Conditions: Neoplasms Carcinoma, Non-Small-Cell Lung
Keywords: Advanced Solid Tumors PD-1 PD1 Programmed Cell Death-1 Programmed Cell Death 1 Programmed Cell Death-Ligand 1 (PD-L1) Programmed Cell Death-Ligand 2 (PD-L2) PDL1 PDL2
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 34
Healthy volunteers: no

Brief summary:
This is an open-label, non-randomized, Phase I study of epacadostat (INCB024360) alone and in combination with pembrolizumab with chemotherapy and pembrolizumab without chemotherapy in participants with advanced solid tumors. The primary objective of the trial is to evaluate the safety and tolerability of epacadostat administered alone and in combination with pembrolizumab with and without chemotherapy.

With protocol amendment 02 (26-April-2019), treatment with epacadostat was stopped in the "Epacad+Pembro+Cisplatin+Pemetrexed", "Epacad+Pembro+Carboplatin+Pemetrexed", and "Epacad+Pembro+Carboplatin+Paclitaxel" study arms.

Detailed description:

Arms:
arm 1: Participants received 25 mg of epacadostat orally twice daily (BID) alone on Days 1-5 of Cycle 1 (28-day cycle) with a washout on Days 6 and 7. On Day 8 participants received a one-time intravenous (IV) infusion of 200 mg pembrolizumab while continuing to receive 25 mg of epacadostat BID on Days 8-28. For each 21-day cycle thereafter, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 25 mg of epacadostat BID on Days 1-21 for up to 35 cycles (approximately 2 years). arm 2: Participants received 100 mg of epacadostat orally BID alone on Days 1-5 of Cycle 1 (28-day cycle) with a washout on Days 6 and 7. On Day 8 participants received a one-time IV infusion of 200 mg pembrolizumab while continuing to receive 100 mg of epacadostat BID on Days 8-28. For each 21-day cycle thereafter, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 100 mg of epacadostat BID on Days 1-21 for up to 35 cycles (approximately 2 years). arm 3: For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 25 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). arm 4: For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and received 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). arm 5: For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of 75 mg/m\^2 cisplatin and 500 mg/m\^2 pemetrexed on Day 1. Treatment with epacadostat was stopped with protocol amendment 02. arm 6: For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of Area Under the Curve (AUC) 5 carboplatin and 500 mg/m\^2 pemetrexed on Day 1. Treatment with epacadostat was stopped with protocol amendment 02. arm 7: For each 21-day cycle, participants received a one-time IV infusion of 200 mg pembrolizumab on Day 1 and 100 mg of epacadostat orally BID on Days 1-21 for up to 35 cycles (approximately 2 years). For the first 4 cycles, participants also received a one-time IV infusion of AUC 6 carboplatin and 200 mg/m\^2 paclitaxel on Day 1. Treatment with epacadostat was stopped with protocol amendment 02.

Interventions: intervention 1: Epacadostat 25 mg intervention 2: Epacadostat 100 mg intervention 3: pembrolizumab 200 mg intervention 4: Cisplatin 75 mg/m^2 intervention 5: Carboplatin Area Under the Curve (AUC) 5 intervention 6: Pemetrexed 500 mg/m^2 intervention 7: Paclitaxel 200 mg/m^2 intervention 8: Carboplatin AUC 6
Intervention descriptions: intervention 1: Oral administration intervention 2: Oral administration intervention 3: Intravenous (IV) infusion intervention 4: IV infusion intervention 5: IV infusion intervention 6: IV infusion intervention 7: IV infusion intervention 8: IV infusion

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
Document Date: 
A Phase I Study of INCB024360 (epacadostat) Alone, 
INCB024360 in combination with Pembrolizumab (MK-3475), 
and INCB024360 and Pembrolizumab in combination with
Chemotherapy in Patients with Advanced Solid Tumors 
(KEYNOTE-434)
26-Apr-2019
NCT02862457


Product:  MK-3475
1
Protocol/Amendment No.: 434-02 
MK-3475-434-02 Final Protocol
26-Apr-2019
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase I Study of INCB024360 (epacadostat) Alone, INCB024360 in combination with 
Pembrolizumab (MK-3475), and INCB024360 and Pembrolizumab in combination with 
Chemotherapy in Patients with Advanced Solid Tumors (KEYNOTE-434)
  
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 12
1.0
TRIAL SUMMARY.................................................................................................. 15
2.0
TRIAL DESIGN........................................................................................................ 16
2.1
Trial Design ........................................................................................................... 16
2.2
Trial Diagram........................................................................................................ 19
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 23
3.1
Primary Objective(s) & Hypothesis(es).............................................................. 23
3.2
Secondary Objective(s) & Hypothesis(es)........................................................... 23
3.3
Exploratory Objectives......................................................................................... 23
4.0
BACKGROUND & RATIONALE.......................................................................... 23
4.1
Background ........................................................................................................... 23
4.1.1
Pharmaceutical and Therapeutic Background .................................................... 23
4.1.1.1
Inhibition of PD-1 as a Target for Cancer ................................................... 24
4.1.1.2
Inhibition of Indoleamine 2,3–Dioxygenase as a Target for Cancer........... 25
4.1.1.3
Combined Immune Checkpoint Inhibition .................................................. 26
4.1.2
Pre-clinical and Clinical Trials ........................................................................... 27
4.1.3
Ongoing Clinical Trials....................................................................................... 27
4.2
Rationale................................................................................................................ 27
4.2.1
Rationale for the Trial and Selected Subject Population .................................... 27
4.2.2
Rationale for Dose Selection/Regimen/Modification......................................... 28
4.2.2.1
Justification for Treatment Regimen ........................................................... 28
4.2.2.2
Rationale for a Fixed Dose of MK-3475 ..................................................... 29
4.2.2.3
Rationale for Chemotherapy Dosing Regimens .......................................... 30
4.2.3
Rationale for Endpoints ...................................................................................... 30
4.2.3.1
Safety Endpoints.......................................................................................... 30
4.2.3.2
Efficacy Endpoints....................................................................................... 31
4.2.3.3
Pharmacokinetic/Pharmacodynamic/Immunogenicity Endpoints............... 32
 
