Clinical trial NCT03277352
Conditions: Advanced Malignancies Metastatic Cancer
Keywords: cervical cancer endometrial cancer gastric cancer (including stomach and gastroesophageal junction (GEJ)) esophageal cancer hepatocellular carcinoma (HCC) melanoma (mucosal or cutaneous) Merkel cell carcinoma mesothelioma microsatellite instability-high (MSI-H) solid tumors non-small cell lung cancer (NSCLC) ovarian cancer squamous cell carcinoma of the head and neck (SCCHN) small cell lung cancer (SCLC) renal cell carcinoma (RCC) triple-negative breast cancer (TNBC) urothelial carcinoma glucocorticoid-induced tumor necrosis factor receptor (GITR)
Sponsor: Incyte Biosciences International Sàrl
Start date: 2017-11-21; Completion date: 2020-07-01
Enrollment: 10 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to determine the safety, tolerability, and efficacy of INCAGN01876 when given in combination with immune therapies.

Detailed description:

Arms: arm 1: INCAGN01876 in combination with pembrolizumab and epacadostat
Interventions: intervention 1: INCAGN01876 intervention 2: Epacadostat intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: In Phase 1 subjects will receive INCAGN01876 administered intravenously (IV) at the protocol-defined dose and schedule according to cohort and treatment group enrollment. In Phase 2, subjects will be administered IV study drug at the recommended dose from Phase 1. intervention 2: Epacadostat will be self-administered orally at the protocol-defined dose. intervention 3: Pembrolizumab will be administered IV at the protocol-defined dose.

Protocol documents:
Prot_000.pdf: 
Official Title: 
A Phase 1/2 Safety and Efficacy Study of INCAGN01876 in Combination With 
Immune Therapies in Subjects With Advanced or Metastatic Malignancies 
NCT Number: 
NCT03277352 
Document Date: 
Clinical Study Protocol: 24 August 2017 


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Protocol INCAGN 1876-202 Amendment 1 
24 AUG 2017 
CONFIDENTIAL 
Clinical Study Protocol 
INCAGN 1876-202
A Phase 1/2 Safety and Efficacy Study of INCAGN01876 in 
Combination With Immune Therapies in Subjects With Advanced 
or Metastatic Malignancies 
Product: 
INCAGN01876 
IND Number: 
 
EudraCT Number: 
2017-001951-29 
Phase of Study: 
1/2 
Sponsor: 
Incyte Biosciences International Sàrl 
Route de la Corniche 1 
1066 Epalinges, Switzerland 
Date of Protocol: 
23 JUN 2017 
Date of Amendment 1: 
24 AUG 2017 
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, Good Clinical Practices as defined in Title 21 of the 
US Code of Federal Regulations Parts 11, 50, 54, 56, and 312, as well as ICH GCP consolidated guidelines (E6) and 
applicable regulatory requirements. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without the prior 
written consent of Incyte Corporation. 


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Protocol INCAGN 1876-202 Amendment 1 
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CONFIDENTIAL 
INVESTIGATOR'S AGREEMENT 
I have read the INCAGN 1876-202 Protocol Amendment 1 (dated 24 AUG 2017) and agree to 
conduct the study as outlined.  I agree to maintain the confidentiality of all information received 
or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 














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Study Population:  Key inclusion and exclusion criteria are noted below.  Full subject eligibility criteria 
are located in the body of the Protocol. 
Key Inclusion Criteria: 
• Locally advanced or metastatic disease; locally advanced disease must not be amenable to resection 
with curative intent. 
• Phase 1 (Part 1 and Part 2):  Subjects with advanced or metastatic cervical cancer, endometrial cancer, 
gastric cancer (including stomach and GEJ), esophageal cancer, HCC, melanoma (mucosal or 
cutaneous), Merkel cell carcinoma, mesothelioma, MSI-H solid tumors, NSCLC, ovarian cancer, 
SCCHN, SCLC, RCC, TNBC, and UC (or alternative tumor types with medical monitor approval). 
• Phase 1 (Part 1 and Part 2):  Subjects who have disease progression after treatment with available 
therapies that are known to confer clinical benefit or who are intolerant to treatment.  There is no limit 
to the number of prior treatment regimens. 
• Phase 2:  Subjects with advanced or metastatic melanoma, RCC, and UC.  
− For subjects with melanoma:  mucosal or cutaneous melanoma is acceptable; however, subjects 
with ocular melanoma are excluded.  Subjects should have documented BRAF mutation status or 
consent to BRAF mutation testing during the screening period.  BRAF mutation status determined as 
part of a panel of genetic tests performed in a gene expression analysis will also satisfy the inclusion 
criterion for BRAF mutation testing. 
Note:  Should not have received prior therapy for advanced or metastatic disease.  Adjuvant regimens 
given within 6 months of screening will be counted as first-line therapy. 
Note:  Should not have received prior therapy that included an immune therapy (eg, anti-cytotoxic 
T-lymphocyte–associated protein 4 (CTLA-4) or programmed cell death protein 1 (PD-1)/ 
programmed cell death protein ligand 1 (PD-L1) inhibitor, indoleamine 2,3-dioxygenase (IDO) 
inhibitor, tumor necrosis factor super family (TNFSF) agonist, or other antibodies or drugs 
specifically targeting T-cell costimulation or checkpoint pathways, etc).   
− For subjects with RCC:  histologically confirmed RCC that is predominantly clear-cell. 
Note:  Should not have received prior therapy for advanced or metastatic disease.  Adjuvant regimens 
given within 6 months of screening would be counted as first-line therapy. 
Note:  Should not have received prior therapy that included an immune therapy (eg, anti–CTLA-4 or 
PD-1/PD-L1 inhibitor, IDO inhibitor, TNFSF agonist, or other antibodies or drugs specifically 
targeting T-cell costimulation or checkpoint pathways, etc). 
− For subjects with UC:  histologically confirmed UC of the renal pelvis, ureter, bladder, or urethra 
that is transitional cell type or mixed histology (predominantly transitional cell) type. 
Note:  Should not have received prior therapy for advanced or metastatic disease.  Adjuvant regimens 
given within 6 months of screening will be counted as first-line therapy. 
Note:  Should not have received prior therapy that included an immune therapy (eg, anti–CTLA-4 or 
PD-1/PD-L1 inhibitor, IDO inhibitor, TNFSF agonist, or other antibodies or drugs specifically 
targeting T-cell costimulation or checkpoint pathways, etc). 
− For subjects in the biopsy cohort:  willingness to undergo pretreatment and on treatment tumor 
biopsies (core or excisional).  Must have melanoma (mucosal or cutaneous), RCC, or UC.   
Note:  A baseline biopsy obtained for other purposes (ie, not an INCAGN 1876-202 procedure) 
before signing the informed consent form (ICF) may be used if the subject has not had any 
intervening systemic therapy from the time of the biopsy to the start of treatment (ie, Cycle1 Day 1) 
and if a minimum of 20 slides or preferably 1 tissue block can be submitted. 
• Presence of measureable disease based on RECIST v1.1.   
• Eastern Cooperative Oncology Group performance status of 0 or 1. 
 


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Key Exclusion Criteria:   
• Laboratory and medical history parameters not within the Protocol-defined range.   
− Absolute neutrophil count < 1.0 × 109/L. 
− Platelets < 75 × 109/L. 
− Hemoglobin < 9 g/dL or < 5.6 mmol/L. 
− Serum creatinine > 1.5 × institutional upper limit of normal (ULN) OR measured or calculated 
creatinine clearance < 50 mL/min for subjects with creatinine levels > 1.5 × ULN. 
− Aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase ≥ 2.5 × ULN.   
− Total bilirubin ≥ 1.2 × ULN is excluded unless conjugated bilirubin ≤ ULN (conjugated bilirubin only 
needs to be tested if total bilirubin exceeds ULN).  If there is no institutional ULN, then direct 
bilirubin must be < 40% of total bilirubin to be eligible. 
− International normalized ratio, prothrombin time, or activated partial thromboplastin time 
> 1.5 × ULN. 
• Prior treatment with any TNFSF agonist (eg, glucocorticoid-induced tumor necrosis factor receptor 
[GITR], OX40, 4-1BB/CD137, CD27, etc) for any indication. 
• Transfusion of blood products (including platelets or red blood cells) or administration of colony-
stimulating factors within 14 days before study Day 1. 
• Receipt of anticancer medications or investigational drugs within the following intervals before the first 
administration of study treatment: 
− ≤ 14 days for chemotherapy, targeted small molecule therapy, or radiation therapy.   
Note:  Subjects must not have had radiation pneumonitis as a result of treatment.  A 1-week washout 
is permitted for palliative radiation to non-central nervous system (CNS) disease with medical 
monitor approval. 
Note:  Bisphosphonates and denosumab are permitted concomitant medications. 
− ≤ 28 days for prior immune therapy or persistence of active cellular therapy (ie, chimeric antigen 
receptor T-cell therapy; other cellular therapies must be discussed with the medical monitor to 
determine eligibility). 
− ≤ 28 days for a prior monoclonal antibody used for anticancer therapy, with the exception of 
denosumab. 
− ≤ 7 days for immune-suppressive–based treatment for any reason. 
Note:  Use of inhaled or topical steroids or corticosteroid use for radiographic procedures is 
permitted. 
Note:  Must not require chronic use of corticosteroids.  The use of physiologic corticosteroid 
replacement therapy may be approved after consultation with the medical monitor.   
− ≤ 28 days or 5 half-lives (whichever is longer) before the first dose for all other investigational agents 
or devices.  For investigational agents with long half-lives (eg, > 5 days), enrollment before the fifth 
half-life requires medical monitor approval. 
• Has not recovered to ≤ Grade 1 from toxic effects of prior therapy (including prior immune therapy) 
and/or complications from prior surgical intervention before starting therapy 
Note:  Subjects with stable chronic conditions (≤ Grade 2) that are not expected to resolve (such as 
neuropathy and alopecia) are exceptions and may enroll. 
Note:  Subjects with a history of any grade immune-related ocular AE (eg, episcleritis, scleritis, uveitis) 
will be excluded. 
Note:  Subjects with a history of a Grade 3 or higher immune-related AE from prior immunotherapies 
are excluded from the dose-escalation portion of the study. 
• Active autoimmune disease that required systemic treatment in the past (ie, use of disease-modifying 
agents, corticosteroids, or immunosuppressive drugs). 
Note:  Subjects who have not required systemic treatment in the past 2 years should discuss their case 
with the medical monitor to determine eligibility. 




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Study Schedule/Procedures:   
Subjects will have regularly scheduled study visits at the clinical site on Day 1 of each cycle.  Additional 
study visits may be required during some cycles to monitor for safety, efficacy, 
 
  Study visits are as follows: 
Screening:  Up to 28 days before enrollment.  Screening will begin at the time that the subject signs the 
ICF and will continue until the date that the subject is enrolled in the study (Cycle 1 Day 1). 
Cycle 1 and Cycle 6:  Day 1, Day 8, and Day 15 (± 1 day). 
All other treatment cycles:  Day 1 (± 3 days). 
Efficacy assessments:  Every 9 weeks (± 7 days).  After 12 months, efficacy assessments will occur 
every 12 weeks (± 7 days) until disease progression is determined. 
End of treatment (EOT):  ± 3 days of withdrawal from study. 
Safety follow-up:  30 days (+ 7 days) and 60 days (+ 7 days) after EOT. 
Disease status follow-up:  Subjects who discontinue treatment for reasons other than disease progression 
will continue to be assessed every 9 weeks (± 7 days) for their disease status for 12 months.  After 
12 months, radiologic assessments will be performed every 12 weeks and should continue until a new 
anticancer therapy is started, documented disease progression, death, the end of the study, or withdrawal 
of consent. 
Survival follow-up:  Once a subject has received the last dose of study treatment, has confirmed disease 
progression, or starts a new anticancer therapy, the subject moves into the survival follow-up period and 
should be contacted at least every 12 weeks (± 7 days) to assess for survival status until death, withdrawal 
of consent, or the end of the study, whichever occurs first.  This follow-up may occur through a phone 
call, email, or visit by the subject or the subject's caregiver. 
Estimated Duration of Participation:  Subjects may continue on treatment as long as they are receiving 
benefit and do not meet withdrawal criteria, or for up to 24 months from the first dose of study treatment, 
whichever occurs first.  All subjects will be followed for survival.  Study participation, including 
post-treatment follow-up, is expected to average approximately 12 to 18 months per individual subject. 
Estimated Number of Subjects: 
• Phase 1 Dose Escalation (Part 1) – Approximately 12 to 36 evaluable subjects. 
Note:  The minimum number of subjects assumes that the starting dose is 1.0 mg/kg. 
Note:  The maximum number of subjects assumes that DLTs are observed in all dose cohorts to a 
maximum of 9 subjects per cohort across all treatment groups. 
• Phase 1 Safety Expansion (Part 2) – Approximately 24 evaluable subjects. 
• Phase 2 Stage 1 – Approximately 100 evaluable subjects. 
• Biopsy cohorts – Approximately 30 evaluable subjects. 
• Phase 2 Stage 2 – Up to 172 evaluable subjects. 
Note:  The maximum number of subjects assumes that all treatment groups and all tumor types proceed 
to Stage 2. 
Principal Coordinating Investigator:  
, MD, 
, USA 
Statistical Methods:   
Primary Endpoint:  In Phase 2, a Simon 2-stage design will be applied for each tumor type within a 
treatment group.  The planned Simon 2-stage designs are summarized in Table S5.  Each Simon 2-stage 
design will have a stopping rule to allow for early termination of a particular cohort at the end of Stage 1 
if there are insufficient responses observed while enrolling enough subjects to predict possible target 
responses worthy of cohort expansion and potential further evaluation in future studies.  For the RCC and 


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CONFIDENTIAL 
UC cohorts, the insufficient response rates are obtained from historical data, and the Simon 2-stage 
designs allowing early termination are based on ORR.  For the melanoma cohort, the insufficient response 
rate is obtained from historical data, and the primary endpoint for the Simon 2-stage design allows for 
early termination based on CRR. 
Table S5:  Planned Simon 2-Stage Designs for Phase 2 
Indication 
Combination 
r1 
n1 
r 
n2 
n 
p0 
p1 
Melanoma (CRR) 
GITR + Pembro + Epacadostat 
6 
21 
18 
31 
52 
26% 
45% 
RCC (ORR) 
GITR + Pembro + Epacadostat 
8 
19 
25 
31 
50 
40% 
60% 
UC (ORR) 
GITR + Pembro + Epacadostat 
3 
10 
14 
24 
34 
30% 
55% 
• r1:  If r1 or fewer responses are observed during Stage 1, then the study cohort is stopped early for 
futility. 
• n1:  Number of subjects initially enrolled in Stage 1. 
• n2:  Number of subjects enrolled in Stage 2. 
• r:  If r or fewer responses are observed by the end of Stage 2, then no further investigation of the drug 
combination is warranted in the selected tumor type. 
• n:  Total number of subjects. 
• p0:  Insufficient response rate. 
• p1:  Target response rate. 
The proposed designs for each tumor type will be used for any planned Simon 2-stage design (including 
concurrent and sequential dosing).  Each Simon 2-stage design is set up to have a 1-sided Type I error of 
0.05 and a power of 85%.  The response rates for each tumor type will be estimated with 95% confidence 
intervals.  Formal quarterly safety reviews will be conducted to review efficacy and safety data with the 
obligation to hold a safety review meeting every 6 months.  
Secondary Endpoints:  
Objective response rate as assessed by RECIST v1.1 and mRECIST will be summarized for the RCC and 
UC cohorts.  Disease control rate as assessed by RECIST v1.1 and mRECIST will be summarized for 
each cohort.  Duration of response as assessed by RECIST v1.1 and mRECIST, PFS as determined by 
RECIST v1.1 and mRECIST, and OS will be analyzed by the Kaplan-Meier method for each cohort.  
Duration of disease control as assessed by RECIST v1.1 and mRECIST will be estimated with 95 % 
confidence intervals in each cohort.   
Integrated Bayesian Futility Analysis:  
When each subject enrolls in Phase 2, an integrated analysis of tumor and dosing strategies specific to 
Treatment Groups C and D will be conducted.  Tumor types within a treatment group will be jointly 
analyzed using a Bayesian model, allowing sharing of information across tumor types.  Similar sharing 
will be applied separately for tumor types across treatment groups.  The integrated Bayesian analysis will 
terminate a cohort within a treatment group if the cohort appears unlikely to achieve higher response rates 
with INCAGN01876 than with the background therapy alone.  Enrollment in a treatment group-tumor 
type combination may be suspended if the maximum of the 2 probabilities of success calculated using the 
integrated Bayesian approach with sharing based on tumor types and sharing based on treatment group is 
less than 20%.  Collection of response data will be based on investigator assessments entered into an 
interactive response technology system and analyzed separately from the clinical database.  Additional 
information regarding the futility analysis is detailed in the full Protocol. 


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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................21 
1. 
INTRODUCTION ......................................................................................................24 
1.1. 
Background .................................................................................................................24 
1.1.1. 
The Role of the Immune System in Cancer ................................................................24 
1.1.2. 
Glucocorticoid-Induced Tumor Necrosis Factor Receptor and the Tumor 
Necrosis Factor Super Family ....................................................................................24 
1.1.3. 
Glucocorticoid-Induced Tumor Necrosis Factor Receptor and Activated 
T Cells .........................................................................................................................25 
1.1.4. 
Glucocorticoid-Induced Tumor Necrosis Factor Receptor and T Regulatory 
Cells ............................................................................................................................25 
1.1.5. 
Immune Modulators ....................................................................................................26 
1.1.6. 
Programmed Cell Death Protein 1 and Indoleamine 2,3-Dioxygenase 1 
Inhibition in Advanced or Metastatic Cancers ...........................................................26 
1.1.7. 
Combined Inhibition With Anti–Glucocorticoid-Induced Tumor Necrosis 
Factor Receptor and Immune Therapies .....................................................................26 
1.2. 
Overview of INCAGN01876 ......................................................................................27 
1.2.1. 
Preclinical Safety of INCAGN01876 .........................................................................28 
1.2.2. 
Clinical Pharmacology ................................................................................................28 
1.2.3. 
Clinical Safety of INCAGN01876 ..............................................................................28 
1.3. 
Overview of Epacadostat ............................................................................................29 
1.3.1. 
Clinical Summary of Epacadostat ..............................................................................29 
1.3.2. 
Clinical Safety and Potential Risks of Epacadostat in Combination With 
Pembrolizumab ...........................................................................................................30 
1.4. 
Overview Pembrolizumab ..........................................................................................30 
1.4.1. 
Pembrolizumab Summary ..........................................................................................30 
1.4.2. 
Risks From Pembrolizumab .......................................................................................30 
1.5. 
Study Rationale ...........................................................................................................31 
1.5.1. 
Rationale for the Study Population .............................................................................31 
1.5.2. 
Rationale for the Dose and Schedule of Combination Therapies ...............................32 
1.5.3. 
Rationale for the Dose of Epacadostat ........................................................................33 
1.5.4. 
Rationale for the Study Endpoints ..............................................................................33 
1.5.4.1. 
Efficacy Endpoints ......................................................................................................33 


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1.6. 
Risks and Benefits of Combination Immunotherapy ..................................................35 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................35 
2.1. 
Study Objectives .........................................................................................................35 
2.1.1. 
Primary Objectives .....................................................................................................35 
2.1.2. 
Secondary Objectives .................................................................................................35 
 
36 
2.2. 
Study Endpoints ..........................................................................................................36 
2.2.1. 
Primary Endpoints ......................................................................................................36 
2.2.2. 
Secondary Endpoints ..................................................................................................36 
 
37 
3. 
SUBJECT ELIGIBILITY ...........................................................................................37 
3.1. 
Subject Inclusion Criteria ...........................................................................................37 
3.2. 
Subject Exclusion Criteria ..........................................................................................39 
4. 
INVESTIGATIONAL PLAN .....................................................................................42 
4.1. 
Overall Study Design ..................................................................................................42 
4.1.1. 
Phase 1 – Dose Escalation (Part 1) .............................................................................43 
4.1.1.1. 
Treatment Group A (INCAGN01876 + Pembrolizumab) ..........................................44 
4.1.2. 
Phase 1 – Safety Expansion (Part 2) ...........................................................................45 
4.1.2.1. 
Treatment Group B (INCAGN01876 + Epacadostat Run-In Followed by 
INCAGN01876 + Pembrolizumab + Epacadostat) ....................................................46 
4.1.3. 
Phase 2 – Dose Expansion ..........................................................................................46 
4.2. 
Measures Taken to Avoid Bias ...................................................................................47 
4.3. 
Number of Subjects ....................................................................................................48 
4.3.1. 
Planned Number of Subjects ......................................................................................48 
4.3.2. 
Replacement of Subjects .............................................................................................48 
4.4. 
Duration of Treatment and Subject Participation .......................................................48 
4.5. 
Overall Study Duration ...............................................................................................49 
4.6. 
Study Termination ......................................................................................................49 
5. 
TREATMENT ............................................................................................................49 
5.1. 
Treatment Assignment ................................................................................................49 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................49 
5.1.2. 
Randomization and Blinding ......................................................................................49 
5.2. 
Study Drugs ................................................................................................................50 


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5.2.1. 
INCAGN01876 ...........................................................................................................50 
5.2.1.1. 
Description and Administration ..................................................................................50 
5.2.1.2. 
Supply, Packaging, and Labeling ...............................................................................50 
5.2.1.3. 
Storage ........................................................................................................................50 
5.2.2. 
Epacadostat .................................................................................................................51 
5.2.2.1. 
Description and Administration ..................................................................................51 
5.2.2.2. 
Supply, Packaging, and Labeling ...............................................................................51 
5.2.2.3. 
Storage ........................................................................................................................51 
5.2.3. 
Pembrolizumab ...........................................................................................................51 
5.2.3.1. 
Description and Administration ..................................................................................51 
5.3. 
Treatment Compliance ................................................................................................52 
5.3.1. 
Treatment Compliance of INCAGN01876, Pembrolizumab, and Epacadostat .........52 
5.4. 
Treatment Interruptions and Adjustments ..................................................................52 
5.4.1. 
Dose Modifications .....................................................................................................52 
5.4.2. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose ................52 
5.4.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................54 
5.4.4. 
Follow-Up of Dose-Limiting Toxicities .....................................................................54 
5.4.5. 
Procedures for Cohort Review and Dose Escalation ..................................................54 
5.4.6. 
Criteria and Procedures for Dose Interruptions and Adjustments ..............................54 
5.4.7. 
Management of Immune-Related Adverse Events .....................................................60 
5.4.8. 
Management of Infusion Reactions ............................................................................60 
5.4.9. 
Procedure for Subjects Exhibiting Serotonin Syndrome ............................................62 
5.4.10. 
Criteria for Permanent Discontinuation of Study Treatment ......................................62 
5.5. 
Withdrawal of Subjects From Study Treatment .........................................................63 
5.5.1. 
Withdrawal Criteria ....................................................................................................63 
5.5.2. 
Withdrawal Procedures ...............................................................................................64 
5.6. 
Concomitant Medications ...........................................................................................64 
5.6.1. 
Permitted Medications ................................................................................................64 
5.6.2. 
Restricted Medications ...............................................................................................65 
5.6.3. 
Prohibited Medications ...............................................................................................65 
6. 
STUDY ASSESSMENTS ..........................................................................................67 
6.1. 
Screening ....................................................................................................................73 
6.2. 
Treatment ....................................................................................................................73 


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6.3. 
End of Treatment ........................................................................................................73 
6.4. 
Follow-Up ...................................................................................................................73 
6.4.1. 
Safety Follow-Up ........................................................................................................73 
6.4.2. 
Disease Status Follow-Up ...........................................................................................74 
6.4.3. 
Survival Follow-Up ....................................................................................................74 
6.5. 
End of Study ...............................................................................................................74 
6.6. 
Unscheduled Visits .....................................................................................................75 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................75 
7.1. 
Administration of Informed Consent Form ................................................................75 
7.2. 
Interactive Response Technology System Procedure .................................................75 
7.3. 
Demography and Medical History ..............................................................................76 
7.3.1. 
Demographics and General Medical History .............................................................76 
7.3.2. 
Disease Characteristics and Treatment History ..........................................................76 
7.4. 
Prior and Concomitant Medications and Procedures ..................................................76 
7.5. 
Poststudy Anticancer Therapy Status .........................................................................76 
7.6. 
Safety Assessments .....................................................................................................76 
7.6.1. 
Adverse Events ...........................................................................................................76 
7.6.2. 
Physical Examinations ................................................................................................77 
7.6.2.1. 
Comprehensive Physical Examination .......................................................................77 
7.6.2.2. 
Targeted Physical Examination ..................................................................................77 
7.6.3. 
Vital Signs and Weight ...............................................................................................77 
7.6.4. 
Electrocardiograms .....................................................................................................77 
7.6.5. 
Laboratory Assessments .............................................................................................78 
7.6.5.1. 
Pregnancy Testing ......................................................................................................78 
7.6.5.2. 
Hepatitis Screening Tests ...........................................................................................79 
7.7. 
Efficacy Assessments .................................................................................................79 
7.7.1. 
Modified Response Evaluation Criteria in Solid Tumors ...........................................79 
7.7.2. 
Response Evaluation Criteria in Solid Tumors Version 1.1 Tumor Imaging .............81 
7.7.2.1. 
Response Evaluation Criteria in Solid Tumors Version 1.1 Tumor Imaging 
During Screening ........................................................................................................81 
7.7.2.2. 
Response Evaluation Criteria in Solid Tumors Version 1.1 Tumor Imaging 
During Treatment ........................................................................................................81 


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7.7.2.3. 
Response Evaluation Criteria in Solid Tumors Version 1.1Tumor Imaging 
During Follow-Up ......................................................................................................82 
7.8. 
Performance and Quality-of-Life Assessments ..........................................................82 
7.8.1. 
Eastern Cooperative Oncology Group Performance Status ........................................82 
 
82 
 
82 
 
84 
 
84 
 
84 
 
84 
 
84 
 
 
 
 
7.11. 
Other Study Procedures ..............................................................................................86 
7.11.1. 
Distribution of Subject Reminder Cards .....................................................................86 
7.11.2. 
Data Collection for Survival Follow-Up ....................................................................86 
8. 
SAFETY MONITORING AND REPORTING .........................................................87 
8.1. 
Adverse Events ...........................................................................................................87 
8.1.1. 
Definitions ..................................................................................................................87 
8.1.2. 
Reporting ....................................................................................................................87 
8.2. 
Laboratory Test Abnormalities ...................................................................................88 
8.3. 
Serious Adverse Events ..............................................................................................89 
8.3.1. 
Definitions ..................................................................................................................89 
8.3.2. 
Reporting ....................................................................................................................89 
8.4. 
Emergency Unblinding of Treatment Assignment .....................................................90 
8.5. 
Pregnancy ...................................................................................................................91 
8.6. 
Warnings and Precautions ..........................................................................................91 
8.7. 
Data Monitoring Committee .......................................................................................91 
8.8. 
Product Complaints ....................................................................................................92 
9. 
STATISTICS ..............................................................................................................92 
9.1. 
Study Populations .......................................................................................................92 
9.2. 
Selection of Sample Size ............................................................................................92 
9.2.1. 
Sample Size for Phase 1 (Part 1) ................................................................................92 


