Conditions: Lung Cancer
Keywords: Non-small cell lung cancer programmed cell death protein 1 (PD-1) antibody indoleamine 2,3-dioxygenase (IDO) inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: no

Brief summary:
The purpose of this study was to evaluate the efficacy and safety of the combination of nivolumab plus epacadostat in combination with platinum chemotherapy compared with platinum chemotherapy alone, in participants with treatment-naïve Stage 4 or recurrent non-small cell lung cancer (NSCLC).

Detailed description:

Arms:
arm 1: Nivolumab plus epacadostat in combination with platinum doublet arm 2: Platinum doublet chemotherapy arm 3: Nivolumab plus placebo in combination with platinum doublet chemotherapy.

Interventions: intervention 1: Nivolumab intervention 2: Epacadostat intervention 3: Placebo intervention 4: Carboplatin intervention 5: Cisplatin intervention 6: Gemcitabine intervention 7: Paclitaxel intervention 8: Pemetrexed
Intervention descriptions: intervention 1: Nivolumab administered intravenously at the protocol-defined dose every 3 weeks. intervention 2: Epacadostat administered orally at the protocol-defined dose twice daily. intervention 3: Matching placebo for epacadostat administered orally twice daily. intervention 4: Carboplatin administered intravenously at the protocol-defined dose every 3 weeks for up to 4 cycles. intervention 5: Cisplatin administered intravenously at the protocol-defined dose every 3 weeks for up to 4 cycles. intervention 6: Gemcitabine administered intravenously at the protocol-defined dose every 3 weeks for up to 4 cycles. intervention 7: Paclitaxel administered intravenously at the protocol-defined dose every 3 weeks for up to 4 cycles. intervention 8: Pemetrexed administered intravenously at the protocol-defined dose every 3 weeks for up to 4 cycles. Optional continuation maintenance every 3 weeks, if eligible.

Protocol document:
Prot_000.pdf: 
Page: 1 
Protocol Number: CA2099NC / INCB 24360-309 
IND Number: 135,467 
EX-US Non-IND 
EUDRACT Number: 2017-003304-43 
Date: 15-Sep-2017
Revised Date: 23-Oct-2017
Clinical Protocol CA2099NC / INCB 24360-309 / NCT03348904
A Phase 3, Randomized, Global Trial of Nivolumab and Epacadostat with Platinum Doublet 
Chemotherapy versus Platinum Doublet Chemotherapy in First-line Treatment of Stage IV or 
Recurrent Non-Small Cell Lung Cancer (NSCLC) 
ECHO 309, Epacadostat Clinical Development in Hematology and Oncology  
CheckMate 9NC, CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 
Revised Protocol Number: 01 
Study Director 
Medical Monitor 
, PhD 
, MD 
 
 
Telephone (office): 
 
Telephone (office): 
 
24-hr Emergency Telephone Number
USA: 
International: 
Global Sponsor of the Study: 
Incyte Corporation (Referenced herein as Sponsor) 
1801 Augustine Cut-Off 
Wilmington, Delaware, 19803, U.S.A. 
(In collaboration with Bristol-Myers Squibb Research and Development) 
Bristol-Myers Squibb Research and Development 
3401 Princeton Pike 
Lawrenceville, NJ 08648 
This study is co-funded by Incyte and Bristol-Myers Squibb Research and Development and will 
be executed by Bristol-Myers Squibb Research and Development on behalf of the sponsor, 
Incyte Corporation. 


Clinical 
Protocol 
CA2099NC / INCB 24360-309 
BMS-
936558 
Nivolumab  
 
 
This document is the confidential and proprietary information of Bristol-Myers Squibb 
Company and its global affiliates (BMS). By reviewing this document, you agree to keep it 
confidential and to use and disclose it solely for the purpose of assessing whether your 
organization will participate in and/or the performance of the proposed BMS sponsored 
study. Any permitted disclosures will be made only on a confidential "need to know" basis 
within your organization or to your independent ethics committee(s). Any other use, copying, 
disclosure or dissemination of this information is strictly prohibited unless expressly 
authorized in writing by BMS. Any supplemental information (eg, amendments) that may 
be added to this document is also confidential and proprietary to BMS and must be kept in 
confidence in the same manner as the contents of this document. Any person who receives 
this document without due authorization from BMS is requested to return it to BMS or 
promptly destroy it. All other rights reserved. References to BMS in this protocol may apply 
to partners to which BMS has transferred obligations, eg, a Contract Research Organization 
(CRO). 
Replace all previous version(s) of the protocol with this revised protocol and please provide a copy 
of this revised protocol to all study personnel under your supervision, and archive the previous 
versions. 
 
 


Clinical 
Protocol 
CA2099NC / INCB 24360-309 
BMS-
936558 
Nivolumab  
 
 
OVERALL RATIONALE FOR DRAFT REVISED PROTOCOL 01: 
The CA2099NC revised protocol complies with the 
 to require ALK and 
ROS1 testing and to identify expected toxicities from study drugs.  
 
SUMMARY OF KEY CHANGES FOR DRAFT REVISED PROTOCOL 01 
Section 
Number & 
Title 
Description of Change 
Brief Rationale 
Section 2 
Schedule of 
Assessments 
ALK and ROS1 rearrangement 
tests are required as part of 
inclusion/exclusion criteria 
ALK and ROS1 testing are required 
 
 
Section 
6.2 
Exclusion 
Criteria 
Exclusion 
criteria 
1b) 
was 
modified to exclude ALK and 
ROS1 rearrangements. 
Exclusion criteria was updated 
  
 
Appendix 12 
Identify expected toxicities from 
study drugs  
Appendix table added 
 
  
All 
Minor 
formatting 
and 
typographical corrections 
Minor, 
therefore 
have 
not 
been 
summarized 
 
 
 
 


TABLE OF CONTENTS 
TITLE PAGE ................................................................................................................ 
DOCUMENT HISTORY .............................................................................................. 
OVERALL RATIONALE FOR DRAFT REVISED PROTOCOL 01: ....................... 
SUMMARY OF KEY CHANGES FOR DRAFT REVISED PROTOCOL 01 ........... 
TABLE OF CONTENTS .............................................................................................. 
1 SYNOPSIS ................................................................................................................. 
2 SCHEDULE OF ACTIVITIES.................................................................................. 
3 INTRODUCTION ..................................................................................................... 
3.1 Study Rationale ................................................................................................. 
3.1.1 Research Hypothesis ................................................................................ 
3.2 Background ....................................................................................................... 
3.2.1 Inhibition of PD-L1 as a Target for Cancer ............................................ 
3.2.2 Inhibition of Indoleamine 2,3-Dioxygenase as a Target for Cancer ....... 
3.2.3 Combination of IDO1 and Immune Checkpoint Inhibition ...................... 
3.2.4 Combination of Immunotherapy with Chemotherapy .............................. 
3.3 Benefit/Risk Assessment .................................................................................. 
3.3.1 Risks From Nivolumab ............................................................................. 
 
3.3.3 Risks for the Combination of Nivolumab plus Epacadostat in 
Combination with Chemotherapy ............................................................... 
4 OBJECTIVES AND ENDPOINTS ........................................................................... 
5 STUDY DESIGN....................................................................................................... 
5.1 Overall Design .................................................................................................. 
5.1.1 Data Monitoring Committee and Other External Committees ................ 
5.1.1.1 Independent Data Monitoring Committee ...................................... 
5.2 Number of Participants ..................................................................................... 
5.3 End of Study Definition .................................................................................... 
5.4 Scientific Rationale for Study Design............................................................... 
5.4.1 Rationale for Chemotherapy in NSCLC .................................................. 
5.4.2 Rationale for PD-1 Inhibitor and IDO1 Inhibitor in Combination with 
Chemotherapy ............................................................................................. 
5.4.2.1 Rationale for Overall Survival and Progression-free Survival as 
Co-Primary Endpoints .......................................................................... 
5.4.3 Rationale for Participant Selection ......................................................... 
5.5 Justification for Dose ........................................................................................ 
5.5.1 Justification for Nivolumab Dose ............................................................ 
5.5.3 Rationale for Shorter Infusion Times for Nivolumab .............................. 
5.5.4 Rationale for the Duration of Treatment with Nivolumab and 
Epacadostat/Placebo for Epacadostat ........................................................ 
5.5.5 Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease .................................................................................... 
6 STUDY POPULATION ............................................................................................ 
6.1 Inclusion Criteria .............................................................................................. 
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6.2 Exclusion Criteria ............................................................................................. 
6.3 Lifestyle Restrictions ........................................................................................ 
6.4 Screen Failures .................................................................................................. 
6.4.1 Retesting During Screening or Lead-In Period ....................................... 
7 TREATMENT ........................................................................................................... 
7.1 Treatments Administered .................................................................................. 
7.1.1 All Arms ................................................................................................... 
7.1.2 Nivolumab ................................................................................................ 
7.1.3 Epacadostat/Placebo for Epacadostat ..................................................... 
7.1.4 Platinum Doublet Chemotherapy ............................................................ 
7.1.4.1 Cisplatin /Gemcitabine ................................................................... 
7.1.4.2 Carboplatin/ Gemcitabine .............................................................. 
7.1.4.3 Cisplatin/Carboplatin and Pemetrexed with or without Pemetrexed 
Continuation Maintenance.................................................................... 
7.1.4.4 Carboplatin/Paclitaxel .................................................................... 
7.2 Method of Treatment Assignment .................................................................... 
7.3 Blinding............................................................................................................. 
7.4 Dosage Modifications ....................................................................................... 
7.4.1 Management Algorithms for Immuno-Oncology Agents ......................... 
7.4.2 Dose Modifications for Immunotherapy (Nivolumab and 
Epacadostat/Placebo for Epacadostat) (Arms A and C) ............................ 
7.4.2.1 Dose Delay Criteria for Nivolumab and Epacadostat/Placebo for 
Epacadostat (Arms A and C) ................................................................ 
7.4.2.2 Dose Modification Criteria for Nivolumab and 
Epacadostat/Placebo for Epacadostat (Arms A and C) ....................... 
7.4.2.3 Recommended Management for Serotonin Syndrome .................... 
7.4.3 Dose Modifications for Chemotherapy .................................................... 
7.4.3.1 Recommended Chemotherapy Dose Reductions for Hematologic 
Toxicity .................................................................................................. 
7.4.3.2 Chemotherapy Dose Reductions for Non-Hematologic Toxicities . 
7.4.4 Treatment of Nivolumab-related Infusion Reactions ............................... 
7.4.5 Criteria to Resume Dosing....................................................................... 
7.4.5.1 Criteria to Resume Nivolumab/Epacadostat/Placebo for 
Epacadostat Dosing .............................................................................. 
7.4.5.2 Criteria to Resume Treatment with Chemotherapy ........................ 
7.5 Preparation/Handling/Storage/Accountability .................................................. 
7.5.1 Retained Samples for Bioavailability / Bioequivalence ........................... 
7.6 Treatment Compliance ...................................................................................... 
7.7 Concomitant Therapy........................................................................................ 
7.7.1 Prohibited and/or Restricted Treatments................................................. 
7.7.2 Other Restrictions and Precautions ......................................................... 
7.7.3 Imaging Restriction and Precaution ........................................................ 
7.7.3.1 Radiation Restriction ...................................................................... 
7.7.4 Permitted Therapy ................................................................................... 
7.7.4.1 Supportive Care Guidelines ............................................................ 
7.8 Treatment After the End of the Study ............................................................... 
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Nivolumab
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8 DISCONTINUATION CRITERIA ........................................................................... 
8.1 Discontinuation from Study Treatment ............................................................ 
8.1.1 Nivolumab and Epacadostat/Placebo for Epacadostat Dose 
Discontinuation (Arms A and C)................................................................. 
8.1.2 Chemotherapy Dose Discontinuation ...................................................... 
8.1.3 Nivolumab and Epacadostat/ Placebo for Epacadostat Treatment Beyond 
Disease Progression ................................................................................... 
8.1.4 Post Study Treatment Study Follow-up.................................................... 
8.2 Discontinuation from the Study ........................................................................ 
8.3 Lost to Follow-Up ............................................................................................. 
9 STUDY ASSESSMENTS AND PROCEDURES ..................................................... 
9.1 Efficacy Assessments ........................................................................................ 
9.1.1 Imaging Assessments for the Study .......................................................... 
9.1.2 Independent Review of Progression ......................................................... 
9.2 Adverse Events ................................................................................................. 
9.2.1 Time Period and Frequency for Collecting AE and SAE Information .... 
9.2.2 Method of Detecting AEs and SAEs ......................................................... 
9.2.3 Follow-up of AEs and SAEs ..................................................................... 
9.2.4 Regulatory Reporting Requirements for SAEs ......................................... 
9.2.5 Pregnancy ................................................................................................ 
9.2.6 Laboratory Test Result Abnormalities ..................................................... 
9.2.7 Potential Drug Induced Liver Injury (DILI) ............................................ 
9.2.8 Other Safety Considerations .................................................................... 
9.3 Overdose ........................................................................................................... 
9.4 Safety ................................................................................................................ 
9.4.1 Physical Examinations ............................................................................. 
9.4.2 Clinical Safety Assessments ..................................................................... 
9.4.2.1 Clinical Safety Laboratory Assessments ......................................... 
9.4.2.2 Electrocardiogram 12-lead Assessment ......................................... 
9.4.3 Imaging Safety Assessment ...................................................................... 
 
9.6 Pharmacodynamics ........................................................................................... 
9.7 Pharmacogenomics ........................................................................................... 
 
 
 
 
 
 
 
 
 
 
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BMS-936558
CA2099NC / INCB 24360-309
Nivolumab
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11 REFERENCES ........................................................................................................ 
12 APPENDICES ......................................................................................................... 
APPENDIX 1 ABBREVIATIONS AND TRADEMARKS ........................................ 
APPENDIX 2 STUDY GOVERNANCE CONSIDERATIONS ................................. 
APPENDIX 3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, 
FOLLOW UP AND REPORTING ......................................................................... 
APPENDIX 4 WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION ..................................................................... 
APPENDIX 5 ECOG PERFORMANCE STATUS ..................................................... 
APPENDIX 6 MANAGEMENT ALGORITHMS ....................................................... 
APPENDIX 7 DOSE MODIFICATIONS FOR EPACADOSTAT/PLACEBO FOR 
EPACADOSTAT .................................................................................................... 
APPENDIX 8 MONOAMINE OXIDASE INHIBITORS AND DRUGS 
ASSOCIATED WITH SIGNIFICANT MONOAMINE OXIDASE INHIBITORY 
ACTIVITY .............................................................................................................. 
APPENDIX 9 UGT1A9 INHIBITORS AND INDUCERS ......................................... 
APPENDIX 10 RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS ........................ 
APPENDIX 11 COUNTRY SPECIFIC REQUIREMENTS ....................................... 
APPENDIX 12 EXPECTED TOXICITIES FOR NIVOLUMAB, EPACADOSTAT, 
CARBOPLATIN, CISPLATIN, GEMCITABINE, PACLITAXEL, AND 
PEMETREXED ...................................................................................................... 
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Clinical 
Protocol 
CA2099NC / INCB 24360-309 
BMS-
936558 
Nivolumab  
 
 
1 
SYNOPSIS 
Protocol Title: A Phase 3, Randomized, Global Trial of Nivolumab and Epacadostat with 
Platinum Doublet Chemotherapy versus Platinum Doublet Chemotherapy in First-line 
Treatment of Stage IV or Recurrent Non-Small Cell Lung Cancer (NSCLC) 
ECHO 309. Epacadostat Clinical Development in Hematology and Oncology 
CheckMate 9NC, CHECKpoint pathway and nivoluMAb clinical Trial Evaluation 
Study Phase: 3 
Rationale: Stage IV non-small cell lung cancer (NSCLC) patients have limited treatment options. 
Despite treatment with platinum chemotherapy, the standard of care for first-line therapy for 
patients with metastatic NSCLC, median survival is approximately 10 months and 5-year survival 
rate is less than 5%. Blockade of immune-checkpoint pathways is now an important therapeutic 
modality for treatment of NSCLC cancer as demonstrated by the clinical utility of PD-1/PD-L1 
antibodies. However, multiple immune inhibitory mechanisms occur concurrently within the 
tumor microenvironment suggesting that combination therapies may be required for optimal 
therapeutic benefit. Ongoing studies are exploring combinations of checkpoint inhibitors as well 
as combinations of checkpoint inhibitors with chemotherapy. The indoleamine-2,3-dioxygenase 
(IDO) pathway is a distinct key immune regulatory pathway responsible for induction and 
maintenance of tumor tolerance. Small molecule inhibitors of IDO1 may provide an innovative 
method to treat advanced malignancies in combination with other anticancer strategies. IDO1 
inhibitors are currently being broadly investigated in combination with immune-based therapies 
and chemotherapy in multiple tumor types. 
This study is being conducted to evaluate the combination of nivolumab, a PD-1 antibody, plus 
epacadostat, an inhibitor of IDO1, in combination with platinum chemotherapy compared with 
platinum chemotherapy alone, in participants with treatment naïve, Stage 4, or recurrent NSCLC. 
A third arm of nivolumab plus placebo for epacadostat in combination with platinum 
chemotherapy will allow estimation of the contribution of components. 
Study Population: Participants with treatment naïve, Stage 4 or recurrent NSCLC; unresectable 
after standard-of-care therapy may enroll. 
Key Inclusion Criteria 
x Histologically confirmed stage IV or recurrent NSCLC per the 8th International Association 
for the Study of Lung Cancer (IASLC) of squamous or non-squamous histology 
x No prior systemic therapy (including targeted therapy for EGFR and ALK/ROS1) given as 
primary therapy for advanced disease  
x Participants with tumors not expressing PD-L1 or expressing PD-L1 at levels between 1 and 
49% assessed using validated test at central laboratory in fresh or recent archival tissue 
obtained no greater than 3 months prior to study enrollment 


Clinical 
Protocol 
CA2099NC / INCB 24360-309 
BMS-
936558 
Nivolumab  
 
 
x  ECOG Performance Status of ≤ 1 
x Measurable disease by CT or MRI per RECIST 1.1 criteria 
x Key Exclusion Criteria 
x Participants with known EGFR mutations, ALK translocations, or ROS1 rearrangements, 
which are sensitive to available targeted inhibitor therapy 
x Participants with interstitial lung disease or active, non-infectious pneumonitis including 
symptomatic and/or requiring treatment 
x Unevaluable PD-L1status or PD-L1 status of t 50% by a central laboratory  
x Participants with an active, known or suspected autoimmune disease. Participants with type I 
diabetes mellitus, or hypothyroidism only requiring hormone replacement, skin disorders not 
requiring systemic treatment are permitted to enroll. 
x Participants with untreated CNS metastases. Participants are eligible if CNS metastases have 
been adequately treated and have neurologically returned to baseline (except for residual signs 
or symptoms related to the CNS treatment) for at least 2 weeks prior to randomization. 
 
Objectives and Endpoints: 
Objective 
Endpoint 
Primary 
To compare overall survival (OS) and progression-free survival 
(PFS) per blinded independent central review (BICR) of 
nivolumab plus epacadostat in combination with chemotherapy 
(Arm A) to chemotherapy (Arm B) in treatment naïve, Stage 4 or 
recurrent NSCLC participants whose tumors express PD-L1 at 0 
to 49%. 
OS 
PFS assessed by BICR 
Secondary 
To compare objective response rate (ORR) and to estimate of 
duration of response (DOR) as assessed by BICR of  nivolumab 
plus epacadostat in combination with chemotherapy (Arm A) to 
chemotherapy (Arm B) in treatment naïve, Stage 4 or recurrent 
NSCLC participants whose tumors express PD-L1 at 0 to 49%. 
ORR and DOR assessed by BICR 
To estimate OS, and PFS, ORR, and DOR per BICR assessment, 
of nivolumab and placebo for epacadostat in combination with 
chemotherapy (Arm C) in treatment naïve, Stage 4 or recurrent 
NSCLC participants whose tumors express PD-L1 at 0 to 49%. 
OS 
PFS, ORR, and DOR per BICR assessment 


Clinical 
Protocol 
CA2099NC / INCB 24360-309 
BMS-
936558 
Nivolumab  
 
 
Objective 
Endpoint 
 


Clinical 
Protocol 
CA2099NC / INCB 24360-309 
BMS-
936558 
Nivolumab  
 
 
Overall Design: 
 
 
Protocol CA2099NC/INCB 24360-309 is a phase 3, randomized, 3 arm trial in participants 
t 18 years old with treatment naïve, Stage 4 or recurrent NSCLC. Participants must have tumors 
not expressing PD-L1 (0%) or expressing PD-L1 at levels between 1 and 49% for whom platinum 
doublet chemotherapy is standard therapy. Patients with PD-L1 levels of t 50% are eligible to 
receive pembrolizumab monotherapy as first line treatment for their disease and are therefore 
excluded from the study. 
The primary objective of the study is to compare PFS and OS in participants treated with 
nivolumab plus epacadostat in combination with platinum doublet chemotherapy versus platinum 
doublet chemotherapy alone. A third arm will assess the efficacy of nivolumab plus placebo for 
epacadostat in combination with platinum doublet chemotherapy in order to estimate the 
contribution of components. Participants will be stratified by PD-L1 status (0% and 1-49%), 
gender (male and female), and histology (squamous and non-squamous). 
The study will be open labelled, except that administration of epacadostat will be double blinded 
between Arm A and Arm C. Epacadostat will be administered to all participants in Arm A; placebo 
for epacadostat will be administered to all participants in Arm C. All participants in Arms A and 
C will receive unblinded nivolumab. All participants in the study (Arms A, B, and C) will receive 
platinum doublet chemotherapy.  
Platinum doublet chemotherapy will be based on tumor histology, for up to 4 cycles: 
x Squamous histology: gemcitabine with cisplatin, or gemcitabine with carboplatin, or paclitaxel 
with carboplatin 


Clinical 
Protocol 
CA2099NC / INCB 24360-309 
BMS-
936558 
Nivolumab  
 
 
x Non-squamous histology: Pemetrexed with either cisplatin or carboplatin; optional 
continuation maintenance therapy with pemetrexed 
 
Treatment Arms and Duration: Approximately 630 participants will be randomized into 1 of 
the 3 treatment arms in a 2:2:1 ratio in the study. These arms include: 
x Arm A: nivolumab plus epacadostat in combination with platinum doublet chemotherapy 
(n = 252) 
x Arm B: platinum doublet chemotherapy (n = 252) 
x Arm C: nivolumab plus placebo for epacadostat in combination with platinum doublet 
chemotherapy (n = 126) 
 
Participants will undergo tumor assessments by CT or MRI every 6 weeks (r7 days) from the date 
of randomization until Week 48 and then every 12 weeks (r7 days) until progression or treatment 
is discontinued, whichever occurs later. Tumor scans will be evaluated by blinded independent 
central review (BICR). 
 
 
 
The post-treatment follow-up begins when the decision to discontinue a participant from all 
treatment is made. Participants without BICR-confirmed disease progression will continue to have 
tumor assessments (if clinically feasible) according to the schedule in Table 2-3.  
Participants will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline, or are deemed irreversible. All adverse events will be documented for a minimum of 
100 days after the last dose of study medication. 
After completion of the first 2 follow-up visits, participants will be followed every 3 months for 
survival. Survival follow-up visits may be performed by phone contact or office visit. BMS may 
request that survival data be collected on all randomized participants outside of the protocol-
defined window. At that time of this request, each participant will be contacted to determine their 
survival status unless the participant had withdrawn consent for all contact. 
The total duration of the study from start of randomization to final analysis of PFS is expected to 
be approximately 25 months, assuming 18 months accrual duration. Final analysis of OS is 
expected to be 38 months after the start of randomization. The study will end once survival 
follow-up has concluded.  
Number of Participants: Approximately 900 participants will be screened and approximately 
630 participants will be randomized.  


Clinical 
Protocol 
CA2099NC / INCB 24360-309 
BMS-
936558 
Nivolumab  
 
 
Study treatment:  
Study Drug for CA2099NC / INCB 24360-309 
Medication  
Potency  
IP/Non-IP  
Nivolumab 
10 mg/ml 
IP 
Carboplatin 
10 mg/ml 
IP 
Cisplatin 
1 mg/ml 
IP 
Epacadostat 
100 mg and 25 mg tablets 
IP 
Epacadostat matching placebo 
(100 mg and 25 mg tablets) 
Not applicable 
IP 
Gemcitabine 
1000 mg/vial 
IP 
Pemetrexed 
500 mg/vial 
IP 
Paclitaxel 
100 mg/vial (6mg/mL) 
IP 
 
 
 


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Clinical Protocol 
 
CA2099NC / INCB 24360-309 
BMS-936558 
 
Nivolumab  
 
 
Table 2-2: 
Short-term Procedural Outline (CA2099NC / INCB 24360-309) 
Procedure 
Cycle 1 Day 1 
(Cycle = 21 days) 
During Each 
Subsequent 
Treatment Visita  
(Cycle = 21 days) 
Notesb 
Study Drug 
 
 
 
Dispense Study Drug 
X 
X 
First dose to be administered within 3 calendar days of randomization.  
For participants with squamous cell histology on gemcitabine, gemcitabine 
is dispensed and administered on Day 1 and Day 8 of each 21 day cycle, 
through cycle 4.   
Safety Assessments 
Targeted Physical 
Examination, Vital Signs, 
Performance Status  
X 
X 
Weight, BP, HR, Temperature, and Performance Status (see Appendix 5). 
Targeted physical examination as clinically indicated. 
Adverse Event Assessments 
Continuously  
Record at each visit. 
SAEs should be approved in RAVE within 5 days from entry. 
Concomitant Medication 
Review 
Continuously 
Record at each visit.  
Laboratory Tests 
Hematology, Chemistry, 
Coagulation 
X 
X 
Refer to Section 9.4.2 for clinical safety laboratory assessments 
Pregnancy Test  
X 
X 
WOCBP only: Serum or urine pregnancy test (minimum sensitivity of 
25 IU/L or equivalent units of HCG). 
ECG (12-lead) 
X 
See notes 
Pre-dose 12-lead ECG on C1D1, C2D1, and end of treatment. 
Clinically significant abnormal ECG findings (by investigator judgment) 
will require triplicate ECGs. See Section 9.4.2.2 
Efficacy Assessments 
Body Imaging 
See notes 
See Section 9.1.1  
Tumor assessments should occur every 6 weeks (r 7 days) until Week 48, 
then every 12 weeks (r 7 days) from randomization until BICR confirmed 
disease progression, lost to follow-up, or withdrawal of consent.  


