A Phase 1/2, Open-Label, Dose-Escalation, Safety, Tolerability, and Efficacy Study of Epacadostat and Nivolumab in Combination With Immune Therapies in Subjects With Advanced or Metastatic Malignancies (ECHO-208)
Phase: PHASE1
Conditions: Solid Tumors
Sponsor: Incyte Corporation

 
Official Title: 
A Phase 1/2, Open-Label, Dose-Escalation, Safety, Tolerability, and Efficacy 
Study of Epacadostat and Nivolumab in Combination With Immune 
Therapies in Subjects With Advanced or Metastatic Malignancies (ECHO-
208) 
NCT Number: 
NCT03347123 
 
Document Date: 
 
Clinical Study Protocol version 2: 05 December 2018 
 
 
 
 
 
 
 
 

Incyte Corporation 
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Protocol INCB 24360-208 Am 2 
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Clinical Study Protocol 
 
INCB 24360-208 
A Phase 1/2, Open-Label, Dose-Escalation, Safety, Tolerability, and 
Efficacy Study of Epacadostat and Nivolumab in Combination With 
Immune Therapies in Subjects With Advanced or Metastatic 
Malignancies (ECHO-208) 
 
 
 
 
Product: 
Epacadostat (INCB024360) 
IND Number: 
135,201 
EudraCT Number: 
2017-001743-12   
Phase of Study: 
1/2 
Sponsor: 
 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
12 JUL 2017 
Amendment (Version) 1:  
31 JUL 2017 
Amendment (Version) 2:  
05 DEC 2018 
 
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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INVESTIGATOR'S AGREEMENT 
I have read the INCB 24360-208 Protocol Amendment 2 (dated 05 DEC 2018) 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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Overall Study Design:  
Note:  Amendment 2 will serve to close the study to further enrollment; the primary purpose of the 
amendment is to provide an updated assessment schedule for subjects enrolled to date (Treatment 
Group A only).  No subjects were enrolled into Treatment Group B. 
This is an open-label, nonrandomized, Phase 1/2 study to determine the safety, tolerability, and efficacy 
of epacadostat when given in combination with nivolumab and ipilimumab, and in combination with 
nivolumab and lirilumab.  The study will be conducted in 2 independent treatment groups:  Treatment 
Group A will evaluate the combination of epacadostat, nivolumab, and ipilimumab; Treatment Group B 
will evaluate the combination of epacadostat, nivolumab, and lirilumab.  Each treatment group will be 
investigated in 2 phases: 
• Phase 1 will consist of a standard 3 + 3 + 3 dose-escalation design to define the MTD or PAD of
epacadostat with nivolumab and ipilimumab (Treatment Group A) and with nivolumab and lirilumab
(Treatment Group B) in subjects with advanced or metastatic solid tumors; 
 and preliminary efficacy will also be explored during this portion.
• Phase 2 will evaluate the efficacy of the MTD or PAD of epacadostat when given in combination with
nivolumab and ipilimumab, and in combination with nivolumab and lirilumab, as determined in each
of the Phase 1 treatment groups in select solid tumors, and will further evaluate the safety, 
of the combinations.
Treatment Group A will enroll 2 tumor-specific expansion cohorts (Cohorts A1 and A2):  Cohort A1 will 
include subjects with unresectable or metastatic MEL who have not received prior systemic therapy for 
advanced or metastatic disease; Cohort A2 will include subjects with advanced or metastatic NSCLC who 
have received no more than 1 prior line of platinum-based chemotherapy therapy for advanced or 
metastatic disease.   
Treatment Group B will enroll 1 expansion cohort (Cohort B1); Cohort B1 will include subjects with 
recurrent or metastatic SCCHN who have received no more than 1 prior line of platinum-based 
chemotherapy for recurrent or metastatic disease. 
Phase 1 - Dose Escalation 
Dose escalation in Treatment Groups A and B will be conducted using a standard 3 + 3 + 3 design as per 
the dose-escalation schedule outlined in Table S1.  A minimum of 3 evaluable subjects will be enrolled in 
each treatment group beginning with Dose Level 1 (starting dose of epacadostat 50 mg twice daily [BID] 
in Treatment Groups A and B). 
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Phase 2 - Dose Expansion 
The Phase 2 dose expansion cohorts will begin when the MTD or PAD of epacadostat has been 
determined in Phase 1 for the respective treatment group.  This portion of the study will evaluate the 
efficacy of the MTD or PAD of epacadostat and will further evaluate the safety, 
 
 of the combinations.   
Treatment Group A will enroll 2 expansion cohorts in parallel: 
• Cohort A1:  Approximately 35 subjects with unresectable or metastatic MEL who have not received 
prior systemic treatment for advanced or metastatic disease.  Serial pretreatment and on-treatment 
biopsies are required for all subjects enrolled, if clinically feasible.  
• Cohort A2:  Approximately 35 subjects with advanced or metastatic NSCLC without known driver 
mutations (including EGFR, BRAF, ALK, and ROS1) who have received no more than 1 prior line of 
therapy for advanced or metastatic disease.  Serial pre-treatment and on-treatment biopsies are 
required for all subjects enrolled, if clinically feasible.   
Treatment Group B will enroll 1 expansion cohort: 
• Cohort B1:  Approximately 35 subjects with recurrent or metastatic SCCHN who have received no 
more than 1 prior line of platinum-based chemotherapy for recurrent or metastatic disease.  Serial 
pretreatment and on-treatment biopsies are required for all subjects enrolled, if clinically feasible.  
Enrollment into the Phase 2 expansion cohorts will begin when the MTD or PAD of epacadostat for the 
corresponding treatment group in Phase 1 has been determined; however, priority will be given to any 
open dose-escalation cohorts in Phase 1. 
In Phase 2 of the study, toxicities will continue to be monitored.  If the cumulative incidence of ≥ Grade 3 
immune-related AEs is > 40% after a cumulative minimum of 10 subjects have been enrolled into the 
expansion cohorts within each treatment group, further enrollment in those expansions will be interrupted 
until the sponsor, investigators, and regulatory authorities (if applicable) determine the appropriate course 
of action.  If an expansion cohort in a particular treatment group is discontinued because of toxicity, a 
new expansion may be initiated at a previously tested lower dose level of epacadostat. 
The sponsor may elect to prioritize enrollment to specific treatment groups or expansion cohorts based on 
emerging safety or efficacy data in collaboration with investigational sites. 
Study Population: 
Inclusion Criteria: 
Phase 1 only: 
• Subjects with histologically or cytologically confirmed locally advanced or metastatic solid tumors who 
have disease progression on or after treatment with available therapies that are known to confer clinical 
benefit, or who are intolerant to treatment, or who refuse standard treatment.   
Note:  Locally advanced disease must not be amenable to resection with curative intent.   
• Has received no more than 2 prior treatment regimens (including chemotherapy and/or targeted therapy; 
not including neoadjuvant and/or adjuvant therapy) for advanced or metastatic disease.  
• Has baseline core or excisional tumor archival biopsy specimen available or willingness to undergo a 
pretreatment biopsy to obtain the specimen.  Archival specimen must be a tumor block or 25 unstained 
slides (minimum of 20).  A formalin-fixed paraffin-embedded (FFPE) tumor tissue block is preferred.  
If a block is not available, a minimum of 20 to 25 unstained freshly cut slides may be submitted to the 
testing laboratory as specified Laboratory Manual.   
Note:  Unstained slides must have been prepared from an FFPE block obtained within 6 months before 
screening.  
 
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Key Exclusion Criteria: 
• Laboratory and medical history parameters not within the Protocol-defined range; all screening 
laboratory tests should be performed within 7 days of Cycle 1 Day 1.  If the screening laboratory tests 
outlined below were performed more than 7 days before Cycle 1 Day 1, the hematology, serum 
chemistry, and liver chemistry test results must be confirmed on Cycle 1 Day 1 before initiation of 
study treatment. 
− Absolute neutrophil count < 1.5 × 109/L. 
− Platelets < 100 × 109/L. 
− Hemoglobin < 9 g/dL or < 5.6 mmol/L (transfusion is acceptable to meet this criterion). 
− Serum creatinine ≥ 1.5 × institutional upper limit of normal (ULN), or measured or calculated 
creatinine clearance (CrCl) < 50 mL/min for subjects with creatinine levels > 1.5 × institutional ULN 
(glomerular filtration rate can also be used in place of CrCl). 
− Phase 1 only:  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥ 1.5 × 
institutional ULN. 
− Phase 2 only:  AST or ALT ≥ 2.5 × institutional ULN. 
− Total bilirubin ≥ 1.5 × institutional ULN or conjugated (direct) bilirubin ≥ institutional ULN.  If an 
institutional ULN for conjugated bilirubin is not available, then conjugated bilirubin should be < 40% 
of total bilirubin to be considered eligible. 
− International normalized ratio or prothrombin time > 1.5 × institutional ULN. 
− Activated partial thromboplastin time > 1.5 × institutional ULN unless subject is receiving 
anticoagulant therapy, as long as PTT is within therapeutic range of intended use of anticoagulants. 
− Phase 1 only:  Albumin ≤ 3.0 g/dL or with medical monitor approval.  
• Receipt of anticancer medications or investigational drugs within the following interval before the first 
administration of study drug: 
− ≤ 21 days for chemotherapy or targeted small-molecule therapy 
Note:  Use of bisphosphonates is permitted. 
− ≤ 28 days for previous monoclonal antibody used for anticancer therapy. 
Note:  Use of denosumab is permitted. 
− ≤ 28 days or 5 half-lives (whichever is longer) before Cycle 1 Day 1 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. 
• Previous radiotherapy within 7 days of Cycle 1 Day 1 (except for radiation to central nervous system 
(CNS), which requires a ≥ 28-day washout as described below).  Subjects must also not require chronic 
use of corticosteroids and must not have had radiation pneumonitis as a result of treatment.  
• 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 Cycle 1 Day 1 and any 
neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases 
or cerebral edema, and have not required steroids for at least 14 days before Cycle 1 Day 1. 
• Prior treatment with any immune checkpoint inhibitor (eg, anti–cytotoxic T-lymphocyte–associated 
protein 4 [CTLA-4], anti−programmed cell death protein 1/programmed cell death ligand 1 [anti–
PD-1/PD-L1], anti−PD-2/PD-L2, anti−killer cell immunoglobulin-like receptor, and any other antibody 
or drug specifically targeting T-cell costimulation) and/or an IDO inhibitor.  Subjects who have 
received experimental vaccines or other immune therapies should be discussed with the medical 
monitor to confirm eligibility. 
Note:  Subjects in Cohort A1 who received adjuvant anti−CTLA-4 therapy and had disease progression 
≥ 6 months after completion of planned treatment may enroll.  
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• Any unresolved toxicity > Grade 1 from previous anticancer therapy, except for stable chronic toxicities 
not expected to resolve, such as peripheral neurotoxicity, alopecia, and fatigue. 
• Subjects who are receiving an immunologically based treatment for any reason, including chronic use of 
systemic steroid or at doses ≥ 10 mg/day prednisone equivalent within 7 days before the first dose of 
study drug.  Use of inhaled or topical steroids or systemic corticosteroids < 10 mg prednisone 
equivalent is permitted. 
• Receipt of a live vaccine within 30 days of planned start of study therapy. 
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 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. 
• Active infection requiring systemic therapy. 
• Subjects with any active or inactive autoimmune disease or syndrome (eg, rheumatoid arthritis, 
moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) that has required systemic 
treatment in the past 2 years or who are receiving systemic therapy for an autoimmune or inflammatory 
disease (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).   
Note:  Exceptions include subjects with vitiligo or resolved childhood asthma/atopy, hypothyroidism 
stable on hormone replacement, controlled asthma, or Type I diabetes, Graves' disease, or Hashimoto's 
disease that are treated and controlled, or with medical monitor approval. 
• Evidence of interstitial lung disease or active, noninfectious pneumonitis, including symptomatic and/or 
pneumonitis requiring treatment.  
• History of organ transplant that requires use of immunosuppressive therapy. 
• Has known history of or is positive for hepatitis B (hepatitis B surface antigen [HbsAg] reactive) or 
hepatitis C.  
− Hepatitis B virus DNA must be undetectable and HBsAg negative at the screening visit. 
− Hepatitis C antibody testing is allowed for screening purposes in countries where hepatitis C virus 
(HCV) RNA is not part of standard of care.  In these cases, HCV antibody−positive subjects will be 
excluded.   
− Subjects who have had definitive treatment for HCV are permitted if HCV RNA is undetectable at the 
screening visit. 
Note:  Testing must be performed to determine eligibility.  
• Known history of human immunodeficiency virus (HIV; HIV 1/2 antibodies). 
• History or presence of an abnormal ECG that, in the investigator's opinion, is clinically meaningful.  
Screening QTc interval > 480 milliseconds is excluded (corrected by Fridericia or Bazett formula).  In 
the event that a single QTc is > 480 milliseconds, the subject may be enrolled if the average QTc for 
3 consecutive ECGs is < 480 milliseconds.  For subjects with an intraventricular conduction delay (QRS 
interval > 120 milliseconds), 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. 
• Clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 
6 months of Cycle 1 Day 1, New York Heart Association Class III or IV congestive heart failure.  
Medically controlled arrhythmia stable on medication is permitted.  
• Bleeding associated with tumors that invade or are adjacent to major blood vessels, as shown 
unequivocally by imaging studies, or history of bleeding related to disease under study within 3 months 
of enrollment. 
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• History or current evidence of any condition, therapy, or laboratory abnormality that might confound 
the results of the study, interfere with the subject's participation for the full duration of the study, or is 
not in the best interest of the subject to participate, in the opinion of the treating investigator. 
• Women who are pregnant or breastfeeding. 
Epacadostat, Dosage, and Mode of Administration:   
In Phase 1, the dose of epacadostat will be dependent on treatment group and dose level assignment.  In 
Phase 2, the dose of epacadostat will be dependent upon the MTD or PAD determined in Phase 1.   
Epacadostat is an investigational agent and will be self-administered BID orally beginning on Cycle 1 
Day 1 and continuously thereafter for both treatment groups.  All BID doses will be taken in the morning 
and evening, approximately 12 hours apart without regard to food.  If a dose is missed by more than 
4 hours, then that dose should be skipped and the next scheduled dose should be taken at the usual time. 
Note: Subjects who are ongoing on study treatment as of the date of Amendment 2 may discontinue 
epacadostat at the discretion of the treating investigator.  
Combination Therapy, Dosage, and Mode of Administration: 
Treatment Group A: 
Nivolumab will be administered as a 240 mg IV infusion over 30 minutes (± 5 minutes) on Day 1 of each 
cycle, until loss of clinical benefit.  Nivolumab will be administered after epacadostat and will be 
administered starting with Cycle 1 for all subjects.  Intrasubject dose escalation of nivolumab is not 
allowed.  
Ipilimumab will be administered as a 1 mg/kg IV infusion over 30 minutes (± 5 minutes) on Day 1 of 
Cycle 1 and then Day 1 of every third cycle thereafter (ie, Cycle 4, Cycle 7, etc).  Ipilimumab will be 
administered after nivolumab on visit days when both agents are given.  Intrasubject dose escalation of 
ipilimumab is not allowed. 
Treatment Group B: 
Nivolumab will be administered as a 240 mg IV infusion over 30 minutes (± 5 minutes) on Day 1 of each 
cycle until loss of clinical benefit.  Nivolumab will be administered after epacadostat and will be 
administered starting with Cycle 1 for all subjects.  Intrasubject dose escalation of nivolumab is not 
allowed.  
Lirilumab will be administered as a 240 mg IV infusion over 60 minutes (± 5 minutes) on Day 1 of 
Cycle 1 and then Day 1 of every other cycle thereafter (ie, Cycle 3, Cycle 5, etc).  Lirilumab will be 
administered after nivolumab on visit days when both agents are given.  Intrasubject dose escalation of 
lirilumab is not allowed. 
Treatment Cycles and Duration of Treatment: 
Study treatment will be administered in continuous 14-day cycles.  Subjects will continue to receive study 
treatment for up to 2 years as long as the subject is deriving benefit and has not met any of the 
Protocol-defined conditions for treatment discontinuation.  Intrasubject dose-escalation is not permitted. 
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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
LIST OF ABBREVIATIONS ........................................................................................................22 
1. 
INTRODUCTION ......................................................................................................25 
1.1. 
Background .................................................................................................................25 
1.1.1. 
The Role of the Immune System in Cancer and Overall Study Rationale .................25 
1.1.2. 
Inhibition of Indoleamine 2,3-Dioxygenase 1 as a Target for Cancer .......................25 
1.1.3. 
Inhibition of Killer Cell Immunoglobulin-Like Receptors as a Target for 
Cancer .........................................................................................................................26 
1.2. 
Overview of Epacadostat ............................................................................................27 
1.2.1. 
Risks From Epacadostat .............................................................................................27 
1.3. 
Overview of Lirilumab ...............................................................................................28 
1.3.1. 
Risks From Lirilumab .................................................................................................29 
1.4. 
Overview of Nivolumab .............................................................................................29 
1.4.1. 
Risks From Nivolumab ...............................................................................................29 
1.4.2. 
Risks From Nivolumab in Combination With Ipilimumab ........................................30 
1.4.3. 
Risks From Nivolumab in Combination With Lirilumab ...........................................30 
1.4.4. 
Risks From Nivolumab in Combination With Epacadostat .......................................30 
1.5. 
Overview of Ipilimumab .............................................................................................31 
1.5.1. 
Risks From Ipilimumab ..............................................................................................31 
1.5.2. 
Risks From Ipilimumab in Combination With Epacadostat .......................................31 
1.6. 
Overall Risk/Benefit Assessment of the Combination Regimens ..............................32 
1.7. 
Rationale for Dose and Schedule of the Combination Therapies ...............................33 
1.8. 
Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab ......................34 
1.9. 
Rationale for Efficacy Endpoints................................................................................35 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................37 
3. 
SUBJECT ELIGIBILITY ...........................................................................................39 
3.1. 
Subject Inclusion Criteria ...........................................................................................39 
3.2. 
Subject Exclusion Criteria ..........................................................................................41 
4. 
INVESTIGATIONAL PLAN .....................................................................................45 
4.1. 
Overall Study Design ..................................................................................................45 
4.1.1. 
Phase 1 – Dose Escalation ..........................................................................................46 
4.1.2. 
Phase 2 – Dose Expansion ..........................................................................................48 
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4.2. 
Measures Taken to Avoid Bias ...................................................................................48 
4.3. 
Number of Subjects ....................................................................................................49 
4.3.1. 
Planned Number of Subjects ......................................................................................49 
4.3.2. 
Replacement of Subjects .............................................................................................49 
4.4. 
Duration of Treatment and Subject Participation .......................................................49 
4.5. 
Overall Study Duration ...............................................................................................49 
4.6. 
Study Termination ......................................................................................................50 
5. 
TREATMENT ............................................................................................................50 
5.1. 
Treatment Assignment ................................................................................................50 
5.1.1. 
Subject Numbering and Treatment Assignment .........................................................50 
5.1.2. 
Randomization and Blinding ......................................................................................50 
5.2. 
Study Drugs ................................................................................................................51 
5.2.1. 
Epacadostat .................................................................................................................51 
5.2.1.1. 
Supply, Packaging, and Labeling ...............................................................................51 
5.2.1.2. 
Storage ........................................................................................................................51 
5.2.2. 
Nivolumab ..................................................................................................................51 
5.2.2.1. 
Description and Administration ..................................................................................51 
5.2.2.2. 
Supply, Packaging, and Labeling ...............................................................................51 
5.2.3. 
Ipilimumab ..................................................................................................................52 
5.2.3.1. 
Description and Administration ..................................................................................52 
5.2.3.2. 
Supply, Packaging, and Labeling ...............................................................................52 
5.2.4. 
Lirilumab ....................................................................................................................53 
5.2.4.1. 
Description and Administration ..................................................................................53 
5.2.4.2. 
Supply, Packaging, and Labeling ...............................................................................53 
5.3. 
Treatment Compliance ................................................................................................53 
5.4. 
Treatment Interruptions and Adjustments ..................................................................53 
5.4.1. 
Dose Modifications .....................................................................................................53 
5.4.2. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose ................54 
5.4.2.1. 
Management of Dose-Limiting Toxicities or Other Urgent Situations ......................55 
5.4.2.2. 
Follow-Up of Dose-Limiting Toxicities .....................................................................56 
5.4.3. 
Procedures for Cohort Review and Dose Escalation ..................................................56 
5.4.4. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Treatment ....................................................................................................................56 
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5.4.4.1. 
Epacadostat Dose Modifications ................................................................................56 
5.4.4.2. 
Nivolumab, Ipilimumab, and Lirilumab Dose Modifications ....................................57 
5.4.5. 
Management of Immune-Related Adverse Events .....................................................58 
5.4.5.1. 
Procedures and Guidelines for Pneumonitis ...............................................................60 
5.4.5.2. 
Procedures and Guidelines for Enterocolitis ..............................................................60 
5.4.5.3. 
Procedures and Guidance for Hepatitis ......................................................................62 
5.4.5.4. 
Procedures for Immune-Mediated Dermatitis ............................................................63 
5.4.5.5. 
Procedures for Immune-Mediated Neuropathies ........................................................63 
5.4.5.6. 
Procedures for Immune-Mediated Endocrinopathies .................................................64 
5.4.5.7. 
Procedures for Other Immune-Mediated Adverse Reactions, Including 
Ocular Manifestations .................................................................................................65 
5.4.6. 
Procedure for Subjects Exhibiting Serotonin Syndrome ............................................66 
5.4.7. 
Management of Infusion Reactions ............................................................................67 
5.4.8. 
Criteria for Permanent Discontinuation of Study Treatment ......................................69 
5.5. 
Withdrawal of Subjects From Study Treatment .........................................................69 
5.5.1. 
Withdrawal Criteria ....................................................................................................69 
5.5.1.1. 
Treatment After Initial Evidence of Radiologic Evidence of Disease 
Progression .................................................................................................................70 
5.5.2. 
Withdrawal Procedures ...............................................................................................72 
5.6. 
Concomitant Medications ...........................................................................................72 
5.6.1. 
Permitted Medications ................................................................................................72 
5.6.2. 
Restricted Medications ...............................................................................................73 
5.6.3. 
Prohibited Medications ...............................................................................................73 
6. 
STUDY ASSESSMENTS ..........................................................................................74 
6.1. 
Screening ....................................................................................................................83 
6.2. 
Treatment ....................................................................................................................83 
6.3. 
End of Treatment ........................................................................................................83 
6.4. 
Follow-Up ...................................................................................................................83 
6.4.1. 
Safety Follow-Up ........................................................................................................83 
6.5. 
End of Study ...............................................................................................................84 
6.6. 
Unscheduled Visits .....................................................................................................84 
7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES ...........................85 
7.1. 
Administration of Informed Consent Form ................................................................85 
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7.2. 
Interactive Response Technology Procedure ..............................................................85 
7.3. 
Demography and Medical History ..............................................................................85 
7.3.1. 
Demographics and General Medical History .............................................................85 
7.3.2. 
Disease Characteristics and Treatment History ..........................................................85 
7.4. 
Prior and Concomitant Medications and Procedures ..................................................85 
7.5. 
Safety Assessments .....................................................................................................86 
7.5.1. 
Adverse Events ...........................................................................................................86 
7.5.2. 
Physical Examinations ................................................................................................86 
7.5.2.1. 
Comprehensive Physical Examination .......................................................................86 
7.5.2.2. 
Targeted Physical Examination ..................................................................................86 
7.5.3. 
Vital Signs and Weight ...............................................................................................87 
7.5.4. 
12-Lead Electrocardiograms .......................................................................................87 
7.5.5. 
Laboratory Assessments .............................................................................................87 
7.5.5.1. 
Serum Chemistry ........................................................................................................88 
7.5.5.2. 
Liver Chemistry ..........................................................................................................88 
7.5.5.3. 
Hematology .................................................................................................................88 
7.5.5.4. 
Coagulation Panel .......................................................................................................88 
7.5.5.5. 
Endocrine Function .....................................................................................................88 
7.5.5.6. 
Urinalysis ....................................................................................................................88 
7.5.5.7. 
Hepatitis Screening Tests ...........................................................................................88 
7.5.5.8. 
Pregnancy Testing ......................................................................................................89 
7.6. 
Efficacy Assessments .................................................................................................89 
7.6.1. 
Assessment of Disease ................................................................................................89 
7.6.2. 
Initial Tumor Imaging .................................................................................................89 
7.6.3. 
Tumor Imaging During the Study...............................................................................90 
 