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9.2.2. 
Sample Size for Phase 1 (Part 2) ................................................................................93 
9.2.3. 
Sample Size for Phase 2 .............................................................................................93 
9.3. 
Level of Significance ..................................................................................................94 
9.4. 
Statistical Analyses .....................................................................................................95 
9.4.1. 
Efficacy Analyses .......................................................................................................95 
9.4.1.1. 
Primary Efficacy Analyses .........................................................................................95 
9.4.1.2. 
Secondary Efficacy Analyses .....................................................................................95 
9.4.2. 
Safety Analyses ..........................................................................................................95 
9.4.2.1. 
Adverse Events ...........................................................................................................95 
9.4.2.2. 
Clinical Laboratory Tests ...........................................................................................95 
9.4.2.3. 
Vital Signs ..................................................................................................................96 
9.4.2.4. 
Electrocardiograms .....................................................................................................96 
 
96 
 
97 
9.5. 
Analyses for the Data Monitoring Committee ............................................................97 
9.6. 
Interim Analysis ..........................................................................................................97 
9.6.1. 
Simon 2-Stage Design ................................................................................................97 
9.6.2. 
Integrated Bayesian Futility Analysis .........................................................................97 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ..........................................................................................................99 
10.1. 
Investigator Responsibilities .......................................................................................99 
10.2. 
Accountability, Handling, and Disposal of Study Drugs .........................................100 
10.3. 
Data Management .....................................................................................................101 
10.4. 
Data Privacy and Confidentiality of Study Records .................................................101 
10.5. 
Financial Disclosure .................................................................................................102 
10.6. 
Publication Policy .....................................................................................................102 
11. 
REFERENCES .........................................................................................................103 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................108 
APPENDIX B. PROCEDURES AND SUPPORTIVE CARE GUIDELINES FOR 
SUBJECTS EXHIBITING IMMUNE-RELATED ADVERSE EVENTS ..............109 
APPENDIX C. PROHIBITED MONOAMINE OXIDASE INHIBITORS AND 
DRUGS ASSOCIATED WITH SIGNIFICANT MONOAMINE OXIDASE 
INHIBITORY ACTIVITY .......................................................................................116 




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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation 
Definition 
 
 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
ADCP 
antibody-dependent cell-mediated phagocytosis 
AE 
adverse event 
AGM 
African green monkey 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate transaminase 
BID 
twice a day 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CPI 
checkpoint inhibitor 
CR 
complete response 
CRR 
complete response rate 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte−associated protein 4 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
 
 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
Fc 
fragment, crystallizable 
FcγR 
Fc-gamma receptor 
FDA 
Food and Drug Administration 
 
 
GCP 
Good Clinical Practice 
GEJ 
gastroesophageal junction 
GI 
gastrointestinal 


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Abbreviation 
Definition 
GITR 
glucocorticoid-induced tumor necrosis factor receptor 
GITRL 
glucocorticoid-induced tumor necrosis factor receptor ligand 
HBV 
hepatitis B virus 
HCC 
hepatocellular carcinoma 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
IB 
Investigator's Brochure 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
IDO 
indoleamine 2,3-dioxygenase 
IEC 
independent ethics committee 
IgG 
immunoglobulin G 
IL 
interleukin 
INR 
international normalized ratio 
irAE 
immune-related adverse event 
IRB 
institutional review board 
IRT 
interactive response technology 
IV 
intravenous 
mAb 
monoclonal antibody 
MAOI 
monoamine oxidase inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
mRECIST 
modified Response Evaluation Criteria in Solid Tumors 
MRI 
magnetic resonance imaging 
MSI-H 
microsatellite instability-high 
MTD 
maximum tolerated dose 
NCCN 
National Comprehensive Cancer Network 
NFκB 
nuclear factor kappa-light-chain-enhancer of activated B cells 
NSAID 
nonsteroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
OS 
overall survival 
 
 
PCP 
pneumocystis pneumonia 
 
  
PD-1 
programmed cell death protein 1 
PD-L1 
programmed cell death protein ligand 1 


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Abbreviation 
Definition 
PFS 
progression-free survival 
 
 
PoS 
probability of success  
PR 
partial response 
PT 
prothrombin time 
Q2W 
every 2 weeks 
Q3W 
every 3 weeks 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 
SAE 
serious adverse event 
SCCHN 
squamous cell carcinoma of the head and neck 
SCLC 
small cell lung cancer 
SD 
stable disease 
SNRI 
serotonin/norepinephrine reuptake inhibitors 
SS 
serotonin syndrome 
SSRI 
selective serotonin reuptake inhibitors 
T1DM 
type I diabetes mellitus 
TCR 
T-cell receptor 
Teff 
effector T cells 
TNBC 
triple-negative breast cancer 
TNFRSF 
tumor necrosis factor receptor super family 
TNFSF 
tumor necrosis factor super family 
Treg 
regulatory T cell 
Trp 
tryptophan 
UC 
urothelial carcinoma 
ULN 
upper limit of normal 












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1.3. 
Overview of Epacadostat 
Epacadostat (INCB024360) is an inhibitor of the enzyme IDO1.  Indoleamine 2,3-dioxygenase 1 
mediates the catabolism of the essential amino acid Trp to kynurenine within immune cells and a 
subset of tumor cells.  This catabolism of Trp results in the inhibition of antitumor cell-mediated 
immune responses.  Histologic evaluation of most human cancers shows extensive infiltration by 
inflammatory and immune cells, suggesting that the immune system does recognize and respond 
to the presence of the malignancy (Galon et al 2006); but in most cases, the immune response is 
ineffective in inhibiting or eradicating tumor growth.  Many tumor cells or the infiltrating 
immune cells overexpress IDO1, and there have been multiple lines of evidence to suggest that 
IDO1 is a key regulator in the immunosuppressive mechanisms responsible for tumor escape 
from immune surveillance (Liu et al 2009).  Therefore, inhibition of this enzyme may provide a 
unique method to treat malignancies, either alone or in combination with chemotherapeutics or 
other immune-based therapies. 
1.3.1. 
Clinical Summary of Epacadostat 
Twelve Incyte-sponsored clinical studies have either been completed or are ongoing 
(11 Phase 1/2 studies and 1 Phase 3 study).  Three clinical studies have been completed 
(INCB 24360-101, INCB 24360-102, and INCB 24360-210).  Seven ongoing studies 
(INCB 24360-110, INCB 24360-201, INCB 24360-202, INCB 24360-203, INCB 24360-204, 
INCB 24360-301, and INCB 39110-106) are combination therapy studies.  Two ongoing studies 
(INCB 24360-103 and INCB 24360-104) are monotherapy studies.  As of 29 OCT 2016, 
898 unique subjects have been exposed to INCB024360 in Incyte-sponsored studies as 
monotherapy (149 subjects) and/or in combination with CPI anti−PD-1 targeted therapy 
(543 subjects), anti−PD-L1 targeted therapy (124 subjects), anti−CTLA-4 targeted therapy 
(50 subjects), and a Janus kinase 1 inhibitor (32 subjects).  For a thorough overview of the 
pharmacology of epacadostat and ongoing clinical studies, refer to the INCB024360 IB. 
There are currently 2 ongoing studies evaluating the combination of epacadostat and 
pembrolizumab:  INCB 24360-202 is an ongoing Phase 1/2 study, and INCB 24360-301 
(KEYNOTE-252) is an ongoing Phase 3 study.  In the INCB 24360-202 study, Phase 1 consists 
of a dose-escalation phase followed by Phase 2, which is an open-label, single-arm, cohort 
expansion phase.  The tumor types evaluated in the expansion phase included NSCLC, 
melanoma, transition cell carcinoma of the genitourinary tract, TNBC, SCCHN, ovarian cancer, 
diffuse large B-cell lymphoma, RCC, and MSI-H colorectal cancer.  
Study INCB 24360-301 (KEYNOTE-252) is an ongoing, Phase 3, randomized, double-blind, 
placebo-controlled study of pembrolizumab in combination with epacadostat or placebo in 
subjects with unresectable or metastatic melanoma.  Subjects are randomized 1:1 
(active:placebo) to pembrolizumab plus epacadostat or pembrolizumab plus placebo and 
stratified by PD-L1 expression (positive vs negative/indeterminate) and BRAF mutation status 
(BRAF mutant and received prior BRAF-directed treatment, BRAF mutant with no prior 
BRAF-directed treatment, and BRAF wild type).  Additional Phase 3 studies with epacadostat in 
combination with pembrolizumab are scheduled to open in 2017. 


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1.3.2. 
Clinical Safety and Potential Risks of Epacadostat in Combination With 
Pembrolizumab 
Phase 1 of Study INCB 24360-202 has completed enrollment with a total of 62 subjects.  
Epacadostat
 were tolerated in combination with pembrolizumab 
2 mg/kg or 200 mg IV Q3W.  Preliminary safety results for subjects receiving 
 of 
epacadostat in combination with 200 mg Q3W pembrolizumab in the Phase 2 portion of 
Study INCB 24360-202 were presented at the 2017 ASCO annual meeting.  The most frequently 
reported treatment-related AEs were fatigue (29%), rash (17%), nausea (11%), and pruritus 
(10%).  Rash includes the preferred terms rash, rash generalized, rash macular, rash 
maculopapular, and rash pruritic.  Adverse events of special interest occurred infrequently, with 
only hypothyroidism (5%) and severe skin reaction (3%) occurring in ≥ 3 subjects.  Treatment-
related AEs leading to treatment discontinuation occurred in 4% of subjects, with only arthralgia 
and rash (n = 2 each) occurring in more than 1 subject.  There was 1 treatment-related death due 
to respiratory failure secondary to aspiration pneumonia; however, pneumonitis could not be 
ruled out (Hamid et al 2017b).   
An uncommon risk of IDO1 inhibition is an increase in serotonin levels that could precipitate a 
cluster of AEs termed SS when administered alone or in combination with other serotonergic 
agents.  This rare syndrome has been associated with some MAOIs and combinations of 
serotonergic drugs (Boyer and Shannon 2005).  The clinical manifestations of SS range from 
barely perceptible to lethal; onset is rapid (within 12 hours of drug[s] administration).  As of 
27 FEB 2017, 2 subjects across the epacadostat program (958 subjects treated) have reported SS 
or symptoms of SS, and both were mild in their severity and resolved (refer to the 
INCB024360 IB).  Although this incidence is uncommon, use of MAOIs will be prohibited 
during the study, and all subjects will be assessed for SS symptoms at an appropriate timeframe 
after dosing.  Subjects will be provided with an informative subject leaflet describing the signs 
and symptoms of the syndrome, along with instructions to seek immediate medical care if any of 
these signs or symptoms are observed. 
1.4. 
Overview Pembrolizumab 
1.4.1. 
Pembrolizumab Summary 
Pembrolizumab (KEYTRUDA®) is a PD-1 blocking antibody that has been approved as 
monotherapy in the United States for the treatment of patients with unresectable or metastatic 
melanoma, metastatic NSCLC whose tumors have PD-L1 expression, recurrent or metastatic 
SCCHN, and refractory classical Hodgkin lymphoma (Keytruda 2017). 
1.4.2. 
Risks From Pembrolizumab 
Due to the effects of pembrolizumab on the immune system, immune-mediated adverse reactions 
have been observed in patients treated with this agent.  Guidance is provided in the prescribing 
information for immune-mediated pneumonitis, immune-mediated colitis, immune-mediated 
hepatitis, immune-mediated endocrinopathies, and immune-mediated nephritis and renal 
dysfunction.  Infusion reactions are also possible following administration of pembrolizumab.  
The most common adverse reactions seen in ≥ 20% of patients were fatigue, pruritis, diarrhea, 


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decreased appetite, rash, pyrexia, cough, dyspnea, musculoskeletal pain, constipation, and nausea 
(Keytruda 2017). 
1.5. 
Study Rationale 
1.5.1. 
Rationale for the Study Population 
Most cancers exhibit genetic heterogeneity, which often translates into enhanced tumor 
immunogenicity.  This concept of tumor immunogenicity is well-appreciated for its role in 
eliciting an adaptive immune response and determining the efficacy of immunotherapy.  
Blockade of PD-1/PD-L1 has led to clinical responses in patients with many different types of 
cancer, including melanoma, NSCLC, RCC, SCCHN, gastric cancer, HCC, TNBC, cervical 
cancer, and bladder (Hamid et al 2013, Powels et al 2014, Topalian et al 2014, 
Brahmer et al 2015, Dirix et al 2015, Ferris et al 2016, Frenel et al 2016, Herbst et al 2016, 
Le et al 2016, Melero et al 2016, Rosenberg et al 2016).  The combination of pembrolizumab and 
epacadostat has also demonstrated improved ORR compared with monotherapy PD-1/PD-L1 in a 
variety of tumor types, including melanoma, NSCLC, RCC, SCCHN, and UC (Gangadhar et al 
2017, Lara et al 2017, Hamid et al 2017a, Smith et al 2017); however, further clinical 
improvement is warranted. 
The Phase 2 portion of this study (INCAGN 1876-202) will utilize a Simon 2-stage design to 
evaluate the benefit of the combination of pembrolizumab, epacadostat, and INCAGN01876 
(Simon 1989).  The approximate number of subjects for Stage 1 and Stage 2 for each treatment 
group and tumor type was determined based on an observed improvement in the ORR from the 
INCB 24360-202 study, as outlined below. 
Epacadostat and Pembrolizumab in Melanoma 
Preliminary efficacy results for subjects with melanoma enrolled in the Phase 1 portion of 
Study INCB 24360-202 was presented at the 2016 European Society for Medical Oncology 
annual meeting (Gangadhar et al 2016).  Twenty-two subjects with advanced melanoma were 
enrolled in Phase 1; of the 19 treatment-naive melanoma subjects, 11 subjects (58%) achieved an 
objective response (CR or PR) by RECIST v1.1, with 5 of 19 subjects (26%) achieving a CR.  
.  The 
combination of INCAGN01876, pembrolizumab, and epacadostat will be evaluated to determine 
if the combination regimen can improve the CRR of 26% in this setting. 
Epacadostat and Pembrolizumab in Renal Cell Carcinoma 
Subjects with RCC enrolled in the INCB 24360-202 study showed improved ORR and DCR 
compared with pembrolizumab monotherapy.  Of 30 efficacy-evaluable subjects, 63% (n = 19) 
had 0 to 1 prior line of therapy, and 37% (n = 11) had ≥ 2 prior lines of therapy for advanced 
disease.  The ORR (CR + PR) and DCR (CR + PR + SD) for subjects with 0 to1 prior line of 
therapy were 47% (9/19; 1 CR, 8 PR) and 58% (11/19; 1 CR, 8 PR, 2 SD), respectively.  For 
subjects with ≥ 2 prior lines of therapy, ORR and DCR were 0% and 36% (4/11; all SD), 
respectively.  At the time of the data cutoff, 9/9 responses were ongoing (range, 1+ to 372+ days; 
Lara et al 2017). 






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1.5.4.1.1. Modified Response Evaluation Criteria in Solid Tumors 
Response Evaluation Criteria in Solid Tumors v1.1 will be modified to account for the unique 
tumor response characteristics seen with immunotherapy (Wolchok et al 2009).  
Immunotherapeutic agents may produce antitumor effects by potentiating endogenous cancer-
specific immune responses.  The response patterns seen with such an approach may extend 
beyond the typical time course of responses seen with cytotoxic agents and can manifest a 
clinical response after an initial increase in tumor burden or even the appearance of new lesions.  
Standard RECIST v1.1 may not provide an accurate response assessment of immunotherapeutic 
agents.  Therefore, RECIST v1.1 will be used with the following modifications: 
If radiologic imaging shows initial progressive disease, tumor assessment should be repeated at 
least 4 weeks, but no more than 6 weeks, later in order to confirm disease progression, with the 
option of continuing treatment while awaiting radiologic confirmation of disease progression.   
In subjects who have initial evidence of radiological progression but are clinically stable as 
defined below, it is at the discretion of the treating physician whether to continue them on study 
treatment until repeat imaging is obtained.  This clinical judgment decision should be based on 
subjects' overall clinical condition, including performance status, clinical symptoms, and 
laboratory data.  Subjects may receive treatment while waiting for confirmation of disease 
progression if they are clinically stable, as defined by the following criteria: 
• Absence of clinically significant 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 (eg, cord compression) 
requiring urgent alternative medical intervention. 
If repeat imaging shows < 20% tumor burden compared with nadir, stable or improved previous 
new lesion (if identified as cause for initial disease progression), and stable/improved nontarget 
disease (if identified as cause for initial disease progression), then treatment may be continued or 
resumed.  If repeat imaging confirms disease progression due to any of the scenarios listed 
below, subjects will be discontinued from study treatment.  However, if a subject has confirmed 
radiographic progression (ie, 2 scans at least 4 weeks, but no more than 6 weeks, apart 
demonstrating disease progression) per mRECIST, but the subject is achieving a clinically 
meaningful benefit, an exception to continue treatment may be considered after consultation with 
the medical monitor.  Clinically stable subjects at the confirmatory scan should also have no 
further increase in the target lesions, no unequivocal increase in nontarget lesions, and no 
additional new lesions develop (nonworsening disease progression) to continue study treatment 
(see Section 7.7.1). 
When feasible, subjects should not be discontinued until disease progression is confirmed.  This 
allowance to continue treatment despite initial radiographic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after the 
start of immunotherapy, but with subsequent disease response.  Subjects who are deemed 
clinically unstable are not required to have repeat imaging for radiographic confirmation of 
disease progression. 


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1.6. 
Risks and Benefits of Combination Immunotherapy 
The principal toxicities of administering agents that modulate the immune system are irAEs, 
including skin manifestations, pneumonitis, enterocolitis, and endocrinopathies.  The time of 
onset of irAEs varies, with skin manifestations and GI toxicity seen early and elevated liver 
enzymes and endocrinopathies appearing later (Weber et al 2015).  Immune-related AEs have 
been reported in subjects treated with pembrolizumab and epacadostat.  As the use of 
immunotherapies becomes more prevalent, guidelines for the management of irAEs continue to 
evolve.  Careful monitoring, early diagnosis, and treatment with corticosteroids for more severe 
events is recommended.  Subjects enrolled in this study will be carefully monitored for the onset 
of irAEs, and guidelines for the management of these toxicities are provided in both the Protocol 
(see Section 5.4.7 and Appendix B) and in the prescribing information for pembrolizumab 
(Keytruda 2017). 
The combination of INCAGN01876, pembrolizumab, and epacadostat will be administered in 
Phase 1 to subjects who have exhausted options for treatments that have demonstrated clinical 
benefit.  The combination of pembrolizumab and epacadostat has been shown to be active in a 
number of different types of cancer.  Preclinical studies have shown a benefit in adding 
INCAGN01876 to an anti–PD-1 antibody and epacadostat.  Therefore, it is reasonable to test this 
triplet combination in subjects who have limited options for further treatment.  Subjects with 
melanoma, RCC, and UC will be enrolled in Phase 2 earlier in their course of disease.  The 
doublet therapy of pembrolizumab and epacadostat has already shown clinical benefit in these 
indications, and the safety of the triplet combination would have been assessed in Phase 1 of the 
study prior to enrolling these subjects. 
2. 
STUDY OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objectives 
Phase 1 
• To evaluate the safety, tolerability, and DLTs of INCAGN01876 in combination with 
immune therapies and to define the recommended Phase 2 dose(s) of INCAGN01876 
when given in combination with immune therapies. 
Phase 2 
• To evaluate the efficacy of INCAGN01876 when given in combination with immune 
therapies by assessing ORR or CRR per RECIST v1.1. 
2.1.2. 
Secondary Objectives 
Phase 1 and Phase 2 
• To evaluate the efficacy of INCAGN01876 when given in combination with immune 
therapies by assessing ORR, DOR, DCR, duration of disease control, and PFS per 
RECIST v1.1 and mRECIST. 






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5. Phase 1 (Part 1 and Part 2):  Subjects who have disease progression after treatment with 
available therapies that are known to confer clinical benefit or who are intolerant to 
treatment.  There is no limit to the number of prior treatment regimens. 
6. Phase 2:  Subjects with advanced or metastatic melanoma, RCC, and UC.  
a. For subjects with melanoma:  mucosal or cutaneous melanoma is acceptable; 
however, subjects with ocular melanoma are excluded.  Subjects should have 
documented BRAF mutation status or consent to BRAF mutation testing during the 
screening period.  BRAF mutation status determined as part of a panel of genetic tests 
performed in a gene expression analysis will also satisfy the inclusion criterion for 
BRAF mutation testing. 
Note:  Should not have received prior therapy for advanced or metastatic disease.  
Adjuvant regimens given within 6 months of screening will be counted as first-line 
therapy. 
Note:  Should not have received prior therapy that included an immune therapy 
(eg, anti–CTLA-4 or PD-1/PD-L1 inhibitor, IDO inhibitor, TNFSF agonist, or other 
antibodies or drugs specifically targeting T-cell costimulation or checkpoint 
pathways, etc). 
b. For subjects with RCC:  histologically confirmed RCC that is predominantly 
clear-cell. 
Note:  Should not have received prior therapy for advanced or metastatic disease.  
Adjuvant regimens given within 6 months of screening will be counted as first-line 
therapy. 
Note:  Should not have received prior therapy that included an immune therapy 
(eg, anti–CTLA-4 or PD-1/PD-L1 inhibitor, IDO inhibitor, TNFSF agonist, or other 
antibodies or drugs specifically targeting T-cell costimulation or checkpoint 
pathways, etc). 
c. For subjects with UC:  histologically confirmed UC of the renal pelvis, ureter, 
bladder, or urethra that is transitional cell type or mixed histology (predominantly 
transitional cell) type. 
Note:  Should not have received prior therapy for advanced or metastatic 
disease.  Adjuvant regimens given within 6 months of screening will be counted as 
first-line therapy. 
Note:  Should not have received prior therapy that included an immune therapy 
(eg, anti–CTLA-4 or PD-1/PD-L1 inhibitor, IDO inhibitor, TNFSF agonist, or other 
antibodies or drugs specifically targeting T-cell costimulation or checkpoint 
pathways, etc). 
d. For subjects in the biopsy cohort:  willingness to undergo pretreatment and on 
treatment tumor biopsies (core or excisional; see Section 7.10.4).  Must have 
melanoma (mucosal or cutaneous), RCC, or UC.   
Note:  A baseline biopsy obtained for other purposes (ie, not an INCAGN 1876-202 
procedure) before signing the ICF may be used if the subject has not had any 
intervening systemic therapy from the time of the biopsy to the start of treatment 
(ie, Cycle 1 Day 1) and if a minimum of 20 slides or preferably 1 tissue block can be 
submitted. 


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7. Presence of measureable disease based on RECIST v1.1.  Tumor lesions situated in a 
previously irradiated area, or in an area subjected to other locoregional therapy, are not 
considered measureable unless there has been demonstrated progression in the lesion. 
8. ECOG performance status of 0 or 1. 
9. Willingness to avoid pregnancy or fathering children based on the criteria below: 
a. Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 12 months of amenorrhea). 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening and who agrees to take appropriate precautions to avoid pregnancy (with at 
least 99% certainty) from screening through safety follow-up, or as required in the 
pembrolizumab prescribing information, whichever is longer.  Permitted methods that 
are at least 99% effective in preventing pregnancy (see Appendix A) should be 
communicated to the subject, and her understanding should be confirmed. 
c. Man who agrees to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) from screening through 90 days after the last dose of study 
treatment, or as required in the pembrolizumab prescribing information, whichever is 
longer.  Permitted methods that are at least 99% effective in preventing pregnancy 
(see Appendix A) should be communicated to the subject, and his understanding 
should be confirmed. 
3.2. 
Subject Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Laboratory and medical history parameters not within the Protocol-defined range.  If the 
screening laboratory tests below were conducted > 7 days before treatment initiation, 
then the tests must be repeated and eligibility confirmed before study treatment 
administration on Cycle 1 Day 1. 
a. Absolute neutrophil count < 1.0 × 109/L. 
b. Platelets < 75 × 109/L. 
c. Hemoglobin < 9 g/dL or < 5.6 mmol/L. 
d. Serum creatinine > 1.5 × institutional ULN OR measured or calculated creatinine 
clearance (glomerular filtration rate can also be used in place of creatinine or 
creatinine clearance) < 50 mL/min for subjects with creatinine levels > 1.5 × ULN. 
e. Aspartate aminotransferase, ALT, and alkaline phosphatase ≥ 2.5 × ULN. 
Note:  Subjects with 1) bone metastases and 2) no hepatic parenchymal metastases on 
screening radiographic examinations may enroll if the alkaline phosphatase is 
≤ 5 × ULN.  Subjects with 1) bone metastases and/or 2) hepatic parenchymal 
metastases on screening radiographic examinations may enroll if the alkaline 
phosphatase is ≤ 5 × ULN only with medical monitor approval. 
f. Total bilirubin ≥ 1.2 × ULN is excluded unless conjugated bilirubin ≤ ULN 
(conjugated bilirubin only needs to be tested if total bilirubin exceeds ULN).  If there 
is no institutional ULN, then direct bilirubin must be < 40% of total bilirubin to be 
eligible. 
g. International normalized ratio, PT, or aPTT > 1.5 × ULN. 