Clinical Protocol 
 
CA2099NC / INCB 24360-309 
BMS-936558 
 
Nivolumab  
 
 
Table 2-2: 
Short-term Procedural Outline (CA2099NC / INCB 24360-309) 
Procedure 
Cycle 1 Day 1 
(Cycle = 21 days) 
During Each 
Subsequent 
Treatment Visita  
(Cycle = 21 days) 
Notesb 
Brain Imaging 
See notes 
See Section 9.1.1. Participants with a history of brain metastasis should 
have surveillance MRI approximately every 12 weeks (r 7 days) from 
randomization or sooner if clinically indicated. 


Clinical Protocol 
 
CA2099NC / INCB 24360-309 
BMS-936558 
 
Nivolumab  
 
 
Abbreviations: BMI, body mass index; BP, blood pressure; C1D1, Cycle 1, Day 1; C2D1, Cycle 2, Day 1;  CBC, complete blood count; ECG, electrocardiogram; 
HR, heart rate; 
; SAE, serious adverse event; WOCBP, women of childbearing potential.  
a If a dose is delayed, the procedures scheduled for that same time point should also be delayed to coincide with when that time point’s dosing actually occurs 
(except for Efficacy Assessments [Body Imaging and Brain Imaging]) 
b Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations. 


Clinical Protocol 
 
CA2099NC / INCB 24360-309 
BMS-936558 
 
Nivolumab  
 
 
Table 2-3: 
Long-term Procedural Outline (CA2099NC / INCB 24360-309) 
Procedure 
Follow-Up 
Visit 1 and 2a 
Survival 
Follow-upb 
Notesc 
Safety Assessments 
Targeted Physical Examination 
X 
 
As clinically indicated 
Adverse Events Assessment 
Continuously 
Record at each visit. See Section 9.2 
Nonserious AEs are collected for 100 days post-treatment. 
SAEs should be approved in RAVE within 5 days from entry. 
Review of Concomitant Medications 
Continuously 
Record at each visit. Document subsequent cancer therapy 
Laboratory Tests 
Hematology, Chemistry, Coagulation 
X 
 
At Follow-up visit 1. Repeat at Follow-up Visit 2 if toxicities are present.  
Refer to Section 9.4.2 for clinical safety laboratory assessments 
Pregnancy Test  
See notes 
WOCBP only: Once every 4 weeks for 5 months after the last dose of nivolumab.  
Efficacy Assessment 
Body Imaging 
See notes 
See Section 9.1.1  
x 
Only for participants without BICR confirmed progression.  
x 
Radiographic assessments for participants who have not experienced 
BICR-confirmed PD should be obtained every 6 weeks (r 7 days) from 
randomization until Week 48 and not delayed until follow-up visits 1 and 2.   
x 
After week 48 and if follow-up visits 1 & 2 have been completed, scans should 
be obtained every 12 weeks (r7days) until BICR confirmed PD, lost to 
follow-up, or withdrawal of consent. 
Brain Imaging 
See notes 
See Section 9.1.1.  
Participants with a history of brain metastasis should have surveillance MRI 
approximately every 12 weeks (r 7 days) from randomization or sooner if 
clinically indicated. 


Clinical Protocol 
 
CA2099NC / INCB 24360-309 
BMS-936558 
 
Nivolumab  
 
 
Table 2-3: 
Long-term Procedural Outline (CA2099NC / INCB 24360-309) 
Procedure 
Follow-Up 
Visit 1 and 2a 
Survival 
Follow-upb 
Notesc 
Participant Survival Status 
Survival Status 
X 
X 
During safety follow-up and every 3 months during survival phase; may be 
accomplished by visit, phone contact or email, to include assessment of subsequent 
anti-cancer therapy 
Abbreviations: BMI, body mass index; BP, blood pressure; C1D1, Cycle 1, Day 1; C2D1, Cycle 2, Day 1; CBC, complete blood count; ECG, electrocardiogram: 
HR, heart rate; 
; SAE, serious adverse event; WOCBP, women of childbearing potential.  
a Participants must be followed for at least 100 days after last dose of study treatment. Follow-up visit 1 (FU1) should occur 30 days from the last dose (r 7) days 
or can be performed on the date of discontinuation if that date is greater than 42 days from last dose. Follow-up visit 2 (FU2) occurs approximately 100 days 
(r 7 days) from last dose of study drug. Both Follow Up visits should be conducted in person. 
b Survival Follow-up visits to occur every 3 months (r 14 days) from Follow-up Visit 2. Survival visit may be conducted in person or by telephone. BMS/Incyte 
may request that survival data be collected on all randomized participants outside of the 3 month specified window. At the time of this request, each participant 
will be contacted to determine their survival status unless the participant has withdrawn consent for all contact.  
c Some of the assessments referred to in this section may not be captured as data in the eCRF. They are intended to be used as safety monitoring by the treating 
physician. Additional testing or assessments may be performed as clinically necessary or where required by institutional or local regulations. 


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558 
Nivolumab  
 
 
3 
INTRODUCTION  
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality 
worldwide, accounting for approximately 18% of all cancer deaths.1 Platinum-based doublet 
chemotherapy with paclitaxel and pemetrexed is a standard of care first-line therapy for NSCLC 
patients (without sensitizing epidermal growth factor receptor [EGFR] mutations or anaplastic 
lymphoma kinase [ALK] translocation) with squamous and nonsquamous histologies, 
respectively.2,3 Bevacizumab and maintenance therapy with pemetrexed have improved clinical 
outcomes,4,5,6, but most participants will eventually progress.7 NSCLC has a median survival of 
approximately 10 months, and a 5-year survival rate of less than 5%.3 
Targeting the immune system is a proven and effective approach for the treatment of cancer, and 
immunotherapy is now an accepted therapy in several tumor types. The blocking of immune cell 
co-inhibitory receptors such as cytotoxic T-lymphocyte–associated protein-4 (CTLA-4) by 
ipilimumab; programmed cell death protein 1 (PD-1) by nivolumab, pembrolizumab, and 
avelumab; and programmed cell death ligand 1 (PD-L1) by atezolizumab provide a critical 
mechanism for activating the host immune response against the tumor.7  
Nivolumab is a fully human immunoglobulin (Ig) G4 antibody that blocks the programmed death 
receptor-1 (PD-1). Nivolumab is approved in the U.S. and Europe to treat metastatic NSCLC in 
patients with progression on or after platinum chemotherapy. 
The approval of nivolumab in squamous NSCLC was based on the results of the CheckMate 017 
(CA209017) study, a randomized trial of nivolumab versus docetaxel in patients who had disease 
progression during or after first-line chemotherapy. The median OS for participants in the 
nivolumab arm was 9.2 months, compared to 6 months for those in the docetaxel arm (HR = 0.59). 
Improvement in OS and PFS was observed for nivolumab regardless of PD-L1 expression, though 
there was a trend for better efficacy for those with PD-L1 expressing tumors.8 Treatment-related 
AEs of Grade 3 or 4 were reported in 7% of patients in the nivolumab group, compared with 55% 
of those in the docetaxel group. 
The approval of nivolumab in non-squamous NSCLC was based on a second phase 3 study, 
CheckMate 057 (CA209057), of nivolumab versus docetaxel in participants with 
previously-treated disease.9 The median OS for participants in the nivolumab arm was 12.2 months 
versus 9.4 months for those in the docetaxel arm (hazard ratio [HR] = 0.59). Interaction p-values, 
reported for PD-L1 expression subgroups by each of the predefined expression levels, suggested 
a clinically important signal of a predictive association. Treatment-related AEs of Grade 3 or 4 
were reported in 10% of patients in the nivolumab group, compared with 54% of those in the 
docetaxel group.  
Superior activity of PD-1-directed monotherapy over platinum chemotherapy regimen in 
participants with previously untreated advanced NSCLC was demonstrated in an open-label phase 
3 study with the PD-1 antibody, pembrolizumab (KEYNOTE-024).10 Eligibility in this study was 
restricted to participants with PD-L1 expression t 50% on tumor cells. The pembrolizumab 
monotherapy group showed a significantly longer median PFS of 10.3 months compared with 


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558 
Nivolumab  
 
 
6.0 months with chemotherapy group (HR= 0.50). Estimated OS at 6 months was 80% in the 
pembrolizumab group versus 72% in the chemotherapy group (HR for death = 0.60). The ORR 
was greater in participants treated with PD-1 inhibitor versus chemotherapy (45% vs 28%). 
Treatment-related AEs of any grade were less frequent (occurring in 73% vs 90% of participants), 
as were t Grade 3 treatment-related AEs (27% vs 53%).  
Nivolumab as monotherapy versus chemotherapy in patients with advanced NSCLC was evaluated 
in CheckMate 026 (CA209026), a phase 3, open-label, randomized study. Patients enrolled in the 
trial had received no prior systemic treatment for advanced disease and tested positive for PD-L1 
expression (t1%).11 The trial randomized patients to receive either nivolumab or investigator’s 
choice of platinum doublet chemotherapy in squamous patients and non-squamous patients. The 
primary endpoint of PFS was assessed in patients with t 5% PD-L1 tumor expression. The study 
did not meet its primary objective of demonstrating a statistically significant improvement in PFS 
for nivolumab versus chemotherapy. PFS was 4.2 months in the nivolumab arm versus 5.9 months 
in the chemotherapy arm (HR = 1.15). The OS was similar in both arms (nivolumab 14.4 months 
versus chemotherapy 13.2 months, HR = 1.02), despite 60% of participants in the chemotherapy 
arm subsequently receiving nivolumab. A full evaluation of the CheckMate 026 data remains in 
progress to understand the difference between the KEYNOTE-024 and CheckMate 026 studies. 
The IDO1 pathway is another key regulatory component responsible for the induction and 
maintenance of tumor immune tolerance.  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.12 Both the reduction in local tryptophan levels and the production 
of tryptophan catabolites that are inhibitory to cell proliferation contribute to the 
immunosuppressive effects.13 IDO1 activity also promotes the differentiation of naive T cells to 
cells with a regulatory phenotype (Treg).14 Since increased Treg activity has been shown to 
promote tumor growth, and Treg depletion has been shown to allow an otherwise ineffectual 
antitumor immune response to occur,15 IDO1 expansion of Tregs may provide an additional 
mechanism whereby IDO1 could promote an immunosuppressive environment. Preclinical studies 
demonstrate that IDO1 inhibition dramatically increases the efficacy of various chemotherapeutic 
agents (eg, platinum compounds, taxane derivatives, and cyclophosphamide) without increased 
toxicity.16 Clinically, IDO1 appears to be chronically activated in participants with cancer, and 
IDO1 activation correlates with more extensive disease.17,18 IDO1 has subsequently been found 
to be overexpressed by a wide variety of human tumor cell types, as well as by the dendritic cells 
(DCs) that localize to the tumor-draining lymph nodes.19,20 Increased expression of IDO1 in tumor 
cells has been shown to be an independent prognostic variable for reduced OS in participants with 
melanoma and ovarian, colorectal, and pancreatic cancer. 21,22,23,24,25 
Epacadostat (INCB 24360) is an experimental potent and selective inhibitor of IDO1. Epacadostat 
is being developed for the treatment of malignant diseases. The pharmacology, PK, and toxicology 
have been extensively characterized in nonclinical studies. The safety and efficacy of epacadostat 


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558 
Nivolumab  
 
 
is being explored in clinical studies as monotherapy and in combination with immunotherapies 
and chemotherapy (see Epacadostat Investigator Brochure).  
IDO and the PD-1 ligand, PD-L1, have been shown to be co-expressed in multiple cancer types 
and correlate with poor prognosis. Since multiple immune mechanisms are present concurrently 
within the tumor microenvironment, combination therapies may be required for optimal 
therapeutic effect.26 Data supporting epacadostat combined with nivolumab in participants with 
advanced cancers, including NSCLC and other solid tumors, is reported in a phase 1/2 dose 
escalation and cohort expansion trial (ECHO-204; INCB 24360 204). In the phase 1 dose 
escalation period (n=36), participants received epacadostat 25, 50, 100, or 300 mg twice daily 
(BID) in combination with nivolumab 3 mg/kg every 2 weeks; in the phase 2 cohort expansion 
(205 patients), participants with advanced cancers, including NSCLC and other solid tumors, 
received epacadostat 100 mg or 300 mg BID in combination with nivolumab 240 mg every 2 
weeks. Safety and tolerability was assessed in participants receiving t 1 epacadostat and 
nivolumab dose.27 The combination was generally well tolerated up to the maximum 300 mg 
epacadostat dose. No DLT was observed in phase 1. Most common treatment-related AEs in 
patients treated with epacadostat were rash, fatigue, and nausea. Rash was the most common grade 
t 3 treatment-related AE. Treatment-related AEs led to discontinuation in 7% (100 mg BID 
epacadostat) and 13% (300 mg BID epacadostat) of patients. There were no treatment-related 
deaths. 
Chemotherapy has largely been thought to be immunosuppressive and exert its effect via direct 
cytotoxicity. However, there is an emerging body of evidence to suggest that some chemotherapies 
may influence an immune response to tumors via induction of immunogenic cell death (ICD), 
elimination of immunosuppressive cells, or sensitization of tumor cells to immune effector cells.28 
Platinum agents have demonstrated immunogenic effects via ICD and enhancement of effector 
immune response through PD-L1 receptor expression.29 Paclitaxel and 5-FU have been shown to 
restore antitumor activity of CD8+ T cells.30,31  
Collectively, these data show that the immunogenic effects of conventional chemotherapy and 
rapid emergence of chemotherapy resistance may present as a good rationale to combine 
chemotherapy doublets with immunotherapy, particularly checkpoint inhibitors.32,33 Combining 
immune checkpoint inhibitors with platinum doublets may also provide a rapid and large initial 
response through the action of the cytotoxic chemotherapy, thus releasing tumor antigens in the 
tumor microenvironment to be recognized by the immune system. 
In the phase 1 CheckMate 012 study, 56 patients received first-line nivolumab (5 or 10 mg/kg) 
plus platinum doublet chemotherapy concurrently every 3 weeks for 4 cycles followed by 
nivolumab alone until progression or unacceptable toxicity. Platinum doublet regimens included 
gemcitabine-cisplatin (squamous histology), pemetrexed-cisplatin (non-squamous histology) or 
paclitaxel-carboplatin (all histologies).33 No dose-limiting toxicities occurred during the first 6 
weeks of treatment. The most commonly reported (t 30% of patients) treatment-related AEs of 
any grade were fatigue, nausea, decreased appetite, and alopecia. The most common (t 5% of 


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558 
Nivolumab  
 
 
patients) treatment-related Grade 3 or 4 AEs were pneumonitis, fatigue, and acute renal failure. A 
greater proportion of patients reported onset of treatment-related select AEs during the 
combination period (2 to 29%) than during nivolumab monotherapy (2 to 12%). Treatment-related 
AEs led to discontinuation of all study therapy in 21% of patients. Grade 3 or 4 treatment-related 
AEs led to discontinuation in 14% of patients. The observed frequencies of immune-related AEs 
with combination therapy affecting the skin, gastrointestinal (GI), renal, and pulmonary organs 
was greater than expected with single-agent nivolumab. However, all select AEs were effectively 
managed with corticosteroids, and none resulted in death.  
Confirmed ORRs ranged from 33% to 47%. An additional 27 to 58% of patients across all arms 
had BOR of stable disease, with 7 to 33% of patients had stable disease lasting t 21 weeks. Median 
PFS ranged from 4.8 to 7.1 months; median OS ranged from 11.6 to 19.2 months. Duration of 
response was similar in patients regardless of PD-L1 levels; no clear association was observed 
between PD-L1 levels and PFS or OS. 
Results from the open label cohort (123 participants), phase 2 KEYNOTE-021study investigating 
the efficacy of the combination of first-line PD-1 inhibition (pembrolizumab) and platinum doublet 
chemotherapy (carboplatin-pemetrexed) in participants with advanced NSCLC (non-squamous 
histology) have been reported.34 The chemotherapy-immunotherapy combination showed a 
significant improvement in ORR with a median follow up of 19 months: 57% in the 
pembrolizumab plus chemotherapy regimen group versus 32% in the chemotherapy regimen 
group. Median PFS was 19 months for the pembrolizumab plus chemotherapy arm and 8.9 months 
for chemotherapy alone. Although sample size for individual PD-L1 subgroups were small, there 
was a higher proportion of responses in patients with PD-L1 expression of t 50%. A trend toward 
improvement in OS was observed in the pembrolizumab plus chemotherapy arm:  the combination 
was associated with a 41% reduction in the risk of death (HR=0.59). The median OS was not 
reached in the pembrolizumab plus chemotherapy group, compared to 20.9 months in the 
chemotherapy group.35 
The incidence of t Grade 3 treatment-related adverse events was higher in the pembrolizumab 
plus chemotherapy group (39%), compared with the chemotherapy group (26%), but this had no 
impact on the discontinuation rate (10% and 13%, respectively). The most common 
t Grade 3 treatment-related adverse events in the pembrolizumab plus chemotherapy group were 
anemia and decreased neutrophil count. In the chemotherapy alone group, the most common 
t Grade 3 events were anemia and decreased neutrophil count, pancytopenia, and 
thrombocytopenia. There were 3 treatment-related deaths: 1 in the pembrolizumab plus 
chemotherapy group and with 2 in the chemotherapy group. The incidence of potentially 
immune-mediated adverse events in the pembrolizumab plus chemotherapy group (22%) was 
comparable to that noted for pembrolizumab monotherapy in other studies. Most 
immune-mediated adverse events were of Grade 1 or 2 severity and were manageable without 
treatment discontinuation.36 


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558 
Nivolumab  
 
 
3.1 
Study Rationale  
Both PD-1 and IDO1 have been shown to suppress T-cellmediated antitumor immunity, and 
IDO1 and the PD-1 ligand PD-L1 have been shown to be co-expressed in multiple cancer types 
and to correlate with poor prognosis. Targeting PD-1 assumes that the T cells are essentially 
exhausted and thus tolerant of the tumor and that this exhaustion may be reversed by blocking 
PD-1 signaling. Targeting IDO1 may concurrently decrease infiltration of regulatory CD4+ cells 
and immune suppressive cytokines. This novel combination strategy has strong biologic rationale 
for a number of solid tumors, including NSCLC, and may augment clinical efficacy above that 
demonstrated by these agents individually. Combined inhibition of both pathways may therefore 
lead to greater suppression of anti-tumor immunity and to increased efficacy.  
Based on evolving data, it is hypothesized that chemotherapy may modify the immune response 
to tumours by influencing multiple mechanisms, including inducing of immunogenic cell death, 
stimulating release of tumour antigens and/or depletion of immuno-suppressive regulatory 
T-cells.37,38,39 Therefore, the combination of agents that inhibit PD-1 and IDO1 with chemotherapy 


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558 
Nivolumab  
 
 
has the potential to provide significantly improved anti-tumor activity, thereby potentially 
improving the overall prognosis in patients with advanced stage cancers. 
Based on the above rationale and the available safety and efficacy data, the proposed phase 3 study 
will evaluate the combination of nivolumab with epacadostat and chemotherapy compared with 
chemotherapy as a first-line treatment for treatment naïve, Stage 4 or recurrent NSCLC. A third 
arm of nivolumab plus placebo for epacadostat in combination with platinum chemotherapy will 
allow estimation of contribution of components. 
3.1.1 
Research Hypothesis 
Treatment naïve, Stage 4 or recurrent NSCLC participants with PD-L1 expression of 0 to 49% will 
demonstrate superior PFS and OS with the administration of the combination of nivolumab, 
epacadostat, and platinum doublet chemotherapy, as compared with chemotherapy alone. 
3.2 
Background 
With the availability of anti-PD-1 agents40,41, the treatment landscape in recurrent and metastatic 
NSCLC has changed and future clinical investigations will focus on combinations of checkpoint 
inhibitors with chemotherapy to achieve improved patient outcomes in NSCLC. 
3.2.1 
Inhibition of PD-L1 as a Target for Cancer 
Cancer immunotherapy rests on the premise that tumors can be recognized as foreign rather than 
as self and can be effectively attacked by an activated immune system. An effective immune 
response relies on immune surveillance of tumor antigens expressed on cancer cells that ultimately 
results in an adaptive immune response and cancer cell death. Meanwhile, tumor progression may 
depend upon acquisition of traits that allow cancer cells to evade immunosurveillance and escape 
effective innate and adaptive immune responses.42,43,44 Current immunotherapy efforts attempt to 
break the apparent tolerance of the immune system to tumor cells and antigens by either 
introducing cancer antigens by therapeutic vaccination or by modulating regulatory checkpoints 
of the immune system. T-cell stimulation is a complex process involving the integration of 
numerous positive as well as negative co-stimulatory signals in addition to antigen recognition by 
the T-cell receptor (TCR).45 Collectively, these signals govern the balance between T-cell 
activation and tolerance.  
The PD-1 receptor-ligand interaction is a major pathway stimulated by tumors to suppress immune 
control.46 The normal function of PD-1, expressed on the cell surface of activated T cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 is a member of the CD28 family of T-cell co-stimulatory receptors 
that also includes CD28, CTLA 4, ICOS, and BTLA.47 PD-1 signaling has been shown to inhibit 
CD-28-mediated upregulation of IL-2, IL-10, IL-13, interferon-γ (IFN-γ) and Bcl-xL. PD-1 
expression has also been noted to inhibit T cell activation, and expansion of previously activated 
cells. Evidence for a negative regulatory role of PD-1 comes from studies of PD-1 deficient mice, 
which develop a variety of autoimmune phenotypes.48 These results suggest that PD-1 blockade 
has the potential to activate anti-self T-cell responses, but these responses are variable and 


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dependent upon various host genetic factors. Thus, PD-1 deficiency or inhibition is not 
accompanied by a universal loss of tolerance to self-antigens. 
In vitro, nivolumab (BMS-936558) binds to PD-1 with high affinity (EC50 0.39-2.62 nM), and 
inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2 (IC50 r 1 nM). Nivolumab binds 
specifically to PD-1 and not to related members of the CD28 family such as CD28, ICOS, CTLA-4 
and BTLA. Blockade of the PD-1 pathway by nivolumab results in a reproducible enhancement 
of both proliferation and IFN-γ release in the mixed lymphocyte reaction (MLR). Using a CMV 
re-stimulation assay with human PBMC, the effect of nivolumab on antigen specific recall 
response indicates that nivolumab augmented IFN-γ secretion from CMV specific memory T cells 
in a dose-dependent manner versus isotype-matched control. In vivo blockade of PD-1 by a murine 
analog of nivolumab enhances the anti-tumor immune response and result in tumor rejection in 
several immunocompetent mouse tumor models (MC38, SA1/N, and PAN02).49 
For a thorough discussion of chemistry, pharmacology, efficacy, and safety, see the Nivolumab 
IB. 
3.2.2 
Inhibition of Indoleamine 2,3-Dioxygenase as a Target for Cancer 
Recent interest has focused on the role of IDO1 as a mechanism of induction of tolerance to 
malignancy.50 IDO is a heme-containing, monomeric oxidoreductase that catalyzes the 
degradation of the essential amino acid tryptophan to N-formyl-kynurenine. Kynurenine can be 
subsequently metabolized through a series of enzymatic steps to nicotinamide adenine 
dinucleotide. IDO is the first rate-limiting enzyme in one of the breakdown pathways of 
tryptophan. In another pathway, tryptophan hydroxylase catalysis of tryptophan catabolism leads 
to the formation of serotonin and melatonin.   
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.51 Within 
the immune system, IDO1 activity is specifically induced in cells such as dendritic cells and 
macrophages at localized sites of inflammation.52  
The biological relevance of IDO1 inhibition to immune tolerance was first demonstrated when it 
was shown that treating mice with a small molecule inhibitor of the IDO1 pathway, 
1-methyl-tryptophan, could break the tolerogenic state that protects allogeneic concepti from the 
maternal immune system.19 A critical role for IDO1 in immunomodulation has been confirmed in 
numerous animal models, including models of allograft tolerance, inflammation, and cancer. 
While IDO1 inhibition can exacerbate disease in models of autoimmune disorders, IDO1 null mice 
show no evidence of susceptibility to developing spontaneous autoimmunity or alterations in 
immune system development12, suggesting that IDO1 inhibition, in a therapeutic setting, may 
produce minimal side effects in participants without pre-existing autoimmune conditions. 


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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.16,19 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.20 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 participants with cancer, and IDO1 activation correlates with more 
extensive disease.17,18IDO1 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.19,20 
Increased expression of IDO1 in tumor cells has been shown to be an independent prognostic 
variable for reduced OS in participants with melanoma, ovarian cancer, colorectal, and pancreatic 
cancers.21,22,23,24,25,26 
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 advanced malignancies either alone or in 
combination with chemotherapeutics and/or immunotherapy-based strategies. 
Epacadostat is an inhibitor of IDO1 in development for the treatment of malignant diseases. In 
cell-based assays, epacadostat potently inhibits IDO1 in both human tumor cells and human 
dendritic cells resulting in reduced tryptophan to kyneurinie conversion (IC50 values = 7.1 to 
12.7 nM). Epacadostat does not significantly inhibit other proteins that could impact Trp 
catabolism. To facilitate the clinical development of epacadostat, the pharmacology, PK, and 
toxicology of epacadostat have been extensively characterized in nonclinical studies. For a 
thorough discussion of chemistry, pharmacology, efficacy, and safety, please refer to the 
Epacadostat IB. 
3.2.3 
Combination of IDO1 and Immune Checkpoint Inhibition 
Blockade of immune inhibitory pathways is emerging as an important therapeutic modality for the 
treatment of cancer as evidenced by the clinical responses observed with antibodies to CTLA-4 
and PD-1/PD-L1. Although these single agents have antitumor activity, multiple immune 
inhibitory mechanisms are present concurrently within the tumor microenvironment, suggesting 
that combination therapies may be required for optimal therapeutic effect.26  
As described above, IDO1 is a negative regulatory mechanism that contributes to tumor-derived 
immune suppression. In preclinical models, IDO1 inhibition has been shown to synergize with 
blockade of either antiCTLA-4 or antiPD-1/PD-L1 in delaying tumor growth and increasing 
OS.53,54 This effect was shown to be T-cell dependent, leading to enhanced T-cell proliferation 


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and interleukin-2 production within the tumor and to a marked increase in the effector-to-
regulatory T-cell ratios in the tumor. 
The ongoing phase 1/2 study of the safety, tolerability, and efficacy of epacadostat in combination 
with nivolumab which supports further investigation in CA2099NC is described above in Section 
3.1. For additional information, see the epacadostat IB.  
3.2.4 
Combination of Immunotherapy with Chemotherapy 
Chemotherapy may modify the immune response to tumours by influencing multiple mechanisms, 
including inducing of immunogenic cell death, stimulating release of tumour antigens and/or 
depletion of immuno-suppressive regulatory T-cells.37,38,39 Platinum chemotherapy regimens have 
shown to be safely combined with immunotherapy agents, while improving the efficacy compared 
to the agents individually. Therefore, the combination of agents that inhibit PD-1 and IDO1 with 
chemotherapy has the potential to provide significantly improved anti-tumor activity, thereby 
potentially improving the overall prognosis in patients with advanced stage cancers. 
The currently available data on the combination of immunotherapy with platinum chemotherapy 
is presented in Section 3. 
3.3 
Benefit/Risk Assessment 
3.3.1 
Risks From Nivolumab 
Extensive details on the safety profile of nivolumab are available in the Investigator Brochure. 
Overall, the safety profile of nivolumab is manageable and generally consistent across completed 
and ongoing clinical trials with no MTD reached at any dose tested up to 10 mg/kg. Most AEs 
were low-grade (Grade 1 to 2) with relatively few related high-grade (Grade 3 to 4) AEs. There 
was no pattern in the incidence, severity, or causality of AEs with respect to nivolumab dose level. 
A pattern of immune-related adverse events has been defined, for which management algorithms 
have been developed; these are provided in Appendix 6. Most high-grade events were manageable 
with the use of corticosteroids or hormone replacement therapy (endocrinopathies) as instructed 
in these algorithms.  


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3.3.3 
Risks for the Combination of Nivolumab plus Epacadostat in 
Combination with Chemotherapy  
In a phase 1, CheckMate 012 study (n = 56), nivolumab in combination with platinum doublet 
chemotherapy in chemotherapy-naive NSCLC noted t Grade 3 treatment related AEs were 
observed in 45% of participants. The safety profile of nivolumab plus platinum doublet 
chemotherapy was consistent with that expected for individual agents; however, treatment 
discontinuation related to AEs was greater with the combination. The most commonly reported 
(t 30% of patients) AEs of any grade were fatigue, nausea, decreased appetite, and alopecia. The 
most common (t 5% of patients) treatment-related Grade 3 or 4 AEs were pneumonitis, fatigue, 
and acute renal failure. No treatment-related deaths were reported.33 All select AEs were 
effectively managed with corticosteroids, and none resulted in death. This study shows that 
immunotherapy agents may be safely combined with platinum based chemotherapy agents to 
provide an improvement in efficacy irrespective of the PD-L1 status.  
Results from an open label cohort of a phase 2 study (KEYNOTE-021) to investigate the efficacy 
of the combination of first-line PD-1 inhibition and platinum doublet chemotherapy 
(carboplatin-pemetrexed) in participants with advanced NSCLC have also been reported.34 The 
incidence of t Grade 3 treatment-related adverse events was similar between groups (39% in the 
pembrolizumab plus chemotherapy group and 26% in the chemotherapy alone group). The most 
common t Grade 3 treatment-related adverse events in the pembrolizumab plus chemotherapy 
group were anemia and decreased neutrophil count. In the chemotherapy alone group, the most 
common t Grade 3 events were anemia and decreased neutrophil count, pancytopenia, and 
thrombocytopenia. The incidence of potentially immune-mediated adverse events in the 
pembrolizumab plus chemotherapy group (22%) was comparable to that noted for pembrolizumab 
monotherapy in other studies. 


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4 
OBJECTIVES AND ENDPOINTS 
Table 4-1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary Objective  
x 
To compare overall survival (OS) and progression-free 
survival (PFS) per blinded independent central review 
(BICR) of nivolumab plus epacadostat in combination 
with chemotherapy (Arm A) to chemotherapy (Arm B) in 
treatment naïve, Stage 4 or recurrent NSCLC participants 
whose tumors express PD-L1 at 0 to 49%. 
x 
OS 
x 
PFS assessed by BICR 
 
Secondary Objective 
x 
To compare objective response rate (ORR) and to 
estimate of duration of response (DOR) as assessed by 
BICR of  nivolumab plus epacadostat in combination 
with chemotherapy (Arm A) to chemotherapy (Arm B) in 
treatment naïve, Stage 4 or recurrent NSCLC participants 
whose tumors express PD-L1 at 0 to 49%. 
x 
ORR and DOR assessed by BICR 
x 
To estimate OS, and PFS, ORR, and DOR per BICR 
assessment, of nivolumab and  placebo for epacadostat in 
combination with chemotherapy (Arm C) in treatment 
naïve, Stage 4 or recurrent NSCLC participants whose 
tumors express PD-L1 at 0 to 49%. 
x 
OS 
x 
PFS, ORR, and DOR per BICR assessment 


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Table 4-1: 
Objectives and Endpoints 
Objectives 
Endpoints 
 
5 
STUDY DESIGN  
5.1 
Overall Design 
CA2099NC/INCB 24360-309 is a phase 3, randomized, 3-arm trial in participants with treatment 
naïve, Stage 4 or recurrent NSCLC t 18 years old. The study will enroll participants with PD-L1 
levels from 0 to 49%. Patients with PD-L1 levels of t 50% are excluded, as pembrolizumab 
monotherapy is approved as first line treatment in this population.  
The primary objectives of the study are to compare PFS and OS in participants treated with 
nivolumab plus epacadostat in combination with platinum doublet chemotherapy versus platinum 
doublet chemotherapy alone. A third arm of nivolumab plus placebo for epacadostat in 
combination with platinum doublet chemotherapy will allow estimation of the contribution of 
components. The study arms, specific doses, and treatment frequency for each arm are described 
in Figure 5.1-1 and Table 7.1-1.  
Approximately 900 participants will be screened and 630 participants will be randomized in the 
3 treatment arms in a 2:2:1 ratio in the study: 
x Arm A: nivolumab plus epacadostat in combination with platinum doublet chemotherapy 
(n = 252) 
x Arm B: platinum doublet chemotherapy (n = 252) 
x Arm C: nivolumab plus placebo for epacadostat in combination with platinum doublet 
chemotherapy (n = 126) 
Participants will be stratified by PD-L1 levels (0% and 1 to 49%), gender (male and female), and 
tumor histology (squamous and non-squamous). 
The study design schematic is presented in Figure 5.1-1. 


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Figure 5.1-1: 
Study Design Schematic 
 
Sufficient, recent or archival tumor tissue obtained within 3 months prior to enrollment from a 
metastatic tumor lesion or from an unresectable primary tumor lesion which has not been 
previously irradiated. For randomization, 25 FFPE slides or adequate tissue block for 25 FFPE 
slides from core biopsy, punch biopsy, excisional biopsy or surgical specimen must be submitted 
to the analyzing laboratory. Specimens should contain a minimum of 100 evaluable tumor cells. 
Participants should not have received any systemic anticancer therapy after the date that the 
submitted tumor tissue was obtained. Enrollment of participants with less than the requested 
amount of tumor tissue must be approved by the Medical Monitor.  
Tumor progression or response endpoints will be assessed by the investigator and by BICR using 
RECIST 1.1 criteria. Treatment with study medication will continue until RECIST 1.1-defined 
progression, unacceptable toxicity, withdrawal of consent, or a maximum treatment duration of 24 
months. In specific circumstances, participants may be treated beyond progression as described in 
Section 8.1.3. 
 
 
 The study will end once survival 
follow-up has concluded.  
Physical examinations, vital sign measurements, and clinical laboratory evaluations will be 
performed at selected times throughout the treatment period. Participants will be closely monitored 
for adverse events throughout the study.
 
  
Screening Phase  
The screening phase begins by establishing the participant’s initial eligibility and signing of the 
informed consent form (ICF). Tumor tissue (archival or recent tumor biopsy) must be submitted 
by the site to the analyzing lab for determination of PD-L1 status. A communication (e-mail) will 


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be sent by the analyzing laboratory to site for confirmation upon receiving tumor tissue. 
Participants must have the result of PD-L1 IHC testing from the analyzing laboratory available in 
order to randomize into the study. Patients with tumors unevaluable for PD-L1 will not be enrolled. 
Additional tumor tissue may be required by the Medical Monitor or the analyzing laboratory if 
initial testing is unevaluable. See Section 2 for additional information. All screening assessments 
and procedures must be performed prior to randomization. 
Treatment Phase 
The treatment phase begins with randomization after confirming all eligibility criteria have been 
met. Treatment should begin within 3 calendar days of randomization. Figure 5.1-1 and Table 7.1-
1 describes the study arms.  Each treatment cycle lasts for 21 days.
Follow-up Phase
The post-treatment follow-up begins when the decision to discontinue a participant from all 
treatment is made. Participants who discontinue treatment will continue to have tumor assessments 
(if clinically feasible) according to the schedule in Table 2-3.
Participants will be followed for drug-related toxicities until these toxicities resolve, return to 
baseline, or are deemed irreversible. All adverse events will be documented for a minimum of 
100 days after the last dose of study medication. 
After completion of the first 2 follow-up visits, participants will be followed every 3 months for 
survival. Survival follow-up visits may be performed by phone contact or office visit. BMS/Incyte 
may request that survival data be collected on all randomized participants outside of the 
protocol-defined window. At the time of this request, each participant will be contacted to 
determine their survival status unless the participant had withdrawn consent for all contact. 
5.1.1 
Data Monitoring Committee and Other External Committees 
5.1.1.1 
Independent Data Monitoring Committee  
An independent Data Monitoring Committee (DMC) will be utilized to provide general oversight 
and safety considerations for this study, CA2099NC/INCB 24360-309. The DMC will provide 
recommendations to BMS/Incyte regarding actions the committee deems necessary for the 
continuing protection of participants enrolled in this study. The DMC will review safety data after 
the first 10 participants in each arm have been on-treatment for at least 4 weeks; enrollment will 
not be paused during this review. Additionally, relevant available data from the ongoing 
ECHO-204 study, which includes a cohort assessing the safety and tolerability of the Arm A 
treatment regimen in the same population, may be provided to the DMC. Efficacy and safety data 
will be reviewed every 6 months thereafter. The DMC will be charged with assessing such actions 
in light of an acceptable risk/benefit profile for the nivolumab arms. The DMC will act in an 
advisory capacity to BMS and Incyte and will monitor participant safety data for the study. The 
DMC will be advisory to the clinical study leadership team. The clinical study leadership will have 
responsibility for overall conduct of the study including managing the communication of study 
data. The clinical trial leadership team will be responsible for promptly reviewing the DMC 
recommendations, for providing guidance regarding the continuation or termination of the study, 


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and for determining whether amendments to the protocol or changes to the study conduct are 
required. Details of the DMC responsibilities and procedures will be specified in the DMC charter. 
When required, adjudicated events will be submitted to the DMC and Health Authorities for review 
on a specified timeframe in accordance with the adjudication documentation. 
5.2 
Number of Participants 
Approximately 900 participants will be screened and approximately 630 participants will be 
randomized for study treatment.  
5.3 
End of Study Definition 
The start of the trial is defined as the first participant’s first visit. End of trial is defined as the last 
participant’s last study visit or last survival assessment. Study completion is defined as the final 
date on which data for the primary endpoint was or is expected to be collected, if this is not the 
same. 
5.4 
Scientific Rationale for Study Design 
5.4.1 
Rationale for Chemotherapy in NSCLC 
First-line treatment of advanced NSCLC is histology specific and consists of platinum-based 
chemotherapy doublets. For example, pemetrexed is approved in first-line in combination with 
cisplatin for locally advanced or metastatic non squamous NSCLC. This approval was based on a 
phase 3, randomized study that showed improved survival and decreased toxicity for pemetrexed 
combined with cisplatin in patients with non-squamous histology, in comparison to gemcitabine 
combined with cisplatin.57 Pemetrexed has also been approved as continuation maintenance 
therapy in patients with non-squamous histology, who have not had progressive disease after four 
cycles of a first-line pemetrexed/platinum regimen. In contrast, gemcitabine in combination with 
cisplatin has been demonstrated to yield improved overall survival compared to 
pemetrexed/cisplatin in participants with squamous NSCLC. In squamous NSCLC, carboplatin 
plus paclitaxel is an alternative standard of care preferred in some geographies. 
Although some but not all meta-analyses and randomized studies have demonstrated that 
cisplatin-based regimens may produce improved survival compared to carboplatin-based 
regimens, many participants are not ideal candidates for cisplatin due to its higher toxicity.58 
Prior data from CheckMate 012 suggest similar efficacy and safety when combining nivolumab 
with chemotherapy, regardless of the chemotherapy backbone. 
5.4.2 
Rationale for PD-1 Inhibitor and IDO1 Inhibitor in Combination with 
Chemotherapy 
While chemotherapy has largely been thought to be immunosuppressive and exert its effect via 
direct cytotoxicity, an emerging body of evidence suggests that some chemotherapies may 
influence an immune response to tumors via induction of immunogenic cell death (ICD), 
elimination of immunosuppressive cells, or sensitization of tumor cells to immune effector cells. 
Given these findings, the combination of chemotherapy with immunotherapy is a rational choice, 
especially in participants for whom these chemotherapies are the accepted standard of care. 


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PD-1/PD-L1 blockage is being investigated in combination with chemotherapeutic agents in 
NSCLC. A phase 1 study (n = 56) of nivolumab in combination with platinum doublet 
chemotherapy in chemotherapy-naive NSCLC showed ORR ranging from 33% to 47% and PFS 
from 4.8 to 7.1 months. Treatment-related t Grade 3 AEs were observed in 45% of participants.33 
Promising efficacy signals have been observed in the KEYNOTE-021 study of pembrolizumab in 
combination with platinum doublet chemotherapy from open-label cohorts (n = 74, ORR 
48%-71%, PFS ~10 months, t Grade 3 treatment-related AEs 56%-71%) and a randomized cohort 
of pembrolizumab/platinum doublet chemotherapy versus platinum doublet chemotherapy 
(n = 123, ORR 57% vs 32%, PFS 19 months vs 8.9 months, t Grade 3 treatment-related AEs 39% 
vs 26%). Confirmatory phase 3 clinical studies in advanced/metastatic NSCLC are ongoing for 
these therapies.  
The IDO pathway inhibitor indoximod has been evaluated in combination with chemotherapy in 
clinical studies. In a phase 1 study (n = 27), indoximod in combination with docetaxel in pretreated 
participants with metastatic solid tumors was well-tolerated with no unexpected toxicities and had 
a modest ORR of 18%.59 Based on encouraging activity observed in participants with breast cancer 
from this study, a phase 2 study of indoximod in combination with docetaxel or paclitaxel was 
initiated. Preliminary safety data showed AEs were similar to those typically seen with taxanes, 
and no unexpected AEs were observed.60 Indoximod in combination with gemcitabine and 
paclitaxel in participants with metastatic pancreatic cancer was also well-tolerated in a phase 1/2 
study, and preliminary efficacy showed durable responses in 42% of participants.61  
Overall, the data suggest that combining the IDO1 inhibitor epacadostat, a PD-1 inhibitor, and 
chemotherapy may result in a further increase of immunomodulatory effects in the tumor 
microenvironment, and ultimately improve the overall clinical benefit in participants with 
advanced or metastatic solid tumors without overlapping toxicity profiles. 
For additional information on nivolumab and epacadostat, see the Nivolumab IB and Epacadostat 
IB, respectively. 
5.4.2.1 
Rationale for Overall Survival and Progression-free Survival as Co-
Primary Endpoints  
Overall survival is a universally accepted direct measure of benefit endpoint in oncology trials, 
including NSCLC. Since treatments which may otherwise be administered sequentially are being 
combined in this study, demonstration of survival benefit is considered necessary in order to 
demonstrate clinical relevance. PFS is included as a co-primary endpoint based on its acceptability 
as an endpoint in first line treatment of NSCLC10, particularly if there is large magnitude of the 
effect and favorable risk-benefit. Inclusion of PFS also addresses potential confounding of OS by 
effective subsequent therapies and provides an opportunity for earlier assessment of efficacy that 
could benefit patients. 


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5.4.3 
Rationale for Participant Selection 
As first-line standard of care for participants with EGFR mutations and ALK/ROS1 translocations 
is targeted therapy3 rather than chemotherapy. Participants known to have these abnormalities will 
be excluded from this study. 
In addition, patients with EGFR mutations have a better prognosis, even in the absence of EGFR 
inhibitor therapy and may have an improved response to chemotherapy compared to patients 
without EGFR mutations.62 Excluding these participants will help to reduce the potentially 
confounding effects of these mutations on the study endpoints. 
Patients with PD-L1 levels of t 50% are eligible to receive pembrolizumab monotherapy as first 
line treatment for their disease and are therefore excluded from participation in this study. 
5.5 
Justification for Dose 
5.5.1 
Justification for Nivolumab Dose 
Nivolumab 360 mg will be administered as an IV infusion over 30 minutes every 3 weeks (Q3W). 
Nivolumab has been shown to be safe and well tolerated up to a dose level of nivolumab 10 mg/kg 
Q2W. As population PK (PPK) analyses have shown that the PK of nivolumab are linear over a 
dose range of 0.1 to 10 mg/kg with no differences observed in PK across ethnicities and tumor 
types, the PPK model was used to simulate exposures at different dosing regimens, including 
nivolumab 360 mg Q3W. The simulated steady-state average concentration (Cavgss) following 
administration of nivolumab 360 mg Q3W are expected to be similar to those following 
administration of nivolumab 240 mg Q2W and nivolumab 3 mg/kg Q2W administered to 
participants weighing 80 kg. It should be noted that the steady-state peak concentrations (Cmaxss) 
following nivolumab 360 mg Q3W are predicted to be less than those following the administration 
of nivolumab 10 mg/kg Q2W, providing sufficient safety margins. Finally, nivolumab 360 mg 
Q3W in combination with platinum-doublet chemotherapy dosing is currently being studied for 
the treatment of NSCLC and gastric cancer in a phase 3 study. 


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5.5.3 
Rationale for Shorter Infusion Times for Nivolumab 
Long infusion times place a burden on patients and treatment centers. Previous clinical studies of 
nivolumab monotherapies have used a 60-minute infusion duration for nivolumab. A shortened 
infusion duration of 30 minutes has been implemented across all approved indications and future 
planned indications based on a thorough review of safety data from participants who have received 
nivolumab 3 mg/kg over 30 minutes Q2W in study CA209153 and 480 mg over 30 minutes Q4W 
in study CA209511, and clinical experience with nivolumab up to 10 mg/kg. Using a shorter 
infusion time will reduce a patient’s chair time and part of the distress associated with cancer 
treatment, and ultimately allow for a more efficient utilization of resources in cancer care. 
Nivolumab has been administered safely at doses ranging up to 10 mg/kg over these infusion 
durations. Overall, infusion reactions including high-grade hypersensitivity reactions have been 
uncommon across multiple clinical studies, and all have been managed by following established 
safety algorithms. Differences in exposure using a 30-minute infusion are not expected to have a 
clinically meaningful effect on safety since dose/exposure-response relationships were predicted 
to be relatively flat. 
Based on the data from CA209153, nivolumab can be safely infused over 30 minutes. Specifically, 
the overall safety profile was similar between 30-minute and 60-minute infusion groups, even 
taking into consideration the substantially longer exposure in the 30-minute infusion group in the 
CA209153 study. Despite the longer exposure for participants in the 30-minute infusion group, 
there 
were 
no 
clinically 
meaningful 
differences 
in 
the 
frequency 
of 
hypersensitivity/infusion-related reactions compared to those reported for participants in the 
60-minute infusion group. Hypersensitivity/infusion reactions were generally manageable using 
dosing interruptions, with only a limited impact on the total dose received for that cycle. 
Additionally, nivolumab 10 mg/kg infused over 60 minutes, which corresponds to a higher 
infusion rate than 3 mg/kg or 240 mg infused over 30 minutes, was found to be well tolerated in 2 
studies: CA209003 (MDX1106-03) and CA209010. Furthermore, interim results from study 
CA209511 support the safety of a 30-minute infusion time with a dose of 480 mg nivolumab. 
Overall, no new safety events were identified in participants administered nivolumab over 30 
minutes. Similarly, 30 minute infusion with a dose of 360 mg nivolumab is not expected to present 
any new safety concerns compared to the prior experience. 
5.5.4 
Rationale for the Duration of Treatment with Nivolumab and 
Epacadostat/Placebo for Epacadostat 
The optimal duration of immunotherapy is currently unknown. However, because immunotherapy 
engages the immune system to control the tumor, continuous treatment as is required with targeted 
agents or cytotoxic therapy may not be necessary.  


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Accumulating evidence from different clinical trials in different tumor types with nivolumab or 
nivolumab combined with ipilimumab indicates that most of the responses are generally occurring 
early, with a median time to response of 2-4 months.8,63,64,65,66 A recent analysis in a melanoma 
study suggests the majority of patients who discontinue nivolumab and/or ipilimumab for toxicity 
maintain disease control in the absence of further treatment.67  
For these reasons, treatment with nivolumab and epacadostat/placebo for epacadostat will be given 
for up to 24 months in the absence of disease progression or unacceptable toxicity.  
5.5.5 
Rationale for Permitting Continued Treatment in Select Cases of 
Progressive Disease  
Accumulating clinical evidence indicates some participants treated with immune system 
stimulating agents may develop progression of disease (by conventional response criteria) before 
demonstrating clinical OR and/or SD. This phenomenon was observed in approximately 10% of 
participants in the phase 1 study of nivolumab and also with ipilimumab monotherapy.49 Two 
hypotheses have been put forth to explain this phenomenon. First, enhanced inflammation within 
tumors could lead to an increase in tumor size which would appear as enlarged index lesions and 
as newly visible small non-index lesions. Over time, both the malignant and inflammatory portions 
of the mass may then decrease leading to overt signs of clinical improvement. Alternatively, in 
some individuals, the kinetics of tumor growth may initially outpace anti-tumor immune activity. 
With sufficient time, the anti-tumor activity will dominate and become clinically apparent. 
Therefore participants will be allowed to continue study therapy after initial investigator-assessed 
RECIST 1.1 defined progression if they are assessed to be deriving clinical benefit and tolerating 
study drug. Such participants must discontinue study therapy upon evidence of further progression 
found in Section 8.1.1. 
6 
STUDY POPULATION 
For entry into the study, the following criteria MUST be met. 
6.1 
Inclusion Criteria 
1) Signed Written Informed Consent 
a) Participants must have signed and dated an IRB/IEC approved written informed consent 
form in accordance with regulatory and institutional guidelines. This must be obtained 
before the performance of any protocol related procedures that are not part of normal 
participant care. 
b) Participants must be willing and able to comply with scheduled visits, treatment schedule, 
and laboratory testing. 
2) Type of Participant and Target Disease Characteristics 
a) Recurrent or histologically confirmed stage IV NSCLC per 8th IASLC68 of squamous or 
non-squamous histology that is not amenable to therapy with curative intent (surgery or 
radiation therapy with or without chemotherapy).  
b) No prior treatment with systemic anti-cancer therapy for Stage IV disease. 


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i) Prior adjuvant or neoadjuvant chemotherapy is permitted as long as the last 
administration of the prior regimen occurred at least six months prior to randomization. 
ii) Prior definitive chemoradiation for locally advanced disease is also permitted as long 
as the last administration of chemotherapy or radiotherapy (whichever was given last) 
occurred at least six months prior to randomization. 
c) ECOG Performance Status of 0 to1 
d) Measureable disease by CT or MRI per RECIST 1.1 criteria radiographic tumor assessment 
performed within 28 days prior to randomization 
i) Target lesions may be located in a previously irradiated field if there is documented 
(radiographic) disease progression in that site after the completion of radiation therapy 
e) Documentation of PD-L1 status of 0 to 49% by IHC performed by the central lab prior to 
randomization. Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or 15 
unstained tumor tissue sections, obtained within 3 months prior to enrollment, with an 
associated pathology report, must be submitted to the core laboratory for inclusion. Central 
lab must provide Interactive Response Technology (IRT) with confirmation of receipt of 
evaluable tumor tissue prior to randomization. Biopsy should be excisional, incisional or 
core needle. Fine needle aspiration is unacceptable for submission. 
f) All toxicities or safety issues attributed to prior cancer therapy (systemic anti-cancer 
therapy, radiation or surgery), other than alopecia and fatigue, must have resolved or 
returned to baseline values recorded prior to those cancer therapies at least 2 weeks before 
randomization for the current study. 
3) Age and Reproductive Status 
a) Males and Females, t 18 years or age of majority 
b) Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours 
prior to the start of study treatment. 
c) Women must not be breastfeeding 
d) Women of childbearing potential (WOCBP) must agree to follow instructions for 
method(s) of contraception (Appendix 4) for the duration of treatment with study 
treatments and after the last dose of study treatment (ie, 30 days [duration of ovulatory 
cycle] plus the time required for the investigational drug to undergo approximately 5 half-
lives. WOCBP receiving nivolumab must agree to follow instructions for method(s) of 
contraception for 5 months after the last dose of study treatment. 
e) Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception (Appendix 4) for the duration of treatment with study 
treatments and after the last dose of study treatment (ie, 90 days [duration of sperm 
turnover] plus the time required for the investigational drug to undergo approximately 
5 half-lives). Males who are sexually active with WOCBP receiving nivolumab must agree 
to follow instructions for method(s) of contraception for 7 months after the last dose of 
study treatment. In addition, male participants must be willing to refrain from sperm 
donation during this time. 
f) Azoospermic males are exempt from contraceptive requirements. WOCBP who are 
continuously not heterosexually active are also exempt from contraceptive requirements, 
and still must undergo pregnancy testing as described in this section. 


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Investigators shall counsel WOCBP, and male participants who are sexually active with WOCBP, 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise on the use of highly effective methods of contraception, (Appendix 4) 
which have a failure rate of < 1% when used consistently and correctly. 
6.2 
Exclusion Criteria 
1) Medical Conditions 
a) Participants with known EGFR mutations which are sensitive to available targeted inhibitor 
therapy (including, but not limited to, deletions in exon 19 and exon 21 [L858R] 
substitution mutations) are excluded. All participants with non-squamous histology must 
have been tested for EGFR mutation status. EGFR test should be done locally. Participants 
of non-squamous histology with unknown or indeterminate EGFR status are excluded. 
b) Participants with known ALK or ROS1 rearrangements which are sensitive to available 
targeted inhibitor therapy are excluded. All participants with non-squamous histology must 
have been tested for ALK/ROS1 rearrangement status. ALK/ROS1 tests should be done 
locally. Participants of non-squamous histology with indeterminate ALK and/or ROS1 
status may enroll. 
c) Participants with untreated CNS metastases. Participants are eligible if CNS metastases 
have been adequately treated and have neurologically returned to baseline (except for 
residual signs or symptoms related to the CNS treatment) for at least 2 weeks prior to 
randomization.  
d) Unevaluable PD-L1 status or PD-L1 status of t 50% by IHC performed by a central 
laboratory 
e) Participants with carcinomatous meningitis 
f) Participants with an active, known or suspected autoimmune disease. Participants with 
type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin 
disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or 
conditions not expected to recur in the absence of an external trigger are permitted to enroll. 
g) Participants with a condition requiring systemic treatment with either corticosteroids 
(> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 
14 days of randomization. Inhaled or topical steroids, and adrenal replacement steroid 
doses > 10 mg daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease. 
h) Participants with a history of significant cardiac disease or presence of an abnormality in 
electrocardiograms (ECG) that, in the investigator’s opinion, is medically exclusionary or 
clinically meaningful. 
i) Screening QTc interval > 480 msec (corrected by Fridericia or Bazett formula) is an 
exclusion criteria. In the event that a single QTc is > 480 msec, the participant may 
enroll if the average QTc for 3 ECGs is d480 msec. 
i) Participants with interstitial lung disease or active, non-infectious pneumonitis 
(symptomatic and/or requiring treatment) that may interfere with the detection or 
management of suspected drug-related pulmonary toxicity 


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j) Other active malignancy 
k) Participants with previous malignancies (except non-melanoma skin cancers, and the 
following in situ cancers: bladder, gastric, esophageal, colon, endometrial, 
cervical/dysplasia, melanoma, or breast) unless a complete remission was achieved at least 
2 years prior to study entry AND no additional therapy is required during the study period. 
l) Known history of positive test for human immunodeficiency virus (HIV) or known 
acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed 
at sites where mandated locally. 
m) Known medical condition that, in the investigator’s opinion, would increase the risk 
associated with study participation or study drug administration or interfere with the 
interpretation of safety results.  
n) Participants with serious or uncontrolled medical disorders 
2) Prior/Concomitant Therapy 
a) Prior treatment with anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, IDO1 
targeted agent or any other antibody or drug targeting T cell co-stimulation or checkpoint 
pathways 
b) Participants using UGT1A9 inhibitor or inducer from screening through follow-up period 
(see Appendix 9) 
c) Participants receiving MAOIs (see Appendix 8) or melatonin supplement within the 
21 days before screening.  
d) Treatment with botanical preparations (eg, herbal supplements or traditional Chinese 
medicines) intended for general health support or to treat the disease under study within 
2 weeks prior to randomization/treatment.  
e) Any history of serotonin syndrome after receiving 1 or more serotonergic drugs.  
3) Physical and Laboratory Test Findings 
a) WBC < 2000/μL 
b) Neutrophils < 1500/μL 
c) Platelets < 100 x 103/μL 
d) Hemoglobin < 9.0 g/dL 
e) Serum creatinine >1.5 x ULN or calculated creatinine clearance < 40 mL/min (using the 
Cockcroft-Gault formula) 
f) AST/ALT: > 2.5 x ULN 
g) Total bilirubin >1.5 x ULN (except participants with Gilbert Syndrome who must have a 
total bilirubin level of < 3.0x ULN) 
h) Has known history of or is positive for active Hepatitis B (HBsAg reactive) or has active 
Hepatitis C (HCV RNA). Note: Testing must be performed to determine eligibility.  
i) HBV DNA must be undetectable and HBsAg negative at screening visit. 
ii) Hepatitis C antibody testing is allowed for screening purposes in countries where HCV 
RNA is not part of SOC. In these cases, HCV antibody positive participants will be 
excluded.  
iii) Participants who have had definitive treatment for HCV are permitted if HCV RNA is 
undetectable at screening. 


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i) International normalized ratio (INR) or prothrombin time (PT) > 1.5 × ULN unless 
participant is receiving anticoagulant therapy as long as PT or INR is within therapeutic 
range of intended use of anticoagulants.  
j) Activated partial thromboplastin time (aPTT) > 1.5 × ULN unless participant is receiving 
anticoagulant therapy, as long as PTT is within therapeutic range of intended use of 
anticoagulants. 
4) Allergies and Adverse Drug Reaction 
a) History of allergy or hypersensitivity to platinum-containing compounds or study drug 
components 
5) Other Exclusion Criteria 
a) Prisoners or participants who are involuntarily incarcerated. (Note: under certain specific 
circumstances a person who has been imprisoned may be included or permitted to continue 
as a participant. Strict conditions apply and BMS/Incyte approval is required.) 
b) Participants who are compulsorily detained for treatment of either a psychiatric or physical 
(eg, infectious disease) illness 
 
Eligibility criteria for this study have been carefully considered to ensure the safety of the study 
participants and that the results of the study can be used. It is imperative that participants fully 
meet all eligibility criteria. 
6.3 
Lifestyle Restrictions 
Not applicable. No restrictions are required. 
6.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently [randomized/entered in the study/included in the analysis population]. A minimal 
set of screen failure information is required to ensure transparent reporting of screen failure 
participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements, and to respond to queries from regulatory authorities. Minimal information includes 
date of consent, demography, screen failure details, eligibility criteria, and any serious AEs. 
6.4.1 
Retesting During Screening or Lead-In Period 
Participant Re-enrollment: This study permits the re-enrollment of a participant that has 
discontinued the study as a pre-treatment failure (ie, participant has not been randomized). If 
re-enrolled, the participant must be re-consented. 
Retesting of laboratory parameters and/or other assessments within any single Screening or 
Lead-in period will be permitted (in addition to any parameters that require a confirmatory value). 
The most current result prior to Randomization is the value by which study inclusion will be 
assessed, as it represents the participant’s most current, clinical state. 


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7 
TREATMENT 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo or 
medical device intended to be administered to a study participant according to the study 
randomization or treatment allocation 
Study 
treatment 
includes 
both 
Investigational 
[Medicinal] 
Product 
(IP/IMP) 
and 
Non-investigational [Medicinal] Product (Non-IP/Non-IMP): 
In this protocol, investigational product(s) is/are: 
x Nivolumab  
x Epacadostat 
x Epacadostat matching placebo  
x Carboplatin 
x Cisplatin 
x Gemcitabine 
x Paclitaxel 
x Pemetrexed 
 
An investigational product, also known as investigational medicinal product in some regions, is 
defined a pharmaceutical form of an active substance or placebo being tested or used as a reference 
in a clinical study, including products already with a marketing authorization but used or 
assembled (formulated or packaged) differently than the authorized form, or used for an 
unauthorized indication, or when used to gain further information about the authorized form. 
Other medications used as support or escape medication for preventative, diagnostic, or therapeutic 
reasons, as components of the standard of care for a given diagnosis, may be considered as 
non-investigational products.  
The selection and timing of dose for each participant is as follows in Table 7-1: 


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Table 7-1: 
Study treatments for CA2099NC / INCB 24360-309  
Product Description / Class and 
Dosage Form 
Potency 
IP/Non-
IMP 
Blinded or Open 
Label 
Packaging / 
Appearance 
Storage Conditions 
(per label) 
Nivolumab Injectiona 
10 mg/mL 
IP 
Open Label 
Vials 
Refer to the label or container and/or pharmacy 
manual. 
Cisplatin Concentrate for solution 
for infusion b 
1 mg/mL 
IP 
Open Label 
Vials 
Refer to the label or container and/or pharmacy 
manual. 
Carboplatin Solution for IV 
Injectionb 
10 mg/mL  
IP 
Open Label 
Vials  
Refer to the label or container and/or pharmacy 
manual. 
Epacadostat Tabletsc 
100 mg and 
25 mg  
IP 
Blinded 
Bottles 
Refer to the label or container and/or pharmacy 
manual.  
Epacadostat Matching Placebo 
Not 
applicable 
IP 
Blinded 
Bottles 
Refer to the label or container and/or pharmacy 
manual. 
Gemcitabine Concentrate for 
Solution for Infusion or 
Gemcitabine Powder for Solution 
for Infusionb 
1000 mg / 
vial 
IP 
Open Label 
Vials  
Refer to the label or container and/or pharmacy 
manual. 
Paclitaxel Solution for Injectionb 
100 mg/vial 
(6 mg/mL) 
IP 
Open Label 
Vials  
Refer to the label or container and/or pharmacy 
manual. 
Pemetrexed Powder for Concentrate 
for Solution for Infusionb 
500 mg/ vial 
IP 
Open Label 
Vials  
Refer to the label or container and/or pharmacy 
manual. 
a May be labeled as either “BMS-936558-01” or nivolumab. 
b These products may be obtained by the investigational sites as local commercial product in certain countries if allowed by local regulations. In these cases, 
products may be a different pack size/potency than listed in the table. These products should be prepared/stored/administered in accordance with the package 
insert or summary of product characteristics (SmPC). 
c For participants who cannot swallow tablets but can eat and/or drink, epacadostat/placebo for epacadostat tablets may be crushed and dissolved in water or 
dispersed in a medium such as applesauce, or a nutritional supplement such as Ensure® and administered orally.  In the case of participants who are unable to eat 
or drink by mouth, the epacadostat/placebo for epacadostat tablet(s) may be crushed and dissolved in water and delivered to the participant through a feeding 
tube.  Detailed information is provided in the Pharmacy Manual.  


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7.1 
Treatments Administered 
Table 7.1-1 describes the selection and timing of dose for each participant.  
Table 7.1-1: 
Selection and Timing of Dose 
Study Treatment 
Unit dose 
strength(s)/Dosage 
level(s) 
Dosage formulation 
Frequency of 
Administration 
Route of 
Administration 
Nivolumab  
360 mg 
Q3W 
IV 
Epacadostata 
100 mg 
Twice daily 
Oral 
Epacadostat Matching Placeboa 
 
Twice daily 
Oral 
Doublet Chemotherapyb 
Squamous histology 
Gemcitabine 
+  
Cisplatin 
1000 or 1250 mg/m2 
Q3W  
up to 4 cycles 
(Gemcitabine on days 1,8) 
IV 
75 mg/m2 
Gemcitabine 
+  
Carboplatin  
1000 mg/m2 
Q3W 
up to 4 cycles 
(Gemcitabine on days 1,8) 
IV 
AUC 5 
Paclitaxel 
+  
Carboplatin  
200 mg/m2 
Q3W 
up to 4 cycles 
IV 
AUC 6 
Non-squamous histology 
Cisplatin 
+  
Pemetrexed  
75 mg/m2 
Q3W 
up to 4 cycles 
IV 
500 mg/m2 
Carboplatin  
+  
Pemetrexed 
AUC 5 or 6 
Q3W 
up to 4 cycles 
IV 
500 mg/m2 
Optional Maintenance Treatment Non-squamous histology 
Pemetrexed 
500 mg/m2 
Q3W 
IV 
a For participants who cannot swallow tablets but can eat and/or drink, epacadostat/placebo for epacadostat tablet(s) 
may be crushed and dissolved in water or dispersed in a medium such as applesauce, or a nutritional supplement 
and administered orally.  In the case of participants who are unable to eat or drink by mouth, the epacadostat/placebo 
for epacadostat tablet(s) may be crushed and dissolved in water and delivered to the participant through a feeding 
tube. Detailed information is provided in the Pharmacy Manual. 
b Information on investigator’s selection of chemotherapeutic regimen may be collected, as applicable. 


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7.1.1 
All Arms 
Study treatment should begin within 3 calendar days of randomization and the maximum duration 
of study treatment is 24 months.  
It is important to note that some chemotherapy-related AEs may overlap with suspected 
immune-related AEs potentially related to nivolumab or epacadostat/placebo for epacadostat. In 
these cases, both the treatment management algorithm (Appendix 6 and Section 7.4) for 
nivolumab/epacadostat/placebo for epacadostat and local prescribing guidelines for chemotherapy 
should be reviewed to determine the most appropriate management of study medications (see 
Section 7.4 for dose modification guidance for the study drugs). 
7.1.2 
Nivolumab 
Participants should receive nivolumab at a dose of 360 mg as a 30-minute infusion on Day 1 of 
each treatment cycle every 3 weeks until progression, unacceptable toxicity, withdrawal of 
consent, completion of 24 months of treatment, or the study ends, whichever occurs first.  
Nivolumab Injection, 100 mg/10 mL (10 mg/mL) is to be administered as an IV infusion through 
a 0.2-micron to 1.2-micron pore size, low-protein binding in-line filter at the protocol-specified 
doses. It is not to be administered as an IV push or bolus injection. When the dose is fixed (eg, 
360 mg flat dose), nivolumab injection can be infused undiluted or diluted so as not to exceed a 
total infusion volume of 120 mL. Nivolumab infusion must be promptly followed by a saline flush 
to clear the line. Instructions for dilution and infusion of nivolumab injection may be provided in 
the clinical protocol, pharmacy binder, or pharmacy reference sheet. Care must be taken to assure 
sterility of the prepared solution as the product does not contain any antimicrobial preservative or 
bacteriostatic agent.  
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or polyolefin containers and 
infusion sets, and glass bottles. 
There will be no dose escalations or reductions of nivolumab allowed. Participants may be dosed 
no less than 18 days from the previous dose during Q3W cycles. Premedications are not 
recommended for the first dose of nivolumab.  
Participants should be carefully monitored for infusion reactions during nivolumab administration. 
If an acute infusion reaction is noted, participants should be managed according to Section 7.4.4. 
Doses of nivolumab may be interrupted, delayed, or discontinued depending on how well the 
participant tolerates the treatment. Dosing visits are not skipped, only delayed. See Section 7.4.2.1 
and Section 8.1.1 for additional information on dose delay or dose discontinuation, respectively.  
7.1.3 
Epacadostat/Placebo for Epacadostat 
The starting dose of epacadostat is 100 mg BID daily continuously during Q3W cycles. 
Epacadostat/placebo for epacadostat will be continued until progression, unacceptable toxicity, 
withdrawal of consent, permanent discontinuation of nivolumab, completion of 24 months of 
treatment, or the study ends, whichever occurs first.  


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On Day 1 of each cycle, epacadostat or placebo for epacadostat is administered orally in the clinic 
first followed by IV infusion of nivolumab (see Table 2-2). All other doses should be 
self-administered. All BID doses of epacadostat or placebo for epacadostat will be taken orally, in 
the morning and evening, approximately 12 hours apart without regard to food. If the morning or 
evening dose is missed by more than 4 hours, that dose should be skipped, and the next scheduled 
dose should be taken at the usual time. On days when epacadostat or placebo for epacadostat and 
nivolumab are administered, epacadostat or placebo for epacadostat should administered first, and 
the nivolumab infusion should be started no later than 10 minutes after epacadostat/placebo for 
epacadostat administration.  
Epacadostat or placebo for epacadostat will be given twice daily in combination with nivolumab 
as long as participants are receiving benefit from treatment and have not met any criteria for study 
withdrawal (Section 8.1). Intra-participant dose escalation of epacadostat/placebo for epacadostat 
is not permitted. 
Epacadostat/placebo for epacadostat dose may be dose reduced (to -1 dose level [50 mg BID]), 
delayed, or discontinued depending on how well the participant tolerates the treatment (see Section 
7.4.2.2 for dose modification guidance for epacadostat/placebo for epacadostat). If the nivolumab 
dose is delayed because of an AE), epacadostat/placebo for epacadostat should also be delayed 
(see Section 7.4.2 for exceptions to this guidance). If nivolumab is permanently discontinued for 
any reasons, epacadostat/placebo for epacadostat will be permanently discontinued. Participants 
may complete chemotherapy as prescribed in Section 7.1.4. 
7.1.4 
Platinum Doublet Chemotherapy 
Refer to Table 7.1-1 for specific doses of specific chemotherapy products. Follow the local 
prescribing information of each respective agent for information on administration. Platinum 
doublet chemotherapy will be continued for a maximum of 4 cycles every 3 weeks (r 3 days). In 
Arm A and Arm C, chemotherapy agents should be given after the nivolumab infusion. There is a 
30-minute (60 minutes if required for pre-medication) delay before the start of the chemotherapy 
infusion to monitor the participant for signs of possible nivolumab infusion reactions. 
Chemotherapy agents should be administered according to standard of care or instructional 
practice. 
All participants who will be receiving cisplatin should have audiometric testing performed prior 
to initiation of therapy and prior to subsequent doses of cisplatin, or as per local standards of care. 
Participants who discontinue cisplatin alone may, at the investigator’s discretion, be switched to 
carboplatin treatment for the remainder of the platinum doublet cycles (up to 4 cycles in total).  
Carboplatin dose will be calculated using the Calvert formula as follows: 
x Carboplatin dose (mg) = Target AUC x [(CrCl (ml/min) + 25] 
x Creatinine clearance (CrCl) calculation is based on the Cockroft-Gault formula) and should 
include the most recent serum creatinine and most recent weight. NOTE: If calculation of the 
CrCl by the Cockroft-Gault formula yields a result of > 125 mL/min, then a CrCl should be 
calculated by an alternative formula per institutional standards or capped at 125 mL/min. 


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x The dose of carboplatin may be capped per local standards. 
Investigators must indicate, at the time of randomization, whether or not a participant will be 
treated with pemetrexed continuation maintenance if eligible to do so. If the investigator 
subsequently decides that a participant should not be treated with pemetrexed continuation 
maintenance, even though eligible, or decides to treat a participant for whom the investigator had 
indicated at randomization that maintenance would not be used, this decision must be discussed 
with the Medical Monitor. 
Antiemetic premedication will be administered according to local standards. Recommended 
antiemetic treatments are dexamethasone (dosing according to local standards; an equivalent dose 
of another corticosteroid may be substituted) and a 5-HT3 receptor antagonist (type per 
investigator discretion and local standards-of-care). Additional use of antiemetic premedications 
may be employed at the discretion of the Investigator.  
Administration of chemotherapy may be interrupted, delayed, reduced, or discontinued depending 
on how well the participant tolerates the treatment. See Sections 7.4.3, 7.4.5.2, and 8.1.2 for more 
details regarding dose delays, reductions, retreatment, and discontinuations. 
Premedication for use with pemetrexed: Oral corticosteroid should be given according to local 
standards at a dose equivalent to dexamethasone 4 mg BID on the day prior to, the day of, and the 
day after the administration of pemetrexed. Oral folic acid 350 to 1000 mcg daily should be given 
starting 1 week prior to the first dose of pemetrexed, with at least 5 doses of folic acid administered 
in the 7 days prior to the first dose. Oral folic acid should be continued daily throughout the 
treatment with pemetrexed and for 21 days after the last dose of pemetrexed. Intramuscular (IM) 
injection of vitamin B12 1000 mcg should be given approximately one week prior to the first dose 
of pemetrexed and repeated every 3 cycles thereafter during pemetrexed treatment. Subsequent 
injections of vitamin B12 may be given on the same day as pemetrexed. Participants with 
non-squamous histology may begin folic acid and vitamin B12 prior to randomization in 
anticipation of pemetrexed. 
Premedications for use with paclitaxel: Oral or IV corticosteroid should be given prior to 
paclitaxel according to local standard. Such premedication may consist of oral dexamethasone 20 
mg 12 hours and 6 hours prior to paclitaxel administration. Oral or IV diphenydramine 50 mg (or 
its equivalent) and an H2-blocker (per local standards) should be administered 30 to 60 minutes 
prior to paclitaxel infusion. All participants should be carefully monitored for infusion reactions 
during the paclitaxel administration. Participants should be treated in a facility with the necessary 
medical-resuscitation equipment and medications on hand to manage serious acute infusion 
reactions. 
7.1.4.1 
Cisplatin /Gemcitabine 
Participants will receive gemcitabine at a dose of 1000 or 1250 mg/m2 for a 30-minute IV infusion 
on days 1 and 8 with cisplatin at a dose of 75 mg/m2 as a 30 to 120-minute IV infusion on Day 1 
of a 3-week treatment cycle for up to 4 cycles. Dosing calculations should be based on the body 
surface area calculation and may be capped per local standards. The dose may remain the same if 
the participant’s weight is within 10% of the baseline weight or prior dose weight.  


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Cisplatin will be administered to participants following the end of the gemcitabine infusion. 
Pretreatment hydration for cisplatin can follow local standard of care, or 1 to 2 liters of fluid (per 
local standards) infused IV for 8 to 12 hours prior to cisplatin infusion is recommended. Adequate 
hydration and urinary output must be maintained for at least 24 hours following cisplatin 
administration. Administration and monitoring should be performed according to local standards. 
Use of mannitol following the cisplatin infusion should also follow local standards. 
7.1.4.2 
Carboplatin/ Gemcitabine 
Participants will receive gemcitabine at a dose of 1000 mg/m2 as a 30-minute IV infusion on 
Days 1 and 8 with carboplatin at a dose of AUC 5 as a 30-minute IV infusion, on Day 1 of a 3-week 
cycle, for up to 4 cycles, or at doses per the local prescribing information. Gemcitabine dosing 
calculations should be based on the body surface area calculation. The dose may remain the same 
if the participant’s weight is within 10% of the baseline weight or prior dose weight. Carboplatin 
should be given following gemcitabine on Day 1 of each cycle, and the carboplatin dose will be 
calculated using the Calvert formula. 
7.1.4.3 
Cisplatin/Carboplatin and Pemetrexed with or without Pemetrexed 
Continuation Maintenance 
Cisplatin/ Pemetrexed with or without Pemetrexed Continuation Maintenance 
Participants will receive pemetrexed at a dose of 500 mg/m2 as a 10-minute IV infusion on Day 1 
with cisplatin at a dose of 75 mg/m² as a 120-minute IV infusion on Day 1 of a 3-week treatment 
cycle for up to 4 cycles. (Note: calculated CrCl must be t 45 mg/min for pemetrexed to be dosed.) 
After cycle 4, participants with stable disease or response will discontinue cisplatin and may 
continue pemetrexed at the same dose and schedule as continuation maintenance until progression, 
unacceptable toxicity, withdrawal of consent, or a maximum treatment duration of 24 months. In 
participants who required pemetrexed dose reduction due to toxicity during the 
cisplatin/pemetrexed combination cycles, the dose of pemetrexed may be escalated to 500 mg/m2 
after the discontinuation of cisplatin, at the investigator’s discretion and according to local 
standards, if the prior toxicity was thought to be related mainly to cisplatin. Dosing calculations 
should be based on the body surface area calculation and may be capped per local standards. The 
dose may remain the same if the participant’s weight is within 10% of the baseline weight or prior 
dose weight. Cisplatin will be administered to participants at least 30 minutes following the end 
of the pemetrexed infusion. Pretreatment hydration for cisplatin can follow local standards, or use 
1 to 2 liters of fluid (per local standards) infused IV for 8 to 12 hours prior to cisplatin infusion is 
recommended. Adequate hydration and urinary output must be maintained for at least 24 hours 
following cisplatin administration. Administration and monitoring should be performed according 
to local standards. Use of mannitol following the cisplatin infusion should also follow local 
standards. 
Carboplatin/Pemetrexed with or without Pemetrexed Continuation Maintenance 
Participants will receive pemetrexed at a dose of 500 mg/m2 as a 10-minute IV infusion on Day 1, 
followed by carboplatin at a dose of AUC 5 or 6 as a 30-minute IV infusion, on Day 1 of a 3-week 


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treatment cycle, for up to 4 cycles. After cycle 4, participants with stable disease or response will 
discontinue carboplatin and may continue pemetrexed at the same dose and schedule as 
continuation maintenance until progression, unacceptable toxicity, withdrawal of consent, or a 
maximum treatment duration of 24 months. In participants who required pemetrexed dose 
reduction due to toxicity during the pemetrexed/carboplatin combination cycles, the dose of 
pemetrexed may be escalated to 500 mg/m2 after the discontinuation of carboplatin, at the 
investigator’s discretion and according to local standards, if the prior toxicity was thought to be 
related mainly to carboplatin. 
Pemetrexed dosing calculations should be based on the body surface area calculation. The dose 
may remain the same if the participant’s weight is within 10% weight used to calculate the previous 
dose. The carboplatin dose will be calculated using the Calvert formula. 
7.1.4.4 
Carboplatin/Paclitaxel 
Participants will receive paclitaxel at a dose of 200 mg/m2 as a 180-minute IV infusion, followed 
by carboplatin at a dose of AUC 6 as a 30 to 60-minute IV infusion, both on Day 1 of a treatment 
cycle every 3 weeks for 4 cycles. Paclitaxel dosing calculations should be based on the body 
surface area calculation and may be capped per local standards. The dose may remain the same if 
the s participant’s weight is within 10% of the weight used to calculate the previous dose.
The carboplatin dose will be calculated using the Calvert formula. 
7.2 
Method of Treatment Assignment 
After the participant’s initial eligibility is established and informed consent has been given, the 
participant will be enrolled into the study and assigned a participant number using the centralized 
IRT system. Every person that signs the informed consent form must be assigned a participant 
number by the IRT. Before the study is initiated, each user will receive log in information and 
directions on how to access the IRT. Exact procedures for using the IRT will be detailed in the 
IRT manual.  
Enrolled participants that have met all eligibility criteria will be randomized centrally via the IRT 
system. PD-L1 status will be transferred directly from the analyzing lab to the IRT system.  
Study treatment will be dispensed at the study visits as listed in Schedule of Activities (Section 2).
Participants will be stratified by PD-L1 status, gender, and histology for randomization into Arms 
A, B, or C in 2:2:1 ratio.  
7.3 
Blinding
In this study, participants and investigators are blinded to the epacadostat treatment in Arm A and 
Arm C.  
Blinding of treatment assignment of epacadostat for Arm A and Arm C is critical to the integrity 
of this clinical study. However, in the event of a medical emergency or pregnancy in an individual 
participant in which knowledge of the investigational product is critical to the participant's 
management, the blind for that participant may be broken by the investigator. The participant’s 


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safety takes priority over any other considerations in determining if a treatment assignment should 
be unblinded. 
Before breaking the blind of an individual participant's treatment, the investigator should 
determine that the unblinded information is necessary, ie, that it will alter the participant's 
immediate management. In many cases, particularly when the emergency is clearly not related to 
the investigational product, the problem may be properly managed by assuming that the participant 
is receiving active product. It is highly desirable that the decision to unblind treatment assignment 
be discussed with the Medical Monitor, but the investigator always has ultimate authority for the 
decision to unblind. The Principal Investigator should only call in for emergency unblinding 
AFTER the decision to discontinue the participant has been made. 
For this study, the method of unblinding for emergency purposes is the IRT system.  
In cases of accidental unblinding, contact the Medical Monitor and ensure every attempt is made 
to preserve the blind. 
Any request to unblind a participant for non-emergency purposes should be discussed with the 
Medical Monitor. 
In case of an emergency, the investigator(s) has unrestricted access to randomization information 
via the Interactive Response Technology (IRT) and is capable of breaking the blind through the 
IRT system without prior approval from sponsor. Following the unblinding, the Investigator shall 
notify the Medical Monitor and/or Study Director. 
This information, including the reason for the blind being broken, must be recorded on the 
appropriate study page of the source document. 
7.4 
Dosage Modifications 
Dosing of nivolumab/epacadostat/placebo for epacadostat may be modified or discontinued 
without delay of chemotherapy dosing if the drug-related toxicity is determined by the investigator 
to be immune-related and clearly not related to chemotherapy. Conversely, dosing of one or all of 
the chemotherapy drugs may be dose-modified or discontinued without delay of 
nivolumab/epacadostat/placebo for epacadostat dosing if drug-related toxicity is determined to be 
related to only to chemotherapy drugs and clearly not related to immunotherapy. Refer to the below 
sub-sections, Section 7.4.2, Appendix 6, and Appendix 7 for guidance on dose modifications and 
discontinuation for individual components.   
However, if drug-related toxicity could be attributable to either immunotherapy or chemotherapy 
or if the investigator is unable to determine which study drug is the cause, then drug-related AE is 
considered to be related to both immunotherapy and chemotherapy. In the above scenario where 
the investigator is unable to determine the causality of the AE, except in the case of emergency, 
the Medical Monitor should be consulted before interrupting or restarting therapy. 
In the cases where the AE is considered to be related to both immunotherapy and chemotherapy, 
all the guidance for dose modification and discontinuation for both immunotherapy and 


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chemotherapy should be reviewed to determine the most appropriate management of study 
medication (Section 7.4.2, Appendix 6, and Appendix 7).  
A dose of chemotherapy given more than 3 days after the intended dose date will be considered a 
dose delay. A maximum delay of 8 weeks between doses is allowed. Longer delays will require 
approval from the Medical Monitor. 
7.4.1 
Management Algorithms for Immuno-Oncology Agents 
Immuno-oncology (I-O) agents are associated with AEs that can differ in severity and duration 
than AEs caused by other therapeutic classes. Nivolumab and epacadostat are considered 
immuno-oncology agents in this protocol. Early recognition and management of AEs associated 
with immuno-oncology agents may mitigate severe toxicity. Management Algorithms have been 
developed to assist investigators in assessing and managing the following groups of AEs: 
x Gastrointestinal 
x Renal 
x Pulmonary 
x Hepatic 
x Endocrinopathy 
x Skin 
x Neurological 
 
The above algorithms are found in the nivolumab Investigator Brochure, as well as in Appendix 6. 
7.4.2 
Dose Modifications for Immunotherapy (Nivolumab and 
Epacadostat/Placebo for Epacadostat) (Arms A and C) 
Refer to Appendix 6 and Appendix 7 for the detailed toxicity management algorithm for 
nivolumab and epacadostat/placebo for epacadostat. 
In most cases of immune-related toxicities, decision on dose delay or permanent discontinuation 
will be implemented consistently for both nivolumab and epacadostat/placebo for epacadostat. If 
nivolumab is delayed or permanently discontinued for immune-related toxicity, then 
epacadostat/placebo for epacadostat will be delayed or permanently discontinued as well, and vice-
versa. The following are exceptions to the above guidance: 
x Nivolumab dosing may continue as planned in cases of epacadostat/placebo for epacadostat 
dose delays or discontinuation due to Serotonin Syndrome (See Section 7.4.2.3 for details).  
x Epacadostat/placebo for epacadostat dosing may continue in cases of nivolumab dosing delays 
due to Grade 1-2 immune-mediated dermatitis, except in the cases of suspected 
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) where both the drugs 
will be dose delayed. In cases of confirmed SJS/TEN diagnosis and in cases of Grade 3-4 
immune-related 
dermatitis 
requiring 
permanent 
nivolumab 
discontinuation, 
epacadostat/placebo for epacadostat should also be discontinued. Refer to Appendix 6, 
Appendix 7, and Section 8.1.1 for additional details. If the rash is Grade 3 by BSA and 
otherwise mild, temporarily hold epacadostat/placebo for epacadostat may occur, use topical 
steroids, and resume dose when resolved to < Grade 1. 


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x Epacadostat/placebo for epacadostat dosing may continue if nivolumab dosing is interrupted 
or delayed due to nivolumab-related infusion reactions. However, if nivolumab is permanently 
discontinued, epacadostat/placebo for epacadostat will be discontinued as well. 
x In cases requiring occasional short-term interruptions of one of the two drugs, for reasons other 
than AEs, the dosing for the other drug may continue as planned, eg. nivolumab dosing may 
continue if epacadostat/placebo for epacadostat dose is temporarily interrupted due to patient 
non-compliance. Similarly, epacadostat/placebo for epacadostat dosing may continue if 
nivolumab is temporarily delayed due to scheduling issues. 
 
7.4.2.1 
Dose Delay Criteria for Nivolumab and Epacadostat/Placebo for 
Epacadostat (Arms A and C) 
This section should be reviewed in conjunction with Appendices 6 and 7. Nivolumab and 
epacadostat/placebo for epacadostat administration should be delayed for the following: 
x Grade 2 non-skin, drug-related adverse event, with the exception of fatigue 
x Grade 2 drug-related creatinine, AST, ALT and/or Total Bilirubin abnormalities 
x Grade 3 skin, drug-related adverse event 
x Grade 3 drug-related laboratory abnormality, with the following exceptions:  
 Grade 3 lymphopenia or asymptomatic amylase or lipase does not require dose delay 
 Grade 3 AST, ALT, Total Bilirubin will require dose discontinuation (see Section 8.1.1 
x Serotonin Syndrome will require a delay of epacadostat. Nivolumab dosing can be continued 
(see Section 7.4.2.3 for Serotonin Syndrome management). 
x Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the investigator, warrants delaying the dose of nivolumab/epacadostat/placebo for epacadostat. 
Participants who require delay of nivolumab or epacadostat/placebo for epacadostat should be 
re-evaluated weekly or more frequently if clinically indicated and resume dosing of 
nivolumab/epacadostat/placebo for epacadostat when re-treatment criteria are met. Treatment 
delay up to 8 weeks for nivolumab/epacadostat/placebo for epacadostat is allowable (any dose 
delays greater than 8 weeks will require approval from the Medical Monitor). 
If nivolumab is delayed, epacadostat/placebo for epacadostat should also be delayed. There will 
be no dose reductions for nivolumab. The criteria for dose discontinuation is provided in 
Section 8.1.1.   
7.4.2.2 
Dose Modification Criteria for Nivolumab and Epacadostat/Placebo for 
Epacadostat (Arms A and C) 
No dose reduction for nivolumab are allowed. 
In case of drug-related AEs that may be attributable to epacadostat/placebo for epacadostat, the 
dose can be reduced to -1 dose level (50 mg BID). The criteria for dose reduction, dose delay, and 
dose discontinuation is provided in Appendix 7. Intra-participant dose escalations are not 
permitted. Participants will remain on their assigned dose or a lower dose of epacadostat/placebo 
for epacadostat (if required) because of an AE.  


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7.4.2.3 
Recommended Management for Serotonin Syndrome  
As noted in Section 3.3.2 there is a theoretical chance that epacadostat could cause an increase in 
serotonin levels in the brain that might trigger serotonin syndrome when administered in 
combination with other serotonergic agents.55 This syndrome has been most closely associated 
with use of MAOIs, meperidine/pethidine, linezolid, or methylene blue; all of these agents are 
prohibited during the study. Serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine 
reuptake inhibitors (SNRIs) are permitted in the study. The following procedures will be 
implemented if participants exhibit the signs/symptoms of serotonin syndrome, including tremor, 
hyperreflexia, spontaneous, ocular, or inducible clonus, together with agitation, fever, diaphoresis, 
or muscle rigidity: 
x Immediately interrupt epacadostat/placebo for epacadostat administration.  Administration of 
nivolumab may continue. 
x Immediately interrupt any SSRI or SNRI administration. 
x Provide appropriate medical management of the participant 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). 
x If participant chooses to remain in the study, restart treatment with epacadostat/placebo for 
epacadostat after the SSRI or SNRI has been discontinued, no sooner than 5 half-lives have 
elapsed for the specific SSRI or SNRI in question and after resolution of signs/symptoms of 
serotonin syndrome. The SSRI or SNRI treatment MAY NOT be restarted. 
x If the SSRI/SNRI cannot be stopped, the epacadostat/placebo for epacadostat can be 
discontinued and the participants can continue on-study nivolumab treatment. In this 
circumstance, the study blind will not need to be broken. 
x If participant chooses to withdraw from the study, or must restart treatment with SSRI or SNRI, 
the participant 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 serotonin syndrome. 
7.4.3 
Dose Modifications for Chemotherapy 
This section includes guidance on dose modifications for gemcitabine, pemetrexed, cisplatin, 
carboplatin, and paclitaxel treatment-related toxicities. Investigators should confirm that the local 
prescribing guidelines for individual drugs are also reviewed to determine the most appropriate 
management of study medications. 
Dose Delay: Dosing of both drugs in the platinum doublet chemotherapy regimen should be 
delayed for any of the following on the Day 1 of each cycle: 
x Presence of febrile neutropenia or neutropenia < 1500 cells/mm3 for greater than one week 
despite the use of growth factors 
x Any Grade t 2 non-skin, drug-related adverse event, except for alopecia, fatigue or laboratory 
abnormalities 
x Any Grade 3 skin drug-related AE 
x Any Grade 3 drug-related laboratory abnormality, with the following exceptions: 
 Grade 3 lymphopenia does not require a dose delay 


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 Delay if total bilirubin >1x ULN or if AST and/or ALT > 1.5 x ULN occurs concomitant 
with alkaline phosphatase > 2.5x ULN 
x Any AE, laboratory abnormality or inter-current illness which, in the judgment of the 
investigator, warrants skipping the dose of study medication. 
A dose given more than 3 days after the intended dose date will be considered a dose delay. A 
maximum delay of 8 weeks between doses is allowed. Longer delays may be allowed following 
discussion with the Medical Monitor.  Subsequent dose reductions may be required as described 
below. Participants may receive growth factors (including G-CSF and erythropoietin) at the 
discretion of the investigator. 
Dose Reduction: Dose reductions of chemotherapy may be required, and will be performed 
according to Table 7.4.3-1. Chemotherapy dose reductions are permanent; once the dose of any 
chemotherapy agent is reduced, it may not be re-escalated in subsequent cycles, except as noted 
when starting pemetrexed maintenance therapy. The dose reductions for each agent in the platinum 
doublet chemotherapy regimen are not linked and may be adjusted independently as summarized 
below. 
Table 7.4.3-1: 
Dose Modifications of Chemotherapeutic Agents 
Dose Level 
Gemcitabine 
Pemetrexed 
Cisplatin 
Carboplatin 
Carboplatin 
Paclitaxel 
Starting dose 
1000 or 1250 
mg/m² (with 
cisplatin) or 
1000 mg/m² 
(with 
carboplatin) 
500 mg/m² 
75 mg/m² 
AUC 5 or 6 
with 
pemetrexed/ 
or AUC 5 
with 
gemcitabine 
AUC 6 with 
paclitaxel 
200 mg/m2 
First dose 
reduction 
750 or 950 
mg/m² (with 
cisplatin) or 
750 mg/m² 
(with 
carboplatin 
375 mg/m² 
56 mg/m² 
AUC 4 or 5 
with 
pemetrexed 
or AUC 4 
with 
gemcitabine 
AUC 5 with 
paclitaxel 
150 mg/m2 
Second dose 
reduction 
500 or 625 
mg/m² (with 
cisplatin) or 
500 mg/m² 
(with 
carboplatin) 
250 mg/m² 
38 mg/m² 
AUC 3 or 4 
with 
pemetrexed 
or AUC 3 
with 
AUC 4 with 
paclitaxel 
100 mg/m2 
Third dose 
reduction 
Discontinue 
Discontinue 
Discontinue 
Discontinue 
Discontinue 
Discontinue 
 
Any participants with two prior dose reductions for one agent who experiences a toxicity that 
would cause a third dose reduction must be discontinued from that agent. 


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7.4.3.1 
Recommended Chemotherapy Dose Reductions for Hematologic 
Toxicity  
Dose modifications for hematologic toxicities (according to CTCAE version 4) are summarized in 
Table 7.4.3.1-1. Dose adjustments are based on nadir blood counts (assessed as per local standards) 
since the preceding drug administration. Dose level adjustments for doublet chemotherapy are 
relative to that of the preceding administration. Generally, both chemotherapy agents in the doublet 
chemotherapy regimen should be dose reduced together for hematologic toxicity. After the first 
cycle, growth factors may be used to assist hematologic recovery. Local standards of care should 
be applied in the use of these supportive measures. Additionally, prophylactic antibiotics may be 
used according to local standards. Antibiotic or growth factor use should be reported on the eCRF. 
Table 7.4.3.1-1: 
Dose Modifications for Hematologic Toxicity (Based on Nadir 
Counts) 
Toxicity 
Gemcitabine 
Pemetrexed 
Cisplatin 
Carboplatin 
Paclitaxel 
Neutrophils Count Decreased 
Grade 4  
(< 500/mm3 or 
< 0.5 x 109/L) 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Platelet count Decreased 
Grade 3 
(25,000 - 
< 50,000/mm3; 
25.0 < 50.0 x 
109/L) 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Grade 4  
(< 25,000/mm3; 
< 25.0 x 109/L) 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
 
7.4.3.2 
Chemotherapy Dose Reductions for Non-Hematologic Toxicities  
Dose adjustments for chemotherapy for non-hematologic toxicities during treatment are described 
here. All dose reductions should be made based on the worst grade toxicity. Participants 
experiencing any of the toxicities during the previous cycle should have their chemotherapy 
delayed until retreatment criteria are met and then reduced for all subsequent cycles by 1 dose level 
or discontinued as appropriate. Dose levels for the two drugs in the doublet chemotherapy regimen 
are not linked and may be reduced independently, as summarized in Table 7.4.3.2-1. 


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Table 7.4.3.2-1: 
Dose Modifications for Non-Hematologic Toxicity 
Toxicity 
Gemcitabine 
Pemetrexed 
Cisplatin 
Carboplatin 
Paclitaxel 
Febrile 
Neutropenia 
Grade t 3 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one 
dose level 
Reduce one dose 
level 
Diarrhea Grade t 3 
Reduce one 
dose level 
Reduce one 
dose level 
No change 
No change 
Reduce one dose 
level 
Allergic reactiona 
Grade t 3 
Discontinue 
Discontinue 
Discontinue 
Discontinue 
Discontinue 
Neuropathy 
Grade 2 
No change 
No change 
Reduce one 
dose level 
No change 
Reduce one dose 
level 
Neuropathy 
Grade t 3 
Discontinue 
Discontinue 
Discontinue 
Discontinue 
Discontinue 
Calculated 
creatinine 
clearance 
< 50 mL/min 
No change 
No change 
Discontinue 
Discontinue if 
creatinine 
clearance 
< 20 ml/min 
No change 
Other Grade t 3 
toxicity (except for 
fatigue and transient 
arthralgia and 
myalgia) 
Adjust as 
medically 
indicated 
Adjust as 
medically 
indicated 
Adjust as 
medically 
indicated 
Adjust as 
medically 
indicated 
Adjust as 
medically 
indicated 
a Only the drug(s) causing the hypersensitivity reaction or acute infusion reaction (t Grade 3) require(s) 
discontinuation. All other drugs may be continued. 
 
7.4.4 
Treatment of Nivolumab-related Infusion Reactions 
Since nivolumab contains only human immunoglobulin protein sequences, they are unlikely to be 
immunogenic and induce infusion or hypersensitivity reactions. However, if such a reaction were 
to occur, it might manifest with fever, chills, rigors, headache, rash, pruritus, arthralgias, hypo- or 
hypertension, bronchospasm, or other symptoms. All Grade 3 or 4 infusion reactions should be 
reported within 24 hours to the BMS Medical Monitor and reported as an SAE if criteria are met. 
Infusion reactions should be graded according to National Cancer Institute (NCI) common 
terminology criteria for adverse event (CTCAE, Version 4) guidelines. 
Treatment recommendations are provided below and may be modified based on local treatment 
standards and guidelines, as appropriate: 
For Grade 1 symptoms: (mild reaction; infusion interruption not indicated; intervention not 
indicated) 
x Remain at bedside and monitor participant until recovery from symptoms. The following 
prophylactic premedications are recommended for future infusions: diphenhydramine 50 mg 


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(or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg at least 30 minutes before 
additional nivolumab administrations. 
 
For Grade 2 symptoms: (moderate reaction requires therapy or infusion interruption but responds 
promptly to symptomatic treatment [eg, antihistamines, non-steroidal anti-inflammatory drugs, 
narcotics, corticosteroids, bronchodilators, IV fluids]; prophylactic medications indicated for 
d 24 hours) 
x Stop the nivolumab infusion, begin an IV infusion of normal saline, and treat the participant 
with diphenhydramine 50 mg IV (or equivalent) and/or acetaminophen/paracetamol 325 to 
1000 mg; remain at bedside and monitor participant until resolution of symptoms. 
Corticosteroid and/or bronchodilator therapy may also be administered as appropriate. If the 
infusion is interrupted, then restart the infusion at 50% of the original infusion rate when 
symptoms resolve; if no further complications ensue after 30 minutes, the rate may be 
increased to 100% of the original infusion rate. Monitor participant closely. If symptoms recur, 
then no further nivolumab will be administered at that visit. Administer diphenhydramine 50 
mg IV, and remain at bedside and monitor the participant until resolution of symptoms. The 
amount of study drug infused must be recorded on the electronic case report form (eCRF). 
x For future infusions, the following prophylactic premedications are recommended: 
diphenhydramine 50 mg (or equivalent) and/or acetaminophen/paracetamol 325 to 1000 mg 
should be administered at least 30 minutes before nivolumab. If necessary, corticosteroids (up 
to 25 mg of SoluCortef or equivalent) may be used. 
 
For Grade 3 or 4 symptoms: (severe reaction, 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]. Grade 4: Life threatening; pressor or ventilatory support indicated). 
x Immediately discontinue infusion of nivolumab. Begin an IV infusion of normal saline and 
treat the participant t as follows: Recommend bronchodilators, epinephrine 0.2 to 1 mg of a 
1:1000 solution for subcutaneous administration or 0.1 to 0.25 mg of a 1:10,000 solution 
injected slowly for IV administration, and/or diphenhydramine 50 mg IV with 
methylprednisolone 100 mg IV (or equivalent), as needed. Participant should be monitored 
until the investigator is comfortable that the symptoms will not recur. Nivolumab will be 
permanently discontinued. Investigators should follow their institutional guidelines for the 
treatment of anaphylaxis. Remain at bedside and monitor participant until recovery of the 
symptoms. 
 
In case of late-occurring hypersensitivity symptoms (eg, appearance of a localized or generalized 
pruritus within 1 week after treatment), symptomatic treatment may be given (eg, oral 
antihistamine or corticosteroids). 


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7.4.5 
Criteria to Resume Dosing 
7.4.5.1 
Criteria to Resume Nivolumab/Epacadostat/Placebo for Epacadostat 
Dosing 
Participants may resume treatment with nivolumab when the drug-related AE(s) resolve(s) to 
Grade d 1 or baseline, with the following exceptions: 
x Participants may resume treatment in the presence of Grade 2 fatigue. 
x Participants who have not experienced a Grade 3 drug-related skin AE may resume treatment 
in the presence of Grade 2 skin toxicity. 
x For participants with Grade 2 AST, ALT and/or Total Bilirubin Abnormalities, dosing may 
resume when laboratory values return to baseline and management with corticosteroids, if 
needed, is complete. Participants with combined Grade 2 AST/ALT and total bilirubin values 
meeting discontinuation parameters (Section 8) should have treatment permanently 
discontinued. 
x Drug-related pulmonary toxicity, diarrhea, or colitis must have resolved to baseline before 
treatment is resumed. Participants with persistent Grade 1 pneumonitis after completion of a 
steroid taper over at least 1 month may be eligible for retreatment if discussed with and 
approved by the Medical Monitor. 
x Participants who received systemic corticosteroids for management of any drug-related 
toxicity must be off corticosteroids or have tapered down to an equivalent dose of prednisone 
d 10 mg/day. 
x Drug-related endocrinopathies adequately controlled with only physiologic hormone 
replacement may resume treatment after consultation with the Medical Monitor/designee. 
Adrenal insufficiency requires discontinuation regardless of control with hormone 
replacement. 
x Dose delay of nivolumab which results in treatment interruption of > 8 weeks requires 
treatment discontinuation, with exceptions as noted in Section 8. 
x Participants who delay study treatment due to any Grade 3 amylase or lipase abnormality that 
is not associated with symptoms or clinical manifestations of pancreatitis, which is assessed 
by the investigator not to be related to nivolumab, may resume nivolumab and 
epacadostat/placebo for epacadostat when the amylase or lipase abnormality has resolved to 
Grade < 3. The Medical Monitor should be consulted prior to resuming nivolumab in such 
participants.  
7.4.5.2 
Criteria to Resume Treatment with Chemotherapy  
x Participants may resume treatment with chemotherapy when the ANC returns to 1500/Pl. the 
platelet count returns to 100,000/mm3, and all other drug-related toxicities have returned to 
baseline or Grade 1 (or Grade 2 for alopecia and fatigue). 
x If a participant fails to meet criteria for re-treatment, then re-treatment should be delayed, and 
the participant should be re-evaluated weekly or more frequently as clinically indicated. Any 
participant who fails to recover from toxicity attributable to chemotherapy to baseline or Grade 
1 (except Grade 2 alopecia and fatigue) within 8 weeks from the last dose given should 
discontinue the drug(s) that caused the delay. 


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x When resuming chemotherapy treatment, follow the dose reduction recommendations in 
Section 7.4.3.1. 
 
7.5 
Preparation/Handling/Storage/Accountability 
The investigational product should be stored in a secure area according to local regulations. It is 
the responsibility of the investigator to ensure that investigational product is only dispensed to 
study participants. The investigational product must be dispensed only from official study sites by 
authorized personnel according to local regulations. 
The product storage manager should ensure that the study treatment is stored in accordance with 
the environmental conditions (temperature, light, and humidity) as determined by BMS/Incyte. If 
concerns regarding the quality or appearance of the study treatment arise, the study treatment 
should not be dispensed and contact BMS/Incyte immediately. 
Study treatment not supplied by BMS/Incyte will be stored in accordance with the package insert. 
Investigational product documentation (whether supplied by BMS/Incyte or not) must be 
maintained that includes all processes required to ensure drug is accurately administered. This 
includes documentation of drug storage, administration and, as applicable, storage temperatures, 
reconstitution, and use of required processes (eg, required diluents, administration sets). 
x Infusion-related supplies (eg, IV bags, in-line filters,0.9%NaCl solution) will not be supplied 
by the sponsor and should be purchased locally if permitted by local regulations.  
x For nivolumab, please refer the current version of the Investigator Brochure and/or pharmacy 
reference sheet for ongoing storage, handling, dispensing and infusion information. 
x Epacadostat should be stored at ambient conditions 15qC-30qC or 59qF-86qF.  
x Further guidance and information for final disposition of unused study treatment are provided 
in Appendix 2.   
 
7.5.1 
Retained Samples for Bioavailability / Bioequivalence 
Not applicable. 
7.6 
Treatment Compliance 
Treatment compliance will be monitored by drug accountability as well as the participant’s 
medical record and eCRF. 
7.7 
Concomitant Therapy 
7.7.1 
Prohibited and/or Restricted Treatments 
The following medications are prohibited during the study (unless utilized to treat a drug related 
adverse event): 
x Immunosuppressive agents 
x Immunosuppressive doses of systemic corticosteroids (except as stated in Section 7.7.4) 


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x Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, 
extensive, non-palliative radiation therapy, or standard or investigational agents for treatment 
of NSCLC) 
x Any botanical preparation (eg, herbal supplements or traditional Chinese medicines) intended 
to treat the disease under study or provide supportive care.  
x Administration of live attenuated vaccines within 30 days before the first dose of study 
treatment and while participating in the study is prohibited.  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 which are not allowed. 
x Any melatonin supplements. 
x Any MAOI or drug associated with significant MAO inhibitory activity agents is prohibited 
from 21 days before Day 1 through 2 weeks after the final dose of epacadostat has been taken 
(see Appendix 8). 
x Any UGT1A9 inhibitor or inducer (see Appendix 9) 
 
Participants 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.  
Participants may receive other medications that the investigator deems to be medically necessary. 
The exclusion criteria (Section 6.2) describe other medications that are prohibited during this 
study. There are no prohibited therapies during the post-treatment follow-up phase. 
7.7.2 
Other Restrictions and Precautions 
Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications within 14 days of 
randomization are excluded. Inhaled or topical steroids, and adrenal replacement steroid doses 
> 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease. 
Use of coumarin-based anticoagulants (eg, warfarin [Coumadin], fluindione [Previscan]), and 
vitamin K antagonists are discouraged. Low-dose coumarin-based anticoagulants, eg, warfarin 
1 mg is acceptable; however, doses that increase the INR are discouraged. If an alternative cannot 
be used, the INR should be monitored closely (weekly for the first 4 weeks after initiation of 
therapy and upon discontinuation of epacadostat or matching placebo for epacadostat) 
Use of the anticonvulsant carbamazepine (a UGT1A9 inducer) is discouraged. Because there is a 
potential interaction that could result in lower epacadostat exposures, an alternative to 
carbamazepine should be used, if possible.   
7.7.3 
Imaging Restriction and Precaution 
It is the local imaging facility’s responsibility to determine, based on participant attributes (eg, 
allergy history, diabetic history and renal status), the appropriate imaging modality and contrast 
regimen for each participant. Imaging contraindications and contrast risks should be considered in 


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this assessment. Participant with renal insufficiency should be assessed as to whether or not they 
should receive contrast and if so, what type and dose of contrast is appropriate. Specific to MRI, 
participants with severe renal insufficiency (ie, estimated glomerular filtration rate (eGFR) 
< 30 mL/min/1.73 m2) are at increased risk of nephrogenic systemic fibrosis. MRI contrast should 
not be given to this participant population. In addition, participants are excluded from MRI if they 
have tattoos, metallic implants, pacemakers, etc. 
The ultimate decision to perform MRI in an individual participant in this study rests with the site 
radiologist, the investigator and the standard set by the local Ethics Committee. 
7.7.3.1 
Radiation Restriction 
Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed after consultation 
with the Medical Monitor. 
7.7.4 
Permitted Therapy 
Participants are permitted the use of topical, ocular, intra-articular, intranasal, and inhalational 
corticosteroids (with minimal systemic absorption). Adrenal replacement steroid doses > 10 mg 
daily prednisone are permitted. A brief (less than 3 weeks) course of corticosteroids for 
prophylaxis (eg, contrast dye allergy) or for treatment of non-autoimmune conditions (eg, 
delayed-type hypersensitivity reaction caused by a contact allergen) is permitted. 
7.7.4.1 
Supportive Care Guidelines 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator, including, but not limited to, the items outlined below: 
x Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic therapy 
according to standard institutional practice. Participants should be strongly encouraged to 
maintain liberal oral fluid intake. 
x Anti-infectives: Participants with a documented infectious complication should receive oral or 
IV antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional practice. 
x Immune-related AEs: See Section 7.4.1, Section 7.4.2, Appendix 6, and Appendix 7 regarding 
diagnosis and management of adverse experiences of a potential immunologic etiology. 
x Management of infusion reactions from nivolumab (Section 7.4.4) 
 
7.8 
Treatment After the End of the Study 
At the conclusion of the study, participants who continue to demonstrate clinical benefit will be 
eligible to receive BMS/Incyte supplied study treatment for the maximum treatment duration 
specified in Section 7.1. Study treatment will be provided via an extension of the study, a rollover 
study requiring approval by responsible health authority and ethics committee or through another 
mechanism at the discretion of BMS/Incyte. 


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BMS/Incyte reserves the right to terminate access to BMS/Incyte supplied study treatment if any 
of the following occur: a) the study is terminated due to safety concerns; b) the development of 
the nivolumab or epacadostat is terminated for other reasons, including but not limited to lack of 
efficacy and/or not meeting the study objectives; c) the participant can obtain medication from a 
government sponsored or private health program. In all cases BMS/Incyte will follow local 
regulations. 
8 
DISCONTINUATION CRITERIA 
8.1 
Discontinuation from Study Treatment 
Participants MUST discontinue investigational product (and non-investigational product at the 
discretion of the investigator) for any of the following reasons: 
x Participant’s request to stop study treatment. Participants who request to discontinue study 
treatment will remain in the study and must continue to be followed for protocol specified 
follow-up procedures. The only exception to this is when a participant specifically withdraws 
consent for any further contact with him/her or persons previously authorized by participant to 
provide this information 
x Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator and based on toxicity management algorithm, indicates that 
continued participation in the study is not in the best interest of the participant 
x Termination of the study by Bristol-Myers Squibb (BMS) and Incyte Corporation 
x Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
for treatment of either a psychiatric or physical (eg, infectious disease) illness 
x Additional protocol specified reasons for discontinuation (see Section 8.1.1 and Section 8.1.2) 
x Progressive disease, unless the participant is eligible for treatment through progression as 
determined by the investigator.  
 
If a participant in Arms A or C meets criteria for discontinuation due to drug-related AE and the 
investigator, based on best clinical judgement, is unable to determine whether it is immune-related 
or chemotherapy-related, the participant should discontinue both immunotherapy and 
chemotherapy and be taken off the treatment phase of the study. In these instances, unless in the 
case of emergency, the investigator should consult with the Medical Monitor prior to the treatment 
discontinuation. 
Refer to the Schedule of Activities for data to be collected at the time of treatment discontinuation 
and follow-up and for any further evaluations that can be completed. 
In the case of pregnancy, the investigator must immediately notify the Sponsor/designee of this 
event. In most cases, the study treatment will be permanently discontinued in an appropriate 
manner (eg, dose tapering if necessary for participant safety). Please call the Sponsor/designee 
within 24 hours of awareness of the pregnancy. If the investigator determines a possible favorable 
benefit/risk ratio that warrants continuation of study treatment, a discussion between the 
investigator and the Medical Monitor/designee must occur. 


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All participants who discontinue study treatment should comply with protocol specified follow-up 
procedures as outlined in Section 2. The only exception to this requirement is when a participant 
withdraws consent for all study procedures including post-treatment study follow-up or loses the 
ability to consent freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either 
a psychiatric or physical illness). 
If study treatment is discontinued prior to the participant’s completion of the study, the reason for 
the discontinuation must be documented in the participant’s medical records and entered on the 
appropriate case report form (CRF) page. 
8.1.1 
Nivolumab and Epacadostat/Placebo for Epacadostat Dose 
Discontinuation (Arms A and C) 
Nivolumab/Epacadostat/Placebo for Epacadostat treatment should be permanently discontinued 
for the following: 
x Any Grade 2 drug-related uveitis, eye pain or blurred vision that does not respond to topical 
therapy and does not improve to Grade 1 severity within the re-treatment period OR requires 
systemic treatment  
x Any Grade 3 non-skin, drug-related adverse event lasting > 7 days or recurs, with the following 
exceptions for laboratory abnormalities, drug-related uveitis, pneumonitis, bronchospasm, 
hypersensitivity reactions, infusion reactions, and endocrinopathies: 
 Grade 3 drug-related uveitis, pneumonitis, bronchospasm, neurologic toxicity, 
hypersensitivity reaction, or infusion reaction of any duration requires discontinuation 
 Grade 3 drug-related endocrinopathies, adequately controlled with only physiologic 
hormone replacement do not require discontinuation. Adrenal insufficiency requires 
discontinuation regardless of control with hormone replacement.  
 Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation 
except: 
i Grade 3 drug-related thrombocytopenia > 7 days or associated with bleeding requires 
discontinuation 
i Grade ³ 3 drug-related AST, ALT or Total Bilirubin requires discontinuation* 
i Concurrent AST or ALT > 3 x ULN and total bilirubin > 2x ULN 
* In most cases of Grade 3 AST or ALT elevation, study drug(s) will be permanently discontinued. 
If the investigator determines a possible favorable benefit/risk ratio that warrants continuation of 
study drug(s), a discussion between the investigator and the Medical Monitor/designee must occur. 
x Any Grade 4 drug-related adverse event or laboratory abnormality (including but not limited 
to creatinine, AST, ALT, or Total Bilirubin), except for the following events which do not 
require discontinuation: 
 Grade 4 neutropenia d 7 days 
 Grade 4 lymphopenia or leukopenia or asymptomatic amylase or lipase 
 Isolated Grade 4 electrolyte imbalances/abnormalities that are not associated with clinical 
sequelae and are corrected with supplementation/appropriate management within 72 hours 
of their onset 


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 Grade 4 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, 
or glucose intolerance, which resolve or are adequately controlled with physiologic 
hormone replacement (corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and approval from the 
BMS Medical Monitor/designee. 
x Any event that leads to delay in dosing lasting > 8 weeks from the previous dose requires 
discontinuation, with the following exceptions: 
 Dosing delays to allow for prolonged steroid tapers to manage drug-related adverse events 
are allowed.  
 Dosing delays lasting > 8 weeks from the previous dose that occur for non-drug-related 
reasons may be allowed if approved by the medical monitor/designee.  
x Serotinin Syndrome that does not resolve on treatment would require discontinuation of 
epacadostat/placebo for epacadostat (Section 8.1.1). 
 
Prior to re-initiating treatment in a participant with a dosing delay lasting > 8 weeks, the medical 
monitor/designee must be consulted. Tumor assessments should continue as per protocol even if 
dosing is delayed. Periodic study visits to assess safety and laboratory studies should also continue 
every 6 weeks or more frequently if clinically indicated during such dosing delays. 
Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of the 
Investigator, presents a substantial clinical risk to the participant with continued nivolumab dosing. 
8.1.2 
Chemotherapy Dose Discontinuation 
Chemotherapy treatment should be permanently discontinued for the following: 
x Any drug-related Grade 4 toxicity including laboratory abnormalities the participant will be 
discontinued from the relevant study drug, with the following exceptions: 
 Isolated Grade 4 electrolyte abnormalities not associated with clinical sequelae and are 
adequately managed and corrected within 72 hours of onset 
 Grade 4 neutropenia or lymphopenia d 7 days 
x Any Grade 3 non-skin, drug-related adverse event lasting > 7 days, with the following 
exceptions: 
 Grade 3 drug-related laboratory abnormalities do not require treatment discontinuation, 
except for the following scenarios: 
i Grade 3 drug-related thrombocytopenia associated with bleeding 
i Any of the following drug-related liver function test (LFT) abnormalities: 
o AST or ALT > 8 x ULN 
o Total bilirubin > 5 x ULN 
o Concurrent AST or ALT > 3 x ULN and total bilirubin > 2 x ULN 
o Calculated creatinine decreases to < 50 mL/min based on Cockcroft Gault formula 
on participants receiving cisplatin. Switch to carboplatin is allowed at the discretion 
of investigator for the remaining cycles. 


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x Any dosing delay lasting > 8 weeks, with the following exceptions: 
 Dosing delays to allow for prolonged steroid tapers to manage drug related adverse events 
are allowed. Prior to re-initiating treatment in a participant with a dosing delay lasting > 
8 weeks, the Medical Monitor must be consulted. Tumor assessments should continue as 
per protocol event if dosing is delayed. 
 Dosing delays > 8 weeks that occur for non-drug-related reasons may be allowed if 
approved by the Medical Monitor. Prior to reinitiating treatment in a participant with a 
dosing delay lasting > 8 weeks, the Medical Monitor must be consulted. Tumor 
assessments should continue as per protocol even if dosing is delayed. 
x Any adverse event, laboratory abnormality, or intercurrent illness which, in the judgment of 
the Investigator, presents a substantial clinical risk to the participant with continued treatment.   
8.1.3 
Nivolumab and Epacadostat/ Placebo for Epacadostat Treatment 
Beyond Disease Progression 
Accumulating evidence indicates a minority of participants treated with immunotherapy may 
derive clinical benefit despite initial evidence of PD.49  
Participants treated with nivolumab and epacadostat/ placebo for epacadostat (Arms A and C) will 
be permitted to continue nivolumab and epacadostat/ placebo for epacadostat treatment beyond 
initial RECIST 1.1 defined PD, assessed by the investigator, as long as they meet the following 
criteria: 
x Investigator-assessed clinical benefit. 
x Tolerance of study drug 
x Stable performance status 
x Treatment beyond progression will not delay an imminent intervention to prevent serious 
complications of disease progression (eg, CNS metastases) 
x Participant provides written informed consent prior to receiving additional nivolumab and 
epacadostat/ placebo for epacadostat treatment. All other elements of the main consent 
including description of reasonably foreseeable risks or discomforts, or other alternative 
treatment options will still apply. 
Chemotherapy treatment will not be permitted to continue beyond initial RECIST 1.1 defined PD. 
A radiographic assessment/ scan should be performed within 6 weeks of initial investigator-
assessed progression to determine whether there has been a decrease in the tumor size or continued 
PD. The assessment of clinical benefit should be balanced by clinical judgment as to whether the 
participant is clinically deteriorating and unlikely to receive any benefit from continued treatment 
with nivolumab and epacadostat/ placebo for epacadostat. 
If the investigator feels that the nivolumab and epacadostat/placebo for epacadostat-treated 
participant continues to achieve clinical benefit by continuing treatment, the participant should 
remain on the trial and continue to receive monitoring according to the Time and Events Schedule, 
Table 2-2.  


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For the participants who continue nivolumab and epacadostat/placebo for epacadostat study 
therapy beyond progression, further progression is defined as an additional 10% increase in tumor 
burden with a minimum 5 mm absolute increase from time of initial PD. This includes an increase 
in the sum of diameters of all target lesions and/ or the diameters of new measurable lesions 
compared to the time of initial PD. Nivolumab and epacadostat/ placebo for epacadostat treatment 
should be discontinued permanently upon documentation of further progression. 
New lesions are considered measureable at the time of initial progression if the longest diameter 
is at least 10 mm (except for pathological lymph nodes which must have a short axis of at 
least15 mm). Any new lesion considered non-measureable at the time of initial progression may 
become measureable and therefore included in the tumor burden if the longest diameter increases 
to at least 10 mm (except for pathological lymph nodes which must have a short axis of at least 15 
mm). In situations where the relative increase in total tumor burden by 10% is solely due to 
inclusion of new lesions which become measurable, these new lesions must demonstrate an 
absolute increase of at least 5 mm. 
8.1.4 
Post Study Treatment Study Follow-up 
In this study, PFS and OS are key endpoints of the study. Post study follow-up is of critical 
importance and is essential to preserving participant safety and the integrity of the study. 
Participants who discontinue study treatment must continue to be followed for collection of 
outcome and/or survival follow-up data as required and in line with Section 5 until death or the 
conclusion of the study. 
BMS may request that survival data be collected on all randomized participants outside of the 
protocol defined window (Table 2-3). At the time of this request, each participant will be contacted 
to determine their survival status unless the participant has withdrawn consent for all contacts or 
is lost to follow-up. 
8.2 
Discontinuation from the Study 
Participants who request to discontinue study treatment will remain in the study and must continue 
to be followed for protocol specified follow-up procedures. The only exception to this is when a 
participant specifically withdraws consent for any further contact with him/her or persons 
previously authorized by participant to provide this information.  
x Participants should notify the investigator of the decision to withdraw consent from future 
follow-up in writing, whenever possible. 
x The withdrawal of consent should be explained in detail in the medical records by the 
investigator, as to whether the withdrawal is from further treatment with study treatment only 
or also from study procedures and/or post treatment study follow-up, and entered on the 
appropriate CRF page. 
x In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law. 
x If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 


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8.3 
Lost to Follow-Up 
x All reasonable efforts must be made to locate participants to determine and report their ongoing 
status. This includes follow-up with persons authorized by the participant. 
x Lost to follow-up is defined by the inability to reach the participant after a minimum of three 
documented phone calls, faxes, or emails as well as lack of response by participant to one 
registered mail letter. All attempts should be documented in the participant’s medical records. 
x If it is determined that the participant has died, the site will use permissible local methods to 
obtain date and cause of death. 
x If investigator’s use of third-party representative to assist in the follow-up portion of the study 
has been included in the participant’s informed consent, then the investigator may use a 
Sponsor retained third-party representative to assist site staff with obtaining participant’s 
contact information or other public vital status data necessary to complete the follow-up 
portion of the study.  
x The site staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information. 
x If after all attempts, the participant remains lost to follow-up, then the last known alive date as 
determined by the investigator should be reported and documented in the participant’s medical 
records. 
9 
STUDY ASSESSMENTS AND PROCEDURES 
x Study procedures and timing are summarized in the Schedule of Activities.  
x Protocol waivers or exemptions are not allowed. 
x All immediate safety concerns must be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
treatment. 
x Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. 
x All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria before randomization. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
 EGFR, ALK, and ROS-1 will be assessed locally at screening (refer to Table 2-1)  
x Procedures conducted as part of the participant’s routine clinical management (eg, blood count) 
and obtained before signing of informed consent may be utilized for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been performed 
within the timeframe defined in the Schedule of Activities. 
Additional measures, including non-study required laboratory tests, should be performed as 
clinically indicated or to comply with local regulations. Laboratory toxicities (eg, suspected drug 
induced liver enzyme evaluations) will be monitored during the follow-up phase via on site/local 
labs until all study drug related toxicities resolve, return to baseline, or are deemed irreversible.  
If a participant shows pulmonary-related signs (hypoxia, fever) or symptoms (eg. dyspnea, cough, 
fever) consistent with possible pulmonary adverse events, the participant should be immediately 


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evaluated to rule out pulmonary toxicity, according to the suspected pulmonary toxicity 
management algorithm in the BMS-936558 (nivolumab) and INCB 024360 (epacadostat) 
Investigator Brochures. 
Some of the assessments referred to in this section may not be captured as data in the eCRF. They 
are intended to be used as safety monitoring by the treating physician. Additional testing or 
assessments may be performed as clinically necessary or where required by institutional or local 
regulations 
9.1 
Efficacy Assessments 
Study evaluations will take place in accordance with the Schedule of Activities in Section 2.
Participants will be followed for survival every 3 months via in person or by telephone contact 
after the participants have discontinued study drug treatment. All randomized participants will be 
followed for survival. 
Images will be submitted to an imaging core lab. Sites should be trained prior to scanning the first 
study participant. Image acquisition guidelines and submission process will be outlined in the 
CA2099NC/INCB 24360-309 Imaging Manual to be provided by the core lab.  
9.1.1 
Imaging Assessments for the Study  
Tumor assessment with contrast-enhanced CT scans acquired on dedicated CT equipment is 
preferred for this study. Contrast-enhanced CT of the chest, abdomen, pelvis, and other 
known/suspected sites of disease should be performed for tumor assessments.  
Should a participant have a contraindication for CT intravenous contrast, a non-contrast CT of the 
chest and a contrast-enhanced MRI of the abdomen, pelvis, and other known/suspected sites of 
disease should be obtained.  
Should a participant have contraindication for both MRI and CT intravenous contrasts, a non-
contrast CT of the chest and a non-contrast MRI of the abdomen, pelvis, and other 
known/suspected sites of disease should be obtained.  
Should a participant have contraindication for MRI (eg, incompatible pacemaker) in addition to 
contraindication to CT intravenous contrast, a non-contrast CT of the chest, abdomen, pelvis, and 
other known/suspected sites of disease is acceptable. 
CT and MRI scans should be acquired with slice thickness of 5 mm or less with no intervening 
gap (contiguous). Every attempt should be made to image each participant using an identical 
acquisition protocol on the same scanner for all imaging timepoints.  
Use of CT component of a PET-CT scanner: Combined modality scanning such as with PET-CT 
is increasingly used in clinical care, and is a modality/technology that is in rapid evolution; 
therefore, the recommendations outlined here may change rather quickly with time. At present, 
low dose or attenuation correction CT portions of a combined PET-CT are of limited use in 
anatomically-based efficacy assessments and it is therefore suggested that they should not be 
substituted for dedicated diagnostic contrast enhanced CT scans for anatomically-based RECIST 
measurements. However, if a site can document that the CT performed as part of a PET-CT is of 


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identical diagnostic quality to a diagnostic CT (with IV and oral contrast) then the CT portion of 
the FDG PET-CT can be used for RECIST 1.1 measurements. Note, however, that the PET portion 
of the CT introduces additional data which may bias an investigator if it is not routinely or serially 
performed. 
Participants should undergo tumor assessments by CT or MRI at Screening and every 6 weeks 
(r7 days) from the date of randomization until Week 48 and then every 12 weeks (r7 days) until 
disease progression (based on BICR review) or death.  
MRI of the brain without and with contrast is required during screening for participants with a 
history of or clinical suspicion of brain metastases. All participants with a history of brain 
metastasis should have surveillance MRIs approximately every 12 weeks from the date of 
randomization or sooner if clinically indicated. Previously-treated CNS metastases are not 
considered measurable lesions for purposes of RECIST-determined response.  
Tumor assessments must continue per protocol until RECIST 1.1 progression, confirmed by BICR, 
has occurred.  
Participants with a history of bone metastasis may have a bone scan if clinically indicated. Bone 
scan or PET scan is not adequate for assessment of RECIST 1.1 response in target lesions. In 
selected circumstances where such modalities are the sole modality used to assess certain 
non-target organs, those non-target organs may be evaluated less frequently. For example, bone 
scans may need to be repeated only when complete response is identified in target disease or when 
progression in bone is suspected. 
Assessments of PR and CR must be confirmed at least 4 weeks after initial response. A Best 
Response of SD can only be made after the participant is on-study for a minimum of 35 days from 
the date of randomization. Investigators will also report the number and size of new lesions that 
appear while on study. The time point of tumor assessments will be reported on the eCRF based 
on the investigator’s assessment. For participants who are treated beyond disease progression, 
tumor assessments will continue to be performed until discontinuation of study treatment (typically 
upon evidence of further progression). 
Tumor assessments for all participants should continue as per protocol even if dosing is delayed 
or discontinued. Tumor measurements should be made by the same investigator or radiologist for 
each assessment whenever possible. Change in tumor measurements and tumor response to guide 
ongoing study treatment decisions will be assessed by the Investigator using the RECIST 1.1 
criteria. 
Any additional imaging that may demonstrate tumor response or progression (including scans 
performed at unscheduled time points and/or at an outside institution) should be collected for 
RECIST 1.1 tumor assessment and submitted to the BICR. 
9.1.2 
Independent Review of Progression 
The clinical management of participants during the study will be based upon local radiologic tumor 
measurements. Tumor assessments for each participant should be submitted to the radiology 
vendor as they are performed, on an ongoing basis. The blinded, independent radiologists will 


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review all available tumor assessments for that given participant and determine if RECIST 1.1 
criteria for progression have been met.  
When RECIST 1.1 progression is assessed by the investigator (whether assessed before or after 
the start of palliative local therapy or subsequent therapy), the BICR must be requested. If 
clinically acceptable, subsequent therapy should begin only after RECIST 1.1 progression has been 
assessed by BICR. Participants who start palliative local therapy or subsequent therapy prior to 
BICR review must continue tumor assessments (if clinically feasible) according to the 
protocol-specified schedule. Scans should be submitted to the third-party radiology vendor for 
BICR review. Tumor assessments may be discontinued following BICR confirmed progression. 
In addition, participants receiving treatment beyond progression must continue tumor assessments 
until such treatment has been discontinued. 
Details of the Independent Review of Progression process will be specified in the BICR charter. 


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9.2 
Adverse Events 
The definitions of an AE or serious adverse event (SAE) can be found in Appendix 3. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).  
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs that 
are serious, considered related to the study treatment or the study, or that caused the participant to 
discontinue before completing the study.  
Immune-mediated adverse events are AEs consistent with an immune-mediated mechanism or 
immune-mediated component for which non-inflammatory etiologies (eg, infection or tumor 
progression) have been ruled out. IMAEs can include events with an alternate etiology which were 
exacerbated by the induction of autoimmunity. Information supporting the assessment will be 
collected on the participant’s case report form.
Contacts for SAE reporting are specified in Appendix 3. 
9.2.1 
Time Period and Frequency for Collecting AE and SAE Information 
The collection of nonserious AE information should begin at initiation of study treatment until 
100 days after last dose of study treatment at the timepoints specified in the Schedule of Activities 
(Section 2). Nonserious AE information should also be collected from the start of a placebo lead-
in period or other observational period intended to establish a baseline status for the participants. 
Sections 5.6.1 and 5.6.2 in the Nivolumab IB and Section 5.4 in the Epacadostat IB represent the 
Reference Safety Information to determine expectedness of serious adverse events for expedited 
reporting. For reference safety information on chemotherapy regimens, refer to the drug product 
labels. Following the participant’s written consent to participate in the study, all SAEs, whether 
related or not related to study drug, must be collected, including those thought to be associated 
with protocol-specified procedures. 
All SAEs must be collected that occur during the screening period and within 100 days of 
discontinuation of dosing. If applicable, SAEs must be collected that relate to any later protocol-
specified procedure (eg, a follow-up skin biopsy). 
The investigator must report any SAE that occurs after these time periods and that is believed to 
be related to study drug or protocol-specified procedure. 
x
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the appropriate section of the eCRF section. 
x
All SAEs will be recorded and reported to Sponsor or designee within 24 hours, as indicated 
in Appendix 3.  
x
The investigator will submit any updated SAE data to the sponsor within 24 hours of this being 
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Investigators are not obligated to actively seek AEs or SAEs in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify the sponsor. 
All SAEs must be collected that occur during the screening period and within 100 days of the last 
dose of study treatment. For participants randomized/assigned to treatment and never treated with 
study drug, SAEs should be collected for 30 days from the date of randomization. 
The method of evaluating, and assessing causality of AEs and SAEs and the procedures for 
completing and reporting/transmitting SAE reports are provided in Appendix 3. 
9.2.2 
Method of Detecting AEs and SAEs 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a participant. (In order to prevent reporting bias, participants should 
not be questioned regarding the specific occurrence of one or more AEs.) 
9.2.3 
Follow-up of AEs and SAEs 
x Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious (see Appendix 3). 
x Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study treatment and for those present at the end of study treatment as appropriate. 
x All identified nonserious AEs must be recorded and described on the nonserious AE page of 
the CRF (paper or electronic). Completion of supplemental CRFs may be requested for AEs 
and/or laboratory abnormalities that are reported/identified during the course of the study. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs, and non-serious AEs of special interest (as defined in 
Section 9.2 will be followed until resolution, until the condition stabilizes, until the event is 
otherwise explained, or until the participant is lost to follow-up (as defined in Section 8.3). 
Further information on follow-up procedures is given in Appendix 3. 
9.2.4 
Regulatory Reporting Requirements for SAEs 
x Prompt notification by the investigator to the Sponsor of SAEs is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
product under clinical investigation are met. 
x An investigator who receives an investigator safety report describing SAEs or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will file it along with 
the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
Sponsor or designee will be reporting adverse events to regulatory authorities and ethics 
committees according to local applicable laws including European Directive 2001/20/EC and FDA 
Code of Federal Regulations 21 CFR Parts 312 and 320. A SUSAR (Suspected, Unexpected 
Serious Adverse Reaction) is a subset of SAEs and will be reported to the appropriate regulatory 
authorities and investigators following local and global guidelines and requirements. 


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9.2.5 
Pregnancy 
If, following initiation of the study treatment, it is subsequently discovered that a participant is 
pregnant or may have been pregnant at the time of study exposure, including during at least 
5 half-lives after product administration, the investigator must immediately notify the Medical 
Monitor/designee of this event and complete and forward a Pregnancy Surveillance Form to 
BMS/Incyte Designee within 24 hours of awareness of the event and in accordance with SAE 
reporting procedures described in Appendix 3. 
In most cases, the study treatment will be permanently discontinued in an appropriate manner 
(eg, dose tapering if necessary for participant safety). Please call the Medical Monitor within 24 
hours of awareness of the pregnancy. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS/Incyte or designee. In order for BMS/Incyte or designee to collect any pregnancy 
surveillance information from the female partner, the female partner must sign an informed 
consent form for disclosure of this information. Information on this pregnancy will be collected 
on the Pregnancy Surveillance Form. 
9.2.6 
Laboratory Test Result Abnormalities 
The following laboratory test result abnormalities should be captured on the nonserious AE CRF 
page or SAE Report Form electronic, as appropriate. Paper forms are only intended as a back-up 
option when the electronic system is not functioning. 
x Any laboratory test result that is clinically significant or meets the definition of an SAE  
x Any laboratory test result abnormality that required the participant to have study treatment 
discontinued or interrupted 
x Any laboratory test result abnormality that required the participant to receive specific 
corrective therapy 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value). 
9.2.7 
Potential Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should 
occur prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting 
the defined criteria, must be reported as SAEs (see Section 9.2 and Appendix 3 for reporting 
details). 
Potential drug induced liver injury is defined as:  
1) AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 


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2) Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum alkaline 
phosphatase), 
AND 
3) No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or the 
administration of other drug(s) known to be hepatotoxic. 
9.2.8 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiogram, 
x-ray filming, any other potential safety assessment required or not required by protocol should 
also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
9.3 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that 
is considered both excessive and medically important. All occurrences of overdose must be 
reported as an SAE (see Section 9.2). 
9.4 
Safety 
Planned time points for all safety assessments are listed in the Schedule of Activities. 
9.4.1 
Physical Examinations 
Refer to Schedule of Activities. 
9.4.2 
Clinical Safety Assessments  
9.4.2.1 
Clinical Safety Laboratory Assessments 
Investigators must document their review of each laboratory safety report. 
Table 9.4.2.1-1: 
Clinical Laboratory Assessments 
Hematology - CBC 
Hemoglobin 
Hematocrit 
Total leukocyte count, including differential 
Platelet count 
Coagulation: 
INR 
Prothrombin time 
aPTT (Screening only) 
Chemistry 
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Total bilirubin 
Albumin - screening only 
Sodium 
Potassium 


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Table 9.4.2.1-1: 
Clinical Laboratory Assessments 
Alkaline phosphatase (ALP) 
Lactate dehydrogenase (LDH) 
Creatinine 
Blood Urea Nitrogen (BUN) or serum UREA 
Fasting glucose 
Chloride 
Calcium 
Phosphorus 
TSH, free T3 and free T4 - screening  
TSH, with reflexive fT3 and fT4 if TSH is abnormal - 
on treatment  
Serology 
Hepatitis B/C, (HBV sAG, HBV DNA, HCV antibody or HCV RNA) - screening only  
HIV testing where locally mandated. See Appendix 11.  
Pregnancy test (WOCBP only minimum sensitivity 25 IU/L or equivalent units of HCG). 
Follicle stimulating hormone (FSH) screening -only required to confirm menopause in women < age 55)  
 
9.4.2.2 
Electrocardiogram 12-lead Assessment 
Pre-dose 12-lead ECGs will be obtained at screening, Cycle 1 Day 1, Cycle 2 Day 1 and at the end 
of treatment. If clinically indicated, additional ECGs may be obtained during the study. 
All 12-lead ECGs will be performed with the participant in a recumbent or semirecumbent position 
after 5 minutes of rest. The ECG readings will be interpreted by the investigator at the site to be 
used for eligibility and for immediate participant management. The decision to include or exclude 
a participant or to withdraw a participant from the study treatment based on an ECG flagged as 
"Abnormal, Clinically Significant" is the responsibility of the investigator, in consultation with the 
Medical Monitor, as appropriate. Clinically significant abnormal findings, as determined by 
investigator, will require a triplicate ECG. In the event that a single QTc is > 480 msec at screening, 
the participant may enroll if the average QTc for 3 consecutive ECGs is d 480 msec or with 
approval from the Medical Monitor/designee. Prolonged QTc intervals must be read by a 
cardiologist. For participants with an intraventricular conduction delay (QRS interval > 120 msec) 
at screening, the JTc interval may be used in place of the QTc with Medical Monitor/designee 
approval. In addition, the JTc interval should be used for all subsequent assessments. 
Clinically significant abnormal ECG findings at screening will be recorded as medical history. 
Clinically significant abnormal ECG findings after the first dose of study treatment should be 
recorded as an AE.   
9.4.3 
Imaging Safety Assessment 
Any incidental findings of potential clinical relevance that are not directly associated with the 
objectives of the protocol should be evaluated and handled by the Study Investigator as per 
standard medical/clinical judgment.  


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9.6 
Pharmacodynamics 
See Section 
 for additional information. 
9.7 
Pharmacogenomics 
See Section 
for additional information. 


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12 
APPENDICES


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APPENDIX 1 
ABBREVIATIONS AND TRADEMARKS 
Term 
Definition 
ADA 
Anti-drug antibodies 
AE 
adverse event 
AIDS 
autoimmunity deficiency syndrome 
ALK 
anaplastic lymphoma kinase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AR 
additional research 
AST 
aspartate aminotransferase 
AT 
aminotransaminases 
AUC 
area under the concentration-time curve 
BICR 
Blinded independent central review 
BID, bid 
bis in die, twice daily 
BMI 
body mass index 
BMS 
Bristol-Myers Squibb 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CBC 
complete blood count 
CFR 
code of federal regulations  
CI 
confidence interval 
CLcr 
creatinine clearance 
Cmax, CMAX 
maximum observed concentration 
CNS 
central nervous system 
CONSORT 
Consolidated Standards of Reporting Trials 
CR 
complete response 
CRF 
case report form, paper or electronic 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
cytotoxic T-lymphocyte–associated protein-4 
DMC 
data monitoring committee 


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Term 
Definition 
DOR 
duration of response 
DSM IV 
Diagnostic and Statistical Manual of Mental Disorders (4th Edition) 
ECG 
electrocardiogram 
ECHO 
Epacadostat Clinical Development in Hematology and Oncology 
EOI 
End of Infusion 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
eGFR 
estimated glomerular filtration rate 
egfr 
epidermal growth factor receptor 
FDA 
Food and Drug Administration 
FISH 
fluorescent in-situ hybridization 
FFPE 
formalin-fixed, paraffin-embedded 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
G-CSF 
growth colony stimulating factor 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
HBsAg 
hepatitis b surface antigen 
HBV 
hepatitis b virus 
HCG 
human chorionic gonadotropin 
HCV 
hepatitis c virus 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard ratio 
IASLC 
International Association for the Study of Lung Cancer  
IB 
Investigator Brochure 
ICD 
immunogenic cell death 
ICH 
International Conference on Harmonisation  
IDO1 
indoleamine-2,3-dioxygenase 1 
IEC 
Independent Ethics Committee 
Ig 
immunoglobin 
IMP 
investigational medicinal products 


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Term 
Definition 
INR 
International normalized ratio 
IP 
Investigational Product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IU 
international unit 
IV 
intravenous 
LDH 
lactate dehydrogenase 
MAOI 
monoamine oxidase inhibitors 
MRI 
magnetic resonance imaging 
N 
number of subjects or observations 
N/A 
not applicable 
NCI 
National Cancer Institute 
NSCLC 
non-small cell lung cancer 
NSQ 
nonsquamous 
OR  
objective response 
ORR 
objective response rate 
OS 
overall survival 
PBMC 
peripheral blood mononuclear cells 
PD-1 
program death-1 
PD-L1 
program death ligand-1 
PD 
pharmacodynamics 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PO 
per os (by mouth route of administration) 
PR 
partial response 
PRO 
patient reported outcome 
PS 
performance status 
PVC 
polyvinyl chloride 
PT 
prothrombin time 
QoL 
quality of life 


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Term 
Definition 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SCC 
squamous cell carcinoma 
SD 
standard deviation 
SNP 
 
SNRI 
serotonin/norepinephrine reuptake inhibitor 
SQ 
 
SSRI 
selective serotonin reuptake inhibitor 
TAO 
Trial Access Online, the BMS implementation of an EDC capability 
TCR 
T-cell receptor 
TEAE 
Treatment emergent AE 
TIL 
tumor infiltrating lymphocytes 
T-HALF 
half life 
 
  
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
 
 
WBC 
white blood cell 
WOCBP 
women of childbearing potential 
wt 
wild type 
 


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Clinical Protocol 
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applicable, also by local health authority) except where necessary to eliminate an immediate 
hazard(s) to study subjects.  
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to 
obtaining relevant  approval/favorable opinion(s) the deviation or change will be submitted, as 
soon as possible to: 
x IRB/IEC  
x Regulatory Authority(ies), if applicable by local regulations (per national requirements) 
 
Documentation of approval/favorable opinion signed by the chairperson or designee of the 
IRB(s)/IEC(s) and if applicable, also by local health authority must be sent to BMS/Incyte. 
If an amendment substantially alters the study design or increases the potential risk to the 
participant: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for review 
and approval/favorable opinion; (2) the revised form must be used to obtain consent from subjects 
currently enrolled in the study if they are affected by the amendment; and (3) the new form must 
be used to obtain consent from new subjects prior to enrollment. 
If the revision is done via an administrative letter, investigators must inform their IRB(s)/IEC(s). 
FINANCIAL DISCLOSURE 
Investigators and sub-Investigators will provide the Sponsor/BMS with sufficient, accurate 
financial information in accordance with local regulations to allow the Sponsor/BMS to submit 
complete and accurate financial certification or disclosure statements to the appropriate health 
authorities. Investigators are responsible for providing information on financial interests during 
the course of the study and for 1 year after completion of the study. 
INFORMED CONSENT PROCESS 
Investigators must ensure that subjects are clearly and fully informed about the purpose, potential 
risks, and other critical issues regarding clinical studies in which they volunteer to participate.  
In situations where consent cannot be given to subjects, their legally acceptable representatives (as 
per country guidelines) are clearly and fully informed about the purpose, potential risks, and other 
critical issues regarding clinical studies in which the participant volunteers to participate.  
Sponsor or designee will provide the investigator with an appropriate (i.e., Global or Local) sample 
informed consent form which will include all elements required by ICH, GCP and applicable 
regulatory requirements. The sample informed consent form will adhere to the ethical principles 
that have their origin in the Declaration of Helsinki. 
Investigators must: 
x Provide a copy of the consent form and written information about the study in the language in 
which the participant is most proficient prior to clinical study participation. The language must 
be non-technical and easily understood.  
x Allow time necessary for participant or participant's legally acceptable representative to 
inquire about the details of the study. 


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x Obtain an informed consent signed and personally dated by the participant or the participant's 
legally acceptable representative and by the person who conducted the informed consent 
discussion.  
x Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form 
and any other information to be provided to the subjects, prior to the beginning of the study, 
and after any revisions are completed for new information. 
 
If informed consent is initially given by a participant’s legally acceptable representative or legal 
guardian, and the participant subsequently becomes capable of making and communicating his or 
her informed consent during the study, consent must additionally be obtained from the participant. 
Revise the informed consent whenever important new information becomes available that is 
relevant to the participant's consent. The investigator, or a person designated by the investigator, 
should fully inform the participant or the participant's legally acceptable representative or legal 
guardian, of all pertinent aspects of the study and of any new information relevant to the 
participant's willingness to continue participation in the study. This communication should be 
documented.  
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules applicable to regulatory requirements, the subjects' signed ICF and, in the 
US, the subjects’ signed HIPAA Authorization. 
The consent form must also include a statement that BMS/Incyte and regulatory authorities have 
direct access to participant records.  
Subjects unable to give their written consent (e.g., stroke or subjects with or severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The participant 
must also be informed about the nature of the study to the extent compatible with his or her 
understanding, and should this participant become capable, he or she should personally sign and 
date the consent form as soon as possible. The explicit wish of a participant who is unable to give 
his or her written consent, but who is capable of forming an opinion and assessing information to 
refuse participation in, or to be withdrawn from, the clinical study at any time should be considered 
by the investigator. 
The rights, safety, and well-being of the study subjects are the most important considerations and 
should prevail over interests of science and society. 
SOURCE DOCUMENTS 
The Investigator is responsible for ensuring that the source data are accurate, legible, 
contemporaneous, original and attributable, whether the data are hand-written on paper or entered 
electronically. If source data are created (first entered), modified, maintained, archived, retrieved, 
or transmitted electronically via computerized systems (and/or any other kind of electronic 
devices) as part of regulated clinical trial activities, such systems must be compliant with all 
applicable laws and regulations governing use of electronic records and/or electronic signatures. 
Such systems may include, but are not limited to, electronic medical/health records (EMRs/EHRs), 


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adverse event tracking/reporting, protocol required assessments, and/or drug accountability 
records). 
When paper records from such systems are used in place of electronic format to perform regulated 
activities, such paper records should be certified copies. A certified copy consists of a copy of 
original information that has been verified, as indicated by a dated signature, as an exact copy 
having all of the same attributes and information as the original.  
STUDY TREATMENT RECORDS 
Records for study treatments (whether supplied by BMS/Incyte, its vendors, or the site) must 
substantiate study treatment integrity and traceability from receipt, preparation, administration, 
and through destruction or return. Records must be made available for review at the request of 
BMS/Incyte/designee or a Health Authority. 
If 
Then 
Supplied by BMS/Incyte (or its 
vendors): 
Records or logs must comply with applicable regulations and guidelines and 
should include: 
x 
amount received and placed in storage area 
x 
amount currently in storage area 
x 
label identification number or batch number 
x 
amount dispensed to and returned by each participant, including unique 
participant identifiers 
x 
amount transferred to another area/site for dispensing or storage 
x 
nonstudy disposition (e.g., lost, wasted)  
x 
amount destroyed at study site, if applicable 
x 
amount returned to BMS/Incyte/designee 
x 
retain samples for bioavailability/bioequivalence, if applicable  
x 
dates and initials of person responsible for Investigational Product 
dispensing/accountability, as per the Delegation of Authority Form. 
Sourced by site, and not supplied 
by BMS/Incyte or its vendors 
(examples include IP sourced 
from the sites stock or 
commercial supply, or a specialty 
pharmacy) 
The investigator or designee accepts responsibility for documenting 
traceability and study drug integrity in accordance with requirements 
applicable under law and the SOPs/standards of the sourcing pharmacy.    
BMS or designee will provide forms to facilitate inventory control if the investigational site does not have an 
established system that meets these requirements. 
 
CASE REPORT FORMS 
An investigator is required to prepare and maintain adequate and accurate case histories designed 
to record all observations and other data pertinent to the investigation on each individual treated 
or entered as a control in the investigation. Data that are derived from source documents and 
reported on the CRF must be consistent with the source documents or the discrepancies must be 
explained. Additional clinical information may be collected and analyzed in an effort to enhance 
understanding of product safety. CRFs may be requested for AEs and/or laboratory abnormalities 
that are reported or identified during the course of the study. 


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For sites using the Sponsor or designee electronic data capture tool, electronic CRFs will be 
prepared for all data collection fields except for fields specific to SAEs and pregnancy, which will 
be reported on the electronic SAE form and Pregnancy Surveillance form, respectively.  If 
electronic SAE form is not available, a paper SAE form can be used. Spaces may be left blank 
only in those circumstances permitted by study-specific CRF completion guidelines provided by 
Sponsor or designee.  
The confidentiality of records that could identify subjects must be protected, respecting the privacy 
and confidentiality rules in accordance with the applicable regulatory requirement(s). 
The investigator will maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on CRFs.  
The completed CRF, SAE/pregnancy CRFs, must be promptly reviewed, signed, and dated by the 
investigator or qualified physician who is a subinvestigator and who is delegated this task on the 
Delegation of Authority Form. Subinvestigators in Japan may not be delegated the CRF approval 
task. For electronic CRFs, review and approval/signature is completed electronically through the 
BMS/Incyte/designee electronic data capture tool. The investigator must retain a copy of the CRFs 
including records of the changes and corrections. 
Each individual electronically signing electronic CRFs must meet Sponsor or designee training 
requirements and must only access the BMS/Incyte/designee electronic data capture tool using the 
unique user account provided by Sponsor or designee. User accounts are not to be shared or 
reassigned to other individuals 
MONITORING 
Sponsor or designee representatives will review data centrally to identify potential issues to 
determine a schedule of on-site visits for targeted review of study records.  
Representatives of BMS/Incyte must be allowed to visit all study site locations periodically to 
assess the data quality and study integrity. On site they will review study records and directly 
compare them with source documents, discuss the conduct of the study with the investigator, and 
verify that the facilities remain acceptable .Certain CRF pages and/or electronic files may serve as 
the source documents: 
In addition, the study may be evaluated by Sponsor or designee internal auditors and government 
inspectors who must be allowed access to CRFs, source documents, other study files, and study 
facilities. BMS/Incyte audit reports will be kept confidential. 
The investigator must notify BMS/Incyte promptly of any inspections scheduled by regulatory 
authorities, and promptly forward copies of inspection reports to Sponsor or designee.  
RECORDS RETENTION 
The investigator (or head of the study site in Japan) must retain all study records and source 
documents for the maximum period required by applicable regulations and guidelines, or 
institution procedures, or for the period specified by BMS or designee, whichever is longer. The 


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investigator (or head of the study site in Japan) must contact BMS/Incyte/designee prior to 
destroying any records associated with the study. 
BMS/Incyte or designee will notify the investigator (or head of the study site in Japan) when the 
study records are no longer needed. 
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be 
transferred to a mutually agreed upon designee (e.g., another investigator, study site, IRB). Notice 
of such transfer will be given in writing to BMS/Incyte or designee.  
RETURN OF STUDY TREATMENT 
For this study, study treatments (those supplied by BMS/Incyte, a vendor or sourced by the 
investigator) such as partially used study treatment containers, vials and syringes may be destroyed 
on site.  
If.. 
Then 
Study treatments supplied by BMS/Incyte 
(including its vendors 
Any unused study treatments supplied by BMS/Incyte can only be 
destroyed after being inspected and reconciled by the responsible 
Study Monitor unless study treatments containers must be 
immediately destroyed as required for safety, or to meet local 
regulations (e.g., cytotoxics or biologics). 
If study treatments will be returned, the return will be arranged by 
the responsible Study Monitor. 
Study treatments sourced by site, not 
supplied by BMS/Incyte (or its vendors) 
(examples include study treatments 
sourced from the sites stock or 
commercial supply, or a specialty 
pharmacy) 
It is the investigator’s or designee’s responsibility to dispose of all 
containers according to the institutional guidelines and procedures. 
 
It is the investigator’s or designee’s responsibility to arrange for disposal, provided that procedures 
for proper disposal have been established according to applicable federal, state, local, and 
institutional guidelines and procedures, and provided that appropriate records of disposal are kept. 
The following minimal standards must be met: 
x On-site disposal practices must not expose humans to risks from the drug. 
x On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous substances. 
x Written procedures for on-site disposal are available and followed. The procedures must be 
filed with the site’s SOPs and a copy provided to BMS/Incyte upon request. 
x Records are maintained that allow for traceability of each container, including the date 
disposed of, quantity disposed, and identification of the person disposing the containers. The 
method of disposal, i.e., incinerator, licensed sanitary landfill, or licensed waste disposal 
vendor must be documented. 
x Accountability and disposal records are complete, up-to-date, and available for the Monitor to 
review throughout the clinical trial period. 
 


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It is the investigator’s or designee’s responsibility to arrange for disposal of all empty containers. 
If conditions for destruction cannot be met the responsible Study Monitor will make arrangements 
for return of study treatments provided by BMS/Incyte (or its vendors). Destruction of non- study 
treatments sourced by the site, not supplied by BMS/Incyte, is solely the responsibility of the 
investigator or designee. 
CLINICAL STUDY REPORT AND PUBLICATIONS 
A Signatory Investigator must be selected to sign the clinical study report.  
For this protocol, the Signatory Investigator will be selected as appropriate based on the following 
criteria: 
x External Principal Investigator designated at protocol development 
x National Coordinating Investigator  
x Study Steering Committee chair or their designee 
x Participant recruitment (e.g., among the top quartile of enrollers) 
x Involvement in trial design 
x Regional representation (e.g., among top quartile of enrollers from a specified region or 
country) 
x Other criteria (as determined by the study team) 
 
The data collected during this study are confidential and proprietary to Sponsor or designee. Any 
publications or abstracts arising from this study must adhere to the publication requirements set 
forth in the clinical trial agreement (CTA) governing [Study site or Investigator] participation in 
the study. These requirements include, but are not limited to, submitting proposed publications to 
Sponsor or designee at the earliest practicable time prior to submission or presentation and 
otherwise within the time period set forth in the CTA. 
 


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APPENDIX 3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS: 
DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW UP AND REPORTING 
ADVERSE EVENTS 
Adverse Event Definition: 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment.  
An AE can therefore be any unfavorable and unintended sign (such as an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of study drug, whether or not 
considered related to the study drug. 
SERIOUS ADVERSE EVENTS 
Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose: 
Results in death 
Is life-threatening (defined as an event in which the participant was at risk of death at the time 
of the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe) 
Requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE 
below) 
NOTE:  
The following hospitalizations are not considered SAEs in BMS clinical studies:  
x a visit to the emergency room or other hospital department < 24 hours, that does not result 
in admission (unless considered an important medical or life-threatening event) 
x elective surgery, planned prior to signing consent 
x admissions as per protocol for a planned medical/surgical procedure 
x routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy) 
x medical/surgical admission other than to remedy ill health and planned prior to entry into 
the study. Appropriate documentation is required in these cases 
x admission encountered for another life circumstance that carries no bearing on health status 
and requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason) 
x admission for administration of anticancer therapy in the absence of any other SAEs (applies 
to oncology protocols) 
Results in persistent or significant disability/incapacity 
Is a congenital anomaly/birth defect 


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Serious Adverse Event (SAE) is defined as any untoward medical occurrence that, at any 
dose: 
is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the participant or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) Potential drug induced liver injury (DILI) is also considered an important 
medical event. (See Section 9.2.7 for the definition of potential DILI.)  
 
Suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via the study 
treatment is an SAE.  
Although pregnancy, overdose, cancer, and potential drug induced liver injury (DILI) are not 
always serious by regulatory definition, these events must be handled as SAEs. (See Section 9.2.5 
for reporting pregnancies). 
Any component of a study endpoint that is considered related to study therapy should be reported 
as SAE (e.g., death is an endpoint, if death occurred due to anaphylaxis, anaphylaxis must be 
reported). 
EVALUATING AES AND SAES 
Assessment of Causality 
The causal relationship to study drug is determined by a physician and should be used to assess 
all adverse events (AE). The causal relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and 
the AE. 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal 
relationship.  
 
Follow-up of AEs and SAEs 
If only limited information is initially available, follow-up reports are required. (Note: Follow-
up SAE reports must include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, the SAE report must be updated and submitted within 24 hours to BMS (or 
designee) using the same procedure used for transmitting the initial SAE report. 


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Follow-up of AEs and SAEs 
All SAEs must be followed to resolution or stabilization. 
 
Reporting of SAEs to Sponsor or Designee 
x SAEs, whether related or not related to study drug, and pregnancies must be reported to BMS 
(or designee) within 24 hours of awareness of the event. 
x SAEs must be recorded on the SAE Report Form; pregnancies on a Pregnancy Surveillance 
Form (electronic or paper forms). 
x The preferred method for SAE data reporting collection is through the eCRF. 
x The paper SAE/pregnancy surveillance forms are only intended as a back-up option when 
the eCRF system is not functioning. 
 In this case, the paper forms are to be transmitted via email or confirmed facsimile (fax) 
transmission to: 
SAE Email Address: Refer to Contact Information list. 
SAE Facsimile Number: Refer to Contact Information list. 
For studies capturing SAEs through electronic data capture (EDC), electronic submission is the 
required method for reporting. In the event the electronic system is unavailable for transmission, 
paper forms must be used and submitted immediately. When paper forms are used, the original 
paper forms are to remain on site. 
SAE Telephone Contact (required for SAE and pregnancy reporting): Refer to Contact 
Information list 
 


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APPENDIX 4 
WOMEN OF CHILDBEARING POTENTIAL DEFINITIONS AND 
METHODS OF CONTRACEPTION 
DEFINITIONS 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP 
x Premenarchal 
x Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
x Postmenopausal female 
 A postmenopausal state is defined as 12 months of amenorrhea in a woman over age 45 
years in the absence of other biological or physiological causes. In addition, females under 
the age of 55 years must have a serum follicle stimulating hormone, (FSH) level 
> 40 mIU/mL to confirm menopause. 
 
CONTRACEPTION GUIDANCE FOR FEMALE PARTICIPANTS OF CHILD BEARING 
POTENTIAL 
One of the highly effective methods of contraception listed below is required during study duration 
and until the end of relevant systemic exposure, defined as 5 months weeks after the end of study 
treatment.  
Local laws and regulations may require use of alternative and/or additional contraception methods. 
Highly Effective Contraceptive Methods That Are User Dependent  
Failure rate of <1% per year when used consistently and correctly.a  
x 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulationb  
 oral  
 intravaginal  
 transdermal  
x 
Progestogen-only hormonal contraception associated with inhibition of ovulationb  
 oral  
 injectable  


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Highly Effective Methods That Are User Independent  
x 
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation b 
x Hormonal methods of contraception including oral contraceptive pills containing a 
combination of estrogen and progesterone, vaginal ring, injectables, implants and 
intrauterine hormone-releasing system (IUS)c 
x Intrauterine device (IUD)c 
x 
Bilateral tubal occlusion 
x 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. 
If not, an additional highly effective method of contraception should be used.  
x 
Sexual abstinence  
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 drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant. 
x It is not necessary to use any other method of contraception when complete abstinence is 
elected.  
x WOCBP participants who choose complete abstinence must continue to have pregnancy 
tests, as specified in Section 2.  
x Acceptable alternate methods of highly effective contraception must be discussed in the 
event that the WOCBP participants chooses to forego complete abstinence  
NOTES:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method.  Hormonal contraception is permissible only when there is sufficient evidence that 
the IMP and other study medications will not alter hormonal exposures such that contraception would be 
ineffective or result in increased exposures that could be potentially hazardous.  In this case, alternative methods 
of contraception should be utilized.  
c Intrauterine devices and intrauterine hormone releasing systems are acceptable methods of contraception in the 
absence of definitive drug interaction studies when hormone exposures from intrauterine devices do not alter 
contraception effectiveness 
 
Unacceptable Methods of Contraception 
x Male or female condom with or without spermicide.  Male and female condoms cannot be 
used simultaneously 
x Diaphragm with spermicide 
x Cervical cap with spermicide 
x Vaginal Sponge with spermicide 


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x Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mechanism of action 
x Periodic abstinence (calendar, symptothermal, post-ovulation methods) 
x Withdrawal (coitus interruptus). 
x Spermicide only 
x Lactation amenorrhea method (LAM) 
 
CONTRACEPTION GUIDANCE FOR MALE PARTICIPANTS WITH PARTNER(S) OF 
CHILD BEARING POTENTIAL. 
Male participants with female partners of childbearing potential are eligible to participate if they 
agree to the following during the treatment and until the end of relevant systemic exposure. 
x Inform any and all partner(s) of their participation in a clinical drug study and the need to 
comply with contraception instructions as directed by the investigator. 
x Male participants are required to use a condom for study duration and until end of relevant 
systemic exposure defined as 7 months after the end of study treatment. 
x Female partners of males participating in the study to consider use of effective methods of 
contraception until the end of relevant systemic exposure, defined as 7 months after the end of 
treatment in the male participant. 
x Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile vaginal intercourse or use a male condom during each episode of penile penetration 
during the treatment and until 7 months after the end of study treatment.  
x Refrain from donating sperm for the duration of the study treatment and until 7 months after 
the end of study treatment. 
 
COLLECTION OF PREGNANCY INFORMATION 
Guidance for collection of Pregnancy Information and outcome of pregnancy on the Pregnancy 
Surveillance Form is provided in Section 9.2.5 and the Appendix for Adverse Events and Serious 
Adverse Events Definitions and procedures for Evaluating, Follow-up and Reporting 
 


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APPENDIX 5 
ECOG PERFORMANCE STATUS  
ECOG PERFORMANCE STATUS  
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
Source: Oken MM, Creech RH, Tormey DC, et al. Toxicity and Response Criteria of the Eastern Cooperative 
Oncology Group. Am J Clin Oncol 1982; 5: 649-655. 
 
 


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APPENDIX 6 
MANAGEMENT ALGORITHMS 
 
 


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APPENDIX 7 
DOSE MODIFICATIONS FOR EPACADOSTAT/PLACEBO FOR 
EPACADOSTAT 
The following dose modification criteria should be reviewed in conjunction with the 
immune-related adverse events management algorithm provided in Appendix 6.  
In cases of potential overlapping chemotherapy/immunotherapy-related toxicities, irrespective of 
investigator’s attribution, the Medical Monitor should be consulted prior to continuing dosing or 
restarting therapy.  
Table 12-1: 
Dose Modifications for Epacadostat 
Type of Adverse 
Events 
Grade 
Criteria 
Guidance for dose modification 
Pulmonary Adverse 
Events 
Grade 2 
AE resolves to near baseline in 
0-2 weeks 
Resume at -1 dose level 
AE  does not resolve to near baseline in 
> 2 weeks 
Treat as Grade 3/4. Permanently 
discontinue 
Second episode after re-challenge 
Permanently discontinue 
GI Adverse Events 
Grade 2 
AE resolves to d Grade 1 or baseline in 
0-4 weeks 
Resume at the same dose level 
AE resolves to baseline between 
4-6 weeks 
Resume at -1 dose level 
AE does not resolve to baseline in 
> 6 weeks 
Permanently discontinue 
Hepatic Adverse 
Events 
Grade 2 
AE resolves to d Grade 1 or baseline in 
0-4 weeks 
Resume at the same dose level 
AE resolves to baseline between 
4-6 weeks 
Resume at -1 dose level 
AE does not resolve to baseline in 
> 6 weeks 
Permanently discontinue 
Skin Adverse 
Events 
Grade 3-4 
AE resolves to baseline in 0-4 weeks 
Resume at the same dose level 
AE resolves to baseline between 
4-6 weeks 
Resume at -1 dose level 
AE does not resolve to baseline in 
> 6 weeks 
Permanently discontinue 
Neurological 
Adverse Events 
Grade 2 
AE resolves to baseline in 0-4 weeks 
Resume at the same dose level 
AE resolves to baseline between 
4-6 weeks 
Resume at -1 dose level 
AE does not resolve to baseline in 
> 6 weeks 
Permanently discontinue 


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Table 12-1: 
Dose Modifications for Epacadostat 
Type of Adverse 
Events 
Grade 
Criteria 
Guidance for dose modification 
Endocrine Adverse 
Events 
Grade 2-3a 
AE resolves to d Grade 1 or baseline in 
0-4 weeks 
Resume at the same dose level 
AE resolves to baseline between 
4-6 weeks 
Resume at -1 dose level 
AE does not resolve to baseline in 
> 6 weeks 
Permanently discontinuea 
Hematological 
Adverse Events 
Grade 4 
Grade 4 neutropenia lasting d 7 days 
Grade 4 lymphopenia or leukopenia that 
resolved to d Grade 1 or baseline 
Resume at -1 dose level 
All Grade 4 hematological AEs not 
included above 
Permanently discontinue 
a Grade 2-3 drug-related endocrinopathy adverse events, such as, hyper- or hypothyroidism, or glucose intolerance, 
which are adequately controlled with physiologic hormone replacement (corticosteroids, thyroid hormones) or 
glucose-controlling agents, respectively, may not require discontinuation after discussion with and approval from 
the Medical Monitor/designee. 
 


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APPENDIX 8 
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 9 
UGT1A9 INHIBITORS AND INDUCERS 
Any UGT1A9 inhibitors and inducers include aceclofenac, acitretin, amitriptyline, androsterone, 
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, phenobartital, 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. 
 


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APPENDIX 10 
RESPONSE EVALUATION CRITERIA IN SOLID TUMORS 
GUIDELINES (VERSION 1.1) WITH BMS MODIFICATIONS 
1 
EVALUATION OF LESIONS 
Solid tumors will be evaluated using Response Evaluation Criteria In Solid Tumors version 1.1 
(RECIST 1.1) guideline with BMS modifications.1 
At baseline, tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
1.1 
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
10 mm by CT/MRI scan (scan slice thickness no greater than 5 mm), or t 2x slice thickness if 
greater than 5mm. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be t 15 mm in short axis when assessed by CT/MRI scan (scan slice thickness recommended 
to be no greater than 5 mm). 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
t 15 mm by CT/MRI scan. Only the short axis of these nodes will contribute to the baseline sum. 
The short axis of the node is the diameter normally used by radiologists to judge if a node is 
involved by solid tumor. Nodal size is normally reported as two dimensions in the plane in which 
the image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 
example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 20 mm 
and qualifies as a malignant, measurable node. In this example, 20 mm should be recorded as the 
node measurement. All other pathological nodes (those with short axis t 10 mm but < 15 mm) 
should be considered non-target lesions. Nodes that have a short axis < 10 mm are considered 
non-pathological and should not be recorded or followed. 
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions. 
1.2 
Non-Measurable 
All other lesions are considered non-measurable, including small lesions (longest diameter 
< 10mm or pathological lymph nodes with t 10 to < 15 mm short axis) as well as truly 
non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
Note: Lesions on X-Ray are not to be selected as Target or Non-Target Lesions. 


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1.3 
Special considerations regarding lesion measurability 
1.3.1 
Bone lesions 
x Bone scan, PET scan and plain films are not considered adequate imaging techniques to 
measure bone lesions. However, these techniques can be used to confirm the presence or 
disappearance of bone lesions.  
x Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that 
can be evaluated by cross sectional imaging techniques such as CT or MRI can be considered 
as measurable lesions if the soft tissue component meets the definition of measurability 
described above. 
x Blastic bone lesions are non-measurable. 
 
1.4 
Baseline Documentation Of ‘Target’ And ‘Non-Target’ Lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline (this means in 
instances where patients have only one or two organ sites involved a maximum of two and four 
lesions respectively will be recorded). 
Note: A maximum of two lesions can be selected per organ system. For example, a maximum of 
two lung lesions can be selected (selected from one lung or one lesion from each). A maximum of 
two lymph nodes can be selected at baseline, as the lymphatic system is considered one organ. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does 
not lend itself to reproducible measurement in which circumstance the next largest lesion which 
can be measured reproducibly should be selected. 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline 
sum diameters will be used as reference to further characterize any objective tumor regression in 
the measurable dimension of the disease. 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target lesions and should also be recorded at baseline. Measurements are not required and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple non-target lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph nodes’ 
or ‘multiple liver metastases’). 


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2 
RESPONSE CRITERIA 
2.1 
Evaluation of Target Lesions 
x Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to < 10 mm. 
x Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters. 
x Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
x Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study. 
x Not Evaluable (NE): If one or more target lesions cannot be measured or adequately assessed 
as either fully resolved or too small to measure (due to missing or poor quality images), and 
the sum of diameters of the remaining measured target lesions (if any) has not increased 
sufficiently to meet Progressive Disease as defined above.  
 
2.1.1 
Special Notes on the Assessment of Target Lesions 
2.1.1.1 
Lymph nodes 
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal 
lymph node is defined as having a short axis of < 10 mm. Case report forms or other data collection 
methods may therefore be designed to have target nodal lesions recorded in a separate section 
where, in order to qualify for CR, each node must achieve a short axis < 10 mm. For PR, SD and 
PD, the actual short axis measurement of the nodes is to be included in the sum of target lesions. 
2.1.1.2 
Target lesions that become ‘too small to measure’ 
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (eg, 2 mm). 
However, sometimes lesions or lymph nodes which are recorded as target lesions at baseline 
become so faint on CT scan that the radiologist may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important 
that a value be recorded on the case report form. If it is the opinion of the radiologist that the lesion 
has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is believed to 
be present and is faintly seen but too small to measure, a default value of 5 mm should be assigned 
as the reference diameter. (Note: It is less likely that this rule will be used for lymph nodes since 
they usually have a definable size when normal and are frequently surrounded by fat such as in the 
retroperitoneum; however, if a lymph node is believed to be present and is faintly seen but too 
small to measure, a default value of 5 mm should be assigned in this circumstance as well). This 


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default value is derived from the 5 mm CT slice thickness (but should not be changed with varying 
CT slice thickness). The measurement of these lesions is potentially non-reproducible, therefore 
providing this default value will prevent false responses or progressions based upon measurement 
error. To reiterate, however, if the radiologist is able to provide an actual measure, that should be 
recorded, even if it is below 5 mm. 
2.1.1.3 
Lesions that split or coalesce on treatment 
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between 
them may be maintained that would aid in obtaining maximal diameter measurements of each 
individual lesion. If the lesions have truly coalesced such that they are no longer separable, the 
vector of the longest diameter in this instance should be the maximal longest diameter for the 
‘coalesced lesion’. 
2.2 
Evaluation of Non-Target Lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need 
not be measured and instead should be assessed only qualitatively at the time points specified in 
the protocol. 
x Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be 
non-pathological in size (< 10mm short axis).  
x Non-CR/Non-PD: Persistence of one or more non-target lesion(s)  
x Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  
 
2.2.1 
Special Notes on Assessment of Progression of Non-Target Disease 
The concept of progression of non-target disease requires additional explanation as follows: 
2.2.1.1 
When the patient also has measurable disease 
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there 
must be an overall level of substantial worsening in non-target disease such that, even in presence 
of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. Pleural effusions, pericardial 
effusions and ascites will not be followed as target or non-target lesions and will not contribute to 
response or progression. The designation of overall progression solely on the basis of change in 
non-target disease in the face of SD or PR of target disease will therefore be extremely rare. 
2.2.1.2 
When the patient has only non-measurable disease 
This circumstance arises in some trials when it is not a criterion of study entry to have measurable 
disease. The same general concepts apply here as noted above, however, in this instance there is 
no measurable disease assessment to factor into the interpretation of an increase in non-measurable 
disease burden. Because worsening in non-target disease cannot be easily quantified (by definition: 


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if all lesions are truly non-measurable) a useful test that can be applied when assessing patients for 
unequivocal progression is to consider if the increase in overall disease burden based on the change 
in non-measurable disease is comparable in magnitude to the increase that would be required to 
declare PD for measurable disease: ie, an increase in tumor burden representing an additional 73% 
increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
Examples include, an increase in lymphangitic disease from localized to widespread, or may be 
described as ‘sufficient to require a change in therapy’. If ‘unequivocal progression’ is seen, the 
patient should be considered to have had overall PD at that point. While it would be ideal to have 
objective criteria to apply to non-measurable disease, the very nature of that disease makes it 
impossible to do so; therefore the increase must be substantial. 
2.2.2 
New Lesions 
The appearance of new malignant lesions denotes disease progression; therefore, some comments 
on detection of new lesions are important. There are no specific criteria for the identification of 
new radiographic lesions; however, the finding of a new lesion should be unequivocal: ie, not 
attributable to differences in scanning technique, change in imaging modality or findings thought 
to represent something other than tumor (for example, some ‘new’ bone lesions may be simply 
healing or flare of pre-existing lesions). This is particularly important when the patient’s baseline 
lesions show partial or complete response. For example, necrosis of a liver lesion may be reported 
on a CT scan report as a ‘new’ cystic lesion, which it is not. 
NOTE: Fluid collections (pleural effusions, pericardial effusions, and ascites) will not be 
considered new lesions and will not contribute to response or progression. In the event a new fluid 
collection is seen on a post-baseline imaging exam, a comment may be made, but the appearance 
of a new fluid collection alone should not result in an assessment of Progressive Disease (PD). A 
lesion identified on a follow-up study in an anatomical location that was not scanned at baseline 
is considered a new lesion and will indicate disease progression. An example of this is the patient 
who has visceral disease at baseline and while on study has a CT or MRI brain ordered which 
reveals metastases. The patient’s brain metastases are considered to be evidence of PD even if 
he/she did not have brain imaging at baseline. A lesion identified on Chest X-Ray that was not 
present in prior CT can be considered a new lesion and will result in Progressive Disease (PD). 
If a new lesion is equivocal, for example because of its small size, continued follow-up evaluation 
will clarify if it represents truly new disease. If repeat scans confirm there is definitely a new 
lesion, then progression should be declared using the date of the initial scan. While FDG-PET 
response assessments need additional study, it is sometimes reasonable to incorporate the use of 
FDG-PET scanning to complement CT scanning in assessment of progression (particularly 
possible ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm: 
1. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
2. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD. If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-up 


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CT scans are needed to determine if there is truly progression occurring at that site (if so, the 
date of PD will be the date of the initial abnormal FDG-PET scan). If the positive FDG-PET 
at follow-up corresponds to a pre-existing site of disease on CT that is not progressing on the 
basis of the anatomic images, this is not PD. 
 
2.3 
Response Assessment 
2.3.1 
Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the study treatment until 
disease progression or the last response recorded, taking into account any requirement for 
confirmation and censoring rules regarding subsequent therapy. The patient’s best overall response 
assignment will depend on the findings of both target and non-target disease and will also take into 
consideration the appearance of new lesions. Furthermore, depending on the nature of the study 
and the protocol requirements, it may also require confirmatory measurement. 
2.3.2 
Time Point Response 
At each protocol specified time point, a response assessment occurs. Table 2.3.2-1 provides a 
summary of the overall response status calculation at each time point for patients who have 
measurable disease at baseline. When patients have non-measurable (therefore non-target) disease 
only, Table 2.3.2-2 is to be used.  
Table 2.3.2-1: 
Time Point Response: Patients With Target (± Non-Target) Disease 
Target Lesions 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease and NE = inevaluable 
 
Table 2.3.2-2: 
Time Point Response: Patients with Non-target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558 
Nivolumab  
 
 
Table 2.3.2-2: 
Time Point Response: Patients with Non-target Disease Only 
Non-Target Lesions 
New Lesions 
Overall Response 
Non-CR/non-PD 
No 
Non-CR/non-PDa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
CR = complete response, PD = progressive disease and NE = inevaluable 
a Non-CR/non-PD is preferred over SD for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised. 
 
2.3.3 
Best Overall Response  
Best response determination of complete or partial response requires confirmation: Complete or 
partial responses may be claimed only if the criteria for each are met at a subsequent time point of 
t 4 weeks (28 days) later. In this circumstance, the best overall response can be interpreted as in 
Table 2.3.3-1. When SD is believed to be best response, it must meet the protocol specified 
minimum time from the date of first treatment or randomization date. 
For example, if the first scheduled follow-up imaging visit is Week 6 (r 7 days) for a particular 
protocol, a Best Response of SD can only be made after the subject is on-study for a minimum of 
6 weeks (42 days) minus 7 days, for an absolute minimum time on-study of 35 days from the 
reference start date (reference date is considered Day 1 on study).  If the subject is not on-study 
for at least this amount of time, any tumor assessment indicating stable disease before this time 
period will have a Best Response of NE unless PD is identified. 
Special note on response assessment: When nodal disease is included in the sum of target lesions 
and the nodes decrease to ‘normal’ size (< 10 mm), they may still have a measurement reported 
on scans. This measurement should be recorded even though the nodes are normal in order not to 
overstate progression should it be based on increase in size of the nodes. As noted earlier, this 
means that patients with CR may not have a total sum of ‘zero’ on the case report form (CRF). 
Table 2.3.3-1: 
Best Overall Response (Confirmation of CR and PR Required) 
Overall Response 
First Time Point 
Overall Response 
Subsequent Time Point 
Best Overall Response 
CR 
CR 
CR 
CR 
PR 
SD, PD OR PRa 
CR 
SD 
SD provided minimum criteria for SD duration met, otherwise, 
PD 
CR 
PD 
SD provided minimum criteria for SD duration met, otherwise, 
PD 


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558 
Nivolumab  
 
 
Table 2.3.3-1: 
Best Overall Response (Confirmation of CR and PR Required) 
Overall Response 
First Time Point 
Overall Response 
Subsequent Time Point 
Best Overall Response 
CR 
NE 
SD provided minimum criteria for SD duration met, otherwise, 
NE 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SD provided minimum criteria for SD duration met, otherwise, 
PD 
PR 
NE 
SD provided minimum criteria for SD duration met, otherwise, 
NE 
NE 
NE 
NE 
CR = complete response, PR = partial response, SD = stable disease, PD = progressive disease, and 
NE = inevaluable 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even disease meeting PR 
criteria relative to baseline, makes the disease PD at that point (since disease must have reappeared after CR). Best 
response would depend on whether minimum duration for SD was met. However, sometimes ‘CR’ may be claimed 
when subsequent scans suggest small lesions were likely still present and in fact the patient had PR, not CR at the 
first time point. Under these circumstances, the original CR should be changed to PR and the best response is PR. 
 
2.3.4 
Confirmation Scans 
Verification of Response: To be assigned a status of CR or PR, changes in tumor measurements 
must be confirmed by consecutive or subsequent repeat assessments that should be performed no 
less than 28 days after the criteria for response are first met.  Subsequent documentation of a CR 
may provide confirmation of a previously identified CR even with an intervening NE or PR 
(eg, CR NE CR or CR PR CR). Subsequent documentation of a PR may provide confirmation of 
a previously identified PR even with an intervening NE or SD (eg, PR NE PR or PR SD PR). 
However, only one (1) intervening time point will be allowed between PR/CRs for confirmation. 
Verification of Progression: Progression of disease should be verified in cases where progression 
is equivocal. If repeat scans confirm PD, then progression should be declared using the date of the 
initial scan. If repeat scans do not confirm PD, then the subject is considered to not have 
progressive disease. 
REFERENCES 
1. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009; 45: 228-47. 
 


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558 
Nivolumab  
 
 
APPENDIX 11 
COUNTRY SPECIFIC REQUIREMENTS 
Argentina, Czech Republic, France, Germany, Italy, Spain 
Criterion to exclude HIV positive participants including, but not limited to, the countries 
listed above if required by local regulatory authorities. 
 
Country-specific language 
Section 2 Flow Chart/Time and Events 
Schedule, Table 2-1: Screening 
Assessments- Laboratory Tests 
Add “HIV” to the list of laboratory tests 
Section 6.2 Exclusion Criteria, Exclusion 
criterion 1.l 
“Known history of testing positive for human immunodeficiency virus 
(HIV) or known acquired immunodeficiency syndrome (AIDS)”to be 
replaced with “Positive test for HIV”. 


Protocol 
Number: 
Page 131 
 
 
 
APPENDIX 12 
EXPECTED TOXICITIES FOR NIVOLUMAB, EPACADOSTAT, 
CARBOPLATIN, CISPLATIN, GEMCITABINE, PACLITAXEL, 
AND PEMETREXED 
The table entitled Expected Toxicities for Nivolumab, Epacadostat, Carboplatin, Cisplatin, 
Gemcitabine, Paclitaxel, and Pemetrexed lists the expected toxicities for each study drug in the 
CA2099NC/INCB 24360-309 study. Additional information can be found on each respective study 
drug’s Investigational Brochure and/or Prescribing Information.  
EXPECTED TOXICITIES FOR NIVOLUMAB, EPACADOSTAT, CARBOPLATIN, 
CISPLATIN, GEMCITABINE, PACLITAXEL, AND PEMETREXED 
Expected 
Toxicities 
Immuno-Oncology 
AGENTS 
Chemotherapy AGENTS 
System Organ 
Class 
Preferred Term 
Nivoluma
b 
Epacadost
at 
Carboplati
n 
Cisplati
n 
Gemcitabi
ne 
Paclitax
el 
Pemetrexe
d 
Blood and Lymphatic System Disorders 
Anaemia 
 
X 
X 
X 
X 
X 
X 
Leukopenia 
 
 
X 
X 
 
X 
X 
Neutropenia 
 
 
X 
X 
X 
X 
X 
Thrombocytopeni
a 
 
 
X 
X 
X 
X 
X 
Cardiac Disorders 
Bradycardia 
 
 
 
 
 
X 
 
Hypotension 
 
X 
 
 
 
X 
 
Ear and Labyrinth Disorders 
Ototoxicity 
 
 
X 
X 
 
 
 
Endocrine Disorders 
Hyperthyroidism 
X 
 
 
 
 
 
 
Hypothyroidism 
X 
X 
 
 
 
 
 
Eye Disorders 
Ocular toxicity 
 
 
 
X 
 
 
 
Gastrointestinal Disorders  
Abdominal 
distension  
 
X 
 
 
 
 
 
Abdominal pain 
X 
X 
 
 
 
 
 
Colitis 
X 
 
 
 
 
 
 


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558
Nivolumab  
EXPECTED TOXICITIES FOR NIVOLUMAB, EPACADOSTAT, CARBOPLATIN,
CISPLATIN, GEMCITABINE, PACLITAXEL, AND PEMETREXED
Expected 
Toxicities
Immuno-Oncology
AGENTS
Chemotherapy AGENTS
System Organ 
Class
Preferred Term
Nivoluma
b
Epacadost
at
Carboplati
n
Cisplati
n
Gemcitabi
ne
Paclitax
el
Pemetrexe
d
Constipation
X
X
X
Diarrhoea
X
X
X
X
X
X
X
Dry mouth
X
Nausea 
X
X
X
X
X
X
X
Small intestinal 
obstruction
X
Stomatitis
X
X
X
Vomiting 
X
X
X
X
X
X
X
General Disorders and Administrative Site Conditions
Asthenia 
X
X
X
X
Chills
X
Oedema
X
X
Fatigue 
X
X
X
Mucosal 
inflammation
X
X
X
Pain
X
X
X
Pyrexia
X
X
X
X
Immune System Disorders
Hypersensitivity
X
X
X
Infections and Infestations
Infection
X
X
X
X
X
X
Pneumonia
X
Injury, Poisoning and Procedural Complications
Infusion related 
reaction
X
X
X
X
Investigations
Alanine 
aminotransferase 
increased 
X
X
X
X
Amylase 
increased
X
X


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558
Nivolumab  
EXPECTED TOXICITIES FOR NIVOLUMAB, EPACADOSTAT, CARBOPLATIN,
CISPLATIN, GEMCITABINE, PACLITAXEL, AND PEMETREXED
Expected 
Toxicities
Immuno-Oncology
AGENTS
Chemotherapy AGENTS
System Organ 
Class
Preferred Term
Nivoluma
b
Epacadost
at
Carboplati
n
Cisplati
n
Gemcitabi
ne
Paclitax
el
Pemetrexe
d
Aspartate 
aminotransferase 
increased 
X
X
X
X
X
X
X
Blood alkaline 
phosphatase 
increased
X
X
X
X
Blood bilirubin 
increased
X
X
X
X
Blood creatinine 
increased
X
X
X
X
X
Blood thyroid 
stimulating 
hormone 
increased
X
Blood urea 
increased
X
X
X
Blood uric acid 
increased
X
Electrocardiogram 
abnormal
X
Lipase increased
X
Weight decreased
X
Metabolism And Nutrition Disorders
Decreased 
appetite
X
X
X
Dehydration
X
X
Hyperglycaemia
X
Hypocalcaemia 
X
X
Hypokalaemia 
X
X
X
Hypomagnesemia
X
X
Hyponatraemia
X
X
X
X
Hypophosphatae
mia
X
Musculoskeletal and Connective Tissue Disorders 


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558
Nivolumab  
EXPECTED TOXICITIES FOR NIVOLUMAB, EPACADOSTAT, CARBOPLATIN,
CISPLATIN, GEMCITABINE, PACLITAXEL, AND PEMETREXED
Expected 
Toxicities
Immuno-Oncology
AGENTS
Chemotherapy AGENTS
System Organ 
Class
Preferred Term
Nivoluma
b
Epacadost
at
Carboplati
n
Cisplati
n
Gemcitabi
ne
Paclitax
el
Pemetrexe
d
Arthralgia
X
X
X
Back pain
X
X
Myalgia
X
X
Nervous System Disorders
Dizziness
X
X
Headache
X
X
Paraesthesia
X
Neuropathy 
peripheral
X
X
X
X
Somnolence
X
Psychiatric Disorders
Insomnia
X
Renal and Urinary Disorders
Haematuria
X
Proteinuria
X
Respiratory, Thoracic, And Mediastinal Disorders
Cough
X
X
Dyspnoea
X
X
X
Pneumonitis
X
X
Skin and Subcutaneous Tissue Disorders 
Alopecia
X
X
X
X
X
Dry skin
X
Erythema
X
Pruritus 
X
X
X
Pruritus 
generalised
X
X
Rash 
X
X
X
X
X
Rash maculo-
papular 
X
X
Rash papular 
X


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558
Nivolumab  
EXPECTED TOXICITIES FOR NIVOLUMAB, EPACADOSTAT, CARBOPLATIN,
CISPLATIN, GEMCITABINE, PACLITAXEL, AND PEMETREXED
Expected 
Toxicities
Immuno-Oncology
AGENTS
Chemotherapy AGENTS
System Organ 
Class
Preferred Term
Nivoluma
b
Epacadost
at
Carboplati
n
Cisplati
n
Gemcitabi
ne
Paclitax
el
Pemetrexe
d
Vitiligo
X
Vascular disorders
Haemorrhage
X
X
X
X
Note: MedDRA Medical Dictionary for Regulatory Activities. ICH Version 20. March 2017. 
Sources: 
1)
Incyte Epacadostat (INCB024360) Investigator’s Brochure. Version Number: 09. Report Date: 12 DEC 2016 
Table 23 Expected Treatment-Emergent Adverse Events for Epacadostat Monotherapy (N = 149) and Epacadostat 
Risk section from Global Informed Consent. 
2)
Bristol-Myers Squib Investigator Brochure Nivolumab BMS-936558 MDX1106 ONO-4538. Version no.: 16 
Version date: 23-Jun-2017. Table 5.6.1-1
3)
Carboplatin- carboplatin injection, solution. Sanja Pharmaceutical Prescribing Information March, 2016 and 
National Cancer Institute Cancer Therapeutic Evaluation Program Possible Side Effects of Carboplatin (Table 
Version Date: March 24, 2015)  
4)
Cisplatin-cisplatin injection. BluePoint Laboratories. Prescribing Information April, 2016 and National Cancer 
Institute Cancer Therapeutic Evaluation Program Possible Side Effects of Cisplatin (Table Version Date: April 
20, 2015) 
5)
Gemzar (gemcitabine for injection), for intravenous use. Eli Lilly. Highlights of Prescribing Information. Initial 
U.S. Approval: 1996. Revised: 09/2017.  
6)
Taxol (paclitaxel) injection. Bristol-Myers Squibb. Prescribing Information and Patient Information. Rev April 
2011
7)
Alimta - pemetrexed disodium heptahydrate injection, powder, lyophilized, for solution Eli Lilly and Company. 
Highlights of Prescribing Information. Initial US Approval: 2004. Revised 2/2015. 


Clinical Protocol 
CA2099NC / INCB 24360-309 
BMS-936558
Nivolumab  
DOCUMENT HISTORY 
Document
Date of Issue
Summary of Change
Revised 
Protocol 01
23-Oct-2017
ALK and ROS1 testing are mandatory for participants with nonsquamous 
histology
Table for expected toxicities from study drugs added to Appendix 12
Original 
Protocol
15-Sep-2017
Not applicable


Signature Manifest
Document Number: IC-DEV-PROT-AMEND-0296
Revision: 1
Title: INCB 24360-309 Protocol Amendment 1(ECHO-309 / CA2099NC)
All dates and times are in Eastern Standard Time.
Quick Approval
Approve Now
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Date
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)
21 Nov 2017, 03:06:26 PM
Approved
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Title
Date
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