90 
 
90 
 
90 
 
91 
7.8. 
Other Study Procedures ..............................................................................................92 
7.8.1. 
Distribution of Subject Reminder Cards and Subject Diaries ....................................92 
8. 
SAFETY MONITORING AND REPORTING .........................................................92 
8.1. 
Adverse Events ...........................................................................................................92 
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8.1.1. 
Definitions ..................................................................................................................92 
8.1.2. 
Reporting ....................................................................................................................92 
8.2. 
Laboratory Test Abnormalities ...................................................................................94 
8.3. 
Serious Adverse Events ..............................................................................................94 
8.3.1. 
Definitions ..................................................................................................................94 
8.3.2. 
Reporting ....................................................................................................................95 
8.4. 
Emergency Unblinding of Treatment Assignment .....................................................96 
8.5. 
Pregnancy ...................................................................................................................96 
8.6. 
Warnings and Precautions ..........................................................................................96 
8.7. 
Safety Monitoring Committee ....................................................................................96 
8.8. 
Product Complaints ....................................................................................................97 
9. 
STATISTICS ..............................................................................................................97 
9.1. 
Study Populations .......................................................................................................97 
9.2. 
Selection of Sample Size ............................................................................................98 
9.2.1. 
Sample Size in Phase 1 ...............................................................................................98 
9.2.2. 
Sample Size in Phase 2 ...............................................................................................98 
9.3. 
Level of Significance ..................................................................................................98 
9.4. 
Statistical Analyses .....................................................................................................98 
9.4.1. 
Efficacy Analyses .......................................................................................................99 
9.4.2. 
Safety Analyses ..........................................................................................................99 
9.4.2.1. 
Adverse Events ...........................................................................................................99 
9.4.2.2. 
Clinical Laboratory Tests .........................................................................................100 
9.4.2.3. 
Vital Signs ................................................................................................................100 
9.4.2.4. 
Electrocardiograms ...................................................................................................100 
9.4.2.5. 
Adverse Events of Special Interest ...........................................................................101 
 
101 
 
101 
9.5. 
Analyses for the Safety Monitoring Committee .......................................................101 
9.6. 
Interim Analysis ........................................................................................................101 
10. 
ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ........................................................................................................102 
10.1. 
Investigator Responsibilities .....................................................................................102 
10.2. 
Accountability, Handling, and Disposal of Study Drug ...........................................103 
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10.3. 
Data Management .....................................................................................................104 
10.4. 
Data Privacy and Confidentiality of Study Records .................................................104 
10.5. 
Financial Disclosure .................................................................................................105 
10.6. 
Publication Policy .....................................................................................................105 
11. 
REFERENCES .........................................................................................................106 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS .............................................................................110 
APPENDIX B. MANAGEMENT GUIDELINES FOR IMMUNE-RELATED 
ADVERSE EVENTS................................................................................................111 
APPENDIX C. PHARMACOKINETIC ANALYTICAL PARAMETERS ............................119 
APPENDIX D. MONOAMINE OXIDASE INHIBITORS AND DRUGS 
ASSOCIATED WITH SIGNIFICANT MONOAMINE OXIDASE 
INHIBITORY ACTIVITY .......................................................................................120 
APPENDIX E. RESPONSE EVALUATION CRITERIA IN SOLID TUMORS V1.1 ...........121 
APPENDIX F. PROTOCOL AMENDMENT SUMMARY OF CHANGES ..........................122 
 
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LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this clinical study Protocol. 
Abbreviation 
Definition 
 
  
AE 
adverse event 
ALK 
anaplastic lymphoma kinase gene 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
BCG 
Bacillus Calmette-Guérin 
BID 
twice daily 
BRAF 
BRAF gene 
BMS 
Bristol-Myers Squibb 
CA 
cancer antigen 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL 
clearance 
CNS 
central nervous system 
CR 
complete response  
CrCl 
creatinine clearance 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
circulating tumor DNA 
CTLA-4 
cytotoxic T-lymphocyte–associated protein 4  
DC 
dendritic cell 
DLT 
dose-limiting toxicity 
DOR 
duration of response 
eDMC 
external Data Monitoring Committee 
EOT 
end of treatment 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR 
epidermal growth factor receptor gene 
EU 
European Union 
FDA 
Food and Drug Administration 
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Abbreviation 
Definition 
FFPE 
formalin-fixed paraffin-embedded 
GCP 
Good Clinical Practice 
GFR  
glomerular filtration rate 
GI 
gastrointestinal 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
HPV 
human papillomavirus 
ICF 
informed consent form  
ICH 
International Conference on Harmonisation 
 
 
 
 
IDO1 
indoleamine 2,3-dioxygenase 1 
IEC 
independent ethics committee 
IgG 
immunoglobulin G  
IN 
Investigator Notification 
INR 
international normalized ratio 
 
 
irAE 
immune-related adverse event 
IRB 
institutional review board 
 
 
IRT 
Interactive Response Technology 
 
 
IV 
intravenous 
JTc 
corrected JT interval 
KIR 
killer cell immunoglobulin-like receptor 
MAOI 
monamine oxidase inhibitor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEL 
melanoma 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NK 
natural killer 
nM 
nanomolar 
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Abbreviation 
Definition 
NSCLC 
non−small cell lung cancer 
ORR 
objective response rate 
 
 
PAD 
pharmacologically active dose 
PD 
progressive disease 
PD-1 
programmed cell death protein 1 
PDAC 
pancreatic ductal adenocarcinoma 
PD-L1 
programmed cell death ligand 1  
PD-L2 
programmed cell death ligand 2 
PET 
positron emission tomography  
PET/CT 
positron emission tomography - computed tomography 
PFS 
progression-free survival 
 