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2. Prior treatment with any TNFSF agonist (eg, GITR, OX40, 4-1BB/CD137, CD27, etc) 
for any indication. 
3. Transfusion of blood products (including platelets or red blood cells) or administration of 
colony-stimulating factors (including granulocyte colony-stimulating factor, granulocyte 
macrophage colony-stimulating factor, or recombinant erythropoietin) within 14 days 
before study Day 1. 
4. Receipt of anticancer medications or investigational drugs within the following intervals 
before the first administration of study treatment: 
a. ≤ 14 days for chemotherapy, targeted small molecule therapy, or radiation therapy.   
Note:  Subjects must not have had radiation pneumonitis as a result of treatment.  A 
1-week washout is permitted for palliative radiation to non-CNS disease with medical 
monitor approval. 
Note:  Bisphosphonates and denosumab are permitted concomitant medications. 
b. ≤ 28 days for prior immune therapy or persistence of active cellular therapy 
(ie, chimeric antigen receptor T-cell therapy; other cellular therapies must be 
discussed with the medical monitor to determine eligibility). 
c. ≤ 28 days for a prior mAb used for anticancer therapy, with the exception of 
denosumab. 
d. ≤ 7 days for immune-suppressive–based treatment for any reason. 
Note:  Use of inhaled or topical steroids or corticosteroid use for radiographic 
procedures is permitted. 
Note:  Must not require chronic use of corticosteroids.  The use of physiologic 
corticosteroid replacement therapy may be approved after consultation with the 
medical monitor. 
e. ≤ 28 days or 5 half-lives (whichever is longer) before the first dose for all other 
investigational agents or devices.  For investigational agents with long half-lives 
(eg, > 5 days), enrollment before the fifth half-life requires medical monitor approval. 
5. Has not recovered to ≤ Grade 1 from toxic effects of prior therapy (including prior 
immune therapy) and/or complications from prior surgical intervention before starting 
therapy. 
Note:  Subjects with stable chronic conditions (≤ Grade 2) that are not expected to 
resolve (such as neuropathy and alopecia) are exceptions and may enroll. 
Note:  Subjects with a history of any grade immune-related ocular AE (eg, episcleritis, 
scleritis, uveitis) will be excluded. 
Note:  Subjects with a history of a Grade 3 or higher immune-related AE from prior 
immunotherapies are excluded from the dose-escalation portion of the study. 
6. Receipt of a live vaccine within 30 days of planned start of study treatment. 
Note:  Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, chicken pox/zoster, yellow fever, rabies, Bacillus Calmette-Guérin, and 
typhoid vaccines.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
7. Current use of prohibited medication as described in Section 5.6.3. 


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8. Active autoimmune disease that required systemic treatment in the past (ie, use of 
disease-modifying agents, corticosteroids, or immunosuppressive drugs). 
Note:  Subjects who have not required systemic treatment in the past 2 years should 
discuss their case with the medical monitor to determine eligibility. 
Note:  Subjects with hyper/hypothyroidism, vitiligo, controlled asthma, Type I diabetes, 
Graves' disease, or Hashimoto's disease are eligible to participate. 
Note:  Replacement and symptomatic therapies (eg, levothyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) 
are not considered a form of systemic treatment and are allowed. 
9. Known active CNS metastases and/or carcinomatous meningitis. 
Note:  Subjects with previously treated brain metastases may participate provided that 
they are stable (without evidence of progression by imaging for at least 28 days before 
the first dose of study treatment and any neurologic symptoms have returned to baseline), 
have no evidence of new or enlarging brain metastases or CNS edema, and have not 
required steroids for at least 7 days before the first dose of study treatment. 
10. Known additional malignancy that is progressing or requires active treatment or history 
of other malignancy within 2 years of study entry with the exception of cured basal cell 
or squamous cell carcinoma of the skin, superficial bladder cancer, prostate intraepithelial 
neoplasm, carcinoma in situ of the cervix, other noninvasive or indolent malignancies, or 
cancers from which the subject has been disease-free for > 1 year after treatment with 
curative intent. 
11. Evidence of active noninfectious pneumonitis or history of interstitial lung disease. 
12. Clinically significant or uncontrolled cardiac disease, including unstable angina, acute 
myocardial infarction within 6 months from Day 1 of study treatment administration, 
New York Heart Association Class III or IV congestive heart failure, and arrhythmia not 
controlled with therapy unless approved by the medical monitor. 
13. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically 
meaningful.  Subjects with screening QTc interval > 470 milliseconds (corrected by 
Fridericia) are excluded, unless approved by the medical monitor.  In the event that a 
single QTc is > 470 milliseconds, the subject may enroll if the average QTc for 3 ECGs is 
< 470 milliseconds.  For subjects with an intraventricular conduction delay (QRS interval 
> 120 milliseconds) at screening, the JTc interval may be used in place of the QTc with 
medical monitor approval.  The JTc must be < 340 milliseconds if JTc is used in place of 
the QTc.  Subjects with left bundle branch block are excluded. 
Note:  QTc prolongation due to pacemaker may enroll if the JTc is normal or with 
medical monitor approval. 
14. Evidence of HBV or HCV infection or risk of reactivation.  Hepatitis B virus DNA and 
HCV RNA must be undetectable.  Subjects cannot be positive for HBV DNA, HCV 
RNA, hepatitis B surface antigen, or anti-hepatitis B core antibody without approval from 
the medical monitor. 
Note:  Subjects with no prior history of HBV infection who have been vaccinated against 
HBV and who have a positive antibody against hepatitis B surface antigen test as the only 
evidence of prior exposure may participate in the study. 




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The Phase 2 Dose Expansion will further evaluate the safety, tolerability, and efficacy of the 
recommended dose(s) of INCAGN01876 selected in Phase 1 when given in combination with 
immune therapies.  Subjects with advanced or metastatic melanoma, RCC, and UC will be 
enrolled in Phase 2.  See Figure 1 for overall study design. 
The sponsor may elect to prioritize (or deprioritize) enrollment to specific treatment groups or 
cohorts based on emerging safety or efficacy data in collaboration with investigational sites. 
Figure 1: 
Overall Study Design 
 
4.1.1. 
Phase 1 – Dose Escalation (Part 1) 
A minimum of 3 evaluable subjects will be enrolled in Treatment Group A (see Table 2), 
beginning with INCAGN01876 Dose Cohort 1 (1.0 mg/kg; starting dose; see Table 1).  A higher 
starting dose of INCAGN01876 may be used if safety data are available from the monotherapy 
study (INCANG 1876-101), but it will not exceed 1 dose level below the highest tolerated dose 
of INCAGN01876 monotherapy.  If a higher dose is used, the dose will be communicated to 
investigational sites with an administrative letter.  The first 3 evaluable subjects enrolled within 
an INCAGN01876 dose cohort will be observed for a minimum of 28 days before the next dose 
cohort begins enrollment.  If 0 DLTs occur in a cohort of 3 evaluable subjects, a new cohort of 
3 evaluable subjects will be treated at the next higher dose level.  If 1 of 3 evaluable subjects 
experiences a DLT, that cohort will be expanded to 6 evaluable subjects.  If 1 of 6 evaluable 


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subjects experiences a DLT, a new cohort of 3 evaluable subjects will be treated at the next 
higher dose level.  If 2 of 6 evaluable subjects experience a DLT, that cohort will be expanded to 
9 evaluable subjects.  If ≥ 2 of 3, 3 of 6, or 3 of 9 evaluable subjects experience DLTs within a 
cohort, then that dose level will be determined to have exceeded the MTD, and the previous dose 
level will be considered the MTD.  If only 3 evaluable subjects were treated at the MTD
 
then a minimum of 3 additional evaluable subjects will be enrolled before this dose is 
administered in Phase 2 of the study. 
Additional subjects will be enrolled in a dose cohort to achieve the minimum of 3 evaluable 
subjects.  Subjects who drop out for reasons other than a DLT (eg, events clearly associated with 
the underlying disease, disease progression, concomitant medication, or comorbidity) during the 
DLT observation period will result in the subjects being nonevaluable and replaced.  Dose 
modifications should not be made during the DLT observation period without discussion with 
the medical monitor.  The doses of INCAGN01876 to be evaluated in each treatment group are 
summarized in Table 1. 
Table 1: 
INCAGN01876 Dose Cohorts 
Dose Cohort 
Dose of INCAGN01876 
-1 
0.3 mg/kg 
1 (Starting Dose) 
1.0 mg/kga 
2 
3.0 mg/kg 
3 
5.0 mg/kg 
4 
10.0 mg/kg 
a A higher starting dose of INCAGN01876 may be used if safety data are available from the monotherapy study 
(INCAGN 1876-101), but it will not exceed 1 dose level below the highest tolerated dose of INCAGN01876 monotherapy.  If a 
higher dose is used, the dose will be communicated to investigational sites with an administrative letter. 
4.1.1.1. 
Treatment Group A (INCAGN01876 + Pembrolizumab) 
Treatment Group A will treat subjects with INCAGN01876 at the assigned dose level 
administered Q3W in combination with 200 mg of pembrolizumab administered Q3W and 
epacadostat administered orally BID (see Table 2).  There will be a waiting period 
of 48 hours between dose administration of the first subject and second subject of each 
dosing cohort.  The first 3 evaluable subjects enrolled within a cohort will be observed for 
28 days before the next cohort begins enrollment.  Dose escalation of INCAGN01876 will 
proceed as outlined in Table 1 until the MTD
 of INCAGN01876 in combination with 
pembrolizumab and epacadostat is determined.  Subjects must receive at least 1 dose of the 
cohort-specified dose of INCAGN01876, 1 dose of pembrolizumab, and at least 75% of planned 
doses of epacadostat (42 doses) or have had a DLT during the DLT observation period to be 
considered evaluable. 


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Table 2: 
Phase 1 Dose Escalation of Treatment Group A 
Treatment 
Group A 
INCAGN01876 
Concurrent Dose Administration 
Pembrolizumab 
Epacadostat 
See INCAGN01876 dose cohorts 
(Table 1) Q3W starting at Cycle 1 
200 mg Q3W 
starting at Cycle 1 
 
starting at Cycle 1 
 
4.1.2. 
Phase 1 – Safety Expansion (Part 2) 
Once an INCAGN01876 dose cohort in Treatment Group A is deemed tolerable (ie, no DLTs or 
unacceptable toxicities were observed within the defined DLT observation period of at least 
28 days), up to 6 evaluable subjects will be enrolled in Treatment Group B at the same dose of 
INCAGN01876 (see Figure 2).  For example, if 3.0 mg/kg of INCAGN01876 is tolerated in 
Treatment Group A, then 3.0 mg/kg will be explored in up to 6 evaluable subjects in Treatment 
Group B.  Doses of INCAGN01876 in Treatment Group B will be escalated in parallel to those 
explored in Treatment Group A, but will not exceed the MTD of INCAGN01876 established in 
Treatment Group A.  Alternate dose administration schedules may also be explored depending 
on 
 safety results.  The sponsor may elect to prioritize (or 
deprioritize) enrollment to specific dose cohorts based on emerging safety or efficacy data in 
collaboration with investigational sites. 
Figure 2: 
Phase 1 Safety Expansion (Part 2) 
 


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If the cumulative incidence of Grade 3 or higher INCAGN01876-related AEs occurs in > 40% of 
subjects in a particular treatment group, then further enrollment will be interrupted until the 
sponsor, investigators, and regulatory authorities (if applicable) determine the appropriate course 
of action (eg, lower the dose of INCAGN01876, change dose frequency, etc). 
4.1.2.1. 
Treatment Group B (INCAGN01876 + Epacadostat Run-In Followed by 
INCAGN01876 + Pembrolizumab + Epacadostat) 
Treatment Group B will treat subjects with a single-dose run-in of INCAGN01876 at the 
assigned dose level in combination with 
epacadostat administered orally BID, 
followed by the combination of INCAGN01876 Q3W, 200 mg of pembrolizumab Q3W starting 
at Cycle 2, and 
 epacadostat administered orally BID (see Table 3). 
Table 3: 
Phase 1 Safety Expansion of Treatment Group B 
Treatment 
Group B 
INCAGN01876 
Run-In Followed by Concurrent Dose 
Administration 
Pembrolizumab 
Epacadostat 
See INCAGN01876 dose cohorts 
(Table 1) Q3W starting at Cycle 1 
200 mg Q3W 
starting at Cycle 2 
 
starting at Cycle 1 
 
4.1.3. 
Phase 2 – Dose Expansion 
Phase 2 will further evaluate the safety, tolerability, efficacy,
of 
the immune therapy combinations in subjects with advanced or metastatic melanoma, RCC, and 
UC.  Additional tumor-specific cohorts may be added, by protocol amendment, based on 
emerging data.   
Biopsy cohorts will be added at specific institutions for each treatment group (C and D), where 
serial mandatory pretreatment and on-treatment biopsies will be collected to evaluate changes in 
the tumor microenvironment.  Approximately 15 evaluable subjects who have tumor lesions that 
are amenable to percutaneous biopsy will be enrolled in each biopsy cohort.  The biopsy-specific 
cohorts will be limited to subjects with melanoma (mucosal or cutaneous), RCC, and UC 
(see Section 7.10.4). 
The Phase 2 dose expansion treatment groups and tumor-specific cohorts for each treatment 
group are outlined in Table 4.  A Simon 2-stage design will be used with a stopping rule to allow 
for early termination of a particular cohort at the end of Stage 1 if there are insufficient responses 
observed.  The approximate number of subjects for Stage 1 and Stage 2 for each treatment group 
and tumor type is described in Table 21.  Enrollment in Phase 2 will begin when the MTD 
 
 of INCAGN01876 for a given treatment group in Phase 1 has been determined.   


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Table 4: 
Phase 2 Dose Expansion Treatment Groups 
Dose Expansion Treatment Groups 
Treatment 
Group C 
INCAGN01876 
Concurrent Dose 
Administration 
Pembrolizumab 
Epacadostat 
Tumor Cohorts 
MTD 
 of  
Treatment Group A Q3W 
starting at Cycle 1 
200 mg Q3W 
 starting at Cycle 1 
 
starting at Cycle 1 
Cohort 1 – Biopsy  
Cohort 2 – Melanoma 
Cohort 3 – RCC  
Cohort 4 – UC 
 
Treatment 
Group D 
INCAGN01876 
Run-In Followed by 
Concurrent Dose 
Administration 
Pembrolizumab 
Epacadostat 
Tumor Cohorts 
MTD 
 of 
Treatment Group A Q3W 
starting at Cycle 1 
200 mg Q3W 
starting at Cycle 2 
 
starting at Cycle 1 
Cohort 1 – Biopsy  
Cohort 2 – Melanoma 
Cohort 3 – RCC  
Cohort 4 – UC 
 
In Phase 2 of the study, toxicities will continue to be monitored.  If the cumulative incidence of 
Grade 3 or higher INCAGN01876-related AEs occurs in > 40% of subjects in a particular 
treatment group after 6 subjects have been enrolled, then further enrollment in that treatment 
group will be interrupted until the sponsor, investigators, and regulatory authorities (if 
applicable) determine the appropriate course of action (eg, lower the dose of INCAGN01876, 
change dose frequency, etc).  If a treatment group is discontinued due to toxicity, it may be 
re-initiated at a previously tested lower dose level and/or alternate dosing schedule.  All AEs, 
regardless of the time of occurrence on study, may be considered for DLT determination 
purposes.   
4.2. 
Measures Taken to Avoid Bias 
This is an open-label study.  Assessment of safety using CTCAE v4.03 and efficacy using 
RECIST v1.1 and mRECIST are objective measurements, and only comparisons to pretreatment 
conditions will be made. 


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4.3. 
Number of Subjects 
4.3.1. 
Planned Number of Subjects 
Approximately 166 to 362 subjects may be enrolled as follows: 
• Phase 1 Dose Escalation (Part 1) – Approximately 12 to 36 evaluable subjects. 
Note:  The minimum number of subjects assumes that the starting dose is 1.0 mg/kg. 
Note:  The maximum number of subjects assumes that DLTs are observed in all dose 
cohorts to a maximum of 9 subjects per cohort across all treatment groups. 
• Phase 1 Safety Expansion (Part 2) – Approximately 24 evaluable subjects. 
• Phase 2 Stage 1 – Approximately 100 evaluable subjects. 
• Biopsy cohorts – Approximately 30 evaluable subjects. 
• Phase 2 Stage 2 – Up to 172 evaluable subjects. 
Note:  The maximum number of subjects assumes that all treatment groups and all 
tumor types proceed to Stage 2. 
4.3.2. 
Replacement of Subjects 
Subjects may be replaced for any of the following reasons: 
• In Phase 1, any subject who withdraws from treatment before the completion of the 
DLT observation period for any reason other than a DLT (ie, is not evaluable for 
DLTs; see Section 5.4.2) may be replaced to ensure a minimum number of evaluable 
subjects. 
• In the Phase 2 biopsy cohorts, a subject who has not met the biopsy requirements for 
the study (ie, pre- and on-treatment samples; see Section 7.10.4) may be replaced to 
allow for a minimum number of evaluable biopsied subjects. 
• Subjects who do not meet the eligibility requirements of the study may be replaced 
(see Section 3). 
Subjects who meet any of the criteria for replacement may remain on study for evaluation as 
outlined in Section 9.1 and Section 9.2. 
4.4. 
Duration of Treatment and Subject Participation 
After signing the ICF, screening assessments may be completed over a period of up to 28 days.  
Subjects may continue to receive study treatment as long as they are deriving benefit and have 
not met any of the Protocol-defined criteria for treatment withdrawal (see Section 5.5), or for up 
to 24 months from the first dose of study treatment, whichever occurs first.  If the subject 
discontinues study treatment, then the treatment period will end, and the subject will enter the 
follow-up period (see Section 6.4), for safety and survival.  Study participation, including post-
treatment follow-up, is expected to average approximately 12 to 18 months per individual 
subject. 


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4.5. 
Overall Study Duration 
The study begins when the first subject signs the ICF.  The end of the study will occur when all 
subjects have discontinued treatment, and the last follow-up visit has been performed. 
If there are ≤ 5 subjects on study for more than 6 months, a database lock of the study may occur 
to allow for the analysis of the study data.  Any remaining subjects may continue to receive study 
treatment and be seen by the investigator per usual standard of care for this population.  The 
investigator will be expected to monitor for and report any AEs, SAEs, pregnancies, and deaths 
as detailed in Section 8 and Section 6.4.3.  The remaining subjects are considered to be on study 
until a discontinuation criterion is met and written notification is provided to the sponsor. 
4.6. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study's completion or early termination, send a copy of the notification to the sponsor or 
sponsor's designee, and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively, if required by regulatory decision, or upon 
review of emerging data.  If the study is terminated prematurely, the sponsor will notify the 
investigators, the IRBs and IECs, and regulatory bodies of the decision and reason for 
termination of the study. 
5. 
TREATMENT 
5.1. 
Treatment Assignment 
5.1.1. 
Subject Numbering and Treatment Assignment 
Each subject will be identified in the study by a subject ID number, which is a combination of 
the site ID and subject number.  Site personnel should contact IRT to obtain the subject ID 
number and to confirm that a slot is available during prescreening.  This subject ID number will 
be maintained throughout the study and will not be reassigned.  Subjects who fail screening and 
repeat the screening process due to a change in eligibility status will be assigned a new subject 
ID number.  Site personnel will contact IRT to enroll the subject and to obtain the study drugs 
and treatment group assignment.  All subsequent cycles will follow this process.  Interactive 
Response Technology will also be contacted to order study drug supplies and when subjects are 
discontinued from treatment.  Full details will be provided in the Cohort Management Plan and 
the IRT Manual. 
5.1.2. 
Randomization and Blinding 
This is an open-label nonrandomized study; therefore, randomization and blinding do not apply.   




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that stated in the Protocol.  The Pharmacy Manual contains additional information regarding 
storage of study drug. 
5.2.2. 
Epacadostat 
5.2.2.1. 
Description and Administration 
Epacadostat will be self-administered orally 
 without regard to food.  
Doses will be taken in the morning and evening, approximately 12 hours apart.  If a dose is 
missed by more than 4 hours, then the dose should be skipped, and the next dose should be taken 
at the usual time. 
For subjects enrolled in Phase 1 and Phase 2, Treatment Groups A through D, epacadostat will 
begin on Cycle 1 Day 1 and will be self-administered continuously, 
 
 (see Table 18). 
epacadostat will be administered at 
the clinic and should be taken before the INCAGN01876 infusion.  Treatment will continue as 
long as subjects are deriving benefit and have not met any of the Protocol-defined conditions for 
treatment withdrawal (see Section 5.5) or for up to 24 months from the first dose of study 
treatment, whichever occurs first. 
5.2.2.2. 
Supply, Packaging, and Labeling 
Epacadostat will be available
 
.  In Phase 1, Treatment Groups A and B subjects will receive epacadostat 
according to Table 2 and Table 3, respectively.  In Phase 2, Treatment Groups C and D subjects 
will receive epacadostat according to Table 4.  All tablet excipients comply with the 
requirements of the applicable compendial monographs (Ph. Eur., USP/NF; refer to the 
INCB024360 IB). 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country. 
5.2.2.3. 
Storage 
Bottles should be stored at room temperature (15°C-30°C) and closed tightly to protect the 
tablets from humidity. 
5.2.3. 
Pembrolizumab 
5.2.3.1. 
Description and Administration 
Pembrolizumab will be administered IV as per the prescribing information at a dose of 200 mg 
Q3W (eg, 21 days).   
In the concurrent dose administration, Treatment Groups A and C, pembrolizumab will begin on 
Cycle 1 Day 1.  In the run-in dose administration, Treatment Groups B and D, pembrolizumab 
will begin on Cycle 2 Day 1.  Alternate dose administration schedules may also be explored 
depending on
safety results. 
Pembrolizumab will be administered at least 30 minutes after the end of the INCAGN01876 
infusion (when applicable), and subjects will continue to receive pembrolizumab as long as they 


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are deriving benefit and have not met any of the Protocol-defined conditions for treatment 
withdrawal or for up to 24 months from the first dose of study treatment, whichever occurs first. 
Pembrolizumab is commercially available.  Investigators are responsible for ensuring that 
subjects receive commercially available supplies of pembrolizumab for the entire duration of 
study participation.  Incyte may provide certain standard-of-care medications, such as 
pembrolizumab, where required by applicable law or specific regulation or under other 
circumstances when subjects may not otherwise have access to them.  Pembrolizumab must be 
used in accordance with the storage conditions and shelf life in the manufacturer's approved 
label. 
5.3. 
Treatment Compliance 
5.3.1. 
Treatment Compliance of INCAGN01876, Pembrolizumab, and Epacadostat 
INCAGN01876 and pembrolizumab are administered as IV infusions by site personnel.  Receipt 
of infusions will be documented by the site personnel and monitored by the sponsor or the 
sponsor's designee. 
Epacadostat is an oral medication, and compliance will be calculated based on the drug 
accountability documented by the site personnel and monitored by the sponsor/designee (tablet 
counts).  The objective is 100% compliance, and site personnel should evaluate compliance at 
each visit to take appropriate steps to optimize compliance.  
5.4. 
Treatment Interruptions and Adjustments 
5.4.1. 
Dose Modifications 
Selections and modifications to INCAGN01876 are planned for dose-escalation cohorts 
(see Section 4.1.1).  Treatment interruptions and dose modifications of INCAGN01876 and 
epacadostat may also occur for individual study subjects.  The identification of DLTs will define 
the doses of INCAGN01876 used in planned cohorts (see Section 5.4.2).  Further, the occurrence 
of DLTs and other toxicities (related or unrelated to INCAGN01876) will guide decisions for 
treatment interruptions and discontinuations for individual subjects.  Dose modifications of 
INCAGN01876 and epacadostat should not be made during the DLT observation period without 
discussion with the medical monitor.  Intrasubject dose escalation will not be permitted. 
No dose reductions of pembrolizumab are allowed for the management of toxicities of 
individual subjects.  Doses of pembrolizumab may be delayed for toxicity management 
(see Section 5.4.6).   Pembrolizumab is an approved therapy and has specific subject safety 
management guidelines within the prescribing information; the treating investigator should refer 
to and follow the labeled guidance for pembrolizumab. 
5.4.2. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose 
The observation period for DLTs will begin on Cycle 1 Day 1 and will continue up to and 
including study Day 28 for subjects in Phase 1 Part 1 (Treatment Group A).  All DLTs will be 
assessed by the investigator using CTCAE v4.03 criteria.  A DLT will be defined as the 
occurrence of any toxicity in Table 5, except those that are clearly and incontrovertibly due to 
disease progression or extraneous causes. 


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Individual subject dose reductions of INCAGN01876 and epacadostat may be made based on 
events observed at any time during treatment; however, for the purposes of dose cohort 
escalation/de-escalation, expanding a dose cohort, and determining the MTD of INCAGN01876, 
decisions will be made based on events that are observed during the DLT observation period.  
A lower MTD may subsequently be determined based on relevant toxicities that become evident 
after the end of the DLT observation period. 
Table 5: 
Definition of Dose-Limiting Toxicity 
Nonhematologic toxicity 
• Any liver function abnormalities that meet the definition of Hy's law.a 
• Any grade encephalopathy. 
• Any ≥ Grade 3 nonhematologic toxicity EXCEPT for the following: 
- Transient (≤ 72 hours) abnormal electrolyte values, not clinically complicated, and resolved spontaneously or 
responded to conventional medical interventions.  
- Nausea, vomiting, and diarrhea adequately controlled with supportive care within 48 hours. 
- Changes in cholesterol and triglycerides. 
- An event clearly and incontrovertibly due to disease progression or extraneous causes. 
- ≥ Grade 3 changes in amylase and lipase that are not associated with symptoms or clinical manifestations of 
pancreatitis. 
- Grade 3 fatigue < 1 week. 
- Singular or nonfasting elevations in blood glucose (ie, blood glucose excursions will be considered toxicities if 
fasting blood glucose is elevated on 2 separate occasions). 
- Grade 3 rash in the absence of desquamation, with no mucosal involvement, that does not require systemic 
steroids and that resolves to Grade 1 within 14 days. 
Hematologic toxicity 
• Grade 3 thrombocytopenia with clinically significant bleeding (ie, requires hospitalization, transfusion of blood 
products, or other urgent medical intervention). 
• Grade 4 neutropenia or thrombocytopenia lasting > 7 days. 
• Any grade febrile neutropenia (fever > 101°F/38.3°C).  
• Grade 4 anemia not explained by underlying disease or some other concomitant disorder. 
Immune-related toxicityb 
• ≥ Grade 2 ocular irAEs. 
• Grade 3 irAEs that do not improve to baseline or at least Grade 1 in < 5 days with appropriate care or with 
corticosteroid therapy. 
• Grade 4 irAEs, regardless of duration. 
• ≥ Grade 2 pneumonitis. 
General 
• Any death not clearly due to the underlying disease or extraneous causes. 
• Inability to receive the planned number of doses within the 28-day DLT observation period due to toxicity, 
regardless of grade. 


