                                                                            |                                                                                                                                                  |
| PROTOCOL SYNOPSIS                                                                                                                             |                                                                                                                                                  |
| SCHEMA .                                                                                                                                      |                                                                                                                                                  |
| LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................................................................... 9                     |                                                                                                                                                  |
| 1.                                                                                                                                            | OBJECTIVES .                                                                                                                                     |
| Primary Objective                                                                                                                             |                                                                                                                                                  |
| 1.1.                                                                                                                                          |                                                                                                                                                  |
| 1.2.                                                                                                                                          | Secondary Objectives .                                                                                                                           |
| 1.3.                                                                                                                                          | Exploratory Objectives                                                                                                                           |
| 2.                                                                                                                                            | BACKGROUND                                                                                                                                       |
| Study Disease                                                                                                                                 |                                                                                                                                                  |
| 2.1.                                                                                                                                          | Study Agent/Device/Procedure                                                                                                                     |
| 2.2.                                                                                                                                          |                                                                                                                                                  |
| 2.2.1.                                                                                                                                        | Pharmaceutical and Therapeutic Background................................................................................13                      |
| 2.2.2.                                                                                                                                        | Inhibition of PD-1 as a Target for Cancer                                                                                                        |
| 2.2.3.                                                                                                                                        | Inhibition of Indoleamine 2,3–Dioxygenase as a Target for Cancer                                                                                 |
| 2.2.4.                                                                                                                                        | Combined Immune Checkpoint Inhibition                                                                                                            |
| RATIONALE                                                                                                                                     |                                                                                                                                                  |
| 2.3.                                                                                                                                          |                                                                                                                                                  |
| 2.3.1.                                                                                                                                        | Rationale for Studying Immunotherapy in Advanced or Metastatic Cancers .......................22                                                 |
| Study Design .                                                                                                                                |                                                                                                                                                  |
| 2.4.                                                                                                                                          |                                                                                                                                                  |
| 2.5.                                                                                                                                          | Correlative Studies Background and Rationale .                                                                                                   |
| 3.    PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ........................................................ 26                             |                                                                                                                                                  |
| 3.1.                                                                                                                                          | Subject Population .                                                                                                                             |
| 3.2.                                                                                                                                          | Inclusion Criteria .                                                                                                                             |
| Exclusion Criteria .                                                                                                                          |                                                                                                                                                  |
| 3.3.                                                                                                                                          |                                                                                                                                                  |
| 3.4.                                                                                                                                          | Informed Consent Process                                                                                                                         |
| Randomization Procedures                                                                                                                      |                                                                                                                                                  |
| 3.5.                                                                                                                                          |                                                                                                                                                  |
| 3.6.                                                                                                                                          | Study Timeline .                                                                                                                                 |
| Primary Completion                                                                                                                            |                                                                                                                                                  |
| 3.6.1.                                                                                                                                        |                                                                                                                                                  |
| 3.6.2.                                                                                                                                        | Study Completion .                                                                                                                               |
| TREATMENT PLAN                                                                                                                                |                                                                                                                                                  |
| 4.                                                                                                                                            | Study Procedures                                                                                                                                 |
| 4.1.                                                                                                                                          |                                                                                                                                                  |
| 4.2.                                                                                                                                          | D Duration of Treatment and Subject Participation                                                                                                |
| Screening Phase                                                                                                                               |                                                                                                                                                  |
| 4.3.                                                                                                                                          |                                                                                                                                                  |
| 4.3.1.                                                                                                                                        | Informed Consent .                                                                                                                               |
| General Informed Consent .                                                                                                                    |                                                                                                                                                  |
| 4.3.2.                                                                                                                                        |                                                                                                                                                  |
| 4.3.3.                                                                                                                                        | Inclusion/Exclusion Criteria .................................................................................................................35 |
| 4.3.4.                                                                                                                                        | Demographics and Medical History                                                                                                                 |
| 4.3.5.                                                                                                                                        | Prior Medications                                                                                                                                |
| 4.3.6.                                                                                                                                        | Concomitant Medications                                                                                                                          |
| Disease Details and Treatments ..........................................................................................................36   |                                                                                                                                                  |
| 4.3.7.                                                                                                                                        |                                                                                                                                                  |
| 4.3.7.1.                                                                                                                                      | Disease Details                                                                                                                                  |
| Prior Treatment Details ...................................................................................................................36 |                                                                                                                                                  |
| 4.3.7.2.                                                                                                                                      |                                                                                                                                                  |  
Stanford University Medical Center  
  
| NATIONAL CANCER INSTITUTE-DESIGNATED CANCER CENTER                                                                                          |                                                                                                                                                             |                                      |
|---------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------|
| Subsequent Anti-Cancer Therapy Status ...................................................................................................36 |                                                                                                                                                             |                                      |
| 4.3.7.3.                                                                                                                                    |                                                                                                                                                             |                                      |
| 4.4.                                                                                                                                        | Treatment Phase                                                                                                                                             |                                      |
| Administration of Investigational Products .....................................................................................37          |                                                                                                                                                             |                                      |
| 4.4.1.                                                                                                                                      |                                                                                                                                                             |                                      |
| 4.4.2.                                                                                                                                      | Treatment Compliance ....................................................................................................................37                 |                                      |
| 4.4.2.1.                                                                                                                                    | Epacadostat (INCB024360) ..................................................................................................................37               |                                      |
| 4.4.2.2.                                                                                                                                    | Pembrolizomab (MK-3475)                                                                                                                                     |                                      |
| 4.5.                                                                                                                                        | End of Treatment                                                                                                                                            |                                      |
| Follow-Up Phase                                                                                                                             |                                                                                                                                                             |                                      |
| 4.6.                                                                                                                                        |                                                                                                                                                             |                                      |
| 4.6.1.                                                                                                                                      | Safety Follow-Up Visit .                                                                                                                                    |                                      |
| Follow-Up Period .                                                                                                                          |                                                                                                                                                             |                                      |
| 4.6.2.                                                                                                                                      |                                                                                                                                                             |                                      |
| 4.6.3.                                                                                                                                      | Survival Follow-Up ......................................................................................................................................40 |                                      |
| 4.7.                                                                                                                                        | Unscheduled Visits...................................................................................................................................40     |                                      |
| Second Course Phase                                                                                                                         |                                                                                                                                                             |                                      |
| 4.8.                                                                                                                                        |                                                                                                                                                             |                                      |
| 4.9.                                                                                                                                        | Study Assessments and Procedures .............................................................................................................42            |                                      |
| 4.9.1.                                                                                                                                      | Se                                                                                                                                                          |                                      |
| 4.9.1.1.                                                                                                                                    | Adverse Events                                                                                                                                              |                                      |
| Comprehensive Physical Examination ............................................................................................43           |                                                                                                                                                             |                                      |
| 4.9.1.2.                                                                                                                                    |                                                                                                                                                             |                                      |
| 4.9.1.3.                                                                                                                                    | Targeted Physical Examination .......................................................................................................43                     |                                      |
| 4.9.1.4.                                                                                                                                    | Vital Signs                                                                                                                                                 |                                      |
| Twelve-Lead Electrocardiograms (ECGs) .......................................................................................43             |                                                                                                                                                             |                                      |
| 4.9.1.5.                                                                                                                                    |                                                                                                                                                             |                                      |
| 4.9.1.6.                                                                                                                                    | Laboratory Assessments ...........................................................................................................................44        |                                      |
| 4.9.2.                                                                                                                                      | Efficacy Assessments - Tumor Imaging During the Study ........................................................46                                            |                                      |
| 4.9.3.                                                                                                                                      | T Tumor Biopsy .........................................................................................................................................47  |                                      |
| 4.9.4.                                                                                                                                      | Performance and Quality of Life Assessments ...........................................................................48                                   |                                      |
| 4.9.4.1.                                                                                                                                    | Eastern Cooperative Oncology Group Performance Status ......................................................48                                              |                                      |
| 4.10. General Concomitant Medication and Supportive Care Guidelines ................................................48                      |                                                                                                                                                             |                                      |
| Acceptable Concomitant Medications                                                                                                          |                                                                                                                                                             |                                      |
| 4.10.1.                                                                                                                                     |                                                                                                                                                             |                                      |
| 4.10.2.                                                                                                                                     | Restricted Medications                                                                                                                                      |                                      |
| 4.10.3.                                                                                                                                     | Prohibited Medications ................................................................................................................49                   |                                      |
| 4.10.4.                                                                                                                                     | Supportive Care Guidelines and Handling Immune Related AEs .....................................................50                                          |                                      |
| 4.11.   Diet/Activity/Other Considerations                                                                                                  |                                                                                                                                                             |                                      |
| 4.11.1.                                                                                                                                     | DING IN THE PROPER                                                                                                                                          |                                      |
| 4.11.2.                                                                                                                                     | Contraception                                                                                                                                               |                                      |
| 4.11.3.                                                                                                                                     | Use in Pregnancy                                                                                                                                            |                                      |
| 4.11.4.                                                                                                                                     | Use in Nursing Women .                                                                                                                                      |                                      |
| 4.12. Subject Withdrawal/Discontinuation Criteria                                                                                           |                                                                                                                                                             |                                      |
| Discontinuation of Study Therapy after Complete Response                                                                                    |                                                                                                                                                             |                                      |
| 4.12.1.                                                                                                                                     |                                                                                                                                                             |                                      |
| 4.12.2.                                                                                                                                     | Noncompliance with Oral Epacadostat Dosing ............................................................................57                                   |                                      |
| INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION                                                                                          |                                                                                                                                                             |                                      |
| 5.                                                                                                                                          | 5.1.                                                                                                                                                        | Investigational Products Description |
| Epacadostat                                                                                                                                 |                                                                                                                                                             |                                      |
| 5.1.1.                                                                                                                                      |                                                                                                                                                             |                                      |
| 5.1.2.                                                                                                                                      | Pembrolizumab                                                                                                                                               |                                      |
| 5.2.                                                                                                                                        | Accountability, Handling, and Disposal of Epacadostat and Pembrolizumab ...................................59                                               |                                      |
| DOSE MODIFICATIONS                                                                                                                          |                                                                                                                                                             |                                      |
| 6.                                                                                                                                          |                                                                                                                                                             |                                      |
| 6.1.                                                                                                                                        | Rationale for Dose Modification(s)                                                                                                                          |                                      |
| Dose Modifications of Pembrolizumab and Epacadostat .........................................................................60             |                                                                                                                                                             |                                      |
| 6.2.                                                                                                                                        |                                                                                                                                                             |                                      |  
  
| 6.3.              | Management of Immune-Related Adverse Events (irAEs) 76                                   |
|-------------------|------------------------------------------------------------------------------------------|
| 6.4.              | Procedures for Subjects Exhibiting Serotonin Syndrome (SS) 76                            |
| 7.                | ADVERSE EVENTS AND REPORTING PROCEDURES 77                                               |
| 7.1.              | Adverse Event Definition and Reporting 77                                                |
| 7.2.              | Definition of an Overdose for This Protocol and Reporting of Overdose - Pembrolizumab 81 |
| 7.3.              | Definition of an Overdose for This Protocol and Reporting of Overdose - Epacadostat 82   |
| 7.4.              | Reporting of Pregnancy and Lactation to Merck and Incyte 82                              |
| 7.5.              | Reporting of Adverse Events to Merck and Incyte 83                                       |
| 7.5.1.            | Serious Adverse Events 83                                                                |
| 7.5.2.            | Events of Clinical Interest (ECIs) 87                                                    |
| 7.6.              | Assignment of Intensity and Relationship to Investigational Product (Causality) 88       |
| 7.7.              | Responsibility for Reporting AEs to Regulatory Authorities 88                            |
| 7.8.              | Evaluating Adverse Events 89                                                             |
| 7.9.              | Laboratory Test Abnormalities Definition and Reporting 92                                |
| 7.10.             | Handling of Expedited Safety Reports 92                                                  |
| 7.11.             | Warnings and Precautions 93                                                              |
| 7.12.             | Data Safety Monitoring Committee 93                                                      |
| 8.                | CORRELATIVE/SPECIAL STUDIES 94                                                           |
| 8.1.              | Blood Samples 94                                                                         |
| 8.1.1.            | Required Research Samples 94                                                             |
| 8.2.              | Tissue Samples 94                                                                        |
| 9.                | STUDY CALENDARS 95                                                                       |
| 10.               | MEASUREMENTS 101                                                                         |
| 10.1.             | Tumor Imaging Evaluations 101                                                            |
| 10.2.             | Definition of Measurable/Non-Measurable or Index/Non-Index Lesions 101                   |
| 10.2.1.           | Measurable and Non-Measurable Lesions 101                                                |
| 10.2.2.           | Index and Non-Index Lesions 102                                                          |
| 10.2.3.           | Evaluation of Target Lesions 102                                                         |
| 10.2.4.           | Evaluation of Non-Target Lesions 103                                                     |
| 10.3.             | Assessment of Disease According to RECIST v1.1 and irRC for Solid Tumors 103             |
| 10.4.             | Response Endpoints 105                                                                   |
| 11.               | REGULATORY CONSIDERATIONS 105                                                            |
| 11.1.             | Institutional Review of Protocol 105                                                     |
| 11.2.             | Data and Safety Monitoring Plan 106                                                      |
| 11.3.             | Data Management Plan 106                                                                 |
| 11.4.             | Study Monitoring 106                                                                     |
| 11.5.             | Good Clinical Practice 106                                                               |
| 11.6.             | Protocol Adherence 107                                                                   |
| 11.7.             | Financial Disclosure 108                                                                 |
| 11.8.             | Compliance with Study Registration and Results Posting Requirements 108                  |
| 11.9.             | Quality Control And Quality Assurance 109                                                |
| 11.9.1.           | Pharmaceutical Company Audits 109                                                        |
| 11.9.2.           | Inspection by Regulatory Authorities 109                                                 |
| 11.10. Ethics 109 |                                                                                          |  
  