 
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4.2.3.4
Planned Exploratory Biomarker Research................................................... 32
4.3
Benefit/Risk ........................................................................................................... 34
4.3.1
Benefit/Risk from MK-3475............................................................................... 34
4.3.2
Benefit/Risk from INCB024360......................................................................... 35
4.3.3
Benefit/Risk for the Combination of MK-3475 and INCB024360 .................... 36
5.0
METHODOLOGY ................................................................................................... 37
5.1
Entry Criteria........................................................................................................ 37
5.1.1
Diagnosis/Condition for Entry into the Trial...................................................... 37
5.1.2
Subject Inclusion Criteria.................................................................................... 37
5.1.3
Subject Exclusion Criteria .................................................................................. 39
5.2
Trial Treatment(s) ................................................................................................ 41
5.2.1
Dose Selection/Modification .............................................................................. 42
5.2.1.1
Dose Selection (Preparation) ....................................................................... 42
5.2.1.2
Dose Modification (Escalation/Titration/Other).......................................... 43
5.2.1.2.1
Tolerability Evaluation Rules ............................................................... 43
5.2.1.2.2
Definition of Dose Limiting Toxicity (DLT) ....................................... 45
5.2.1.2.3
Guideline for Dose Modification.......................................................... 46
5.2.1.2.4
Infusion Reaction Dose Modifications ................................................. 56
5.2.1.2.5
Procedures for Subjects Exhibiting Serotonin Syndrome (SS) ............ 58
5.2.2
Timing of Dose Administration.......................................................................... 59
5.2.3
Trial Blinding...................................................................................................... 61
5.3
Randomization or Treatment Allocation............................................................ 61
5.4
Stratification.......................................................................................................... 61
5.5
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 61
5.5.1
Acceptable Concomitant Medications ................................................................ 61
5.5.2
Restricted Medications and Measures................................................................. 61
5.5.3
Prohibited Medications and Measures................................................................ 62
5.6
Rescue Medications & Supportive Care............................................................. 63
5.7
Diet/Activity/Other Considerations..................................................................... 64
5.7.1
Diet...................................................................................................................... 64
5.7.2
Contraception...................................................................................................... 64
5.7.3
Pregnancy............................................................................................................ 65
 
 
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5.7.4
Use in Nursing Women....................................................................................... 65
5.8
Subject Withdrawal/Discontinuation Criteria................................................... 66
5.8.1
Discontinuation of Study Therapy after CR........................................................ 67
5.9
Subject Replacement Strategy............................................................................. 67
5.10
Beginning and End of the Trial ........................................................................... 67
5.11
Clinical Criteria for Early Trial Termination ................................................... 67
6.0
TRIAL FLOW CHART ........................................................................................... 68
6.1
Treatment Phase ................................................................................................... 68
6.1.1
Treatment Phase （Part A Cohort 1）............................................................... 68
6.1.2
Treatment Phase （Part A Cohort 2）............................................................... 72
6.1.3
Treatment Phase （Part B）............................................................................... 76
6.2
Second Course Phase (Retreatment ONLY) ...................................................... 81
7.0
TRIAL PROCEDURES ........................................................................................... 83
7.1
Trial Procedures ................................................................................................... 83
7.1.1
Administrative Procedures.................................................................................. 83
7.1.1.1
Informed Consent......................................................................................... 83
7.1.1.1.1
General Informed Consent.................................................................... 83
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 84
7.1.1.3
Subject Identification Card .......................................................................... 84
7.1.1.4
Medical History ........................................................................................... 84
7.1.1.5
Prior and Concomitant Medications Review............................................... 84
7.1.1.5.1
Prior Medications.................................................................................. 84
7.1.1.5.2
Concomitant Medications..................................................................... 84
7.1.1.6
Assignment of Screening Number............................................................... 85
7.1.1.7
Assignment of Treatment/Randomization Number..................................... 85
7.1.1.8
Trial Compliance (Medication).................................................................... 85
7.1.2
Clinical Procedures/Assessments........................................................................ 86
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 86
7.1.2.1.1
Distribution of Serotonin Syndrome (SS) Information Sheet............... 87
7.1.2.2
Physical Exam.............................................................................................. 87
7.1.2.3
Vital Signs, Height and Weight ................................................................... 87
7.1.2.4
12-lead ECG................................................................................................. 87
 
 
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7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale ........... 87
7.1.2.6
Arterial Blood Oxygen Saturation (SpO2) Measurement ............................ 87
7.1.2.7
Tumor Imaging and Assessment of Disease................................................ 87
7.1.2.7.1
Initial Tumor Imaging........................................................................... 88
7.1.2.7.2
Tumor Imaging During the Study......................................................... 88
7.1.2.7.3
End of Treatment and Follow-up Tumor Imaging................................ 88
7.1.2.7.4
Second Course (Retreatment) Tumor Imaging (Part A for ongoing 
participants only; not for new participants in Part A and all 
participants in Part B) ........................................................................... 88
7.1.2.8
Pulmonary 
Radiographic 
Evaluation 
for 
MK-3475-Induced 
Pneumonitis ................................................................................................. 88
7.1.2.9
Tumor Tissue Collection.............................................................................. 89
7.1.3
Laboratory Procedures/Assessments .................................................................. 89
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 89
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 91
7.1.3.2.1
Blood Sample Collection for PK of MK-3475 ..................................... 91
7.1.3.2.2
Blood Sample Collection for Anti-MK-3475 Antibodies..................... 91
7.1.3.2.3
Blood Sample Collection for PK of INCB024360 ............................... 92
7.1.3.2.4
Blood Sample Collection for Pharmacodynamic Assessments of 
INCB024360......................................................................................... 92
7.1.3.2.5
Blood Collection for RNA Analyses, Biomarker Plasma Analyses,
and Biomarker Serum Analyses ........................................................... 92
7.1.3.3
Planned Genetic Analysis Sample Collection.............................................. 92
7.1.4
Other Procedures................................................................................................. 92
7.1.4.1
Withdrawal/Discontinuation........................................................................ 92
7.1.4.2
Blinding/Unblinding .................................................................................... 93
7.1.4.3
Calibration of Critical Equipment................................................................ 93
7.1.5
Visit Requirements.............................................................................................. 93
7.1.5.1
Screening...................................................................................................... 93
7.1.5.2
Treatment Period.......................................................................................... 94
7.1.5.3
End of Treatment ......................................................................................... 94
7.1.5.4
Post-Trial...................................................................................................... 94
7.1.5.4.1
Safety Follow-Up.................................................................................. 94
7.1.5.4.2
Follow-Up............................................................................................. 94
 
 
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7.1.5.4.3
Survival Follow-Up .............................................................................. 94
7.1.5.5
Second Course Phase (Retreatment Period): Part A only............................ 94
7.2
Assessing and Recording Adverse Events .......................................................... 96
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 96
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 97
7.2.3
Immediate Reporting of Adverse Events to the Sponsor.................................... 97
7.2.3.1
Serious Adverse Events ............................................................................... 97
7.2.3.2
Events of Clinical Interest............................................................................ 98
7.2.4
Evaluating Adverse Events................................................................................. 99
7.2.5
Sponsor Responsibility for Reporting Adverse Events .................................... 102
7.3
TRIAL GOVERNANCE AND OVERSIGHT................................................. 102
7.3.1
Efficacy and Safety Evaluation Committee...................................................... 102
7.3.2
Independent Pulmonary Radiographic Adviser................................................ 102
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 102
8.1
Statistical Analysis Plan Summary ................................................................... 102
8.2
Responsibility for Analyses/In-House Blinding ............................................... 103
8.3
Hypotheses/Estimation ....................................................................................... 103
8.4
Analysis Endpoints ............................................................................................. 103
8.4.1
Safety Endpoints ............................................................................................... 103
8.4.2
Pharmacokinetic Endpoints .............................................................................. 104
8.4.3
ADA Endpoints................................................................................................. 104
8.4.4
Efficacy Endpoints............................................................................................ 104
8.4.5
Exploratory Biomarker Research...................................................................... 105
8.5
Analysis Populations........................................................................................... 105
8.5.1
Safety Analysis Populations ............................................................................. 105
8.5.2
PK/ADA Analysis Populations......................................................................... 105
8.5.3
Efficacy Analysis Populations .......................................................................... 105
8.6
Statistical Methods.............................................................................................. 106
8.6.1
Statistical Methods for Safety Analyses ........................................................... 106
8.6.2
Statistical Methods for Pharmacokinetic Analyses........................................... 106
8.6.3
Statistical Methods for Efficacy Analyses........................................................ 106
 