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Table 5: 
Definition of Dose-Limiting Toxicity (Continued) 
MTD 
• In Phase 1 Part 1(Dose Escalation), the MTD will be defined as 1 dose level below that at which ≥ one-third of 
subjects in a particular cohort have DLTs. 
• In Phase 2 of the study, toxicities will continue to be monitored.  If the cumulative incidence of Grade 3 or higher 
INCAGN01876-related AEs occurs in > 40% of subjects in a particular treatment group after 6 subjects have been 
enrolled, then further enrollment in that treatment group will be interrupted until the sponsor, investigators, and 
regulatory authorities (if applicable) determine the appropriate course of action (eg, lower the dose of 
INCAGN01876, change dose frequency, etc).  If a treatment group is discontinued due to toxicity, it may be 
re-initiated at a previously tested lower dose level and/or alternate dosing schedule.  All AEs, regardless of the 
time of occurrence on study, may be considered for DLT determination purposes.   
a Hy's law is defined as 1) ALT or AST elevation > 3 × ULN, 2) total bilirubin > 2 × ULN without initial findings of cholestasis 
(elevated serum alkaline phosphatase), AND 3) no other apparent possible causes of aminotransferase elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
b Immune-related AEs are a diagnosis of exclusion, after alternative etiologies have been ruled out. 
5.4.3. 
Management of Dose-Limiting Toxicities or Other Urgent Situations 
In all cases, investigators may employ any measures or concomitant medications necessary to 
optimally treat the subject after discussion with the medical monitor (whenever possible). 
5.4.4. 
Follow-Up of Dose-Limiting Toxicities 
Any DLT should be followed until it resolves to baseline or appears to have stabilized for a 
minimum of 4 weeks (eg, 28 days).  During follow-up, subjects should be seen as often as 
clinically indicated to ensure safety. 
5.4.5. 
Procedures for Cohort Review and Dose Escalation 
Telephone conferences will be scheduled by the sponsor with study investigators in order to 
review cohort-specific data and overall safety data, to agree on dose escalation, to adjudicate 
individual high-grade AEs as potentially dose-limiting, and to guide other major study decisions. 
5.4.6. 
Criteria and Procedures for Dose Interruptions and Adjustments 
Treatment with INCAGN01876 in combination with immune therapies may be delayed up to 
4 weeks (ie, 28 days) to allow for resolution of toxicity.  If an interruption or discontinuation 
is necessary, all study treatments should be interrupted or discontinued.  Subjects may 
resume treatment if no medical condition or other circumstance exists that, in the opinion of the 
investigator, would make the subject unsuitable for further participation in the study.  The 
treating investigator should contact the medical monitor to discuss the case of any subject whose 
treatment has been delayed for more than 4 weeks (ie, 28 days) before restarting treatment. 
Instructions for dose interruptions and modifications for INCAGN01876 are outlined in Table 7.  
Doses of epacadostat may be modified according to the guidelines and dose levels described in 
Table 6.  Individual decisions regarding dose interruptions and modifications of INCAGN01876 
and epacadostat should be made using clinical judgment in consultation with the medical 
monitor (whenever possible), taking into account relatedness of the AE to the study treatment 
and the subject's underlying condition.  Adverse events that have a clear alternative explanation, 


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or transient (≤ 72 hours) abnormal laboratory values without associated clinically significant 
signs or symptoms, may be exempt from dose-reduction rules.  
Dose interruptions are permitted in the case of medical/surgical events or logistical reasons not 
related to study treatment (eg, elective surgery, unrelated medical events, subject vacation, 
and/or holidays).  Subjects should be placed back on study treatment within 4 weeks (28 days) of 
the scheduled interruption, unless otherwise discussed with the medical monitor.  The reason for 
interruption should be documented in the subject's source documentation.   
Table 6: Dose Modifications for Epacadostat 
Dose of Epacadostat 
Dose Level -1 
Dose Level -2a 
First Reduction of Epacadostat 
Second Reduction of Epacadostat 
 BID 
 BID 
 BID 
a No more than 2 dose reductions are permitted for epacadostat. 


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Table 7: 
Criteria for Interruption and Restarting of Study Treatment 
Toxicity 
Hold 
Treatment 
for Grade 
Agent 
Timing for 
Restarting 
Treatment 
Dose Level for Restarting 
Treatment 
Treatment Discontinuation 
Diarrhea/colitis 
2-3 
Pembrolizumab 
Toxicity resolves to 
Grade 0-1. 
N/A 
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. 
INCAGN01876 
Grade 2:  N/A 
Grade 3:  Reduce by 1 dose level. 
Epacadostat 
Related:  Reduce by 1 dose level. 
Not Related:  Same dose level. 
4 
Pembrolizumab 
Permanently 
discontinue. 
N/A 
Permanently discontinue. 
INCAGN01876 
Epacadostat 
AST, ALT, or increased bilirubin 
2 
Pembrolizumab 
Toxicity resolves to 
Grade 0-1. 
N/A 
Toxicity does not resolve within 
12 weeks of last dose. 
INCAGN01876 
N/A 
Epacadostat 
Related:  Reduce by 1 dose level. 
Not Related:  Same dose level. 
3-4 
Pembrolizumab 
Permanently 
discontinue (see 
exception below)a. 
N/A 
Permanently discontinue (see 
exception below)a. 
INCAGN01876 
Epacadostat 
T1DM 
(if new onset) or hyperglycemia 
T1DM or 
3-4 
Pembrolizumab 
Hold pembrolizumab, 
INCAGN01876, and 
epacadostat for new 
onset T1DM or 
Grade 3-4 
hyperglycemia 
associated with 
evidence of beta cell 
failure. 
N/A 
Resume study medications when 
subjects are clinically and 
metabolically stable. 
INCAGN01876 
Grade 2:  N/A 
Grade 3-4:  Reduce by 1 dose 
level. 
Epacadostat 
Related:  Reduce by 1 dose level. 
Not Related:  Same dose level. 


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Table 7: 
Criteria for Interruption and Restarting of Study Treatment (Continued) 
Toxicity 
Hold 
Treatment 
for Grade 
Agent 
Timing for 
Restarting 
Treatment 
Dose Level for Restarting 
Treatment 
Treatment Discontinuation 
Hypophysitis 
2-4 
Pembrolizumab 
Toxicity resolves to 
Grade 0-1.  Therapy 
with pembrolizumab, 
INCAGN01876, and 
epacadostat can be 
continued while 
endocrine 
replacement therapy 
is instituted. 
N/A 
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. 
INCAGN01876 
Grade 2:  N/A 
Grade 3:  Reduce by 1 dose level. 
Epacadostat 
Related:  Reduce by 1 dose level. 
Not Related:  Same dose level. 
Hyperthyroidism  
3 
Pembrolizumab 
Toxicity resolves to 
Grade 0-1. 
N/A 
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. 
INCAGN01876 
Reduce by 1 dose level. 
Epacadostat 
Related:  Reduce by 1 dose level. 
Not Related:  Same dose level. 
4 
Pembrolizumab 
Permanently 
discontinue. 
N/A 
Permanently discontinue. 
INCAGN01876 
Epacadostat 
Hypothyroidism 
N/A 
Pembrolizumab 
Therapy with 
pembrolizumab, 
INCAGN01876, and 
epacadostat can be 
continued while 
thyroid replacement 
therapy is instituted. 
N/A 
Therapy with pembrolizumab and 
epacadostat can be continued while 
thyroid replacement therapy is 
instituted. 
INCAGN01876 
Epacadostat 
Infusion reaction 
2 
Pembrolizumabb 
Toxicity resolves to 
Grade 0-1. 
N/A 
N/A 
INCAGN01876b 
Same dose level. 
N/A 
Epacadostat 
Same dose level. 
N/A 
3-4 
Pembrolizumab 
Permanently 
discontinue. 
N/A 
Permanently discontinue. 
INCAGN01876 
Epacadostat 


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Table 7: 
Criteria for Interruption and Restarting of Study Treatment (Continued) 
Toxicity 
Hold 
Treatment 
for Grade 
Agent 
Timing for 
Restarting 
Treatment 
Dose Level for Restarting 
Treatment 
Treatment Discontinuation 
Pneumonitis 
2 
Pembrolizumab 
Toxicity resolves to 
Grade 0-1. 
N/A 
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. 
INCAGN01876 
Reduce by 1 dose level 
Epacadostat 
Related:  Reduce by 1 dose level. 
Not Related:  Same dose level. 
3-4 (or 
recurrent 
Grade 2) 
Pembrolizumab 
Permanently 
discontinue. 
N/A 
Permanently discontinue. 
INCAGN01876 
Epacadostat 
Renal failure or nephritis 
2 
Pembrolizumab 
Toxicity resolves to 
Grade 0-1. 
N/A 
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. 
INCAGN01876 
N/A 
Epacadostat 
Related:  Reduce by 1 dose level. 
Not Related:  Same dose level. 
3-4 
Pembrolizumab 
Permanently 
discontinue. 
N/A 
Permanently discontinue. 
INCAGN01876 
Epacadostat 
Rash 
3c 
Pembrolizumab 
Toxicity resolves to 
Grade 0-1. 
Same dose level. 
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. 
INCAGN01876 
Reduce by 1 dose level. 
Epacadostat 
Related:  Reduce by 1 dose level. 
Not Related:  Same dose level. 
4 
Pembrolizumab 
Permanently 
discontinue. 
N/A 
Permanently discontinue. 
INCAGN01876 
Epacadostat 


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Table 7: 
Criteria for Interruption and Restarting of Study Treatment (Continued) 
Toxicity 
Hold 
Treatment 
for Grade 
Agent 
Timing for 
Restarting 
Treatment 
Dose Level for Restarting 
Treatment 
Treatment Discontinuation 
All other drug-related toxicity 
3 or Severed 
Pembrolizumab 
Toxicity resolves to 
Grade 0-1. 
N/A 
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. 
INCAGN01876 
Reduce by 1 dose level 
Epacadostat 
Related:  Reduce by 1 dose level. 
Not Related:  Same dose level. 
4 
Pembrolizumab 
Permanently 
discontinue. 
N/A 
Permanently discontinue. 
INCAGN01876 
Epacadostat 
a For subjects 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 subjects should be discontinued.  The dose of INCAGN01876 and epacadostat should also be reduced by 1 dose level for subjects with liver metastasis that 
have Grades 3 to 4 AST or ALT elevations. 
b If symptoms resolve within 1 hour of stopping drug infusion, the infusion may be restarted at 50% of the original infusion rate (eg, from 100 mL/h to 50 mL/h).  Otherwise, 
dosing will be held until symptoms resolve, and the subject should be premedicated for the next scheduled dose; see Table 9 for further management details. 
c Subjects with Grade 3 rash in the absence of desquamation, with no mucosal involvement, that does not require systemic steroids, and that resolves to Grade 1 within 14 days do 
not have to hold study treatment. 
d Subjects with intolerable or persistent Grade 2 treatment-related toxicities may hold study treatment at the discretion of the investigator. 


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5.4.7. 
Management of Immune-Related Adverse Events 
INCAGN01876, pembrolizumab, and epacadostat are considered immune modulators, and it is 
possible that irAEs (both nonserious and serious) may occur.  Adverse events of a potential 
immunologic etiology, or irAEs, may be defined as AEs consistent with an immune phenomenon 
associated with drug exposure after all other etiologies have been eliminated.  Immune-related 
AEs may be expected based on the nature of the study treatment, their mechanisms of action, and 
reported experience with these and other immunotherapies.  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.  Suspected irAEs should be discussed with the 
medical monitor when possible. 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of 
treatment-related AEs with potential immunologic etiology are outlined in Table 8.  Detailed 
supportive care guidelines for specific irAEs can be in found in Appendix B.  Pembrolizumab is 
an approved agent and has specific irAE management guidelines within the prescribing 
information; the treating investigator may use labeled guidance or institutional guidelines for the 
management of irAEs if preferred.  For each AE, attempts should be made to rule out other 
causes, including, but not limited to, metastatic disease or bacterial or viral infection, which may 
require specific supportive care.   
Table 8: 
Supportive Care Guidelines for Immune-Related Adverse Events 
CTCAE Grade/Severity 
Supportive Carea 
Grade 1 (mild) 
• Monitor symptoms and provide symptomatic treatment. 
Grade 2 (moderate) 
• Monitor symptoms and provide symptomatic treatment. 
• Consider consultation with specialists as necessary. 
• Consider systemic corticosteroids per institutional standard of care. 
Grade 3-4  
(severe to life-threatening) 
• Monitor symptoms and provide symptomatic treatment. 
• Consider consultation with specialists as necessary. 
• Administer corticosteroids per institutional standard of care. 
• More potent immunosuppressive therapies should be considered for events not 
responding to systemic steroids after discussion with the medical monitor. 
• Study treatment may be permanently discontinued for clinically significant or 
severe irAEs or for events where the steroid course cannot be tapered below 
7.5 mg/day prednisone or equivalent to manage symptoms. 
a Detailed supportive care guidelines for specific irAEs can be found in Appendix B. 
5.4.8. 
Management of Infusion Reactions 
Table 9 shows treatment guidelines for subjects who experience an infusion reaction associated 
with administration of study treatment.  Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 24 hours of completion of the 
infusion.  Pembrolizumab is an approved agent and has specific infusion reaction management 
guidelines within the prescribing information; the treating investigator may use labeled guidance 
or institutional guidelines for the management of infusion reactions if preferred. 


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Table 9: 
Infusion Reaction Treatment Guidelines for Pembrolizumab and 
INCAGN01876 
CTCAE Grade 
Treatment 
Premedication at  
Subsequent Dose Administration 
Grade 1: 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated. 
Increase monitoring of vital signs as clinically 
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  
(eg, 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, the following: 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
Increase monitoring of vital signs as clinically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate.  Otherwise, dose 
administration 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. 
Subject may be premedicated 1.5 h 
(± 30 min) before infusion with the 
following: 
• Diphenhydramine 50 mg orally (or 
equivalent dose of antihistamine). 
• Acetaminophen 500-1000 mg orally 
(or equivalent dose of antipyretic). 
Grade 3: 
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for other 
clinical sequelae (eg, renal 
impairment, pulmonary 
infiltrates). 
Stop infusion. 
Additional appropriate medical therapy may 
include, but is not limited to, the following: 
• IV fluids 
• Antihistamines 
• NSAIDs 
• Acetaminophen 
• Narcotics 
• Oxygen 
• Pressors 
• Corticosteroids 
• Epinephrine 
Increase monitoring of vital signs as clinically 
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. 
No subsequent dose. 
Grade 4: 
Life-threatening; pressor or 
ventilatory support indicated. 
Note:  Appropriate resuscitation equipment should be available in the room, and a physician should be readily available during 
the period of study treatment administration. 


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5.4.9. 
Procedure for Subjects Exhibiting Serotonin Syndrome 
As noted in Section 1.3, there is a chance that epacadostat could cause an increase in serotonin 
levels in the brain that might trigger SS (Boyer and Shannon 2005) when administered in 
combination with other serotonergic agents.  This syndrome has been most closely associated 
with use of MAOIs, meperidine, linezolid, or methylene blue; all of these agents are prohibited 
during the study.  Selective serotonin reuptake inhibitors and SNRIs are permitted in the study.  
The following procedures will be implemented if subjects exhibit the signs/symptoms of SS 
described in Table 10, including tremor; hyperreflexia; and spontaneous, ocular, or inducible 
clonus, together with agitation, fever, diaphoresis, or muscle rigidity: 
• Immediately interrupt epacadostat, pembrolizumab, and INCAGN01876 
administration.   
• 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). 
• If subject chooses to remain in the study, restart treatment with all study medications 
after the SSRI or SNRI has been discontinued and no sooner than when 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 treatment 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 (see Section 6.4).  
Treatment with SSRI or SNRI may be initiated 2 weeks after resolution of signs and 
symptoms of SS. 
Table 10: 
Signs and Symptoms of Serotonin Syndrome 
Tremor and hyperreflexia 
Spontaneous clonus 
Muscle rigidity, temperature > 38°C (100.4°F), and either ocular clonus or inducible clonus 
Ocular clonus and either agitation or diaphoresis 
Inducible clonus and either agitation or diaphoresis 
5.4.10. 
Criteria for Permanent Discontinuation of Study Treatment 
The occurrence of unacceptable toxicity not caused by the underlying malignancy will be 
presumed to be related to study treatment and will require that the study treatment be 
permanently discontinued.  Unacceptable toxicity is defined as follows: 
• Grade 4 or life-threatening AEs, except with approval from the medical monitor. 
• Toxicity requiring more than 2 dose reductions of INCAGN01876 (see Table 1) or 
epacadostat (see Table 6).   
• ≥ Grade 2 ocular irAE. 


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• Occurrence of an AE that is related to treatment, in the judgment of the investigator 
or the medical monitor, and compromises the subject's ability to continue 
study-specific procedures or is considered to not be in the subject's best interest. 
• Persistent AE requiring a delay of treatment for more than 4 weeks (ie, 28 days), 
unless a greater delay has been approved by the sponsor. 
5.5. 
Withdrawal of Subjects From Study Treatment 
5.5.1. 
Withdrawal Criteria 
A subject may choose to withdraw from the study treatment at any time or be withdrawn from 
the study treatment by the investigator or sponsor if the subject is noncompliant with the study 
requirements.  If a subject is withdrawn from study treatment, then every reasonable effort 
should be made to determine the reason for withdrawal, and this information should be recorded 
in the eCRF. 
Subjects must be withdrawn from study treatment for the following reasons: 
• The subject becomes pregnant. 
• Consent is withdrawn.  Subjects may choose to withdraw from the study at any time 
without penalty of jeopardizing their healthcare or loss of benefits to which the 
subject is otherwise entitled. 
Note:  Consent withdrawn means that the subject can no longer be followed and no 
additional data can be collected.  Subjects may choose to discontinue study treatment 
and remain in the study to be followed for progression and survival.  
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• Unacceptable toxicity (see Section 5.4) occurs.  Subjects with unacceptable toxicities 
must be withdrawn from study treatment but will continue in the follow-up phase of 
the study (see Section 6.4). 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
A subject may be discontinued from study treatment as follows: 
• Confirmed radiographic progression of disease per RECIST v1.1.  A subject may be 
granted an exception to continue on treatment with confirmed radiographic 
progression if clinically stable or clinically improved (see Section 7.7.1). 
Note:  For unconfirmed progression, see Section 7.7.1. 
• If, during the course of the study, a subject is found not to have met eligibility criteria 
(see Section 3), the medical monitor, in collaboration with the investigator, will 
determine whether the subject should be withdrawn from study treatment. 
• If a subject is lost to follow-up or noncompliant with study procedures or study 
treatment in the investigator's opinion, the sponsor should be consulted for instruction 
on handling the subject. 


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5.5.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the subject 
will be withdrawn, and the EOT visit should be conducted.  Reasonable efforts should be made 
to have the subject return for all applicable follow-up visits (safety and efficacy; see Section 6.4).  
The last date of the last dose of study treatment and the reason for subject withdrawal will be 
recorded in the eCRF. 
If a subject is withdrawn from the study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal from treatment must be documented in the subject's 
medical record and in the eCRF. 
Note:  The reason for withdrawal from treatment may be different than the reason for 
withdrawal from study.  For example, subjects can discontinue treatment for disease 
progression or toxicity but remain in the study for safety and survival follow-up.   
• The EOT visit should be performed. 
• The date of the EOT visit should be recorded in the eCRF and the IRT system. 
• Subjects must be followed for safety until the time of the follow-up visit or until 
study treatment-related toxicities resolve, return to baseline, or are deemed 
irreversible, whichever is longest. 
• Subjects who discontinue for reasons other than disease progression will continue to 
be followed for disease status as outlined in Section 6.4.2. 
• All subjects who discontinue study treatment will continue to be followed for survival 
as outlined in Section 6.4.3. 
If the subject discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety follow-up, disease assessments, or survival follow-up), then no additional 
data collection should occur; however, subjects will have the option of withdrawing consent 
for study treatment but continuing in the follow-up period of the study for safety, efficacy, 
and survival assessments. 
5.6. 
Concomitant Medications 
All concomitant medications and treatments must be recorded in the eCRF.  Any prior 
medication received up to 28 days before the first dose of study treatment and 60 days after the 
last dose of study treatment or until the subject begins a new anticancer therapy, whichever 
occurs first, will be recorded in the eCRF.  Any addition, deletion, or change in the dose of these 
medications will also be recorded.  Concomitant treatments/procedures that are required to 
manage a subject's medical condition during the study will also be recorded in the eCRF. 
5.6.1. 
Permitted 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 medications will be recorded in the eCRF, including all 


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prescription and over-the-counter medications, herbal supplements, and IV medications and 
fluids.  If changes occur during the study period, documentation of drug regimen, frequency, 
route, and date may also be included in the eCRF.  Note:  The use of bisphosphonates and 
denosumab are permitted in this study. 
5.6.2. 
Restricted Medications 
• Systemic glucocorticoids for any purpose other than prophylaxis for contrast allergies 
for radiographic procedures, to modulate symptoms, or to treat an AE of suspected 
immunologic etiology are restricted and require medical monitor approval.  The use 
of physiologic corticosteroid replacement therapy may be approved after consultation 
with the medical monitor. 
Note:  Inhaled and topical steroids are allowed.  A short course of steroids 
(eg, prednisone or equivalent) at doses ≤ 10 mg/day may be permitted with medical 
monitor approval. 
• Use of the anticonvulsant carbamazepine (a UGT1A9 inducer) is discouraged.  
Because there is a potential interaction that could result in lower epacadostat 
exposures, an alternative to carbamazepine should be used, if possible. 
• Use of coumarin-based anticoagulants (eg, warfarin) with epacadostat is 
discouraged.  Low-dose warfarin (1 mg) is acceptable; however, other higher doses 
are discouraged.  If an alternative to coumarin-based anticoagulants cannot be used, 
the INR should be monitored closely per standards of care when epacadostat is 
started. 
5.6.3. 
Prohibited Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria (see Section 3.2) are 
not allowed during the study.  If there is a clinical indication for one of these medications or 
vaccinations specifically prohibited during the study, discontinuation from study treatment may 
be required.  The investigator should discuss any questions regarding this with the medical 
monitor.  The final decision on any supportive therapy or vaccination rests with the investigator 
and/or the subject's primary physician.  However, the decision to continue the subject on study 
treatment requires the mutual agreement of the investigator, the sponsor, and the subject. 
Subjects are prohibited from receiving the following therapies during the screening and treatment 
periods of this study, unless otherwise indicated: 
• Any anticancer medications, including chemotherapy or biologic therapy other than 
study treatment. 
• Any immunological-based treatment for any reason from screening through the safety 
follow-up visit is prohibited. 
Note:  Completed adjuvant therapy (eg, vaccines) with medical monitor approval, 
inhaled or topical steroids, systemic steroids (eg, prednisone or equivalents) at doses 
≤ 10 mg/day, and immune suppressants are allowed for treatment for irAEs as 
described in Section 5.4.7 and Appendix B, or as prophylaxis for contrast allergy for 
imaging procedures. 
Note:  Allergy shots may be permitted after consultation with the medical monitor. 


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• Investigational agents other than study treatment.  Use of such medications from 
screening through the safety follow-up visit is prohibited. 
• Concomitant radiation therapy. 
Note:  Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case-by-case basis after consultation with the medical 
monitor.  The subject must have clear measurable disease outside of the radiated 
field.  Administration of palliative radiation therapy will be considered clinical 
progression for the purposes of determining PFS. 
• Live vaccines within 30 days before 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, chicken pox, yellow fever, rabies, Bacillus 
Calmette-Guérin, and typhoid (oral) vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed.  However, intranasal 
influenza vaccines are live attenuated vaccines and are not allowed. 
• For cohorts where subjects receive epacadostat, use of any melatonin supplements. 
• For cohorts where subjects receive epacadostat, use of any MAOI or drug associated 
with significant MAOI activity agents is prohibited from 21 days before study Day 1 
through 14 days after the final dose of epacadostat has been administered (refer 
to Appendix C). 
• For cohorts where subjects receive epacadostat, any UGT1A9 inhibitor from 
screening through the safety follow-up, including acitretin, amitriptyline, 
androsterone, cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib, 
estradiol (17-beta), flutamide, gefitinib, gemfibrozil, glycyrrhetinic acid glycyrrhizin, 
imatinib, imipramine, ketoconazole, linoleic acid supplements, mefenamic acid, 
mycophenolic acid, niflumic acid, nilotinib, phenobarbital, phenylbutazone, 
phenytoin, probenecid propofol*, quinidine, ritonavir, sorafenib, sulfinpyrazone, 
valproic acid, and verapamil. 
Note:  Propofol, when used for short-term sedation during surgical/biopsy 
procedures, is allowed after consultation with the sponsor.  The epacadostat dose may 
be taken on the morning of the procedure and the evening dose held following the 
procedure.  Epacadostat may be resumed the next day. 
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 
describe other medications that are prohibited in this study (see Section 3.2).  There are no 
prohibited therapies during the post-treatment follow-up period. 


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6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedule of clinical assessments 
(Table 11), and all laboratory assessments will be performed as indicated in Table 12.  Table 13 
presents a summary of clinical laboratory analytes to be assessed.  The order of assessments is 
suggested by the order of mention within the schedule.  See Section 7 for instructions on each 
assessment.  Further details of study procedures and assessments can be found in the Study 
Reference Manual or applicable procedural documentation. 


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Table 11: 
Schedule of Assessments 
Visit Day (Range) 
Protocol 
Section 
Screening 
Treatmenta 
Post-Treatmentb 
Cycles 1 and 6 
Cycle 2 
All 
Other 
Cycles 
Every 
9 Weeks 
EOT 
Safety 
Follow-Up 
Visit 1 
Safety 
Follow-Up 
Visit 2 
Survival 
Follow-
Up 
D1 
D8 
D15 
D1 
D1 
Disease 
Status 
Every 
12 weeks 
Evaluation/Window 
Days 
-28 to -1 
 
± 1 day 
± 3 days 
± 3 days 
± 3 days 
± 7 days 
± 3 days 
30 days 
(+ 7 days) 
60 days 
(+ 7 days) 
± 7 days 
Informed consent 
7.1 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
3.1, 3.2 
X 
Xc 
 
 
 
 
 
 
 
 
 
Contact IRT 
7.2 
X 
X 
 
 
X 
X 
 
X 
 
 
 
Medical and cancer history 
7.3.1, 
7.3.2 
X 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medications 
7.4 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Administer INCAGN01876 
5.2.1.1 
 
X 
 
 
X 
X 
 
 
 
 
 
Administer pembrolizumab 
5.2.3.1 
 
Xd 
 
 
X 
X 
 
 
 
 
 
Administer/dispense 
epacadostat at site 
5.2.2.1 
 
Xe 
 
 
Xe 
Xe 
 
 
 
 
 
Poststudy anticancer therapy 
status 
7.5 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival status 
6.4.3 
 
 
 
 
 
 
 
 
 
 
X 
Comprehensive physical 
examination (including 
height) 
7.6.2.1 
X 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination 
7.6.2.2 
 
X 
Xf 
Xf 
X 
X 
 
X 
X 
X 
 
Vital signs and weight  
7.6.3 
X 
X 
Xf 
Xf 
X 
X 
 
X 
X 
X 
 
ECOG performance status 
7.8.1 
X 
X 
Xf 
Xf 
X 
X 
 
X 
X 
X 
 
Laboratory assessments 
7.6.5 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
12-Lead ECGg 
7.6.4 
X 
Xh 
 
 
Xh 
 
 
X 
X 
 
 
AE assessment 
7.6.1 
X 
X 
Xf 
Xf 
X 
X 
 
X 
X 
X 
 
Distribute subject reminder 
cards 
7.11.1 
 
X 
X 
X 
X 
X 
 
X 
X 
 
Radiologic tumor 
assessments 
6.4.2, 
7.7 
Xi 
 
 
 
 
 
Xj 
Xk 
Xl 
 
a Treatment cycles will be every 3 weeks (21 ± 3 days). 
b The mandatory safety follow-up visits should be conducted approximately 30 days and 60 days after the last dose of study treatment or before the initiation of a new anticancer 
treatment, whichever comes first. 