  
| 11.10.1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Ethical Conduct of the Study 109                                               |
|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------|
| 11.10.2.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             | Ethics Review 110                                                              |
| 11.11. Data Privacy 111 11.12. Data Handling and Record Keeping 111 11.12.1. Inspection of Records 111 11.12.2. Retention of Records 111 11.13. Confidentiality 112                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  |                                                                                |
| 12.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | STATISTICS CONSIDERATIONS 112                                                  |
| 12.1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Statistical Design 112                                                         |
| 12.2.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Safety Analyses 113                                                            |
| 12.2.1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              | Analysis Plan 113                                                              |
| 12.3.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Secondary Analyses 113                                                         |
| 12.4.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Sample Size 114                                                                |
| 12.5.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | Criteria for Future Studies 114                                                |
| 13.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | REFERENCES 115                                                                 |
| 14.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  | APPENDICES 119                                                                 |
| 14.1.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST 119                              |
| 14.2.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | APPENDIX B: INFORMATION REGARDING EFFECTIVENESS OF CONTRACEPTIVE METHODS 125   |
| 14.3.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | APPENDIX C: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) PERFORMANCE STATUS...126 |
| 14.4.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                | APPENDIX D: PROHIBITED MONOAMINE OXIDASE INHIBITORS AND DRUGS ASSOCIATED WITH  |
| SIGNIFICANT MONOAMINE OXIDASE INHIBITORY ACTIVITY 127 14.5. APPENDIX E: PUBLICATION ON SEROTONIN SYNDROME 128 14.6. APPENDIX F: ADMINISTRATION OF PEMBROLIZUMAB 137 14.7. APPENDIX G: TEMPERATURE AND LIGHT EXCURSION FORM FOR EPACADOSTAT 141 14.8. APPENDIX H: DEFINITION OF irRC 142 14.8.1. Definition of Tumor Response Using irRC 142 14.8.2. Definition of Index Lesions Response Using irRC 142 14.8.3. Definition of Non-Index Lesions Response Using irRC 142 14.8.4. Impact of New Lesions on irRC 142 14.8.5. Definition of Overall Response Using irRC 143 14.8.6. Immune-Related Response Criteria Definitions 144 14.8.7. Immune-Related Best Overall Response Using irRC (irBOR) 144 |                                                                                |
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summary of changes

Compare v3.0 to v3.1 1. George A. Fisher, Jr., MD, PhD replaces Pamela Kunz, MD as Protocol Director and IND Sponsor.  
a. Cover page updated b. Section 7 updated with name of IND Sponsor c. Appendix A updated PROTOCOL SYNOPSIS  
  
  
| TITLE                                    | Phase                                                                                                                                                                        | II Study Of Epacadostat (INCB024360) With   |            |    |
|------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------|------------|----|
| Pembrolizumab                            | (MK-3475)                                                                                                                                                                    | In                                          | Metastatic | Or |
| Unresectable Gastroesophageal            | Junction And                                                                                                                                                                 | Gastric                                     |            |    |
| Adenocarcinoma Requiring Paired Biopsies |                                                                                                                                                                              |                                             |            |    |
| STUDY PHASE                              | II                                                                                                                                                                           |                                             |            |    |
| INDICATION                               | Metastatic or unresectable gastroesophageal junction or  gastric adenocarcinoma having progressed on at least  one line of prior therapy for metastatic disease              |                                             |            |    |
| INVESTIGATIONAL PRODUCTS                 | Epacadostat (INCB024360)  Pembrolizumab (MK 3475)                                                                                                                            |                                             |            |    |
| PRIMARY OBJECTIVE(S)                     | To assess 6-month progression free survival (PFS)                                                                                                                            |                                             |            |    |
| SECONDARY OBJECTIVE(S)                   | To evaluate response rate (RR), overall survival (OS),  and the safety and tolerability of Epacadostat  (INCB024360) in combination with Pembrolizumab  (MK3475) by CTCAE v5 |                                             |            |    |
| TREATMENT SUMMARY                        | Non-randomized, single arm, open-label Oral Epacadostat at 300 mg twice daily + Intravenous  Pembrolizumab at 200 mg every 3 weeks for up to 24  months                      |                                             |            |    |
| SAMPLE SIZE                              | 30 patients undergoing pre-                                                                                                                                                  | and on-treatment tumor                      |            |    |
| biopsies                                 |                                                                                                                                                                              |                                             |            |    |
| STATISTICAL                              | This is a single-stage study for the doublet epacadostat                                                                                                                     |                                             |            |    |
| CONSIDERATIONS                           | and pembrolizumab. A 6-month PFS of 20% was  observed using single agent pembrolizumab and is the  basis for the null hypothesis of the present study [1]. We  will enroll 30 patients over 18 months and follow  patients for at least 6 months. This design has 80%  power to reject a 20% PFS rate, if the true PFS is 39%.  Calculation based on binomial probabilities with a onesided significance of 10%.                                                                                                                                                                              |                                             |            |    |  
SCHEMA
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key inclusion criteria

- Adenocarcinoma of the distal esophagus, gastroesophageal junction or stomach, including patients with HER2 + disease
- Patients must have metastatic or unresectable disease, including those with HER2+
disease having received Herceptin (trastuzumab)
- Must have progressed on at least one line of prior therapy for metastatic disease
- ECOG performance status 0 or 1 - Presence of measurable disease per RECIST v1.1, assessed within 4 weeks prior to study entry
- Tumor deemed amenable to biopsy by core or endoscopic biopsy - Patient willing to undergo two newly-obtained biopsies - before and on-treatment, provided the procedure is not deemed high-risk and is clinically feasible Primary Outcome: To assess 6-month progression free survival (PFS)  
| LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  ADA Antidrug antibody ADL Activities of daily living AE Adverse event AHSCT Autologous hematopoietic stem cell transplant ALP Alkaline phosphatase ALT Alanine aminotransferase ANOVA Analysis of variance aPTT Activated partial thromboplastin time AST Aspartate aminotransferase BID Twice daily BMI Body mass index BSA Body surface area CBC Complete blood count CFR Code of Federal Regulations CI Confidence interval CMAX Maximum concentration of drug CNS Central nervous system CR Complete response CRF Case report/Record form CT Computed tomography CTCAE Common Terminology Criteria for Adverse Events CTLA-4 Cytotoxic T-lymphocyte-associated antigen-4 DC Dendritic cell DLCO Diffuse lung capacity for carbon monoxide DLT Dose Limiting Toxicity DSMB Data Safety Monitoring Board ECG Electrocardiogram ECOG Eastern Cooperative Oncology Group eCRF Electronic case report form EOT End of treatment ER Estrogen receptor FDA Food and Drug Administration FDG Fluorodeoxyglucose FIGO International Federation of Gynecology and Obstetrics FISH Fluorescence in situ hybridization GCP Good Clinical Practice GI Gastrointestinal GLP Good Laboratory Practices GU Genitourinary HBV Hepatitis B virus HCV Hepatitis C virus   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|  
  
  
| HER2        | Human epidermal growth factor receptor 2                    |
|-------------|-------------------------------------------------------------|
| Hgb         | Hemoglobin                                                  |
| HIPAA       | Health Insurance Portability and Accountability Act of 1996 |
| HIV         | Human Immunodeficiency Virus                                |
| HPF         | High-power field                                            |
| HPV         | Human papillomavirus                                        |
| HTN         | Hypertensions                                               |
| ICF         | Informed consent form                                       |
| ICH         | International Conference on Harmonisation                   |
| IDO1        | Indoleamine 2,3 dioxygenase-1                               |
| IEC         | Independent ethics committee                                |
| Ig          | Immunoglobulin                                              |
| IHC         | Immunohistochemistry                                        |
| IN          | Investigator Notification                                   |
| INR         | International normalized ratio                              |
| irAE        | Immune-related adverse event                                |
| IRB         | Institutional Review Board                                  |
| irRC        | Immune-related response criteria                            |
| ITT         | Intent to treat                                             |
| IV          | Intravenous                                                 |
| LFT         | Liver function (chemistry) test                             |
| LH          | Luteinizing hormone                                         |
| LLN         | Lower limit of normal                                       |
| MAOI        | Monoamine oxidase inhibitors                                |
| MedDRA      | Medical Dictionary for Regulatory Activities                |
| MRI         | Magnetic resonance imaging                                  |
| MTD         | Maximum tolerated dose                                      |
| NSAID       | Nonsteroidal anti-inflammatory drug                         |
| NSCLC       | Non-small cell lung cancer                                  |
| ORR         | Objective response rate                                     |
| OS          | Overall survival                                            |
| PAD         | Pharmacologically active dose                               |
| PD          | Pharmacodynamic or progressive disease                      |
| PD-1        | Programmed death receptor 1                                 |
| PD-L1       | Programmed death ligand 1                                   |
| PET         | Positron emission tomography                                |
| PFS         | Progression free survival                                   |
| PgR         | Progesterone receptor                                       |
| PK          | Pharmacokinetic                                             |
| PLT         | Platelet                                                    |
| PR          | Partial response                                            |
| PT          | Prothrombin time                                            |
| RECIST v1.1 | Response Evaluation Criteria In Solid Tumors Version 1.1    |
| RP2D        | Recommended Phase 2 dose                                    |  
  
  
| RR    | Response rate                                 |
|-------|-----------------------------------------------|
| SAE   | Serious adverse event                         |
| SD    | Stable disease                                |
| SNRI  | Serotonin/norepinephrine reuptake inhibitors  |
| SS    | Serotonin syndrome                            |
| SSRI  | Serotonin reuptake inhibitors                 |
| SUSAR | Suspected unexpected serious adverse reaction |
| Treg  | Regulatory T cell                             |
| TTP   | Time to progression                           |
| ULN   | Upper limit of normal                         |
| UNK   | Unknown                                       |
| WBC   | White blood cell                              |
| WHO   | World Health Organization                     |
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1. objectives

1.1. Primary Objective  
1.1.1. To assess 6-month progression free survival (PFS)
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1.2. secondary objectives

1.2.1. To evaluate objective response rate (RR) by RECIST v1.1 and irRC 1.2.2. To evaluate overall survival (OS) 1.2.3. To assess the safety and tolerability of epacadostat in combination with pembrolizumab by NCI CTCAE v5
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1.3. exploratory objectives

1.3.1. To determine the responder rate defined as the proportion of subjects with an increased ratio of CD8+ to Treg cells in on-treatment compared with pretreatment biopsies 1.3.2. To identify putative immunologic biomarkers of tumor response
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2. background 2.1. study disease

Gastroesophageal junction (GEJ) and gastric adenocarcinomas constitute a major health problem worldwide. Gastric cancer is the fourth most prevalent malignancy and the second leading cause of cancer death worldwide [2]. In the United States, an estimated 24,590 cases of gastric cancer will be diagnosed and 10,720 patients will die from this disease in 2015 [3]. Esophageal cancer is overall less common, but the incidence of adenocarcinoma of the esophagus, GEJ and gastric cardia has risen faster than any other malignancy in the last 25 years in the United States and other Western countries [4]. Although treatment for patients with unresectable or metastatic disease remains palliative, chemotherapy improves survival and quality of life when compared to best supportive care [5]. With standard treatment options, the progression free survival (PFS) for unresectable or metastatic disease is 4 to 6 months and median overall survival (OS) is 7 to 10 months. Recent trials in the second-line setting have shown median PFS is 2-3 months and  
  
 median OS is 3-5 months [6, 7]. Data are emerging to suggest a role for checkpoint modulators in GEJ/gastric cancers and include antibodies against PD-L1 (atezolizumab)[8] and CTLA-4 (tremelimumab) [9]. Most recently, the KEYNOTE-012 study (NCT01848834), a multicenter, open-label, study of intravenous pembrolizumab included a cohort of 39 patients with PD-L1 expressing advanced gastric cancer. The majority of patients received ≥ 2 prior therapies. The 6-month PFS was 26%; median PFS was 1.9 months. 6-month OS was 66%, median OS was 11.4 months. 22% of patients achieved a partial response (PR) and 14% achieved stable disease as measured by RECIST v1.1 and central review.[1]
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2.2. study agent/device/procedure