 
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8.7
Interim Analyses ................................................................................................. 106
8.8
Multiplicity .......................................................................................................... 106
8.9
Sample Size and Power Calculations ................................................................ 107
8.10
Compliance (Medication Adherence)................................................................ 107
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 108
9.1
Investigational Product ...................................................................................... 108
9.2
Packaging and Labeling Information ............................................................... 108
9.3
Clinical Supplies Disclosure............................................................................... 108
9.4
Storage and Handling Requirements................................................................ 108
9.5
Discard/Destruction/Returns and Reconciliation ............................................ 109
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 109
10.1
Confidentiality..................................................................................................... 109
10.1.1 Confidentiality of Data ..................................................................................... 109
10.1.2 Confidentiality of Subject Records................................................................... 109
10.1.3 Confidentiality of Investigator Information...................................................... 109
10.1.4 Confidentiality of IRB/IEC Information........................................................... 110
10.2
Compliance with Financial Disclosure Requirements..................................... 110
10.3
Compliance with Law, Audit and Debarment ................................................. 110
10.4
Compliance with Trial Registration and Results Posting Requirements...... 112
10.5
Quality Management System............................................................................. 112
10.6
Data Management............................................................................................... 113
10.7
Publications ......................................................................................................... 113
11.0
LIST OF REFERENCES....................................................................................... 114
12.0
APPENDICES......................................................................................................... 119
12.1
Merck Code of Conduct for Clinical Trials...................................................... 119
12.2
Eastern Cooperative oncology group (ECOG) Performance Status.............. 121
12.3
Common Terminology Criteria for Adverse Events (CTCAE) v4.0.............. 122
12.4
Prohibited Monoamine Oxidase Inhibitors and Drugs Associated with 
Significant Monoamine Oxidase Inhibitory Activity....................................... 123
12.5
Publication on Serotonin Syndrome ................................................................. 124
 
 
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12.6
Description of the iRECIST Process for Assessment of Disease 
Progression .......................................................................................................... 133
12.7
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For 
Evaluating Response in Solid Tumors .............................................................. 134
12.8
List of Abbreviations .......................................................................................... 135
12.9
Clinical Study Conduct System ......................................................................... 138
13.0
SIGNATURES......................................................................................................... 139
13.1
Sponsor's Representative ................................................................................... 139
13.2
Investigator.......................................................................................................... 139
 
 
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LIST OF TABLES
Table 1
Trial Treatments...................................................................................................... 42
Table 2
Dose Evaluation Rules in Part A ............................................................................ 44
Table 3
Dose Evaluation Rules in Part B............................................................................. 45
Table 4
Criteria for Defining Dose-Limiting Toxicities (DLTs)......................................... 46
Table 5
Dose Modification Guidelines for Drug-Related Adverse Events for MK-3475 
and INCB024360.................................................................................................... 48
Table 6
Dose Level Adjustments of INCB024360.............................................................. 56
Table 7
Infusion Reaction Treatment Guidelines................................................................ 57
Table 8
Sign and Symptoms of Serotonin Syndrome.......................................................... 59
Table 9
Warfarin Dose Adjustment Recommendation When Initiating Concurrent 
INCB024360 Treatment......................................................................................... 62
Table 10 Laboratory Tests..................................................................................................... 90
Table 11 Evaluating Adverse Events .................................................................................. 100
Table 12 Product Descriptions ............................................................................................ 108
 
 
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LIST OF FIGURES
Figure 1
Flow of Patients Enrollment in This Study........................................................ 18
Figure 2
Study Design of the cohort to evaluate the DLT of INCB024360 
administered alone (Part A cohort 1)................................................................. 20
Figure 3
Study Design of the cohort to evaluate the DLT of INCB024360 
administered in combination with MK-3475 (Part A cohort 2)......................... 21
Figure 4
Study Design of the cohort to evaluate the DLT of INCB024360 and 
MK-3475 administered in combination with chemotherapy (Part B) as of 
Amendment 01................................................................................................... 22
Figure 5
Study Design as of Amendment 02 in Part B .................................................... 22
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-434-00
10-Jun-2016
Initial protocol
3475-434-01
16-Oct-2017
To add a cohort to investigate the safety and tolerability of 
INCB024360 and MK-3475 in combination with chemotherapy 
in subjects with advanced NSCLC (Part B).  
3475-434-02
26-Apr-2019
Based on results from the KEYNOTE-654 and KEYNOTE-715 
NSCLC studies, INCB024360 + pembrolizumab (KEYNOTE-
654) and INCB024360 + pembrolizumab + chemotherapy 
(KEYNOTE-715) did not meet the pre-specified primary 
endpoint of improvement in the confirmed ORR.  KEYNOTE-
434 has been updated to simplify the trial design and to stop 
administration of INCB044360 in Part B (NSCLC patients).
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
2.0
5.2
5.2.1.2.1
5.2.1.2.3
5.2.2
5.5.2
5.5.3
5.8
5.8.1
6.0
7.1.2
7.1.4.1
7.1.5
7.2.1
8.0
12.6
TRIAL SUMMARY
TRIAL DESIGN
Trial Treatment(s)
Tolerability Evaluation Rules
Guideline for Dose Modification 
Timing of Dose Administration
Restricted Medications and Measures
Prohibited Medications and Measures 
Subject Withdrawal/Discontinuation Criteria 
Discontinuation of Study Therapy after CR 
TRIAL FLOW CHART
Clinical Procedures/Assessments
Withdrawal/Discontinuation
Visit Requirements
Definition of an Overdose for This Protocol 
and Reporting of Overdose to the Sponsor
STATISTICAL ANALYSIS PLAN
Description of the iRECIST Process for 
Assessment of Disease Progression
Revised text and added notes to stop
INCB024360
in Part B
and to 
simplify the trial design in both Parts
were made as follows:
•
remove INCB024360 from Part 
B; 
•
remove second course (except 
for patients already in second 
course before amendment 02 is 
approved); 
•
remove follow-up phase and 
survival follow-up phase;
•
change imaging schedule to “per 
site SOC”; 
•
no
longer use irRECIST
/
iRECIST.
Based on results from the 
KEYNOTE-654 
and 
KEYNOTE-715 
NSCLC 
studies, 
INCB024360 
+ 
pembrolizumab 
(KEYNOTE-654) 
and 
INCB024360 
+ 
pembrolizumab 
+ 
chemotherapy 
(KEYNOTE-715) did not 
meet 
the 
pre-specified 
primary 
endpoint 
of 
improvement 
in 
the 
confirmed 
ORR.  
KEYNOTE-434 has been 
updated to simplify the trial 
design 
and 
to 
stop 
administration 
of 
INCB044360 in Part B 
(NSCLC patients).
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
3.0
OBJECTIVE(S) & HYPOTHESIS(ES)
Addition of notes to clarify that the 
protocol 
will 
stop 
collecting 
efficacy endpoints and exploratory 
objectives may not be pursued.
Based 
on 
results
from 
KEYNOTE-654/
KEYNOTE-715,
the 
collection of efficacy data is 
not required in KEYNOTE-
434 
4.2.3.2
Efficacy Endpoints 
Addition of notes to clarify that 
data for efficacy endpoints will no 
longer be collected, imaging will be 
performed per local standard of 
care and will be assessed by the 
investigator/site radiologist, and the 
use of irRECIST and iRECIST is 
discontinued.
Based 
on 
results 
from 
KEYNOTE-654/
KEYNOTE-715,
the 
collection 
of 
additional 
efficacy data is not required
in KEYNOTE-434.
4.3.3
Benefit/Risk for the Combination of MK-3475 
and INCB024360
Addition 
of 
notes 
to 
clarify 
Benefit/Risk for the Combination 
of MK-3475 and INCB024360.
To update the benefit/risk 
assessment based on results
from 
KEYNOTE-654/
KEYNOTE-715.
 