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c Screening laboratory tests performed more than 7 days before Cycle 1 Day 1 must be repeated and eligibility confirmed before study treatment administration on Cycle 1 Day 1. 
d In Treatment Groups B and D, pembrolizumab administration begins at Cycle 2 Day 1. 
e Epacadostat is only required to be dosed at the site on Day 1 of Cycle 1 and Cycle 2. 
f Only required for Cycle 6 Day 8 and Cycle 6 Day 15 if the subject is experiencing an AE > Grade 2. 
g All 12-lead ECGs will be performed at the study site with the subject in a recumbent or semirecumbent position after 5 minutes of rest and should not be performed within 
15 minutes after a blood sample collection. 
h A 12-lead ECG will be collected before the morning dose of epacadostat on Cycle 1 Day 1 and Cycle 2 Day 1, and 2 hours (± 15 minutes) after the morning dose of epacadostat 
on Cycle 1 Day 1 and Cycle 2 Day 1 (see Table 14). 
i The initial tumor imaging will be performed within 28 days before the first dose of study treatment.  Scans performed as part of routine clinical management are acceptable for 
use as the screening scan if they are of diagnostic quality and performed within 28 days before the first dose of study treatment.  The same imaging technique should be used for 
a subject throughout the study.  Local reading (investigator assessment with site radiology reading) will be used to determine eligibility and for subject management. 
j On-study imaging will be at Week 9 and then every 9 weeks (± 7 days) for the first 12 months and then every 12 weeks (± 7 days) thereafter.  Imaging should follow calendar 
days and should NOT be adjusted for delays in cycle starts.  If imaging shows disease progression, then another imaging assessment should be performed at a minimum of 
4 weeks, but no more than 6 weeks, later to confirm disease progression per mRECIST. 
k If a scan was obtained within 4 weeks prior to the date of treatment discontinuation, then a scan at treatment discontinuation (EOT) is not mandatory.  For subjects who 
discontinue study therapy without confirmed disease progression, a radiologic evaluation should be repeated at the time of treatment discontinuation (ie, date of discontinuation 
± 4 week window). 
l For subjects who discontinue treatment for a reason other than disease progression (eg, toxicity), every effort should be made to collect information regarding disease status 
every 9 weeks (± 7 days) for 12 months and then every 12 weeks (± 7 days) thereafter by radiographic imaging until 1) the start of new anticancer therapy, 2) documented 
disease progression, 3) death, 4) the end of the study, or 5) withdrawal of consent, whichever occurs first.  


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Table 12: 
Schedule of Laboratory Assessments 
Visit Day (Range) 
Protocol 
Section 
Timing of 
Assessment 
Screening 
Treatment 
Post-Treatment 
C1 
C2 
C4 
C6 
C7 
C8 and 
Every 
4th 
Cycle 
All 
Other 
Cycles 
EOT 
Safety 
Follow-
Up 
Visit 1 
Safety 
Follow-
Up 
Visit 2 
D1 
D8 D15 
D1 
D1 
D1 
D8 
D15 
D1 
D1 
D1 
Evaluation/Window 
Days 
-28 to -1 
Predose 
± 1 
day 
± 1 
day 
± 3 
days 
± 3 
days 
± 3 
days 
± 1 
day 
± 1 
day 
± 3 
days 
± 3 days 
± 3 
days 
± 3 
days 
30 days  
(+ 7 
days) 
60 days  
(+ 7 
days) 
Local laboratory testsa 
Comprehensive serum 
chemistriesb 
7.6.5 
N/A 
Xc 
Xd 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
X 
Hematology with 
differential 
7.6.5 
N/A 
Xc 
Xd 
X 
X 
X 
X 
X 
 
 
X 
X 
 
X 
X 
X 
Coagulation panele 
7.6.5 
N/A 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
7.6.5 
N/A 
Xc 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Endocrine function tests 
7.6.5 
N/A 
Xc 
 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
 
HBV and HCV tests 
7.6.5.2 
N/A 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
(childbearing females 
only)f 
7.6.5.1 
N/A 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Urine pregnancy test 
(childbearing females 
only) 
7.6.5.1 
N/A 
 
Xg 
 
 
 




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Table 13: 
Local Laboratory Tests:  Required Analytes 
Serum Chemistries 
Hematology 
Urinalysis 
Hepatitis Screening 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST  
Bicarbonate 
Blood urea nitrogen  
Calcium 
Chloride  
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total bilirubin is 
elevated above ULN) 
Total protein 
Uric acid 
Amylase 
Lipase 
Complete blood count, including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• White blood cell count 
 
Absolute values must be provided 
for WBC differential laboratory 
results: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
HBV surface antigen 
HBV core antibody 
HBV-DNA 
HCV antibody 
HCV-RNA 
PT 
aPTT 
INR 
Pregnancy Testing 
Endocrine Monitoring 
Female subjects of 
childbearing potential only 
require a serum test at 
screening and at EOT. 
Urine pregnancy tests should 
be repeated if required by local 
regulations. 
Thyroid-stimulating hormone (TSH) 
Free thyroxine (T4) 
Total triiodothyronine (T3)/FT3a 
a If considered standard by your region. 


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6.1. 
Screening 
Screening is the interval between signing the ICF and the day the subject is enrolled in the study 
(eg, Cycle 1 Day 1).  Screening may not exceed 28 days.  Informed consent must be obtained 
before performing any study-specific procedures that are not considered standard of care; 
however, procedures conducted as part of the subject's routine clinical management obtained 
before signing the ICF may be used for screening or baseline purposes with approval of the 
medical monitor, provided that the procedure meets the Protocol-defined criteria and has been 
performed in the timeframe of the study.  Assessments that are required to demonstrate eligibility 
may be performed over the course of 1 or more days during the screening process. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment.  Tests with results that fail eligibility requirements may be repeated once during 
screening if the investigator believes the results to be in error.  For screening assessments that are 
repeated, the most recent available result before enrollment will be used to determine subject 
eligibility.  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 (eg, after recovery from an 
infection).  Treatment should start as soon as possible after the date of enrollment. 
6.2. 
Treatment 
The treatment period begins on the day the subject receives the first dose of study treatment 
(eg, Cycle 1 Day 1) through the point at which the investigator determines that the subject will 
be permanently discontinued from study treatment.  Cycle 1 Day 1 must be no more than 28 days 
after the subject has signed the ICF and should be within 3 days of enrollment in the study.  
Subjects will have regularly scheduled study visits as outlined in Table 11, and toxicities will be 
monitored continuously and graded using the CTCAE v4.03 criteria. 
6.3. 
End of Treatment 
When the subject permanently discontinues study treatment, the EOT visit should be conducted.  
If the EOT visit coincides with a regular study visit, the EOT evaluations will supersede those of 
that scheduled visit, and the data should be entered in the EOT visit in the eCRF.  The subject 
should be encouraged to return for the safety and survival follow-up visits. 
6.4. 
Follow-Up 
6.4.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur 30 days (+ 7 days) and 60 days (+ 7 days) after the EOT visit (or after 
the last dose of study treatment if the EOT visit was not performed).  Adverse events and SAEs 
must be reported up until at least 60 days after the last dose of study treatment, until the subject 
starts a new anticancer therapy, or until toxicities resolve, return to baseline, or are deemed 
irreversible, whichever is longer.  Reasonable efforts should be made to have the subject return 
for the follow-up visits and report any AEs that may occur during this period.  If a subject is 
scheduled to begin a new anticancer therapy before the end of the 30-day or 60-day safety 
follow-up period, the safety follow-up visit should occur before the new anticancer therapy is 


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started.  Once the new anticancer therapy has been initiated, AEs and SAEs will no longer be 
collected, and the subject will move into the survival follow-up period. 
6.4.2. 
Disease Status Follow-Up 
Subjects who discontinue study treatment for a reason other than disease progression 
(eg, toxicity) will move into the disease status follow-up period and should be assessed every 
9 weeks (± 7 days), for 12 months.  After 12 months, radiologic assessments will be performed 
every 12 weeks (± 7 days).  Every effort should be made to collect information regarding disease 
status until the first occurrence of any of the following: 
• The start of new anticancer therapy. 
• Documented disease progression. 
• Death. 
• The end of the study. 
• Withdrawal of consent. 
6.4.3. 
Survival Follow-Up 
Once a subject has received the last dose of study treatment, confirmed disease progression, or 
starts a new anticancer therapy, the subject moves into the survival follow-up period and should 
be contacted by telephone, email, or visit by the subject or the subject's caregiver at least every 
12 weeks (± 7 days) to assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first.  After the final primary analysis is performed, the follow-up 
interval for subsequent anticancer treatments and survival may be reduced to every 16 weeks 
(± 7 days) or eliminated. 
6.5. 
End of Study 
The end of the study will occur when all subjects have completed the last study follow-up visit or 
have discontinued study treatment and have completed applicable follow-up assessments.  
Additionally, subjects will be considered as having completed the study if they meet any of the 
following criteria: 
• Subject dies, and a date of death is available. 
• Subject is known to have died; however, the date of death cannot be obtained. 
Note:  Every effort must be made to obtain the date of death. 
• Consent is withdrawn for any further contact related to the study. 
− Every reasonable effort should be made to determine the reason a subject 
withdraws prematurely, and this information should be recorded in the eCRF. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 


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6.6. 
Unscheduled Visits 
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed at those visits should be recorded in the eCRF. 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
Individual study procedures are described in detail below.  It may be necessary to perform these 
procedures at unscheduled timepoints if deemed clinically necessary by the investigator.  
Furthermore, additional evaluations/testing may be deemed necessary for reasons related to 
subject safety.  In some cases, such evaluation/testing may be potentially sensitive in nature 
(eg, HIV, HCV), 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.  Per Section 3.1, subjects of childbearing potential must agree 
to take appropriate measures to avoid pregnancy in order to participate in the study (see 
Appendix A). 
7.1. 
Administration of Informed Consent Form 
Valid informed consent must be obtained from the study subject before conducting any 
study-specific procedures using an ICF approved by the local IRB/IEC that contains all elements 
required by ICH E6 and describes the nature, scope, and possible consequences of the study in a 
form understandable to the study subject.  Local and institutional guidelines for ICF content and 
administration must be followed; the original signed ICF must be retained by the investigator, 
and a copy of the signed ICF must be provided to the study subject.  The informed consent 
process for each subject must be documented in writing within the subject's source 
documentation. 
7.2. 
Interactive Response Technology System Procedure 
The site will contact IRT to obtain a subject ID number when a subject enters the prescreening 
phase.  Upon determining that the subject is eligible for study entry, IRT will be contacted to 
obtain the subject ID number, study drugs, and the treatment group assignment.  Additionally, 
IRT will be contacted to update the subject's disposition, disease response, and for resupply of 
study drugs.  Refer to the Cohort Management Plan and the IRT Manual for detailed instructions.   
During Phase 2 of the study, the IRT system will be updated based on the PoS calculations 
discussed in Section 9.6.  Probability of success calculations will be performed based on 
response data available within the IRT system, and treatment groups may be closed to subject 
assignment if the PoS for a treatment group-tumor type combination is below the futility 
threshold.  Subjects will be assigned sequentially to treatment groups that are open to assignment 
based on these PoS calculations.  Periodically, the sponsor will review the disease response data 
within the IRT system for consistency with the clinical database and request changes to resolve 
discrepancies. 


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7.3. 
Demography and Medical History 
7.3.1. 
Demographics and General 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 current illnesses.  Medical history will include relevant medical or 
surgical treatment within the last 10 years that are considered to be clinically significant by 
the investigator. 
7.3.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and medication history will be collected at screening.  Details 
regarding the subject's malignancy under study, including date of diagnosis, initial and current 
cancer stage, tumor histology, and relevant disease characteristics, and prior treatments, 
including systemic treatments, radiation, and surgical procedures, will be recorded. 
7.4. 
Prior and Concomitant Medications and Procedures 
Prior and concomitant medications and procedures will be reviewed to determine subject 
eligibility.  Any medication received or procedure performed within 28 days before the first dose 
of study treatment, up to the end of the safety follow-up period, or until the subject starts a new 
anticancer therapy, whichever occurs first, will be recorded in the eCRF.  The medication record 
will be maintained after signing the ICF to document concomitant medications, including any 
changes to the dose or regimen.  Concomitant medications include any prescription, 
over-the-counter, natural/herbal preparations, and IV medications and fluids taken or 
administered during the study period.  Concomitant treatments and/or procedures that are 
required to manage a subject's medical condition during the study will also be recorded in the 
eCRF.  See Section 5.6 for details regarding permitted, restricted, and prohibited medications. 
7.5. 
Poststudy Anticancer Therapy Status 
The investigator or qualified designee will review all new anticancer therapy initiated after the 
last dose of study treatment.  If a subject is scheduled to begin a new anticancer therapy within 
30 to 60 days after the last dose of study treatment, the 30-day or 60-day safety follow-up visit 
should occur before the new anticancer therapy is started. 
7.6. 
Safety Assessments 
Pembrolizumab is an approved therapy; therefore, the investigator should refer to and follow the 
safety management guidelines as appropriate within the approved prescribing information. 
7.6.1. 
Adverse Events 
Adverse events will be monitored from the time subjects sign the ICF.  Subjects will be 
instructed to report all AEs during the study and will be assessed for the occurrence of AEs 
throughout the study.  In order to avoid bias in eliciting AEs, subjects will be asked general, 
nonleading questions such as "How are you feeling?"  All AEs (serious and nonserious) must be 
recorded on the source documents and eCRFs regardless of the assumption of a causal 


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relationship with the study treatment.  The definition, reporting, and recording requirements for 
AEs are described in Section 8. 
7.6.2. 
Physical Examinations 
Physical examinations must be performed by a medically qualified individual such as a licensed 
physician, physician's assistant, or an advanced registered nurse practitioner, as local law 
permits.  Clinically notable abnormalities that are considered clinically significant in the 
judgement of the investigator are to be reported as AEs (see Section 8.1.2). 
7.6.2.1. 
Comprehensive Physical Examination 
The comprehensive physical examination will include assessment(s) of the following organ or 
body systems:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular system; 
abdomen (ie, liver, spleen); extremities; and lymph nodes; as well as a brief neurological 
examination.  The comprehensive physical examination should also include a measurement of 
height. 
7.6.2.2. 
Targeted Physical Examination 
The targeted physical examination will be a symptom-directed evaluation conducted by the 
investigator or a medically qualified designee.  The targeted physical examination will include 
assessment(s) of the body systems or organs as indicated by subject symptoms, AEs, or other 
findings.   
7.6.3. 
Vital Signs and Weight 
Vital sign measurements include blood pressure, pulse, respiratory rate, body temperature, and 
pulse oximetry.  Blood pressure and pulse will be taken with the subject in the recumbent, 
semirecumbent, or sitting position after 5 minutes of rest.  Weight will also be assessed at each 
study visit.  Clinically notable abnormalities that are considered clinically significant in the 
judgment of the investigator are to be reported as AEs (see Section 8.1.2).   
7.6.4. 
Electrocardiograms 
All 12-lead ECGs will be performed at the study site as outlined in Table 14 with the subject in a 
recumbent or semirecumbent position after 5 minutes of rest and should not be performed within 
15 minutes after a blood sample collection. 
Table 14: 
Schedule of ECG Assessments 
Visit 
Anytime 
Before the Morning 
Dose of Epacadostat 
2 Hours (± 15 minutes) 
 After the Morning Dose 
of Epacadostat 
Screening 
X 
 
 
Cycle 1 Day 1 
 
X 
X 
Cycle 2 Day 1 
 
X 
X 
EOT 
X 
 
 
Safety Follow-up Visit 1 
X 
 
 


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The 12-lead ECG readings will be interpreted by the investigator at the site to be used for 
immediate subject management.  Additional 12-lead ECGs may be performed as clinically 
indicated to manage subject safety.  The decision to include or exclude a subject or to withdraw a 
subject from study treatment based on an ECG flagged as "Abnormal, Clinically Significant" is 
the responsibility of the investigator in consultation with the medical monitor, as appropriate.  
Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs (see Section 8.1.2). 
In the event that a single QTc is > 470 milliseconds at screening (corrected by Fridericia), the 
subject may enroll if the average QTc for 3 ECGs is < 470 milliseconds or with approval from 
the medical monitor.  For subjects with an intraventricular conduction delay (QRS interval 
> 120 milliseconds) at screening, the JTc interval may be used in place of the QTc with medical 
monitor approval.  The JTc must be < 340 milliseconds if JTc is used in place of the QTc.  
Subjects with left bundle branch block are excluded.  Note:  QTc prolongation due to pacemaker 
may enroll if the JTc is normal or with medical monitor approval.  In addition, the JTc interval 
should be used for all subsequent assessments. 
7.6.5. 
Laboratory Assessments 
A certified laboratory local to the study site and subject will perform all clinical laboratory 
assessments for safety (ie, serum chemistries, hematology assessments, coagulation tests, 
endocrine function, and urinalysis).  The investigative site will enter the laboratory results and 
laboratory normal ranges into the eCRF.  All local laboratory assessments should be performed 
using standard procedures on the days indicated in Table 12.  Table 13 lists the specific 
laboratory analytes required for each test.  Additional testing may be required by the sponsor 
based on emerging safety data.  Additional tests may also be performed if clinically indicated. 
Screening laboratory assessments must be performed within 7 days of Cycle 1 Day 1.  If 
performed more than 7 days before Cycle 1 Day 1, then the tests must be repeated and eligibility 
confirmed before study treatment administration on Cycle 1 Day 1.  Laboratory samples 
collected on Study Day 1 must be performed before study treatment administration.  After 
Cycle 1, predose laboratory procedures can be conducted up to 72 hours before study treatment 
administration (within the 3-day study window), and results should be reviewed by the 
investigator or qualified designee and found to be acceptable before a new cycle of treatment is 
initiated. 
7.6.5.1. 
Pregnancy Testing 
A local laboratory serum pregnancy test will be required for all females of childbearing potential 
during screening and at EOT.  The serum pregnancy test performed at screening must be 
performed within 72 hours before the first dose of study treatment.  Urine pregnancy tests will be 
performed locally as outlined in Table 12, as clinically indicated (eg, in case of loss of menstrual 
cycle, when pregnancy is suspected), or per country-specific requirements (note that 
country-specific requirements for urine pregnancy testing will be outlined and communicated to 
investigational sites under separate cover).  If a urine pregnancy test is positive, then the results 
should be confirmed with a serum pregnancy test. 


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If the serum pregnancy test is negative after a urine pregnancy test was positive, then the 
investigator will assess the potential benefit/risk to the subject and determine whether it is in the 
subject's best interest to resume study treatment and continue participation in the study. 
7.6.5.2. 
Hepatitis Screening Tests 
Hepatitis (HBV and HCV) screening assessments will be performed at the screening visit 
(Table 12) to rule out hepatitis infection; required analytes are shown in Table 13.  Generally, 
hepatitis tests should be performed early in the screening process due to the length of time 
needed to obtain the results.  Additional tests may be performed if clinically indicated. 
7.7. 
Efficacy Assessments 
7.7.1. 
Modified Response Evaluation Criteria in Solid Tumors 
Modified response evaluation criteria in solid tumors 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 (eg, discontinuation of study therapy).  As noted in Section 1.5.4.1 , RECIST v1.1 
will be modified to account for the unique tumor responses seen with immunotherapy 
(Wolchok et al 2009).  Therefore, RECIST v1.1 will be used with the following modifications: 
If radiologic imaging shows progressive disease, tumor assessment should be repeated at a 
minimum of 4 weeks, but no more than 6 weeks, later to confirm disease progression, with the 
option of continuing treatment while awaiting radiologic confirmation of disease progression.  
Table 15 provides instructions on how to proceed with treatment based on subjects' clinical 
statuses once the initial scan showing radiologic evidence of disease progression is observed. 
Subjects may receive treatment while waiting for confirmation of disease progression if they are 
clinically stable, as defined by the following criteria: 
• Absence of clinically significant signs and symptoms (including worsening of 
laboratory values) indicating disease progression. 
• No decline in ECOG performance status. 
• Absence of rapid progression of disease. 
• Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention. 


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Table 15: 
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease 
 
Clinically Stable 
Clinically Unstable 
Tumor Imaging 
Treatment 
Tumor Imaging 
Treatment 
First radiologic 
evidence of 
disease 
progression 
Repeat imaging 
4-6 weeks to 
confirm disease 
progression 
May continue study 
treatment at the 
investigator's 
discretion while 
awaiting confirmatory 
tumor imaging  
Repeat tumor 
imaging 4-6 weeks to 
confirm disease 
progression at the 
investigator's 
discretion only 
Discontinue 
treatment 
Repeat scan 
confirms 
disease 
progression 
No additional 
tumor imaging 
required 
Discontinue treatment 
No additional tumor 
imaging required 
N/A 
Repeat scan 
shows SD, PR, 
or CR 
Continue regularly 
scheduled tumor 
imaging 
assessments 
Continue study 
treatment at the 
investigator's 
discretion 
Continue regularly 
scheduled tumor 
imaging assessments 
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable 
per investigator's 
discretion 
As noted above, if disease progression is observed, the study site may elect to continue 
treatment, to repeat imaging at a minimum of 4 weeks, but no more than 6 weeks, later, and to 
assess tumor response or confirmed disease progression per mRECIST. 
In determining whether or not the tumor burden has increased or decreased, the site study team 
should consider all target lesions, as well as nontarget lesions (refer to RECIST v1.1 guidelines). 
Scenarios where disease progression is confirmed at repeat imaging include the following: 
• Tumor burden remains ≥ 20%, and at least a 5 mm absolute increase is present 
compared with nadir. 
• Nontarget disease resulting in initial disease progression is worse (qualitative). 
• New lesion resulting in initial disease progression is worse (qualitative). 
• Additional new lesion(s) since last evaluation. 
Subjects who are deemed clinically unstable are not required to have repeat tumor imaging for 
confirmation of disease progression.  If radiologic progression is confirmed by subsequent scan, 
then the subject should be discontinued from study treatment.  If radiologic progression is not 
confirmed, then the subject should resume or continue study treatment and have the next tumor 
imaging according to the Protocol schedule (see Table 11).  If disease progression is not 
confirmed, and the subject continues on treatment, then the next scan that documents disease 
progression (and is confirmed by a second scan at least 4 weeks, but no more than 6 weeks, later) 
will be considered the date of disease progression. 


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If a subject has confirmed radiographic progression (ie, 2 scans at least 4 weeks, but no more 
than 6 weeks, apart demonstrating disease progression) per mRECIST, but the subject is 
achieving a clinically meaningful benefit, an exception to continue treatment may be considered 
after consultation with the medical monitor.  Clinically stable subjects at the confirmatory scan 
should also have no further increase in the target lesions, no unequivocal increase in nontarget 
lesions, and no additional new lesions develop (nonworsening disease progression) to continue 
study treatment. 
7.7.2. 
Response Evaluation Criteria in Solid Tumors Version 1.1 Tumor Imaging 
The same imaging technique should be used for a subject throughout the study.  The 
baseline scan must be a contrast CT or MRI, except in circumstances where there is a contrast 
allergy or with medical monitor approval.  When the CT component of a positron emission 
tomography/CT scan uses higher energy and thinner slices, it may be acceptable with medical 
monitor approval.  Images of the chest, abdomen, and pelvis are required for all subjects.  
Additional imaging of anatomical sites (eg, head, neck, brain, etc) should be done as applicable 
for the malignancy under study. 
A CT or MRI scan of the brain will be performed at screening if there are signs or symptoms 
suggesting that the subject has disease involvement in the CNS.  An MRI of the brain will also 
be required at screening for all subjects with melanoma. 
7.7.2.1. 
Response Evaluation Criteria in Solid Tumors Version 1.1 Tumor Imaging 
During Screening 
Initial tumor imaging must be performed within 28 days before the first dose of study treatment.  
The site study team must review prestudy images to confirm that the subject has measurable 
disease per RECIST v1.1.  Tumor lesions that are located in a previously irradiated area or in an 
area subjected to other locoregional therapy should not be selected as target lesions.  If a subject 
only has lesions in an area previously irradiated or subjected to locoregional therapy, then the 
subject will be allowed to enroll.  Additionally, it is recommended that tumor lesions selected 
for biopsy not be selected as target lesions. 
Scans performed as part of routine clinical management are acceptable for use as the screening 
scan if they are of diagnostic quality and performed within 28 days before the first dose of study 
treatment. 
7.7.2.2. 
Response Evaluation Criteria in Solid Tumors Version 1.1 Tumor Imaging 
During Treatment 
The first imaging assessment should be performed 9 weeks after the first dose of 
INCAGN01876 and then every 9 weeks (± 7 days) for the first 12 months and then every 
12 weeks (± 7 days) thereafter until disease progression is determined.  Imaging assessments 
may be done more frequently if clinically indicated.  Imaging should follow calendar days and 
should NOT be delayed for delays in cycle starts. 
Per mRECIST, 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, whichever is clinically indicated. 




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7.10.4. 
Tumor Biopsies 
7.10.4.1. Tumor Tissue Collection Requirements 
During Phase 2 of the study, biopsy cohorts will be added at specific institutions for each 
treatment group, where serial mandatory pretreatment (before Day 1 dose administration) and 
on-treatment biopsies will be collected to evaluate changes in the tumor microenvironment.  
Approximately 15 evaluable subjects who have tumor lesions that are amenable to percutaneous 
biopsy will be enrolled in each biopsy cohort.  The biopsy-specific cohorts will be limited to 
melanoma (mucosal or cutaneous), RCC, and UC.  Detailed instructions for tissue collection, 
processing, and storage can be found in the Laboratory Manual.  Fine- needled aspirates are not 
acceptable.  Mandatory tumor biopsies will be collected as specified below: 
• Screening:  Tumor tissue will be collected during screening.  A fresh biopsy at 
screening is preferred; however, formalin-fixed paraffin embedded tissue is 
acceptable as long as the sample has been collected after the completion of the most 
recent prior systemic therapy.  A minimum of 20 slides or preferably 1 tissue block 
should be submitted before Day 1 dosing.  Biopsies should be performed on lesions 
that have not been exposed to prior radiation (exceptions may be granted with 
sponsor approval).   
Note: Fresh tumor biopsies should be taken from nontarget lesions when possible. 