This is a Phase II study (IND \#133705) of Epacadostat (INCB024360) administered in combination with pembrolizumab (Keytruda®, MK-3475). Epacadostat represents a novel, potent, and selective inhibitor of the enzyme indoleamine 2,3 dioxygenase-1 (IDO-1) in both human tumor cells and human dendritic cells (DCs). Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of the immunoglobulin (Ig)G4/kappa isotype directed against programmed death receptor 1 (PD-1).
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2.2.1. pharmaceutical and therapeutic background

The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been known for decades.[10] Accumulating evidence shows a correlation between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term survival in many solid tumors.
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2.2.2. inhibition of pd-1 as

The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune control. The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy conditions, is to down-modulate unwanted or excessive immune responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig)  
  
 superfamily member related to CD28 and cytotoxic T-lymphocyte-associated antigen-4
(CTLA-4), which has been shown to negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2).[11, 12] The structure of murine PD-1 has been resolved. PD-1 and family members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade. The mechanism by which PD-1 down modulates T-cell responses is similar to but distinct from that of CTLA-4, as both molecules regulate an overlapping set of signaling proteins.[13, 14] PD-1 has been shown to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, Tregs, and natural killer cells.[15, 16] Expression has also been shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and DCs.[17] The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, including nonhematopoietic tissues as well as in various tumors.[13, 18-20] Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular region and contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low levels on various nonhematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted T-cell function in peripheral tissues.[13] Although healthy organs express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with melanoma.[21] This suggests that the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be considered as an attractive target for therapeutic intervention. Pembrolizumab, is a potent and highly selective humanized mAb of the IgG4/kappa isotype  
  
 designed to directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2.  
KeytrudaTM (Pembrolizumab) has recently been approved in the United Stated for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor.
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2.2.3. inhibition of indoleamine 23-dioxygenase

Recent interest has focused on the role of indoleamine 2,3–dioxygenase-1 (IDO-1) as a mechanism of induction of tolerance to malignancy.[22] IDO-1 is a heme-containing, monomeric oxidoreductase that catalyzes the degradation of the essential amino acid tryptophan to N-formyl-kynurenine. Kynurenine can be subsequently metabolized through a series of enzymatic steps to nicotinamide adenine dinucleotide. IDO-1 is the first rate-limiting enzyme in one of the breakdown pathways of tryptophan. In another pathway, tryptophan hydroxylase catalysis of tryptophan leads to the formation of serotonin and melatonin. The expression and activity profiles of IDO-1 are distinct from those of tryptophan dioxygenase, an enzyme predominantly expressed in liver that catalyzes the same enzymatic reaction as IDO-1 and maintains proper tryptophan balance in response to dietary uptake. In contrast to tryptophan dioxygenase, IDO-1 is expressed in a variety of tissues, with particularly high levels found in areas of contact with potential sources of immune challenge (e.g., gut, respiratory tract, placenta, spleen), consistent with a role for regulating tryptophan metabolism in a local microenvironment.[23] Within the immune system, IDO-1 activity is specifically induced in cells such as DCs and macrophages at localized sites of inflammation.[24] IDO-1 driven oxidation of tryptophan results in a strong inhibitory effect on the development of T-cell mediated responses by blocking T-cell activation and inducing T-cell apoptosis.[25] Both the reduction in local tryptophan levels and the production of tryptophan catabolites that are inhibitory to cell proliferation contribute to the immunosuppressive effects.[26] IDO-1 activity also promotes the differentiation of naïve T-cells to cells with a regulatory phenotype (Treg).[27] Since increased Treg activity has been shown to promote tumor growth and Treg depletion has been shown to allow an otherwise ineffectual antitumor immune response to occur[28]. IDO-1 expansion of Tregs may provide an additional mechanism whereby IDO-1 could promote an  
  
  
 immunosuppressive environment. The biological relevance of IDO-1 inhibition to immune tolerance was first demonstrated when it was shown that treating mice with a small molecule inhibitor of the IDO-1 pathway, 1-methyltryptophan, could break the tolerogenic state that protects allogeneic concept from the maternal immune system.[29] A critical role for IDO-1 in immunomodulation has been confirmed in numerous animal models, including models of allograft tolerance, inflammation, and cancer.[23] While IDO-1 inhibition can exacerbate disease in models of autoimmune disorders[23], IDO-1 null mice show no evidence of susceptibility to developing spontaneous autoimmunity or alterations in immune system development[25], suggesting that IDO-1 inhibition, in a therapeutic setting, may produce minimal side effects in subjects without pre-existing autoimmune conditions. Within the context of cancer, there are several lines of evidence to suggest that IDO-1 is a key regulator of the immunosuppressive mechanisms responsible for tumor escape from immune surveillance. Several groups have demonstrated that blockade of IDO-1 activity can directly influence the ability of tumor-bearing animals to reject tumors.[30, 31] In addition, studies with 1-methyl-tryptophan, demonstrate that IDO-1 inhibition dramatically increases the efficacy of various chemotherapeutic agents (e.g., platinum compounds, taxane derivatives, cyclophosphamide) without increased toxicity.[31] Although the specific mechanisms responsible for this potentiation remain to be fully elucidated, the effects were not observed in T- cell deficient animals, suggesting that the results may be the consequence of the disablement of immunosuppressive mechanisms that exist within the tumor microenvironment. Based on studies examining serum levels of tryptophan and kynurenine, IDO-1 appears to be chronically activated in subjects with cancer, and IDO-1 activation correlates with more extensive disease.[32, 33] IDO-1 has subsequently been found to be overexpressed by a wide variety of human tumor cell types as well as by the DCs that localize to the tumor draining lymph nodes.[30, 34] Increased expression of IDO-1 in tumor cells has been shown to be an independent prognostic variable for reduced overall survival (OS) in subjects with melanoma, ovarian, colorectal, and pancreatic cancers.[35-40] Together, these results suggest that the IDO-1 pathway is a key regulatory element responsible  
  
 for the induction and maintenance of tumor immune tolerance. Small molecule inhibitors of IDO-1 may provide an innovative and tractable method to treat advanced malignancies either alone or in combination with chemotherapeutics and/or immunotherapy-based strategies.
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2.2.4. combined immune checkpoint inhibition

Blockade of immune inhibitory pathways is emerging as an important therapeutic modality for the treatment of cancer as evidenced by the clinical responses observed with antibodies to CTLA-4 and PD-1/PD-L1. Ipilimumab, a fully human, IgG1 mAb blocking CTLA-4, improved OS in patients with advanced melanoma.[41, 42] Nivolumab, a fully human IgG4 antibody blocking PD-1, produced durable objective responses in patients with melanoma, renal cell cancer, and non-small cell lung cancer (NSCLC).[43-45] Although these single agents have antitumor activity, multiple immune inhibitory mechanisms are present concurrently within the tumor microenvironment, suggesting that combination therapies may be required for optimal therapeutic effect.[46] For example, CTLA-4 and PD-1 appear to play complementary roles in regulating adaptive immunity. Whereas PD-1 contributes to T-cell exhaustion in peripheral tissues, CTLA-4 inhibits at earlier points in T-cell activation. In preclinical models, combined blockade of PD-1 and CTLA-4 achieved more pronounced antitumor activity than blockade of either pathway alone.[47, 48] On the basis of these observations, a Phase 1 study was conducted to investigate the safety and efficacy of combined CTLA-4 and PD-1 blockade (with the use of ipilimumab and nivolumab, respectively) in patients with advanced melanoma. The overall response rate (ORR) (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease [SD] for ≥ 24 weeks) was observed in 65% of subjects. In 17 subjects treated at the maximum doses that were associated with an acceptable level of adverse events (AE), 53% of subjects had an objective response compared with ipilimumab monotherapy (10.9%), all with tumor reduction of ≥ 80%. Grade 3 or 4 AEs related to therapy occurred in 53% of subjects in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among subjects in the sequenced-regimen group,  
  
 18% had Grade 3 or 4 AEs related to therapy and the ORR was 20%. Grade 3 or 4 AEs, regardless of attribution, were observed in 72% of subjects, and Grade 3 or 4 treatment-related AEs were noted in 53%. Serious adverse events (SAE) related to treatment were reported in 49% of patients in the concurrent regimen group. Common Grade 3 or 4 selected AEs that were related to the therapy included hepatic events (15%), gastrointestinal events (9%), and renal events (6%). Isolated cases of pneumonitis and uveitis were observed. In both regimen groups, treatment-related AEs were manageable and generally reversible with the use of immunosuppressants (or hormone-replacement therapy for endocrinopathies) according to previously established algorithms.[49] As described above, IDO-1 is another negative regulatory mechanism that contributes to tumor-derived immune suppression. In preclinical models, IDO-1 inhibition has been shown to synergize with blockade of either anti−CTLA-4 or anti−PD-1/PD-L1 in delaying tumor growth and increasing OS.[50, 51] This effect was shown to be T-cell dependent, leading to enhanced T-cell proliferation and interleukin-2 production within the tumor and to a marked increase in the effector-to-regulatory T-cell ratios in the tumors. The IDO-1 inhibitor epacadostat has completed a Phase 1 study and has several ongoing Phase 1 and Phase 2 studies in combination with immune-targeted agents, such as anti–PD-1, anti– PD-L1, and anti–CTLA-4 antibodies. In an ongoing study combining epacadostat and ipilimumab (INCB 24360-201) subjects received ipilimumab (3 mg/kg IV every 3 weeks x 4) with epacadostat at doses of 25 mg BID, 50 mg BID continuous, 50 mg BID intermittent (2 weeks on, 1 week off), and 75 mg (50 mg morning/25 mg night). A total of 42 subjects were enrolled: 25 mg BID (n=8), 50 mg BID (continuous) (n=18), 50 mg BID (intermittent) (n=9), and 75 mg (n=7). DLTs were: 25 mg BID, Grade 3 increased AST (n=1); 50 mg BID (continuous), Grade 3 diarrhea (n=1), Grade 3 increased ALT/AST (n=2), Grade 3 colitis (n=1), and Grade 3 pneumonitis (n=1); 50 mg BID (intermittent), Grade 3 colitis (n=1); 75 mg, Grade 3 rash (n=1). The most common all grade irAEs were rash (52.4%), pruritus (16%), diarrhea (33.3%), increased ALT (21.4%), increased AST (16.7%), and hypothyroidism (11.9%). Grade ≥3 irAEs occurred in 40% of subjects. The most common Grade ≥ 3 irAEs were increased AST (9.5%), increased ALT (7.1%), and colitis (9.5%). Among 32 immunotherapy-naïve subjects, ORR was 31.3% (10/32) per irRC and 28.1% (9/32) per RECIST v1.1; complete response (CR)  
  
 rate per both criteria was 9.4%. At data cutoff (August 2015), responses were ongoing in 6 subjects. The disease control rate (DCR) (CR + partial response [PR] + stable disease [SD]) was 62.5% (20/32) per irRC and 53.1% (17/32) per RECIST v1.1. Median progression free survival (PFS) was 8.2 months by irRC and 5.3 months by RECIST v1.1. Among 10 subjects previously treated with immunotherapy, the DCR by both criteria was 30% by irRC and RECIST v1.1 (all SDs). In a recent Phase 1 study (INC 24360-202), safety, efficacy, and tolerability of the combination of pembrolizumab at a dose of 2 mg/kg IV every 3 weeks in combination with epacadostat at doses of 25 mg BID, 50 mg BID, 100 mg BID, and 300 mg BID and epacadostat 300 mg BID in combination with fixed dose of pembrolizumab 200 mg IV every 3 weeks in subjects with various solid tumors have been evaluated. A total of 61 subjects were enrolled as of October 2015. Preliminary safety data (unaudited) was evaluated for 56 out of 61 subjects: 25 mg BID (n=4), 50 mg BID (n=19), 100 mg BID (n=18), and 300 mg (n=15). The most common AEs (≥15%) any grade were rash, fatigue, nausea, cough, diarrhea, pyrexia, arthralgia, back pain, dyspnea and constipation; the majority of these were grade 1 or 2. Grade ≥3 irAEs were rash (n=3), AST increased (n=1) and bilirubin increased (n=1). Additional Grade ≥3 treatment-related AEs were mucosal inflammation, and neurologic event not otherwise specified (NOS) (n=1 each). The neurological event NOS, ataxia, was observed in a single subject, who had a history of brain metastases and prior radiotherapy, due to recurrent brain metastases. AEs were, in general, well-tolerated. The events of rashes observed at the 300 mg BID cohort were reversible with dose interruptions and medical treatment. The total dose interruptions were higher in the 300 mg BID group with 6/15 interrupting epacadostat due to AEs compared to 1 subject in 100 mg BID, 2 subjects in 50 mg BID and 1 subject in 25 mg BID. The safety profile for the 300mg bid dose of epacadostat in combination with pembrolizumab in the Phase I/II study (INCB24360-202) did not exceed the MTD in that study. While there was a higher incidence of grade 3 rash in the 300mg bid cohort compared to the 100mg bid cohort, these did not qualify as protocol-specified DLTs. The dose combination of 100mg bid epacadostat plus pembrolizumab for the Phase III melanoma study (INCB24360-301) is based upon a benefit/risk assessment made specifically in melanoma in collaboration with Merck. In the INCB24360-202 study, there was evidence of  
  
 improved efficacy in melanoma subjects at all doses of epacadostat of from 50 to 300mg bid.  
Given that melanoma is an immunotherapy responsive tumor, and lower doses of epacadostat appeared to have similar activity, the decision was made to take the 100mg bid dose combination forward because of the lower incidence of dose interruptions and dose reductions compared to the 300mg bid dose. However, in other tumor types, which appear to demonstrate more resistance to known immunotherapies, we believe that greater target coverage for inhibition of IDO1 may be necessary. The PK/PD modelling suggests that doses of 100mg bid epacadostat achieve an average IC50 at trough in most patients. At 300mg bid, epacadostat achieves target inhibition above the IC90 at trough. Greater target inhibition may be necessary in more resistant tumors, and potentially balances benefit/risk in favor of the higher epacadostat dose combination given that the dose does not exceed the MTD. We now have a larger dataset with respect to the 300 mg bid dose in combination with anti-PD-1 and anti-PD-L1 antibodies. 300 mg is tolerated, and we have seen an increase in the incidence of grade 3 rash. However, these have been manageable with dose interruptions and occasionally with steroids. Our current thinking is to maximize the dose of epacadostat at 300mg bid in nonmelanoma tumor types in order to achieve optimal target coverage. In summary, both IDO-1 and PD-1 have been shown to suppress T-cell mediated antitumor immunity, and IDO-1 and the PD-1 ligand PD-L1 have been shown to be coexpressed in multiple cancer types and to correlate with poor prognosis. Combined inhibition of both pathways may therefore lead to greater suppression of antitumor immunity and to increased efficacy.
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2.3. rationale

The goal of cancer immunotherapy is to initiate or reinitiate a self-sustaining cycle of cancer immunity, enabling it to amplify and propagate. Cancer immunotherapies must overcome the negative feedback mechanisms inherent in most cancers. The current approach will attempt to further amplify an immune response by targeting multiple nonredundant immune checkpoints. Expression of IDO-1 represents an early checkpoint that results in a diminished immune response and tolerance to tumor antigen. Data are emerging to suggest a role for checkpoint  
  
 modulators in GEJ/gastric cancers and we propose a single-institution, phase II, single-arm, nonrandomized study investigating epacadostat and pembrolizumab in advanced GEJ and gastric adenocarcinoma. An open-label Phase I trial (Protocol 001) is being conducted to evaluate the safety and clinical activity of single agent pembrolizumab. The dose escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks in subjects with advanced solid tumors. All three dose levels were well tolerated and no dose-limiting toxicities were observed. This first in human study of pembrolizumab showed evidence of target engagement and objective evidence of tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg every 2 weeks). No maximum tolerated dose (MTD) has been identified to date. Recent data from other clinical studies within the pembrolizumab program has shown that a lower dose of pembrolizumab and a less frequent schedule may be sufficient for target engagement and clinical activity. PK data analysis of pembrolizumab administered every 2 weeks and every 3 weeks showed slow systemic clearance, limited volume of distribution, and a long half-life (refer to IB). Pharmacodynamic (PD) data (IL-2 release assay) suggested that peripheral target engagement is durable (>21 days). This early pharmacokinetic (PK) and PD data provides scientific rationale for testing an every 2 week and every 3 week dosing schedule. A population PK analysis has been performed using serum concentration time data from 476 patients. Within the resulting population PK model, clearance and volume parameters of pembrolizumab were found to be dependent on body weight. The relationship between clearance and body weight, with an allometric exponent of 0.59, is within the range observed for other antibodies and would support both body weight normalized dosing or a fixed dose across all body weights. Pembrolizumab has been found to have a wide therapeutic range based on the melanoma indication. The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg every 3 week body weight based regimen are anticipated to remain well within the established exposure margins of 0.5 - 5.0 for pembrolizumab in the melanoma indication. The exposure margins are based on the notion of similar efficacy and safety in melanoma at 10 mg/kg every 3 weeks vs. the proposed dose regimen of 2 mg/kg every 3 weeks (i.e., 5-fold higher dose and exposure). The population PK evaluation revealed that there was no significant impact of  
  
 tumor burden on exposure. In addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there are no anticipated changes in exposure between different indication settings. The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid tumors is based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg every 3 weeks in melanoma patients, 2) the flat exposure-response relationships of pembrolizumab for both efficacy and safety in the dose ranges of 2 mg/kg every 3 weeks to 10 mg/kg every 3 weeks, 3) the lack of effect of tumor burden or indication on distribution behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption that the dynamics of pembrolizumab target engagement will not vary meaningfully with tumor type. The choice of the 200 mg every 3 weeks as an appropriate dose for the switch to fixed dosing is based on simulations performed using the population PK model of pembrolizumab showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will maintain individual patient exposures in the exposure range established in melanoma as associated with maximal efficacy response, and 3) will maintain individual patients exposure in the exposure range established in melanoma that are well tolerated and safe. A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to reduce potential for dosing errors. A fixed dosing scheme will also reduce complexity in the logistical chain at treatment facilities and reduce wastage.
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2.3.1. rationale for studying immunotherapy

Cancer immunotherapies have recently have been approved by the United States Food and Drug Administration (FDA) in several tumor indications to date, such as melanoma and NSCLC. The efficacy of pembrolizumab was investigated in a multicenter, open-label, randomized (1:1), dose study in subjects with unresectable or metastatic melanoma with progression of disease; refractory to 2 or more doses of ipilimumab (3 mg/kg or higher) and, if BRAF V600 mutationpositive, a BRAF or MEK inhibitor; and disease progression within 24 weeks following the last  
  
 dose of ipilimumab. There were 173 subjects enrolled and the ORR was 24%, with 8 subjects with ongoing responses of 6 months or longer. There were also objective responses in subjects with and without BRAF V600 mutation-positive melanoma (Pembrolizumab package insert, 6/2015). Similarly, nivolumab demonstrated activity when given alone in subjects with progression of disease on or following ipilimumab treatment and, if BRAF V600 mutationpositive, a BRAF inhibitor. The study enrolled 120 subjects and the ORR was 32%, with 13 subjects with ongoing responses of 6 months or longer. There were also objective responses in subjects with and without BRAF V600 mutation-positive melanoma (Nivolumab package insert, 3/2105). More recently, nivolumab was tested in previously untreated melanoma without BRAF mutation, which similarly showed good response rates and improvement in OS when compared to dacarbazine. At 1 year, the overall rate of survival was 72.9% (95% confidence interval [CI], 65.5 to 78.9) in the nivolumab group, as compared with 42.1% (95% CI, 33.0 to 50.9) in the dacarbazine group (hazard ratio for death, 0.42; 99.79% CI, 0.25 to 0.73; p < 0.001). The ORR was 40.0% (95% CI, 33.3 to 47.0) in the nivolumab group versus 13.9% (95% CI, 9.5 to 19.4) in the dacarbazine group (odds ratio, 4.06; p < 0.001).[53] Nivolumab was also recently approved as a single agent for the treatment of subjects with metastatic squamous NSCLC with progression on or after platinum-based chemotherapy based on demonstration of superior overall survival versus docetaxel, with 41% reduction in risk of death in a prespecified interim analysis of a Phase 3 clinical study. The median OS was 9.2 months in the nivolumab group and 6 months in the docetaxel group. First-line data in advanced or metastatic melanoma with pembrolizumab versus ipilimumab was recently presently at the annual meeting of the American Association for Cancer Research (AACR), with an estimated 46.4% 6-month PFS rate for pembrolizumab 2 mg/kg every 3 weeks versus 26.5% for ipilimumab. The ORR was 32.9% for pembrolizumab 2 mg/kg every 3 weeks versus 11.9% for ipilimumab. Responses were ongoing in 96.7% of subjects after a median follow-up of 7.9 months.[54] Median PFS was 4.1 months for pembrolizumab versus 2.8 months for ipilimumab. The hazard ratio for the disease progression for pembrolizumab every 3 weeks versus ipilimumab was 0.58 (95% CI, 0.47 to 0.72; p < 0.001). At the time of the data cutoff for the second interim analysis in this study, which was driven by a minimum follow-up duration of 12 months for all subjects, 289 deaths occurred. One-year estimates of survival for  
  
 subjects receiving pembrolizumab every 3 weeks was 68.4% as compared with ipilimumab 58.2% (hazard ratio for death as compared with ipilimumab group 0.69; 95% CI, 0.52 to 0.90; p
= 0.0036). Because the OS results were superior to those for the ipilimumab group, the independent Data Monitoring Committee (DMC) recommended stopping the study early to allow subjects in the ipilimumab group the option of receiving pembrolizumab.[54] In 38 subjects with previously treated advanced NSCLC treated with pembrolizumab at a dose of 10 mg/kg every 3 weeks, an ORR of 24% as measured by the irRC was observed,[45] with similar results using RECIST v1.1 (21%). Most responses were observed by the first planned assessment at week 9. Median duration of response by irRC has not been reached with a median duration of follow-up of 62 weeks. The median OS for all 38 subjects treated with pembrolizumab was 51 weeks. An immunohistochemistry (IHC) assay was used to evaluate PD-L1 expression in subject's baseline tumor biopsies. A modified H-score scoring system of PD-L1 expression was established for NSCLC by analyzing tumor specimens from resected NSCLC specimens. This scoring system was then applied to the samples from this portion of the study. Pretreatment tumor PD-L1 expression was a statistically significant predictor of response. In subjects with evaluable tumor PD-L1 expression, the majority of confirmed responses by RECIST v1.1 (and irRC) occurred in subjects with tumors strongly positive for PD-L1. A total of 35 subjects from this study had evaluable tumor samples and a clinical response assessed. Seven of the 35 subjects had a clinical response (20%) by investigator-assessed irRC. Six responders (26%) were observed among the 23 subjects whose tumors expressed PD-L1. Of note, these 6 responders clustered at the higher end of the modified H-score. Six of 9 subjects (67%) whose tumors expressed PD-L1 to an extent above the preliminary cut point had a clinical response. Only 1 response was noted among the 12 subjects whose tumors did not express PD-L1. A training set comprising approximately 140 tumor samples and their associated clinical outcome data were used to assess an optimal cut point for PD-L1 positivity. An optimal PD-L1 cut point was identified by receiver operator characteristic curve analyses and by considering clinical implications of false-positive and false-negative results. Cut points were identified based on a proportions score method of IHC analysis, with the tumors expressing at or greater than the highest cut point (proportions score ≥ 50%) referred to as PD-L1 strong tumors, and tumors  
  
 expressing > 1% but < 50% referred to as the PD-L1 weak tumors. Outcomes based in irRC were used as the primary outcome for the analysis. Based on the training set, the positive predictive value for subjects in the strong category was 42%, while maintaining a negative predictive value of 92% for subjects in the weak or null category.[55] This study completed, and a total of 495 subjects received pembrolizumab either 2 mg/kg every 2 weeks or 10 mg/kg every 3 weeks or 10 mg/kg every 2 weeks, and 182 subjects were assigned to the training group or a validation group (313 subjects). Among all subjects, the ORR was 19.4%, and the median duration of response was 12.5 months. The median duration of PFS was 3.7 months, and the median duration of OS
was 12.0 months. PD-L1 expression in at least 50% of tumor cells was selected as the cutoff from the training group. Among subjects with a proportion score of at least 50% in the validation group, the response rate was 45.2%. Among all subjects with a proportion score of at least 50%, median PFS was 6.3 months; median OS was not reached. In summary, pembrolizumab had an acceptable side-effect profile and showed antitumor activity in subjects with advanced NSCLC. PD-L1 expression in at least 50% of tumor cells correlated with improved efficacy of pembrolizumab.[56] Data are emerging to suggest a role for checkpoint modulators in GEJ/gastric cancers and include antibodies against PD-L1 (atezolizumab)[8] and CTLA-4 (tremelimumab).[9] In an open-label, Phase 1b study, the safety, tolerability, and antitumor activity of pembrolizumab were assessed in subjects with advanced solid tumors in the KEYNOTE-012 study (Clinicaltrials.gov: NCT01848834). In this study a cohort of 39 patients with PD-L1 expressing advanced gastric cancer, 22% of patients achieved a partial response (PR) and 14% achieved stable disease as measured by RECIST v1.1 and central review.[57] Targeting PD-1 assumes that the T-cells are essentially exhausted (and thus tolerant of the tumor) and that this exhaustion may be reversed by blocking PD-1 signaling. Targeting IDO-1 will concurrently decrease infiltration of regulatory CD4+ cells and immune-suppressive cytokines. This novel combination strategy has strong biologic rationale and may augment and deepen response rates over and above that demonstrated with single agent PD-1 blockade. Thus, there is a strong rationale for therapies aimed at restoring antitumor immunocompetence and establishing a rationale for inhibiting IDO-1 and the PD-1/PD-L1 pathways. In summary, both IDO-1 and PD-1 have been shown to suppress T-cell mediated antitumor  
  
 immunity, and IDO-1 and the PD-1 ligand PD-L1 have been shown to be coexpressed in multiple cancer types and to correlate with poor prognosis. Combined inhibition of both pathways may therefore lead to greater suppression of antitumor immunity and to increased efficacy.
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2.4. study design

This is a single institution, non-randomized, single arm, open-label study for the doublet epacadostat and pembrolizumab. The primary purpose of this protocol is treatment, designed to evaluate one or more interventions for treating a disease, syndrome or condition.
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2.5. correlative studies background and

Blood and tissue will be collected for future correlative studies and stored at Stanford. For further information, see Section 9.0 o Blood: Plasma, and PBMC will be collected every three weeks for correlative studies.  
o Tissue: Pre and on-treatment (day 42 ± 5 days) tissue biopsies will be collected for correlative studies.
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3. participant selection and enrollment

For entry into the study, the following criteria must be met. Please refer to Appendix A for the eligibility and verification checklist to assist with patient enrollment.
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3.1. subject population

Subjects with metastatic or recurrent distal esophageal (within 5 cm of the GEJ), GEJ, or gastric adenocarcinoma who have had disease progression on at least one prior therapy or be intolerant to that therapy if they have not progressed. If the patient is HER2 + they must have received Herceptin (trastuzumab). At Stanford Cancer Institute (SCI) there will be 30 patients enrolled over the recruitment period.
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3.2. inclusion criteria

In order to be eligible for participation in this study, the subject must meet all of the following:
study 3.2.1. Age ≥ 18 years of age on day of signing informed consent.  
  
 3.2.2. Be willing and able to provide written informed consent/assent for the 3.2.3. Histologically or cytologically confirmed adenocarcinoma of the distal esophagus, gastroesophageal junction or stomach, including patients with HER2+ disease. Distal esophagus is defined as within 5 centimeters of the GEJ.  
3.2.4. Patients must have metastatic or unresectable disease, including those with HER2+ disease. to study entry.  
3.2.5. Must have progressed on at least one line of prior therapy for metastatic disease, or be intolerant to that therapy if they have not progressed, and for HER2+ disease should have received prior trastuzumab.  
3.2.6. Life expectancy ≥ 12 weeks 3.2.7. Have a performance status of 0 or 1 on the ECOG Performance Scale. 3.2.8. Have measurable disease per RECIST v1.1, assessed within 4 weeks prior 3.2.9. Tumor deemed amenable to biopsy by core for metastatic site or endoscopic biopsy for primary tumor (for both before and on-treatment biopsies).  
3.2.10. Patient must be willing to undergo two biopsies - before and on-treatment, provided the procedure is not deemed high-risk and is clinically feasible.  
3.2.11. Demonstrate adequate organ function as defined in **Table 1**, all screening labs should be performed within 7 days of treatment initiation.  
| System                                        | Laboratory Value                                                                            |
|-----------------------------------------------|---------------------------------------------------------------------------------------------|
| Hematological Absolute neutrophil count (ANC) | ≥1,500 /mcL                                                                                 |
| Platelets                                     | ≥100,000 / mcL                                                                              |
| Hemoglobin                                    | ≥9 g/dL or ≥5.6 mmol/L without transfusion or EPO  dependency (within 7 days of assessment) |
| Renal Serum creatinine OR                     | ≤1.5 X upper limit of normal (ULN) OR                                                       |
| Measured or calculateda creatinine            |                                                                                             |
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table 1 adequate organ function

| clearance (GFR can also be used in place of  creatinine or CrCl)                                                     | ≥60 mL/min for subject with creatinine levels > 1.5  X institutional ULN                                                                          |
|----------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------|
| Hepatic                                                                                                              | ≤ 1.5 X ULN OR                                                                                                                                    |
| Total bilirubin                                                                                                      | Direct bilirubin ≤ ULN for subjects with total  bilirubin levels > 1.5 ULN                                                                        |
| AST (SGOT) and ALT (SGPT)                                                                                            | ≤ 2.5 X ULN OR ≤ 5 X ULN for subjects with liver metastases                                                                                       |
| Albumin                                                                                                              | >2.5 mg/dL                                                                                                                                        |
| Coagulation                                                                                                          | ≤1.5 X ULN unless subject is receiving  anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants  |
| International Normalized Ratio (INR) or Prothrombin Time (PT)                                                        | ≤1.5 X ULN unless subject is receiving  anticoagulant therapy as long as PT or PTT is within therapeutic range of  intended use of anticoagulants |
| Activated Partial Thromboplastin  Time (aPTT) aCreatinine clearance should be calculated per institutional standard. |                                                                                                                                                   |  
  
  
  
  
will be required.  
3.2.12. Female subject of childbearing potential should have a negative urine or  
  
  
serum pregnancy within 3 days prior to receiving the first dose of study medication.  
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 3.2.13. Female subjects of childbearing potential must be willing to use an adequate method of contraception starting with the date of consent through 120 days after the last dose of study medication. *Note: Abstinence is acceptable if this is the* usual lifestyle and preferred contraception for the subject.  
3.2.14. Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the date of consent through 120 days after the last dose of study therapy. *Note: Abstinence is acceptable if this is the usual lifestyle* and preferred contraception for the subject.  
3.2.15. Must be able to swallow pills.
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3.3. exclusion criteria

The subject must be excluded from participating in the study if the subject:
of their excipients.  
3.3.1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first planned dose of treatment.  
3.3.2. Has known hypersensitivity to pembrolizumab and/or Epacadostat or any 3.3.3. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or to baseline) from adverse events due to agents administered more than 4 weeks earlier. Note that denosumab for treatment for bone metastases is allowed.  
3.3.4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ Grade 1 or to baseline) from adverse events due to a previously administered agent.  
- *Note:* Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study.  
- *Note:* If subject received major surgery, they must have recovered adequately  
  
  
from surgery prior to starting therapy.  
3.3.5. Have been treated on any Merck-sponsored pembrolizumab-containing gastric cancer pivotal trial will require prior authorization by Merck in order to enroll in this study. pneumonitis 3.3.6. Has had prior therapy with IDO-inhibitors 3.3.7. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.  
3.3.8. Has known history of, or any evidence of active, non-infectious therapy.  
3.3.9. Has received a live vaccine within 30 days of planned start of study Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are *live attenuated vaccines, and are not allowed.*
3.3.10. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Patient with prior CNS metastases treated w/ prior RT will also need all of the following: A. 2 months off RT before starting study or 4 weeks following XRT if MRI is stable and the patient is off steroids, B. Baseline MRI with no edema, and C. stable for at least 8 weeks.  
3.3.11. Has known additional malignancy that has progressed or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially  
  
 curative therapy.  
3.3.12. Has active infection requiring systemic therapy 3.3.13. Has a known history of active TB (Bacillus Tuberculosis) 3.3.14. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g.,
HCV RNA [qualitative] detected)
3.3.15. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study medication antibodies)
3.3.16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 3.3.17. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with pre-screening or screening visit through 120 days after the last dose of study treatment 3.3.18. Has had monoamine oxidase inhibitors within 21 days before screening 3.3.19. Has any history of serotonin syndrome after receiving 1 or more serotonergic drugs absorption 3.3.20. Has presence of a gastrointestinal condition that may affect drug 3.3.21. Use of systemic corticosteroids 3.3.22. Has history or presence of an abnormal electrocardiogram (ECG) which, in the investigator's opinion, is clinically significant.  
- QTcF > 480 ms or presence of a Left Bundle Branch Block (LBBB). If the QRS
duration > 120ms, the JTc can be used in place of the QTcF. The JTc must be < 340 ms.  
3.3.23. Has history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.  
3.3.24. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study.  
3.3.25. Has known allergy or reaction to any component of either study drug or  
  
  
  
formulation components.
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3.4. informed consent process

All participants must be provided a consent form describing the study with sufficient information for participants to make an informed decision regarding their participation. Participants must sign the IRB approved informed consent prior to participation in any study specific procedure. The participant must receive a copy of the signed and dated consent document. The original signed copy of the consent document must be retained in the medical record or research file. The granting of informed consent must be documented in writing, using an ICF that contains all the elements required by ICH E6 and describes the nature, scope, and possible consequences of the study in a form understandable to the study subject. Subjects of childbearing potential must agree to take appropriate measures to avoid pregnancy in order to participate in the study.
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3.5. randomization procedures

This is an open-label single-arm study, therefore, the investigator and subject will know the treatment administered and there is no randomization.
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3.6. study timeline 3.6.1. primary

The study is expected to reach its accrual goal within 18 months from the time enrollment begins. Patients are anticipated to stay on treatment for 6 months. Thus, primary completion will take approximating 6 months from date of last patient enrolled. Upon completion of the last patient's last treatment, all patients will remain in long-term follow-up for evaluation of survival.  
3.6.2. **Study Completion**
Patients will be followed for progression and survival. Estimated study completion is approximately 4 years from when study opens.
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4. treatment plan 4.1. study

The schedule of events calendar (Section 9) summarizes the study procedures to be performed at each visit. Individual study procedures are described in detail below. It may be necessary to  
  
 perform these procedures at unscheduled time points if deemed clinically necessary by the investigator. Furthermore, additional evaluations/testing may be deemed necessary by the investigator and/or Merck and Incyte for reasons related to subject safety. In some cases, such evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional informed consent be obtained from the subject. In these cases, such evaluations/testing will be performed in accordance with those regulations.
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4.2. duration of treatment and

Each subject enrolled in the study will continue receiving combination study treatment in continuous 21-day cycles for up to 24 months, and then treatment with monotherapy epacadostat may continue as long as the subject is receiving benefit from treatment and has not had disease progression or met any criteria for study withdrawal. If the subject discontinues all study treatment, the treatment phase will end, and the subject will enter the follow-up phase. Study participation is expected to average about 6 months.
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4.3. screening phase 4.3.1. informed

The screening phase will be up to 28 days. Screening is the interval between the signing of the informed consent document and the day the subject receives the first dose of treatment on the study (Cycle 1 Day 1). Informed consent must be obtained before performing any study-specific procedures. Assessments that are required to demonstrate eligibility may be performed over the course of 1 or more days during this phase.
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4.3.2. general informed consent

Consent must be documented by the subject's dated signature or by the subject's legally acceptable representative's dated signature on a consent form along with the dated signature of the person conducting the consent discussion. A copy of the signed and dated consent form should be given to the subject before participation in the study. The initial informed consent form, any subsequent revised written informed consent form and  
  
 any written information provided to the subject must receive the IRB/ERC's approval/favorable opinion in advance of use. The subject or his/her legally acceptable representative should be informed in a timely manner if new information becomes available that may be relevant to the subject's willingness to continue participation in the study. The communication of this information will be provided and documented via a revised consent form or addendum to the original consent form that captures the subject's dated signature or by the subject's legally authorized representative's dated signature. Specifics about a study and the study population will be added to the consent form template at the protocol level. The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations.  
4.3.3. **Inclusion/Exclusion Criteria**
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure that the subject qualifies for the study prior to starting them on the study. Results from the screening visit evaluations will be reviewed to confirm subject eligibility before enrollment or the administration of study drug. Tests with results that fail eligibility requirements may be repeated once during the screening phase if the investigator believes the results to be in error. Additionally, a subject who fails screening may repeat the screening process 1 time if the investigator believes there has been a change in eligibility status (e.g., after recovery from an infection).
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4.3.4. demographics and medical history

Demographic data and a complete medical and medication history will be collected at screening by the investigator or qualified designee and will include date of birth, race, ethnicity, medical and surgical history, and concurrent illnesses assessed using the NCI CTCAE v5. Medical history should include all active conditions, and any condition diagnosed within the prior 10 years that are considered to be clinically significant by the investigator. Details regarding the disease for which the subject has enrolled in this study (e.g., date of diagnosis, primary tumor histology, prior systemic therapies, surgeries, radiation therapy, and stage of cancer) will be recorded separately and not listed in medical history.
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4.3.5. prior medications

The investigator or qualified designee will review prior medication use, including any Protocol-  
 specified washout requirement, and record prior medication taken by the subject within 28 days before starting the study. Treatment for the disease for which the subject has enrolled in this study will be recorded separately and not listed as a prior medication.
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4.3.6. concomitant medications

The investigator or qualified designee will record medication, if any, taken by the subject during the study. Concomitant medications include any prescription, over-the-counter, or natural/herbal preparations taken or administered during the study period. All medications related to reportable SAEs and AEs should be recorded. All clinical, efficacy and laboratory procedures and assessments that will be administered at screening phase and treatment cycles are listed below.
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4.3.7. disease details and treatments

The investigator or qualified designee will obtain prior and current details regarding disease status.
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4.3.7.2. prior treatment details

The investigator or qualified designee will review all prior cancer treatments including systemic treatments, radiation therapy, and surgeries.
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4.3.7.3. subsequent anti-cancer therapy status

The investigator or qualified designee will review all new anti-neoplastic therapy initiated after the last dose of study treatment. If a subject initiates a new anti-cancer therapy within 30 days after the last dose of study treatment, the 30-day Safety Follow-up visit must occur before the first dose of the new therapy. Once new anti-cancer therapy has been initiated, the subject will move into survival follow-up.
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4.4. treatment phase

The treatment period with the combination therapy will continue every 21 days for up to 24 months. Single agent epacadostat may continue indefinitely beyond 24 months provided the patient has benefit.
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4.4.1. administration of investigational products

Study treatment should be administered on day 1 of each cycle (21 day cycles) after all procedures/assessments have been completed as detailed in the schedule of events calendar. Study treatment may be administered up to 3 days before or after the originally scheduled day 1 of each cycle due to administrative reasons. All study treatments will be administered on an outpatient basis.
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4.4.2. treatment compliance

Treatment compliance with all study-related medications should be emphasized to the subject by the site personnel, and appropriate steps should be taken to optimize compliance during the study. Subjects will bring all bottles of unopened, empty, and unused epacadostat drug with them to each study visit. Investigative site staff will perform a count of returned tablets to assess compliance, and this information will be entered into the electronic case report form (eCRF).
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4.4.2.1. epacadostat (incb024360)

Site staff will dispense medication sufficient for a 3-week cycle (21 days). Subjects will be administered study drug at 300 mg oral, twice daily, continuous dosing. All twice daily doses of epacadostat will be taken orally in the morning and evening, approximately 12 hours apart without regard to food. If the morning or evening dose is missed by more than 4 hours, that dose should be skipped and the next scheduled dose should be taken at the usual scheduled time. Doses of epacadostat will be self-administered except on the day of the cycle that the patient is visiting the study clinic for infusion (Day 1 of each cycle); epacadostat will be taken prior to pembrolizumab infusion. Epacadostat compliance will be calculated based on the drug accountability documented and monitored by the site staff (tablet counts and pill diary). The objective is 100% compliance and investigators and their staff should evaluate compliance at each visit, and take appropriate steps to optimize compliance. If the subject falls below 85% compliance, based on 2 subsequent visits, then it will need to be addressed immediately, and could be means to remove the subject from  
  
 the study. Epacadostat will be given daily in combination with pembrolizumab every 3 weeks for up to 24 months provided subjects are receiving benefit from treatment and have not had disease progression or met any criteria for study withdrawal. Intrasubject escalation of epacadostat is not permitted. Single agent epacadostat may be continued beyond 24 months provided the patient has benefit. Subjects will receive treatment in continuous 21 day cycles; however, treatment may include temporary interruptions to allow for resolution of certain toxicities. Interruptions from the protocol-specified treatment plan for > 12 weeks between epacadostat and pembrolizumab doses due to toxicity require consultation between Merck/Incyte and the investigator and written documentation of the collaborative decision on subject management.
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4.4.2.2. pembrolizomab (mk-3475)

Pembrolizumab 200 mg will be administered as a 30-minute intravenous (IV) infusion every 3 weeks (± 3 days) and will make every effort to target infusion timing to be as close to 30 minutes as possible. However, given the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted (i.e., infusion time is 30 minutes -5 min/+10 min). Pembrolizumab may be administered through a peripheral line or indwelling catheter. Intrasubject dose escalation of pembrolizumab is not permitted. The total volume of study treatment infused will be compared to the total volume prepared to determine compliance with each dose administered. Whenever possible, the lowest infusion rate should be used that will allow completion of the infusion within 30 minutes. Maximum rate should not exceed 6.7 mL/min through a peripheral line or indwelling catheter, however when necessary to infuse a larger volume (i.e. 250 mL), the flow rate may go as high as 10 ml/min (maximum) in order to keep the infusion within the window as defined above. Use 30 mL normal saline to flush the infusion line at the end of the infusion. Do not co-administer other drugs through the same infusion line. See Appendix F which contains specific instructions for the preparation of the pembrolizumab  
  
 infusion fluid and administration of infusion solution.
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4.5. end of treatment

If a decision is made that the subject will permanently discontinue study drug, the end of treatment visit should be conducted approximately 30 days after the last dose of study medication. When a subject discontinues/withdraws prior to study completion, all applicable activities scheduled for the final study visit should be performed at the time of discontinuation. Any AEs which are present at the time of discontinuation/withdrawal should be followed in accordance with the safety requirements outlined in Section 7. Subjects who a) attain a CR or b) complete 24 months of treatment with pembrolizumab and epacadostat may discontinue treatment with the option of restarting treatment in the future if/when they meet the criteria specified in Section 4.8. After discontinuing treatment following assessment of CR, these subjects should return to the site for a Safety Follow-up Visit (described in Section 4.6.1) and then proceed to the Follow-Up Period of the study (described in Section 4.6.2).
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4.6. follow-up phase 4.6.1. safety

The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the last dose of study treatment or before the initiation of a new anti-cancer treatment, whichever comes first. All AEs that occur prior to the Safety Follow-Up Visit should be recorded. Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 or until the beginning of a new anti-neoplastic therapy, whichever occurs first. SAEs that occur within 30 days of the final dose on the study or before initiation of a new anti-cancer treatment should also be followed and recorded. Subjects who are eligible for retreatment with pembrolizumab (as described in Section 4.8) may have up to two safety follow-up visits, one after the Treatment Period and one after the Second Course Phase.  
4.6.2. Follow-Up **Period**
Subjects who discontinue study treatment for a reason other than disease progression will move into the Follow-Up Phase and should be assessed every 9 weeks (± 7 days) by radiologic imaging to monitor disease status. Every effort should be made to collect information regarding  
  
 disease status until the start of new anti-neoplastic therapy, disease progression, death, end of the study or if the subject begins retreatment with pembrolizumab as detailed in Section 4.8, Second Course Phase. Information regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria in Section 4.8, Second Course Phase (Retreatment Period), will move from the Follow-up Phase to the Second Course Phase when they experience disease progression.
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4.6.3. survival follow-up

Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the subject moves into the survival follow-up phase and should be contacted by telephone every 12 weeks (~ 3 months) to assess for survival status until death, withdrawal of consent, or the end of the study, whichever occurs first.
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4.7. unscheduled visits

Unscheduled study visits with the study team may occur at any time if medically warranted. Any assessments performed at those visits should be recorded in the eCRF.
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4.8. second course phase

Subjects who stop pembrolizumab and epacadostat with SD or better may be eligible for up to one year of additional pembrolizumab and epacadostat therapy if they progress after stopping study treatment. This retreatment is termed the Second Course Phase of this study and is only available if the study remains open and the subject meets the following conditions:
- **Either**
o Stopped initial treatment with pembrolizumab and epacadostat after attaining an investigator-determined confirmed CR according to RECIST 1.1, and
- Was treated for at least 24 weeks with pembrolizumab before discontinuing therapy.  
- Received at least two cycles of treatment with pembrolizumab and epacadostat beyond the date when the initial CR was declared. OR
o Had SD, PR or CR and stopped pembrolizumab and epacadostat treatment after 24  
  
  
  
months of study therapy for reasons other than disease progression or intolerability.
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and

- Experienced an investigator-determined confirmed radiographic disease progression after stopping their initial treatment with pembrolizumab
- Did not receive any anti-cancer treatment since the last dose of pembrolizumab
- Has an ECOG performance status of 0 or 1 - Demonstrates adequate organ function as defined by the eligibility criteria Section 3.3. - Female subject of childbearing potential should have a negative serum or urine pregnancy test within 3 days prior to receiving retreatment with study medication.  
- Female subject of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. Subjects of child bearing potential are those who have not been surgically sterilized or have been free from menses for > 1 year.  
- Male subject should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.  
- Does not have a history or current evidence of any condition, therapy, or laboratory abnormality that might interfere with the subject's participation for the full duration of the study or is not in the best interest of the subject to participate, in the opinion of the treating investigator.  
Subjects who restart treatment will be retreated at the same dose and dose interval as when they last received pembrolizumab and epacadostat. Treatment will be administered for up to one additional year. Visit requirements are outlined in Section 9, schedule of events calendar.
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4.9. study assessments and procedures

4.9.1. Safety Assessments 4.9.1.1. Adverse Events  
The investigator or qualified designee will assess each subject to evaluate for potential new or worsening AEs as specified in the schedule of events calendar and more frequently if clinically indicated. Adverse experiences will be graded and recorded throughout the study and during the follow-up period according to NCI CTCAE Version 5. Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, and action taken with regard to study treatment. Please refer to Section 7 for detailed information regarding the assessment and recording of AEs. Adverse events will be monitored from the time the subject begins treatment. Subjects will be instructed to report all AEs during the study and will be assessed for the occurrence of AEs throughout the study. In order to avoid bias in eliciting AEs, subjects will be asked general, nonleading questions such as "How are you feeling?" All AEs (serious and nonserious) must be recorded on the source documents and eCRFs regardless of the assumption of a causal relationship with the study drug. The definition, reporting, and recording requirements for AEs are described in Section 7. All AEs of unknown etiology associated with epacadostat and pembrolizumab exposure should be evaluated to determine if it is possibly an AE of a potentially immunologic etiology. See Section 7 regarding the identification, evaluation, and management of AEs of potential immunological etiology. Events of clinical interest (ECI) identified after signing consent through 100 days following cessation of treatment, regardless of initiation of new anticancer therapy, must be reported to Merck and Incyte within 10 days of the event. Subjects should be assessed for possible ECIs prior to each dose. Laboratory results should be evaluated and subjects should be asked for signs and symptoms suggestive of an irAE. Subjects who develop an ECI thought to be immune-related should have additional testing to rule out other etiologic causes. If laboratory results or symptoms indicate a possible immune-related ECI, then additional testing should be performed to rule out other etiologic causes. If no other  
  
 cause is found, then it is assumed to be immune-related.
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4.9.1.2. comprehensive physical examination

The investigator or qualified designee will perform a complete physical exam during the screening period. Clinically significant abnormal findings should be recorded as medical history. A full physical exam should be performed during screening, The comprehensive physical examination will include the following organ or body system assessments: skin, head, eyes, ears, nose, and throat, thyroid, lungs, cardiovascular system, abdomen (liver, spleen), extremities, lymph nodes, and a brief neurological examination. Before the first dose of study treatment, clinically significant abnormal findings should be recorded as medical history. After the first dose of study treatment, new clinically significant abnormal findings should be recorded as AEs.
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4.9.1.3. targeted physical examination

For cycles that do not require a full physical examination per the schedules of assessments, the investigator or qualified designee will perform a directed physical examination as clinically indicated before study treatment administration. A targeted physical examination will be a symptom-directed evaluation conducted by the investigator or designee. The targeted physical examination will include assessment(s) of the body systems or organs, as indicated by subject symptoms, AEs, or other findings. New clinically significant abnormal findings should be recorded as AEs.
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4.9.1.4. vital signs

The investigator or qualified designee will take vital signs at screening, prior to the administration of each dose of pembrolizumab treatment, and at treatment discontinuation as specified in the schedule of events calendar (Section 9). Vital signs should include temperature, pulse, respiratory rate, weight and blood pressure. Height will be collected at Cycle 1 Day 1 only.
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4.9.1.5. twelve-lead electrocardiograms (ecgs)

Baseline ECG will be obtained during screening period prior to the first dose of epacadostat. Subsequent ECGs will be obtained as clinically indicated and at EOT. Clinically significant abnormal findings prior to beginning therapy should be recorded as medical history. Clinically  
  
  
 significant abnormal findings after beginning therapy or changes from baseline should be recorded as AEs.  
The 12-lead ECG will be interpreted by the investigator at the site and will be used for immediate subject management. The decision to include or exclude a subject or withdraw a subject from the study based on an ECG flagged as "Abnormal, Clinically Significant" is the responsibility of the investigator, as appropriate. The correction method (Fredericia or Bazett) used for calculating QTc will need to be provided in the eCRF.
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4.9.1.6. laboratory assessments

Details regarding specific laboratory procedures/assessments to be performed in this study are provided below (hematology, chemistry and urinalysis). Laboratory tests should be conducted up to 2 days prior to dosing. If laboratory tests at screening are done within 7 days of Cycle 1 Day 1 they do not need to be repeated at that visit. Results must be reviewed by the investigator or qualified designee and found to be acceptable prior to each dose of study treatment.
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hematology lipid panel coagulation panel

Hematology, lipid panel, coagulation panel, and endocrine function will all be analyzed by the site laboratory prior to beginning treatment. Any subjects on coumadin-based anticoagulants that need weekly INR monitoring for the first 4 weeks with initiation of treatment will perform the INR testing locally. These labs should be drawn as 12 hour fasting. See Table 2 for more details about specific tests that need to be collected.
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tumor tissue sample molecular testing

Tumor molecular profiling will be performed on archival or newly obtained tumor tissue. These tests can be historical or obtained during the course of the study.
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urinalysis

Urinalysis will be analyzed by the site laboratory. Serum Chemistry and Liver Function Tests  
  
 All serum chemistry testing (screening, Cycle 1 Day 1, and Day 1 of each cycle) will be performed fasting by the site's laboratory, as well as any additional LFT monitoring if it is required. Liver function test monitoring for persistent low-grade abnormalities does not need to be monitored twice a week indefinitely. Appropriate LFT monitoring intervals should be discussed with Merck and Incyte for these circumstances.
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pregnancy testing

Serum or urine pregnancy tests will be analyzed by the site laboratory during screening and must be within 3 days before first dose of study treatment. Subsequently, pregnancy tests will be conducted only as medically indicated. If a subject inadvertently becomes pregnant while on treatment with epacadostat and pembrolizumab, the subject will immediately be withdrawn from the study. The site will contact the subject at least monthly and document the subject's status until the first well-baby visit to determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. The outcome of the pregnancy will be reported without delay and within 24 hours if the outcome is an SAE (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication to the mother or newborn). The study investigator will make every effort to obtain permission to follow the outcome of the pregnancy and report the condition of the fetus or newborn. If a male subject impregnates his female partner, the study personnel at the site must be informed immediately and the pregnancy reported and followed as described above and in Section 7.  
| Hematology               | Chemistry                  | Urinalysis             | Other                                  |
|--------------------------|----------------------------|------------------------|----------------------------------------|
| Hematocrit               | Albumin                    | Blood                  | Serum β-human chorionic  gonadotropin† |
| Hemoglobin               | Alkaline phosphatase       | Glucose                | PT/INR                                 |
| Platelet count           | Alanine aminotransferase   | Protein                | aPTT                                   |
| (ALT)                    |                            |                        |                                        |
| White Blood Cell Count   | Aspartate aminotransferase | Specific gravity       | Total triiodothyronine (T3) (if        |
| (total and differential) | (AST)                      | applicable)            |                                        |
| Red Blood Cell Count     | Lactate dehydrogenase      | Urine pregnancy test † | Free thyroxine (T4) (if                |  
| Hematology                                                                                                                                                                                                      | Chemistry                         | Urinalysis                  | Other   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------|-----------------------------|---------|
| (LDH)                                                                                                                                                                                                           | applicable)                       |                             |         |
| Absolute Neutrophil                                                                                                                                                                                             | Carbon Dioxide                    | Thyroid stimulating hormone |         |
| Count                                                                                                                                                                                                           | (TSH)                             |                             |         |
| (CO2 or bicarbonate)                                                                                                                                                                                            |                                   |                             |         |
| Absolute Lymphocyte                                                                                                                                                                                             | Blood for correlative studies and |                             |         |
| Count                                                                                                                                                                                                           | future research                   |                             |         |
| Uric Acid Calcium Chloride Glucose Phosphorus Potassium  Sodium Magnesium Total Bilirubin Direct Bilirubin (If total  bilirubin is elevated above  the upper limit of normal) Total protein Blood Urea Nitrogen |                                   |                             |         |
| † Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum  pregnancy test will be required.                                                        |                                   |                             |         |
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4.9.2. efficacy assessments - tumor

Initial tumor imaging must be performed within 28 days before the first planned dose of study treatment. The site study team must review pre-study images to confirm the subject has measurable disease per RECIST v1.1 for solid tumors and irRC. A standard, full assessment for lesions should be conducted at baseline, including CT or MRI scans of chest, abdomen, and pelvis for solid tumors. The same modality (CT and/or MRI) should be used for follow-up assessments every 9 weeks, including radiological assessments of all sites of disease present at baseline unless otherwise medically indicated. In addition to radiological monitoring, all other lesions observed at the screening visit should be followed. Baseline scan must be a contrast computed tomography (CT) with contrast of the chest/abdomen/pelvis, except in circumstances where there is a contrast allergy. Tumor imaging may be performed by CT and/or MRI, but investigator should do their best, as medically appropriate, to keep with the same imaging technique per subject throughout the study. Scans must be a contrast CT and/or MRI, except in circumstances where there is a  
  
 contrast allergy. Imaging should be performed every 9 weeks (± 7 days) or more frequently if clinically indicated. Imaging should not be delayed for delays in cycle starts or extension of combination treatment cycle intervals. Per irRC, response should be confirmed by a repeat radiographic assessment not less than 4 weeks from the date the response was first documented. The scan for confirmation of response may be performed at the earliest 4 weeks after the first indication of response, or at the next scheduled scan (9 weeks later), whichever is clinically indicated. Imaging should continue to be performed until documented disease progression, the start of new anticancer treatment, withdrawal of consent, death, or the end of the study, whichever occurs first. Disease progression should be confirmed at least 4 weeks after the first scan indicating progressive disease in clinically stable subjects. Subjects who have unconfirmed disease progression may continue on treatment until progression is confirmed provided they have met the conditions detailed in Section 10.
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4.9.3. tumor biopsy

Fresh tumor biopsies (defined as a biopsy specimen taken since completion of the most recent prior chemotherapy regimen) will be required at baseline and on treatment of the same lesion (day 42 +/- 5 days). Patients are not required to have PD-1 expression testing for enrollment on the study. All sites of disease that are amendable to biopsy are allowable per protocol. Measurable lesions that are the only site of measurability per RECIST v1.1 cannot be biopsied due to obstruction of measurement. Additionally, previously irradiated lesions cannot be biopsied due to potential for necrotic and nonviable tissue. Standard techniques will be used for all biopsies, which may include CT, ultrasound, or endoscope depending on site of biopsiable lesion. The sample should be obtained as core or endoscopic. Fine needle aspirations (FNA) samples are acceptable. The total number of core biopsies obtained should be approximately 6-15, with an average of 10.
4.9.4. performance and quality of
4.9.4.1. eastern cooperative oncology group

The investigator or qualified designee will assess ECOG performance status (Appendix C) at  
 screening, prior to the administration of each dose of study treatment and discontinuation of study treatment as specified in the schedule of events calendar (Section 9).
4.9.4. performance and quality of
4.10. general concomitant medication and

Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the study. If there is a clinical indication for one of these or other medications or vaccinations specifically prohibited during the study, discontinuation from study therapy may be required. The investigator should discuss any questions regarding this with the Merck and Incyte clinical team. The final decision on any supportive therapy rests with the principal investigator and/or the subject's primary treating physician. However, the decision to continue the subject on study therapy schedule requires the mutual agreement of the investigator, Merck and Incyte, and the subject.
4.9.4. performance and quality of
4.10.1. acceptable concomitant medications

All treatments that the investigator considers necessary for a subject's welfare may be administered at the discretion of the investigator in keeping with the community standards of medical care. All concomitant medication will be recorded on the eCRF, including all prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur during the study period, documentation of drug dosage, frequency, route, and date may also be included on the CRF. All concomitant medications received within 28 days before the first dose of study treatment and 30 days after the last dose of study treatment should be recorded. Concomitant medications administered for 30 days after the last dose of study treatment should be recorded for SAEs. Bone protectants (bisphosphonates and denosumab) are allowed for treatment of bone metastases while patients are on the study.
4.9.4. performance and quality of
4.10.2. restricted medications

Low-dose Coumadin (1 mg) is acceptable; however, standard dose levels of Coumadin are  
 prohibited given fluctuations in INR.
4.9.4. performance and quality of
4.10.3. prohibited medications

Subjects are prohibited from receiving the following therapies during the screening and treatment phase (including retreatment for post-complete response relapse) of this study:
- Antineoplastic systemic chemotherapy or biological therapy - Any immunological-based treatment for any reason - Investigational medications other than pembrolizumab or epacadostat - Radiation therapy
− Note: Palliative radiation therapy to a symptomatic solitary lesion or to the brain may be allowed at the investigator's discretion.  
- Live vaccines within 30 days prior to the first dose of study treatment and while participating in the study. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine.  
- Systemic glucocorticoids for any purpose other than to modulate symptoms from an event of clinical interest of suspected immunologic etiology.  
- Any melatonin supplements. - Any MAOI or drug associated with significant MAO inhibitory activity agents is prohibited from 21 days before Day 1 through 2 weeks after the final dose of INCB024360 has been taken (see 14.3).  
- Any UGT1A9 inhibitor, including: acitretin, amitriptyline, androsterone, cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, estradiol (17-beta), flutamide, geftinib, gemfibrozil, glycyrrhetinic acid glycyrrhizin, imatinib, imipramine, ketoconazole, linoleic acid, mefenamic acid, mycophenolic acid, niflumic acid, nilotinib, phenobartital, phenylbutazone, phenytoin, probenecid,  
  
 propofol, quinidine, ritonavir, Sorafenib, sulfinpyrazone, valproic acid, and verapmil.  
Subjects who, in the assessment by the investigator, require the use of any of the aforementioned  
 treatments for clinical management should be removed from the study. Subjects may receive other medications that the investigator deems to be medically necessary. The exclusion criteria (Section 3.3) describes other medications that are prohibited during this study. There are no prohibited therapies during the post-treatment follow-up phase.
4.9.4. performance and quality of
4.10.4. supportive care guidelines and

Subjects should receive appropriate supportive care measures as deemed necessary by the treating investigator. Suggested supportive care measures for the management of AEs with potential immunologic etiology are outlined below in section 6.2. Where appropriate, these guidelines include the use of oral or intravenous treatment with corticosteroids as well as additional anti-inflammatory agents if symptoms do not improve with administration of corticosteroids. Note that several courses of steroid tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For each disorder, attempts should be made to rule out other causes such as metastatic disease or bacterial or viral infection, which might require additional supportive care. The treatment guidelines are intended to be applied when the investigator determines the events to be related to pembrolizumab and/or epacadostat. If after the evaluation the event is determined not to be related, the investigator does not need to follow the treatment guidance (as outlined below). It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or skin photography as part of evaluation of the event. Pembrolizumab may cause severe or life threatening infusion-reactions. Signs and symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are provided in Table 3.  
| NCI CTCAE Grade   | Treatment   | Premedication at  subsequent dosing   |
|-------------------|-------------|---------------------------------------|  
| NCI CTCAE Grade                                                                                                                                                                                     | Treatment                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           | Premedication at  subsequent dosing   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------|
| Grade 1 Mild reaction; infusion  interruption not indicated;  intervention not indicated                                                                                                            | Increase monitoring of vital  signs as medically indicated  until the subject is deemed  medically stable in the opinion  of the investigator.                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      | None                                  |
| Grade 2 Requires infusion interruption  but responds promptly to  symptomatic treatment (e.g.,  antihistamines, NSAIDS,  narcotics, IV fluids);  prophylactic medications  indicated for ≤ 24 hours | Stop Infusion and monitor  symptoms. Additional appropriate medical  therapy may include but is not  limited to: - IV fluids - Antihistamines - NSAIDS - Acetaminophen - Narcotics Increase monitoring of vital  signs as medically indicated  until the subject is deemed  medically stable in the opinion  of the investigator. If symptoms resolve within one  hour of stopping drug infusion,  the infusion may be restarted at  50% of the original infusion  rate (e.g., from 100 mL/hr to 50  mL/hr). Otherwise dosing will  be held until symptoms resolve  and the subject should be  premedicated for the next  scheduled dose. Subjects who develop Grade 2  toxicity despite adequate  premedication should be  permanently discontinued  from further study treatment  administration. | Subject may be  premedicated 1.5h (± 30  minutes) prior to infusion  of pembrolizumab (MK3475) with: Diphenhydramine 50 mg  orally (or equivalent dose  of antihistamine). Acetaminophen 500- 1000 mg orally (or  equivalent dose of  antipyretic).                                       |
| Grades 3 or 4 Grade 3: Prolonged (i.e., not rapidly  responsive to symptomatic  medication and/or brief  interruption of infusion);  recurrence of symptoms                                         | Stop Infusion. Additional appropriate medical  therapy may include but is not  limited to: IV fluids Antihistamines NSAIDS                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          | No subsequent dosing                  |  
  
  
| NCI CTCAE Grade                                                                                                                                                                                                                                                       | Treatment                                                           | Premedication at  subsequent dosing   |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------|---------------------------------------|
| following initial improvement;  hospitalization indicated for  other clinical sequelae (e.g.,  renal impairment, pulmonary  infiltrates) Grade 4: Life-threatening; pressor or  ventilatory support indicated                                                         | Acetaminophen Narcotics Oxygen Pressors Corticosteroids Epinephrine |                                       |
| Increase monitoring of vital  signs as medically indicated  until the subject is deemed  medically stable in the opinion  of the investigator. Hospitalization may be  indicated. Subject is permanently  discontinued from further  study treatment  administration. |                                                                     |                                       |
| Appropriate resuscitation equipment should be available in the room and a physician readily  available during the period of drug administration.                                                                                                                      |                                                                     |                                       |  
  
  
  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as medical / surgical events or logistical reasons not related to study therapy. Subjects should be placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for interruption should be documented in the patient's study record.  
- Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration should be given in subsequent cycles to the administration of prophylactic antiemetic therapy according to standard institutional practice. Subjects should be strongly encouraged to maintain liberal oral fluid intake.  
- Anti-infectives: Subjects with a documented infectious complication should receive oral or IV antibiotics or other anti-infective agents as considered appropriate by the treating investigator for a given infectious condition, according to standard institutional practice.
4.11. diet/activity/other considerations
4.11.1. diet

Subjects should maintain a normal diet unless modifications are required to manage an AE such as diarrhea, nausea or vomiting.
4.11. diet/activity/other considerations
4.11.2. contraception

Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if pembrolizumab has transient adverse effects on the composition of sperm. For this study, male subjects will be considered to be of non-reproductive potential if they have azoospermia (whether due to having had a vasectomy or due to an underlying medical condition). Female subjects will be considered of non-reproductive potential if they are either: (1) postmenopausal (defined as at least 12 months with no menses without an alternative medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient);
OR (2) had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; OR (3) has a congenital or acquired condition that prevents childbearing. Female and male subjects of reproductive potential must agree to avoid becoming pregnant or impregnating a partner, respectively, while receiving study drug and for 120 days after the last dose of study drug by complying with one of the following:
(1) practice abstinence†from heterosexual activity; OR (2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
- intrauterine device (IUD) - vasectomy of a female subject's male partner - contraceptive rod implanted into the skin  
  
Combination method (requires use of two of the following):  
  
  
- diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide) - cervical cap with spermicide (nulliparous women only) - contraceptive sponge (nulliparous women only) - male condom or female condom (cannot be used together) - hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject's preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception. ‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an acceptable method of contraception for subjects participating at sites in this country/region.  
Subjects should be informed that taking the study medication may involve unknown risks to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate in the study subjects of childbearing potential must adhere to the contraception requirement (described above) from the day of study medication initiation (or 14 days prior to the initiation of study medication for oral contraception) throughout the study period up to 120 days after the last dose of study therapy. If there is any question that a subject of childbearing potential will not reliably comply with the requirements for contraception, that subject should not be entered into the study.  
4.11.3. **Use in Pregnancy**
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab and/or Epacadostat, the subject will immediately be removed from the study. The site will contact the subject at least monthly and document the subject's status until the pregnancy has been completed or terminated. The outcome of the pregnancy will be reported to Merck and Incyte without delay if the outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other disabling or life-threatening complication to the mother or newborn).  
  
 The study investigator will make every effort to obtain permission to follow the outcome of the pregnancy and report the condition of the fetus or newborn to Merck and Incyte. If a male subject impregnates his female partner, the study personnel at the site must be informed immediately and the pregnancy reported to Merck and Incyte and followed as described.
4.11. diet/activity/other considerations
4.11.4. use in nursing women

It is unknown whether pembrolizumab nor Epacadostat is excreted in human milk. Since many drugs are excreted in human milk, and because of the potential for serious adverse reactions in the nursing infant, subjects who are breast-feeding are not eligible for enrollment.
4.11. diet/activity/other considerations
4.12. subject withdrawal/discontinuation criteria

Subjects may withdraw consent at any time for any reason or be dropped from the study at the discretion of the investigator should any untoward effect occur. In addition, a subject may be withdrawn by the investigator or the Sponsor if enrollment into the study is inappropriate, the study plan is violated, or for administrative and/or other safety reasons. A subject must be discontinued from the study for any of the following reasons:
- The subject or legal representative (such as a parent or legal guardian) withdraws consent.  
- Confirmed radiographic disease progression Note: For unconfirmed radiographic disease progression, please see Section 10.  
Note: A subject may be granted an exception to continue on treatment with confirmed radiographic progression if clinically stable or clinically improved
- Unacceptable adverse experiences
- Intercurrent illness that prevents further administration of treatment - Investigator's decision to withdraw the subject - The subject has a confirmed positive serum pregnancy test
- The subject is lost to follow-up - Completed 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication, whichever is later. Note: 24 months of study medication is calculated from the date of first dose. Subjects who stop pembrolizumab after 24 months may be eligible for up to one year of additional  
  
 study treatment if they progress after stopping study treatment provided they meet the requirements detailed in Section 4.8.  
- Administrative reasons The EOT and Follow-up visit procedures are listed in Section 9 (Study Calendar) and Section 4 (Visit Requirements). After the end of treatment, each subject will be followed up to 30 days or until new anti-cancer treatment is initiated, whichever occurs first for adverse event monitoring, including SAEs. Subjects who discontinue for reasons other than progressive disease will have post-treatment follow-up for disease status until disease progression, initiating a non-study cancer treatment, withdrawing consent or becoming lost to follow-up. After documented disease progression each subject will be followed by telephone for overall survival until death, withdrawal of consent, or the end of the study, whichever occurs first.
4.11. diet/activity/other considerations
4.12.1. discontinuation of study therapy

Discontinuation of treatment may be considered for subjects who have attained a confirmed CR that have been treated for at least 24 weeks with pembrolizumab and epacadostat and had at least two treatments with pembrolizumab beyond the date when the initial CR was declared. Subjects who then experience radiographic disease progression may be eligible for up to one year of additional treatment with pembrolizumab and epacadostat via the Second Course Phase at the discretion of the investigator if no cancer treatment was administered since the last dose of pembrolizumab, the subject meets the safety parameters listed in the inclusion and exclusion criteria, and the study is open. Subjects will resume therapy at the same dose and schedule at the time of initial discontinuation.
4.11. diet/activity/other considerations
4.12.2. noncompliance with oral epacadostat

Each patient will be given an oral medication diary to take home and record the dosing  
  
  
information including times of day and number of pills taken to ensure they are taking the medication as prescribed at home. Compliance of > 85% based on pill reconciliation and home diary entries at ≥ 2 consecutive visits will be strongly encouraged.
4.11. diet/activity/other considerations
5. investigational agent/device/procedure information 5.1.

Detailed pharmaceutical and therapeutic background of pembrolizumab and epacadostat is provided in the respective IBs. The investigator shall take responsibility for and shall take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, distribution and usage of investigational products in accordance with the protocol and any applicable laws and regulations.  
$$5.1.1.$$
4.11. diet/activity/other considerations
5.1.1.1. packaging labeling and preparation

The study drug will be available as 100 mg tablets packaged in high-density polyethylene bottles. All tablet excipients comply with the requirements of the applicable compendial monographs (Ph. Eur., USP/NF). All Incyte investigational product labels will be in the local language and will comply with the legal requirements of each country.
4.11. diet/activity/other considerations
5.1.1.2. storage and stability

Clinical supplies of epacadostat should be stored under ambient conditions, between 15°C to 30°C (59°F to 86°F). Study drug must be stored in a locked storage area with limited access. If epacadostat is exposed outside of the defined temperature ranges please quarantine the affected bottles and complete and submit the Temperature and Light Excursion Form (Appendix G) to Incyte according to the instructions on the form. Incyte will provide guidance as to whether the bottles will need to be destroyed based on the information that has been provided on the form. If epacadostat is exposed outside of the defined temperature ranges please quarantine the affected bottles and complete and submit the Temperature and Light Excursion Form (Appendix G) to Incyte according to the instructions on the form. Incyte will provide guidance as to whether the bottles will need to be destroyed based on the information that has been provided on  
  
 the form.  
$$5.1.2.$$
4.11. diet/activity/other considerations
5.1.2.1. packaging labeling and preparation

Clinical supplies will be provided by Merck and will be affixed with a clinical label in accordance with regulatory requirements. Details on preparation and administration of pembrolizumab (MK-3475) are provided in the Appendix F.  
| Product Name & Potency    | Dosage Form            |
|---------------------------|------------------------|
| Pembrolizumab 100 mg/ 4mL | Solution for Injection |
4.11. diet/activity/other considerations
5.1.2.2. storage and stability

Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified on the label. Receipt and dispensing of study drug must be recorded by an authorized person at the study site. Clinical supplies may not be used for any purpose other than that stated in the Protocol. Open-label vials of pembrolizumab should be stored between 2°C to 8°C (36°F to 46°F) in a locked storage area protected from light with limited access. Vials should be stored in the original box to ensure the drug product is protected from light. A maximum 12 hours of light exposure is permitted for the pembrolizumab vials. Pembrolizumab solutions may be stored at room temperature for a cumulative time of up to 4 hours. This includes room temperature storage of drug product solution in vial, room temperature storage of admixture solution in the IV bags and the duration of infusion. IV bags containing pembrolizumab may be stored under refrigeration at 2°C to 8°C (36°F to 46°F) for up to 20 hours. If refrigerated, allow the IV bags to come to room temperature prior to use.
4.11. diet/activity/other considerations
5.2. accountability handling and disposal

Responsibility for drug accountability at the study site rests with the investigator; however, the investigator may assign some of the drug accountability duties to an appropriate pharmacist or other designee. Inventory and accountability records must be maintained and readily available for inspection by any study monitor and are open to inspection at any time by any applicable regulatory authorities. The investigator or designee will be expected to collect and retain all used, unused, and partially used containers of study drug according to their institution policies. The investigator or designee must maintain records that document:
- Delivery of study drug to the study site.  
- Inventory of study drug at the site.  
- Subject use of the study drug including pill or unit counts from each supply dispensed.
- Return of study drug to the investigator or designee by subjects.  
These records should include dates, quantities, batch or serial numbers (if available), and the unique code numbers (if available) assigned to the investigational product and study subjects. The investigational product must be used only in accordance with the protocol. The investigator will also maintain records adequately documenting that the subjects were provided the correct study drug specified. Completed accountability records will be archived by the site. At the completion of the study, the investigator or designee will oversee destruction according to institutional standard operating procedures. The investigator is responsible for keeping accurate records of the clinical supplies received from Merck or designee, the amount dispensed to and returned by the subjects and the amount remaining at the conclusion of the study. Upon completion or termination of the study, all unused and/or partially used pembrolizumab will be destroyed at the site per institutional policy. It is the investigator's responsibility to arrange for disposal of all empty containers, provided that procedures for proper disposal have  
  
 been established according to applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate records of disposal are kept.
4.11. diet/activity/other considerations
6. dose modifications 6.1. rationale

Subjects may require modification of epacadostat if necessitated by drug-related AEs, including irAEs; dose reductions of pembrolizumab are prohibited.  
| Epacadostat Dose Level Table   |            |
|--------------------------------|------------|
| Dose Level                     | Dose in mg |
| Starting Dose (0)              | 300mg BID  |
| First Dose Reduction (-1)      | 200mg BID  |
| Second Dose Reduction (-2)     | 100mg BID  |  
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks (~ 21 days) of the scheduled interruption, unless otherwise discussed with Merck and Incyte. The reason for interruption should be documented in the patient's study record.  
In some circumstances, it may be necessary to temporarily interrupt both study treatments as a result of AEs that may have an unclear relationship to study drug(s). Treatment with both study drugs should be withheld for drug-related Grade 4 hematologic toxicities, non-hematological toxicity ≥ Grade 3 (including laboratory abnormalities), and severe or life-threatening AEs.