 
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.2.1.2.5
5.5.3
12.4
Procedures for Subjects Exhibiting Serotonin 
Syndrome (SS)
Prohibited Medications and Measures
Prohibited Monoamine Oxidase Inhibitors and 
Drugs Associated with Significant Monoamine 
Oxidase Inhibitory Activity
Updated information regarding the 
risks of SS
with the use of 
INCB024360 was provided. Texts
were revised to clarify that the use 
of MAOIs is no longer prohibited 
in the study.
To 
align 
with 
current 
practices 
across 
the 
INCB024360 development 
program as supported in the 
current 
version 
of 
the 
INCB024360 IB.
7.3.2
Independent Pulmonary Radiographic Adviser
Revised 
texts 
that 
pulmonary 
radiographic 
changes 
by 
an 
independent 
pulmonary 
radiographic 
adviser 
will 
be 
reviewed as necessary.
Based on the current data in 
this study, review by an 
independent 
pulmonary 
radiographic adviser should 
be conducted as necessary.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase I study of INCB024360 (epacadostat) alone/combo with MK-
3475 and Chemotherapy in solid tumors
Sponsor Product Identifiers
MK-3475 (pembrolizumab), INCB024360 (epacadostat)
Trial Phase
Phase I
Clinical Indication
Advanced solid tumors
Trial Type
Interventional
Type of control
No treatment control
Route of administration
MK-3475: Intravenous, INCB024360: oral
Trial Blinding
Unblinded Open-label
Treatment Groups
Part A (Solid tumors)

Cohort 1 (To assess the safety and tolerability of INCB024360 
administered alone)
Dose Level 1: INCB024360 25 mg BID alone, followed by 
INCB024360 25 mg BID + MK-3475 200 mg Q3W
Dose Level 2: INCB024360 100 mg BID alone, followed by 
INCB024360 100 mg BID + MK-3475 200 mg Q3W

Cohort 2 (To assess the safety and tolerability of INCB024360
administered in combination with MK-3475)
Dose Level 1: INCB024360 25 mg BID + MK-3475 200 mg
Q3W
Dose Level 2: INCB024360 100 mg BID + MK-3475 200 mg
Q3W
Part B (NSCLC)

Cohort 1: MK-3475 200 mg Q3W in combination with Cisplatin 
and Pemetrexed (Non-Squamous)

Cohort 2: MK-3475 200 mg Q3W in combination with 
Carboplatin and Pemetrexed (Non-Squamous)

Cohort 3: MK-3475 200 mg Q3W in combination with 
Carboplatin and Paclitaxel (Squamous and Non-Squamous)
NOTE: The original study design allocate participants into 2
Parts: INCB024360 + pembrolizumab and INCB024360 + 
pembrolizumab +
chemotherapy. As of
Amendment 02, 
INCB024360 is stopped from Part B of original treatment cohorts. 
Thus, participants remaining in Part B receive pembrolizumab 
plus chemotherapy as per protocol, based on the cohort to which 
they were originally assigned, unless they choose to discontinue
from the study completely and be treated with standard of care.
Number of trial subjects
Approximately 15 (Part A) and 18 (Part B) subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 2 years
from the time the first subject signs the informed consent until the last 
subject’s last study-related phone call or visit.
 
 
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Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the informed consent form (ICF) through the final protocol-specified 
contact.  After a screening phase of 4 weeks, eligible subjects will be 
assigned to receive trial treatment until the subject meets the 
discontinuation criteria such as progressive disease (PD), unacceptable 
adverse event(s), or until the subject has received 35 administrations 
of MK-3475 (approximately 2 years) (Section 5.8).  For Part A,
subjects who are already in second course before Amendment 02 is 
approved would be eligible to continue to receive trial treatment for up 
to 17 additional administrations of INCB024360 +
MK-3475
(approximately one year) upon experiencing PD (Section 7.1.5.5).  
Otherwise subjects in Part A and part B will not receive INCB024360, 
and also will not receive second course (additional 17 administrations 
of MK-3475).
After the end of treatment, each subject will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy 
for 90 days and 120 days (or 30 days if the subject initiates new 
anticancer therapy) as described under section 7.2 of the protocol.  
As of Amendment 02, the last study visit is the Safety Follow-up
Visit.
A list of abbreviations used in this document can be found in Section 12.8.
2.0 TRIAL DESIGN
2.1
Trial Design
NOTE: As of Amendment 02, INCB024360 is removed from the treatment groups in Part B. 
Participants may choose to discontinue from the study and be treated as per standard of care 
or continue on study. All participants in Part B remaining on study receive pembrolizumab 
plus chemotherapy, as per protocol. For Part A only, the Second Course Phase is applied to 
the subjects who are already in second course as of Amendment 02. Second course is no 
longer available for new participants in Part A or Part B. The last study visit is the Safety
Follow-up Visit, and there will be no follow-up for survival status. All imaging will be
performed as per local standard of care; data will not be collected or sent for central imaging 
vender. This section has been updated accordingly.
This is an
open-label,
non-randomized,
multi-center, Phase
I study of MK-3475
(pembrolizumab), 
INCB024360
(epacadostat)
, 
INCB024360
(epacadostat)
and 
chemotherapy in Japanese subjects with advanced solid tumors to be conducted in 
conformance with Good Clinical Practices.  The primary objective of the trial was to evaluate 
the safety and tolerability of INCB024360 administered alone and in combination with MK-
3475 in subjects with advanced solid tumors and the safety and tolerability of INCB024360 
and MK-3475 in combination with chemotherapy in subjects with advanced NSCLC.  
In this study, we evaluated the safety and tolerability of the dose of INCB024360 alone and 
in combination with MK-3475 in advanced solid tumors (Part A Cohort 1 and 2, 
respectively) and INCB024360 and MK-3475 in combination with chemotherapy with each 
chemotherapy Cohort in advanced NSCLC (Part B Cohort 1, 2 and 3).
 