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8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
For the purposes of this Protocol, an AE is defined as any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related, that occurs 
after a subject provides informed consent.  Abnormal laboratory values or test results occurring 
after informed consent constitute AEs only if they induce clinical signs or symptoms, are 
considered clinically meaningful, require therapy (eg, hematologic abnormality that requires 
transfusion), or require changes in the study treatment. 
8.1.2. 
Reporting 
Adverse events that begin or worsen after informed consent should be recorded on the Adverse 
Events form of the eCRF.  Conditions that were already present at the time of informed consent 
should be recorded on the Medical History form in the eCRF.  Monitoring for the occurrence of 
new AEs should be continued for at least 60 days after the last dose of study treatment or until 
the start of new anticancer therapy, whichever occurs first.  Adverse events (including laboratory 
abnormalities that constitute AEs) should be described using a diagnosis whenever possible 
rather than by individual underlying signs and symptoms.   
The term "disease progression" should be recorded as an AE/SAE only if there are no other 
identifiable AEs/SAEs associated with the disease progression at the time of reporting.  For 
events associated with disease progression, the relevant signs and symptoms should be reported 
using a diagnosis whenever possible rather than individual underlying signs and symptoms.  
When a clear diagnosis cannot be identified, each sign or symptom should be reported as a 
separate AE.  If the events resulting from disease progression meet the criteria for an SAE 
(eg, resulted in hospitalization, a life-threatening event, or death), the specific event(s) should be 
reported as an SAE(s) as described in Section 8.3.2.  In both cases (ie, AEs or SAEs related to 
disease progression), it should be indicated that each event (reported as a diagnosis or as signs 
and symptoms) is related to disease progression on the Adverse Events form of the eCRF. 
The severity of AEs will be assessed using CTCAE v4.03 Grades 1 through 5.  If an event is not 
classified by CTCAE, the severity of the AE will be graded according to the scale below to 
estimate the grade of severity: 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate activities of daily living. 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care activities of 
daily living. 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death due to AE 


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The occurrence of AEs should be sought by nondirective questioning of the subject during the 
screening process after signing the ICF and at each visit during the study.  Adverse events may 
also be detected when they are volunteered by the subject during the screening process or 
between visits, or through physical examination, laboratory test, or other assessments.  To the 
extent possible, each AE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 5). 
• Whether there is at least a reasonable possibility that the AE is related to the study 
treatment:  suspected (yes) or not suspected (no). 
− Note:  causality assessment for each agent administered per study must be 
indicated. 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study treatment. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per SAE definition provided in Section 8.3.1. 
Unlike routine safety assessments, SAEs are monitored continuously and have special reporting 
requirements (see Section 8.3.2). 
All AEs should be treated appropriately.  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event form, and the treatment 
should be specified on the Prior/Concomitant Medications or Procedures and Non-Drug Therapy 
form in the eCRF. 
Once an AE is detected, it should be followed until it has resolved or until it is judged to be 
permanent; assessment should be made at each visit (or more frequently if necessary) of any 
changes in severity, the suspected relationship to study treatment, the interventions required to 
treat the event, and the outcome. 
When the severity of an AE changes over time for a reporting period (eg, between visits), each 
change in severity will be reported as a separate AE until the event resolves.  For example, 
2 separate AEs will be reported if a subject has Grade 1 diarrhea meeting the definition of an AE 
that lasts for 3 days before worsening to a Grade 3 severity.  The Grade 1 event will be reported 
as an AE with a start date equal to the day the event met the Grade 1 AE definition and a stop 
date equal to the day that the event increased in severity from Grade 1 to Grade 3.  The Grade 3 
event will also be reported as an AE with the start date equal to the day the event changed in 
intensity from Grade 1 to Grade 3 and a stop date equal to the day that the event either changed 
severity again or resolved. 
8.2. 
Laboratory Test Abnormalities 
Laboratory abnormalities that constitute an AE in their own right (considered clinically 
meaningful, induce clinical signs or symptoms, require concomitant therapy, or require changes 
in study treatment) should be recorded on the Adverse Event form in the eCRF.  Whenever 
possible, a diagnosis rather than a symptom should be provided (eg, "anemia" instead of "low 


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hemoglobin").  Laboratory abnormalities that meet the criteria for AEs 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. 
Laboratory abnormalities that do not meet the definition of an AE should not be reported as AEs 
(see Section 8.1.2).  A Grade 3 or 4 AE does not automatically indicate an SAE unless it meets 
the definition of serious, as defined in Section 8.3.1.  A dose modification for the laboratory 
abnormality may be required (see Section 5.4) and should not contribute to the designation of a 
laboratory test abnormality as an SAE. 
8.3. 
Serious Adverse Events 
8.3.1. 
Definitions 
An SAE is defined as an event that meets at least 1 of the following criteria: 
• Is fatal or life-threatening. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is a result of: 
− A routine treatment or monitoring of the studied indication not associated with 
any deterioration in condition.  
− An elective surgery or preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since signing the 
ICF. 
− A treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of an SAE and not resulting in hospital admission. 
− Any social reasons and respite care, in the absence of any deterioration in the 
subject's general condition. 
• Results in persistent or significant disability, incapacity, or a substantial disruption of 
a person's ability to conduct normal life functions. 
• Constitutes a congenital anomaly or birth defect. 
• Is considered to be an important medical event or a medically significant event that 
may not result in death, be immediately life-threatening, or require hospitalization, 
but may be considered serious when, based on appropriate medical judgment, the 
event may jeopardize the subject or may require medical or surgical intervention to 
prevent 1 of the outcomes listed above. 
8.3.2. 
Reporting 
Every SAE, regardless of suspected causality (eg, relationship to study treatment or study 
procedure or disease progression), occurring after the subject has signed the ICF through the last 
study visit (or 60 days after the last dose of study treatment or until the subject receives a new 
anticancer therapy, whichever occurs earlier) must be reported to the sponsor (or designee) 
within 24 hours of learning of its occurrence, unless otherwise specified by the Protocol.  Any 


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SAEs occurring more than 60 days after the last dose of study treatment should be reported to the 
sponsor or its designee only if the investigator suspects a causal relationship to the study 
treatment.   
Information about all SAEs is collected and recorded on the Adverse Event form of the eCRF.  
The investigator must assess and record the causal relationship of each SAE to each specific 
study treatment.  The investigator must also complete the Incyte SAE Report Form, in English, 
and send the completed and signed form to the sponsor or designee within 24 hours of becoming 
aware of the SAE.  The investigator must provide a causality assessment, that is, assess whether 
there is at least a reasonable possibility that the SAE is related to the specific study treatment:  
suspected (yes) or not suspected (no).  Refer to the Incyte Reference Guide for Completing the 
Serious Adverse Event Report Form. 
The contact information of the sponsor's study-specific representatives is listed in the 
investigator manual provided to each site.  The original copy of the SAE Report Form and the 
confirmation sheet must be kept at the study site. 
Investigational site personnel must report any new information regarding the SAE within 
24 hours of becoming aware of the information in the same manner that the initial SAE Report 
Form was sent.  Follow-up information is recorded on an amended or new SAE Report Form, 
with an indication that it is follow-up to the previously reported SAE and the date of the original 
report.  The follow-up report should include information that was not provided on the previous 
SAE Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment 
provided, action taken with study treatment because of the SAE (eg, dose reduced, interrupted, or 
discontinued), or subject disposition (eg, continued or withdrew from study participation).  Each 
recurrence, complication, or progression of the original event should be reported as follow-up to 
that event, regardless of when it occurs. 
If the SAE is not documented in the IB for the study drugs (new occurrence) and is thought to be 
related to the sponsor's study drugs, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification to inform all investigators involved in any study 
with the same drug that this SAE has been reported.  Suspected Unexpected Serious Adverse 
Reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC, or as per national regulatory requirements 
in participating countries. 
8.4. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 


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8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study treatment 
may have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a subject during maternal or paternal exposure to study 
treatment, the following procedures should be followed in order to ensure subject safety: 
• The study treatment must be discontinued immediately (female subjects only). 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
• A serum pregnancy test must be performed to confirm the urine pregnancy test result.  
If a negative serum test does not confirm the urine pregnancy result, then: 
− The investigator will use his or her expert judgment, based on an assessment of 
the potential benefit/risk to the subject, to determine whether it is in the subject's 
best interest to resume study treatment and continue participation in the study. 
• The EOT visit evaluations must be performed. 
Data on fetal outcome and breastfeeding are collected for regulatory reporting and drug safety 
evaluation.  Follow-up should be conducted for each pregnancy 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, by following 
until the first well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy form 
and reported by the investigator to the sponsor or its designee.  Pregnancy follow-up information 
should be recorded on the same form and should include an assessment of the possible causal 
relationship to the sponsor's study drugs to any pregnancy outcome, as well as follow-up to the 
first well-baby visit or the duration specified in local regulations, whichever is later.  Refer to the 
Incyte Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy must be recorded on the SAE Report Form and 
submitted to the sponsor or designee. 
8.6. 
Warnings and Precautions 
Special warnings or precautions for the study drugs (INCAGN01876 and epacadostat), derived 
from safety information collected by the sponsor or its designee, and are presented in the 
INCAGN01876 IB and the INCB024360 IB.  Additional safety information collected between 
IB updates will be communicated in the form of Investigator Notifications.  Any important new 
safety information should be discussed with the subject during the study, as necessary.  If new 
significant risks are identified, they will be added to the ICF. 
8.7. 
Data Monitoring Committee 
Formal safety reviews will be conducted by the study team and an independent internal review 
committee, at least every 6 months, to review efficacy and safety data.  Details regarding data 
monitoring will be addressed in the Data Monitoring Charter. 




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(see Section 4.1.1).  Based on this algorithm, a minimum of 3 evaluable subjects will be enrolled 
in each cohort with a maximum of 9 evaluable subjects in each cohort. 
The probabilities of dose escalation from a given dose level for the various DLT rates are 
provided in Table 20. 
Table 20: 
Probability of Dose Escalation for Various Dose-Limiting Toxicity Rates 
True DLT Rate 
Probability of Dose Escalation 
20% 
78.4% 
30% 
56.1% 
40% 
35.0% 
50% 
18.9% 
60% 
8.8% 
For example, if the true DLT rate is 50% at a given dose level, there is an 18.9% chance that the 
dose would be escalated.  Further, if the true DLT rate is 20%, there is a 78.4% chance that the 
dose would be escalated.  If the MTD is not determined at the highest dose level tested during 
the study, then the MTD is at or above the highest dose level.  The MTD is below the lowest 
dose level of INCAGN01876 if the Cohort 1 dose is not well-tolerated. 
9.2.2. 
Sample Size for Phase 1 (Part 2) 
Once an INCAGN01876 dose cohort in Treatment Group A is deemed tolerable, up to 
6 evaluable subjects will be enrolled in Treatment Group B at the same dose of INCAGN01876.  
For example, if 3 mg/kg of INCAGN01876 is tolerated in Treatment Group A, then 3.0 mg/kg 
will be explored in up to 6 evaluable subjects in Treatment Group B. 
9.2.3. 
Sample Size for Phase 2 
Phase 2 will further evaluate the safety, tolerability, preliminary efficacy, 
 
 of the immune therapy combinations as part of dose expansion cohorts in Treatment 
Groups C and D.  In Phase 2, a Simon 2-stage design will be run for each tumor type within a 
given treatment group.   
The sample size for each tumor type within a given treatment group will be guided by the Simon 
2-stage design.  The planned Simon 2-stage designs are summarized in Table 21.  Each Simon 
2-stage design will have a stopping rule to allow early termination of a particular cohort at the 
end of Stage 1 if there are insufficient responses observed, while enrolling enough subjects to 
predict possible target responses worthy of cohort expansion and potentially further evaluation in 
future studies. 
The individual Simon 2-stage designs run for each tumor type within each treatment group will 
have design parameters that are determined by historical response rates.  For the RCC and UC 
cohorts, the insufficient response rates are obtained from historical data, and the Simon 2-stage 
designs allowing early termination are based on ORR.  For the melanoma cohort, the insufficient 
response rate is obtained from historical data, and the primary endpoint for the Simon 2-stage 
design allows for early termination based on CRR.  The same Simon 2-stage design parameters 
will be used for the alternative dosing sequences represented by Treatment Groups C and D in 


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the same tumor type.  For example, the RCC cohorts in Treatment Groups C and D will use the 
same Simon 2-stage parameters. 
In order to determine whether the target response rate (p1%) is likely, an initial number of 
evaluable subjects (n1 subjects) will be treated at the MTD 
 and schedule of 
INCAGN01876 within the corresponding tumor type and treatment group and will be enrolled in 
a cohort (Stage 1).  If there are r1 or fewer responses in the cohort, it will be concluded that the 
true response rate is unlikely to be greater than or equal to the target rate, and no more subjects 
will be enrolled in that tumor type cohort for that treatment group in Stage 2.  In the cohorts in 
which greater than r1 responses are observed among the Stage 1 subjects, n2 additional evaluable 
subjects will be treated in Stage 2 to estimate the response rate.  At the end of Stage 2, if 
≤ r subjects have responded among the n evaluable subjects, the triplet combination dosing 
sequence will be declared nonpromising for that cohort.  In other words, after the study is 
finished, if there is a sufficient number of responses in the 2 stages combined, the triplet 
combination dosing sequence is considered promising; otherwise it is considered nonpromising.  
The detailed calculations for each tumor-specific cohort are based on a 1-sided Type I error of 
0.05 and power of 85%.  The individual p0 and p1 values for the tumor types are listed in 
Table 21. 
A second approach to determining whether the treatment is active across the cohorts will use an 
integrated Bayesian futility analysis of tumor and dosing strategies specific to Treatment 
Groups C and D (see Section 9.6.2).  
Formal quarterly safety reviews will be conducted to review efficacy and safety data with the 
obligation to hold a safety review meeting every 6 months.  
Table 21: 
Planned Simon 2-Stage Designs for Phase 2 
Indication 
Combination 
r1 
n1 
r 
n2 
n 
p0 
p1 
Melanoma (CRR) 
GITR + Pembro + Epacadostat 
6 
21 
18 
31 
52 
26% 
45% 
RCC (ORR) 
GITR + Pembro + Epacadostat 
8 
19 
25 
31 
50 
40% 
60% 
UC (ORR) 
GITR + Pembro + Epacadostat 
3 
10 
14 
24 
34 
30% 
55% 
9.3. 
Level of Significance 
For the primary efficacy endpoints, the 1-sided Type I error will be controlled at 0.05 for each 
individual cohort expansion.  Note that this level of significance does not account for the 
multiple expansion cohorts.  For other endpoints, confidence intervals will be reported at a 95% 
confidence level. 


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9.4. 
Statistical Analyses 
9.4.1. 
Efficacy Analyses 
9.4.1.1. 
Primary Efficacy Analyses 
In Phase 2, ORR, defined as the percentage of subjects having CR or PR per RECIST v1.1 will 
be summarized by tumor type.  For CPI-naive melanoma subjects, CRR, defined as the 
percentage of subjects who have a CR per RECIST v1.1, will be summarized. 
9.4.1.2. 
Secondary Efficacy Analyses 
Disease control rate, defined as the percentage of subjects having CR, PR, or SD, as per 
RECIST v1.1 and mRECIST. 
Progression-free survival, DOR, and duration of disease control (CR, PR, and SD) will be 
estimated using the Kaplan-Meier method as per RECIST v1.1 and mRECIST.  Overall survival 
will be estimated using the Kaplan-Meier method. 
In Phase 2, ORR, defined as the percentage of subjects having CR or PR per RECIST v1.1 and 
mRECIST will be summarized by tumor type. 
9.4.2. 
Safety Analyses 
9.4.2.1. 
Adverse Events 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after the 
first dose of study treatment.  Analysis of AEs will be limited to TEAEs, but data listings will 
include all AEs regardless of their timing to study treatment administration.  Adverse events will 
be tabulated by the MedDRA preferred term and system organ class.  Severity of AEs will be 
based on the CTCAE v4.03, using Grades 1 through 5. 
The subset of AEs considered by the investigator to have a relationship to study treatment will be 
considered to be treatment-related AEs.  If the investigator does not specify the relationship of 
the AE to study treatment, the AE will be considered treatment-related.  The incidences of AEs 
and treatment-related AEs will be tabulated. 
9.4.2.2. 
Clinical Laboratory Tests 
Laboratory test values outside of the normal range will be assessed for severity based on the 
normal ranges for the clinical reference laboratory.  The incidence of abnormal laboratory values 
and shift tables relative to baseline will be tabulated. 
Laboratory data will be classified into Grades 1 through 4 using CTCAE v4.03.  The following 
summaries will be produced for the laboratory data: 
• Number and percentage of subjects with worst postbaseline CTCAE grade (regardless 
of baseline value).  Each subject will be counted only for the worst grade observed 
postbaseline. 
• Shift tables from baseline to the worst postbaseline value using CTCAE grade. 






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A second approach to determining whether the treatment is active or not across the cohorts will 
use an integrated Bayesian analysis of tumor and dosing strategies specific to Treatment 
Groups C and D based on Simon et al (2016).  Pooling is performed within dosing strategies and 
tumor types to determine if INCAGN01876 is active within any of the given dosing strategies, 
given tumor types, or given dosing strategy-tumor type combinations.  The first Bayesian 
pooling analysis will allow sharing of information within a tumor type across dosing strategies 
based on a joint Bayesian prior.  The joint Bayesian prior incorporates the unacceptable and 
target response rates from the Simon 2-stage designs with a parameter indicating the prior 
probability of homogeneity within the tumor types, which controls the degree of information 
sharing.  A separate analysis will allow sharing of information for dosing strategies across tumor 
types using a separate joint Bayesian prior.  For this analysis, the joint Bayesian prior 
incorporates the unacceptable and target response rates from the Simon 2-stage designs with a 
parameter indicating the prior probability of homogeneity within the dosing strategies, which 
controls the degree of information sharing. 
Each time a subject with the tumor type of interest is enrolled, 2 PoS calculations will be 
performed using the evaluable subjects:  the PoS within tumor type (tumor typei and dosing 
strategyj), PoS1ij, and PoS within dosing strategy (tumor typei and dosing strategyj), PoS2ij. 
Based on the results of the 2 calculated posterior PoS values, a tumor-sequence pair (i,j) will be 
considered open for enrollment if the maximum of PoS1ij and PoS2ij is greater than or equal to 
20%.  Otherwise the tumor-sequence pair will be suspended. 
At the end of the study, overall PoS tests will be performed using both PoS1ij and PoS2ij.  
A tumor-sequence strategy will be considered successful if either PoS1ij or PoS2ij is > 80%. 


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10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
10.1. 
Investigator Responsibilities 
This study will be performed in accordance with ethical principles that originate in the 
Declaration of Helsinki and conducted in adherence to the study Protocol; GCPs as defined in 
Title 21 of the US CFR Parts 11, 50, 54, 56, and 312; ICH E6 GCP consolidated guidelines; and 
local regulatory requirements as applicable to the study locations. 
The investigator will be responsible for: 
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
subject records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all subjects. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other 
study-related documents.  The investigator must immediately notify the sponsor 
when contacted by any regulatory authority for the purposes of conducting an 
inspection. 
• Obtaining informed consent and ensuring that the study subjects' questions have been 
answered and the subjects fully understand study procedures: 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the subject.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to subject records. 


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• Obtaining approval from the IRB/IEC before the start of the study and for any 
changes to the clinical study Protocol, important Protocol deviations, routine updates, 
and safety information in accordance with institutional requirements and local law. 
− The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements 
and with the policies and procedures established by the IRB/IEC. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling subjects who have met the 
specified eligibility criteria. 
• Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  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. 
− All eCRF 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.  
The sponsor will retain the original eCRF data and audit trail. 
10.2. 
Accountability, Handling, and Disposal of Study Drugs 
The investigator is responsible for drug accountability at the study site; however, some of the 
drug accountability duties may be assigned to an appropriate pharmacist or other designee.  
Inventory and accountability records must be maintained and readily available for inspection by 
the study monitor and are open to inspection at any time by any applicable regulatory authorities.  
The investigator or designee must maintain records that document: 
• Delivery of study drugs to the study site. 
• Inventory of study drugs at the site. 
• Lot numbers and/or vial numbers (as applicable) of study drug used to prepare the 
infusion solution. 
• Subject use of the study drugs including pill or unit counts from each supply 
dispensed. 
• Return of study drugs to the investigator or designee by subjects. 


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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 specified 
study drugs.  These records should include dates, quantities, and any available batch or serial 
numbers or unique code numbers assigned to the investigational product and study subjects. 
Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drugs 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study drugs back to the sponsor or its designee for destruction according to institutional standard 
operating procedures.  If local procedures mandate on-site destruction of investigational supply, 
the site should (where local procedures allow) maintain the investigational supply until the study 
monitor inspects the accountability records in order to evaluate compliance and accuracy of 
accountability by the investigative site.  At sites where the study drugs is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
10.3. 
Data Management 
Data management will be performed in a validated database via an EDC system.  All data entry, 
verification, and validation will be performed in accordance with the current standard operating 
procedures of the Data Management Department at the sponsor or its designee.  The database 
will be authorized for lock once all defined procedures are completed. 
The investigator will be provided with access to an EDC system so that an eCRF can be 
completed for each subject.  Entries made in the eCRF must be verifiable against source 
documents; if updates to the database are not possible, any discrepancies should be explained 
and documented.  The investigator will be responsible for reviewing all data and eCRF entries, 
and will sign and date the designated forms in each subject's eCRF, verifying that the 
information is true and correct.  The investigator is responsible for the review and approval of all 
query responses. 
Protocol deviations will be identified and recorded in the Protocol Deviation form of the eCRF.  
The study monitor will reference the Monitoring Plan in order to ensure that each issue identified 
is appropriately documented, reported, and resolved in a timely manner in accordance with the 
plan's requirements. 
10.4. 
Data Privacy and Confidentiality of Study Records 
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, Health Insurance 
Portability and Accountability Act of 1996).  Appropriate consent and authorizations for use and 
disclosure and/or transfer (if applicable) of protected information must be obtained. 
Subject names will not be supplied to the sponsor or its designee, if applicable.  Only the subject 
number and subject's initials (subject's initials will only be recorded if allowable by local 
regulations) will be recorded in the eCRF, where permitted; if the subject's name appears on any 
other document (eg, 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 


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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. 
10.5. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to FDA 
Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators (ie, "covered 
studies") are required to submit a completed Clinical Investigator Financial Disclosure 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 subinvestigator who is directly 
involved in the treatment or evaluation of research subjects, including the spouse and each 
dependent child of the clinical investigator or subinvestigator.  These requirements apply to both 
US and foreign clinical investigators conducting covered clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure 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 obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
10.6. 
Publication Policy 
By signing the study Protocol, the investigator and his or her institution agree that the results of 
the study may be used by the sponsor, Incyte Biosciences International Sàrl (Incyte), for the 
purposes of national and international registration, publication, and information for medical and 
pharmaceutical professionals.  Study results will be published in accordance with applicable 
local and national regulations.  If necessary, the authorities will be notified of the investigator's 
name, address, qualifications, and extent of involvement.  The terms regarding the publication of 
study results are contained in the agreement signed with the sponsor or its designee.  A signed 
agreement will be retained by the sponsor or its designee. 


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11. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For Subjects Participating in the Study: 
The following methods that can achieve a failure rate of less than 1% per year when used 
consistently and correctly are considered as highly effective birth control methods.  
Such methods include: 
• Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation1 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation1 
− oral 
− injectable 
− implantable2 
• Intrauterine device (IUD)2 
• Intrauterine hormone-releasing system (IUS)2 
• Bilateral tubal occlusion2 
• Vasectomized partner2,3 
• Sexual abstinence4 
 
1  Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy of the 
contraception method. 
2  Contraception methods that in the context of this guidance are considered to have low user dependency. 
3  Vasectomised partner is a highly effective method of avoiding pregnancy, provided that partner is the sole sexual 
partner of the female of childbearing potential trial participant and that the vasectomized partner has received 
medical assessment of the surgical success.  
4  In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the 
preferred and usual lifestyle of the subject. 
Source:  CTFG 2014. 


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APPENDIX B. PROCEDURES AND SUPPORTIVE CARE GUIDELINES 
FOR SUBJECTS EXHIBITING IMMUNE-RELATED 
ADVERSE EVENTS 
Immune-Related 
Adverse Event 
(irAE) 
Supportive Care 
Pneumonitis 
For Grade 2 (mild to moderate new symptoms): 
• Monitor symptoms daily and consider hospitalization.  
• Promptly start systemic steroids per institutional standard of care.  
• Consider adding prophylactic antibiotics for opportunistic infections in the case 
of prolonged steroid administration. 
• Re-imaging as clinically indicated. 
• If no improvement within 3 to 5 days, additional work-up should be considered, 
and prompt treatment with IV methylprednisolone should be started. 
• If still no improvement within 3 to 5 days despite IV methylprednisone, consider 
starting immunosuppressive therapy (eg, infliximab) after discussing with the 
medical monitor. 
Caution:  Important to rule out sepsis and to refer to the infliximab label for 
general guidance before using infliximab.  
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungal, or anti-pneumocystis pneumonia (PCP) 
treatment (refer to current National Comprehensive Cancer Network [NCCN] 
Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]).  
• Consider pulmonary and infectious disease consult.  
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, life 
threatening): 
• Promptly initiate empiric IV methylprednisolone or equivalent.  
• Carefully monitor subject and institute medical intervention as appropriate for 
the management of symptoms.  Consider obtaining pulmonary and infectious 
disease consult.  
• If no improvement within 3 to 5 days, additional work-up should be considered, 
and prompt treatment with additional immunosuppressive therapy (eg, 
infliximab) should be started after discussing with the medical monitor. 
Caution:  Rule out sepsis and refer to infliximab label for general guidance 
before using infliximab.  
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and in particular, anti-PCP treatment (refer 
to current NCCN Guidelines for treatment of cancer-related infections 
[Category 2B recommendation]). 


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Immune-Related 
Adverse Event 
(irAE) 
Supportive Care 
Diarrhea/Colitis 
Note:  Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (eg, diarrhea, abdominal pain, and blood or mucus in stool, with or 
without fever) and of bowel perforation (eg, peritoneal signs and ileus). 
For Grade 2 (mild to moderate new symptoms): 
• Consider symptomatic treatment, including hydration, electrolyte replacement, 
dietary changes (eg, American Dietetic Association colitis diet), and loperamide 
and/or budesonide. 
• Promptly start systemic steroids per institutional standard of care. 
• If event is not responsive within 3 to 5 days or worsens, GI consult should be 
obtained for consideration of further work-up, and prompt treatment with IV 
methylprednisolone should be started. 
• If still no improvement within 3 to 5 days, consider starting immunosuppressive 
therapy (eg, infliximab) after discussing with the medical monitor. 
Caution:  Important to rule out bowel perforation and refer to infliximab label 
for general guidance before using infliximab. 
• Consult medical monitor if no resolution to ≤ Grade 1 in 3 to 4 days. 
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
For Grade 3 or 4 (severe or new symptoms, new/worsening diarrhea, life 
threatening): 
• Treatment with systemic corticosteroids should be initiated per institutional 
standard of care. 
• Manage symptoms and consider GI consult for further work-up as appropriate. 
• If still no improvement within 3 to 5 days, consider starting immunosuppressive 
therapy (eg, infliximab) after discussing with the medical monitor. 
Caution:  Ensure GI consult to rule out bowel perforation and refer to infliximab 
label for general guidance before using infliximab. 
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 


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Immune-Related 
Adverse Event 
(irAE) 
Supportive Care 
Hepatitis 
For Grade 2 (mild to moderate new symptoms): 
• Observe subject with regular and frequent checking of liver chemistries until 
improving or resolved. 
• Rule out non-irAE etiologies. 
• If event is persistent (> 3-5 days) or worsens, consider starting systemic steroids 
per institutional standard of care. 
• If still no improvement within 3 to 5 days, consider additional work-up and 
prompt treatment with IV methylprednisolone. 
• If still no improvement within 3 to 5 days, consider starting immunosuppressive 
therapy (eg, mycophenolate mofetil) after discussing with the medical monitor. 
• Infliximab should NOT be used. 
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
For Grade 3 or 4 (severe or new symptoms, new/worsening hepatitis, life 
threatening): 
• Promptly initiate empiric IV methylprednisolone or equivalent. 
• If still no improvement within 3 to 5 days, consider starting treatment with 
immunosuppressive therapy (eg, mycophenolate mofetil) after discussing with 
the medical monitor. 
• Infliximab should NOT be used. 
• Consider hepatology consult for additional work-up, as appropriate. 
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 


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CONFIDENTIAL 
Immune-Related 
Adverse Event 
(irAE) 
Supportive Care 
Dermatitis 
Note:  Monitor subjects for signs and symptoms of dermatitis such as rash and 
pruritus.  Unless an alternate etiology has been identified, signs or symptoms of 
dermatitis should be considered immune-mediated.  If there is any bullous 
formation, the medical monitor should be contacted, and study treatment should be 
discontinued. 
For Grade 2 (mild to moderate new symptoms): 
• Consider dermatology consult. 
• Consider symptomatic treatment per institutional standard of care. 
• Consider moderate-strength topical steroid. 
• If no improvement of rash/skin lesions occurs within 3 to 5 days, or rash/skin 
lesions are worsening despite symptomatic treatment and/or use of moderate-
strength topical steroid, discuss with medical monitor, and promptly start 
systemic steroids. 
For Grade 3 or 4 (severe or new symptoms, new/worsening dermatitis, life 
threatening): 
• Consider dermatology consult. 
• Promptly initiate empiric IV methylprednisolone or equivalent. 
• Carefully monitor subject, and institute medical intervention as appropriate for 
the management of symptoms.   
• Consider hospitalization. 
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 
• Discuss with medical monitor. 


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CONFIDENTIAL 
Immune-Related 
Adverse Event 
(irAE) 
Supportive Care 
Renal Failure or 
Nephritis 
Note:  Subjects should be monitored for signs and symptoms that may be related to 
changes in renal function.  Subjects should be thoroughly evaluated to rule out any 
alternative etiology.  Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events (eg, Grade 2) in order to prevent 
potential progression to higher grade event. 
For Grades 2 to 4:  
• Carefully monitor subject and institute medical intervention as appropriate for 
the management of symptoms.  Consider consult with nephrologist, if clinically 
indicated.   
• If event is persistent (> 3-5 days) or worsens, promptly start systemic steroids per 
institutional standard of care. 
• If event is not responsive within 3 to 5 days or worsens despite steroids, 
additional work-up should be considered, and prompt treatment with IV 
methylprednisolone started. 
• Once improving, gradually taper steroids over ≥ 4 weeks and consider 
prophylactic antibiotics, antifungals, and anti-PCP treatment (refer to current 
NCCN Guidelines for treatment of cancer-related infections [Category 2B 
recommendation]). 


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Immune-Related 
Adverse Event 
(irAE) 
Supportive Care 
Endocrinopathies 
Note:  Subjects should be monitored for clinical signs and symptoms of 
hypophysitis, adrenal insufficiency (including adrenal crisis), and hyperthyroidism 
or hypothyroidism.  Subjects may present with fatigue, headache, mental status 
changes, abdominal pain, unusual bowel habits, and hypotension, or nonspecific 
symptoms that may resemble other causes, such as brain metastasis or underlying 
disease.  Unless an alternate etiology has been identified, signs or symptoms of 
endocrinopathies should be considered immune-mediated. 
For Grade 2 (mild to moderate new symptoms):  
• In hypophysitis, treat with systemic corticosteroids per institutional standard of 
care.  When symptoms improve to ≤ Grade 1, steroid taper should be started and 
continued over ≥4 weeks.  Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
Note:  These suggested supportive care measures also apply to Grade 3 
hypophysitis. 
• In hyperthyroidism, nonselective beta-blockers (eg, propranolol) are suggested as 
initial therapy. 
• In hypothyroidism, thyroid hormone replacement therapy with levothyroxine or 
liothyronine is indicated per standard of care. 
Note:  Isolated hypothyroidism may be treated with replacement therapy without 
treatment interruption and without corticosteroids. 
• Evaluate endocrine function and, as clinically indicated, consider pituitary scan. 
• For subjects with abnormal endocrine work-up, except for those with isolated 
hypothyroidism, consider short-term, high-dose corticosteroids 
(eg, methylprednisolone or IV equivalent) and initiate appropriate hormone 
replacement therapy. 
• For subjects with normal endocrine work-up (eg, labs or magnetic resonance 
imaging [MRI]), repeat labs or MRI as clinically indicated. 
For Grade 3 or 4 (severe or new symptoms, new/worsening endocrinopathies, 
life threatening): 
• Hypothyroidism may be treated with replacement therapy without treatment 
interruption and without corticosteroids. 
• In hyperthyroidism, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids.  Consider initiation of systemic corticosteroids at a dose of 1 
to 2 mg/kg per day of prednisone or equivalent, and initiate appropriate hormone 
replacement therapy.  Once improving, gradually taper immunosuppressive 
steroids over ≥ 4 weeks. 
• In hypophysitis, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids.  When symptoms improve to ≤ Grade 1, steroid taper should be 
started and continued over ≥ 4 weeks.  Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
• For adrenal crisis, severe dehydration, hypotension, or shock:  immediately 
initiate IV corticosteroids with mineralocorticoid activity. 
• Consult endocrinologist. 
• Consult medical monitor. 


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Immune-Related 
Adverse Event 
(irAE) 
Supportive Care 
Neuropathies 
Note:  Monitor subjects for symptoms of motor or sensory neuropathy such as 
unilateral or bilateral weakness, sensory alterations, or paresthesia. 
For Grade 2 (mild to moderate new symptoms):  
• Consider systemic corticosteroids per institutional standard of care in addition to 
appropriate symptomatic treatment. 
• If no improvement within 3 to 5 days, consider additional work-up and treating 
with additional immunosuppressive therapy (eg, IV immunoglobulin G [IgG]) 
after discussing with the medical monitor. 
For Grade 3 or 4 (severe or new symptoms, new/worsening neuropathies, life 
threatening): 
• Consider initiation of systemic corticosteroids (IV administration should be 
strongly considered) for severe neuropathies. 
• Institute medical intervention as appropriate for management of severe 
neuropathy. 
• If no improvement within 3 to 5 days despite IV corticosteroids, consider 
additional workup and treating with additional immunosuppressive therapy 
(eg, IV IgG) after discussing with the medical monitor. 
• Once stable, gradually taper steroids over ≥ 4 weeks. 
 


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APPENDIX C. PROHIBITED MONOAMINE OXIDASE INHIBITORS 
AND DRUGS ASSOCIATED WITH SIGNIFICANT 
MONOAMINE OXIDASE INHIBITORY ACTIVITY 
Monoamine Oxidase Inhibitors 
Drugs Associated With Significant Monoamine 
Oxidase Inhibitory Activity 
Hydrazines (eg, phenelzine) 
Meperidine 
Caroxazone 
Linezolid 
Echinopsidine 
Methylene blue 
Furazolidone 
 
Tranylcypromine 
 
Brofaromine 
 
Metralindole 
 
Minaprine 
 
Moclobemide 
 
Pirlindole 
 
Toloxatone 
 
Lazabemide 
 
Pargyline 
 
Rasagiline 
 
Selegiline 
 
 

SAP_001.pdf: 




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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY INFORMATION, OBJECTIVES, AND ENDPOINTS.................................9 
2.1. 
Protocol and Case Report Form Version ......................................................................9 
2.2. 
Study Objectives ...........................................................................................................9 
2.2.1. 
Primary Objectives .......................................................................................................9 
2.2.2. 
Secondary Objectives ...................................................................................................9 
 
9 
2.3. 
Study Endpoints ..........................................................................................................10 
2.3.1. 
Primary Endpoints ......................................................................................................10 
2.3.2. 
Secondary Endpoints ..................................................................................................10 
 
11 
3. 
STUDY DESIGN .......................................................................................................11 
3.1. 
Overall Study Design ..................................................................................................11 
3.1.1. 
Phase 1 – Dose Escalation (Part 1) .............................................................................12 
3.1.1.1. 
Treatment Group A:  INCAGN01876 + Pembrolizumab...........................................13 
3.1.2. 
Phase 1 – Safety Expansion (Part 2) ...........................................................................14 
3.1.2.1. 
Treatment Group B:  INCAGN01876 + Epacadostat Run-In Followed by 
INCAGN01876 + Pembrolizumab + Epacadostat ......................................................15 
3.1.3. 
Phase 2 – Dose Expansion ..........................................................................................15 
3.2. 
Randomization ............................................................................................................17 
3.3. 
Control of Type I Error ...............................................................................................17 
3.4. 
Sample Size Considerations .......................................................................................17 
3.4.1. 
Sample Size in Phase 1 Part 1 .....................................................................................17 
3.4.2. 
Sample Size in Phase 1 Part 2 .....................................................................................18 
3.4.3. 
Sample Size for Phase 2 .............................................................................................18 
3.5. 
Schedule of Assessments ............................................................................................19 
4. 
DATA HANDLING DEFINITIONS AND CONVENTIONS ..................................19 
4.1. 
Scheduled Study Evaluations and Study Periods .......................................................19 
4.1.1. 
Day 1 ...........................................................................................................................19 
4.1.2. 
Study Day ...................................................................................................................19 
4.1.3. 
Baseline Value ............................................................................................................20 


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4.1.4. 
Handling of Missing and Incomplete Data .................................................................20 
4.1.5. 
Cycle Length and Duration .........................................................................................20 
4.2. 
Variable Definitions ....................................................................................................21 
4.2.1. 
Age ..............................................................................................................................21 
4.2.2. 
Prior and Concomitant Medication .............................................................................21 
5. 
STATISTICAL METHODOLOGY ...........................................................................21 
5.1. 
General Methodology .................................................................................................21 
5.2. 
Treatment Groups .......................................................................................................21 
5.3. 
Analysis Populations ..................................................................................................22 
5.3.1. 
Full Analysis Set .........................................................................................................22 
5.3.2. 
Response Evaluable Populations ................................................................................22 
6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES ...............................................................................................................23 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease History .............23 
6.1.1. 
Demographics .............................................................................................................23 
6.1.2. 
Baseline Disease Characteristics and Disease History ...............................................23 
6.1.3. 
Prior Therapy ..............................................................................................................23 
6.1.4. 
Medical History ..........................................................................................................23 
6.2. 
Disposition of Subjects ...............................................................................................23 
6.3. 
Protocol Deviations ....................................................................................................23 
6.4. 
.....................................................................................................................24 
6.4.1. 
 .....................................................................................24 
6.4.2. 
 .....................................................................................24 
6.4.3. 
 ...........................................................................................24 
6.5. 
Prior and Concomitant Medication .............................................................................24 
7. 
EFFICACY .................................................................................................................25 
7.1. 
General Considerations ...............................................................................................25 
7.2. 
Analysis of the Objective Response Rate ...................................................................25 
7.2.1. 
Objective Response Rate and Best Overall Response by RECIST v1.1 ....................25 
8. 
SAFETY AND TOLERABILITY ..............................................................................26 
8.1. 
General Considerations ...............................................................................................26 
8.2. 
Adverse Events ...........................................................................................................26 
8.2.1. 
Adverse Event Definitions ..........................................................................................26 


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8.2.2. 
Dose-Limiting Toxicities ............................................................................................27 
8.2.3. 
Adverse Events of Special Interest .............................................................................27 
8.2.3.1. 
Immune-Related Adverse Events ...............................................................................27 
8.2.3.2. 
Infusion-Related Reactions .........................................................................................27 
8.2.4. 
Adverse Event Summaries ..........................................................................................27 
8.3. 
Clinical Laboratory Tests ...........................................................................................28 
8.3.1. 
Laboratory Value Definitions .....................................................................................28 
8.3.2. 
Laboratory Value Summaries .....................................................................................28 
8.4. 
Vital Signs ..................................................................................................................29 
8.5. 
Electrocardiograms .....................................................................................................29 
8.6. 
Physical Examinations ................................................................................................30 
9. 
INTERIM ANALYSES ..............................................................................................30 
10. 
CHANGES AND MODIFICATIONS TO THE ANALYSIS PLAN ........................31 
10.1. 
Changes to Protocol-Defined Analyses ......................................................................31 
10.1.1. 
Sample Size Deviation ................................................................................................31 
10.1.1.1. 
Sample Size in Phase 1 Part 1 .....................................................................................31 
10.1.1.2. 
Sample Size in Phase 2 ...............................................................................................31 
10.1.2. 
Efficacy Analyses .......................................................................................................31 
10.1.3. 
Safety Analyses ..........................................................................................................31 
10.1.4. 
Interim Analyses .........................................................................................................31 
11. 
REFERENCES ...........................................................................................................32 
APPENDIX A. PLANNED TABLES AND FIGURES .............................................................33 
 


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LIST OF TABLES 
Table 1: 
INCAGN01876 Dose Cohorts ....................................................................................13 
Table 2: 
Phase 1 Dose Escalation of Treatment Group A ........................................................14 
Table 3: 
Phase 1 Safety Expansion of Treatment Group B ......................................................15 
Table 4: 
Phase 2 Dose Expansion Treatment Groups ...............................................................16 
Table 5: 
Probability of Dose Escalation for Various Dose-Limiting Toxicity Rates ...............17 
Table 6: 
Planned Simon 2-Stage Designs for Phase 2 ..............................................................19 
Table 7: 
RECIST v1.1 Evaluation Criteria for Overall Response:  Measurable Disease 
at Baseline ...................................................................................................................25 
Table 8: 
Identification of Records for Postbaseline By-Visit Summaries ................................28 
Table 9: 
Criteria for Clinically Notable Vital Sign Abnormalities ...........................................29 
Table 10: Criteria for Clinically Notable Electrocardiogram Abnormalities .............................30 
Table 11: Statistical Analysis Plan Versions ..............................................................................31 
 
LIST OF FIGURES 
Figure 1: 
Overall Study Design ..................................................................................................12 
Figure 2: 
Phase 1 Safety Expansion (Part 2) ..............................................................................14 
 




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Abbreviation 
Term 
PFS 
progression-free survival 
 
 
PR 
partial response 
PT 
preferred term 
Q3W 
every 3 weeks 
QTcB 
QT interval corrected using the Bazett formula 
QTcF 
QT interval corrected using the Fridericia formula 
RCC 
renal cell carcinoma 
RP2D 
recommended Phase 2 dose 
SD 
stable disease 
SAP 
Statistical Analysis Plan 
SCCHN 
squamous cell carcinoma of the head and neck 
SCLC 
small cell lung cancer 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
  
 
TMF 
trial master file 
TNBC 
triple-negative breast cancer 
UC 
urothelial carcinoma 
WHO 
World Health Organization  










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Figure 1: 
Overall Study Design 
 
3.1.1. 
Phase 1 – Dose Escalation (Part 1) 
A minimum of 3 evaluable subjects will be enrolled in Treatment Group A (see Table 2), 
beginning with INCAGN01876 Dose Cohort 1 (1.0 mg/kg; starting dose; see Table 1).  A higher 
starting dose of INCAGN01876 may be used if safety data are available from the monotherapy 
study (INCAGN 1876-101), but it will not exceed 1 dose level below the highest tolerated dose 
of INCAGN01876 monotherapy.  If a higher dose is used, the dose will be communicated to 
investigational sites with an administrative letter.  The first 3 evaluable subjects enrolled within 
an INCAGN01876 dose cohort will be observed for a minimum of 28 days before the next dose 
cohort begins enrollment.  If 0 DLTs occur in a cohort of 3 evaluable subjects, a new cohort of 
3 evaluable subjects will be treated at the next higher dose level.  If 1 of 3 evaluable subjects 
experiences a DLT, that cohort will be expanded to 6 evaluable subjects.  If 1 of 6 evaluable 
subjects experiences a DLT, a new cohort of 3 evaluable subjects will be treated at the next 
higher dose level.  If 2 of 6 evaluable subjects experience a DLT, that cohort will be expanded to 
9 evaluable subjects.  If ≥ 2 of 3, 3 of 6, or 3 of 9 evaluable subjects experience DLTs within a 
cohort, then that dose level will be determined to have exceeded the MTD, and the previous dose 
level will be considered the MTD.  If only 3 evaluable subjects were treated at the MTD
, 
then a minimum of 3 additional evaluable subjects will be enrolled before this dose is 
administered in Phase 2 of the study. 


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Additional subjects will be enrolled in a dose cohort to achieve the minimum of 3 evaluable 
subjects.  Subjects who drop out for reasons other than a DLT (eg, events clearly associated with 
the underlying disease, disease progression, concomitant medication, or comorbidity) during the 
DLT observation period will result in the subjects being nonevaluable and replaced.  Dose 
modifications should not be made during the DLT observation period without discussion with 
the medical monitor.  The doses of INCAGN01876 to be evaluated in each treatment group are 
summarized in Table 1. 
Table 1: 
INCAGN01876 Dose Cohorts 
Dose Cohort 
Dose of INCAGN01876 
-1 
0.3 mg/kg 
1 (Starting Dose) 
1.0 mg/kg
a 
2 
3.0 mg/kg 
3 
5.0 mg/kg 
4 
10.0 mg/kg 
a A higher starting dose of INCAGN01876 
 was used based on safety data from the monotherapy study 
(INCAGN 1876-101), but it did not exceed 1 dose level below the highest tolerated dose of INCAGN01876 
monotherapy.  The higher dose was communicated to investigational sites with an administrative letter. 
3.1.1.1. 
Treatment Group A:  INCAGN01876 + Pembrolizumab 
Treatment Group A will treat subjects with INCAGN01876 at the assigned dose level 
administered Q3W in combination with 200 mg of pembrolizumab administered Q3W and 
 epacadostat administered orally BID (see Table 2).  There will be a waiting period 
of 48 hours between dose administration of the first subject and second subject of each 
dosing cohort.  The first 3 evaluable subjects enrolled within a cohort will be observed for 
28 days before the next cohort begins enrollment.  Dose escalation of INCAGN01876 will 
proceed as outlined in Table 1 until the MTD
 of INCAGN01876 in combination with 
pembrolizumab and epacadostat is determined.  Subjects must receive at least 1 dose of the 
cohort-specified dose of INCAGN01876, 1 dose of pembrolizumab, and at least 75% of planned 
doses of epacadostat (42 doses) or have had a DLT during the DLT observation period to be 
considered evaluable. 


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Table 2: 
Phase 1 Dose Escalation of Treatment Group A 
Treatment 
Group A 
INCAGN01876 
Concurrent Dose Administration 
Pembrolizumab 
Epacadostat 
See INCAGN01876 dose cohorts 
(Table 1) Q3W starting at Cycle 1 
200 mg Q3W 
starting at Cycle 1 
 
starting at Cycle 1 
 
3.1.2. 
Phase 1 – Safety Expansion (Part 2) 
Once an INCAGN01876 dose cohort in Treatment Group A is deemed tolerable (ie, no DLTs or 
unacceptable toxicities were observed within the defined DLT observation period of at least 
28 days), up to 6 evaluable subjects will be enrolled in Treatment Group B at the same dose of 
INCAGN01876 (see Figure 2).  For example, if 3.0 mg/kg of INCAGN01876 is tolerated in 
Treatment Group A, then 3.0 mg/kg will be explored in up to 6 evaluable subjects in Treatment 
Group B.  Doses of INCAGN01876 in Treatment Group B will be escalated in parallel to those 
explored in Treatment Group A, but will not exceed the MTD of INCAGN01876 established in 
Treatment Group A.  Alternate dose administration schedules may also be explored depending 
on
safety results.  The sponsor may elect to prioritize (or 
deprioritize) enrollment to specific dose cohorts based on emerging safety or efficacy data in 
collaboration with investigational sites. 
If the cumulative incidence of Grade 3 or higher INCAGN01876-related AEs occurs in > 40% of 
subjects in a particular treatment group, then further enrollment will be interrupted until the 
sponsor, investigators, and regulatory authorities (if applicable) determine the appropriate course 
of action (eg, lower the dose of INCAGN01876, change dose frequency, etc). 
Figure 2: 
Phase 1 Safety Expansion (Part 2) 
 


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3.1.2.1. 
Treatment Group B:  INCAGN01876 + Epacadostat Run-In Followed by 
INCAGN01876 + Pembrolizumab + Epacadostat 
Treatment Group B will treat subjects with a single-dose run-in of INCAGN01876 at the 
assigned dose level in combination with 
 epacadostat administered orally BID, 
followed by the combination of INCAGN01876 Q3W, 200 mg of pembrolizumab Q3W starting 
at Cycle 2, and 
 epacadostat administered orally BID (see Table 3). 
Table 3: 
Phase 1 Safety Expansion of Treatment Group B 
Treatment 
Group B 
INCAGN01876 
Run-In Followed by Concurrent Dose 
Administration 
Pembrolizumab 
Epacadostat 
See INCAGN01876 dose cohorts 
(Table 1) Q3W starting at Cycle 1 
200 mg Q3W 
starting at Cycle 2 
 
starting at Cycle 1 
 
3.1.3. 
Phase 2 – Dose Expansion 
Phase 2 will further evaluate the safety, tolerability, efficacy, 
 
 in subjects with advanced or metastatic melanoma, RCC, and 
UC.  Additional tumor-specific cohorts may be added, by protocol amendment, based on 
emerging data. 
Biopsy cohorts will be added at specific institutions for each treatment group (C and D), where 
serial mandatory pretreatment and on-treatment biopsies will be collected to evaluate changes in 
the tumor microenvironment.  Approximately 15 evaluable subjects who have tumor lesions that 
are amenable to percutaneous biopsy will be enrolled in each biopsy cohort.  The biopsy-specific 
cohorts will be limited to subjects with melanoma (mucosal or cutaneous), RCC, and UC (refer 
to the Protocol, Section 7.10.4). 
The Phase 2 dose expansion treatment groups and tumor-specific cohorts for each treatment 
group are outlined in Table 4.  A Simon 2-stage design will be used with a stopping rule to allow 
for early termination of a particular cohort at the end of Stage 1 if there are insufficient responses 
observed (Simon 1989).  The approximate number of subjects for Stage 1 and Stage 2 for each 
treatment group and tumor type is described in Table 6.  Enrollment in Phase 2 will begin when 
the MTD
 of INCAGN01876 for a given treatment group in Phase 1 has been 
determined. 




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In Phase 2 of the study, toxicities will continue to be monitored.  If the cumulative incidence of 
Grade 3 or higher INCAGN01876-related AEs occurs in > 40% of subjects in a particular 
treatment group after 6 subjects have been enrolled, then further enrollment in that treatment 
group will be interrupted until the sponsor, investigators, and regulatory authorities (if 
applicable) determine the appropriate course of action (eg, lower the dose of INCAGN01876, 
change dose frequency, etc).  If a treatment group is discontinued due to toxicity, it may be 
re-initiated at a previously tested lower dose level and/or alternate dosing schedule.  All AEs, 
regardless of the time of occurrence on study, may be considered for DLT determination 
purposes. 
3.2. 
Randomization 
Not applicable. 
3.3. 
Control of Type I Error 
For the primary efficacy endpoints, the 1-sided Type I error will be controlled at 0.05 for each 
individual cohort expansion.  Note that this level of significance does not account for the 
multiple expansion cohorts.  For other endpoints, CIs will be reported at a 95% confidence level. 
3.4. 
Sample Size Considerations 
3.4.1. 
Sample Size in Phase 1 Part 1 
The primary objective of Phase 1 of the study is to evaluate the safety, tolerability, and DLTs of 
INCAGN01876 in combination with immune therapies and to determine the RP2Ds of 
INCAGN01876 when given in combination with immune therapies.  The total number of 
subjects will depend on the number of dose levels tested before the recommended dose(s) are 
established.  Dose escalation will follow the 3 + 3 + 3 design algorithm (see Section 3.1.1).  
Based on this algorithm, a minimum of 3 evaluable subjects will be enrolled in each cohort with 
a maximum of 9 evaluable subjects in each cohort. 
The probabilities of dose escalation from a given dose level for the various DLT rates are 
provided in Table 5. 
Table 5: 
Probability of Dose Escalation for Various Dose-Limiting Toxicity Rates 
True DLT Rate 
Probability of Dose Escalation 
20% 
78.4% 
30% 
56.1% 
40% 
35.0% 
50% 
18.9% 
60% 
8.8% 


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For example, if the true DLT rate is 50% at a given dose level, there is an 18.9% chance that the 
dose would be escalated.  Further, if the true DLT rate is 20%, there is a 78.4% chance that the 
dose would be escalated.  If the MTD is not determined at the highest dose level tested during 
the study, then the MTD is at or above the highest dose level.  The MTD is below the lowest 
dose level of INCAGN01876 if the Cohort 1 dose is not well-tolerated. 
3.4.2. 
Sample Size in Phase 1 Part 2 
Once an INCAGN01876 dose cohort in Treatment Group A is deemed tolerable, up to 
6 evaluable subjects will be enrolled in Treatment Group B at the same dose of INCAGN01876.  
For example, if 3.0 mg/kg of INCAGN01876 is tolerated in Treatment Group A, then 3.0 mg/kg 
will be explored in up to 6 evaluable subjects in Treatment Group B. 
3.4.3. 
Sample Size for Phase 2 
Phase 2 will further evaluate the safety, tolerability, preliminary efficacy, 
 
 of the immune therapy combinations as part of dose expansion cohorts in Treatment 
Groups C and D.  In Phase 2, a Simon 2-stage design will be run for each tumor type within a 
given treatment group. 
The sample size for each tumor type within a given treatment group will be guided by the Simon 
2-stage design.  The planned Simon 2-stage designs are summarized in Table 6.  Each Simon 
2-stage design will have a stopping rule to allow early termination of a particular cohort at the 
end of Stage 1 if there are insufficient responses observed, while enrolling enough subjects to 
predict possible target responses worthy of cohort expansion and potentially further evaluation in 
future studies. 
The individual Simon 2-stage designs run for each tumor type within each treatment group will 
have design parameters that are determined by historical response rates.  For the RCC and UC 
cohorts, the insufficient response rates are obtained from historical data, and the Simon 2-stage 
designs allowing early termination are based on ORR.  For the melanoma cohort, the insufficient 
response rate is obtained from historical data, and the primary endpoint for the Simon 2-stage 
design allows for early termination based on CRR.  The same Simon 2-stage design parameters 
will be used for the alternative dosing sequences represented by Treatment Groups C and D in 
the same tumor type.  For example, the RCC cohorts in Treatment Groups C and D will use the 
same Simon 2-stage parameters. 
In order to determine whether the target response rate (p1) is likely, an initial number of 
evaluable subjects (n1 subjects) will be treated at the MTD 
 and schedule of 
INCAGN01876 within the corresponding tumor type and treatment group and will be enrolled in 
a cohort (Stage 1).  If there are r1 or fewer responses in the cohort, it will be concluded that the 
true response rate is unlikely to be greater than or equal to the target rate, and no more subjects 
will be enrolled in that tumor type cohort for that treatment group in Stage 2.  In the cohorts in 
which greater than r1 responses are observed among the Stage 1 subjects, n2 additional evaluable 
subjects will be treated in Stage 2 to estimate the response rate.  At the end of Stage 2, if 
≤ r subjects have responded among the n evaluable subjects, the triplet combination dosing 
sequence will be declared nonpromising for that cohort.  In other words, after the study is 
finished, if there is a sufficient number of responses in the 2 stages combined, the triplet 
combination dosing sequence is considered promising; otherwise it is considered nonpromising.  




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4.1.3. 
Baseline Value 
Baseline is the last nonmissing measurement obtained before the first administration of 
INCAGN01876, pembrolizumab, or epacadostat, unless otherwise defined. 
When scheduled assessments and unscheduled assessments occur on the same day and time of 
the assessment or time of first dose is not available, use the following convention to determine 
baseline: 
 If both a scheduled and an unscheduled visit are available on the day of the first dose 
and the time is missing, use the scheduled assessment as baseline. 
 If all scheduled assessments are missing on the day of the first dose and an 
unscheduled assessment is available, use the unscheduled assessment as baseline. 
4.1.4. 
Handling of Missing and Incomplete Data 
In general, values for missing data will not be imputed unless methods for handling missing data 
are specified in this section or relevant sections. 
Partial disease/cancer diagnosis date will be handled as follows: 
 If only the day is missing, then the imputed day will be the first of the month. 
 If both the month and day are missing, then the imputed day and month will be 
01 JAN. 
 No imputation will be done if the date is completely missing. 
Missing or partial date of last dose will be handled as follows: 
 If only the day is missing, then the imputed date of the last dose will be the earlier 
date of the first day of the month or the date that the subject discontinued treatment. 
 Otherwise, the date that the subject discontinued treatment will be used as the date of 
the last dose. 
For relevant efficacy endpoints, partial death date will be imputed as follows: 
 If mmyyyy for the last contact date = mmyyyy for the death date, then the death date 
will be set to the day after the last contact date. 
 If mmyyyy for the last contact date < mmyyyy for the death date, then the death date 
will be set to the first day of the death month. 
 Otherwise, the partial death date will not be imputed. 
4.1.5. 
Cycle Length and Duration 
Cycle 1 Day 1 is the day that the first dose of study drug is administered.  Scheduled cycle length 
is 21 days.  Actual Day 1 of subsequent cycles will correspond with the first day of 
administration of INCAGN01876 in that cycle; thus, treatment cycles may become out of sync 
with the originally planned schedule and cycle length may be different from 21 days.  The date 
of the Day 1 of subsequent cycles recorded on the eCRF will be used as the Day 1 of the 
subsequent cycles. 


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4.2. 
Variable Definitions 
The following variables will only be calculated if not reported on the eCRF. 
4.2.1. 
Age 
Subject age will be calculated as the integer part of the number of years from date of birth to the 
date of signing the ICF, using the following formula: 
Age = integer part of (date of informed consent – date of birth + 1) / 365.25. 
4.2.2. 
Prior and Concomitant Medication 
Prior medication is defined as any nonstudy medication started before the first dose of 
INCAGN01876, pembrolizumab, or epacadostat. 
Concomitant medication is defined as any nonstudy medication that is started accordingly: 
 Before the date of first administration of INCAGN01876, pembrolizumab, or 
epacadostat and is ongoing throughout the study or ends on/after the date of first 
study drug administration. 
 On/after the date of first administration of INCAGN01876, pembrolizumab, or 
epacadostat and is ongoing or ends during the course of study drug. 
A prior medication could also be classified as "both prior and concomitant medication" if the end 
date is on or after first dose of INCAGN01876, pembrolizumab, or epacadostat.  In the listing, it 
will be indicated whether a medication is prior-only, concomitant-only, or both prior and 
concomitant medication. 
For the purposes of analysis, all medications will be considered concomitant medications unless 
the medications can unequivocally be defined as not concomitant. 
5. 
STATISTICAL METHODOLOGY 
5.1. 
General Methodology 
Unless otherwise noted, SAS® software (SAS Institute Inc, Cary, NC; v9 or later) will be used 
for the generation of all tables, graphs, and statistical analyses.  Descriptive summaries for 
continuous variables will include, but not be limited to, the number of observations, mean, 
standard deviation, median, minimum, and maximum.  Descriptive summaries for categorical 
variables will include the number and percentage of subjects in each category. 
5.2. 
Treatment Groups 
This is an open-label, nonrandomized, Phase 1/2 study to determine the safety, tolerability, and 
efficacy of INCAGN01876 when given in combination with immune therapies. 




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6. 
BASELINE, EXPOSURE, AND DISPOSITION VARIABLES AND 
ANALYSES 
Appendix A provides a list of data displays.  Sample data displays will be provided in a separate 
document. 
6.1. 
Baseline and Demographics, Physical Characteristics, and Disease 
History 
6.1.1. 
Demographics 
The following demographics will be summarized for the FAS population
 
:  age, sex, race, ethnicity, weight, 
and height. 
6.1.2. 
Baseline Disease Characteristics and Disease History 
Disease histology, stage at initial diagnosis, current stage, and primary site of disease will be 
summarized for all subjects in the FAS population
 
.  ECOG performance status will also be 
summarized for all subjects in the FAS population
 
. 
6.1.3. 
Prior Therapy 
Number of prior systemic cancer therapy regimens will be summarized for all subjects in the 
FAS population
 
.  Regimen name, component drugs, start and stop date, route of the medication, 
purpose of the regimen, best response, reason for discontinuation, and date of 
relapse/progression will be listed. 
Number of subjects who received prior radiation and number of subjects who had prior surgery 
or surgical procedure for the malignancies under study will be listed. 
6.1.4. 
Medical History 
Medical history recorded on the eCRF will be presented in the subject data listings. 
6.2. 
Disposition of Subjects 
The number and percentage of subjects who were enrolled, treated, discontinued study treatment 
with a primary reason for discontinuation, and withdrawn from the study with a primary reason 
for withdrawal will be summarized for the FAS population 
 
. 
6.3. 
Protocol Deviations 
Protocol deviations recorded on the eCRF will be presented in the subject data listings. 


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6.4. 
Exposure 
6.4.1. 
Exposure for INCAGN01876 
For subjects in the FAS population, exposure to INCAGN01876 will be summarized 
descriptively as the following: 
 Total number of infusions:  Total number of infusions per subject with a nonzero 
dose of INCAGN01876. 
6.4.2. 
Exposure for Pembrolizumab 
The exposure for pembrolizumab will be summarized the same as that for INCAGN01876 in 
Section 6.4.1. 
6.4.3. 
Exposure for Epacadostat 
For subjects in the FAS population, exposure to epacadostat will be summarized descriptively as 
the following: 
 Duration of treatment (days):  Date of last dose of epacadostat – date of first dose 
of epacadostat + 1. 
6.5. 
Prior and Concomitant Medication 
For subjects in the FAS population, prior medications and concomitant medications will be 
coded using the WHO Drug Dictionary and summarized by WHO drug class and WHO drug 
term for the FAS population
 
.  Results will be summarized as number and percentage of subjects 
with prior and concomitant medications by PT and WHO drug class. 


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7. 
EFFICACY 
Appendix A provides a list of data displays.  Sample data displays will be provided in a separate 
document. 
7.1. 
General Considerations 
Due to the early discontinuation of study enrollment, only ORR using RECIST v1.1 will be 
summarized for the FAS population
 
. 
7.2. 
Analysis of the Objective Response Rate 
7.2.1. 
Objective Response Rate and Best Overall Response by RECIST v1.1 
Best overall response is defined as the best response recorded postbaseline prior to and including 
the first PD, in the order of CR, PR, SD, PD, and NE.  In the case of SD, measurements must 
meet the SD criteria at least once after the date of first dose of study treatment at a minimum 
interval of 56 (63 – 7) days.  Subjects who fail to meet this criterion will have a best overall 
response of PD if the next available assessment indicates PD or NE if there is no additional 
assessment available. 
Objective response rate, defined as the proportion of subjects with overall responses, will be 
summarized for all subjects in the FAS population
 
. 
For subjects with measurable disease at baseline, the RECIST v1.1 assessment criteria presented 
in Table 7 can be used to determine the overall disease status at a given timepoint based on the 
target lesion, nontarget lesion, and new lesion assessment. 
Table 7: 
RECIST v1.1 Evaluation Criteria for Overall Response:  Measurable Disease 
at Baseline 
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD or NE 
No 
PR 
SD 
Non-PD or NE 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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8. 
SAFETY AND TOLERABILITY 
Appendix A provides a list of data displays.  Sample data displays will be provided in a separate 
document. 
8.1. 
General Considerations 
Summary tables may be replaced with listings when appropriate.  For instance, an AE frequency 
table may be replaced with a listing if it only contains a few unique PTs reported on relatively 
few subjects. 
Unless otherwise stated, table summaries will be limited to TEAEs. 
8.2. 
Adverse Events 
8.2.1. 
Adverse Event Definitions 
A TEAE is any AE either reported for the first time or worsening of a pre-existing event after 
first dose of study drug.  Analysis of AEs (as discussed below) will be limited to TEAEs, but 
data listings will include all AEs regardless of their timing in relation to study drug 
administration. 
Adverse events will be tabulated by MedDRA PT and SOC.  Severity of AEs will be graded 
using the NCI CTCAE.  The CTCAE v4.03 is used for this study.  The CTCAE reporting 
guidelines and grading details are available on the Cancer Therapy Evaluation Program website. 
The subset of AEs considered by the investigator to be related to INCAGN01876, 
pembrolizumab, or epacadostat will be considered to be treatment-related AEs.  If the 
investigator does not specify the relationship of the AE to study treatment, the AE will be 
considered to be treatment-related.  The incidence of AEs and treatment-related AEs will be 
tabulated.  In addition, serious AEs will also be tabulated. 
A grading (severity) scale is provided for each AE term.  If the toxicity is not included in the 
CTCAE v4.03 criteria, it will be rated on a scale of 1 to 5 as follows:  1 = mild, 2 = moderate, 
3 = severe, 4 = life threatening, and 5 = death related to AE.  All toxicities will be graded based 
on the worst level reached, not the level they may have reached if they had not been treated.  
When the intensity of an AE changes over time for a reporting period (eg, between visits), each 
change in intensity will be collected as an AE until the event resolves.  Only the worst grade will 
be reported in AE summaries.  Also, the Grade 3 or higher AEs will be reported in a listing. 
Any missing onset date, causality, or severity must be queried for resolution.  Unresolved 
missing causality and severity will be handled according to the following rules: 
 An unresolved missing causality will be considered treatment-related. 
 An unresolved missing severity will be identified as an unknown severity.  
For purposes of analysis, all AEs will be considered TEAEs unless the AE can unequivocally be 
defined as not treatment-emergent. 


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8.2.2. 
Dose-Limiting Toxicities 
The number of subjects with DLTs and the type of DLT will be listed.  An AE for a subject will 
be identified as a DLT if the event is recorded as a Protocol-defined DLT on the AE eCRF. 
8.2.3. 
Adverse Events of Special Interest 
8.2.3.1. 
Immune-Related Adverse Events 
The subjects with irAEs and type of irAE will be listed.  Adverse event terms will be reviewed 
periodically without respect to treatment group by the medical monitor and clinical scientist to 
determine which AE terms correspond to irAEs.  This periodic review may also occur after 
database lock.  The medical monitor and clinical scientist will also review investigator-reported 
AEs to determine whether they qualify as irAEs.  For example, a rash will be counted as an irAE 
even if the investigator did not report it as an irAE. 
8.2.3.2. 
Infusion-Related Reactions 
Infusion-related reactions, defined as AEs that are identified as infusion-related reaction by the 
investigator on the infusion-related reaction case report form, will be listed.  The listing will 
include the treatment group, dose level, cycle number, study day, date of onset of AE, date of the 
associated infusion, and signs and symptoms of the infusion related reaction. 
8.2.4. 
Adverse Event Summaries 
An overall summary of AEs for the FAS population
 
 will include: 
 Number (%) of subjects reporting any TEAEs 
 Number (%) of subjects reporting any serious TEAEs 
 Number (%) of subjects reporting any Grade 3 or higher TEAEs 
 Number (%) of subjects reporting any TEAEs related to INCAGN01876 
 Number (%) of subjects reporting any TEAEs related to pembrolizumab 
 Number (%) of subjects reporting any TEAEs related to epacadostat 
 Number (%) of subjects who permanently discontinued study treatment because of 
TEAEs 
 Number (%) of subjects who had a fatal TEAE 
The following summaries will be produced by MedDRA term: 
 Summary of TEAEs by SOC and PT 
 Summary of TEAEs by PT in decreasing order of frequency 
 Summary of TEAEs by SOC, PT, and maximum severity 
 Summary of Grade 3 or higher TEAEs by SOC and PT 
 Summary of INCAGN01876 treatment-related AEs by SOC and PT 


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 Summary of pembrolizumab treatment-related AEs by SOC and PT 
 Summary of epacadostat treatment-related AEs by SOC and PT 
 Summary of TEAEs with a fatal outcome by SOC and PT 
 Summary of serious TEAEs by SOC and PT 
 Summary of serious TEAEs by PT in descending order of frequency 
 Summary of nonserious TEAEs by SOC and PT 
 Summary of INCAGN01876 treatment-related serious TEAEs by SOC and PT 
 Summary of pembrolizumab treatment-related serious TEAEs by SOC and PT 
 Summary of epacadostat treatment-related serious TEAEs by SOC and PT 
 Summary of TEAEs leading to discontinuation of study treatment by SOC and PT 
8.3. 
Clinical Laboratory Tests 
8.3.1. 
Laboratory Value Definitions 
Laboratory baseline values will be determined according to Section 4.1.3.  If there are multiple 
values that meet the criteria for baseline, additional rules may be provided after consultation with 
the medical monitor to delineate which value will be defined as baseline. 
Laboratory test values outside the normal range will be assessed for severity based on CTCAE 
grade or similar criteria where clinical intervention is required for CTCAE grading.  The shift 
tables relative to baseline will be tabulated. 
8.3.2. 
Laboratory Value Summaries 
All test results and associated normal ranges from local laboratories will be reported in SI units.  
All tests with numeric values will have a unique unit per test.  Any laboratory test results and 
associated normal ranges from local laboratories will be converted to SI units.  For the limited 
number of cases where the associated normal ranges from a local laboratory cannot be obtained 
despite due diligence, if query is unsuccessful at resolving the issue and analysis is mandatory 
then the clinical scientist and medical monitor can provide a suitable normal range to be used in 
determining CTC grading and flags for above and below normal. 
When there are multiple laboratory nonmissing values for a subject's particular test within a visit 
window, the convention described in Table 8 will be used to determine the record used for 
by-visit tabulations and summaries. 
Table 8: 
Identification of Records for Postbaseline By-Visit Summaries 
Priority 
Laboratory Visit 
Proximity to Visit 
Window 
Tiebreaker 
1 
Scheduled 
In-window 
Use smallest laboratory 
sequence number 
2 
Unscheduled 
In-window 
3 
Scheduled 
Out-of-window 


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For test results that will be summarized with available normal ranges, the number and percentage 
of subjects with the laboratory values being low (but never high), normal, high (but never low), 
and both low and high will be calculated for each test.  This shift summary will be produced for 
each test for the FAS population.  The denominator for the percentage calculation will use the 
number of subjects in the baseline category (ie, low, high, normal, missing) as the denominator 
for the percentage in each of the categories during the treatment period. 
In cases where differentials of hematology parameters are obtained without corresponding 
absolute count data, efforts will be made to investigate if the conversion to an absolute value will 
lead to additional abnormalities.  This will be discussed with the clinical team regarding 
appropriate documentation and action. 
8.4. 
Vital Signs 
Values at each scheduled visit including systolic blood pressure, diastolic blood pressure, pulse, 
respiration rate, body temperature, and pulse oximetry will be listed. 
Criteria for clinically notable vital sign abnormalities are defined in Table 9.  The abnormal 
values for subjects exhibiting clinically notable vital sign abnormalities will be listed along with 
their assigned treatment group.  Alert vital signs are defined as an absolute value outside the 
defined range and percentage change from baseline greater than 25%.  The abnormal values for 
subjects exhibiting alert vital sign abnormalities will be listed. 
Table 9: 
Criteria for Clinically Notable Vital Sign Abnormalities 
Parameter 
High Threshold 
Low Threshold 
Systolic blood pressure 
> 155 mmHg 
< 85 mmHg 
Diastolic blood pressure 
> 100 mmHg 
< 40 mmHg 
Pulse 
> 100 bpm 
< 45 bpm 
Temperature 
> 38ºC 
< 35.5ºC 
Respiratory rate 
> 24 breaths/min 
< 8 breaths/min 
Pulse oximetry 
NA 
< 90 
8.5. 
Electrocardiograms 
Twelve-lead ECGs including PR, QRS, QT, QTcF, QTcB, RR, and JTc intervals will be 
obtained for each subject during the study.  Values at each scheduled visit will be listed for each 
ECG parameter.  Baseline will be determined as the average of all nonmissing values before the 
first administration of INCAGN01876, pembrolizumab, or epacadostat. 
Criteria for clinically notable ECG abnormalities are defined in Table 10.  Subjects exhibiting 
clinically notable ECG abnormalities will be listed with study visit and assigned treatment group.  
Abnormal values for subjects with alert ECG values, defined as both the absolute value and the 
percentage change from baseline being outside normal ranges, will be identified and listed. 


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Table 10: 
Criteria for Clinically Notable Electrocardiogram Abnormalities 
Parameter 
High Threshold 
Low Threshold 
QTcF  
> 460 ms 
< 295 ms 
PR 
> 220 ms 
< 75 ms 
QRS  
> 120 ms 
< 50 ms 
QT 
> 500 ms 
< 300 ms 
RR  
> 1330 ms 
< 600 ms 
JTc 
> 340 ms 
< 245 ms 
QTcF = Fridericia correction. 
Note:  QTcB uses the same thresholds as those for QTcF. 
8.6. 
Physical Examinations 
Weight at each scheduled visit will be obtained and listed for each subject during the study. 
9. 
INTERIM ANALYSES 
Since study enrollment discontinued prior to the interim analyses, no interim analyses will be 
conducted. 




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11. 
REFERENCES 
Simon R. Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989;10:1-10. 


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APPENDIX A. PLANNED TABLES AND FIGURES 
Due to the early termination of study enrollment, a synoptic CSR will be provided.  This 
appendix provides a list of the planned tables and listings for the synoptic CSR.  Standard tables 
will follow the conventions in the Standard Safety Tables initial version.  Shells are provided for 
nonstandard tables.  In-text tables are not needed for the synoptic CSR. 
The list of tables and listings and the shells are to be used as guidelines.  Modifications of the list 
or shells that do not otherwise affect the nature of the analysis will not warrant an amendment to 
the SAP. 
Tables 
Table No. 
Title 
Population 
Standard 
Baseline and Demographic Characteristics 
1.1  Disposition 
1.1.1 
Analysis Populations 
FAS 
X 
1.1.2 
Summary of Subject Disposition 
FAS 
X 
1.2  Demography 
1.2.1 
Summary of Demographics 
FAS 
X 
1.3  Baseline Characteristics 
1.3.1 
Summary of Baseline Disease Characteristics and 
Disease History 
FAS 
 
1.4  Prior Medication and Concomitant Medication 
1.4.1 
Summary of Prior Cancer Therapy 
FAS 
 
1.4.2 
Summary of Prior Medications 
FAS 
X 
1.4.3 
Summary of Concomitant Medications 
FAS 
X 
Efficacy 
2.1.1 
Summary of Objective Response Rate Under 
RECIST v1.1 
Response Evaluable 
 
Safety 
3.1  Dose Exposure 
3.1.1 
Summary of Drug Exposure to INCAGN01876 
INCAGN01876 
FAS 
 
3.1.2 
Summary of Drug Exposure to Pembrolizumab 
Pembrolizumab 
FAS 
 
3.1.3 
Summary of Drug Exposure to Epacadostat 
Epacadostat 
FAS 
 
3.2  Adverse Events 
3.2.1 
Overall Summary of Treatment-Emergent Adverse 
Events 
FAS 
X 
3.2.2 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
FAS 
X 
3.2.3 
Summary of Treatment-Emergent Adverse Events by 
MedDRA Preferred Term in Decreasing Order of 
Frequency 
FAS 
X 
3.2.4 
Summary of Treatment-Emergent Adverse Events by 
MedDRA System Organ Class, Preferred Term, and 
Maximum Severity 
FAS 
X 
3.2.5 
Summary of Grade 3 or Higher Treatment-Emergent 
Adverse Events by MedDRA System Organ Class and 
Preferred Term 
FAS 
X 


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Table No. 
Title 
Population 
Standard 
3.2.6.1 
Summary of INCAGN01876 Treatment-Related 
Adverse Events by MedDRA System Organ Class and 
Preferred Term 
INCAGN01876 
FAS 
X 
3.2.6.2 
Summary of Pembrolizumab Treatment-Related 
Adverse Events by MedDRA System Organ Class and 
Preferred Term 
Pembrolizumab 
FAS 
X 
3.2.6.3 
Summary of Epacadostat Treatment-Related Adverse 
Events by MedDRA System Organ Class and Preferred 
Term 
Epacadostat 
FAS 
X 
3.2.7 
Summary of Treatment-Emergent Adverse Events 
With a Fatal Outcome by MedDRA System Organ 
Class and Preferred Term 
FAS 
X 
3.2.8 
Summary of Serious Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred 
Term 
FAS 
X 
3.2.9 
Summary of Serious Treatment-Emergent Adverse 
Events by Preferred Term in Decreasing Order of 
Frequency 
FAS 
X 
3.2.10
a 
Summary of Nonserious Treatment-Emergent Adverse 
Events by MedDRA System Organ Class and Preferred 
Term 
FAS 
X 
3.2.11.1 
Summary of INCAGN01876 Treatment-Related 
Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
INCAGN01876 
FAS 
X 
3.2.11.2 
Summary of Pembrolizumab Treatment-Related 
Serious Treatment-Emergent Adverse Events by 
MedDRA System Organ Class and Preferred Term 
Pembrolizumab 
FAS 
X 
3.2.11.3 
Summary of Epacadostat Treatment-Related Serious 
Treatment-Emergent Adverse Events by MedDRA 
System Organ Class and Preferred Term 
Epacadostat 
FAS 
X 
3.2.12 
Summary of Treatment-Emergent Adverse Events 
Leading to Discontinuation of Study Treatment by 
MedDRA System Organ Class and Preferred Term 
FAS 
X 
3.3  Laboratory 
3.3.1  
Shift Summary of Hematology Laboratory Values in 
CTC Grade - To the Worst Abnormal Value  
FAS 
X 
3.3.2 
Shift Summary of Chemistry Laboratory Values in 
CTC Grade - To the Worst Abnormal Value 
FAS 
X 
a Nonserious TEAE table will be generated for the study with expressed purpose of clinical trial results posting. 


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Listings 
Listing No. 
Title 
2.1  Discontinued Subjects (Subject Disposition) 
2.1.1 
Subject Enrollment and Disposition Status 
2.1.2 
Subject Inclusion and Exclusion Criteria Violations 
2.2  Protocol Deviations 
2.2.1 
Protocol Deviations and Violations 
2.3  Data Excluded From
, Efficacy, and/or Safety Analyses 
2.3.1 
Analysis Population 
2.4  Demography and Baseline (Including Prior and Concomitant Medications) 
2.4.1 
Demographic Characteristics 
2.4.2 
Baseline Disease Characteristics for Solid Tumor Types 
2.4.3 
Disease History 
2.4.4 
Prior Radiation Treatment 
2.4.5 
Prior Systemic Therapy 
2.4.6 
Prior Surgery or Surgical Procedure 
2.4.7 
Medical History 
2.4.8 
Prior and Concomitant Medication 
2.6  Efficacy 
2.6.1 
Best Overall Response Under RECIST v1.1 
2.6.2 
ECOG Performance Status 
2.7  Adverse Events (and Exposure) 
2.6.1.1 
Study Drug Administration for INCAGN01876  
2.6.1.2 
Study Treatment Administration for Pembrolizumab 
2.6.1.3 
Study Treatment Administration for Epacadostat 
2.6.2 
Adverse Events  
2.6.3 
Dose-Limiting Toxicities 
2.6.4 
Serious Adverse Events 
2.6.5 
Fatal Adverse Events 
2.6.6 
Adverse Events Leading to Discontinuation of INCAGN01876 
2.6.7 
Immune-Related Adverse Events 
2.6.8 
Infusion Reactions 
2.8  Laboratory Data 
2.7.1 
Clinical Laboratory Values - Hematology 
2.7.2 
Clinical Laboratory Values - Chemistry 
2.7.3 
Clinical Laboratory Values - Coagulation 
2.7.4 
Clinical Laboratory Values - Urinalysis 
2.7.5 
Clinical Laboratory Values - Endocrine 
2.7.6 
Clinical Laboratory Values - Serology 
2.7.7 
Pregnancy 
2.9  Vital Signs 
2.8.1 
Vital Signs 
2.10  ECGs 
2.9.1 
12-Lead ECG Values 
2.11  Physical Examinations 
2.11.1 
Body Weight