 
PR 
partial response 
PT 
prothrombin time 
Q2W 
once every 2 weeks 
Q3W 
once every 3 weeks 
Q4W 
once every 4 weeks 
Q6W 
once every 6 weeks 
QTc 
corrected QT interval 
RCC 
renal cell carcinoma 
RECIST v1.1 
Response Evaluation Criteria In Solid Tumors version 1.1 
ROS1 
ROS1 gene 
RP2D 
recommended Phase 2 dose 
SAE 
serious adverse event 
SCCHN 
squamous cell carcinoma of the head and neck 
SD 
stable disease 
SMC 
Safety Monitoring Committee 
SmPC 
summary of product characteristics 
SNRI 
serotonin norepinephrine reuptake inhibitor 
SS 
serotonin syndrome 
SSRI 
selective serotonin reuptake inhibitor  
SUSAR 
suspected unexpected serious adverse reaction 
Treg 
T regulatory cell 
ULN 
upper limit of normal 
US 
United States of America 
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1. 
INTRODUCTION 
1.1. 
Background 
1.1.1. 
The Role of the Immune System in Cancer and Overall Study Rationale 
The immune response is controlled by a series of checks and balances to allow for robust 
immune responses to pathogens while preventing either an excessive inflammatory event or an 
autoimmune response.  Through immune surveillance, the immune system has also been shown 
to recognize, attack, and destroy tumor cells (Wolchok and Saenger 2008).  Targeting the 
immune system as an anticancer strategy is a proven and effective approach for the treatment of 
many types of cancer, and immunotherapy is now an accepted standard of care in several tumor 
types.  Approved checkpoint inhibitors, including the PD-1–blocking antibody nivolumab and 
the CTLA-4 blocking antibody ipilimumab, allow for the immune response to continue to 
proliferate in spite of inhibitory signals.  Both of these agents have demonstrated antitumor 
activity when administered as monotherapy, and emerging data suggest that combined blockade 
of both targets results in an enhanced antitumor response (Larkin et al 2015, Hellmann et al 
2016, Goldman et al 2017); however, despite the encouraging activity observed with dual PD-1 
and CTLA-4 blockade, multiple other immune inhibitory mechanisms are present concurrently 
within the tumor microenvironment, suggesting that combination approaches targeting additional 
mechanisms of immune tolerance may be required for optimal therapeutic effect (Quezada and 
Peggs 2013).  Two promising approaches to overcoming these mechanisms include inhibition of 
IDO1 and blockade of KIR inhibitory receptors.  
1.1.2. 
Inhibition of Indoleamine 2,3-Dioxygenase 1 as a Target for Cancer 
IDO1 is a heme-containing, monomeric oxidoreductase that catalyzes the degradation of the 
essential amino acid tryptophan to N-formyl-kynurenine.  Kynurenine can be subsequently 
metabolized through a series of enzymatic steps to nicotinamide adenine dinucleotide.  IDO1 is 
the first rate-limiting enzyme in one of the catabolic pathways of tryptophan. 
The expression and activity profiles of IDO1 are distinct from those of tryptophan dioxygenase, 
an enzyme predominantly expressed in liver that catalyzes the same enzymatic reaction as IDO1 
and maintains proper tryptophan balance in response to dietary uptake.  In contrast to tryptophan 
dioxygenase, IDO1 is expressed in a variety of tissues, with particularly high levels found in 
areas of contact with potential sources of immune challenge (eg, gut, respiratory tract, placenta, 
spleen), consistent with a role for regulating tryptophan metabolism in a local microenvironment 
(Mellor and Munn 2004).  Within the immune system, IDO1 activity is specifically induced in 
cells such as DCs and macrophages at localized sites of inflammation (Munn and Mellor 2007). 
IDO1-driven oxidation of tryptophan results in a strong inhibitory effect on the development of 
T-cell–mediated responses by blocking T-cell activation and inducing T-cell apoptosis 
(Mellor et al 2003).  Both the reduction in local tryptophan levels and the production of 
tryptophan catabolites that are inhibitory to cell proliferation contribute to the 
immunosuppressive effects (Frumento et al 2002) such as DC maturation and T-cell growth 
arrest and cell death (Mellor and Munn 1999).  IDO1 activity also promotes the differentiation of 
naive T cells to cells with a regulatory phenotype (Treg; Fallarino et al 2006).  Because increased 
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Treg activity has been shown to promote tumor growth, and Treg depletion has been shown to 
allow an otherwise ineffectual antitumor immune response to occur (Zou 2006), IDO1-driven 
expansion of Tregs may provide an additional mechanism whereby IDO1 could promote an 
immunosuppressive environment. 
A critical role for IDO1 in immunomodulation has been confirmed in numerous animal models, 
including models of allograft tolerance, inflammation, and cancer (Mellor and Munn 2004).  
While IDO1 inhibition can exacerbate disease in models of autoimmune disorders 
(Mellor and Munn 2004), IDO1 null mice show no evidence of susceptibility to developing 
spontaneous autoimmunity or alterations in immune system development (Mellor et al 2003), 
suggesting that IDO1 inhibition, in a therapeutic setting, may produce minimal side effects in 
subjects without pre-existing autoimmune conditions. 
Within the context of cancer, there are several lines of evidence to suggest that IDO1 is a key 
regulator of the immunosuppressive mechanisms responsible for tumor escape from immune 
surveillance.  Several groups have demonstrated that blockade of IDO1 activity can directly 
influence the ability of tumor-bearing animals to reject tumors (Uyttenhove et al 2003, 
Muller et al 2005).  In addition, studies with 1-methyl-tryptophan demonstrate that IDO1 
inhibition dramatically increases the efficacy of various chemotherapeutic agents (eg, platinum 
compounds, taxane derivatives, cyclophosphamide) without increased toxicity (Muller et al 
2005).  Although the specific mechanisms responsible for this potentiation remain to be fully 
elucidated, the effects were not observed in T-cell–deficient animals, suggesting that the results 
may be the consequence of the disablement of immunosuppressive mechanisms that exist within 
the tumor microenvironment. 
Based on studies examining serum levels of tryptophan and kynurenine, IDO1 appears to be 
chronically activated in subjects with cancer, and IDO1 activation correlates with more extensive 
disease (Huang et al 2010, Weinlich et al 2007).  IDO1 has subsequently been found to be 
overexpressed by a wide variety of human tumor cell types, as well as by the DCs that localize to 
the tumor-draining lymph nodes (Uyttenhove et al 2003, Munn et al 2004).  Increased expression 
of IDO1 in tumor cells has been shown to be an independent prognostic variable for reduced OS 
in subjects with MEL, head and neck, ovarian, colorectal, and pancreatic cancers (Okamoto et al 
2005, Laimer et al 2011, Brandacher et al 2006, Ino et al 2006, Nakamura et al 2007, Witkiewicz 
et al 2008, Hamid et al 2009). 
Together, these results suggest that the IDO1 pathway is a key regulatory element responsible for 
the induction and maintenance of tumor immune tolerance.  Small molecule inhibitors of IDO1 
may provide an innovative and tractable method to treat malignancies.  
1.1.3. 
Inhibition of Killer Cell Immunoglobulin-Like Receptors as a Target for Cancer 
Natural killer cells constitute 15% of peripheral blood lymphocytes and play a vital role in the 
innate immune system's ability to combat viral infections and cancers by secreting 
immunoregulatory cytokines and by killing infected or transformed cells (Purdy et al 2009).  
Activation of NK cells, which is regulated by the balance of positive and negative receptor 
signaling, results in release of granules containing perforin and granzymes into target cells to 
induce apoptosis, as well as release of cytokines and chemokines into the micro-environment to 
recruit other immune cells (Purdy et al 2009, Kohrt et al 2014).  The concurrent release of 
cytokines and chemokines results in a microenvironmental milieu that recruits other immune 
cells.  
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Natural killer cells have the capability of binding every cell in the body (Ljunggren et al 1990).  
Binding of normal cells does not result in cytotoxic activity because of the ability of NK cells to 
simultaneously use a different set of receptors to bind major histocompatibility complex Class I 
molecules.  Binding to HLA is used as a mechanism to distinguish self from nonself, and this 
recognition controls the activational state of NK cells.  Thus, KIR/HLA interaction directly 
affects NK cell responsiveness.  There are both inhibitory and activating KIRs, which is a factor 
that results in diversity of KIR inheritance and expression.  KIR is also expressed on NK cells 
and a small subset of T cells (Uhrberg et al 2001).  Thus, mechanistically, blockade of inhibitory 
KIR could induce antitumor effects by allowing for NK cell (and possibly some T cell) 
activation. 
1.2. 
Overview of Epacadostat 
Epacadostat is a novel, potent, and selective inhibitor of the IDO1 enzyme in both human tumor 
cells and human DCs.  With the recent emergence of immune checkpoint inhibitors targeting 
PD-1, PD-L1, and CTLA-4, epacadostat is being investigated in combination with several of 
these agents across multiple tumor types in several ongoing Phase 1, 2, and 3 studies.  Refer to 
the current Investigator's Brochure for additional details regarding epacadostat (epacadostat IB) 
for preclinical and clinical study data. 
1.2.1. 
Risks From Epacadostat 
In the first-in-human study in subjects with refractory solid tumors (INCB 24360-101), 
epacadostat monotherapy was well-tolerated at doses ranging from 50 mg QD to 700 mg BID 
(Beatty et al 2013).  Twenty-five of the 52 subjects (48.1%) administered epacadostat had a 
single SAE.  The most frequently reported SAEs were disease progression (7.7%), followed by 
abdominal pain, nausea, and hypoxia (5.8% each).  Treatment-emergent AEs were reported in all 
subjects.  The most commonly reported treatment-related AEs were fatigue and nausea (48.1%).  
The incidence and severity of fatigue were not dose-related.  Two DLTs occurred:  1 DLT of 
radiation pneumonitis at the 300 mg dose level and 1 DLT of fatigue at the 400 mg BID dose 
level. 
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).  Based on 
preliminary studies in the rat, concentrations of epacadostat in the cerebrospinal fluid were below 
the quantifiable limit of detection (2 nM) after IV dosing, and total brain homogenate 
concentrations were approximately 15% of corresponding plasma concentrations.  In another 
preclinical study in rats, the effect of epacadostat on the brain extracellular fluid concentration of 
serotonin was evaluated either alone or when co-administrated with the mechanism of action 
inhibitor linezolid with or without the SSRI fluoxetine.  Both control conditions resulted in 2- to 
6-fold increases in serotonin.  In contrast, neither epacadostat alone or in combination with 
linezolid had an effect on the brain extracellular serotonin levels.  These preclinical data suggest 
that SS is unlikely after treatment with either epacadostat alone or in combination with MAOIs 
such as linezolid (Zhang et al 2016).  Therefore, taken together, epacadostat exhibits apparent 
limited penetration across the blood-brain barrier and is likely not associated with significant 
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effects on tryptophan metabolism in the brain that may affect brain serotonin levels.  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.  One subject from 
Study INCB 24360-202 reported chills, increased blood pressure, and temperature (all Grade 1) 
on Cycle 1 Day 1 and resolved within 1 week while dosing was stopped.  The subject was taking 
an SSRI, and although he experienced mild symptoms, the full constellation of SS was not 
observed, nor could it be ruled out.  The SSRI was discontinued and subject restarted epacadostat 
about 1 week later at the same dose level of 100 mg BID without further incident.  The other 
subject from Study INCB 24360-202 reported Grade 1 tremors and Grade 2 agitation on Cycle 4 
Day 5 and was assessed for SS on Cycle 5 Day 1.  The subject was not on an SSRI but on a 
medication for anxiety (alprazolam).  The events resolved and the dosing with epacadostat was 
interrupted for 1 week.  Re-treatment started with a lower dose of epacadostat at 50 mg BID PO 
from 75 mg BID on Cycle 5 Day 3.  Although the incidence is uncommon, use of MAOIs will be 
prohibited during the study.  A list of prohibited MAOIs is provided in Appendix D.  Subjects 
will be provided with a 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. 
1.3. 
Overview of Lirilumab  
Lirilumab is a fully human monoclonal antibody that is designed to act as a checkpoint inhibitor 
by blocking the interaction between KIR2DL-1,-2,-3 inhibitory receptors and their ligands 
facilitating activation of NK cells and potentially some subsets of T cells, ultimately leading to 
antitumor activity. 
Lirilumab is being studied as a potential immunotherapy alone and in combination with other 
agents in subjects with various hematologic malignancies and solid tumors.  As of 15 JUL 2016, 
a total of 377 subjects have been treated in 1 concluded, 1 terminated, and 3 ongoing clinical 
trials assessing safety, PK, biomarker modulation, and clinical activity.  The first is a 
monotherapy, dose-escalation, Phase 1 study to determine the MTD.  The second is a 
double-blind, placebo-controlled, Phase 2 study of lirilumab in subjects with acute myeloid 
leukemia who are in complete remission but ineligible for allogeneic transplant.  One-third of 
subjects in this study will receive placebo.  The third, fourth, and fifth are Phase 1/2 studies of 
lirilumab in combination with the anti–PD-1 antibody nivolumab, the anti–CTLA-4 antibody 
ipilimumab, and the SLAMF7 antibody elotuzumab, respectively, to determine whether 
coordinate modulation of the innate and adaptive immune systems results in greater clinical 
benefit.  Preliminary data from an initial cohort of subjects in a study exploring lirilumab with 
nivolumab suggest a strong signal of potential efficacy (Leidner et al 2016).  Specifically, 
preliminary data in 29 evaluable subjects with SCCHN treated with the combination showed an 
ORR of 24% (7/29) in the all comer population and an ORR of 41% (7/17) in the PD-L1+ 
(≥ 1%) population.  No responses (0/12) were observed in the PD-L1− population.  Put into 
context, nivolumab monotherapy in a similar population of patients with previously treated 
SCCHN (recently approved by the US FDA for the treatment of patients with recurrent or 
metastatic SCCHN with disease progression on or after platinum-based therapy) showed an ORR 
of 13.1% (32/240) in all SCCHN subjects and an ORR of 17.0% (15/88) in subjects with ≥ 1% 
PD-L1 expression.  Also of note, in 5 out of the 7 lirilumab plus nivolumab responders, the 
reduction in tumor burden was substantial, exceeding greater than 80%.  Responses appeared 
durable, with the median DOR not reached.  These results indicate lirilumab plus nivolumab may 
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have clinically meaningful greater clinical activity than nivolumab alone, particularly in inflamed 
(PD-L1+) tumors and with little added toxicity.  Refer to the current lirilumab IB for additional 
details regarding lirilumab for preclinical and clinical study data.   
1.3.1. 
Risks From Lirilumab 
As of the data cutoff for the current lirilumab IB (15 JUL 2016), 377 subjects have been treated 
with lirilumab or placebo in 1 Phase 1/2 study (ongoing), 3 Phase 1 studies (1 concluded, 
1 ongoing, and 1 terminated), and 1 ongoing Phase 2 study.  Of those subjects, 37 subjects 
received lirilumab monotherapy, 152 subjects received either lirilumab monotherapy or placebo 
in a 2:1 ratio, 149 subjects received lirilumab in combination with nivolumab, 22 subjects 
received lirilumab in combination with ipilimumab, and 17 subjects received elotuzumab in 
combination  with  lirilumab.  In   total,   approximately 326 subjects received lirilumab.  The 
majority of AEs in these 5 studies were mild or moderate (Grade  1  or  2),  self-limiting,  and  
manageable.  The most  common  related  AEs  in  the monotherapy trials were asthenia, fatigue, 
pruritus, infusion-related reaction, chills, and neutropenia.  The most common related AEs in the 
combination studies were fatigue, nausea, cough, diarrhea, and pyrexia.  Additional details on the 
safety profile of lirilumab are available in the lirilumab IB. 
1.4. 
Overview of Nivolumab 
Nivolumab (OPDIVO®) is a fully human IgG4 monoclonal antibody that binds to PD-1 and 
blocks interaction with PD-L1 and PD-L2 and restores T-cell antitumor function (Brahmer et al 
2010).  Nivolumab has been approved as monotherapy in the United States for metastatic 
NSCLC that has progressed on or after platinum-based chemotherapy, for advanced RCC after 
previous antiangiogenic therapy, for classical Hodgkin lymphoma that has relapsed or progressed 
after autologous hematopoietic stem cell transplantation and post-transplantation brentuximab 
vedotin, for recurrent or metastatic SCCHN with disease progression on or after platinum-based 
therapy, and for locally advanced metastatic urothelial carcinoma with disease progression 
during or after platinum-containing chemotherapy or disease progression within 12 months of 
neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.  Nivolumab is also 
approved in combination with ipilimumab in patients with unresectable or metastatic MEL 
(Opdivo 2017).  Nivolumab is approved in the European Union as monotherapy or in 
combination with ipilimumab for advanced (unresectable or metastatic) MEL, as monotherapy 
for locally advanced or metastatic NSCLC after prior chemotherapy, for advanced RCC after 
prior therapy, for recurrent or metastatic SCCHN, and for Hodgkin lymphoma following 
autologous stem cell transplant and treatment with brentuximab vedotin (Opdivo SmPC 2015). 
1.4.1. 
Risks From Nivolumab 
Overall, the safety profile of nivolumab monotherapy is manageable and generally consistent 
across completed and ongoing clinical studies, with no MTD reached at any dose tested up to 
10 mg/kg.  There was no pattern in the incidence, severity, or causality of AEs with respect to 
nivolumab dose level.  The most common adverse reactions (≥ 20%) reported have been fatigue, 
rash, musculoskeletal pain, pruritus, diarrhea, nausea, asthenia, cough, dyspnea, constipation, 
decreased appetite, back pain, arthralgia, upper respiratory tract infection, and pyrexia.  Most 
AEs were low grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs.  
Infusion reactions are also possible following administration of nivolumab.  The safety profile of 
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nivolumab combination therapy varies with the agent combined with nivolumab but is generally 
consistent with the safety profiles observed with either agent alone, and in some cases, both 
frequency and severity of AEs were greater than those observed with either agent alone. 
A pattern of immune-related AEs has been defined, including pneumonitis, colitis, hepatitis, 
endocrinopathies, nephritis and renal dysfunction, skin adverse reactions, and encephalitis, for 
which management algorithms have been developed; these are provided in Appendix B.  Most 
high-grade events were manageable with the use of corticosteroids, or hormone replacement 
therapy for endocrinopathies, as instructed in these algorithms.  Nivolumab should not be used in 
subjects with active autoimmune disease, given the mechanism of action of the antibody. 
Additional details on the safety profile of nivolumab, including results from other clinical 
studies, are also available in the nivolumab IB. 
1.4.2. 
Risks From Nivolumab in Combination With Ipilimumab 
The combination of nivolumab and ipilimumab was initially explored in subjects with advanced 
or metastatic MEL using doses of 1 mg/kg nivolumab and 3 mg/kg ipilimumab given Q3W for 
4 doses followed by 3 mg/kg nivolumab administered Q2W.  The toxicity of the combination 
was significantly higher than either agent alone with 36.4% of subjects discontinuing treatment 
due to an AE and 68.7% of subjects experiencing Grade 3 or 4 AEs (Larkin et al 2015).  More 
recent published data have demonstrated that lower doses and less frequent administration of 
ipilimumab improves the toxicity profile of the combination (Antonia et al 2016, Hellmann et al 
2016).  In a study of 3 mg/kg nivolumab administered Q2W plus 1 mg/kg ipilimumab 
administered Q6W in first-line NSCLC, only 13% of subjects discontinued due to a 
treatment-related AE, and only 33% had a Grade 3 or 4 treatment-related AE (Hellmann et al 
2016).  The most common AEs seen in this treatment group were skin events (36% overall, 5% 
Grade 3 or 4), endocrine (20% overall, 5% Grade 3 or 4), and GI (23% overall, 5% Grade 3 or 
4).  Additional details regarding the safety profile of nivolumab and ipilimumab given in 
combination may be found in the nivolumab IB. 
1.4.3. 
Risks From Nivolumab in Combination With Lirilumab 
As of 30 AUG 2016, a total of 159 subjects had been treated with the combination of lirilumab 
and nivolumab.  Adverse events evaluated as related to treatment were reported in 114 subjects 
(72%); Grade 3 to 4 treatment-related AEs were reported in 24 subjects (15%).  The most 
common related AEs reported in > 10% subjects were fatigue (20.8%), pruritus (18.9%), 
infusion-related  reaction (17.6%), and rash (16.4%).  Amylase increased and lipase increased 
were reported in 4 subjects (2.7%).  There were no related Grade 5 events reported.  Twelve 
subjects (7.5%) reported related events leading to study discontinuation.  Additional details 
regarding the safety profile of nivolumab and lirilumab given in combination may be found in 
the lirilumab IB. 
1.4.4. 
Risks From Nivolumab in Combination With Epacadostat 
The combination of epacadostat with nivolumab is being explored in Study INCB 24360-204, a 
Phase 1/2 open-label study of subjects with advanced solid tumors and lymphoma evaluating 
escalating doses of epacadostat in combination with nivolumab.  No DLTs were observed during 
the dose escalation portion of the study, in which doses of 25 mg BID, 50 mg BID, 100 mg BID 
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and 300 mg BID were evaluated in a 3 + 3 + 3 design in combination with nivolumab 3 mg/kg 
Q2W.  Epacadostat doses of 100 mg BID and 300 mg BID were selected for Phase 2 evaluation, 
and nivolumab was converted to a flat dose of 240 mg Q2W.  As of the data cutoff dated 
13 FEB 2017, the most common (≥ 10%) AEs related to study drug (epacadostat or nivolumab) 
in subjects treated with 100 mg BID (n = 69) and 300 mg (n = 161) were rash (35% and 32%, 
respectively), fatigue (23% and 38%, respectively), nausea (19% and 20%, respectively), 
diarrhea (12% and 16%, respectively), nausea (19% and 10%, respectively) and AST increased 
(15% and 10%, respectively).  Treatment-related Grade 3 or 4 AEs were 25% in subjects treated 
with 100 mg BID and 27% in subjects treated with 300 mg BID.   Rash was the most common 
≥ Grade 3 treatment-related AE at the 100 mg BID and 300 mg dose levels (10% and 15%).  
Adverse events led to discontinuation in 6% and 12% of subjects receiving 100 mg BID and 
300 mg BID, respectively.  There were no treatment-related deaths (Perez et al 2017).   
1.5. 
Overview of Ipilimumab 
Ipilimumab (YERVOY®) is a fully human monoclonal IgG1κ CTLA-4–blocking antibody that 
binds to the CTLA-4 antigen expressed on a subset of T cells from human and nonhuman 
primates.  Ipilimumab is approved in the US and EU as a monotherapy and in combination with 
nivolumab for the treatment of patients with advanced MEL.  Refer to the Yervoy prescribing 
information and SmPC for updated information regarding approved indications (Yervoy 2017). 
1.5.1. 
Risks From Ipilimumab 
Ipilimumab may cause immune-related adverse reactions, including hepatitis, enterocolitis, 
dermatitis, neuropathies, endocrinopathies and other immune-mediated adverse reactions.  
Guidance for the management of these events are provided in Appendix B.  The approved dose 
of ipilimumab is 3 mg/kg Q3W for 4 doses.  The most common AEs (≥ 5%) seen at the approved 
dose are fatigue, diarrhea, pruritus, rash, and colitis.  Additional common adverse 
reactions (≥ 5%), seen in patients receiving a higher dose of 10 mg/kg, include nausea, vomiting, 
headache, weight loss, pyrexia, decreased appetite, and insomnia (Yervoy 2017).  
Additional details on the safety profile of ipilimumab, including results from clinical studies, are 
available in the ipilimumab IB. 
1.5.2. 
Risks From Ipilimumab in Combination With Epacadostat 
The combination of epacadostat with ipilimumab was explored in Study INCB 24360-201, a 
Phase 1/2 open-label study of subjects with advanced MEL, using 3 mg/kg ipilimumab given 
Q3W for 4 doses in combination with a starting dose of epacadostat of 300 mg BID.  Five of 
7 subjects enrolled at the 300 mg BID epacadostat dose developed clinically significant ALT 
elevations after 30 to 76 days on treatment; none of these subjects had elevated bilirubin, 
evidence of liver failure, or other evidence of severe liver injury; enrollment was stopped.  These 
subjects were discontinued from therapy and were treated with IV Solu-Medrol® followed by 
oral prednisone on a tapering schedule and recovered normal liver function; the ALT elevations 
were reversible with corticosteroids and treatment discontinuation.  Enrollment was restarted at 
25 mg BID (n = 8), and subsequent cohorts of 50 mg BID continuous (n = 18), 50 mg BID 
intermittent (2 weeks on epacadostat/1 week off; n = 9), and 75 mg total daily dose (n = 7) were 
enrolled.  Among all doses, the most frequently reported AE was fatigue (66%).  Other AEs that 
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occurred in > 25% of subjects included rash (54.0%), constipation and pruritus (40.0% each), 
diarrhea and nausea (32.0% each), ALT increased (28.0%), decreased appetite (26.0%), and 
headache (26.0%).  The most frequently reported AE related to study drug (epacadostat or 
ipilimumab) was fatigue (44.0%).  Other treatment-related AEs that occurred in ≥ 20% of 
subjects included rash (40.0%), pruritus (30.0%), ALT increased (28.0%), and AST 
increased (24.0%).  Immune-related AEs were generally Grade 1/2 and manageable with 
continued administration or temporary dose interruption; 1 subject each discontinued for 
immune-related Grade 3 colitis and Grade 3 salivary amylase elevation.  There were no 
treatment-related deaths reported (epacadostat IB). 
1.6. 
Overall Risk/Benefit Assessment of the Combination Regimens 
There continues to be a significant unmet need for patients with advanced and metastatic solid 
tumors who have either not responded to standard treatment or for whom standard treatments 
provide suboptimal outcomes. 
Doublet combinations of nivolumab and ipilimumab, and nivolumab and lirilumab, have 
demonstrated enhanced clinical activity compared with monotherapy with a manageable safety 
profile (Larkin et al 2015, Hellmann et al 2016, Goldman et al 2017).  Additionally, recent 
evidence has emerged suggesting that epacadostat may enhance the clinical activity of PD-1–
targeting agents in a variety of tumor types, including MEL (Gangadhar et al 2016, Perez et al 
2017), NSCLC (Gangadhar et al 2017), and SCCHN (Perez et al 2017, Hamid et al 2017) with 
minimal additive toxicity.  The totality of these data suggest that the proposed combinations to 
be evaluated in this study (nivolumab/ipilimumab/epacadostat and 
nivolumab/lirilumab/epacadostat) may provide additional clinical benefit beyond that which has 
been observed in the aforementioned doublet regimens.  
While the addition of epacadostat to each of the doublet combinations of nivolumab and 
ipilimumab, and nivolumab and lirilumab, has the potential for increased clinical benefit, the 
combination of 3 immune-targeting therapies also has the potential for increased frequencies of 
AEs.  The principle toxicities of administering agents that modulate the immune system are 
irAEs including skin manifestations, pneumonitis, hepatitis, 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).  As the use of 
immunotherapies become 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 the Protocol. 
The risks of nivolumab and ipilimumab are well-characterized and described in more detail in 
Section 1.4.2.  Additionally, the risks of nivolumab and ipilimumab in combination with 
epacadostat are detailed in Section 1.4.4 and Section 1.5.2, respectively.  Of note, a lower dose 
and less frequent administration of ipilimumab (1 mg/kg Q6W) was selected for combination 
with epacadostat in Treatment Group A to minimize AEs based on emerging safety data with the 
nivolumab and ipilimumab combination (Antonia et al 2016, Hellmann et al 2016) and the prior 
clinical experience with epacadostat and ipilimumab.  
The emerging safety profile of nivolumab and lirilumab, as detailed in Section 1.4.3, is generally 
consistent with that observed with nivolumab monotherapy.  However, addition of epacadostat in 
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the Treatment Group B combination may result in increased risk of irAEs.  Appropriate safety 
monitoring will be performed during the study to detect any additive toxicity and management 
guidelines are provided for management of irAEs. 
1.7. 
Rationale for Dose and Schedule of the Combination Therapies 
The initial epacadostat dose selected in Treatment Group A, to be administered in combination 
with nivolumab and ipilimumab, is 50 mg BID.  Based on DLTs observed in Phase 1, the dose 
may be subsequently escalated to 100 mg BID, or the dose may be de-escalated to 25 mg BID.  
The initial dose selected is based on the safety and tolerability profile of the ipilimumab and 
epacadostat doublet observed in Study INCB 24360-201 (see Section 1.5.2), where 50 mg BID 
epacadostat were generally well-tolerated with higher dose intensity ipilimumab (3 mg/kg 
Q3W × 4 doses) than will be used in this study.  
The starting dose of epacadostat in Treatment Group B, to be administered in combination with 
nivolumab and lirilumab, is 50 mg BID.  Based on DLTs observed in Phase 1, the dose may be 
subsequently escalated to a maximum dose of 100 mg BID, or the dose may be de-escalated to 
25 mg BID.  The initial dose selected is based on the acceptable safety and tolerability profile of 
the nivolumab and epacadostat doublet discussed in Section 1.4.4, as well as the emerging safety 
profile of the nivolumab and lirilumab combination. 
In the first-in-human study INCB 24360-101, a detailed interrogation of the effect of dose and 
exposure on the pharmacodynamics effect of epacadostat on the tryptophan pathway was 
performed.  Using an ex vivo assay optimized for determining the inhibition of the metabolism of 
tryptophan to kynurenine by IDO1, epacadostat treatment produced significant dose-dependent 
reductions in plasma kynurenine levels and in the plasma kynurenine/tryptophan ratio at all 
doses and in all patients.  Near maximal changes were observed at doses of ≥ 100 mg BID with 
> 80% to 90% inhibition of IDO1 achieved throughout the treatment period.  Complete 
inhibition of IDO1 is not required for maximally effective activity in preclinical models; 
however, maximally effective doses in nonclinical models result in exposures that are 
comparable to monotherapy doses of 50 mg BID to 300 mg BID in humans. 
In April 2018, eDMC review of ECHO-301/KEYNOTE-252 study, a Phase 3 study evaluating 
pembrolizumab 200 mg Q3W in combination with epacadostat 100 mg BID versus 
pembrolizumab 200 mg Q3W with placebo as first-line treatment in subjects with unresectable 
or metastatic melanoma, concluded that the coprimary endpoint of improvement in progression-
free survival was not met (HR = 1.00; 95% CI 0.83 to 1.21) and that the coprimary endpoint of 
improvement in overall survival was also not expected to reach statistical significance 
(HR = 1.13; 95% CI: 0.86 to 1.49).  Based on these results, and on the recommendation of the 
eDMC, the study was stopped.  The safety profile observed in the ECHO-301/KEYNOTE-252 
study was consistent with that observed in previously reported studies of epacadostat in 
combination with pembrolizumab (Long et al 2018). 
In the context of the ECHO-301/KEYNOTE-252 outcome and the ECHO-208 study design, 
which limits epacadostat doses to ≤ 100 mg BID, the sponsor will allow for withdrawal of 
epacadostat for subjects who are continuing on treatment on or after the effective date of 
Amendment 2 at the discretion of the treating investigator. 
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The FDA approved dose of nivolumab (240 mg Q2W) has been selected for use in combination 
with ipilimumab and epacadostat in Treatment Group A and lirilumab and epacadostat in 
Treatment Group B. 
The ipilimumab dose of 1 mg/kg Q6W will be used in combination with nivolumab and 
epacadostat in Treatment Group A; although the approved dose of ipilimumab in combination 
with nivolumab is 3 mg/kg Q3W, recent published data have demonstrated that lower doses and 
less frequent administration of ipilimumab improves the toxicity profile of the combination with 
similar efficacy, as discussed in Section 1.4.2.  
Lirilumab is being studied as a potential immunotherapy alone and in combination with other 
agents in subjects with various hematologic malignancies and solid tumors with body weight 
normalized dosing (mg per kg).  A preliminary PK analysis of data collected from 3 studies 
suggests that lirilumab PK is linear, with dose proportional exposures over a dose range of 0.1 to 
10 mg/kg.  Lirilumab Cl and volume of distribution was found to increase with increasing body 
weight, but the increase was less than proportional, indicating that a mg per kg dose represents 
an overadjustment for the effect of body weight on lirilumab PK.  Conversely, given the 
relationship between lirilumab PK and body weight, a flat dose is expected to lead to lower 
exposures in heavier subjects, relative to the exposures in lighter subjects. 
Table 1 presents summary statistics of the estimated lirilumab peak and trough concentrations 
after the first dose and steady state (Cmin1, Cmax1, Cmin,ss, and Cmax,ss) in subjects receiving 
3 mg/kg, together with corresponding statistics of exposures predicted for a flat lirilumab dose of 
240 mg.  It should be noted that a dose of lirilumab 240 mg is identical to a dose of 3 mg/kg for 
subjects weighing 80 kg.  As evident from the data presented in Table 1, the geometric mean 
values of Cmin1, Cmax1, Cmin,ss, and Cmax,ss with flat dosing are slightly higher (< 10% difference) 
than those produced by a 3 mg/kg dose. 
Table 1: 
Summary Statistics of Predicted Lirilumab Exposure 
Lirilumab Dose 
Cmin1 Geo. Mean 
[μg/mL] (cv %) 
Cmax1 Geo. Mean 
[μg/mL] (cv %) 
Cmin,ss Geo. Mean 
[μg/mL] (cv %) 
Cmax,ss Geo. Mean 
[μg/mL] (cv %) 
240 mg 
8.897 (61.06) 
66.113 (40.06) 
14.262 (85.26) 
83.209 (41.25) 
3 mg/kg 
8.261 (58.61) 
61.513 (37.54) 
13.263 (81.98) 
77.678 (38.49) 
Refer to the lirilumab IB for additional details.  
1.8. 
Rationale for Shorter Infusion Times for Nivolumab and Ipilimumab 
Long infusion times place a burden on patients and treatment centers.  Establishing that 
nivolumab and ipilimumab can be safely administered using shorter infusion times of 30 minutes 
duration will diminish the burden, provided that there is no change in the safety profile.  Previous 
clinical studies of nivolumab and ipilimumab monotherapies and the combination of nivolumab 
and ipilimumab have used a 60-minute infusion duration for nivolumab and a 90-minute infusion 
duration for ipilimumab (1-3 mg/kg dosing for both).  However, both nivolumab and ipilimumab 
have been administered at up to 10 mg/kg with the same infusion duration (ie, 60 minutes). 
Establishing that nivolumab can be safely administered using a shorter infusion time 
(30 minutes) is under investigation.  Previous clinical studies of nivolumab monotherapy have 
used a 60-minute infusion duration, wherein nivolumab has been safely administered up to 
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Table 2: 
Study Objectives and Endpoints (Continued) 
3. 
SUBJECT ELIGIBILITY 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or subject safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential. 
3.1. 
Subject Inclusion Criteria 
A subject who meets all of the following criteria may be included in the study: 
Phase 1 only: 
1. Subjects with histologically or cytologically confirmed locally advanced or metastatic 
solid tumors who have disease progression on or after treatment with available therapies 
that are known to confer clinical benefit, or who are intolerant to treatment, or who refuse 
standard treatment.  
Note:  Locally advanced disease must not be amenable to resection with curative intent.   
2. Has received no more than 2 prior treatment regimens (including chemotherapy and/or 
targeted therapy; not including neoadjuvant and/or adjuvant therapy) for advanced or 
metastatic disease.  
3. Has baseline core or excisional tumor archival biopsy specimen available or willingness 
to undergo a pretreatment biopsy to obtain the specimen.  Archival specimen must be a 
tumor block or 25 unstained slides (minimum of 20).  A FFPE tumor tissue block is 
preferred.  If a block is not available, a minimum of 20 to 25 unstained freshly cut slides 
may be submitted to the testing laboratory as specified Laboratory Manual.   
Note:  Unstained slides must have been prepared from an FFPE block obtained within 
6 months before screening.  
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All subjects (Phase 1 and Phase 2): 
8. Ability to comprehend and willingness to sign an ICF. 
9. Men or women aged 18 years or older. 
10. Presence of measurable disease per RECIST v1.1 (Appendix E).  Tumor lesions located 
in a previously irradiated area, or in an area subjected to other locoregional therapy, are 
considered measurable if progression has been demonstrated in the lesion following such 
therapy. 
11. ECOG performance status of 0 or 1. 
12. Expected survival of ≥ 12 weeks. 
13. Willingness and ability to comply with the scheduled visits, treatment plan, and 
laboratory tests. 
14. Willingness to avoid pregnancy or fathering children based on the following criteria: 
a. Woman of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 12 months of amenorrhea and at least 51 years of age). 
b. Woman of childbearing potential who has a negative serum pregnancy test at 
screening (within 72 hours of Day 1) and who agrees to take appropriate precautions 
to avoid pregnancy (with at least 99% certainty) from screening through at least 
5 months after the last dose of study treatment.  Permitted methods that are at least 
99% effective in preventing pregnancy (see Appendix A) should be communicated to 
the subject and their understanding confirmed. 
c. Man who agrees to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) from screening through at least 7 months after the last dose of 
study treatment.  Permitted methods that are at least 99% effective in preventing 
pregnancy (see Appendix A) should be communicated to the subject and their 
understanding 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; all 
screening laboratory tests should be performed within 7 days of Cycle 1 Day 1.  If the 
screening laboratory tests outlined below were performed more than 7 days before 
Cycle 1 Day 1, the hematology, serum chemistry, and liver chemistry test results must be 
confirmed on Cycle 1 Day 1 before initiation of study treatment 
a. ANC < 1.5 × 109/L. 
b. Platelets < 100 × 109/L. 
c. Hemoglobin < 9 g/dL or < 5.6 mmol/L (transfusion is acceptable to meet this 
criterion). 
d. Serum creatinine ≥ 1.5 × institutional ULN, or measured or calculated CrCl 
< 50 mL/min for subjects with creatinine levels > 1.5 × institutional ULN (GFR can 
also be used in place of CrCl). 
e. Phase 1 only:  AST or ALT ≥ 1.5 × institutional ULN. 
Phase 2 only:  AST or ALT ≥ 2.5 × institutional ULN. 
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f. Total bilirubin ≥ 1.5 × institutional ULN or conjugated (direct) bilirubin 
≥ institutional ULN.  If an institutional ULN for conjugated bilirubin is not available, 
then conjugated bilirubin should be < 40% of total bilirubin to be considered eligible. 
g. INR or PT > 1.5 × institutional ULN. 
h. aPTT > 1.5 × institutional ULN unless subject is receiving anticoagulant therapy, as 
long as PTT is within therapeutic range of intended use of anticoagulants. 
i. Phase 1 only:  Albumin ≤ 3.0 g/dL or with medical monitor approval. 
2. Receipt of anticancer medications or investigational drugs within the following interval 
before the first administration of study drug: 
a. ≤ 21 days for chemotherapy or targeted small molecule therapy. 
Note:  Use of bisphosphonates is permitted. 
b. ≤ 28 days for previous monoclonal antibody used for anticancer therapy. 
Note:  Use of denosumab is permitted. 
c. ≤ 28 days or 5 half-lives (whichever is longer) before Cycle 1 Day 1 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. 
3. Previous radiotherapy within 7 days of Cycle 1 Day 1 (except for radiation to CNS, 
which requires a ≥ 28-day washout as described below).  Subjects must also not require 
chronic use of corticosteroids and must not have had radiation pneumonitis as a result of 
treatment. 
4. 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 
Cycle 1 Day 1 and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases or cerebral edema, and have not required 
steroids for at least 14 days before Cycle 1 Day 1. 
5. Prior treatment with any immune checkpoint inhibitor (eg, anti–CTLA-4, anti–
PD-1/PD-L1, anti–PD-2/PD-L2, anti-KIR, and any other antibody or drug specifically 
targeting T-cell costimulation) and/or an IDO inhibitor.  Subjects who have received 
experimental vaccines or other immune therapies should be discussed with the medical 
monitor to confirm eligibility.  
Note:  Subjects in Cohort A1 who received adjuvant anti−CTLA-4 therapy and had 
disease progression ≥ 6 months after completion of planned treatment may enroll. 
6. Any unresolved toxicity > Grade 1 from previous anticancer therapy, except for stable 
chronic toxicities not expected to resolve, such as peripheral neurotoxicity, alopecia, and 
fatigue. 
7. Subjects who are receiving an immunologically based treatment for any reason, including 
chronic use of systemic steroid or at doses ≥ 10 mg/day prednisone equivalent within 
7 days before the first dose of study drug.  Use of inhaled or topical steroids or systemic 
corticosteroids < 10 mg prednisone equivalent is permitted. 
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8. Receipt of a live vaccine within 30 days of planned start of study therapy. 
Note:  Examples of live vaccines include but are not limited to the following:  measles, 
mumps, rubella, chicken pox/zoster, yellow fever, rabies, BCG, and typhoid 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. 
9. Active infection requiring systemic therapy. 
10. Subjects with any active or inactive autoimmune disease or syndrome (eg, rheumatoid 
arthritis, moderate or severe psoriasis, multiple sclerosis, inflammatory bowel disease) 
that has required systemic treatment in the past 2 years or who are receiving systemic 
therapy for an autoimmune or inflammatory disease (ie, with use of disease-modifying 
agents, corticosteroids, or immunosuppressive drugs). 
Note:  Exceptions include subjects with vitiligo or resolved childhood asthma/atopy, 
hypothyroidism stable on hormone replacement, controlled asthma, or Type I diabetes, 
Graves' disease, or Hashimoto's disease that are treated and controlled, or with medical 
monitor approval. 
11. Evidence of interstitial lung disease or active, noninfectious pneumonitis, including 
symptomatic and/or pneumonitis requiring treatment.  
12. History of organ transplant that requires use of immunosuppressive therapy. 
13. Has known history of or is positive for hepatitis B (HBsAg reactive) or hepatitis C.  
a. HBV DNA must be undetectable and HBsAg negative at the screening visit. 
b. Hepatitis C antibody testing is allowed for screening purposes in countries where 
HCV RNA is not part of standard of care.  In these cases, HCV antibody−positive 
subjects will be excluded.   
c. Subjects who have had definitive treatment for HCV are permitted if HCV RNA is 
undetectable at the screening visit. 
Note:  Testing must be performed to determine eligibility. 
14. Known history of HIV (HIV 1/2 antibodies). 
15. 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, or other noninvasive or indolent 
malignancy, or cancers from which the subject has been disease-free for ≥ 1 year, 
following treatment with curative intent, with medical monitor approval.  
16. Any history of SS after receiving 1 or more serotonergic drugs. 
17. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically 
meaningful.  Screening QTc interval > 480 milliseconds is excluded (corrected by 
Fridericia or Bazett formula).  In the event that a single QTc is > 480 milliseconds, the 
subject may be enrolled if the average QTc for 3 consecutive ECGs is 
< 480 milliseconds.  For subjects with an intraventricular conduction delay (QRS interval 
> 120 milliseconds), 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. 
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18. Clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction within 6 months of Cycle 1 Day 1, New York Heart Association Class III or IV 
or congestive heart failure.  Medically controlled arrhythmia stable on medication is 
permitted.  
19. Known allergy or reaction to any components of epacadostat, nivolumab, ipilimumab, or 
lirilumab.   
20. Presence of a GI condition (eg, inflammatory bowel disease, Crohn's disease, ulcerative 
colitis) that may affect drug absorption.  
Note:  Subjects with feeding tubes must be approved for inclusion in the study by the 
medical monitor. 
21. Use of MAOIs or drug that has significant MAOI activity (eg, meperidine, linezolid, 
methylene blue) within the 21 days before screening.  See Appendix D for prohibited 
medications associated with MAO inhibition. 
22. Use of any UGT1A9 inhibitor or inducer from screening through follow-up period, 
including the following:  diclofenac, imipramine, ketoconazole, mefenamic acid, and 
probenecid.  See Section 5.6.3 for a complete list of UGT1A9 inhibitor and inducers. 
23. Bleeding associated with tumors that invade or are adjacent to major blood vessels, as 
shown unequivocally by imaging studies, or history of bleeding related to disease under 
study within 3 months of enrollment. 
24. History or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the subject's participation for the 
full duration of the study, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator. 
25. Women who are pregnant or breastfeeding.  
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Figure 1: 
Study Design 
 