 
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NOTE: The original study design allocated participants into 2 Parts: INCB024360 + 
pembrolizumab (Figure 2 and Figure 3) and INCB024360 + pembrolizumab + chemotherapy
(Figure 4). As of Amendment 02, INCB024360 is stopped from Part B (Figure 5). Thus, 
participants remaining in Part B receive pembrolizumab plus chemotherapy as per protocol, 
based on the cohort to which they were originally assigned, unless they choose to discontinue 
from the study completely and be treated with standard of care. No second course will be 
available for new participants.
Part A (Advanced Solid Tumor)

Cohort 1 (To assess the safety and tolerability of INCB024360 administered alone)
Dose Level 1: INCB024360 25 mg BID alone, followed by INCB024360 25 mg BID + 
MK-3475 200 mg Q3W
Dose Level 2†: INCB024360 100 mg BID alone, followed by INCB024360 100 mg 
BID + MK-3475 200 mg Q3W
† In the Dose Level 2 (100 mg BID), we enrolled 3 patients to evaluate the safety, 
tolerability and pharmacokinetics (PK)of INCB024360 administered alone, and to 
evaluate the safety and PK of INCB024360 in combination with MK-3475. 

Cohort 2 (To assess the safety and tolerability of INCB024360 administered in 
combination with MK-3475)
Dose Level 1: INCB024360 25 mg BID + MK-3475 200 mg Q3W
Dose Level 2: INCB024360 100 mg BID + MK-3475 200 mg Q3W
This study will utilize a modified Toxicity Probability Interval (TPI) method [1] design that 
will evaluate the safety and tolerability of the dose of INCB024360 alone and in combination 
with MK-3475 and include up to 9 subjects (up to 3 subjects for Dose Level 2 in Cohort 1) at 
the identified dose of INCB024360 for further evaluation. A maximum of 42 subjects will be 
enrolled in this trial. The final number will depend on empirical safety data and observed 
dose-limiting toxicities (DLTs) (Note: A total of 15 patients were enrolled in Part A).  
Cohorts of 3-9 patients will be hospitalized and monitored during the first 1 week of DLT 
evaluation period for INCB024360 alone + 21-day administered INCB024360 in 
combination with MK-3475 (Cycle 1 of Cohort 1) or 21-day of DLT evaluation period for 
INCB024360 in combination with MK-3475 (Cycle 1 of Cohort 2).  
There is no data of clinical studies to evaluate the tolerability of INCB024360 administered 
alone in Japanese patients, so we will enroll the patients as follows (Figure 1);
 
 
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Figure 1
Flow of Patients Enrollment in This Study
1) Three patients will be initially enrolled at Dose Level 1 of Cohort 1, and following those 
3 patients, dosing will proceed based on observed DLTs in cohorts of size 3 as 
appropriate.
2) After the assessment of tolerability of 1), three patients will be initially enrolled at Dose 
Level 1 of Cohort 2, and following those 3 patients, dosing will proceed based on 
observed DLTs in cohorts of size 3 as appropriate.
3) After the assessment of tolerability of 2), the administration of Dose Level 2 of Cohort 2 
will be started and the assessment of tolerability will be evaluated by enrolling at least 6 
patients. At the same timing, three patients will be enrolled at Dose Level 2 of Cohort 1 
to evaluate the safety, tolerability and PK of INCB024360 administered alone, and the 
safety and PK on INCB024360 administered in combination with MK-3475.
In the safety assessments, if 0 of 3, ≤1 of 6, or ≤3 of 9 patients experience a DLT at the dose 
level, it will be considered to be tolerated.  The definition of DLT specific guidelines and the 
dose finding rule are outlined in Sections 5.2.1.2.2 and 5.2.1.2.1. 
In the first cycle (cycle 1) of cohort 1, INCB024360 will be orally administered alone for 5 
days (Day 1-5) followed by 2 days rest period (Day 6-7), and then INCB024360 will be 
orally administered for 21 days (Day 8-28) in combination with the 200 mg dose of 
MK-3475 intravenously administered Q3W (Day 8).  In the subsequent cycles (Cycle 2 and 
onwards), INCB024360 BID and MK-3475 Q3W will be administered in 21-day period. In 
Cohort 2, INCB024360 BID and MK-3475 Q3W will be administered in 21-day period from 
Cycle 1.
Part B (NSCLC)
NOTE: The DLT evaluation of INCB024360 and MK-3475 in combination with 
chemotherapy was conducted according to the following as of Amendment 01. As of 
Amendment 02, INCB024360 is removed from all original treatment cohorts.
INCB024360 and MK-3475 in combination with chemotherapy will be administered in this 
part. 
The investigator will perform screening test after informed consent to confirm that the 
candidate meet all the criteria determined in the protocol. The investigators will inform the 
Sponsor of the chemotherapy (Cohort) that Investigators will select prior to treatment 
 
 
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allocation. Following the investigators confirm the eligibility of the patient based on results 
from the screening test, he/she will assign allocation number to each eligible patient 
according to order of the registration. 6 advanced NSCLC patients will be enrolled in each 
cohort.
If the sponsor and DMC determine that 3 more additional patients are needed to evaluate the 
safety and tolerability, 3 additional patients will be added in the cohorts after the amendment.

The assessment of tolerability of INCB024360 100 mg BID and MK-3475 200 mg 
Q3W in combination with cisplatin 75 mg/m2 Q3W and pemetrexed 500 mg/m2 Q3W
(Non-Squamous). As of Amendment 02, INCB024360 is removed.

The assessment of tolerability of INCB024360 100 mg BID and MK-3475 200 mg 
Q3W in combination with carboplatin AUC 5 Q3W and pemetrexed 500 mg/m2 Q3W
(Non-Squamous). As of Amendment 02, INCB024360 is removed.

The assessment of tolerability of INCB024360 100 mg BID and MK-3475 200 mg 
Q3W in combination with carboplatin AUC 6 Q3W and paclitaxel 200 mg/m2 Q3W
(Squamous and Non-Squamous). As of Amendment 02, INCB024360 is removed.
Subjects will be treated with INCB024360 and MK-3475 in combination with chemotherapy
for 4 cycles, followed by in combination with pemetrexed in cohort 1 and 2.
Cohorts of 6 patients will be hospitalized and monitored during the first 3 week of DLT 
evaluation period for INCB024360 and MK-3475 in combination with chemotherapy.  In the 
safety assessments, if 0 of 3 or ≤2 of 6 patients experience a DLT at the dose level, it will be 
considered to be tolerated.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
2.2
Trial Diagram
The trial designs as of Amendment 01 are depicted in Figure 2, Figure 3 and Figure 4. The 
trial designs in Part B as of Amendment 02 are depicted in Figure 5.
 
 
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Figure 2
Study Design of the cohort to evaluate the DLT of INCB024360 administered 
alone (Part A cohort 1)
Retreatment is no longer available with Amendment 02 if they did not already start second 
course.
 
 
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Figure 3
Study Design of the cohort to evaluate the DLT of INCB024360 administered in 
combination with MK-3475 (Part A cohort 2)
Retreatment is no longer available with Amendment 02 if they did not already start second 
course.
 
 
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Figure 4
Study Design of the cohort to evaluate the DLT of INCB024360 and MK-3475 
administered in combination with chemotherapy (Part B) as of Amendment 01
Figure 5
Study Design as of Amendment 02 in Part B
No retreatment will be available.
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective(s) & Hypothesis(es)
Objective: To evaluate the Cohort specific safety and tolerability of INCB024360 
administered alone and in combination with MK-3475 (Part A Cohort 1 and 2, respectively), 
and INCB024360 and MK-3475 in combination with chemotherapy (Part B Chemotherapy 
Cohort 1, 2 and 3).
3.2
Secondary Objective(s) & Hypothesis(es)
1) Objective:
To evaluate the pharmacokinetic/pharmacodynamics
profiles of 
INCB024360 alone and in combination with MK-3475 (Part A Cohort 1 and 2, 
respectively), and INCB024360 and MK-3475 in combination with chemotherapy
(Part B Chemotherapy Cohort 1, 2 and 3).
3.3
Exploratory Objectives
1) Objective:  To evaluate the presence of anti-MK-3475 antibodies when administered 
concomitantly.
2) Objective:  To evaluate the anti-tumor activity (ORR, DOR and PFS by RECIST 1.1 
and irRECIST/iRECIST as assessed by local site, and OS) of INCB024360 in 
combination with MK-3475 and INCB024360 and MK-3475 in combination with 
chemotherapy.
3) Objective:  To evaluate the correlation between PD-L1 expression levels,
indoleamine 2,3-dioxygenase-1 (IDO1) expression, and tumor response when 
administered concomitantly.
4) Objective: To identify molecular (genomic, metabolic and/or proteomic) biomarkers 
that may be indicative of clinical response/resistance, safety, pharmacodynamic 
activity, and/or the mechanism of action of MK-3475 and INCB024360.
4.0 BACKGROUND & RATIONALE
4.1
Background
Refer to the respective Investigator’s Brochure (IB) for detailed background information on 
MK-3475 and INCB024360. Refer to the individual package inserts for each component of
chemotherapy.
4.1.1
Pharmaceutical and Therapeutic Background
INCB024360 (epacadostat) represents a novel, potent, and selective inhibitor of the enzyme 
indoleamine 2,3-dioxygenase-1 (IDO1) in both human tumor cells and human dendritic cells 
(DCs).  MK-3475 (pembrolizumab) is a potent and highly selective humanized monoclonal 
antibody (mAb) of the immunoglobulin IgG4/kappa isotype designed to directly block the 
interaction between PD-1 (programmed cell death-1) and its ligands PD-L1 and PD-L2.  This 
blockade enhances functional activity of the target lymphocytes to facilitate tumor regression 
 
 
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and ultimately immune rejection.  For a thorough discussion of the pharmacology of 
MK-3475 and INCB024360, refer to the IBs.
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [2].  The inability of the immune system to 
control tumor growth does not appear to result from an inability to recognize the tumor as 
foreign.  Tumor cells have been shown to evade immune destruction despite displaying 
recognizable antigens on their surface and despite the presence of high avidity T cells that are 
specific for these antigens [3], [4].  Histologic evaluation of many human cancers shows 
extensive infiltration by inflammatory and immune cells [5], suggesting that the immune 
system responds less effectively to malignancy.  These observations have led to the 
hypothesis that dominant mechanisms of immune tolerance or immune suppression are 
responsible for the immune system's inability to effectively respond in a way that 
consistently results in rejection.  
There are a number of inhibitory mechanisms that have been identified to be involved in 
tumor mediated immune suppression and include expression of the programmed death ligand 
1 (PD-L1), which can engage the inhibitory receptor PD-1 on activated T cells; the presence 
of the tryptophan-catabolizing enzyme IDO1, which exposes the exquisite sensitivity of T 
cells to tryptophan depletion and tryptophan metabolites; and infiltration with FoxP3+ 
regulatory T cells (Treg), which can mediate extrinsic suppression of effector T-cell function.
Therefore, agents that target these negative regulatory pathways and thereby allow the 
expansion of effector T cells present in the tumor may be beneficial in the clinic.
4.1.1.1
Inhibition of PD-1 as a Target for Cancer
The PD-1 receptor-ligand interaction is a major pathway stimulated by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to CD28 and cytotoxic T-lymphocyte-
associated antigen-4 (CTLA-4), which has been shown to negatively regulate antigen 
receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [6], [7].  The 
mechanism by which PD-1 down modulates T-cell responses is similar to but distinct from 
that of CTLA-4, as both molecules regulate an overlapping set of signaling proteins [8], [9].  
PD-1 has been shown to be expressed on activated lymphocytes including peripheral CD4+ 
and CD8+ T-cells, B-cells, Tregs, and natural killer cells [10], [11].  
Expression has also been shown during thymic development on CD4-CD8- (double negative) 
T cells as well as subsets of macrophages and dendritic cells [12].  The ligands for PD-1 (PD-
L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell types, 
including nonhematopoietic tissues as well as in various tumors [13], [14], [15], [9].  Binding 
of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor.  
PD-L1 is expressed at low levels on various nonhematopoietic tissues, most notably on 
vascular endothelium, whereas PD-L2 protein is only detectably expressed on antigen-
presenting cells found in lymphoid tissue or chronic inflammatory environments.  PD-L2 is 
thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T-cell function in peripheral tissues [9].  Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
 
 
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levels of this T-cell inhibitor.  High expression of PD-L1 on tumor cells (and to a lesser 
extent of PD-L2) has been found to correlate with poor prognosis and survival in various 
cancer types, including renal cell carcinoma [16], pancreatic carcinoma [17], hepatocellular 
carcinoma [18], and ovarian carcinoma [19].  Furthermore, PD-1 has been suggested to 
regulate tumor-specific T-cell expansion in subjects with melanoma [20].  This suggests that 
the PD-1/PD-L1 pathway plays a critical role in tumor immune evasion and should be 
considered as an attractive target for therapeutic intervention.
4.1.1.2
Inhibition of Indoleamine 2,3–Dioxygenase as a Target for Cancer
Recent interest has focused on the role of indoleamine 2,3–dioxygenase (IDO1) as a 
mechanism of induction of tolerance to malignancy [21].  IDO1 is a heme-containing, 
monomeric oxidoreductase that catalyzes the degradation of the essential amino acid 
tryptophan to N-formyl-kynurenine.  Kynurenine can be subsequently metabolized through a 
series of enzymatic steps to nicotinamide adenine dinucleotide.  IDO1 is the first rate-
limiting enzyme in one of the breakdown pathways of tryptophan.  In another pathway, 
tryptophan hydroxylase catalysis of tryptophan leads to the formation of serotonin and 
melatonin.  
The expression and activity profiles of 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 
(e.g., gut, respiratory tract, placenta, spleen), consistent with a role for regulating tryptophan 
metabolism in a local microenvironment  [22].  Within the immune system, IDO1 activity is 
specifically induced in cells such as DCs and macrophages at localized sites of inflammation 
[23].  
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 
[24].  Both the reduction in local tryptophan levels and the production of tryptophan 
catabolites that are inhibitory to cell proliferation contribute to the immunosuppressive 
effects [25].  IDO1 activity also promotes the differentiation of naive T cells to cells with a 
regulatory phenotype (Treg) [26].  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 [27], IDO1 expansion of Tregs may provide an additional 
mechanism whereby IDO1 could promote an immunosuppressive environment.
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 [28].  A critical role for IDO1 in immunomodulation has been 
confirmed in numerous animal models, including models of allograft tolerance, inflammation, 
and cancer [22].  While IDO1 inhibition can exacerbate disease in models of autoimmune 
disorders [22], IDO1 null mice show no evidence of susceptibility to developing spontaneous 
autoimmunity or alterations in immune system development [24], suggesting that IDO1 
inhibition, in a therapeutic setting, may produce minimal side effects in subjects 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 [29], [30].  In addition, studies 
with 1-methyl-tryptophan, demonstrate that IDO1 inhibition dramatically increases the 
efficacy of various chemotherapeutic agents (e.g., platinum compounds, taxane derivatives, 
cyclophosphamide) without increased toxicity [30]. Although the specific mechanisms 
responsible for this potentiation remain to be fully elucidated, the effects were not observed 
in T-celldeficient animals, suggesting that the results may be the consequence of the 
disablement 
of 
immunosuppressive 
mechanisms 
that 
exist 
within 
the 
tumor 
microenvironment.
Based on studies examining serum levels of tryptophan and kynurenine, IDO1 appears to be 
chronically activated in subjects with cancer, and IDO1 activation correlates with more 
extensive disease [31], [32].  IDO1 has subsequently been found to be overexpressed by a 
wide variety of human tumor cell types as well as by the DCs that localize to the tumor 
draining lymph nodes [29].  Increased expression of IDO1 in tumor cells has been shown to 
be an independent prognostic variable for reduced overall survival (OS) in subjects with 
melanoma, ovarian, colorectal, and pancreatic cancers [33], [34], [35], [36], [37].  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.
4.1.1.3
Combined Immune Checkpoint Inhibition
Blockade of immune inhibitory pathways is emerging as an important therapeutic modality 
for the treatment of cancer as evidenced by the clinical responses observed with antibodies to 
CTLA-4 and PD-1/PD-L1.  Ipilimumab, a fully human, IgG1 monoclonal antibody blocking 
CTLA-4, improved OS in patients with advanced melanoma [10], [38].  Nivolumab/MK-
3475, a fully human IgG4 antibody blocking PD-1, produced durable overall responses in 
patients with melanoma, renal cell cancer, and non-small cell lung cancer (NSCLC) [39], 
[40], [41].  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 [42].
As described above, IDO1 is another 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 [43], [44].  This effect was shown to be T-cell dependent, leading 
to enhanced T-cell proliferation and interleukin-2 production within the tumor and to a 
marked increase in the effector-to-regulatory T cell ratios in the tumors. 
In Phase I/II study of INCB024360 in combination with MK-3475 (INCB24360-202), 60 
subjects were enrolled as of the data cutoff (29-October-2015) and were treated with 
INCB024360 25 mg BID (n=4), 50 mg BID (n=20), 100 mg BID (n=18), and 300 mg BID 
(n=18) in combination with MK-3475 2 mg/kg or 200 mg IV Q3W.  Based on the 
preliminary, unaudited data as of the data cutoff (29-October-2015), no Grade 4 treatment-
related AEs were reported.  Three subjects (5%) discontinued for a treatment-related AE: 
 
 
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Grade 3 arthralgia, Grade 3 AST increased, and Grade 2 nervous system disorder. No 
treatment-related deaths occurred.  Treatment-emergent AEs were reported in 44 subjects 
(73.0%).  The most frequently reported AEs (≥10%) were rash (27%) followed by fatigue 
(23%).
In summary, both IDO1 and PD-1 have been shown to suppress T-cellmediated antitumor
immunity, and IDO1 and the PD-1 ligand PD-L1 have been shown to be coexpressed in 
multiple cancer types and to correlate with poor prognosis.  Combined inhibition of both 
pathways may therefore lead to greater suppression of antitumor immunity and to increased 
efficacy.  Preclinical and clinical data indicate that these pathways are important in various 
cancers.  Refer to Section 4.2.1.1 for the safety and efficacy data from Phase I/II study 
(INCB 24360-202).
4.1.2
Pre-clinical and Clinical Trials
Refer to the IBs for MK-3475 and INCB024360 for preclinical and clinical study data.
4.1.3
Ongoing Clinical Trials
Refer to the IBs for MK-3475 and INCB024360 for ongoing clinical study data.
4.2
Rationale
4.2.1
Rationale for the Trial and Selected Subject Population
Non-clinical data and clinical data obtained with non-Japanese subjects so far supports the 
clinical development of MK-3475 in Japanese.  If the safety profile is acceptable in Japanese 
subjects, this study will support the regulatory approval of this combination and further 
development in Japan. The patients with advanced solid tumors and NSCLC will be enrolled 
into Part A and B respectively.
In an ongoing dose-escalation and expansion Phase 1/2 study of MK-3475 in combination 
with INCB024360 subjects with Stage IIIB, IV, or recurrent NSCLC, melanoma, transitional 
cell carcinoma (TCC), renal cell carcinoma (RCC), triple negative breast cancer (TNBC),
endometrial adenocarcinoma (EA), or squamous cell carcinoma of the head and neck 
(SCCHN) are being enrolled in ex-Japan (INCB 24360-202). Subjects previously treated 
with PD-1 or CTLA-4 targeted therapies were excluded. Safety, tolerability, and investigator-
assessed tumor response (RECIST 1.1) were evaluated.  
As of 27-Feb-2017, among the 40 evaluable previously-treated participants with NSCLC, the 
ORR was 35% and DCR was 60%, which includes 2 participants with a CR. PD-L1 TPS test 
results were available in 28/40 efficacy-evaluable participants. Among the participants 
treated with the recommended dose of epacadostat 100 mg BID, ORR and DCR for 
participants with TPS ≥50% and ≤2 prior treatments were 43% (3/7; all PR) and 57% (4/7; 1 
SD), respectively; for participants with TPS <50% and ≤2 prior treatments, ORR and DCR 
were 33% (6/18; 1 CR) and 56% (10/18; 4 SD), respectively. For participants with ≤2 prior 
treatments whose PD-L1 status was unknown, the ORR and DCR were 45% (5/11, 1 CR) 
and 73% (3 SD), respectively [45]. 
In the Phase 2 study KEYNOTE-021 Cohort G, pembrolizumab plus pemetrexed and 
carboplatin showed statistically significant increases in objective response rate (ORR) and 
 
 
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PFS compared to pemetrexed and carboplatin alone in participants with non-squamous 
advanced NSCLC, regardless of PD-L1 status. These results established pembrolizumab plus 
chemotherapy as an efficacious option for first-line (1L) therapy in patients with NSCLC. 
The data from KEYNOTE-021 Cohort G led to US FDA approval; these findings are being 
further evaluated in the ongoing Phase 3 studies KEYNOTE-189 (non-squamous) and 
KEYNOTE-407 (squamous).
KEYNOTE-024 was a multicenter, international, randomized, open-label, controlled study of 
IV pembrolizumab monotherapy versus the choice of multiple SOC platinum based 
chemotherapies in participants previously untreated for their Stage IV 1L NSCLC (squamous 
and non-squamous), whose tumors expressed PD-L1 at TPS ≥50%, and in whom EGFR or 
ALK-directed therapy is not indicated. During screening, 1653 participants provided 
evaluable tissue for PD-L1 evaluation with 500 participants yielding a TPS ≥50% (30.2%). 
First-line treatment with pembrolizumab (n=154) significantly prolonged PFS (HR 0.50; 
95% confidence interval (CI): 0.37, 0.68; p<0.001) and OS (HR 0.60; 95% CI: 0.41, 0.89; p 
= 0.005) compared with SOC chemotherapy (n=151), inclusive of pemetrexed maintenance 
for participants with non-squamous tumors. In addition, pembrolizumab was associated with 
a higher ORR, including a higher complete response (CR) rate, as well as a longer DOR as 
compared to SOC. Pembrolizumab was better tolerated than chemotherapy and AEs were 
easily managed. The observed safety profile of the pembrolizumab arm was consistent with 
the safety profile for pembrolizumab established to date. Based on the mechanism of action 
of pembrolizumab, immune-related AEs (irAEs), including pneumonitis, occurred at a 
greater frequency with pembrolizumab compared to chemotherapy. Most irAEs were of 
Grade 1 or 2 severity and none led to death. These data underscore the substantial benefit of 
pembrolizumab as initial therapy for participants with previously untreated, advanced 
NSCLC whose tumors express high levels of PD-L1 (TPS ≥50%), in whom EGFR or ALK-
directed therapy is not indicated.
4.2.2
Rationale for Dose Selection/Regimen/Modification
4.2.2.1
Justification for Treatment Regimen
The dose selected for the current study was formed on the basis of having a well-tolerated 
safety profile as monotherapy and in combination with MK-3475, a robust objective response 
rate, durable disease control rates, as well as providing optimal target inhibition of IDO1 
based on nonclinical models.  Doses of INCB024360 of up to 700 mg BID as monotherapy 
have been well tolerated and doses of 25 mg BID to 300 mg BID in combination with 
MK-3475, nivolumab, durvalumab and atezolizumab are currently being evaluated in several 
ongoing Phase II studies. Doses of MK-3475 2 mg/kg and 200 mg Q3W flat dose have been 
studied in the ongoing Phase I/II study of MK-3475 in combination with INCB024360. 
Reductions in tumor burden were seen in 15 of 19 evaluable subjects across doses of 25 mg 
BID to 100 mg BID in combination with MK-3475 2 mg/kg and 200 mg Q3W flat dosing. 
Objective responses were observed across all dose levels tested and this combination has 
been well tolerated. The starting dose of INCB024360 when evaluating the tolerability of 
INCB024360 in combination with MK-3475 is 25 mg BID in which no DLT was observed 
when administered in combination with MK-3475 in global phase 1/2 study (INCB24360-
202 study). Before the evaluation of tolerability of INCB024360 in combination with 
 
 
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MK-3475, the tolerability of INCB024360 administered alone will be evaluated in the same 
dose (25 mg BID).   
Based on a PK-pharmacodynamic model for epacadostat, the Cavg for nearly all participants 
exceeded the IC50, the range of active drug exposure seen in nonclinical models in the first-
in-human study, INCB 24360-101, a detailed review of the effect of dose and exposure on 
the pharmacodynamics effect of epacadostat on the tryptophan pathway was performed. 
Using an ex vivo assay optimized for determining the inhibition of the metabolism of 
tryptophan to kynurenine by IDO1, epacadostat treatment produced significant dose-
dependent reductions in plasma kynurenine levels and in the plasma kynurenine/tryptophan 
ratio at all doses and in all patients. Near maximal changes were observed at doses of ≥100 
mg BID with >80% to 90% inhibition of IDO1 achieved throughout the dosing period [46].
This study is a first clinical trial for INCB024360 in Japan, so PK and preliminary safety will 
be assessed as monotherapy during the first week of Cycle 1.  INCB024360 will be 
administered alone in the initial 5 days (Day 1-5 of Cycle 1), in order to reach the steady-
state of INCB024360 to assess PK parameters.  This will be followed by a 2 days washout
period (Day 6-7 of Cycle 1) (calculated based on 5-times the longest t1/2 of 6 hours of 
INCB024360 at a dose of 300 mg BID) so that trough levels will not be detectable for the PK 
assessments of combination part with MK-3475 starting from Day 8 of Cycle 1.  The 7-day
duration of INCB024360 monotherapy would be appropriate to evaluate safety and 
pharmacokinetics, considering the benefit for subjects as INCB024360 monotherapy was 
likely to be less efficacious from the available clinical data.
4.2.2.2
Rationale for a Fixed Dose of MK-3475
The planned dose of pembrolizumab for this trial is 200 mg every 3 weeks (Q3W). Based on 
the totality of data generated in the Keytruda development program, 200 mg Q3W is the 
appropriate dose of pembrolizumab across all indications and regardless of tumor type. As 
outlined below, this dose is justified by: 

Clinical data from eight randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg every two weeks (Q2W), 

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically 
based pharmacokinetic [PBPK] analysis) at 200 mg Q3W
Among the eight randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 
mg/kg Q3W vs. 10 mg/kg Q2W (KN001 B2, KN001 D, KN002, KN010 and KN021), and 
three studies compared 10 mg/kg Q3W vs. 10 mg/kg Q2W (KN001 B3, KN001 F2 and 
KN006). All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5 to 7.5 fold difference in exposure. 
 
 
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The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses 
studied. Subsequently, flat dose-/exposure-response relationships were also observed in other 
tumor types including head and neck cancer, bladder cancer, gastric cancer and classical 
Hodgkin Lymphoma, confirming 200 mg Q3W as the appropriate dose independent of the 
tumor type. These findings are consistent with the mechanism of action of pembrolizumab, 
which acts by interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Secondly, a PBPK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was 
selected for evaluation across all pembrolizmab protocols.
Furthermore, PK of MK-3475 in Japanese patients are similar to that in non-Japanese 
patients. Thus the 200 mg Q3W fixed dose regimen is considered an appropriate fixed dose 
for other solid tumor indications as well.
4.2.2.3
Rationale for Chemotherapy Dosing Regimens
The dosing regimens of chemotherapy represent the SOC per the approved product labels.
Chemotherapy may be reduced, interrupted, or discontinued at the Investigator’s discretion 
using the approved product labels and local regulations.
4.2.3
Rationale for Endpoints
4.2.3.1
Safety Endpoints
NOTE: As of Amendment 02, INCB024360 is stopped from Part B.
The primary safety objective of this study is to characterize the safety and tolerability of 
INCB024360 alone and in combination with MK-3475 in subjects with advanced solid 
tumors.  In addition to general laboratory tests, immune laboratory test will be evaluated 
considering the mode of action of MK-3475.  The primary safety analysis will be based on 
subjects who experienced toxicities as defined by CTCAE criteria.  Safety will be assessed 
by quantifying the toxicities and grades experienced by subjects who have received 
INCB024360 alone and in combination with MK-3475, including serious adverse events 
(SAEs).  
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0.  The 
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant 
medications administered will be recorded.  AEs will be analyzed including but not limited to 
all AEs, SAEs, fatal AEs, and laboratory changes.  Since pneumonitis has been previously 
 
 
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reported in clinical studies of anti-PD-1 antibodies including MK-3475, pulmonary 
radiographic changes and its features will be evaluated by investigators and an independent 
radiologist from a potential risk of pneumonitis.  
4.2.3.2
Efficacy Endpoints
NOTE: As of Amendment 02, data for efficacy endpoints, including disease assessments 
based on imaging, are no longer being collected. