Clinical trial NCT03196232
Conditions: Gastric Adenocarcinoma Gastroesophageal Junction Adenocarcinoma Recurrent Esophageal Carcinoma Recurrent Gastric Carcinoma Stage IV Esophageal Cancer AJCC v7 Stage IV Gastric Cancer AJCC v7 Unresectable Esophageal Carcinoma
Sponsor: George Albert Fisher
Start date: 2017-09-13; Completion date: 2018-05-29
Enrollment: 3 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase 2 trial evaluates the benefit of epacadostat plus pembrolizumab in combination to treat patients with gastroesophageal junction or gastric cancer that has spread to other parts of the body and cannot be removed by surgery. Epacadostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as pembrolizumab, may block tumor growth in different ways by targeting certain cells. Giving epacadostat and pembrolizumab may work better in treating patients with gastroesophageal junction or gastric cancer.

Detailed description:
Patients receive epacadostat orally (PO) twice daily (BID) on Days 1 to 21 and pembrolizumab intravenously (IV) over 30 minutes on Day 1. Courses repeat every 21 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 9 weeks for 18 months, and then every 12 weeks thereafter.

PRIMARY OBJECTIVES:

Assess 6-month progression free survival (PFS).

SECONDARY OBJECTIVES:

* To evaluate objective response rate (RR) by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1 and immune-related response criteria (irRC).
* Evaluate overall survival (OS).
* Assess the safety and tolerability of epacadostat in combination with pembrolizumab by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03.

TERTIARY OBJECTIVES:

* Determine the responder rate defined as the proportion of subjects with an increased ratio of CD8+ to Treg cells in on-treatment compared with pre-treatment biopsies.
* Identify putative immunologic biomarkers of tumor response.

Arms: arm 1: Participants receive oral epacadostat BID on Days 1 to 21 and pembrolizumab IV over 30 minutes on Day 1, with cycles repeating every 21 days for up to 24 months, in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: Epacadostat intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Given PO intervention 2: Given IV

Protocol documents:
Prot_SAP_000.pdf: 
 
1 
Protocol Version # 3.1 
 
 September 10, 2018 
 
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 
Phone: (xxx) xxx-xxxx 
Fax: (xxx) xxx-xxxx 
 
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. 
Tel:  xxx-xxx-xxxx 
Fax: xxx-xxx-xxxx 
 
 
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 
 


 
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TABLE OF CONTENTS 
SUMMARY OF CHANGES ........................................................................................................ 6 
PROTOCOL SYNOPSIS ............................................................................................................ 7 
SCHEMA ................................................................................................................................ 8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................................. 9 
1. 
OBJECTIVES .................................................................................................................. 12 
1.1. 
Primary Objective ........................................................................................................................ 12 
1.2. 
Secondary Objectives .................................................................................................................. 12 
1.3. 
Exploratory Objectives ................................................................................................................. 12 
2. 
BACKGROUND .............................................................................................................. 12 
2.1. 
Study Disease ............................................................................................................................... 12 
2.2. 
Study Agent/Device/Procedure ................................................................................................... 13 
2.2.1. 
Pharmaceutical and Therapeutic Background .................................................................. 13 
2.2.2. 
Inhibition of PD-1 as a Target for Cancer .......................................................................... 13 
2.2.3. 
Inhibition of Indoleamine 2,3–Dioxygenase as a Target for Cancer ................................. 15 
2.2.4. 
Combined Immune Checkpoint Inhibition ........................................................................ 17 
2.3. 
Rationale ...................................................................................................................................... 20 
2.3.1. 
Rationale for Studying Immunotherapy in Advanced or Metastatic Cancers .................. 22 
2.4. 
Study Design ................................................................................................................................ 26 
2.5. 
Correlative Studies Background and Rationale ........................................................................... 26 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ........................................... 26 
3.1. 
Subject Population ..................................................................................................................... 27 
3.2. 
Inclusion Criteria .......................................................................................................................... 27 
3.3. 
Exclusion Criteria ......................................................................................................................... 30 
3.4. 
Informed Consent Process ........................................................................................................... 33 
3.5. 
Randomization Procedures.......................................................................................................... 33 
3.6. 
Study Timeline ............................................................................................................................. 33 
3.6.1. 
Primary Completion .......................................................................................................... 33 
3.6.2. 
Study Completion ............................................................................................................. 33 
4. 
TREATMENT PLAN ........................................................................................................ 33 
4.1. 
Study Procedures ......................................................................................................................... 33 
4.2. 
Duration of Treatment and Subject Participation ....................................................................... 34 
4.3. 
Screening Phase ........................................................................................................................... 34 
4.3.1. 
Informed Consent ............................................................................................................. 34 
4.3.2. 
General Informed Consent ............................................................................................... 34 
4.3.3. 
Inclusion/Exclusion Criteria .............................................................................................. 35 
4.3.4. 
Demographics and Medical History .................................................................................. 35 
4.3.5. 
Prior Medications .............................................................................................................. 36 
4.3.6. 
Concomitant Medications ................................................................................................. 36 
4.3.7. 
Disease Details and Treatments ....................................................................................... 36 
4.3.7.1. 
Disease Details .................................................................................................................. 36 
4.3.7.2. 
Prior Treatment Details .................................................................................................... 36 


 
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4.3.7.3. 
Subsequent Anti-Cancer Therapy Status .......................................................................... 36 
4.4. 
Treatment Phase.......................................................................................................................... 37 
4.4.1. 
Administration of Investigational Products ...................................................................... 37 
4.4.2. 
Treatment Compliance ..................................................................................................... 37 
4.4.2.1. 
Epacadostat (INCB024360) ............................................................................................... 37 
4.4.2.2. 
Pembrolizomab (MK-3475) ............................................................................................... 38 
4.5. 
End of Treatment ......................................................................................................................... 39 
4.6. 
Follow-Up Phase .......................................................................................................................... 39 
4.6.1. 
Safety Follow-Up Visit ....................................................................................................... 39 
4.6.2. 
Follow-Up Period .............................................................................................................. 39 
4.6.3. 
Survival Follow-Up ............................................................................................................ 40 
4.7. 
Unscheduled Visits ....................................................................................................................... 40 
4.8. 
Second Course Phase ................................................................................................................... 40 
4.9. 
Study Assessments and Procedures ............................................................................................ 42 
4.9.1. 
Safety Assessments ........................................................................................................... 42 
4.9.1.1. 
Adverse Events .................................................................................................................. 42 
4.9.1.2. 
Comprehensive Physical Examination .............................................................................. 43 
4.9.1.3. 
Targeted Physical Examination ......................................................................................... 43 
4.9.1.4. 
Vital Signs .......................................................................................................................... 43 
4.9.1.5. 
Twelve-Lead Electrocardiograms (ECGs) .......................................................................... 43 
4.9.1.6. 
Laboratory Assessments ................................................................................................... 44 
4.9.2. 
Efficacy Assessments – Tumor Imaging During the Study ................................................ 46 
4.9.3. 
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 
4.10.1. 
Acceptable Concomitant Medications .............................................................................. 48 
4.10.2. 
Restricted Medications ..................................................................................................... 49 
4.10.3. 
Prohibited Medications .................................................................................................... 49 
4.10.4. 
Supportive Care Guidelines and Handling Immune Related AEs ...................................... 50 
4.11. Diet/Activity/Other Considerations ............................................................................................. 53 
4.11.1. 
Diet .................................................................................................................................... 53 
4.11.2. 
Contraception ................................................................................................................... 53 
4.11.3. 
Use in Pregnancy............................................................................................................... 54 
4.11.4. 
Use in Nursing Women ..................................................................................................... 55 
4.12. Subject Withdrawal/Discontinuation Criteria ............................................................................. 55 
4.12.1. 
Discontinuation of Study Therapy after Complete Response ........................................... 56 
4.12.2. 
Noncompliance with Oral Epacadostat Dosing ................................................................ 57 
5. 
INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION .................................... 57 
5.1. 
Investigational Products Description ........................................................................................... 57 
5.1.1. 
Epacadostat ...................................................................................................................... 57 
5.1.2. 
Pembrolizumab ................................................................................................................. 58 
5.2. 
Accountability, Handling, and Disposal of Epacadostat and Pembrolizumab ............................. 59 
6. 
DOSE MODIFICATIONS .................................................................................................. 60 
6.1. 
Rationale for Dose Modification(s) .............................................................................................. 60 
6.2. 
Dose Modifications of Pembrolizumab and Epacadostat ........................................................... 60 


 
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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 


 
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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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Protocol Version # 3.1 
 
 September 10, 2018 
 
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 


 
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Protocol Version # 3.1 
 
 September 10, 2018 
 
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 
CONSIDERATIONS 
This is a single-stage study for the doublet epacadostat 
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 one-
sided significance of 10%.   
 
 


 
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SCHEMA  
  
  
 
 
 
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) 
 
 
 
 


 
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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 


 
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 September 10, 2018 
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 


 
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 September 10, 2018 
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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 September 10, 2018 
 
1. OBJECTIVES 
1.1. Primary Objective 
1.1.1. 
To assess 6-month progression free survival (PFS) 
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 
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 pre-
treatment 
 
 biopsies 
1.3.2. 
To identify putative immunologic biomarkers of tumor response 
 
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 


 
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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] 
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).  
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. 
2.2.2. 
Inhibition of PD-1 as a Target for Cancer 
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 


 
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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. 


 
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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.  
2.2.3. 
Inhibition of Indoleamine 2,3–Dioxygenase as a Target for Cancer 
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 


 
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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-methyl-
tryptophan, 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] 


 
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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. 
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 


 
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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, 


 
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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 


 
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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 non-
melanoma 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.   
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 


 
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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, non-
randomized 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 


 
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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. 
2.3.1. 
Rationale for Studying Immunotherapy in Advanced or Metastatic 
Cancers 
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 mutation-


 
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positive, 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 mutation-
positive, 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 


 
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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 


 
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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. 


 
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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.   
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. 
2.5. Correlative Studies Background and Rationale 
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. 
 
3. PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES 
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.  
 
3.2. Inclusion Criteria 
In order to be eligible for participation in this study, the subject must meet all of the following: 
 


 
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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 
study 
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. 
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 
to study entry. 
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.   
Table 1:  Adequate Organ Function Laboratory Values 
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 
Measured or calculateda creatinine 
≤1.5 X upper limit of normal (ULN) OR 
 


 
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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 
Total bilirubin 
≤ 1.5 X ULN OR 
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 
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) 
≤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 
 
aCreatinine clearance should be calculated per institutional standard. 


 
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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 
will be required.   
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. 
3.3. Exclusion Criteria 
The subject must be excluded from participating in the study if the subject: 
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 
of their excipients.  
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. 


 
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• 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.  
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 
pneumonitis  
3.3.9. 
Has received a live vaccine within 30 days of planned start of study 
therapy. 
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 


 
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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 
3.3.16. 
Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2  
antibodies) 
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 
3.3.20. 
Has presence of a gastrointestinal condition that may affect drug 
absorption 
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. 


 
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3.3.25. 
Has known allergy or reaction to any component of either study drug or 
formulation components. 
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. 
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. 
3.6. Study Timeline 
3.6.1. 
Primary Completion 
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.  
4. TREATMENT PLAN 
4.1. Study Procedures 
The schedule of events calendar (Section 9) summarizes the study procedures to be performed at 


 
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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.  
4.2. Duration of Treatment and Subject Participation 
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. 
4.3. Screening Phase 
4.3.1. 
Informed Consent 
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. 
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. 


 
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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). 
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. 
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. 
4.3.7. 
Disease Details and Treatments 
4.3.7.1. 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
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. 
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. 
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. 
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).  
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, 


 
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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. 
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.  


 
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See Appendix F which contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
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). 
4.6. Follow-Up Phase 
4.6.1. 
Safety Follow-Up Visit 
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 


 
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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.   
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.  
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. 
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. 


 
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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. 
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, non-
leading 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 


 
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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. 
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. 
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.   
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. 
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 


 
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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. 
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. 
Hematology, Lipid Panel, Coagulation Panel, Serology, and Endocrine Function Testing  
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. 
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.  
Urinalysis 
Urinalysis will be analyzed by the site laboratory. 


 
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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.    
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. 
Table 2: Required Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin†  
Hemoglobin 
Alkaline phosphatase 
Glucose 
PT/INR 
Platelet count 
Alanine aminotransferase 
(ALT) 
Protein 
aPTT 
White Blood Cell Count 
(total and differential) 
Aspartate aminotransferase 
(AST) 
Specific gravity  
Total triiodothyronine (T3) (if 
applicable) 
Red Blood Cell Count 
Lactate dehydrogenase 
Urine pregnancy test † 
Free thyroxine (T4) (if 


 
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Hematology 
Chemistry 
Urinalysis 
Other 
(LDH) 
applicable) 
Absolute Neutrophil 
Count 
Carbon Dioxide  
  (CO2 or bicarbonate) 
 
Thyroid stimulating hormone 
(TSH) 
Absolute Lymphocyte 
Count 
 
Blood for correlative studies and 
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.   
 
 
4.9.2. 
Efficacy Assessments – Tumor Imaging During the Study 
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 


 
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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. 
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.  


 
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4.9.4. 
Performance and Quality of Life Assessments 
4.9.4.1. 
Eastern Cooperative Oncology Group Performance Status 
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).   
4.10. 
General Concomitant Medication and Supportive Care Guidelines 
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. 
4.10.1. 
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. 


 
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4.10.2. 
Restricted Medications  
Low-dose Coumadin (1 mg) is acceptable; however, standard dose levels of Coumadin are 
prohibited given fluctuations in INR. 
 
4.10.3. 
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, 


 
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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. 
4.10.4. 
Supportive Care Guidelines and Handling Immune Related AEs 
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.  
 
Table 3: Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
subsequent dosing 


 
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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 (MK-
3475) 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 


 
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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. 


 
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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. 
4.11.2. 
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  


 
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• 
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 


 
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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. 
4.11.4. 
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. 
4.12. 
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 


 
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Protocol Version # 3.1 
 
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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. 
4.12.1. 
Discontinuation of Study Therapy after Complete Response 
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.   


 
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4.12.2. 
Noncompliance with Oral Epacadostat Dosing 
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. 
5. INVESTIGATIONAL AGENT/DEVICE/PROCEDURE INFORMATION 
5.1. Investigational Products Description 
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. 
Epacadostat  
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. 
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 


 
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whether the bottles will need to be destroyed based on the information that has been provided on 
the form. 
5.1.2. 
Pembrolizumab 
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 
 
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.  


 
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5.2. Accountability, Handling, and Disposal of Epacadostat and Pembrolizumab 
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 


 
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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. 
6. DOSE MODIFICATIONS 
6.1. Rationale for Dose Modification(s) 
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. 
6.2. Dose Modifications of Pembrolizumab and Epacadostat 
AEs (both non-serious and serious) associated with pembrolizumab and epacadostat exposure 
may represent an immunologic etiology.  These adverse events may occur shortly after the first 
dose or several months after the last dose of treatment. Based on existing clinical trial data, most 
irAEs were reversible and could be managed with interruptions of pembrolizumab and 


 
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Protocol Version # 3.1 
 
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epacadostat, administration of corticosteroids and/or other supportive care. For suspected irAEs, 
ensure adequate evaluation to confirm etiology or exclude other causes. Based on the severity of 
irAEs, withhold or permanently discontinue pembrolizumab and epacadostat and administer 
corticosteroids. Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided in Table 4.  
 
See Sections 4.10.4 for additional supportive care guidelines, including use of corticosteroids if 
necessary. Patients requiring treatment with corticosteroids for irAEs should be held through 
completion of taper, unless otherwise discussed and approved by Merck and Incyte. 
In case toxicity does not resolve to Grade 1 within 12 weeks after last dose of study treatment 
should be discontinued only after consultation with Merck and Incyte.  With investigator and 
Merck and Incyte agreement, subjects with a laboratory AE still at Grade 2 after 12 weeks may 
continue treatment in the study only if asymptomatic and controlled. 
General Instructions for management of irAE 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and 
continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed 
after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. For 
subjects with Grade 3 or 4 immune-related endocrinopathy, pembrolizumab may be 
resumed when AE improves to Grade 2 or lower and is controlled with hormonal 
replacement therapy.   
3. For situation where pembrolizumab is withheld initially, pembrolizumab should be 
permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 
weeks. However, subjects with asymptomatic  
4. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed 
by oral steroid. Other immunosuppressive treatment should be initiated if irAEs cannot 
be controlled by corticosteroids 
 


 
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Protocol Version # 3.1 
 
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Table 4: Dose Modification Guidelines for Drug Immune-Related AEs associated with epacadostat 
and pembrolizumab 
General instructions for AEs associated with Pembrolizumab: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and 
continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed 
after AE has been reduced to Grade 1 or 0 and corticosteroid has been tapered. 
Pembrolizumab should be permanently discontinued if AE does not resolve within 12 
weeks of last dose or corticosteroids cannot be reduced to ≤10 mg prednisone or 
equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed 
by oral steroid. Other immunosuppressive treatment should be initiated if irAEs cannot 
be controlled by corticosteroids. 
 
 
The below table represents guidelines and are not required management for immune-related AEs and can be implemented at the 
discretion of the investigator.  Specialist referral (Endocrinology, Pulmonary, GI, etc) is encouraged if questions arise about 
appropriate management. 


 
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Protocol Version # 3.1 
 
 September 10, 2018 
 
Note: Unless listed below, Grade 1 for all disease groups: continue therapy, treat symptoms, close monitoring for worsening symptoms, educate patient to report worsening 
immediately, if worsens: Treat as Grade (G) 2 or 3/4.   
 
 


 
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Protocol Version # 3.1 
 
 September 10, 2018 
Toxicity 
Hold Treatment 
For Grade 
Management + Timing for Restarting 
Treatment 
Follow-up 
Treatment Discontinuation 
Type 1 diabetes 
mellitus (if new 
onset) or 
Hyperglycemia1 
Type 1 diabetes 
mellitus (if new 
onset, including 
diabetic 
ketoacidosis 
[DKA]) or ≥ Grade 
3 Hyperglycemia, if 
associated with 
ketosis (ketonuria) 
or metabolic 
acidosis (DKA) 
 
- Delay therapy for new onset Type 1 
diabetes mellitus or Grade 3-4 
hyperglycemia associated with evidence of 
beta cell failure. 
 
- Insulin replacement therapy is 
recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated 
with metabolic acidosis or ketonuria.  
 
- Evaluate patients with serum glucose and a 
metabolic panel, urine ketones, glycosylated 
hemoglobin, and C-peptide.  
 
- Resume therapy when patients are 
clinically and metabolically stable  
 
 
________ 
Discontinue Pembrolizumab and 
Epacadostat if not clinically and 
metabolically stable 
Hyperthyroidism1 
Grade 2 
 
- Continue therapy. 
 
- Non-selective beta blockers (e.g. 
propranolol) are suggested as initial therapy. 
 
________ 
________ 
Grade 3 
 
- Delay therapy 
 
- Resume therapy with one dose reduction 
when toxicity resolves to Grade 0-1 
 
-Treat with non-selective beta-blockers or 
thionamides as appropriate 
 
- Treat with an initial dose of IV 
corticosteroid followed by oral 
corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be 
started and continued over no less than 4 
weeks. 
Replacement of appropriate hormones may 
be required as the steroid dose is tapered. 
 
________ 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks 


 
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Protocol Version # 3.1 
 
 September 10, 2018 
-Consider endocrine consult 
 
Grade 4 
 
- Discontinue therapy permanently.  
 
- Treat with an initial dose of IV 
corticosteroid followed by oral 
corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be 
started and continued over no less than 4 
weeks. 
 
- Consider endocrine consult 
 
_________ 
Permanently discontinue 
Hypothyroidism1 
Grade 2-4 
 
- Continue therapy at same doses. 
 
- Thyroid hormone replacement therapy, 
with levothyroxine or liothyroinine, is 
indicated per standard of care. 
 
-Consider endocrine consult for Grade 3-4 
 
________ 
Discontinue Pembrolizumab and 
Epacadostat if not clinically and 
metabolically stable 
Thyroid disorders can occur at any time during treatment. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on 
clinical evaluation) and for clinical signs and symptoms of thyroid disorders 
 
 
 
 
Hypophysitis 
 
 
 
 
Grade 2 
 
 
- Delay therapy 
 
- 1.0 to 2.0 mg/kg/day methylprednisolone 
IV or IV equivalent and initiate hormonal 
replacement as clinically indicated 
 
- Can resume once metabolically and 
clinically stable and on doses of steroids < 
10mg/day prednisone equivalent. 
 
- Consult endocrinology for all grades 
 
________ 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks 
Grades 3-4 
- Discontinue therapy permanently.  
________ 
Permanently discontinue 


 
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Protocol Version # 3.1 
 
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Suspicion of adrenal 
crisis (e.g. severe 
dehydration, 
hypotension, shock 
out of proportion to 
current illness1 
 
 
- Delay therapy 
 
- Rule out sepsis 
 
- Stress dose of IV steroids with 
mineralocorticoid activity 
 
- IV fluids 
 
- Consult endocrinologist 
 
- If adrenal crisis ruled out, then treat as 
above for symptomatic endocrinopathy.  
 
- Can resume once metabolically and 
clinically stable and on doses of steroids < 
10mg/day prednisone equivalent.  
 
________ 
________ 
Diarrhea/Colitis1 
 
Grade 2 
Diarrhea: 4-6 
stools/day over 
baseline; IV fluids 
indicated < 24 hours 
(hrs); not interfering 
with ADL.  
Colitis: abdominal 
pain; blood in stool 
 
 
-Delay therapy for 5-7 days and reevaluate. 
 
-Resume therapy with same dose when 
toxicity resolves to Grade 0-1 
 
-Symptomatic treatment  
 
-Drink liberal liquids if not feasible 
administer fluids via IV infusion 
 
 
If improves for to grade 1: 
- Resume therapy with same dose 
  
If persists > 5-7 days or recur: 
- 1.0-2.0 mg/kg/day methylprednisolone or oral 
equivalent 
- When symptoms improve to grade 1, taper 
steroids over at least 4 weeks, consider 
prophylactic antibiotics for opportunistic 
infections, and resume therapy. 
 
If worsens or persists >3-5 days with oral 
steroids: 
- Treat as Grade 3/4    
 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks 


 
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Protocol Version # 3.1 
 
 September 10, 2018 
Grade 3 
Diarrhea: >7 
stools/day over 
baseline; IV fluids 
≥24 hrs; interfering 
with ADL.  
Colitis: severe 
abdominal pain, 
medical intervention 
indicated, peritoneal 
signs 
 
 
- Delay therapy for 3-5 days and reevaluate. 
 
-Resume therapy with one dose reduction 
when toxicity resolves to Grade 0-1. 
 
- 1.0 to 2.0 mg/kg/day methylprednisolone 
IV or IV equivalent. 
 
- Add prophylactic antibiotics for 
opportunistic infections 
 
- Consider lower endoscopy 
 
-Drink liberal liquids if not feasible 
administer fluids via IV infusion 
 
 
If improves: 
- Continue steroids until grade 1, then taper over 
at least 4 weeks. 
 
If persists > 3-5 days, or recurs after 
improvement: 
- GI referral, and consideration of Infliximab 5 
mg/kg under supervision by gastroenterologist (if 
no contraindication) 
 
Note: Infliximab should not be used in cases of 
perforation or sepsis  
 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks 
Grade 4 
life-threatening, 
perforation 
 
- Discontinue therapy permanently.  
 
- 1.0 to 2.0 mg/kg/day methylprednisolone 
IV or IV equivalent. 
 
- Add prophylactic antibiotics for 
opportunistic infections 
 
- Consider lower endoscopy 
 
-Drink liberal liquids if not feasible 
administer fluids via IV infusion 
 
 
If improves: 
- Continue steroids until grade 1, then taper over 
at least 4 Weeks.  
 
If persists > 3-5 days, or recurs after 
improvement: 
- GI referral, and consideration of Infliximab 5 
mg/kg under supervision by gastroenterologist (if 
no contraindication) 
 
Note: Infliximab should not be used in cases of 
perforation or sepsis  
 
Permanently discontinue 
AST, ALT, or 
Increased Bilirubin1 
 
Grade 1 
AST or ALT > ULN 
TO 3.0 x ULN 
and/or T. bili > ULN 
- 1.5 x ULN 
 
 
- Continue therapy 
 
- Continue liver function tests (LFT) monitoring 
per protocol 
 
 
Grade 2 
AST or ALT > 3.0 
to ≤ 5 x ULN and/or 
T. bili > 1.5 to 3 x 
ULN 
 
- Delay therapy for 5-7 days and reevaluate. 
 
- Resume therapy with same dose when 
toxicity resolves to Grade 0-1 
 
 
If returns to baseline: 
- Resume routine monitoring, resume therapy 
same dose. 
 
If elevation persist > 5-7 days or worsen: 
Toxicity does not resolve within 12 
weeks of last dose 


 
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Protocol Version # 3.1 
 
 September 10, 2018 
- Increase frequency of monitoring to every 
3 days. 
 
- 0.5-1.0 mg/kg/day methylprednisolone or oral 
equivalent and when LFT returns to grade 1 or 
baseline, a steroid taper should be started and 
continued over no less than 4 weeks, consider 
prophylactic antibiotics for opportunistic 
infections, and resume therapy with same dose. 
 
Grade 3-4 
AST or ALT > 5 x 
ULN and/or T. bili > 
3 x ULN 
 
 
- Discontinue therapy permanently (see 
exception below)a  
(Therapy may be delayed rather 
discontinued if AST/ALT ≤ 8 x ULN and 
T.bili ≤ 5 x ULN) 
 
- Increase frequency of monitoring to every 
1-2 days 
 
- 1.0 to 2.0 mg/kg/day methylprednisolone 
IV or IV equivalent 
(The recommended starting dose for grade 4 
hepatitis is 2 mg/kg/day methylprednisolone 
IV) 
 
- Add prophylactic antibiotics for 
opportunistic infections 
 
- Consult gastroenterologist 
 
 
If returns to grade 2: 
- Taper steroids over at least 4 weeks 
 
If does not improve in > 3-5 days, or worsens 
or rebounds: 
- Add mycophenolate mofetil 1g twice daily 
(BID) 
- If no response within an additional 3-5 days, 
consider other immunosuppressants per local 
guidelines. 
 
Permanently discontinue 
Neurological1 
 
Grade 2 
Moderate 
symptoms; Limiting 
instrumental ADL 
 
 
- Delay therapy.  
 
- Resume therapy with same dose when 
toxicity resolves to Grade 0-1 
 
- Treat symptoms per local guidelines 
 
- Consider 0.5 to 1.0 mg/kg/day 
methylprednisolone IV or PO equivalent. 
 
-If ≥ Grade 2 Neurologic AE consider 
Neurology consult and brain imaging 
 
 
If improves to baseline: 
- Resume therapy with same dose when toxicity 
resolves to Grade 0-1  
 
If worsens: 
- Treat as Grade 3-4  
 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks  
 
 
 
 
- Discontinue therapy  
 
If improves to grade 2: 
Permanently discontinue 


 
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Protocol Version # 3.1 
 
 September 10, 2018 
Grade 3-4 
Severe symptoms; 
Limiting self-care 
ADL; Life-
threatening 
 
 
- If ≥ Grade 2 Neurologic AE consider 
Neurology consult and brain imaging 
 
- Treat symptoms per local guidelines 
 
- 1.0-2.0 mg/kg/day IV methylprednisolone 
or IV equivalent 
 
- Add prophylactic antibiotics for 
opportunistic infections 
 
- Taper steroids over at least 4 weeks 
 
If worsens or atypical presentation: 
- Consider IVIG or other immunosuppressive 
therapies per local guidelines. 
 
 
Pneumonitis1 
 
Grade 1 
Radiographic 
changes only 
 
 
- Consider delay of therapy 
 
- Monitor for symptoms every 2-3 days 
 
- Consider Pulmonary and Infectious 
Disease (ID) consults 
 
- Re-image at least every 3 weeks 
 
_________ 
 
Grade 2 
Mild to moderate 
new symptoms 
 
 
- Delay therapy 
 
-Resume therapy with same dose when 
toxicity resolves to Grade 0-1 
 
- For recurrent Grade 2 Pneumonitis 
discontinue therapy 
 
- Pulmonary and ID consults 
 
- Monitor symptoms daily, consider 
hospitalization 
 
- 1.0-2.0 mg/kg/day methylprednisolone IV 
or oral equivalent, followed by taper 
 
- Add prophylactic antibiotics for 
opportunistic infections 
 
- Consider bronchoscopy, lung biopsy 
 
- Re-image every 1-3 days 
 
If improves: 
- When symptoms return to near baseline, taper 
steroids over at least 4 weeks and then resume 
therapy with same dose and consider prophylactic 
antibiotics 
 
If not improving after 2 weeks or worsening: 
- Treat as Grade 3-4  
 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks 
 
 
Grade 3-4 
 
- Discontinue therapy  
 
If improves to baseline: 
- Taper steroids over at least 6 weeks 
 
Permanently discontinue 


 
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Protocol Version # 3.1 
 
 September 10, 2018 
Severe new 
symptoms; 
New/worsening 
hypoxia; Life-
threatening 
 
- Hospitalize  
 
- Pulmonary and ID consults 
 
- 2-4 mg/kg/day methylprednisolone IV or 
IV equivalent 
 
- Add prophylactic antibiotics for 
opportunistic infections 
 
- Consider bronchoscopy, lung biopsy 
 
If not improving after 48 hours or worsening: 
- Add additional immunosuppression (e.g. 
infliximab, cyclophosphamide, intravenous 
immunoglobulin (IVIG), or mycophenolate 
mofetil). 
Renal Failure or 
Nephritis1 
 
Grade 1 
Creatinine > ULN 
and > than baseline 
but ≤ 1.5 x baseline 
 
 
- Continue therapy  
 
- Monitor creatinine weekly 
 
If returns to baseline: 
- Resumes routine creatinine monitoring per 
protocol 
 
________ 
 
Grade 2 
Creatinine > 1.5 x 
baseline to 3.0 x 
ULN 
 
 
- Delay therapy 
 
-Resume therapy with same dose when 
toxicity resolves to Grade 0-1 
 
- Monitor Creatinine every 2-3 days 
 
- 1.0 -2.0 mg/kg/day methylpredniolone IV 
or oral equivalent. 
 
- Consider renal biopsy 
 
 
If returns to Grade 1: 
- Taper steroids over at least 4 weeks, consider 
prophylactic antibiotics for opportunistic 
infections, and resume therapy with same dose 
and routine creatinine monitoring.  
 
If elevations persist > 7 days or worsen: 
- Treat as Grade 4  
 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks 
 
Grade 3-4 
Creatinine > 3 x 
baseline to > 6 x 
ULN 
 
 
- Discontinue therapy permanently 
 
- Monitor Creatinine daily 
 
- 1.0-2.0 mg/kg/day methylpredniolone IV 
or IV equivalent 
 
- Consult nephrologist 
 
- Consider renal biopsy 
 
If returns to grade 1: 
- Taper steroids over at least 4 weeks and add 
prophylactic antibiotics for opportunistic 
infections. 
 
Permanently discontinue 


 
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Protocol Version # 3.1 
 
 September 10, 2018 
 
Skin1 
Grade 1 
Covering < 10% 
body surface area 
(BSA)* 
 
 
- Continue therapy 
 
- Symptomatic therapy (e.g. antihistamines, 
topical steroids) 
 
If persists > 1-2 weeks or recurs: 
- Continue therapy 
- Consider skin biopsy  
- Consider 0.5-1.0 mg/kg/day methylprednisolone 
IV or oral equivalent. Once improving, taper 
steroids over at least 4 weeks, consider 
prophylactic antibiotics for opportunistic 
infections. 
________ 
Grade 2 
Covering 10-30% 
BSA* 
 
- Symptomatic therapy (e.g. antihistamines, 
topical steroids) 
-Delay therapy for 1-2 weeks and 
reevaluate. 
 
-Resume therapy with same dose when 
toxicity resolves to Grade 0-1 
 
 
If persists > 1-2 weeks or recurs: 
- Consider skin biopsy  
- Delay therapy 
- Consider 0.5-1.0 mg/kg/day methylprednisolone 
IV or oral equivalent. Once improving, taper 
steroids over at least 4 weeks, consider 
prophylactic antibiotics for opportunistic 
infections, and resume therapy with same dose  
 
If worsens: 
- Treat as Grade 3-4  
 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks 
Grade 3 
Covering > 30% 
BSA 
 
 
- Delay treatment and consider oral steroids 
if necessary.  
 
-  Resume therapy with one dose reduction 
when toxicity resolves to Grade 0-1 
 
- If the rash is grade 3 only based on BSA, 
and is otherwise mild and responds to dose 
interruption and topical steroids, can 
consider resuming at the same dose. 
 
- Consider skin biopsy 
 
If improves to grade 1: 
- Taper steroids over at least 4 weeks and add 
prophylactic antibiotics for opportunistic 
infections 
- Resume therapy with one dose reduction when 
toxicity resolves to Grade 0-1 
 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks 


 
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Protocol Version # 3.1 
 
 September 10, 2018 
- Dermatology consult 
 
- 1.0-2.0 mg/kg/day IV methylprednisolone 
or IV equivalent 
 
 
Grade 4 
Any % BSA; 
Life-threatening 
consequences 
(Refer to NCI CTCAE 
v5 for term-specific 
grading criteria) 
 
 
- Discontinue therapy permanently 
 
- Consider skin biopsy 
 
- Dermatology consult 
 
- 1.0-2.0 mg/kg/day IV methylprednisolone 
or IV equivalent 
 
Permanently discontinue 
Permanently discontinue 
Myocarditis 
Grade 1 or 2 
 
-  Delay therapy 
 
- Administer corticosteroids 
 
________ 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks 
Grade 3 or 4 
 
- Discontinue therapy permanently 
 
- Administer corticosteroids 
 
Permanently Discontinue 
Permanently Discontinue 
All Other Drug-
Related Toxicityc 
Grade 3 or Severe 
(meeting SAE 
criteria) 
or intolerable/ 
persistent Grade 2 
 
- Delay therapy 
 
-Resume therapy with same dose when 
toxicity resolves to Grade 0-1 
 
- Based on severity of AE administer 
corticosteroids 
 
- If an SAE, consider dose reduction. 
 
- Ensure adequate evaluation to confirm 
etiology or exclude other causes 
 
 
________ 
Toxicity does not resolve within 12 
weeks of last dose or inability to 
reduce corticosteroid to 10 mg or less 
of prednisone or equivalent per day 
within 12 weeks 
Grade 4 
or recurrent Grade 
3 
- Permanently discontinue 
 
- Based on severity of AE administer 
corticosteroids 
________ 
Permanently discontinue 


 
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Protocol Version # 3.1 
 
 September 10, 2018 
 
 
- Ensure adequate evaluation to confirm 
etiology or exclude other causes 
 
 
Note: Permanently discontinue for any severe (meeting SAE criteria) or Grade 3 drug-related AE that recurs or any life-threatening event. 
 
 
1. 
In general, for disease group GI, Hepatic, Endocrinopathy, Pulmonary, Renal, Neurological and skin:  
• 
Rule out non-inflammatory causes. If non-inflammatory causes are identified, treat accordingly and continue I-O therapy. 
• 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
For the below disease groups, also:  
• 
For Endocrinopathy AE management: 
Consider visual field testing, endocrinology consultation, and imaging.  
• 
For GI AE management:  
Opiates/narcotics may mask symptoms of perforation. Infliximab should not be used in cases of perforation or sepsis.  
• 
For Hepatic AE management: 
Consider imaging for obstruction. 
• 
For Pulmonary AE management: 
Evaluate with imaging and pulmonary consultation.  
• 
For Renal AE management: 
Patients on IV steroids may be switched to an equivalent dose of oral corticosteroids (e.g. prednisone) at start of tapering or earlier, once sustained clinical improvement is 
observed. Lower bioavailability of oral corticosteroids should be taken into account when switching to the equivalent dose of oral corticosteroids. 
 
a For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 1 week 
then patients should be discontinued. 
b 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 pre-medicated for the next scheduled dose. 
c Patients with intolerable or persistent Grade 2 drug-related AE may delay study medication at physician discretion.  Permanently discontinue study drug for persistent Grade 2 AEs for 
which treatment with study drug has been held, that do not recover to Grade 0-1 within 12 weeks of the last dose. 


 
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 September 10, 2018 
Table 5: Dose Modification Guidelines for Non-immune Drug-Related Adverse Events 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
Treatment 
Restart 
Dose/Schedule for Treatment Restart 
Discontinue Subject 
(After Consultation 
with Merck & Incyte) 
Epacadostat 
(INCB024360) 
Pembrolizumab  
(MK-3475) 
Hematologic toxicity 
1, 2 
No 
N/A 
N/A 
N/A 
N/A 
3 
Yes 
Toxicity resolves 
to ≤ Grade 1 or 
baseline 
First occurrence, restart at 
same dose.  
 
Second occurrence or more, 
reduce dose when resuming.  
 
Restart at same dose and 
schedule.  See Sections 
4.10.4. and 6.3. for 
recommendations regarding 
immune-mediated AEs. 
Toxicity does not resolve 
within 12 weeks of last 
infusion. 
4 
Yes 
N/A 
N/A 
N/A 
Permanently discontinue 
Non-hematologic toxicity, 
excluding immune related 
AEs in Table 4 
Note: Exception to be treated 
to similar Grade 1 toxicity: 
• 
Grade 2 alopecia 
• 
Grade 2 fatigue 
• 
Grade 3 rash in the 
absence of 
desquamation, no 
mucosal 
involvement, does 
not require 
1 
No 
N/A 
N/A 
N/A 
N/A 
2 
Consider 
holding for 
persistent 
symptoms 
Toxicity resolves 
to ≤ Grade 1 or 
baseline 
 
Reduce 1 dose level 
Restart at same dose and 
schedule.  See Sections 
4.10.4. and 6.3. for 
recommendations regarding 
immune-mediated AEs. 
Toxicity does not resolve 
within 12 weeks of last 
infusion 
3 
Yes 
Toxicity resolves 
to ≤ Grade 1 or 
baseline 
 
Reduce 1 dose level 
Restart at same dose and 
schedule.  See Sections 
4.10.4. and 6.3. for 
recommendations regarding 
immune-mediated AEs. 
Toxicity does not resolve 
within 12 weeks of last dose 
or inability to reduce 
corticosteroid to 10 mg or 
less of prednisone or 
equivalent per day within 12 
weeks 


 
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Protocol Version # 3.1 
 
 September 10, 2018 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
Treatment 
Restart 
Dose/Schedule for Treatment Restart 
Discontinue Subject 
(After Consultation 
with Merck & Incyte) 
Epacadostat 
(INCB024360) 
Pembrolizumab  
(MK-3475) 
systemic steroids, 
and resolves to 
Grade 1 within 
14 days 
For additional information 
regarding AE with potential 
immune etiology, see 
Sections 4.10.4 and 6.3. 
 
4 
Yes 
N/A 
N/A 
N/A 
Permanently discontinue 
 
Note:  Subjects who experience a recurrence of the same severe or life-threatening AE at the same grade or greater with re-challenge 
of the combination should be discontinued from study treatment immediately and not re-challenged. 


 
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6.3. Management of Immune-Related Adverse Events (irAEs) 
Events of clinical interest of a potential immunologic etiology or irAEs may be defined as an 
AE of unknown etiology, associated with drug exposure and consistent with an immune 
phenomenon.  irAEs may be predicted based on the nature of the pembrolizumab or 
epacadostat compounds, their mechanism of action, and reported experience with 
immunotherapies that have a similar mechanism of action.  Special attention should be paid 
to AEs that may be suggestive of potential irAEs.  An irAE can occur shortly after the first 
dose or several months after the last dose of treatment.   
If an irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, 
toxin or other etiologic causes before labeling an AE as an irAE.  Subjects who develop a 
≥ Grade 2 irAE should be discussed immediately with the sponsor.  Please refer to Table 4 in 
Section 6.2. 
6.4. Procedures for Subjects Exhibiting Serotonin Syndrome (SS) 
There is a theoretical chance that epacadostat could cause an increase in serotonin levels in 
the brain that might trigger SS when administered in combination with other serotonergic 
agents.  This syndrome has been most closely associated with use of MAOIs, Demerol®, 
linezolid, or methylene blue; all of these agents are prohibited during the study.  Serotonin 
reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) are 
permitted in the study.  The following procedures will be implemented if subjects exhibit the 
signs/symptoms of SS including tremor; hyperreflexia; spontaneous, ocular, or inducible 
clonus; together with agitation, fever, diaphoresis, or muscle rigidity: 
• Immediately 
interrupt 
epacadostat 
administration. 
Administration 
of 
pembrolizumab may continue. 
• Immediately interrupt any SSRI or SNRI administration. 
• Provide appropriate medical management of the subject until all signs/symptoms 
are resolved (eg, IV fluids and/or sympathomimetic amines for hypotension, 
benzodiazepines for agitation, administration of 5-hydroxytryptamine antagonists 
such as cyproheptadine). 


 
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• If subject chooses to remain in the study, restart treatment with epacadostat after 
the SSRI or SNRI has been discontinued, no sooner than 5 half-lives have elapsed 
for the specific SSRI or SNRI in question, and after resolution of signs/symptoms 
of SS.  The SSRI or SNRI dosing MAY NOT be restarted. 
• If subject chooses to withdraw from the study, or must restart treatment with SSRI 
or SNRI, the subject should be scheduled for a follow-up visit.  Treatment with 
SSRI or SNRI may be initiated 2 weeks after resolution of signs and symptoms of 
SS. 
7. ADVERSE EVENTS AND REPORTING PROCEDURES 
7.1. Adverse Event Definition and Reporting 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An adverse event can therefore be any unfavorable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product or protocol-specified 
procedure, whether or not considered related to the medicinal product or protocol-specified 
procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Merck’s product, is also an AE. 
AEs can be spontaneously reported or elicited during open-ended questioning, examination, 
or evaluation of a subject. In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs. 
AEs will be graded according to NCI CTCAE v5.  Both serious and non-serious AEs will be 
clearly noted in source documentation and listed on study specific eCRFs.  The investigator 
or designee will assess each AE to determine whether it is unexpected according to the 
informed consent document, protocol document, or IBs, and related to the investigation. 
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 
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Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using the study 
specific eCRF regardless of the event’s relatedness to the investigation. Events meeting the 
IRB definition of ‘Unanticipated Problem’ will be reported to the IRB within 10 working 
days of investigator determination expedited reporting is required, or within 5 working days 
for deaths or life-threatening experiences. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered AEs.  Examples of this 
may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from 
abuse and from withdrawal. Progression of the cancer under study is not considered an AE.  
All AEs/SAEs that occur after the consent form has been signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the study, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
From the time of treatment allocation/randomization through initiation of a new anticancer 
therapy, all AEs must be reported by the investigator. Such events will be recorded at each 
examination on the AE eCRF.  The reporting timeframe for AEs meeting any serious criteria 
is described in section 7.1. The investigator will make every attempt to follow all subjects 
with non-serious AEs for outcome. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status); subjects will begin AE collection after signing 
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Epacadostat Adverse Event reporting: 
1. 
Initial Serious Adverse events (SAEs) and/or subsequent follow-up reports should 
be reported via email to: IncytePhVOpsIST@incyte.com.  SAE reports should be 
for a single subject with any additional documents (i.e. discharge summary, 
relevant test results) included for the same subject as individual attachments to the 
email. One email can have multiple attachments as long as each attachment 
contains relevant information for the same subject. 
2. 
Please email your SAE form with a cover sheet and any additional attachments to 
the IST email address: IncytePhVOpsIST@incyte.com. 
3. 
Telerx C3i is the PhV Clinical Research Organization (CRO) for Incyte.  They will 
be contacting you for SAE follow-up requests and data clarifications by sending 
you a data clarification form (DCF).  See follow-up section for details on this 
process.  The following is general contact information for Telerx C3i. 
TELERX C3I (Incyte PhV CRO) 
US SAE fax number 1-866-726-9234  
• Initial reports 
Incyte needs to be notified within 24 hrs of learning of an event as well as providing a 
completed SAE form emailed to IncytePhVOpsIST@incyte.com. 
1. 
SAE reporting for each subject begins the day patient start treatment and up to 30 
days after subject has completed or discontinued from the study or until new anti-
cancer treatment is initiated, whichever occurs first. 
2. 
All SAE notices are sent from the site to Incyte via a central email address: 
IncytePhVOpsIST@incyte.com established for IST sites for this process. 
3. 
SAEs, occurring using Incyte Study drug, are reported in accordance with the 
effective protocol.  SAEs occurring with any another commercial drug are reported 
to manufacturer of that drug in accordance with regulations and protocol. 


 
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4. 
SAEs related to concomitant medications/drug delivery systems are reported 
directly to the manufacturers of those drugs/devices in accordance with the 
package insert. Meaning, follow the SAE manufacturer reporting requirements for 
all medication other than Epacadostat. 
5. 
All SAE details are recorded on the SAE Report form, regardless of causality to 
the investigational product and sent via email in accordance with the protocol.  If a 
non-serious Adverse Event (AE) becomes serious, the process for SAE reporting is 
followed.   
6. 
Additional information requested upon internal Incyte review will be asked by 
Telerx C3i in the form of a Data Clarification Form (DCF).  
• Follow-up reports 
1. 
Follow-up SAE reports are sent via email to IncytePhVOpsIST@incyte.com from 
the Investigator site.  
2. 
Telerx C3i tracks any critical outstanding follow-up items and questions and 
contacts the investigational site via a faxed DCF for the additional requested 
information until all outstanding queries are resolved.  A sample of this form is 
included in Appendix III.  This includes requests for hospital discharge summaries, 
autopsy reports, and death certificates (if applicable), results of relevant laboratory, 
and diagnostic tests.  The investigational site faxes the additional information to 
Telerx C3i, using the Telerx C3i SAE fax number.  The site personnel will update 
all relevant data on the appropriate SAE Report Form or equivalent to include any 
new or changed information.  The Incyte Safety Representative (IC SR) will 
monitor outstanding queries and take appropriate action needed for resolution. 
3. 
Any serious SAE upgraded to death or life-threatening requires that the follow up 
report be emailed to: IncytePhVOpsIST@incyte.com email address within 24 
hours. 


 
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• Regulatory Reporting  
The Investigator Sponsor (George A. Fisher, Jr., MD, PhD) of the IST trial is responsible for 
meeting expedited reporting requirements to Health Authorities and all participating 
investigators under their institution’s IND.  Incyte is responsible for meeting expedited 
reporting requirements to Health Authorities (HAs) in their respective territory and for cross 
reporting any Serious Unexpected Suspected Adverse Reaction (SUSAR) originating from 
IST sponsored studies to Incyte’s IND, NDA, and Incyte investigators from Incyte sponsored 
trials as required. 
• Reporting of Pregnancy 
An “Initial Pregnancy Report” or equivalent must be completed in full and emailed to 
IncytePhVOpsIST@incyte.com within 24 hrs of discovery of a pregnancy of a subject who 
has taken the Incyte product or the pregnancy of a partner for a subject who has taken the 
Incyte product.  The “Follow-up Pregnancy Report Form” or equivalent must be completed 
and emailed to IncytePhVOpsIST@incyte.com within 30 days after delivery, so that Incyte is 
provided with information regarding the outcome of the pregnancy.  If the pregnancy results 
in any events which meet the serious criteria (i.e., miscarriage or termination), the SAE 
reporting process needs to be followed and the timelines associated with an SAE should be 
followed. 
7.2. Definition of an Overdose for This Protocol and Reporting of Overdose - 
Pembrolizumab 
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 
1,000 mg or greater (≥5 times the indicated dose).  No specific information is available on 
the treatment of overdose of pembrolizumab. Appropriate supportive treatment should be 
provided if clinically indicated. In the event of overdose, the subject should be observed 
closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
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associated clinical symptoms or abnormal laboratory results, the overdose is reported as a 
non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours 
to Merck Global Safety Attn: Worldwide Product Safety; FAX 215 993-1220)  
7.3. Definition of an Overdose for This Protocol and Reporting of Overdose – 
Epacadostat  
There has been no clinical experience with overdose of Epacadostat. Treatment of overdose 
should consist of general supportive measures. 
7.4. Reporting of Pregnancy and Lactation to Merck and Incyte 
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the study. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the study, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of study product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be 
reported by the investigator.  All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to Merck Global Safety (Attn: Worldwide 
Product Safety; FAX 215 993-1220) AND Incyte (IncytePhVOpsIST@incyte.com) 


 
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7.5. Reporting of Adverse Events to Merck and Incyte 
7.5.1. 
Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
investigational product that: 
• Results in death; 
• Is life threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically must have caused 
death if it were more severe); 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event  
• Note: The following hospitalizations are not considered SAEs: 
o A visit to the emergency room or other hospital department lasting less than 
24 hours that does not result in admission (unless considered an “important 
medical event” or a life-threatening event). 
o Elective surgery planned before signing consent 
o Admission per protocol for planned medical/surgical procedure (e.g., 
mediport placement) 
o Routine health assessment requiring admission for baseline/trending of health 
status (e.g., routine colonoscopy) 
o Medical/surgical admission for purpose other than remedying ill health state 
that was planned before study entry. Appropriate documentation is required in 
these cases. 
o Admission encountered for another life circumstance that carries no bearing 
on health status and requires no medical/surgical intervention (e.g., lack of 
housing, economic inadequacy, caregiver respite, family circumstances, 
administrative) 
• Note: In addition to the above criteria, AEs meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Merck in the same 


 
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timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
o Is a new cancer (that is not a condition of the study); 
o Is associated with an overdose. 
For the time period beginning when the consent form has been signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study that occurs 
to any subject must be reported to the FDA through appropriate channels and within 10 
working days to Merck Global Safety and Incyte Global Safety if it causes the subject to be 
excluded from the study, or is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment allocation/randomization through 30 days 
following the final dose, any SAE or follow-up to a SAE, including death due to any cause 
other than progression of the cancer under study, whether or not related to the study products, 
must be reported to the FDA as appropriate and within 10 working days to Merck Global 
Safety and Incyte team. 
Additionally, any SAE, considered by an investigator to be related to Merck product at any 
time after signing consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to Merck Global Safety. 
 
Incyte Serious Adverse Event specifics for reporting: 
1. Initial Serious Adverse events (SAEs) and/or subsequent follow-up reports should be 
reported via email to: IncytePhVOpsIST@incyte.com.  SAE reports should be for a single 
subject with any additional documents (i.e. discharge summary, relevant test results) 
included for the same subject as individual attachments to the email. One email can have 
multiple attachments as long as each attachment contains relevant information for the 
same subject. 


 
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2. Please email your SAE form with a cover sheet and any additional attachments to the IST 
email address: IncytePhVOpsIST@incyte.com. 
 
3. Telerx C3i is the PhV Clinical Research Organization (CRO) for Incyte.  They will be 
contacting you for SAE follow-up requests and data clarifications by sending you a data 
clarification form (DCF).  See follow-up section for details on this process.  The following 
is general contact information for Telerx C3i. 
TELERX C3I (Incyte PhV CRO) 
US SAE fax number 1-866-726-9234  
• Initial reports 
Incyte needs to be notified within 24 hrs of learning of an event as well as providing a 
completed SAE form emailed to IncytePhVOpsIST@incyte.com. 
1. SAE reporting for each subject begins the day patient start treatment and up to 30 days 
after subject has completed or discontinued from the study or until new anti-cancer 
treatment is initiated, whichever occurs first. 
2. All SAE notices are sent from the site to Incyte via a central email address: 
IncytePhVOpsIST@incyte.com established for IST sites for this process. 
 
3. SAEs, occurring using Incyte Study drug, are reported in accordance with the effective 
protocol.  SAEs occurring with any another commercial drug are reported to manufacturer 
of that drug in accordance with regulations and protocol. 
 
4. SAEs related to concomitant medications/drug delivery systems are reported directly to 
the manufacturers of those drugs/devices in accordance with the package insert. Meaning, 
follow the SAE manufacturer reporting requirements for all medication other than 
Epacadostat. 
 


 
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5. All SAE details are recorded on the SAE Report form, regardless of causality to the 
investigational product and sent via email in accordance with the protocol.  If a non-
serious Adverse Event (AE) becomes serious, the process for SAE reporting is followed.   
 
6. Additional information requested upon internal Incyte review will be asked by Telerx C3i 
in the form of a Data Clarification Form (DCF).  
• Follow-up reports 
1. Follow-up SAE reports are sent via email to IncytePhVOpsIST@incyte.com from the 
Investigator site.  
2. Telerx C3i tracks any critical outstanding follow-up items and questions and contacts the 
investigational site via a faxed DCF for the additional requested information until all 
outstanding queries are resolved.  A sample of this form is included in Appendix III.  This 
includes requests for hospital discharge summaries, autopsy reports, and death certificates 
(if applicable), results of relevant laboratory, and diagnostic tests.  The investigational site 
faxes the additional information to Telerx C3i, using the Telerx C3i SAE fax number.  
The site personnel will update all relevant data on the appropriate SAE Report Form or 
equivalent to include any new or changed information.  The Incyte Safety Representative 
(IC SR) will monitor outstanding queries and take appropriate action needed for 
resolution. 
3. Any serious SAE upgraded to death or life-threatening requires that the follow up report 
be emailed to: IncytePhVOpsIST@incyte.com email address within 24 hours. 
• Regulatory Reporting  
The Investigator Sponsor (George A. Fisher, Jr., MD, PhD) of the IST trial is responsible for 
meeting expedited reporting requirements to Health Authorities and all participating 
investigators under their institution’s IND.  Incyte is responsible for meeting expedited 
reporting requirements to Health Authorities (HAs) in their respective territory and for cross 
reporting any Serious Unexpected Suspected Adverse Reaction (SUSAR) originating from 
IST sponsored studies to Incyte’s IND, NDA, and Incyte investigators from Incyte sponsored 
trials as required. 


 
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• Reporting of Pregnancy 
An “Initial Pregnancy Report” or equivalent must be completed in full and emailed to 
IncytePhVOpsIST@incyte.com within 24 hrs of discovery of a pregnancy of a subject who 
has taken the Incyte product or the pregnancy of a partner for a subject who has taken the 
Incyte product.  The “Follow-up Pregnancy Report Form” or equivalent must be completed 
and emailed to IncytePhVOpsIST@incyte.com within 30 days after delivery, so that Incyte is 
provided with information regarding the outcome of the pregnancy.  If the pregnancy results 
in any events which meet the serious criteria (i.e., miscarriage or termination), the SAE 
reporting process needs to be followed and the timelines associated with an SAE should be 
followed. 
 
All subjects with SAEs must be followed up for outcome. 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally, investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) and Incyte (IncytePhVOpsIST@incyte.com) 
at the time of submission to FDA.  
 
7.5.2. 
Events of Clinical Interest (ECIs) 
Selected non-serious and SAEs are also known as ECIs, must be reported within 10 working 
days to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220).  
For the time period after the consent has been signed through 30 days following the safety 
follow-up, any ECI, or follow up to an ECI, whether or not related to study products, must be 
reported within 10 working days to Merck Global Safety. 
ECIs for this study include: 
1. An overdose of drug;   
2. An elevated AST or ALT lab value that is ≥ 3 x ULN and an elevated total bilirubin 
lab value that is ≥ 2 x ULN and, at the same time, an alkaline phosphatase lab value that 


 
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is < 2 x ULN, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  
7.6. Assignment of Intensity and Relationship to Investigational Product (Causality)  
Causal relationship to investigational product as determined by the investigator(s) should be 
defined based on the definitions below: 
• Related: There is a reasonable causal relationship to investigational product 
administration and the adverse event. 
• Not Related: There is not a reasonable causal relationship to investigational product 
administration and the adverse event. 
The expression “reasonable causal relationship” is meant to convey in general that there are 
facts (e.g., evidence such as de-challenge/re-challenge) or other arguments to suggest a 
positive causal relationship. 
7.7. Responsibility for Reporting AEs to Regulatory Authorities 
All AEs will be reported to regulatory authorities, IRB/IECs and investigators in accordance 
with all applicable global laws and regulations.  


 
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7.8. Evaluating Adverse Events 
All investigators who are qualified physicians and delegated, can evaluate for AEs. All AEs 
will be graded based on the NCI CTCAE v.5. Any AE which changes in grade over the 
course of a given episode will have each change of grade recorded independently in the 
appropriate eCRF. All adverse events regardless of grade must be evaluated for seriousness 
and causality to the investigational agents. See Table 6 for further guidance on evaluating an 
AE by grade, seriousness, and causality. 
 


 
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Table 6:Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all AEs for the following: 
V4.03  
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or 
hospitalization indicated; disabling; limiting self-care ADL. 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
Grade 5 
Death  
Seriousness 
A SAE is any AE occurring at any dose or during any use of an investigational drug that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: 
This does not include an AE that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of 
stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to 
treat a pre-existing condition that has not worsened is not a SAE.  A pre-existing condition is a clinical condition that is diagnosed prior to 
the use of the agent and is documented in the patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to Merck and Incyte within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any AE associated with an overdose is considered a SAE for collection purposes. An 
overdose that is not associated with an AE is considered a non-serious ECI and must be reported within 24 hours to Merck and Incyte. 
 
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a 
SAE when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention 
to prevent one of the outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the AE. If less than 1 day, indicate the appropriate length of time. 
Action taken  
Did the AE cause drug to be discontinued? 
Relationship 
to Study 
Drug  
Did study drug cause the AE? The determination of the likelihood that the investigational agent caused the AE will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the 
causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be 
retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing 
the likelihood of a relationship between the test drug and the AE based upon the available information. 
The following components are to be used to assess the relationship between the investigational agents and the AE; the greater the 
correlation with the components and their respective elements (in number and/or intensity), the more likely product caused the AE: 
 
Exposure 
Is there evidence that the subject was actually exposed to the investigational drug such as: reliable history, acceptable 
compliance assessment (pill count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in 


 
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bodily specimen? 
 
Time Course 
Did the AE follow in a reasonable temporal sequence from administration of drug?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to studies with investigational medicinal 
drug)? 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other 
host or environmental factors? 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
Dechallenge 
Was drug discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE 
resolved/improved despite continuation of the product; or (3) the study is a single-dose drug study); or (4) drug(s) is/are 
only used one time.) 
Rechallenge 
Was the subject re-exposed to drug on this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the study is a 
single-dose drug study); or (3) product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS AND WHICH MAY HAVE 
BEEN CAUSED BY DRUG, OR IF REEXPOSURE TO DRUG POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE MERCK 
AND INCYTE AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with 
StudyTreatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding drug or drug class 
pharmacology or toxicology? 
The assessment of relationship will be reported on the CRFs by an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of product 
relationship). 
Yes, there is a reasonable 
possibility of product 
relationship. 
There is evidence of exposure to drug.  The temporal sequence of the AE onset relative to the administration of drug is 
reasonable.  The AE is more likely explained by drug than by another cause. 
No, there is not a reasonable 
possibility of product 
relationship 
Subject did not receive the investigational drugs OR temporal sequence of the AE onset relative to administration of 
drug is not reasonable OR the AE is more likely explained by another cause than the drug.  (Also entered for a subject 
with overdose without an associated AE.) 


 
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7.9. Laboratory Test Abnormalities Definition and Reporting 
Laboratory abnormalities that constitute an AE in their own right (are considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study drug), should be recorded on the AE page of the eCRF. Whenever possible, a diagnosis 
rather than a symptom should be provided (e.g., anemia instead of low hemoglobin).  Laboratory 
abnormalities that meet the criteria for AEs (all grades) should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found.  When an abnormal 
laboratory test result corresponds to a sign or symptom of a previously reported AE, it is not 
necessary to separately record the laboratory test result as an additional event. 
A Grade 3 or 4 (severe) AE, as per CTCAE v5, does not automatically indicate an SAE unless it 
meets the definition of serious, as defined in Section 7.5.1, and/or per the investigator's 
discretion.  A dose interruption or adjustment for the laboratory abnormality may be required and 
should not contribute to the designation of a laboratory test abnormality as an SAE. 
7.10. 
Handling of Expedited Safety Reports 
In accordance with local regulations, Merck and Incyte will notify investigators of all SAEs that 
are suspected (related to the investigational products) and unexpected (i.e., not previously 
described in the IBs) regarding the drugs under study at other sites in other investigations. In the 
European Union (EU), an event meeting these criteria is termed a Suspected, Unexpected 
Serious Adverse Reaction (SUSAR). Investigator notification of these events will be in the form 
of an expedited safety report (ESR).  
Other important findings which may be reported by the sponsor as an ESR include: increased 
frequency of a clinically significant expected SAE, an SAE considered associated with study 
procedures that could modify the conduct of the study, lack of efficacy that poses significant 
hazard to study subjects, clinically significant safety finding from a nonclinical (e.g., animal) 
study, important safety recommendations from a study data monitoring committee, or sponsor 
decision to end or temporarily halt a clinical study for safety reasons. 
Upon receiving an ESR from Merck and/or Incyte, the investigator must review and retain the 
ESR with the IBs. Where required by local regulations or when there is a central IRB/IEC for the 
study, the sponsor will submit the ESR to the appropriate IRB/IEC. The investigator and 


 
 
 
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IRB/IEC will determine if the informed consent requires revision. The investigator should also 
comply with the IRB/IEC procedures for reporting any other safety information.  
In addition, suspected serious adverse reactions (whether expected or unexpected) shall be 
reported by Merck and Incyte to the relevant competent health authorities in all concerned 
countries according to local regulations (either as expedited and/or in aggregate reports). 
7.11. 
Warnings and Precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided IB.  Additional 
safety information collected between IB updates will be communicated in the form of 
Investigator Notifications (INs).  Any important new safety information should be discussed with 
the subject during the study as needed.  If new, significant risks are identified, they will be added 
to the ICF. 
7.12. 
Data Safety Monitoring Committee 
There will be no formal external data monitoring committee for this open-label study. This study 
will be monitored per standard Stanford’s data and safety monitoring schedule.


 
 
 
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8.  
CORRELATIVE/SPECIAL STUDIES  
Blood and tissue will be collected during the context of the study for future correlative studies 
including organoids (tissue) and immune markers (blood). Section 9 outlines the frequency of the 
testing being done and then being stored with the intent to analyze in the future.  
For the context of this particular protocol, we will only be collecting and storing blood, serum, 
plasma, and tissue that could be used for the indicated testing in the future.  
8.1. Blood Samples  
8.1.1. 
Required Research Samples 
Blood will be collected in green and purple top tubes. One 10 mL purple top EDTA tube for 
whole blood collection and three 10 mL green top tubes for plasma will be collected every 3 
weeks prior to pembrolizumab infusion for storage for future research. All these samples will be 
processed and stored frozen at -80°C.  
8.2. Tissue Samples 
Pre-treatment and on-treatment biopsies are to be collected on patients when safe and feasible. 
Details and methods for obtaining, processing, and shipping the fresh tumor biopsy are as 
follows: 
• 6-15 (average 10) core biopsies measuring  at least 4mm, if possible 10mm will be 
obtained from an accessible and safe primary or metastatic tumor site 
• When feasible, all core samples should be obtained from the same lesion/location at the 
appropriate time point 
• When feasible, 16-18 gauge needles should be used to obtain core samples. FNA samples 
are acceptable 
• Samples should contain at minimum 20% tumor viability as measured by adequate 
number of living cells based on H&E slide 
• Specimens will be collected/stored in FFPE or as a single cell suspension via the 
Correlatives Sciences Unit SOP. 


 
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9. STUDY CALENDARS 
Schedule of Events  
Screening 
Treatment Phase1 
EOT 
Post-Treatment 
C1D1 
C2D1 
C3D1 
Day 1 All 
Subsequent 
Cycles 
Discontinuation 
Visit 
Follow-Up Visits 
Survival 
Follow-Up 
Evaluation/Window 
Day -28 
to Day -1 
Day 1 
± 3 
Days 
± 3 
Days 
± 3 Days 
+ 5 Days 
Every 9 Weeks 
After 
Discontinuation 
(± 7 Days) 
Every 12 Weeks  
(± 7 Days) 
ADMINISTRATIVE PROCEDURES 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
Prior medical and cancer history 
X 
 
 
 
 
 
 
 
Concomitant medications review 
X 
X 
X 
X 
X 
X 
 
 
Administer Pembrolizumab2 
 
X 
X 
X 
X 
 
 
 
Administer Epacadostat3 
 
X 
X 
X 
X 
 
 
 
Survival follow-up 
 
 
 
 
 
 
 
X 
CLINICAL PROCEDURES AND ASSESSMENTS 
Comprehensive physical exam 
X 
 
 
 
 
X 
 
 
Targeted physical exam 
 
X 
X 
X 
X 
 
X 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
X 
 
 
1 Treatment cycles are every 3 weeks (~ 21 days ± 3 days).   
2 Fixed dose at 200 mg per IV every 3 weeks. 
3 Fixed dose at 300 mg orally twice daily every day, all 21 days of each cycle. 


 
 
 
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Screening 
Treatment Phase1 
EOT 
Post-Treatment 
C1D1 
C2D1 
C3D1 
Day 1 All 
Subsequent 
Cycles 
Discontinuation 
Visit 
Follow-Up Visits 
Survival 
Follow-Up 
Evaluation/Window 
Day -28 
to Day -1 
Day 1 
± 3 
Days 
± 3 
Days 
± 3 Days 
+ 5 Days 
Every 9 Weeks 
After 
Discontinuation 
(± 7 Days) 
Every 12 Weeks  
(± 7 Days) 
Vital signs and weight 
X 
X4 
X 
X 
X 
X 
X 
 
12-lead ECG  
X 
 
 
 
 
X 
 
 
AE assessment  
 
X 
X 
X 
X 
X 
X 
X 
EFFICACY MEASUREMENTS 
Radiologic tumor assessment 
X5 
 
 
 
X6,7 
X8,9 
X6 
 
LABORATORY ASSESSMENTS10,11,12 
Comprehensive serum chemistry 
X 
X 
X 
X 
X 
X 
X 
 
Tumor molecular profiling13 
X 
 
 
 
 
 
 
 
 
4 Height only required to be collected at Cycle 1 Day 1. 
5 Initial tumor imaging will be performed within 28 days before the first dose of study treatment. A CT chest/abdomen/pelvis with IV contrast is preferred. MRI abdomen with 
gadolinium is acceptable for patients with contrast allergies. 
6 Imaging on-study will be performed every 9 weeks (± 5 days) after the first dose of study treatment for the first 18 months then every 12 weeks thereafter. On-study imaging 
should follow calendar days and not be adjusted for delays in cycle starts or extension of treatment cycles due to toxicity. The same imaging technique should be used in a subject 
throughout the study. 
7 Per the RECIST v1.1 and irRC, if imaging shows progressive disease, the imaging assessment should be performed at a minimum of 4 weeks later to confirm progression as 
described. 
8 For patients that discontinue treatment for reasons other than disease progression, every effort should be made to continue monitoring their disease status by radiographic 
imaging at the imaging interval that was used at the time they came off study until 1) start of new anti-cancer therapy, 2) documented disease progression, 3) death, or 4) end of 
study, whichever occurs first. 
9 If a prior scan was obtained within 4 weeks before the date of discontinuation, then a scan at the discontinuation visit is not required. In subjects who discontinue study drug 
without confirmed disease progression, a radiological evaluation should be repeated at the time of treatment discontinuation (i.e., date of discontinuation ± 4 week window). 
10 If labs at screening are collected within 7 days of Cycle 1 Day 1, these do not need to be repeated at this visit.  
11 Pre-dose laboratory results need to be within 2 days of dosing at all cycles. 
12 See Table 2 for complete listing of all required laboratory tests required. 


 
 
 
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Screening 
Treatment Phase1 
EOT 
Post-Treatment 
C1D1 
C2D1 
C3D1 
Day 1 All 
Subsequent 
Cycles 
Discontinuation 
Visit 
Follow-Up Visits 
Survival 
Follow-Up 
Evaluation/Window 
Day -28 
to Day -1 
Day 1 
± 3 
Days 
± 3 
Days 
± 3 Days 
+ 5 Days 
Every 9 Weeks 
After 
Discontinuation 
(± 7 Days) 
Every 12 Weeks  
(± 7 Days) 
Hematology with differential 
X 
X 
X 
X 
X 
X 
X 
 
Lipid panel 
X 
X 
X 
X 
X 
X 
 
 
Coagulation panel (PT, aPTT, 
INR14 
X 
 
 
 
 
 
 
 
Endocrine function testing15 
X 
X 
X 
X 
X 
 
X 
 
Serum pregnancy test or urine16 
X 
 
 
 
 
 
 
 
Tumor Markers17 
 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
 
 
Required research samples (blood) 
 
X18 
X 
X 
X 
 
 
 
 
 
 
TUMOR BIOPSY/ARCHIVAL TISSUE COLLECTION 
Fresh tissue collection for 
Correlative studies (tissue) 19 
X 
 
 
X 
 
 
 
 
 
13 Tumor molecular profilingcan be performed on archived tissue or newly obtained during the study participation 
14 If a coumadin-based anticoagulant is given, INR should be monitored weekly for the first 4 weeks after initiation of therapy and again upon discontinuing epacadostat. 
15 TSH required at all day 1 visits, T3 and fT4 only required if TSH is abnormal or patient is symptomatic. 
16 For women of childbearing potential, a serum pregnancy test is required at screening but must be within 3 days before first dose of study treatment. Pregnancy tests (serum or 
urine) should be repeated as needed if required by institutional regulations.  
17 CEA and CA19-9 will be checked at baseline on C1D1 prior to Pembrolizumab and Epacadostat and, if elevated, followed every 9 weeks during therapy. 
18 Before pembrolizumab dose every 3 weeks 
19 Fresh tumor biopsy will be collected pre-treatment (between day -14 to day 0) and on treatment (day 42 ± 5 days). For additional reference go to section 4.9.3 and 8.2 


 
 
 
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Schedule of Events – Second Course Phase/Retreatment20 
Progression 
Treatment Phase21 
EOT 
Post-Treatment 
C1D1 
C2D1 
C3D1 
Day 1 All 
Subsequent 
Cycles 
Discontinuation 
Visit 
Follow-Up Visits 
Survival 
Follow-Up 
Evaluation/Window 
Day -14 to 
Day -1 
Day 1 
± 3 
Days 
± 3 
Days 
± 3 Days 
+ 5 Days 
Every 9 Weeks 
After 
Discontinuation 
(± 7 Days) 
Every 12 Weeks  
(± 7 Days) 
ADMINISTRATIVE PROCEDURES 
Re-check inclusion/exclusion 
criteria22 
X 
X 
 
 
 
 
 
 
Updated medical and cancer 
history 
X 
 
 
 
 
 
 
 
Concomitant medications 
review 
X 
X 
X 
X 
X 
X 
 
 
Administer Pembrolizumab23 
 
X 
X 
X 
X 
 
 
 
Administer Epacadostat24 
 
X 
X 
X 
X 
 
 
 
Survival follow-up 
 
 
 
 
 
 
 
X 
CLINICAL PROCEDURES AND ASSESSMENTS 
Comprehensive physical exam 
X 
 
 
 
 
X 
 
 
Targeted physical exam 
 
X 
X 
X 
X 
 
 
 
ECOG performance status 
X 
X 
X 
X 
X 
X 
 
 
 
20 Fresh tissue collection not required during the second course phase. 
21 Treatment given every 3 weeks (~ 21 days ± 3 days).  
22 Patient must meet required re-start criteria as defined in Section 4.8.  
23 Fixed dose at 200 mg per IV every 3 weeks. 
24 Fixed dose, resume with the same dose level of first course, orally twice daily every day, all 21 days of each cycle. 


 
 
 
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Progression 
Treatment Phase21 
EOT 
Post-Treatment 
C1D1 
C2D1 
C3D1 
Day 1 All 
Subsequent 
Cycles 
Discontinuation 
Visit 
Follow-Up Visits 
Survival 
Follow-Up 
Evaluation/Window 
Day -14 to 
Day -1 
Day 1 
± 3 
Days 
± 3 
Days 
± 3 Days 
+ 5 Days 
Every 9 Weeks 
After 
Discontinuation 
(± 7 Days) 
Every 12 Weeks  
(± 7 Days) 
Vital signs and weight 
X 
X25 
X 
X 
X 
X 
 
 
12-lead ECG  
 
 
 
 
 
X 
 
 
AE assessment  
X26 
X 
X 
X 
X 
X 
X 
X 
EFFICACY MEASUREMENTS 
Radiologic tumor assessment 
X27 
 
 
 
X28,29 
X 
X 
 
LABORATORY ASSESSMENTS 
Comprehensive serum 
chemistry 
X 
X 
X 
X 
X 
X 
X 
 
Hematology with differential 
X 
X 
X 
X 
X 
X 
X 
 
Lipid panel 
X 
X 
X 
X 
X 
X 
 
 
Coagulation panel (PT, aPTT, 
INR) 
X 
 
 
 
 
 
 
 
Endocrine function testing 
X 
X 
X 
X 
X 
 
X 
 
 
25 Height required to be collected at Cycle 1 Day 1 only. 
26 All AEs from previous treatment with pembrolizumab and epacadostat must be ≤ grade 1 and stable. 
27 For subjects that have had a scan within 14 days of restarting therapy due to progression, scan does not need to be repeated pre-dosing. 
28 Imaging in the second course phase will be performed every 9 weeks (± 5 days) after the first dose of study treatment for the first 18 months then every 12 weeks thereafter. On-
study imaging should follow calendar days and not be adjusted for delays in cycle starts or extension of treatment cycles due to toxicity. The same imaging technique should be 
used in a subject throughout the study. 
29 Per the RECIST v1.1 and irRC, if imaging shows progressive disease, the imaging assessment should be performed at a minimum of 4 weeks later to confirm progression as 
described. 


 
 
 
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Progression 
Treatment Phase21 
EOT 
Post-Treatment 
C1D1 
C2D1 
C3D1 
Day 1 All 
Subsequent 
Cycles 
Discontinuation 
Visit 
Follow-Up Visits 
Survival 
Follow-Up 
Evaluation/Window 
Day -14 to 
Day -1 
Day 1 
± 3 
Days 
± 3 
Days 
± 3 Days 
+ 5 Days 
Every 9 Weeks 
After 
Discontinuation 
(± 7 Days) 
Every 12 Weeks  
(± 7 Days) 
Serum pregnancy test or urine 
X30 
 
 
 
 
 
 
 
Tumor Markers 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
X 
X 
X 
X 
X 
 
 
Required research samples 
 
X31 
X 
X 
X 
 
 
 
 
30 For women of childbearing potential, a pregnancy test must be done within 3 days of dosing on the second course phase. 
32 Before pembrolizumab dose every 3 weeks 


 
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10. MEASUREMENTS 
10.1. 
Tumor Imaging Evaluations  
Imaging of the chest, abdomen and pelvis is required at screening/baseline, every 9 weeks (± 5 
days) for the first 18 months, then every 12 weeks thereafter regardless of the location of known 
metastases. Similar methods of tumor assessment and similar techniques must be used to 
characterize each identified and reported lesion at screening/baseline and during subsequent 
tumor assessments. Imaging-based evaluation is preferred to clinical examination. All 
measurements should be taken and recorded in metric notation using a ruler or calipers.  
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan 
based on the assumption that CT slice thickness is 5 mm or less. If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans), but NOT for the chest.  
RECIST v1.1 will be applied by the site as the primary measure for assessment of tumor 
response and as a basis for protocol guidelines related to disease status (e.g., discontinuation of 
study therapy).  RECIST v1.1 will be adapted for defining progressive disease (PD) as follows to 
account for the unique tumor response seen in this class of therapeutics. 
10.2. 
Definition of Measurable/Non-Measurable or Index/Non-Index Lesions 
10.2.1. 
Measurable and Non-Measurable Lesions 
Measurable lesions are lesions that can be accurately measured in two perpendicular diameters, 
with at least one diameter ≥ 10 mm and the other dimension ≥ 10 mm (10 mm x 10 mm for spiral 
CT). The area will be defined as the product of the largest diameter with its perpendicular. Skin 
lesions can be considered measurable. 
Non-measurable (evaluable) lesions are all other lesions, including unidimensionally 
measurable disease and small lesions (lesions without at least one diameter ≥ 20 mm), and any of 
the following: 
• Lesions occurring in a previously irradiated area (unless they are documented as new 
lesions since the completion of radiation therapy), bone lesions, leptomeningeal disease, 
ascites, pleural or pericardial effusion, lymphangitis cutis/pulmonitis, abdominal masses 


 
 
 
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that are not pathologically/cytologically confirmed and followed by imaging techniques 
and cystic lesions. 
All measurable and non-measurable lesions should be measured at screening/baseline and at the 
defined tumor assessment time points (~ every 9 weeks ± 5 days for the first 18 months then 
every 12 weeks thereafter). Extra assessments may be performed, as clinically indicated, if there 
is a suspicion of progression. 
10.2.2. 
Index and Non-Index Lesions 
All measurable lesions, up to a maximum of five lesions per organ and ten lesions in total, 
should be identified as index lesions to be measured and recorded in the medical record at 
Screening. The index lesions should be representative of all involved organs. In addition, index 
lesions should be selected based on their size (lesions with the longest diameters), their 
suitability for accurate repeat assessment by imaging techniques, and how representative they are 
of the patient’s tumor burden. At screening, a sum of the products of diameters (SPD) for all 
index lesions will be calculated and considered the baseline sum of the products of diameters. 
Response criteria to be followed are listed below. The baseline sum will be used as the reference 
point to determine the objective tumor response of the index lesions at tumor assessment. 
Measurable lesions, other than index lesions, and all sites of non-measurable disease, will be 
identified as non-index lesions. Non-index lesions will be recorded in the medical record and 
should be evaluated at the same assessment time points as the index lesions. In subsequent 
assessments, non-index lesions will be recorded as “stable or decreased disease,” “absent,” or 
“progression.” 
10.2.3. 
Evaluation of Target Lesions 
Complete Response: Complete disappearance of all target lesions. 
Partial Response: Decrease, relative to baseline, of 30% or greater in the sum of the diameters 
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Stable Disease: Does not meet criteria for complete or partial response, in the absence of 
progressive disease. Subject with PR or CR that is not confirmed after at least 6 weeks are scored 
as SD unless they have new primary lesions. 
Progressive Disease: At least 20% increase in the sum of the products of all target lesions 
(taking as reference the smallest sum recorded at or following baseline) and/or the appearance of 
any new lesion(s). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. 
10.2.4. 
Evaluation of Non-Target Lesions 
Complete Response: Complete disappearance of all non-target lesions and normalization of 
tumor marker level. All lymph nodes must be non-pathological in size (< 10 mm in short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits.  
Progressive Disease: Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. 
10.3. 
Assessment of Disease According to RECIST v1.1 and irRC for Solid 
Tumors 
If imaging shows PD, tumor assessment should be repeated ≥ 4 weeks later to confirm PD with 
the option of continuing treatment for clinically stable subjects.  Clinically stable is defined by 
the following criteria: 
• Absence of signs and symptoms indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease 
Absence of progressive tumor at critical anatomical sites (e.g., cord compression) requiring 
urgent alternative medical intervention. 
 


 
 
 
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Table 7: 
Imaging and Treatment after First Radiographic Evidence of Progression  
 
In determining whether the tumor burden has increased or decreased, investigators should 
consider all target lesions as well as non-target lesions. Subjects who are deemed clinically 
unstable are not required to have repeat imaging for confirmation.  If radiologic progression is 
confirmed, then the subject will be discontinued from study treatment as specified in the 
protocol, and the first radiographic evidence of PD should be the date of progression.  If 
radiologic progression is not confirmed, then the subject should resume/continue study treatment 
and have their next scan according to the Protocol-specified schedule.  If progression is not 
confirmed and the subject continues on treatment, the next scan that documents disease 
progression (and is confirmed by a second scan at least 4 weeks later), will be considered the 
date of disease progression. 
Note:  If a subject with confirmed radiographic progression (i.e., 2 scans at least 28 days apart 
demonstrating progressive disease) is clinically stable or clinically improved, and there is no 
further increase in the tumor dimensions at the confirmatory scan, an exception may be 
considered to continue treatment if in the best interest of the patient clinically. Meaning, the 
investigator can continue if the risk-benefit is acceptable to continue the patient on study. 
Clinically stable subjects should also have at the confirmatory scan no further increase in the 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
First radiologic 
evidence of PD  
Repeat imaging at 
≥ 4 weeks to 
confirm PD  
May continue study 
treatment at the 
investigator's 
discretion while 
awaiting 
confirmatory scan  
Repeat imaging at 
≥ 4 weeks to 
confirm PD if 
possible  
Discontinue 
treatment  
Repeat scan 
confirms PD  
No additional 
imaging required  
Discontinue 
treatment  
No additional 
imaging required  
N/A  
Repeat scan shows 
SD, PR, or CR  
Continue regularly 
scheduled imaging 
assessments every 
9 weeks  
Continue study 
treatment at the 
investigator's 
discretion  
Continue regularly 
scheduled imaging 
assessments every 
9 weeks  
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per investigator's 
discretion  


 
 
 
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target lesions, no unequivocal increase in non-target lesions, and no additional new lesions 
develop (non-worsening PD) to continue study treatment. 
Imaging during the follow-up period is to be repeated every 9 weeks (63 ± 5 days) for subjects 
who discontinue study treatment for reasons other than disease progression until the subject 
experiences confirmed disease progression or starts a new antineoplastic therapy. 
10.4. Response Endpoints 
Pembrolizumab and epacadostat are expected to trigger immune-mediated responses, which 
require activation of the immune system prior to the observation of clinical response. Such 
immune activation may take weeks to months to be evident. 
Table 8: Response Evaluations based on Endpoints 
 
Progression Free 
Survival (PFS) 
Response Rate 
(RR) 
Overall Survival 
(OS) 
Safety 
Primary or 
Secondary 
Primary 
Secondary 
Secondary 
Secondary 
 
Definition and 
Time Frame 
Time from first 
treatment to 
documented disease 
progression or death 
due to any cause 
Defined as 
proportion of 
patients with 
RECIST v1.1 
response (sum of 
partial and complete 
responses). 
Time from first 
treatment until the 
day of death due to 
any cause 
Assessed on the 
basis of adverse 
events (AEs; graded 
according to the 
National Cancer 
Institute Common 
Terminology 
Criteria for Adverse 
Events, version 4.03) 
Safety Issue 
(Yes/No) 
No 
No 
No 
Yes 
Relevant Subset 
Patients who receive 
baseline imaging 
and at least first 
follow-up imaging at 
9 weeks.  
Patients who receive 
baseline imaging 
and at least first 
follow-up imaging at 
9 weeks. 
All enrolled patients 
Patients who receive 
at least 1 dose of 
pembrolizumab. 
Measurement 
Method 
CT or MRI every 9 
weeks  
CT or MRI every 9 
weeks 
CT or MRI every 9 
weeks 
CTCAE v5 
Measurement Time 
Points 
Every 9 weeks 
Every 9 weeks 
Every 9 weeks 
Day 1 of each cycle 
 
11. REGULATORY CONSIDERATIONS 
11.1. 
Institutional Review of Protocol 
The protocol, the proposed informed consent and all forms of participant information related to 
the study (e.g. advertisements used to recruit participants) will be reviewed and approved by the 


 
 
 
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Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 
made to the protocol will be submitted as a modification and will be approved by the IRB prior 
to implementation.  The Protocol Director will disseminate the protocol amendment information 
to all participating investigators. 
11.2. 
Data and Safety Monitoring Plan 
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study. The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include review of the 
following types of documents participating in the study: regulatory binders, case report forms, 
eligibility checklists, and source documents.  In addition, the DSMC will regularly review 
serious adverse events and protocol deviations associated with the research to ensure the 
protection of human subjects.  Results of the DSMC audit will be communicated to the IRB and 
the appropriate regulatory authorities at the time of continuing review, or in an expedited 
fashion, as needed. 
11.3. 
Data Management Plan 
The Protocol Director, or his/her designee, will prepare and maintain adequate and accurate 
participant case histories with observations and data pertinent to the study.  Study specific CRFs 
will document treatment outcomes for data analysis.  CRFs will be developed using the OnCore 
database system and will be maintained by the study team. CRFs will be electronic and only 
accessible to the research team via password, dual-authentication database. All research charts 
will be kept in a locked office. 
11.4. 
Study Monitoring 
The study will be monitored by Stanford’s internal Data Safety Monitoring Committee (DSMC) 
on an annual basis per institutional guidelines.  
11.5. 
Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 


 
 
 
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underlying European Union Directive 2001/20/EC and the United States Code of Federal 
Regulations, Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol and any amendments 
and the subject informed consent will receive IRB/IEC approval/favorable opinion prior to 
initiation of the study. 
All potential serious breaches must be reported to Genentech immediately. A serious breach is a 
breach of the conditions and principles of GCP in connection with the study or the protocol, 
which is likely to affect, to a significant degree, the safety or physical or mental integrity of the 
subjects of the study or the scientific value of the study. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective task(s). This study will not use the services of study 
personnel where sanctions have been invoked or where there has been scientific misconduct or 
fraud (e.g., loss of medical licensure, debarment). 
Systems with procedures that ensure the quality of every aspect of the study will be 
implemented. 
11.6. 
Protocol Adherence 
The principal investigator must obtain IRB or IEC approval for the investigation.  Initial IRB or 
IEC approval and all materials approved by the IRB or IEC for this study including the subject 
ICF and recruitment materials must be maintained by the investigator and made available for 
inspection. 
Each investigator must adhere to the Protocol as described in this document and agree that 
changes to the Protocol, with the exception of medical emergencies, must be discussed and 
approved, firstly, by the sponsor or its designee and, secondly, by the IRB or IEC.  Each 
investigator is responsible for enrolling subjects who have met the Protocol inclusion and 
exclusion criteria.  The IRB that granted original approval, or the IRB currently responsible for 
overseeing the conduct of the study, must be notified of all changes in and deviations from the 
Protocol that may increase risk to the subject, and/or that may adversely affect the rights of the 


 
 
 
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subject or validity of the investigation.  The investigator must send a copy of the approval letter 
from the IRB to the sponsor or its designee and retain the original in the site study regulatory 
file. 
Major eligibility deviations must be reported to the IRB in accordance with the IRB 
requirements.  During the course of the study, the monitor must notify the sponsor or its designee 
of subjects found not to have met eligibility criteria.  The medical monitor, in collaboration with 
the investigator, will determine if the subject should be withdrawn from the study. 
11.7. 
Financial Disclosure 
All clinical investigators participating in clinical studies subject to FDA Regulation Title 21 
Code of Federal Regulations (CFR) Part 54 – Financial Disclosure by Clinical Investigators, are 
required before study initiation to submit a completed Clinical Investigator Financial Disclosure 
Request Form that sufficiently details any financial interests and arrangements that apply.  For 
the purpose of this regulation, clinical investigator is defined as any investigator or sub-
investigator who is directly involved in the treatment or evaluation of research subjects, 
including the spouse and each dependent child of the clinical investigator.  These requirements 
apply to both US and foreign clinical investigators conducting covered clinical studies. 
Any new investigators or sub-investigators added to the covered clinical study during its conduct 
must also submit a completed Clinical Investigator Financial Disclosure Request Form.  During a 
covered clinical study, any changes to the financial information previously reported by a clinical 
investigator must be reported to the sponsor or its designee.  At the conclusion of the covered 
clinical study, the clinical investigators will be reminded of their obligation to report to the 
sponsor or its designee any changes to the financial information previously reported.  The 
clinical investigators will also be reminded that they must report any changes in their financial 
information for a period of 1 year after completion of the covered clinical study. 
11.8. 
Compliance with Study Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the study is solely 
responsible for determining whether the study and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 


 
 
 
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will allow subjects to identify potentially appropriate studies for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
study locations and study site contact information.     
11.9. 
Quality Control And Quality Assurance  
11.9.1. 
Pharmaceutical Company Audits 
At some point during the study, individuals from the Merck and/or Incyte Quality Assurance 
department and/or their authorized representative may visit the investigator's site to conduct an 
audit of the study.  The purpose of this visit will be to determine the investigator's adherence to 
the protocol, applicable regulations, and outlined procedures, in addition to assessing the 
accuracy of the study data.  Before initiating this audit, the investigator will be contacted by the 
company(ies) to arrange a convenient time for this visit.  The investigator and staff are expected 
to cooperate with the auditors and allow access to all subject records supporting the CRFs and 
other study-related documents. 
11.9.2. 
Inspection by Regulatory Authorities 
At some point during the investigational product's development program, a regulatory authority 
may visit the investigator to conduct an inspection of the study and the site.  The investigator and 
staff are expected to cooperate with the inspectors and allow access to all source documents 
supporting the CRFs and other study-related documents.  The investigator must immediately 
notify the sponsor when contacted by any regulatory authority for purposes of conducting an 
inspection.  
11.10. 
Ethics 
11.10.1. 
Ethical Conduct of the Study 
This study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and conducted in adherence to the study Protocol, GCPs as defined in 
Title 21 of the US CFR Parts 50, 54 56, 312, and Part 11, as well as ICH GCP consolidated 
guidelines (E6) and applicable regulatory requirements. 


 
 
 
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11.10.2. 
Ethics Review 
It is the responsibility of the investigator to assure that all aspects of the ethics review are 
conducted in accordance with the Declaration of Helsinki as described in the ICH E6:  Guideline 
for GCP, and/or local laws, whichever provides the greatest level of protection for the study 
participants.  The Protocol and any information supplied to the subject to obtain informed 
consent, including written ICFs, subject recruitment procedures (e.g., advertisements), and 
written information to be provided to subjects (information leaflets), must be reviewed and 
approved by a qualified IRB/IEC before enrollment of participants in the study.  Before initiation 
of the study, the sponsor or its designee must receive documentation of the IRB or IEC approval, 
which specifically identifies the study/Protocol, and a list of the committee members. 
The principal investigator is responsible for informing the IRB or IEC of any amendment to the 
Protocol in accordance with local requirements.  Protocol amendments and revisions to the ICF 
must be submitted to and approved by the IRB or IEC. 
Investigators must submit progress reports to the IRB or IEC in accordance with the IRB or IEC 
requirements and local regulations.  Annual re-approval of the study must be obtained.  Copies 
of progress reports and annual re-approvals must be sent to the sponsor or its designee. 
The principal investigator is also responsible for providing the IRB or IEC with reports of any 
reportable serious adverse drug reactions from any other study conducted with the investigational 
product.  The sponsor or its designee will provide this information to the principal investigator. 
When the sponsor or its designee provides the investigator with a safety report, the investigator is 
responsible for ensuring that the safety report is reviewed and processed in accordance with 
regulatory requirements and with the policies and procedures established by their respective 
IRBs. 
After completion or termination of the study, the investigator must submit a final report to the 
IRB or IEC and to the sponsor or its designee. 
The investigator, as part of the records retention requirements for the study, must maintain 
documentation of all submissions, correspondence, and approvals to and from the IRB or IEC. 


 
 
 
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Each clinical investigator is responsible to conduct the study in accordance with the Protocol, all 
applicable laws, regulations, and GCP according to ICH guidelines. 
11.11. 
Data Privacy 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor (or its designee) are responsible for ensuring that 
sensitive information is handled in accordance with local requirements (eg, HIPAA).  
Appropriate consent and authorizations for use and disclosure and/or transfer (if applicable) of 
protected information must be obtained. 
11.12. 
Data Handling and Record Keeping  
11.12.1. 
Inspection of Records 
The investigator must ensure that all records pertaining to the conduct of the clinical study (as 
listed above) are adequately maintained for a period of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or at least 2 years have elapsed since the formal termination of 
clinical development of the investigational product. 
11.12.2. 
Retention of Records 
The principal investigator must maintain all documentation relating to the study for a period of 
2 years after the last marketing application approval, or if not approved, 2 years following the 
termination of the test article for investigation.  If it becomes necessary for the sponsor or the 
regulatory authority to review any documentation relating to the study, the investigator must 
permit access to such records. 
The investigator must not destroy any records associated with the study without receiving 
approval from Incyte and/or Merck.  The investigator must notify the sponsor or its designee in 
the event of accidental loss or destruction of any study records.  If the investigator leaves the 
institution where the study was conducted, the sponsor or its designee must be contacted to 
arrange alternative record storage options. 


 
 
 
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Whenever possible, an original recording of an observation must be retained as the source 
document.  However, a photocopy of a record is acceptable, provided it is legible and is a 
verified copy of the original document. 
All CRF data entered by the site (including audit trail), as well as computer hardware and 
software (for accessing the data), will be maintained or made available at the site in compliance 
with applicable record retention regulations. 
11.13. 
Confidentiality 
Subject names will not be supplied to Merck, Incyte or its designee if applicable.  Only the 
subject number and subject's initials will be recorded in the CRF, where permitted; if the 
subject's name appears on any other document (e.g., laboratory report), it must be obliterated on 
the copy of the document to be supplied to the sponsor or its designee.  Study findings stored on 
a computer will be stored in accordance with local data protection laws.  The subjects will be 
informed that representatives of the sponsor or its designee, IRB or IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
12. STATISTICS CONSIDERATIONS 
12.1. 
Statistical Design 
This is a single-stage study for the doublet epacadostat 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 (Bang, abstract 4001, GI ASCO 2015). 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 one-sided 
significance of 10%.  The level of significance for the primary endpoint in Phase 2 is one-sided 
10%, which is deemed acceptable for a proof-of-concept study.   


 
 
 
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12.2. 
Safety Analyses 
12.2.1. 
Analysis Plan 
The analysis will be done on the intent to treat population and patients who drop out will be 
censored at the point of last follow up.  
The primary endpoint of the study is 6-month Progression-free survival (PFS), which is defined 
as number of days from the first day of taking study dose to the earlier of death or disease 
progression by RECIST v1.1 for solid tumors. Median PFS will be estimated using the 
Kaplan-Meier method. 
12.3. 
Secondary Analyses 
Secondary efficacy analysis will be conducted for the efficacy evaluable population. Secondary 
endpoints and analyses are as follows:  
To evaluate response rate (RR). Response will be determined by RECIST v1.1 for solid tumors.  
The 95% exact CI for the RR will be estimated using the Clopper-Pearson method.  For objective 
responders, the duration of response is the time from the first objective response contributing to 
an objective response, to the first objective response of PD (by RECIST v1.1) occurring after the 
first objective response contributing to the objective response.   
To evaluate overall survival (OS). Time-to-event data will be analyzed by the Kaplan-Meier 
method, treating subjects with no observed death or progression as censored at their last date 
known to be alive.  For the OS analysis, the nonparametric Kaplan-Meier method will be used to 
estimate the survival time distribution and the median survival.  
To assess the safety and tolerability of epacadostat in combination with pembrolizumab.  AEs 
will be coded by the MedDRA, and incidences will be tabulated by preferred term and system 
organ class for all events, related events, and events ≥ Grade 3.  Severity of AEs will be based on 
the CTCAE v5 scale as indicated.  Quantitative safety variables and their changes from baseline 
(laboratory, vital signs) will be summarized with descriptive statistics.  Clinically significant 
abnormal values will be flagged and tabulated based on predefined criteria.  Exposure will be 
analyzed by describing dose intensity, which is defined as the dose-received divided by the dose 
planned over a given time interval.  This will be done by cycle as well as overall cycles received 
for epacadostat and pembrolizumab.  For each cycle, incidences of dose reductions and cycle 


 
 
 
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delays will also be tabulated, by reason for the reduction or delay.  The percentage of subjects 
with any delay and/or reduction will also be calculated. 
Clinical Laboratory Tests. The clinical laboratory data will be analyzed using summary statistics 
(e.g., means and frequencies), and no formal statistical comparisons among the treatments are 
planned.  In addition, distributions of key laboratory parameters (including hemoglobin, 
neutrophils, and platelets) will be plotted over time; these values will also be classified into 
CTCAE toxicity grades and tabulated.  Descriptive statistics and mean change from baseline will 
be determined for vital signs at each assessment time.  Vital sign results will be reviewed for 
clinically notable abnormalities. 
12.4. 
Sample Size 
We will enroll 30 patients over 18 months and follow patients for at least 6 months.  
12.5. 
Criteria for Future Studies 
If the sample size is justified by precision only, state the outcomes that constitute success.  If the 
protocol is part of a sequence of studies, state the statistical criteria that will be applied.  If this is 
a pilot study, state what result would convince you to begin a fully powered study. 


 
 
 
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13. REFERENCES 
 
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Parfitt, J.R., Z. Miladinovic, and D.K. Driman, Increasing incidence of adenocarcinoma 
of the gastroesophageal junction and distal stomach in Canada -- an epidemiological 
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Wagner, A., Chemotherapy for advanced gastric cancer. Cochrane Database Syst Rev, 
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Fuchs, C.S., et al., Ramucirumab monotherapy for previously treated advanced gastric or 
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Wilke, H., et al., Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients 
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Herbst, R., et al., A study of MPDL3280A, an engineered PD-L1 antibody in patients with 
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Disis, M.L., Immune regulation of cancer. J Clin Oncol, 2010. 28(29): p. 4531-8. 
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Talmadge, J.E., M. Donkor, and E. Scholar, Inflammatory cell infiltration of tumors: 
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Usubutun, A., et al., Prognostic factors in renal cell carcinoma. J Exp Clin Cancer Res, 
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Hiraoka, N., Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol, 2010. 15(6): p. 544-51. 
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Nobili, C., et al., Prolonged survival of a patient affected by pancreatic adenocarcinoma 
with massive lymphocyte and dendritic cell infiltration after interleukin-2 
immunotherapy. Report of a case. Tumori, 2008. 94(3): p. 426-30. 
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Hodi, F.S. and G. Dranoff, The biologic importance of tumor-infiltrating lymphocytes. J 
Cutan Pathol, 2010. 37 Suppl 1: p. 48-53. 
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Kloor, M., Lymphocyte infiltration and prognosis in colorectal cancer. Lancet Oncol, 
2009. 10(9): p. 840-1. 
17. 
Hillen, F., et al., Leukocyte infiltration and tumor cell plasticity are parameters of 
aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother, 2008. 


 
 
 
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57(1): p. 97-106. 
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Lee, H.E., et al., Prognostic implications of type and density of tumour-infiltrating 
lymphocytes in gastric cancer. Br J Cancer, 2008. 99(10): p. 1704-11. 
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Leffers, N., et al., Prognostic significance of tumor-infiltrating T-lymphocytes in primary 
and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol Immunother, 
2009. 58(3): p. 449-59. 
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Nishimura, H., T. Honjo, and N. Minato, Facilitation of beta selection and modification 
of positive selection in the thymus of PD-1-deficient mice. J Exp Med, 2000. 191(5): p. 
891-8. 
21. 
Liotta, F., et al., Frequency of regulatory T cells in peripheral blood and in tumour-
infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma. BJU Int, 
2011. 107(9): p. 1500-6. 
22. 
Godin-Ethier, J., et al., Indoleamine 2,3-dioxygenase expression in human cancers: 
clinical and immunologic perspectives. Clin Cancer Res, 2011. 17(22): p. 6985-91. 
23. 
Mellor, A.L. and D.H. Munn, IDO expression by dendritic cells: tolerance and 
tryptophan catabolism. Nat Rev Immunol, 2004. 4(10): p. 762-74. 
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Munn, D.H. and A.L. Mellor, Indoleamine 2,3-dioxygenase and tumor-induced 
tolerance. J Clin Invest, 2007. 117(5): p. 1147-54. 
25. 
Mellor, A.L., et al., Cutting edge: induced indoleamine 2,3 dioxygenase expression in 
dendritic cell subsets suppresses T cell clonal expansion. J Immunol, 2003. 171(4): p. 
1652-5. 
26. 
Frumento, G., et al., Tryptophan-derived catabolites are responsible for inhibition of T 
and natural killer cell proliferation induced by indoleamine 2,3-dioxygenase. J Exp Med, 
2002. 196(4): p. 459-68. 
27. 
Fallarino, F., et al., The combined effects of tryptophan starvation and tryptophan 
catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype 
in naive T cells. J Immunol, 2006. 176(11): p. 6752-61. 
28. 
Zou, W., Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol, 
2006. 6(4): p. 295-307. 
29. 
Munn, D.H., et al., Prevention of allogeneic fetal rejection by tryptophan catabolism. 
Science, 1998. 281(5380): p. 1191-3. 
30. 
Uyttenhove, C., et al., Evidence for a tumoral immune resistance mechanism based on 
tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med, 2003. 9(10): p. 1269-
74. 
31. 
Muller, A.J., et al., Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory 
target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nat Med, 
2005. 11(3): p. 312-9. 
32. 
Huang, L., et al., Dendritic cells, indoleamine 2,3 dioxygenase and acquired immune 
privilege. Int Rev Immunol, 2010. 29(2): p. 133-55. 
33. 
Weinlich, G., et al., Decreased serum tryptophan concentration predicts poor prognosis 
in malignant melanoma patients. Dermatology, 2007. 214(1): p. 8-14. 
34. 
Munn, D.H., et al., Expression of indoleamine 2,3-dioxygenase by plasmacytoid dendritic 
cells in tumor-draining lymph nodes. J Clin Invest, 2004. 114(2): p. 280-90. 
35. 
Okamoto, A., et al., Indoleamine 2,3-dioxygenase serves as a marker of poor prognosis 
in gene expression profiles of serous ovarian cancer cells. Clin Cancer Res, 2005. 
11(16): p. 6030-9. 


 
 
 
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36. 
Brandacher, G., et al., Prognostic value of indoleamine 2,3-dioxygenase expression in 
colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res, 2006. 12(4): p. 
1144-51. 
37. 
Ino, K., et al., Indoleamine 2,3-dioxygenase is a novel prognostic indicator for 
endometrial cancer. Br J Cancer, 2006. 95(11): p. 1555-61. 
38. 
Nakamura, T., et al., Expression of indoleamine 2, 3-dioxygenase and the recruitment of 
Foxp3-expressing regulatory T cells in the development and progression of uterine 
cervical cancer. Cancer Sci, 2007. 98(6): p. 874-81. 
39. 
Witkiewicz, A., et al., Expression of indoleamine 2,3-dioxygenase in metastatic 
pancreatic ductal adenocarcinoma recruits regulatory T cells to avoid immune detection. 
J Am Coll Surg, 2008. 206(5): p. 849-54; discussion 854-6. 
40. 
Hamid, O., et al., Association of baseline and on-study tumor biopsy markers with 
clinical activity in patients (pts) with advanced melanoma treated with ipilimumab. J Clin 
Oncol 27:15s, 2009 (suppl; abstr 9008), 2009. 
41. 
Robert, C., et al., Ipilimumab plus dacarbazine for previously untreated metastatic 
melanoma. N Engl J Med, 2011. 364(26): p. 2517-26. 
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Hodi, F.S., et al., Improved survival with ipilimumab in patients with metastatic 
melanoma. N Engl J Med, 2010. 363(8): p. 711-23. 
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Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in 
cancer. N Engl J Med, 2012. 366(26): p. 2443-54. 
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Hamid, O., et al., Safety and tumor responses with lambrolizumab (anti-PD-1) in 
melanoma. N Engl J Med, 2013. 369(2): p. 134-44. 
45. 
Wolchok, J.D., et al., Guidelines for the evaluation of immune therapy activity in solid 
tumors: immune-related response criteria. Clin Cancer Res, 2009. 15(23): p. 7412-20. 
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Quezada, S.A. and K.S. Peggs, Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the 
host immune response against cancer. Br J Cancer, 2013. 108(8): p. 1560-5. 
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Curran, M.A., et al., PD-1 and CTLA-4 combination blockade expands infiltrating T cells 
and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl 
Acad Sci U S A, 2010. 107(9): p. 4275-80. 
48. 
Selby, M., et al., Antitumor activity of concurrent blockade of immune checkpoint 
molecules CTLA-4 and PD-1 in preclinical models. J Clin Oncol 31, 2013 (suppl; abstr 
3061), 2013. 
49. 
Yervoy [package insert]. Princeton, NJ: Bristol-Myers Squibb, 2012. 
50. 
Holmgaard, R.B., et al., Indoleamine 2,3-dioxygenase is a critical resistance mechanism 
in antitumor T cell immunotherapy targeting CTLA-4. J Exp Med, 2013. 210(7): p. 1389-
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51. 
Spranger, S., et al., Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor 
microenvironment is driven by CD8(+) T cells. Sci Transl Med, 2013. 5(200): p. 
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Gibney, G., et al., Preliminary results from a phase 1/2 study of INCB024360 combined 
with ipilimumab (ipi) in patients (pts) with melanoma. J Clin Oncol 32:5s, 2014 (suppl; 
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Robert, C., et al., Nivolumab in previously untreated melanoma without BRAF mutation. 
N Engl J Med, 2015. 372(4): p. 320-30. 
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55. 
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Muro, K., et al., Relationship between PD-L1 expression and clinical outcomes in 
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1112-20. 
 
 
 
 
 


 
 
 
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14. APPENDICES 
 
14.1. 
APPENDIX A: PARTICIPANT ELIGIBILITY CHECKLIST  
Protocol Title: 
Phase II Study Of Epacadostat (INCB024360) With 
Pembrolizumab (MK-3475) In Metastatic Or Unresectable 
Gastroesophageal Junction And Gastric Adenocarcinoma 
Requiring Paired Biopsies 
Protocol Number: 
IRB-40823 / GI0015 
Principal Investigator: 
George A. Fisher, Jr., MD, PhD 
 
I. Subject Information: 
Subject Name/ID: 
 
Gender:    
 Male     
 Female 
 
 
II. Inclusion/Exclusion Criteria 
 
 
Yes 
No 
Supporting 
Documentation* 
 
Inclusion Criteria 
 
1. Age ≥ 18 years of age on day of signing informed 
consent 
 
 
      
2. Be willing and able to provide written informed consent 
for the study 
 
 
      
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 cm of the 
GEJ 
 
 
      
4. Patients must have metastatic or unresectable disease, 
including those with HER2+ disease 
 
 
      
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; for HER2+ disease 
patients should have received prior trastuzumab   
 
 
      


 
 
 
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6. Life expectancy of ≥ 12 weeks 
 
 
      
7. Have a performance status of 0 or 1 (ECOG) 
 
 
      
8. Have measurable disease per RECIST v1.1 assessed 
within 4 weeks prior to study entry 
 
 
      
9. Tumor deemed amenable to biopsy by core for 
metastatic site or endoscopic biopsy for primary tumor 
(for both before and on-treatment biopsies) 
 
 
      
10. Patient must be willing to undergo 2 biopsies – before 
and on-treatment, provided the procedure is not deemed 
high-risk and is clinically feasible.  
 
 
      
11. Demonstrate adequate organ function within 7 days 
before treatment initiation, as defined below: 
• Absolute neutrophil count ≥ 1500 /mcL 
• Platelets ≥ 100,000 /mcL 
• Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L without 
transfusion or EPO dependency (within 7 days of 
assessment) 
• Serum creatinine ≤ 1.5 x ULN or measured 
creatinine clearance ≥ 60 mL/min (for subjects that 
have creatinine levels > 1.5 x ULN) 
• Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ 
ULN 
• AST and ALT ≤ 2.5 x ULN (for subjects that have 
liver metastases, ≤ 5 x ULN) 
• Albumin ≥ 2.5 mg/dL 
• INR or PT ≤ 1.5 x ULN (if subjects are on 
anticoagulation therapy, PT/INR must be within 
therapeutic range) 
• aPTT ≤ 1.5 x ULN (if subjects are on 
anticoagulation therapy, PT/INR must be within 
therapeutic range) 
 
 
      
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 negative, a serum 
pregnancy test will be required 
 
 
      
13. Female subjects of childbearing potential must be 
willing to use an adequate method of contraception 
 
 
      


 
 
 
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starting with the date of consent through 120 days after 
the last dose of study medication 
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 medication 
 
 
      
15. Must be able to swallow pills 
 
 
      
 
Exclusion Criteria 
 
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  
 
 
      
2. Has known hypersensitivity to pembrolizumab and/or 
epacadostat or any of their excipients 
 
 
      
3. Has had a prior anti-cancer monocloncal antibody 
within 4 weeks prior to day 1 or who has not recovered 
(i.e., ≤ grade 1 or to baseline) from AEs due to agents 
administered more than 4 weeks earlier.  
• Denosumab for treatment for bone metastases is 
allowed 
 
 
      
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 AEs due to previously administered 
agents 
• Subjects with ≤ grade 2 neuropathy are an 
exception to this criterion and may qualify for 
the study 
• If subjects have received major surgery, they 
must have recovered adequately from surgery 
prior to starting therapy 
 
 
      
5. Patients who 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 
 
 
      
6. Prior therapy with IDO-inhibitors 
 
 
      
7. Has active autoimmune disease that has required 
 
 
      


 
 
 
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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 
8. Has known history of, or any evidence of active, non-
infectious pneumonitis 
 
 
      
9. Has received a live vaccine within 30 days of planned 
start of therapy 
• Seasonal influenza vaccines for injection are 
generally inactivated flu vaccines and are 
allowed; however intranasal influenza vaccines 
(e.g., FluMist®) are live attenuated vaccines and 
are NOT allowed 
 
 
      
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 4 
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 
• Carcinomatous meningitis is excluded regardless 
of clinical stability 
• Patient with prior CNS metastases treated w/ 
prior RT will also need: 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 MFI with no edema., and C. stable for 
at least 8 weeks. 
 
 
      
11. Has known additional malignancy that is progressing 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 
 
 
      


 
 
 
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12. Has active infection requiring systemic therapy 
 
 
      
13. Has a known history of active TB (bacillus tuberculosis) 
 
 
      
14. Has known active Hepatitis B (e.g., HBsAg reactive) or 
Hepatitis C (e.g., HCV RNA [qualitative] detected   
 
 
      
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 treatment 
 
 
      
16. Has a known history of Human Immunodeficiency 
Virus (HIV) (HIV 1/2  antibodies) 
 
 
      
17. Is pregnant or breastfeeding, or expecting to conceive or 
father children within projected duration of the study, 
starting with pre-screening or screening visit through 
120 days after the last dose of study treatment 
 
 
      
18. Has had Monoamine oxidase inhibitors within 21 days 
before screening 
 
 
      
19. Has any history of serotonin syndrome after receiving 1 
or more serotonergic drugs 
 
 
      
20. Has presence of a gastrointestinal condition that may 
affect drug absorption 
 
 
      
21. Use of systemic corticosteroids 
 
 
      
22. Has history or presence of an abnormal 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. 
 
 
      
23. Has history or current evidence of any condition, 
therapy, or laboratory abnormality that might confound 
the results of the study, interfere with the subjects 
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 investigator 
 
 
      
24. Has known psychiatric or substance abuse disorders that 
would interfere with cooperation with the requirements 
of the study 
 
 
      
25. Has known allergy or reaction to any component of 
either study drug or formulation components 
 
 
      
 


 
 
 
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*All subject files must include supporting documentation to confirm subject eligibility.  
The method of confirmation can include, but is not limited to, laboratory test results, 
radiology test results, subject self-report, and medical record review.   
 
 
III. Statement of Eligibility 
By signing this form of this study, I verify that this subject is [
 eligible / 
 ineligible] for 
participation in the study. This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the Stanford IRB, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
 
 
Treating Physician Signature: 
Date: 
Printed Name: 
 
Secondary Reviewer Signature: 
Date: 
Printed Name: 
 
Study Coordinator Signature: 
Date: 
Printed Name: 


 
 
 
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14.2. 
APPENDIX B: INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
 
For Subjects Participating in the Study: 
The following methods have been determined to be more than 99% effective (< 1% failure rate 
per year when used consistently and correctly and are permitted under this Protocol for use by 
the subject and his/her partner: 
• Complete abstinence from sexual intercourse 
• Double barrier methods: 
− Condom with spermicide in conjunction with use of an intrauterine device 
− Condom with spermicide in conjunction with use of a diaphragm 
• Birth control patch or vaginal ring 
• Oral, injectable, or implanted contraceptives 
• Surgical sterilization (tubal ligation or vasectomy) 


 
 
 
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14.3. 
APPENDIX C: EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., 
Horton, J., Davis, T.E., McFadden, E.T., Carbone, P.P.: Toxicity And Response 
Criteria Of The Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 
1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair. 
 


 
 
 
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14.4. 
APPENDIX D: PROHIBITED MONOAMINE OXIDASE INHIBITORS AND 
DRUGS 
ASSOCIATED 
WITH 
SIGNIFICANT 
MONOAMINE 
OXIDASE 
INHIBITORY ACTIVITY 
 
Monoamine Oxidase Inhibitors  
Drugs Associated With 
Significant Monoamine 
Oxidase Inhibitory Activity 
 
UGT1A9 inhibitor 
Hydrazines (example phenelzine) 
Isocarboxazid 
Tranylcypromine 
Brofaromine 
Rasagiline 
Selegiline 
Meperidine 
Linezolid 
Methylene blue 
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. 
 


 
 
 
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14.5. 
APPENDIX E: PUBLICATION ON SEROTONIN SYNDROME 
 


 
 
 
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14.6. 
APPENDIX F: ADMINISTRATION OF PEMBROLIZUMAB 
Administration of pembrolizumab will be witnessed by the investigator and/or site staff. The 
total volume of study treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered. 
On day 1 of every cycle subjects will receive a 200 mg flat dose of pembrolizumab on an every-
3-week schedule; this is 2 vials of 100 mg/4mL per infusion. Intrasubject dose escalation of 
pembrolizumab is not permitted.    
Formulation and administration instructions for pembrolizumab are provided below. 
• Pembrolizumab infusion solutions should be prepared in 0.9% Sodium Chloride Injection, 
USP (normal saline) or 5% Dextrose Injection, USP (5% dextrose) and the final 
concentration of Pembrolizumab in the infusion solutions should be between 1.0 mg/mL and 
10.0 mg/mL.  
• Pembrolizumab SHOULD NOT BE MIXED WITH OTHER RECONSTITUTION 
DILUENTS.  
• Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration. Discard the drug product vial if extraneous particulate matter other 
than translucent to white proteinaceous particles are observed. 
• Do not use Pembrolizumab if discoloration is observed. 
• DO NOT SHAKE OR FREEZE THE VIAL(S). 
• DO NOT ADMINISTER THE PRODUCT AS AN [INTRAVENOUS (IV) PUSH OR 
BOLUS]. 
• DO NOT COMBINE, DILUTE OR ADMINISTER THE PRODUCT AS AN INFUSION 
WITH OTHER MEDICINAL PRODUCTS. 
Preparation of Infusion Solution 
• Aseptic technique must be strictly observed throughout the preparation procedure preferably 
in a biologic safety cabinet or hood since no anti-microbial preservative is present in the 
solutions.  


 
 
 
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• Equilibrate required number of Pembrolizumab vials to room temperature 
• Choose a suitable infusion bag size so that the following conditions are met: 
o Concentration of Pembrolizumab is between 1.0 mg/mL and 10.0 mg/mL 
o The infusion volume to bag capacity ratio should not be less than 0.3.  In other 
words, the bag must be filled to at least 30% of its capacity.   
• Choose a suitable infusion bag material. The bag may be empty  or it may contain normal 
saline The following infusion bag materials are compatible with Pembrolizumab:  
▪ PVC plasticized with DEHP 
▪ Non-PVC (polyolefin) 
▪ EVA 
▪ PE lined polyolefin 
*Contact Sponsor for materials not listed above 
• Calculate the volume of Pembrolizumab and normal saline required to prepare the infusion 
(admixture) bag 
 
 
Volume of Pembrolizumab (mL) = required dose amount (mg) / 25.0 (mg/mL) 
 
 
Volume of normal saline = total infusion volume – volume of Pembrolizumab 
from above 
• If a bag pre-filled with normal saline is being used, remove the excess volume of normal 
saline using a sterile syringe (Polypropylene, latex-free) attached to a suitable needle. Keep 
in consideration the excess bag fill volume as well as the volume of reconstituted 
Pembrolizumab to be added to the bag to prepare the infusion solution. 
• If an empty bag is being used, withdraw the necessary volume of normal saline from another 
appropriate bag and inject into the empty bag. Keep in consideration the volume of 
reconstituted Pembrolizumab to be added to the bag to prepare the infusion solution. 


 
 
 
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• Withdraw the required volume of Pembrolizumab from the vial(s) (up to 4 mL from each 
vial) using a sterile syringe attached to a suitable needle. The vial(s) may need to be inverted 
to remove solution. 
 
Volume of Pembrolizumab (mL) = required dose amount (mg) / 25.0 (mg/mL) 
Note: If it is necessary to use several vials, it is advisable to withdraw from several vials into 
a suitable size single use syringe using a new needle for each vial.  
• Add the required Pembrolizumab into the infusion IV bag containing normal saline and 
gently invert the bag 10-15 times to mix the solution. 
Infusion Instructions 
• Pembrolizumab infusions should be administered over a period of 30 minutes, with a 
window of -5 and +10 minutes, using an infusion pump. A central catheter is not required for 
infusion; however if a subject has a central venous catheter in place, it is recommended that 
it be used for the infusion.  
The following infusion set materials are compatible with Pembrolizumab: 
o PVC Infusion set that is plasticized using DEHP 
o PVC and tri-(2-ethylhexyl) trimellitate (TOTM) infusion set 
o Polyethylene lined PVC infusion set 
o PVC Infusion set that is plasticized using Di-2-ethylhexyl Terephthalate (DEHT) 
o Polyurethane set 
• A sterile, non-pyrogenic, low-protein binding 0.2 to 5 µm in-line-filter made of 
polyethersulfone (PES) must be used during administration to remove any adventitious 
particles.  If the infusion set does not contain 0.2 to 5 µm in-line filter, it is recommended to 
use 0.2 to 5 µm add-on filter which may contain an extension line (Note: the materials of the 
extension line and filter should be as mentioned above). 
• Attach the infusion line to the pump and prime the line, either with normal saline (at least 25 
mL) or with infusion solution as per local SOP, before starting the infusion. 


 
 
 
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• Infuse Pembrolizumab over approximately 30 minutes, with a window of -5 and +10 
minutes, through a peripheral line or indwelling catheter.  
o Whenever possible, the lowest infusion rate should be used that will allow 
completion of the infusion within the 30 minutes 
o Maximum rate of infusion should not exceed 6.7 mL/min. through a peripheral line 
or indwelling catheter. However, when it is necessary to infuse a larger volume (i.e. 
250 mL), the flow rate may go as high as 10 mL/mL (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 infusion.  If institutional 
guidelines do not allow the flushing of the infusion line at the completions of the infusion, 
please prepare excess volume of drug/diluent admixture solution that is required to make up 
for the volume of the dosing solution lost in the infusion line.  For example if a subject is 
receiving 100 mL IV infusion and it is known that 18mL will be left in the infusion line 
since the line is not flushed, the pharmacist should prepare 118 mL of drug/diluent 
admixture solution in a 200 mL bag to make sure that the 100 mL will be delivered to the 
subject. 
• DO NOT CO-ADMINISTER OTHER DRUGS THROUGH THE SAME INFUSION LINE. 
• UNUSED INFUSION SOLUTION FOR INJECTION SHOULD NOT BE USED FOR 
ANOTHER INFUSION OF THE SAME SUBJECT OR DIFFERENT SUBJECT. 
• Discard any unused portion left in the vial, as the product contains no preservative. 
 


 
 
 
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14.7. 
APPENDIX G: TEMPERATURE AND LIGHT EXCURSION FORM FOR 
EPACADOSTAT 
 
 


 
 
 
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14.8. 
APPENDIX H: DEFINITION OF irRC 
14.8.1. 
Definition of Tumor Response Using irRC 
The sum of the products of diameters at tumor assessment using the irRC for progressive disease 
incorporates the contribution of new measurable lesions. Each net percentage change in tumor 
burden per assessment using irRC criteria accounts for the size and growth kinetics of both old 
and new lesions as they appear. 
14.8.2. 
Definition of Index Lesions Response Using irRC 
• irComplete Response (irCR): Complete disappearance of all index lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
• irPartial Response (irPR): Decrease, relative to baseline, of 50% or greater in the 
sum of the products of the two largest perpendicular diameters of all index and all 
new measurable lesions (i.e., percentage change in tumor burden). Note: the 
appearance of new measurable lesions is factored into the overall tumor burden, but 
does not automatically qualify as progressive disease until the SPD increases by ≥ 
25% when compared to SPD at nadir. 
• irStable Disease (irSD): Does not meet criteria for irCR or irPR, in the absence of 
progressive disease. 
• irProgressive Disease (irPD): At least 25% increase percentage change in tumor 
burden (i.e., taking sum of the products of all index lesions and any new lesions) 
when compared to SPD at nadir. 
14.8.3. 
Definition of Non-Index Lesions Response Using irRC 
• irComplete Response (irCR): Complete disappearance of all non-index lesions. This 
category encompasses exactly the same subjects as “CR” by the mWHO criteria. 
• irPartial Response (irPR) or irStable Disease (irSD): non-index lesion(s) are not 
considered in the definition of PR, these terms do not apply. 
• 
irProgressive Disease (irPD): Increases in number or size of non-index lesion(s) 
does not constitute progressive disease unless/until the percentage change in tumor 
burden increases by 25% (i.e., the SPD at nadir of the index lesions increases by the 
required amount). 
14.8.4. 
Impact of New Lesions on irRC 
New lesions in and by themselves do not qualify as progressive disease. However their 
contribution to total tumor burden is included in the SPD which in turn feeds into the irRC 


 
 
 
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criteria for tumor response. Therefore, new non-measurable lesions will not discontinue any 
subject from the study. 
14.8.5. 
Definition of Overall Response Using irRC 
Overall response using irRC will be based on these criteria: 
• Immune-Related Complete Response (irCR): Complete disappearance of all tumor 
lesions (index and nonindex together with no new measurable/unmeasurable lesions) 
for at least 6 weeks from the date of documentation of complete response.  
• Immune-Related Partial Response (irPR): The sum of the products of the two 
largest perpendicular diameters of all index lesions is measured and captured as the 
SPD baseline. At each subsequent tumor assessment, the sum of the products of the 
two largest perpendicular diameters of all index lesions and of new measurable 
lesions are added together to provide the Immune Response Sum of Product 
Diameters (irSPD). A decrease, relative to baseline of the irSPD compared to the 
previous SPD baseline, of 50% or greater is considered an irPR.  
• Immune-Related Stable Disease (irSD): irSD is defined as the failure to meet 
criteria for immune complete response or immune partial response, in the absence of 
progressive disease.  
• Immune-Related Progressive Disease (irPD): It is recommended in difficult cases 
to confirm PD by serial imaging. Any of the following will constitute progressive 
disease: 
o At least 25% increase in the sum of the products of all index lesions over baseline 
SPD calculated for the index lesions. 
o At least a 25% increase in the sum of the products of all index lesions and new 
measurable lesions (irSPD) over the baseline SPD calculated for the index lesions. 


 
 
 
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14.8.6. 
Immune-Related Response Criteria Definitions 
Index 
Lesion 
Definition 
Non-
Index 
Lesion 
Definition 
New 
Measurable 
Lesions 
New 
Unmeasurable 
Lesions 
Percent change in 
tumor burden 
(including 
measurable new 
lesions when present) 
Overall 
irRC 
Response 
Complete 
Response 
Complete 
Response 
No 
No 
-100% 
irCR 
Partial 
Response 
Any 
Any 
Any 
> -50% 
irPR 
<-50% to <+25% 
irSD 
>+25% 
irPD 
Stable 
Disease 
Any 
Any 
Any 
<-50% to <+25% 
irSD 
>+25% 
irPD 
Progressive 
Disease 
Any 
Any 
Any 
>+25% 
irPD 
 
14.8.7. 
Immune-Related Best Overall Response Using irRC (irBOR)  
irBOR is the best confirmed irRC overall response over the study as a whole, recorded between 
the date of first dose until the last tumor assessment before subsequent therapy (except for local 
palliative radiotherapy for painful bone lesions) for the individual subject in the study. For the 
assessment of irBOR, all available assessments per subject are considered. 
irCR or irPR determinations included in the irBOR assessment must be confirmed by a second 
(confirmatory) evaluation meeting the criteria for response and performed no less than 6 weeks 
after the criteria for response are first met.