4.1.1. 
Phase 1 – Dose Escalation 
Dose escalation in Treatment Groups A and B will be conducted using a standard 3 + 3 + 3 
design as per the dose-escalation schedule outlined in Table 3.  A minimum of 3 evaluable 
subjects will be enrolled in each treatment group beginning with Dose Level 1 (starting dose of 
epacadostat 50 mg BID in Treatment Groups A and B).  
In Treatment Group A, the first 3 evaluable subjects at each dose level will be observed for a 
minimum of 42 days before the next dose level begins enrollment.  To be evaluable for 
tolerability, subjects must receive at least 75% of planned epacadostat doses (63/84) at the 
specified dose level, 3 doses of nivolumab, and 1 dose of ipilimumab, or subjects must 
experience a DLT during the DLT observation period. 
In Treatment Group B, the first 3 evaluable subjects at each dose level will be observed for a 
minimum of 42 days before the next dose level begins enrollment.  To be evaluable for 
tolerability, subjects must receive at least 75% of planned epacadostat doses (63/84) at the 
specified dose level, 3 doses of nivolumab, and 2 doses of lirilumab, or subjects must experience 
a DLT during the DLT observation period.    
Subjects who discontinue for reasons other than a DLT (eg, events clearly associated with the 
underlying disease, disease progression, concomitant medication, comorbidity, or an AE clearly 
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4.1.2. 
Phase 2 – Dose Expansion 
The Phase 2 dose expansion cohorts will begin when the MTD or PAD of epacadostat has been 
determined in Phase 1 for the respective treatment group.  This portion of the study will evaluate 
the efficacy of the MTD or PAD of epacadostat and will further evaluate the safety, 
 
 of the combinations. 
Treatment Group A will enroll 2 expansion cohorts in parallel: 
• Cohort A1:  Approximately 35 subjects with unresectable or metastatic MEL who 
have not received prior systemic treatment for advanced or metastatic disease.  Serial 
pretreatment and on-treatment biopsies are required for all subjects enrolled, if 
clinically feasible. 
• Cohort A2:  Approximately 35 subjects with advanced or metastatic NSCLC without 
known driver mutations (including EGFR, BRAF, ALK, and ROS1) who have 
received no more than 1 prior line of therapy for advanced or metastatic disease.  
Serial pretreatment and on-treatment biopsies are required for all subjects enrolled, if 
clinically feasible. 
Treatment Group B will enroll 1 expansion cohort: 
• Cohort B1:  Approximately 35 subjects with recurrent or metastatic SCCHN who 
have received no more than 1 prior line of platinum-based chemotherapy for recurrent 
or metastatic disease.  Serial pretreatment and on-treatment biopsies are required for 
all subjects enrolled, if clinically feasible. 
Enrollment into the Phase 2 expansion cohorts will begin when the MTD or PAD of epacadostat 
for the corresponding treatment group in Phase 1 has been determined; however, priority will be 
given to any open dose-escalation cohorts in Phase 1. 
In Phase 2 of the study, toxicities will continue to be monitored.  If the cumulative incidence of 
≥ Grade 3 immune-related AEs is > 40% after a cumulative minimum of 10 subjects have been 
enrolled into the expansion cohorts within each treatment group, further enrollment in those 
expansions will be interrupted until the sponsor, investigators, and regulatory authorities (if 
applicable) determine the appropriate course of action.  If an expansion cohort in a particular 
treatment group is discontinued because of toxicity, a new expansion may be initiated at a 
previously tested lower dose level of epacadostat. 
The sponsor may elect to prioritize enrollment to specific treatment groups or expansion cohorts 
based on emerging safety or efficacy data in collaboration with investigational sites. 
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 
 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 141 subjects may be enrolled into the study at approximately 15 to 20 sites. 
Treatment Group A: 
• Phase 1:  Approximately 18 subjects. 
• Phase 2:  Cohort A1 – approximately 35 subjects 
Cohort A2 – approximately 35 subjects  
Treatment Group B: 
• Phase 1:  Approximately 18 subjects. 
• Phase 2:  Cohort B1 – approximately 35 subjects. 
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) or who does not have the required exposure to the study 
drugs during the DLT evaluation period, may be replaced to ensure a minimum 
number of evaluable subjects. 
• Subjects who do not meet the eligibility requirements of the study may be replaced. 
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.  
Each subject enrolled in the study may continue to receive study treatment in continuous 14-day  
cycles for up to 2 years, as long as they are deriving benefit and have not met any of the 
Protocol-defined conditions for treatment withdrawal (see Section 5.5.1).  If the subject 
discontinues study treatment, the treatment period will end and the subject will enter the safety 
follow-up period (see Section 6.4).  Study participation, including post-treatment safety 
follow-up, is expected to average approximately 12 to 18 months per individual subject. 
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 have been ≤ 5 subjects on study for more than 6 months, a database lock of the study 
may occur to allow 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 SAEs, AEs of 
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special interest, and pregnancies, as detailed in Section 8.  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 staff should contact the IRT to obtain the subject ID number 
during screening.  This subject ID number will be maintained throughout the study and will not 
be reassigned.  Subjects who fail screening and are repeating the screening process due to a 
change in eligibility status will be assigned a new subject ID number.  For subjects who signed 
an ICF but are not treated, refer to the eCRF Completion Guidelines for instructions on which 
eCRFs to complete. 
Site staff will contact the IRT to enroll the subject and obtain the initial assignment for the 
relevant treatments.  The investigator or designee will select the assigned treatments from the 
stock that correspond to the number provided by the IRT, record the unique identifiers in the 
eCRF, and dispense the treatment to the subject.  All subsequent dispensing of relevant 
treatments should follow this process.  Full details will be provided in the IRT manual.  
If a subject is mistakenly dispensed a bottle of study drug that is not the bottle assigned by the 
IRT, then the IRT help desk must be notified immediately.  The reason for the misallocation of 
the study drug must be documented by the study site. 
5.1.2. 
Randomization and Blinding 
This is an open-label nonrandomized study; therefore, randomization and blinding do not apply. 
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5.2. 
Study Drugs 
5.2.1. 
Epacadostat 
For all subjects, epacadostat will be self-administered beginning on Cycle 1 Day 1 and 
continuously thereafter.  Doses will be taken BID, in the morning and evening, approximately 
12 hours apart without regard to food.  If a dose is missed by more than 4 hours, then that dose 
should be skipped and the next dose should be taken at the next scheduled timepoint. 
On Cycle 1 Day 1, Cycle 1 Day 8, and Cycle 2 Day 1, the morning dose of epacadostat will be 
administered at the study site, as these study visits coincide 
.  On 
visit days when nivolumab and ipilimumab (Treatment Group A) or nivolumab and lirilumab 
(Treatment Group B) are administered, epacadostat should be taken before the start of any 
infusions. 
Note: Subjects who are ongoing on study treatment as of the date of Amendment 2 may 
discontinue epacadostat at the discretion of the treating investigator (see Section 1.7).  
5.2.1.1. 
Supply, Packaging, and Labeling 
Epacadostat will be available as 25 mg and 100 mg tablets packaged in high-density 
polyethylene bottles.  In Phase 1, subjects will receive epacadostat according to dose level 
assignment (Table 3).  In Phase 2, all subjects will receive epacadostat at the MTD or PAD 
identified in Phase 1.  All tablet excipients comply with the requirements of the applicable 
compendial monographs (Ph. Eur., USP/NF; refer to the epacadostat IB). 
All Incyte investigational product labels will be in the local language and will comply with the 
legal requirements of each country. 
5.2.1.2. 
Storage 
Clinical supplies must be stored as described in the epacadostat IB. 
5.2.2. 
Nivolumab 
5.2.2.1. 
Description and Administration 
Subjects will receive nivolumab 240 mg as a 30-minute IV infusion (± 5 minutes) on Day 1 of 
each 14-day cycle, starting at Cycle 1 Day 1.  Intrasubject dose escalation of nivolumab is not 
permitted.  Nivolumab will be administered after epacadostat.  Sites are instructed to wait at least 
30 minutes after the nivolumab infusion is completed before administering subsequent infusions 
of ipilimumab (Treatment Group A) or lirilumab (Treatment Group B). 
Details on the preparation and administration are provided in the Pharmacy Manual. 
5.2.2.2. 
Supply, Packaging, and Labeling  
The investigator will take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of nivolumab in 
accordance with the protocol and any applicable laws and regulations.  Nivolumab clinical 
supplies will be provided by BMS and will be labeled in accordance with local regulatory 
requirements. 
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The nivolumab product description is provided in Table 4.  Refer to the nivolumab IB for 
additional details. 
Table 4: 
Nivolumab Product Description 
Product 
Description 
and Regimen 
Form 
Potency 
Primary 
Packaging 
Volume/ 
Label Type 
Secondary 
Packaging/ 
 Label Type 
Appearance 
Storage 
Conditions 
Nivolumab 
(BMS-936558) 
solution for 
injection. 
100 mg 
(10 mg/mL) 
10 mg/mL 
vial/open-label 
5 vials per carton/ 
open-label 
Clear to opalescent 
colorless to pale 
yellow liquid, may 
contain particles. 
2°C to 8°C.  
Protect from 
light and 
freezing. 
5.2.3. 
Ipilimumab 
5.2.3.1. 
Description and Administration 
Subjects in Treatment Group A will receive ipilimumab 1 mg/kg as a 30-minute IV infusion 
(± 5 minutes) starting at Cycle 1 Day 1 and Q6W thereafter on Day 1 of every third treatment 
cycle (eg, Cycle 4, Cycle 7, etc).  Intrasubject dose escalation of ipilimumab is not permitted.  
When administered on the same day, ipilimumab will be administered at least 30 minutes after 
the completion of the nivolumab infusion. 
Details on the preparation and administration are provided in the Pharmacy Manual. 
5.2.3.2. 
Supply, Packaging, and Labeling  
The investigator will take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of ipilimumab 
in accordance with the protocol and any applicable laws and regulations.  Ipilimumab clinical 
supplies will be provided by BMS and will be labeled in accordance with local regulatory 
requirements. 
The ipilimumab product description is provided in Table 5.  Refer to the ipilimumab IB for 
additional details. 
Table 5: 
Ipilimumab Product Description 
Product 
Description 
and Regimen 
Form 
Potency 
Primary 
Packaging 
Volume/   
Label Type 
Secondary 
Packaging/ 
Label Type 
Appearance 
Storage 
Conditions 
Ipilimumab 
(BMS-734016) 
solution for 
injection. 
200 mg/40 mL   
(5 mg/mL) 
5 mg/mL 
vial/open-label 
4 vials per 
carton/ 
open-label 
Clear to slightly 
opalescent, colorless 
to pale yellow liquid, 
may contain particles. 
2°C to 8°C.  
Protect from 
light and 
freezing. 
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5.2.4. 
Lirilumab 
5.2.4.1. 
Description and Administration 
Subjects in Treatment Group B will receive lirilumab 240 mg as a 60-minute IV infusion 
(± 5 minutes) starting at Cycle 1 Day 1 and Q4W thereafter on Day 1 of every other treatment 
cycle (eg, Cycle 3, Cycle 5, etc).  Intrasubject dose escalation of lirilumab is not permitted.  
When administered on the same day, lirilumab will be administered at least 30 minutes after the 
completion of the nivolumab infusion. 
Details on the preparation and administration are provided in the Pharmacy Manual. 
5.2.4.2. 
Supply, Packaging, and Labeling 
The investigator will take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of lirilumab in 
accordance with the protocol and any applicable laws and regulations.  Lirilumab clinical 
supplies will be provided by BMS and will be labeled in accordance with local regulatory 
requirements. 
The lirilumab product description is provided in Table 6.  Refer to the lirilumab IB for additional 
details. 
Table 6: 
Lirilumab Product Description 
Product 
Description 
and Regimen 
Form 
Potency 
Primary 
Packaging 
Volume/   
Label Type 
Secondary 
Packaging/ 
Label Type 
Appearance 
Storage 
Conditions 
Lirilumab 
(BMS-986015) 
solution for 
injection. 
100 mg/10 mL 
(10 mg/mL) 
10 mg/mL 
vial/open-label 
6 vials per 
carton/ 
open-label 
Clear to opalescent, 
colorless liquid, 
may contain few 
particles. 
2°C to 8°C.  
Protect from 
light and 
freezing. 
5.3. 
Treatment Compliance 
Epacadostat is an oral medication, and compliance will be calculated by the sponsor based on the 
drug accountability documented by the site staff and monitored by the sponsor/designee (tablet 
counts).  The objective is 100% compliance, and site staff should evaluate compliance at each 
visit and take appropriate steps to optimize compliance. 
Nivolumab, ipilimumab, and lirilumab are administered as an IV infusion by site personnel.  
Receipt of infusions will be documented by the site staff and monitored by the sponsor/designee. 
5.4. 
Treatment Interruptions and Adjustments 
5.4.1. 
Dose Modifications 
Modifications to epacadostat dosing are planned for the Phase 1 dose-escalation cohorts (see 
Section 4.1.1).  Dose modifications in the form of interruption or discontinuation for any of the 
study treatment components (epacadostat, nivolumab, ipilimumab [Treatment Group A] or 
lirilumab [Treatment Group B]) may also be needed for individual subjects in the event of a DLT 
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or AE (related or unrelated to treatment).  Intrasubject dose escalation for epacadostat, 
nivolumab, ipilimumab, or lirilumab is not permitted. 
5.4.2. 
Dose-Limiting Toxicity and Determination of Maximum Tolerated Dose 
A DLT will be defined as the occurrence of any of the toxicities in Table 7 occurring from 
Cycle 1 Day 1 up to and including Day 42 for Treatment Groups A and B in Phase 1, except 
those with a clear alternative explanation (eg, disease progression) or transient (≤ 72 hours) 
abnormal laboratory values without associated clinically significant signs or symptoms based on 
investigator determination.  Immune-related AEs of Grade 3 that improve to Grade 1 or lower 
within 14 days after the initiation of supportive care or corticosteroid therapy may be deemed a 
non-DLT.  All DLTs will be assessed by the investigator using CTCAE v4.03 criteria.  
To be evaluable for tolerability, subjects in Treatment Group A must receive at least 75% of 
planned epacadostat doses (63/84) at the specified dose level, 3 doses of nivolumab, and 1 dose 
of ipilimumab, or subjects must experience a DLT during the DLT observation period.  Subjects 
in Treatment Group B must receive at least 75% of planned epacadostat doses (63/84) at the 
specified dose level, 2 doses of nivolumab, and 2 doses of lirilumab, or subjects must experience 
a DLT during the DLT observation period. 
Individual subject dose reductions may be made based on events observed at any time during 
treatment with study drug; however, for the purposes of dose cohort escalation/de-escalation, 
expanding a dose cohort, and determining the MTD of epacadostat, decisions will be made based 
on events that are observed from the first day of study drug administration through the 
above-defined DLT observation period for each treatment group.  A lower MTD may 
subsequently be determined based on relevant toxicities that become evident after the DLT 
observation period. 
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5.4.2.2. 
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 30 days.  During follow-up, subjects should be seen as often as medically indicated 
to assure safety. 
5.4.3. 
Procedures for Cohort Review and Dose Escalation 
Regular 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, adjudicate 
individual high-grade AEs as potentially dose-limiting, and guide other major study decisions. 
5.4.4. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Treatment 
General guidelines for management of toxicities are provided in Table 9.  Study treatment may 
be delayed up to 4 weeks (28 days) to allow for resolution of toxicity.  If a dose interruption is 
necessary, all study treatment components should be interrupted.   
Subjects may resume treatment if no medical condition or other circumstance exists that, in the 
opinion of the investigator, would make further participation in the study unsuitable.  The 
treating investigator should contact the sponsor to discuss the case of any subject whose 
treatment has been delayed for more than 4 weeks (28 days) before restarting treatment with the 
study drugs. 
Individual decisions regarding dose interruption or reduction should be made using clinical 
judgment and in consultation with the sponsor's medical monitor, taking into account relatedness 
of the AE to the study drug and the subject's underlying condition.  Adverse events that have a 
clear alternative explanation 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 therapy (eg, elective surgery, unrelated medical events, subject vacation, and/or 
holidays).  Subjects should be placed back on study therapy 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 study record. 
5.4.4.1. 
Epacadostat Dose Modifications 
Table 8 describes epacadostat dose reductions that may occur due to any related AEs.  Dose 
reductions should occur in a step-wise fashion from the initial starting dose of the cohort, and a 
maximum of 2 dose reductions of epacadostat are allowed for the management of an AE.  If an 
AE recurs/does not return to baseline after the second dose reduction of epacadostat, then the 
subject must permanently discontinue epacadostat.  
The lowest permissible dose of epacadostat is 25 mg BID.  If a subject does not tolerate 25 mg 
BID, then the subject must permanently discontinue epacadostat.  If epacadostat is discontinued 
after 2 dose reductions, or if a 25 mg BID dose is not tolerated, the subject may resume treatment 
with nivolumab monotherapy (or nivolumab with ipilimumab, if applicable) once criteria for 
restarting study treatment have been met with approval from the medical monitor.  
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Table 8: 
Dose Reductions of Epacadostat (Treatment Groups A and B) 
Dose of Epacadostat 
Dose Level -1 
Dose Level -2 
First Reduction of  Epacadostat 
Second Reduction of  Epacadostat 
100 mg BID 
50 mg BID 
25 mg BID 
50 mg BID 
25 mg BID 
N/A – Discontinue Treatment 
25 mg BID 
N/A – Discontinue Treatment 
N/A – Discontinue Treatment 
5.4.4.2. 
Nivolumab, Ipilimumab, and Lirilumab Dose Modifications 
There will be no dose reductions of nivolumab, ipilimumab, or lirilumab allowed for the 
management of toxicities of individual subjects.  Doses of these agents are held for toxicity 
management, per Table 9.  See Section 5.4.5 for dose modification and toxicity management 
guidelines pertaining to specific irAEs. 
Table 9: 
General Guidelines for Interruption and Restarting of Study Treatment 
CTCAE  
Grade/Severity 
Hold 
Treatment 
(Y/N) 
Timing for  
Restarting 
Treatment 
Dose Level for 
Restarting  
Epacadostat 
Dose Level for 
Restarting Nivolumab 
and Ipilimumab 
(Treatment Group A), 
or Nivolumab and 
Lirilumab     
(Treatment Group B) 
Treatment 
Discontinuation 
1-2 
(Mild-moderate) 
No 
Continue treatment 
at the discretion of 
the investigator. 
N/A – If held, 
restart at same 
dose. 
NA - If held, restart at 
same dose. 
N/A 
3
a 
(Severe) 
Yes 
Toxicity resolves to 
Grade 0-1. 
Reduce by 
1 dose level.
b 
Restart same dose. 
Toxicity does not 
resolve within 
4 weeks (28 days) of 
last dose, except by 
approval of the 
medical monitor. 
OR 
Second occurrence of 
previously resolved 
Grade 3 AE. 
4
c 
(Life-threatening) 
Yes 
Permanent 
discontinuation, 
except by approval 
of the medical 
monitor. 
If continuing, 
toxicity must 
resolve to 
Grade 0-1. 
Permanent 
discontinuation, 
except by 
approval of the 
medical monitor. 
If continuing, 
reduce by 1 dose 
level.b 
Permanent 
discontinuation, except 
by approval of the 
medical monitor.c 
If continuing, restart 
same dose. 
Permanent 
discontinuation for 
any severe or 
life-threatening event, 
except by approval of 
the medical monitor. 
a Grade 3 amylase or lipase abnormalities that are not associated with symptoms or clinical manifestations of pancreatitis do not 
require a dose delay.  It is recommended to consult with the medical monitor for Grade 3 amylase or lipase abnormalities. 
b See Table 8 for epacadostat dose reduction guidelines.  See Section 5.4.8 for study treatment withdrawal criteria.  
c Isolated Grade 4 lipase or amylase abnormalities not associated with symptoms or clinical manifestations of pancreatitis may 
not require treatment discontinuation.  Medical monitor should be consulted for any Grade 4 amylase or lipase abnormality. 
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5.4.5. 
Management of Immune-Related Adverse Events 
Adverse events of a potential immunologic etiology or irAEs may be defined as an AE 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 mechanism of action, and reported experience with these and other immunotherapies.  If an 
irAE is suspected, efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or 
other etiologic causes before categorizing an AE as an irAE.  Subjects who develop a ≥ Grade 2 
irAE should be discussed immediately with the sponsor. 
Elevations in amylase or lipase that are ≥ Grade 3 do not require dose interruption or reduction if 
the subject is asymptomatic or if the elevation is clinically insignificant or has been discussed 
with the medical monitor. 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested measures for the management of drug-related AEs with 
potential immunologic etiology are outlined in Table 10.  Detailed management guidelines for 
specific irAEs can be in found in Section 5.4.5.1 through Section 5.4.5.7 and Appendix B.  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 might require specific supportive care.   
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Table 10: 
General Guidelines for Immune-Related Adverse Events 
irAE 
Guidance for 
Interrupting or 
Discontinuing Study 
Treatment  
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic 
treatment. 
Grade 2 
May withhold study 
treatment per 
investigator's discretion. 
May resume treatment if improves to 
Grade ≤ 1 within 6 weeks.  If AE resolves 
within 4 weeks, subject may restart at the 
same dose and schedule.   
For an AE that does not resolve within 
4 weeks, epacadostat should be reduced 
1 dose level
a, but nivolumab and 
ipilimumab (Treatment Group A) or 
lirilumab (Treatment Group B) will be 
restarted at the same dose and schedule.  
If AE does not resolve within 6 weeks, 
study treatment with all study drugs 
should be discontinued or discussed with 
medical monitor. 
Consider systemic 
corticosteroids in addition to 
appropriate symptomatic 
treatment. 
Grade 3  
Withhold study treatment 
until AE improves to 
Grade ≤ 1. 
Discontinue if unable to 
reduce corticosteroid 
dose to < 10 mg/day of 
prednisone or equivalent 
within 6 weeks of 
toxicity. 
 
Any restart of study treatment must be 
discussed with medical monitor.  
Epacadostat should be reduced 1 dose 
level after AE has resolved to Grade ≤ 1. 
Systemic corticosteroids are 
indicated in addition to 
appropriate symptomatic 
treatment.  May use 1 to 
2 mg/kg prednisone or 
equivalent per day. 
Steroid taper should be 
considered once symptoms 
improve to ≤ Grade 1 and 
tapered over at least 4 weeks 
in most cases. 
Grade 4 
Discontinue study 
treatment.a 
Not applicable.  Any exceptions require 
medical monitor approval. 
Systemic corticosteroids are 
indicated in addition to 
appropriate symptomatic 
treatment.  May use 1 to 
2 mg/kg prednisone or 
equivalent per day. 
Steroid taper should be 
considered once symptoms 
improve to ≤ Grade 1 and 
tapered over at least 4 weeks 
in most cases. 
a See Section 5.4.8 for study treatment withdrawal criteria. 
Note:  Detailed management guidelines for specific irAEs can be found in Sections 5.4.5.1 through 5.4.5.7. 
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5.4.5.1. 
Procedures and Guidelines for Pneumonitis 
All study treatment should be interrupted in subjects with symptomatic pneumonitis and an 
immediate evaluation should be performed.  The evaluation may include bronchoscopy to rule 
out other causes such as infection.  If the subject is determined to have study drug−associated 
pneumonitis, the recommended treatment plan is detailed in Table 11. 
Table 11: 
Guidelines for Management of Noninfectious Pneumonitis 
Study Drug(s) 
Associated 
Pneumonitis 
Withhold/Discontinue 
Nivolumab and 
Epacadostat 
Guidance for Restarting Study Treatment 
Supportive Care 
Grade 1 
(asymptomatic) 
No action. 
Not applicable. 
Intervention not 
indicated. 
Grade 2 
Withhold study 
treatment. 
First episode of pneumonitis: 
• If improves to near baseline:   
o Decrease the dose of epacadostat by 
1 dose level; for nivolumab and 
ipilimumab (Treatment Group A) or 
lirilumab (Treatment Group B), restart 
at same dose and schedule subsequent 
cycles. 
• If not improved after 2 weeks or 
worsening permanently discontinue all 
study treatment.   
Second episode of pneumonitis: 
• Permanently discontinue all study 
treatment if, upon rechallenge, subject 
develops pneumonitis ≥ Grade 2. 
Systemic 
corticosteroids are 
indicated.  Taper if 
necessary. 
Grade 3 and 4 
Discontinue study 
treatment. 
Not applicable.  Any exceptions require 
medical monitor approval. 
Systemic 
corticosteroids are 
indicated.  The use 
of infliximab may 
be indicated as 
appropriate.  See to 
Appendix B for 
additional 
recommendations. 
Note:  See Appendix B for additional guidance regarding management of noninfectious pneumonitis.  
5.4.5.2. 
Procedures and Guidelines for Enterocolitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as diarrhea, 
abdominal pain, mucus or blood in stool, with or without fever) and of bowel perforation (such 
as peritoneal signs and ileus).  In symptomatic subjects, infectious etiologies should be ruled out 
and endoscopic evaluation should be considered for persistent or severe symptoms.  All study 
treatment should be interrupted immediately for Grade ≥ 2 enterocolitis.  Recommendations for 
management of enterocolitis are shown in Table 12, as well as additional information in 
Appendix B. 
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Table 12: 
Guidelines for Management of Enterocolitis 
Study 
Drug(s) 
Associated 
Enterocolitis 
Withhold/Discontinue  
Nivolumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
All subjects who experience 
diarrhea should be advised to 
drink liberal quantities of clear 
fluids.  If sufficient oral fluid 
intake is not feasible, fluid and 
electrolytes should be 
substituted via IV infusion.  An 
antidiarrheal can be started. 
Grade 2 
Withhold study 
treatment. 
 
May return to treatment if improves 
to ≤ Grade 1.  If AE resolves within 
4 weeks, subject may restart at the 
same dose and schedule for both 
nivolumab and ipilimumab 
(Treatment Group A) or lirilumab 
(Treatment Group B). 
For an AE that resolves to ≤ Grade 1 
between 4 and 6 weeks after onset, 
epacadostat should be reduced 1 dose 
level, but nivolumab and ipilimumab 
(Treatment Group A) or lirilumab 
(Treatment Group B) may be 
restarted at the same dose and 
schedule.  If AE does not resolve to 
≤ Grade 1 within 6 weeks, all study 
treatment should be discontinued or 
discussed with medical monitor. 
An antidiarrheal should be 
started.  If symptoms are 
persistent for > 1 week, 
systemic corticosteroids should 
be initiated (eg, 0.5-1 mg/kg 
per day of prednisone or 
equivalent).  When symptoms 
improve to ≤ Grade 1, 
corticosteroid taper should be 
started and continued over at 
least 1 month. 
Grade 3 and 4 
Discontinue study 
treatment. 
Not applicable.  Any exceptions 
require medical monitor approval. 
Treatment with systemic 
corticosteroids should be 
initiated at a dose of 1 to 
2 mg/kg per day of prednisone 
or equivalent.  Systemic 
corticosteroids are indicated.  
The use of infliximab may be 
indicated as appropriate.  When 
symptoms improve to 
≤ Grade 1, corticosteroid taper 
should be started and continued 
over at least 1 month. 
Note:  See Appendix B for additional guidance regarding management of enterocolitis. 
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5.4.5.3. 
Procedures and Guidance for Hepatitis 
Liver chemistry tests (hepatic transaminase and bilirubin levels) should be monitored and signs 
and symptoms of hepatotoxicity should be assessed before each dose of nivolumab and 
epacadostat.  In subjects with hepatotoxicity, infectious or malignant causes should be ruled out 
and frequency of LFT monitoring should be increased until resolution.  Recommendations for 
management of hepatitis are shown in Table 13 as well as additional information for 
management and follow-up in Appendix B.  
Table 13: 
Recommended Approach for Handling Hepatitis 
Study Drug(s) 
Associated 
Hepatitis 
Withhold/Discontinue 
Nivolumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Increase frequency of LFT 
monitoring to twice per week 
until LFTs return to baseline, or 
consult with medical monitor. 
Note:  Twice weekly testing is 
not required for subjects with 
Grade 1 LFT values at baseline 
until Grade ≥ 2 LFT elevations 
are observed. 
Grade 2 
Withhold study 
treatment. 
If AE resolves to ≤ Grade 1 or 
baseline within 4 weeks, subject 
may restart at the same dose and 
schedule for both nivolumab and 
ipilimumab (Treatment Group A) 
or lirilumab (Treatment Group B).  
For an AE that resolves to 
≤ Grade 1 between 4 and 6 weeks 
after onset, epacadostat should be 
reduced 1 dose level, but 
nivolumab and ipilimumab 
(Treatment Group A) or lirilumab 
(Treatment Group B) may be 
restarted at the same dose and 
schedule.  If AE does not resolve to 
≤ Grade 1 within 6 weeks, all study 
treatment should be discontinued. 
Increase frequency of LFT 
monitoring to twice per week 
until LFTs return to baseline.  If 
elevation persists for > 1 week, 
systemic corticosteroids should 
be initiated (eg, 0.5 mg/kg per 
day of prednisone or 
equivalent).  When symptoms 
improve to ≤ Grade 1, 
corticosteroid taper should be 
started and continued over at 
least 1 month. 
Grades 3 and 4 
Discontinue study 
treatment. 
Not applicable.  Any exceptions 
require medical monitor approval. 
Increase frequency of LFT 
monitoring to every 1-2 days.  
Treatment with systemic 
corticosteroids should be 
initiated at a dose of 1 to 
2 mg/kg per day of prednisone 
or equivalent.  When symptoms 
improve to ≤ Grade 1, 
corticosteroid taper should be 
started and continued over at 
least 1 month. 
Note:  See Appendix B for additional guidance regarding management of hepatitis.  
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5.4.5.4. 
Procedures for Immune-Mediated Dermatitis 
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.  Recommendations for management of dermatitis are shown in Table 14 as 
well as additional information for management and follow-up in Appendix B. 
Table 14: 
Recommended Approach for Handling Dermatitis 
irAE 
Withhold/Discontinue 
Nivolumab and Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
For mild to moderate 
dermatitis, such as localized 
rash and pruritus, treat 
symptomatically.  
Administer topical or 
systemic corticosteroids if 
there is no improvement of 
symptoms within 1 week. 
Grade 2 
No action. 
Not applicable. 
For mild to moderate 
dermatitis, such as localized 
rash and pruritus, treat 
symptomatically.  
Administer topical or 
systemic corticosteroids if 
there is no improvement of 
symptoms within 1 week. 
Grades 3 
and 4 
Withhold study treatment in 
subjects with moderate to 
severe signs and symptoms of 
rash.   
Permanently discontinue study 
treatment in subjects with 
Stevens-Johnson syndrome, 
toxic epidermal necrolysis, or 
rash complicated by full 
thickness dermal ulceration or 
by necrotic, bullous, or 
hemorrhagic manifestations. 
If AE resolves to baseline within 
4 weeks, subject may restart at 
the same dose and schedule for 
both epacadostat and nivolumab 
and ipilimumab (Treatment 
Group A) or lirilumab (Treatment 
Group B).  For an AE that 
resolves to ≤ Grade 1 between 
4 and 6 after onset, epacadostat 
should be reduced 1 dose level, 
but nivolumab and ipilimumab 
(Treatment Group A) or lirilumab 
(Treatment Group B) may be 
restarted at the same dose and 
schedule.  If AE does not resolve 
to ≤ Grade 1 within 6 weeks, all 
study treatment should be 
discontinued or discussed with 
medical monitor. 
Administer systemic 
corticosteroids at a dose of 
1 to 2 mg/kg per day of 
prednisone or equivalent.  
When dermatitis is 
controlled, corticosteroid 
tapering should occur over a 
period of at least 1 month. 
Note:  See Appendix B for additional guidance regarding management of dermatitis.  
5.4.5.5. 
Procedures for Immune-Mediated Neuropathies 
Subjects should be monitored for symptoms of motor or sensory neuropathy such as unilateral or 
bilateral weakness, sensory alterations, or paresthesia.  Recommendations for management of 
neuropathies are shown in Table 15 as well as additional information for management and 
follow-up in Appendix B.  
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Table 15: 
Recommended Approach for Handling Neuropathies 
irAE 
Withhold/Discontinue 
Nivolumab and Epacadostat 
Guidance for Restarting 
Study Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic 
treatment. 
Grade 2 
May withhold study 
treatment. 
If AE resolves to ≤ Grade 1 or 
baseline within 4 weeks, 
subject may restart at the same 
dose and schedule for 
epacadostat, nivolumab and 
ipilimumab (Treatment 
Group A) or lirilumab 
(Treatment Group B).  For an 
AE that does not resolve within 
4 weeks, epacadostat should be 
reduced 1 dose level but 
nivolumab ipilimumab 
(Treatment Group A) or 
lirilumab (Treatment Group B) 
may be restarted at the same 
dose and schedule.  If AE does 
not resolve within 6 weeks, 
study treatment with both 
study drugs should be 
discontinued or discussed with 
medical monitor. 
Consider systemic 
corticosteroids in addition to 
appropriate symptomatic 
treatment. 
Grades 3 and 4 
Discontinue study treatment. 
Not applicable.  Any 
exceptions require medical 
monitor approval. 
Consider initiation of systemic 
corticosteroids at a dose of 1 to 
2 mg/kg per day prednisone or 
equivalent for severe 
neuropathies.   
Institute medical intervention 
as appropriate for management 
of severe neuropathy.   
Note:  See Appendix B for additional guidance regarding management of neuropathies. 
5.4.5.6. 
Procedures for Immune-Mediated Endocrinopathies 
Subjects should be monitored for clinical signs and symptoms of hypophysitis, adrenal 
insufficiency (including adrenal crisis), and hyper- or hypothyroidism.  Subjects may present 
with fatigue, headache, mental status changes, abdominal pain, unusual bowel habits, and 
hypotension or with nonspecific symptoms which 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. 
Thyroid function tests and clinical chemistries should be monitored at the start of treatment, 
before each dose, and as clinically indicated based on symptoms.  In a limited number of 
subjects, hypophysitis has been diagnosed by imaging studies through enlargement of the 
pituitary gland.  Recommendations for management of endocrinopathies are shown in Table 16.  
For additional information on detailed management of asymptomatic TSH elevation versus 
symptomatic endocrinopathy, see Appendix B. 
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Table 16: 
Recommended Approach for Handling Endocrinopathies 
irAE 
Withhold/Discontinue 
Nivolumab and 
Epacadostat 
Guidance for Restarting Study 
Treatment 
Supportive Care 
Grade 1 
No action. 
Not applicable. 
Provide symptomatic 
treatment. 
Grade 2 
May withhold study 
treatment. 
If AE resolves within 4 weeks, subject 
may restart at the same dose and schedule 
for epacadostat, nivolumab, and 
ipilimumab (Treatment Group A) or 
lirilumab (Treatment Group B).  For an 
AE that does not resolve within 4 weeks, 
epacadostat should be reduced 1 dose 
level but nivolumab and ipilimumab 
(Treatment Group A) or lirilumab 
(Treatment Group B) may be restarted at 
the same dose and schedule.  If AE does 
not resolve within 6 weeks, study 
treatment should be discontinued. 
Initiate systemic corticosteroids 
treatment at a dose of 1 to 
2 mg/kg per day of prednisone 
or equivalent, and initiate 
appropriate hormone 
replacement therapy. 
Grade 3  
Withhold or discontinue 
study treatment.  
 
 
If AE resolves or is controlled within 
4 weeks, subject may restart at the same 
dose and schedule for epacadostat, 
nivolumab and ipilimumab (Treatment 
Group A) or lirilumab (Treatment Group 
B).  For an AE that does not resolve 
within 4 weeks, epacadostat should be 
reduced 1 dose level, but nivolumab and 
ipilimumab (Treatment Group A) or 
lirilumab (Treatment Group B) may be 
restarted at the same dose and schedule.  
If AE does not resolve within 6 weeks, 
study treatment should be discontinued. 
Consider initiating systemic 
corticosteroids treatment at a 
dose of 1 to 2 mg/kg per day of 
prednisone or equivalent, and 
initiate appropriate hormone 
replacement therapy. 
Grade 4  
Discontinue study 
treatment. 
Not applicable.  Any exceptions require 
medical monitor approval. 
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.   
Note:  See Appendix B for additional guidance regarding management of endocrinopathies. 
5.4.5.7. 
Procedures for Other Immune-Mediated Adverse Reactions, Including Ocular 
Manifestations 
All study treatment should be permanently discontinued for severe immune-mediated adverse 
reactions.  Systemic corticosteroids treatment should be initiated at a dose of 1 to 2 mg/kg per 
day of prednisone or equivalent for severe immune-mediated adverse reactions. 
Corticosteroid eye drops should be administered to subjects who develop uveitis, iritis, or 
episcleritis.  All study treatment should be permanently discontinued for immune-mediated 
ocular disease that is unresponsive to local immunosuppressive therapy.   
For additional management and follow-up guidance for renal immune events see Appendix B. 
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5.4.6. 
Procedure for Subjects Exhibiting Serotonin Syndrome 
As noted in Section 1.2.1, there is a risk that epacadostat may 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. 
Serotonin syndrome usually manifests with autonomic changes, mental status changes, and 
neurological findings.  These mild, moderate, and severe signs and symptoms of SS (summarized 
in Table 17) should be evaluated in the context of possible comorbid conditions as well. 
The following procedures will be implemented if subjects exhibit the signs/symptoms of SS 
described in Table 17, including tremor; hyperreflexia; and spontaneous, ocular, or inducible 
clonus, together with agitation, fever, diaphoresis, or muscle rigidity: 
• Immediately interrupt all treatment 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 etiologies other than SS are excluded, nivolumab and ipilimumab administration 
may be resumed unless other AE management guidelines apply for the specific event. 
• If subject chooses to withdraw from the study or must restart treatment with SSRI or 
SNRI, the subject should be scheduled for a follow-up visit.  Treatment with SSRI or 
SNRI may be initiated 2 weeks after resolution of signs and symptoms of SS. 
• If a subject had experienced moderate or severe unconfounded SS in the opinion of 
the investigator, without concomitant SSRI or SNRI use, or serotonergic concomitant 
medications, only nivolumab/ipilimumab administration may be resumed; 
epacadostat treatment should be permanently discontinued. 
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Table 17: 
Sign and Symptoms of Serotonin Syndrome 
Seriousness 
Autonomic Signs 
Neurological Signs 
Mental Status 
Other 
Mild 
Afebrile or low-
grade fever 
Tachycardia 
Mydriasis 
Diaphoresis or 
shivering 
Intermittent tremor 
Akathisia 
Myoclonus 
Mild hyperreflexia 
Restlessness 
Anxiety 
 
Moderate 
Increased tachycardia 
Fever (up to 41°C) 
Diarrhea with 
hyperactive bowel 
sounds 
Diaphoresis with 
normal skin color 
Hyperreflexia 
Inducible clonus 
Ocular clonus (slow 
continuous lateral 
eye movements) 
Myoclonus 
Easily startled 
Increased confusion 
Agitation and 
hypervigilance 
Rhabdomyolysis 
Metabolic acidosis 
Renal failure 
Disseminated 
intravascular 
coagulopathy 
(secondary to 
hyperthermia) 
Severe 
Temperature often 
more than 41°C 
(Secondary to 
increased tone) 
Increased muscle 
tone (lower limb > 
upper) 
Spontaneous clonus 
Substantial 
myoclonus or 
hyperreflexia 
Delirium 
Coma 
As above 
Source:  Boyer and Shannon 2005. 
5.4.7. 
Management of Infusion Reactions 
Table 18 shows treatment guidelines for subjects who experience an infusion reaction associated 
with administration of nivolumab, ipilimumab, or lirilumab.  Signs and symptoms usually 
develop during or shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.   
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Table 18: 
Infusion Reaction Treatment Guidelines 
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 
medically indicated until the subject is 
deemed medically stable, in the opinion of the 
investigator. 
None. 
Grade 2: 
Requires infusion interruption 
but responds promptly to 
symptomatic treatment  
(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 
medically 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 
medically indicated until the subject is 
deemed medically stable, in the opinion of the 
investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further study treatment. 
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 readily available during the period of 
drug administration. 
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5.4.8. 
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 drug 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 epacadostat, or dose reductions 
below 25 mg BID.   
• ≥ Grade 2 ocular irAE. 
• Occurrence of an AE that is related to treatment with the study drug that, in the 
judgment of the investigator or the sponsor's medical monitor, 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 therapy for more than 4 weeks (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 
Subjects may withdraw consent at any time for any reason or be withdrawn from study treatment 
at the discretion of the investigator should any untoward effect occur.  In addition, a subject may 
be withdrawn by the investigator or the sponsor if enrollment in the study is inappropriate, the 
study plan is violated, or for administrative and/or other safety reasons. 
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 health care 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. 
• Further participation would be injurious to the subject's health or well-being, in the 
investigator's medical judgment. 
• Unacceptable toxicity (see Section 5.4.8).  Subjects with unacceptable toxicities must 
be withdrawn from study treatment but will continue in the safety follow-up period of 
the study (see Section 6.4). 
• The subject has received study treatment for 2 years (ie, 24 months have elapsed 
since Cycle 1 Day 1). 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
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If a follow-up scan was not performed after unconfirmed PD (eg, due to patient refusal or patient 
death), the initial date of unconfirmed progression will be considered the date of PD.   
Table 19: 
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease 
 
Clinically Stable 
Clinically Unstable 
Imaging 
Treatment 
Imaging 
Treatment 
Initial unconfirmed 
progressive disease 
(iUPD) OR 
subsequent iUPD 
after iSD, iPR or iCR. 
Repeat imaging at 
≥ 4 and ≤ 8 weeks to 
confirm PD. 
May continue study 
treatment at the 
investigator's 
discretion while 
awaiting 
confirmatory scan. 
Repeat imaging at 
≥ 4 weeks to confirm 
PD if possible. 
Discontinue 
treatment. 
Next evaluable  scan 
confirms PD (iCPD). 
No additional 
imaging required. 
Discontinue 
treatment. 
No additional 
imaging required. 
N/A 
Repeat scan shows 
iUPD, iSD, iPR, or 
iCR.
a 
Continue regularly 
scheduled imaging 
assessments at 8 and 
16 weeks after the 
start of treatment and 
then every 12 weeks 
(± 7 days) thereafter. 
Continue study 
treatment at the 
investigator's 
discretion. 
Continue regularly 
scheduled imaging 
assessments at 8 and 
16 weeks after the 
start of treatment and 
then every 12 weeks 
(± 7 days) thereafter. 
May restart study 
treatment if condition 
has improved and/or 
is clinically stable 
per investigator's 
discretion. 
a iSD, iPR, and iCR is based on baseline or nadir. 
In determining whether the tumor burden has increased or decreased, investigators should 
consider all baseline and any new target lesions as well as baseline and any new nontarget 
lesions.  
Progressive disease (iCPD) is confirmed if further increase in tumor burden, compared to the last 
assessment, is seen as evidenced by one or more of the following: 
• Continued increase in tumor burden (from iUPD) where RECIST 1.1 definitions of 
progression had been met (from nadir) in target, nontarget disease or new lesions 
− Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum; 
− Continued unequivocal progression in nontarget disease with an increase in tumor 
burden; 
− Increase in size of previously identified new lesion(s) (an increase of at least 
5 mm in the absolute value of the sum of those considered to be target new 
lesions) or additional new lesions 
• RECIST v1.1 criteria are met in lesions types (target or nontarget or new lesions) 
where progression was not previously identified, including the appearance of 
additional new lesions. 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned 
(iUPD if the criteria are still met, but no worsening, or iSD, iPR, or iCR if those criteria are met 
compared to baseline).  As can be seen in Table 19, the prior documentation of iUPD does not 
preclude assigning iCR, iPR, or iSD in subsequent time-point assessments or as best overall 
response providing that iCPD is not documented at the next assessment after iUPD. 
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5.5.2. 
Withdrawal Procedures 
In the event that the decision is made to permanently discontinue the study drug, the subject will 
be withdrawn from the study and the EOT visit should be conducted.  Reasonable efforts should 
be made to have the subject return for the safety follow-up visit (see Section 6.4).  The last date 
of the last dose of study drug and the reason for subject withdrawal will be recorded in the eCRF. 
If a subject is withdrawn from all study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal 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.  
• The EOT visit should be performed. 
• The date of the EOT visit should be recorded in the eCRF and IRT. 
• Subjects must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities resolve, return to baseline, or are deemed irreversible, or 
until the subject begins new anticancer therapy, whichever is longest. 
If the subject discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety 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 
safety follow-up period. 
5.6. 
Concomitant Medications 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the study.  If there is a clinical indication for one of these or other medications, 
discontinuation from study therapy may be required.  The investigator should discuss any 
questions regarding this with the sponsor.  The final decision on any supportive therapy rests 
with the investigator and/or the subject's primary physician.  However, the decision to continue 
the subject on study therapy requires the mutual agreement of the investigator, the sponsor, and 
the subject. 
All concomitant medications received within 28 days before the first dose of study treatment and 
30 days after the last dose of study treatment should be recorded.  Concomitant medications 
administered in the 30 days after the last dose of study treatment should be recorded for SAEs 
and AEs as defined in Section 8. 
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 medication will be recorded on the eCRF, including all 
prescription, over-the-counter, 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 on the eCRF. 
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5.6.2. 
Restricted Medications 
• Systemic steroids may be used at doses ≤ 10 mg/day prednisone or equivalents. 
• Use of coumarin-based anticoagulants is discouraged.  Low-dose warfarin (1 mg) is 
acceptable; however, doses that increase the INR are discouraged and will require 
dose modification.  If an alternative to coumarin-based anticoagulants cannot be used, 
dose modifications of the warfarin may be needed.  Based on the observed magnitude 
of epacadostat/warfarin PK interaction and PK/pharmacodynamic modeling results, 
for an epacadostat dose of 300 mg BID, the dose of warfarin should be reduced by 
approximately one-third after initiation of epacadostat administration based on 
approximately 30% to 40% reduction in S- and R-warfarin oral clearance values.  
Close INR monitoring is recommended for subjects on a stable dose of warfarin who 
are starting treatment with epacadostat.  Based on PK/pharmacodynamic modeling, 
recommendations for warfarin dose modifications for subjects receiving other 
epacadostat doses are summarized in Table 20 based on the INR before starting 
epacadostat. 
Table 20: 
Recommendations for Warfarin Dose Modifications 
Stable Baseline INR 
Epacadostat Dose 
≤ 100 mg BID 
200 mg BID 
300 mg BID 
INR ≤ 2.5 
Close INR monitoring 
Close INR monitoring 
Reduce warfarin by 
~33% and monitor INR 
INR > 2.5 
Close INR monitoring 
Reduce warfarin by 
20%-25% and 
monitor INR 
Reduce warfarin by 
~33% and monitor INR 
• Use of the anticonvulsant carbamazepine (a UGT1A9 inducer) is prohibited; an 
alternative to carbamazepine should be used, if possible. 
5.6.3. 
Prohibited Medications 
Subjects are prohibited from receiving the following therapies starting from screening through 
EOT period of this study unless otherwise noted below: 
• Any investigational medication other than the study drugs.  
• Any anticancer medications, including chemotherapy or biologic therapy other than 
the study medications. 
• Any chronic immunosuppressive treatment for any reason.  (Note:  Inhaled or topical 
steroids are allowed, and systemic steroids at doses ≤ 10 mg/day of prednisone or 
equivalents are allowed, as described in Section 5.6.2, and immune suppressants are 
allowed for short-term treatment for immune toxicities or as prophylaxis for contrast 
allergy for imaging procedures.) 
• Radiation therapy. 
Note:  In the presence of a mixed response (some lesions improving or stable and 
other lesions progressing), radiation therapy to a symptomatic solitary lesion or to the 
brain is allowed.  
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• Administration of a live attenuated vaccine 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, BCG, and typhoid 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. 
• Any MAOI or drug associated with significant MAOI activity agents is prohibited 
from 21 days before Day 1 through 2 weeks after the final dose of epacadostat has 
been administered (see Appendix D). 
• Any immunologic-based treatment for any reason from screening through follow-up 
visit is prohibited. 
Note:  Completed adjuvant therapy (eg, vaccines) with medical monitor approval, 
inhaled or topical steroids, and systemic steroids at doses ≤ 10 mg/day prednisone 
equivalents are allowed, as described in Section 5.6.2.   
• Any UGT1A9 inhibitor or inducer, including aceclofenac, acitretin, amitriptyline, 
androsterone, carbamazepine, cyclosporine, dasatinib, diclofenac, diflunisal, 
efavirenz, erlotinib, estradiol (17-beta), flutamide, gefitinib, gemfibrozil, 
glycyrrhetinic acid, glycyrrhizin, imatinib, imipramine, ketoconazole, lamotrigine, 
linoleic acid supplements, mefenamic acid, mycophenolic acid, niflumic acid, 
nilotinib, oxcarbazepine, phenobarbital, phenylbutazone, phenytoin, probenecid 
propofol, quinidine, rifampin, 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 medical monitor.  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 (Section 3.2) describe other medications that are prohibited during this 
study.  There are no prohibited therapies during the post-treatment follow-up period. 
6. 
STUDY ASSESSMENTS 
All study assessments will be performed as indicated in the schedule of clinical assessments 
(Table 21 and Table 23), and all laboratory assessments will be performed as indicated in 
Table 22 and Table 24.  Table 25 presents a summary of local 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. 
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Table 21: 
Schedule of Clinical Assessments – Treatment Group A (Epacadostat + Nivolumab + Ipilimumab) 
Visit 
Screening 
Treatment Period (14-Day Cycles) 
EOT 
Safety Follow-Up
b 
Comments 
Cycles 1 Through 3 
Cycle 4 
and 
Beyond 
Disease 
Status
a 
Day 1 
Day 8 
Day 1 
See 
Footnote a 
30 Days 
After EOT 
100 Days 
After EOT 
Evaluation/Window 
Days -28 
to -1 
± 3 Days 
± 1 Day 
± 3 Days 
± 7 Days + 7 Days 
+ 7 Days 
± 7 Days 
Administrative Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
Contact IRT 
X 
X 
 
X 
 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Prior medical and cancer 
history 
X 
 
 
 
 
 
 
 
 
Prior and concomitant 
medications 
X 
X 
X 
X 
 
X 
X 
X 
 
Reminder card 
 
X 
X 
X 
 
X 
X 
 
 
Clinical Procedures/Assessments 
Comprehensive physical 
examination and height 
X 
 
 
 
 
 
 
 
 
Targeted physical 
examination 
 
X 
X
b 
X 
 
X 
X 
X 
 
Vital signs and weight 
X 
X 
X 
X 
 
X 
X 
X 
 
ECOG performance status 
X 
 
 
 
 
 
 
 
 
Laboratory assessments 
X 
X 
X 
X 
 
X 
X 
 
See Table 22 for required laboratory 
assessments. 
12-Lead ECG  
X 
X* 
 
 
 
X 
 
 
* Cycle 1 Day 1 and Cycle 2 Day 1.  
See Section 7.5.4 for details. 
AE assessment 
X 
X 
X 
X 
 
X 
X 
X 
 
Tumor tissue collection 
X 
 
 
 
 
 
 
 
Only Phase 1 subjects.  See Table 22 for 
Phase 2 fresh biopsy collection timepoints. 
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Table 22: 
Schedule of Laboratory Assessments – Treatment Group A (Epacadostat + Nivolumab + Ipilimumab) 
Visit 
Screening 
Treatment Period (14-Day Cycles) 
EOT 
Follow-Up 
Comments 
Cycles 1 Through 3 
Cycle 4 and 
Beyond 
30 Days 
After EOT 
Day 1 
Day 8 
Day 1 
Evaluation/Window 
Days -28 
to -1 
± 3 Days 
± 1 Day 
± 3 Days 
+ 7 Days 
+ 7 Days 
Local Laboratory Tests
a 
Serum chemistry 
X 
X 
X 
X 
X 
X 
Additional assessment of serum chemistry as clinically indicated. 
Hematology with differential 
X 
X 
 
X 
X 
X 
Additional assessment of hematology as clinically indicated. 
Liver chemistry tests 
X 
X 
X 
X 
X 
X 
If baseline liver chemistry tests are WNL and increase to ≥ Grade 1, 
testing should be performed twice weekly until resolved to baseline.  If 
baseline liver chemistry tests were Grade 1 at baseline and increase to 
≥ Grade 2, twice weekly testing should be performed until resolved to 
≤ Grade 1. 
Coagulation panel 
X 
 
 
X 
X 
 
Screening, Cycle 4, and every 3rd cycle thereafter. 
Endocrine function tests 
X 
 
 
X 
X 
X 
Screening, Cycle 4, and every 3rd cycle thereafter. 
Urinalysis 
X 
 
 
 
X 
 
 
Hepatitis B and C 
X 
 
 
 
 
 
 
Serum pregnancy test
b 
(childbearing females only) 
X 
 
 
 
X 
 
Required for all women of childbearing potential during screening; 
must be within 72 hours before the first dose of study treatment. 
a All safety laboratory assessments will be performed locally. 
b Urine pregnancy tests may be conducted at additional time points as medically indicated. 
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Table 23: 
Schedule of Clinical Assessments – Treatment Group B (Epacadostat + Nivolumab + Lirilumab) 
Visit 
Screening 
Treatment Period (14-Day Cycles) 
EOT 
Follow-Up 
Comments 
Cycles 1 
Through 3 
Cycle 4 and 
Beyond 
Disease 
Status
a 
Safety
b 
Disease 
Status
c Survival 
Day 1 
Day 8 
Day 1 
Q8W 
30 Days 
After EOT 
100 Days 
After EOT 
150 Days 
After EOT Q8W 
Q12W 
Evaluation/Window 
Days -28 
to -1 
± 3 Days ± 1 Day 
± 3 Days 
± 7 Days + 7 days + 7 Days 
± 7 Days 
± 7 Days ± 7 Days ± 7 Days 
Administrative Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Contact IRT 
X 
X 
 
X 
 
X 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Prior medical and cancer 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and concomitant 
medications 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
Reminder card  
 
X 
X 
X 
 
X 
X 
X 
 
 
 
 
Poststudy anticancer 
therapy status 
 
 
 
 
 
 
X 
X 
X 
X 
X 
 
Survival status 
 
 
 
 
 
 
 
 
 
 
X 
 
Clinical Procedures/Assessments 
Comprehensive physical 
examination and height 
X 
 
 
 
 
 
 
 
 
 
 
 
Targeted physical 
examination 
 
X 
X
d 
X 
 
X 
X 
X 
X 
 
 
Only required for Day 8 
visits if there are ongoing 
AEs > Grade 2. 
Vital signs and weight 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
ECOG performance status 
X 
X 
 
X 
 
 
X 
X 
X 
 
 
 
Laboratory assessments 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
See Table 22 for required 
laboratory assessments. 
HPV status 
X 
 
 
 
 
 
 
 
 
 
 
Subjects with SCCHN 
(oropharyngeal only) must 
have documentation of HPV 
status (eg, p16 expression). 
12-Lead ECG  
X 
X* 
 
 
 
X 
 
 
 
 
 
* Cycle 1 Day 1 and Cycle 2 
Day 1. 
See Section 7.5.4 for details. 
AE assessment 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
 
 
Tumor tissue collection 
X 
 
 
 
 
 
 
 
 
 
 
Only Phase 1 subjects.  See 
Table 24 for Phase 2 fresh 
biopsy collection timepoints. 
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Table 24: 
Schedule of Laboratory Assessments – Treatment Group B (Epacadostat + Nivolumab + Lirilumab) 
Visit 
Screening 
Treatment Period (14-Day Cycles) 
EOT 
Follow-Up 
Comments 
Cycles 1 
Through 3 
Cycle 4 and 
Beyond 
30 Days After 
EOT 
Day 1 
Day 8 
Day 1 
Evaluation/Window 
Days -28 
to -1 
± 3 Days ± 1 Day 
± 3 Days 
+ 7 Days 
± 7 Days 
Local Laboratory Tests
a 
Serum chemistry 
X 
X 
X 
X 
X 
X 
Additional assessment of serum chemistry as clinically indicated. 
Hematology with differential 
X 
X 
 
X 
X 
X 
Additional assessment of hematology as clinically indicated. 
Liver chemistry tests 
X 
X 
X 
X 
X 
X 
If baseline liver chemistry tests are WNL and increase to 
≥ Grade 1, testing should be performed twice weekly until 
resolved to baseline.  If baseline liver chemistry tests were Grade 1 
at baseline and increase to ≥ Grade 2, twice weekly testing should 
be performed until resolved to ≤ Grade 1. 
Coagulation panel 
X 
 
 
X 
X 
 
Screening, Cycle 4, and every 3rd cycle thereafter. 
Endocrine function tests 
X 
 
 
X 
X 
X 
Screening, Cycle 4, and every 3rd cycle thereafter. 
Urinalysis 
X 
 
 
 
X 
 
 
Hepatitis B and C 
X 
 
 
 
 
 
 
Serum pregnancy test
b 
(childbearing females only) 
X 
 
 
 
X 
 
Required for all women of childbearing potential during screening 
and must be within 72 hours before the first dose of study 
treatment. 
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Table 24: 
Schedule of Laboratory Assessments – Treatment Group B (Epacadostat + Nivolumab + Lirilumab) 
(Continued) 
Visit 
Screening 
Treatment Period (14-Day Cycles) 
EOT 
Follow-Up 
Comments 
Cycles 1 
Through 3 
Cycle 4 and 
Beyond 
30 Days After 
EOT 
Day 1 
Day 8 
Day 1 
Evaluation/Window 
Days -28 
to -1 
± 3 Days ± 1 Day 
± 3 Days 
+ 7 Days 
± 7 Days 
a All safety laboratory assessments will be performed locally. 
b Urine pregnancy tests may be conducted at additional time points as medically indicated. 
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Table 25: 
Local Laboratory Tests:  Required Analytes 
Serum Chemistries 
Hematology 
Urinalysis 
Hepatitis Screening 
Endocrine Function Tests 
Albumin 
Bicarbonate 
Blood urea nitrogen 
Calcium 
Chloride  
Creatinine 
Glucose 
Lactate dehydrogenase 
Phosphate 
Potassium 
Sodium 
Total protein 
Uric acid 
Amylase 
Lipase 
Complete blood count, including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• White blood cell count 
 
Differential count, including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
 
Absolute values must be provided 
for:  
• Lymphocytes 
• Neutrophils 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Hepatitis B surface antigen 
HBV-DNA 
HCV-RNA or HCV antibody where 
is HCV RNA is not SOC 
Adrenocorticotropic hormone 
Serum cortisol (9 AM)
a 
Luteinizing hormone
b 
Prolactin 
TSH 
Free thyroxine (T4) 
Total triiodothyronine (T3) 
Serum testosterone (9AM)a,b 
Liver Chemistry Tests 
Pregnancy Testing 
Coagulation 
Alkaline phosphatase 
ALT 
AST 
Total bilirubin 
Direct bilirubin (if total bilirubin is 
elevated above ULN) 
Female subjects of childbearing 
potential only require a serum test at 
screening. 
Pregnancy tests (serum or urine) 
should be repeated if required by 
local regulations. 
PT or INR 
aPTT or PTT 
a Serum cortisol and testosterone ideally should be drawn close to 9 AM but can be performed any time before 12 PM. 
b Not needed in women, surgically castrated men, or men taking LH-releasing hormone agonist therapy.
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6.1. 
Screening 
Screening is the interval between signing the ICF and the day when the subject is enrolled and 
receives the first dose of study treatment (Cycle 1 Day 1); the total screening period must not 
exceed 28 days.  Informed consent must be obtained before performing any study-specific 
procedures that are not considered standard of care.  Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during the screening 
process. 
Procedures conducted as part of the subject's routine clinical management (eg, blood count, 
imaging) and obtained before the signing of informed consent may be used for screening or 
baseline purposes, provided the procedure meets the Protocol-defined criteria and has been 
performed in the timeframe of the study.  All information associated with eligibility requirements 
must be entered into the appropriate eCRF pages. 
Results from the screening visit evaluations will be reviewed to confirm subject eligibility before 
enrollment or administration of study treatment.  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. 
6.2. 
Treatment 
The treatment period begins on the day the subject receives the first dose of study treatment 
(Cycle 1 Day 1) through the point at which the investigator determines 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 no more than 3 days after the date of enrollment into the 
study (ie, enrollment in the IRT system).  At Cycle 1 Day 1, results from screening visit 
evaluations should be reviewed to determine whether the subject continues to meet the eligibility 
requirements as specified in the Protocol.  Subjects will have regularly scheduled study visits as 
outlined in Table 21 and Table 22 (as applicable to treatment group assignment), and toxicities 
will be monitored continuously and will be graded using NCI CTCAE v4.03. 
6.3. 
End of Treatment 
When the subject permanently discontinues all components of 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 from the EOT visit should be entered 
into the eCRF.  The subject should be encouraged to return for the safety follow-up visit. 
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 
visits, which should occur approximately 30 days (+ 7 days), 100 days (± 7 days), and 150 days 
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(± 7 days; Treatment Group B only) 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 
100 days after the last dose of study treatment for Treatment Group A, up until at least 150 days 
after the last dose of study treatment for Treatment Group B, 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 to 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 safety 
follow-up period, the applicable safety follow-up visit should be performed before new 
anticancer therapy is started.  After the safety follow-up period, there will be no additional 
assessments and the study will be considered complete.  
6.5. 
End of Study 
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 this study. 
− Subjects may choose to withdraw from the study at any time without penalty of 
jeopardizing their health care or loss of benefits to which they are otherwise 
entitled.  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. 
• The subject completes the safety follow-up period. 
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. 
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7. 
CONDUCT OF STUDY ASSESSMENTS AND PROCEDURES 
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 source documentation.  
Subjects of childbearing potential must agree to take appropriate measures to avoid pregnancy in 
order to participate in the study (see Appendix A). 
7.2. 
Interactive Response Technology Procedure 
IRT will be contacted to obtain a subject identification number when a subject enters the 
screening period.  Upon determining that the subject is eligible for study entry, IRT will be 
contacted to enroll the subject and obtain treatment group assignment.  Additionally, IRT will be 
contacted at each Day 1 visit during the treatment period, as appropriate, to update the relevant 
treatment supply.  IRT will also be contacted at the last dose of study treatment. 
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 should include all active conditions 
and any condition considered to be clinically significant by the investigator. 
7.3.2. 
Disease Characteristics and Treatment History 
Details regarding the disease for which the subject has enrolled in this study (eg, date of 
diagnosis, primary tumor histology, previous systemic therapies, surgeries, radiation therapy, and 
stage of cancer) will be collected at screening.  In addition, disease-relevant biomarker 
information is required where available (eg, NSCLC:  EGFR, BRAF, ALK, and ROS1 status; 
MEL:  V600-activating BRAF mutation status; SCCHN:  HPV status, p16 status [if primary 
tumor location is oropharynx]; PDAC:  CA 19-9 level; CRC:  MSI status, CEA level; gastric 
cancer:  EBV status, H. pylori status, CA 19-9 level; ovarian cancer:  BRCA1 and BRCA2 
status, CA 125 level).  These items will be recorded separately and will not be listed in medical 
history. 
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 Cycle 1 
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Day 1 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, or 
natural/herbal preparations 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 restricted and 
prohibited medications. 
7.5. 
Safety Assessments 
7.5.1. 
Adverse Events  
Adverse events will be monitored from the time the subject signs 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 
relationship with the study drug.  The definition, reporting, and recording requirements for AEs 
are described in Section 8. 
7.5.2. 
Physical Examinations 
Clinically notable abnormalities that are considered clinically significant in the judgment of the 
investigator are to be reported as AEs. 
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. 
7.5.2.1. 
Comprehensive Physical Examination 
The comprehensive physical examination will include height and the following organ or body 
system assessments:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; cardiovascular 
system; abdomen (liver, spleen); extremities; lymph nodes; and a brief neurologic examination.  
Clinically significant abnormal findings before Cycle 1 Day 1 should be recorded as medical 
history.  New clinically significant abnormal findings observed after Cycle 1 Day 1 should be 
recorded as AEs. 
7.5.2.2. 
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. 
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7.5.5.1. 
Serum Chemistry 
A comprehensive serum chemistry will be performed as indicated in Table 22 and Table 24; 
required analytes for this panel are listed in Table 25.  Additional assessment of serum chemistry 
may be conducted as clinically indicated (ie, if results are abnormal).  Appropriate monitoring 
intervals should be discussed with the medical monitor in these circumstances.  Serum chemistry 
tests will be performed by the site's local laboratory. 
7.5.5.2. 
Liver Chemistry 
Liver chemistry tests will be performed as indicated in Table 22 and Table 24; required analytes 
for this panel are listed in Table 25.  Liver chemistry testing will be performed weekly during the 
first 3 treatment cycles.  If liver chemistry tests are elevated, see the guidance in Section 5.4.5.3.  
Liver chemistry test monitoring for persistent low-grade abnormalities does not need to be 
monitored on a biweekly basis indefinitely.  Appropriate LFT monitoring intervals should be 
discussed with the medical monitor for these circumstances.  Liver chemistry tests will be 
performed by the site's local laboratory. 
7.5.5.3. 
Hematology 
Hematology with differential will be performed as indicated in Table 22 and Table 24; required 
analytes for this panel are listed in Table 25.  Additional assessment of hematology with 
differential may be conducted as clinically indicated (ie, if results are abnormal).  Appropriate 
monitoring intervals should be discussed with the medical monitor in these circumstances.  
Hematology with differential will be performed by the site's local laboratory. 
7.5.5.4. 
Coagulation Panel 
A coagulation panel will be performed as indicated in Table 22 and Table 24; required analytes 
for this panel are listed in Table 25.  The coagulation panel will be analyzed by the site's local 
laboratory. 
7.5.5.5. 
Endocrine Function 
Endocrine function tests will be performed as indicated in Table 22 and Table 24; required 
analytes for this panel are listed in Table 25.  The endocrine function tests will be analyzed by 
the site's local laboratory. 
7.5.5.6. 
Urinalysis 
Urinalysis will be performed as indicated in Table 22 and Table 24; required analytes for this 
panel are listed in Table 25.  The urinalysis results will be analyzed by the site's local laboratory. 
7.5.5.7. 
Hepatitis Screening Tests 
Hepatitis screening assessments will be performed at the screening visit to rule out hepatitis 
infection; required analytes are shown in Table 25.  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. 
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7.5.5.8. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential at screening and 
at the EOT visit.  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 conducted as 
outlined in Table 12 and Table 24, as medically indicated, or per country-specific requirements.  
Urine pregnancy tests will be done locally.  If a urine pregnancy test is positive, the results 
should be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, 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 drug and continue participation in the study. 
7.6. 
Efficacy Assessments 
7.6.1. 
Assessment of Disease 
Overall tumor response will be assessed using RECIST v1.1 
 may be 
used to guide treatment decisions for discontinuation of therapy due to disease progression.  
See Section 5.5.1.1 for specific guidance regarding continuation of therapy after iUPD is 
observed.  
7.6.2. 
Initial Tumor Imaging 
Initial tumor imaging must be performed within 28 days before the first dose of treatment.  The 
site study team must review prestudy images to confirm that the subject has measurable disease 
per RECIST v1.1. 
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 
treatment.  The same imaging technique should be used for an individual 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 PET/CT uses 
higher energy and thinner slices, it may be acceptable with medical monitor approval.  A 
standard, full assessment for lesions should be conducted at baseline, including CT or MRI scans 
of chest, abdomen, and pelvis; subjects with SCCHN should also have imaging of the neck 
performed.  Computed tomography 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 MEL.  Brain MRIs 
should also be considered when disease burden due to any targeted tumor types is extensive 
(ie, when ≥ 3 metastatic disease sites are involved).  The same modality (CT or MRI) should be 
used for follow-up assessments, including radiologic assessments of all sites of disease present at 
baseline, at 8 and 16 weeks (± 7 days) after the start of treatment, and then 12 weeks (± 7 days) 
thereafter until the end of study treatment.  In addition to radiologic monitoring, all other lesions 
observed at the screening visit should be followed. 
For selection of target lesions, RECIST v1.1 should be followed.  For example, RECIST v1.1 
discourages selection of target lesions inside the field of previous irradiation.  Lesions situated in 
a previously irradiated area or in an area subjected to other locoregional therapy are usually not 
considered measurable, unless the area is the solitary site of measurable disease, AND there has 
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been demonstrated progression in the lesion.  Also, if a subject has only 1 measurable lesion, this 
lesion should not be biopsied. 
7.6.3. 
Tumor Imaging During the Study 
Tumor imaging, including photographs, should be continued on-treatment if skin lesion is 
present and assessed clinically, and the same imaging technique should be used to assess disease 
status throughout the study.  Imaging should be performed at 8 and 16 weeks (± 7 days) from the 
first dose of treatment and then every 12 weeks (± 7 days) thereafter or more frequently if 
clinically indicated until the end of study treatment.  Imaging should follow calendar days 
starting with Day 1 of study treatment and should not be adjusted for delays in cycle starts. 
Per RECIST v1.1 
, 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 of 4 weeks after the first indication of 
response or at the next scheduled scan, whichever is clinically indicated. 
Imaging should continue to be performed until documented iCPD (see Section 5.5.1.1), 
discontinuation of all study treatment, withdrawal of consent, death, or the end of the study, 
whichever occurs first. 
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7.8. 
Other Study Procedures 
7.8.1. 
Distribution of Subject Reminder Cards and Subject Diaries 
Subjects will be provided with reminder cards at each visit.  All necessary instructions, such as 
administration instructions for epacadostat, concomitant medications, and reminders of visits to 
conduct laboratory tests, should be provided to the subject in writing on this reminder card, or on 
accompanying written materials.  Subject diaries will be provided for the purpose of 
documenting epacadostat administration and AEs.  The subject diary will have an area on which 
the date and time of the last dose of epacadostat taken before each visit will be recorded as well 
as the time (and content, if applicable to the visit) of the last meal.  On Cycle 1 Day 1, subjects 
will also be given an SS information sheet for signs and symptoms of SS.  This information sheet 
also instructs subjects to seek immediate medical care if any of these symptoms are observed. 
8. 
SAFETY MONITORING AND REPORTING 
8.1. 
Adverse Events 
8.1.1. 
Definitions 
For the purposes of this Protocol, an adverse event (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 drug(s). 
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 100 days after the last dose of study treatment for 
Treatment Group A, and 150 after the last dose of study treatment for Treatment Group B.  
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. 
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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 
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 drug. 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, 
recovering/resolving, recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per serious adverse event (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 the study drug, the interventions required to 
treat the event, and the outcome. 
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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 drug) 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 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.  
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 a 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. 
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• 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 drug(s) or study 
procedure or disease progression), occurring after the subject has signed the ICF through the last 
study visit (or 100 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 
SAEs occurring more than 100 days for Treatment Group A and 150 days for Treatment Group 
B after the last dose of study drug should be reported to the sponsor or its designee only if the 
investigator suspects a causal relationship to the study drugs.   
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 the study 
treatment.  The investigator must also complete the Incyte Serious Adverse Event 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 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 drug 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 drug (new occurrence) and is thought to be 
related to the sponsor's study drug, 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 (IN) to inform all investigators involved in any 
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study with the same drug that this SAE has been reported.  Suspected Unexpected Serious 
Adverse Reactions (SUSARs) 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. 
8.5. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug 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 drug, 
the following procedures should be followed in order to ensure subject safety: 
• The study drug 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. 
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 drug 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 drug, derived from safety information collected by 
the sponsor or its designee, are presented in the Investigator's Brochure (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. 
Safety Monitoring Committee 
For Phase 1, approximately weekly, the sponsor will conduct telephone conferences with 
investigators to review dose level–specific data, overall safety data from prior dose levels (if 
applicable), and to agree on dose escalation, dose de-escalation, and cohort expansion decisions.  
For Phase 2, a safety monitoring committee (SMC) will review safety data at regular intervals 
throughout the study.  The frequency of meetings will be contingent upon enrollment and 
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9.2. 
Selection of Sample Size 
9.2.1. 
Sample Size in Phase 1 
A 3 + 3 + 3 dose escalation design will be used in Phase 1 to determine the MTD or PAD and 
DLT(s) of epacadostat when given in combination with nivolumab and ipilimumab (Treatment 
Group A) and nivolumab and lirilumab (Treatment Group B).  The total number of subjects will 
depend on the frequency of DLTs and number of dose levels tested before MTD or PAD is 
established.  Based on 3 + 3 + 3 design algorithm, within each treatment group, a minimum of 
3 subjects and up to 9 subjects will be enrolled at each dose level. 
9.2.2. 
Sample Size in Phase 2 
The Phase 2 dose expansions will evaluate the efficacy and further evaluate the safety, 
tolerability, 
 of the MTD or PAD of epacadostat determined 
in each of the Phase 1 treatment groups in select solid tumors.  A sample size of 35 subjects is 
expected to be enrolled in Cohorts A1, A2, and B1 (Table 30).  The sample size for the 
Cohort A1 (MEL) yields a power of 80% to detect a target ORR of about 20% increase 
(Ha:  79%) from historical response rate (H0:  59%).  For Cohort A2 (NSCLC), this yields a 
power of 80% to detect a target ORR of about 22% increase (Ha:  52%) from historical response 
rate (H0:  30%).  For Cohort B1 (SCCHN), this yields a power of 80% to detect a target ORR of 
about 22% increase (Ha:  46%) from historical response rate (H0:  24%).  This assumes a 1-sided 
alpha of 5%.  Subjects who undergo serial prestudy and on-treatment tumor biopsies in 
expansion Cohorts A1, A2, and B1 may be at risk of being nonevaluable for response; therefore, 
additional subjects may be enrolled in a specific efficacy expansion cohort to achieve a minimum 
35 response-evaluable subjects.   
Table 30: 
Sample Size Calculation for Each Phase 2 Cohort:  Comparing to a Known 
Proportion 
Efficacy Expansion Cohort 
H0 
Ha 
Sample Size 
MEL (A1) 
59% 
79% 
35 
NSCLC (A2) 
30% 
52% 
35 
SCCHN (B1) 
24% 
46% 
35 
9.3. 
Level of Significance 
Phase 1 of the study is exploratory and no formal statistical tests will be performed.  Unless 
otherwise specified, all CIs will be at the 95% confidence level. 
The level of significance for each of the Phase 2 cohorts (A1, A2, and B1) is 1-sided 5% for the 
analysis of the primary endpoint of ORR. 
9.4. 
Statistical Analyses 
Note:  As Amendment 2 will serve to discontinue the study to further enrollment, limited safety 
and efficacy analyses will be performed.  Listings will be substituted for summary tables for 
efficacy analyses.  Summary tables will only be provided for selected safety analyses. 
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the AE to study drug, the AE will be considered treatment-related.  The incidence of AEs and 
treatment-related AEs will be tabulated. 
9.4.2.2. 
Clinical Laboratory Tests 
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. 
• For laboratory parameters where CTCAE grades are not defined, shift tables to the 
worst postbaseline value using the low/normal/high classifications based on 
laboratory reference ranges. 
9.4.2.3. 
Vital Signs 
Descriptive statistics and mean change from baseline will be determined for vital signs (blood 
pressure, pulse, respiratory rate, and body temperature) at each assessment time.  Vital sign 
results will be reviewed for clinically notable abnormalities (see Table 31), and subjects 
exhibiting clinically notable vital sign abnormalities will be listed.  A value will be considered an 
"alert" value if it is outside the established range and shows a > 25% change from baseline. 
Table 31: 
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/min 
< 8/min 
9.4.2.4. 
Electrocardiograms 
Descriptive statistics and mean change from baseline will be determined for each ECG parameter 
at each assessment time.  Electrocardiogram results will be reviewed for clinically notable 
abnormalities according to predefined criteria (Table 32).  Subjects exhibiting clinically notable 
ECG abnormalities will be listed. 
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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 Drug 
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 drug to the study site. 
• Inventory of study drug at the site. 
• Subject use of the study drug including pill or unit counts from each supply 
dispensed. 
• Return of study drug to the investigator or designee by subjects. 
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 
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study drug.  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 drug 
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 drug 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 drug 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 Electronic Data Capture 
(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, HIPAA).  
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 
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 
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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 Code of Federal Regulations (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 Corporation (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. 
REFERENCES 
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Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: 
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Gangadhar TC, Hamid O, Smith DC, et al. Epacadostat (INCB024360) plus pembrolizumab in 
patients with advanced melanoma and select solid tumors: updated phase 1 results from ECHO 
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ASCO Annual Meeting 2017; June 2-6, 2017; Chicago, IL; Abstract 9014. 
Goldman JW, Antonia SJ, Gettingger SN, et al 2017  Nivolumab plus ipilimumab as first-line 
treatment for advanced NSCLC: 2-yr OS and long-term outcomes from CheckMate 012.  Poster 
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Hamid O, Chasalow SD, Tsuchihashi S, Alaparthy S, Galbraith S, Berman D. Association of 
baseline and on-study tumor biopsy markers with clinical activity in patients with advanced 
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Hamid O, Bauer TM, Spira AI, et al.  Epacadostat plus pembrolizumab in patients with SCCHN: 
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Hellmann MD, Gettinger SN, Goldman J, et al. CheckMate 012: Safety and efficacy of first-line 
nivolumab and ipilimumab in advanced NSCLC. J Clin Oncol 2016;34(suppl):Abstract 3001. 
Huang L, Baban B, Johnson BA 3rd, Mellor AL. Dendritic cells, indoleamine 2,3 dioxygenase 
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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 
• Vasectomised 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 provided of avoiding pregnancy that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised 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. MANAGEMENT GUIDELINES FOR IMMUNE-RELATED 
ADVERSE EVENTS  
These general guidelines constitute guidance to the investigator and may be supplemented by 
discussions with the medical monitor representing the sponsor.  The guidance applies to all 
immuno-oncology (I-O) agents and regimens.  
 
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice.  Noninflammatory etiologies should be considered and appropriately 
treated.  
 
Corticosteroids are a primary therapy for I-O drug-related adverse events.  The oral equivalent of 
the recommended IV doses may be considered for ambulatory patients with low-grade toxicity.  
The lower bioavailability of oral corticosteroids should be taken into account when switching to 
the equivalent dose of oral corticosteroids.  
 
Consultation with a medical or surgical specialist, especially prior to an invasive diagnostic or 
therapeutic procedure, is recommended.  
The frequency and severity of the related adverse events covered by these algorithms will depend 
on the I-O agent or regimen being used. 
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APPENDIX D. 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 
 
 
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APPENDIX E. RESPONSE EVALUATION CRITERIA IN SOLID 
TUMORS V1.1 
RECIST v1.1* will be used in this study for assessment of tumor response.  While either 
computed tomography or magnetic resonance imaging may be used, as per RECIST v1.1, 
computed tomography is the preferred imaging technique in this study. 
* As published in the European Journal of Cancer: 
Source:  Eisenhauer et al 2009. 
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APPENDIX F. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
31 JUL 2017 
Amendment (Version) 2: 
05 DEC 2018 
Amendment 2 (05 DEC 2018)  
Overall Rationale for the Amendment: 
The primary purpose of this amendment is to close the study to future enrollment and provide 
guidance for subjects continuing on study treatment under a simplified assessment schedule, and 
to allow for the discontinuation of epacadostat while continuing treatment with nivolumab and 
ipilimumab. 
1. Synopsis; Section 4.1, Overall Study Design; Section 9.4, Statistical Analyses 
Description of change:  Note was added indicating that Amendment 2 will serve to close 
the study to further enrollment and update the assessment schedule for subjects enrolled 
to date in Treatment Group A, and that limited safety and efficacy analyses will be 
performed. 
Rationale for change: To state the purpose of Amendment 2. 
2. Synopsis; Section 1.7, Rationale for Dose and Schedule of the Combination 
Therapies; Section 5.2.1, Epacadostat 
Description of change:  The option to discontinue epacadostat treatment while 
continuing nivolumab and ipilimumab treatment was added.  
Rationale for change: In the Phase 3 ECHO-301/KEYNOTE-252 study evaluating 
pembrolizumab plus epacadostat 100 mg BID versus pembrolizumab alone, the 
combination of pembrolizumab and epacadostat did not result in greater clinical benefit 
than pembrolizumab alone.  Thus, it is unlikely that doses of epacadostat being evaluated 
in the ECHO-208 study in combination with nivolumab and ipilimumab will result in 
clinical benefit. 
3. Synopsis; Section 6, Study Assessments (Table 21); Section 5.5, Withdrawal of 
Subjects From Study Treatment; Section 6.3, End of Treatment; Section 6.4, 
Follow-Up; Section 6.5, End of Study; Section 7.5, Poststudy Anticancer Therapy; 
Section 7.10.2, Data Collection for Survival Follow-Up 
Description of change:  The post-treatment disease status and survival follow-up periods 
have been removed from the Protocol. 
Rationale for change:  The sponsor has determined that post-treatment disease status 
and survival follow-up data are no longer needed.  
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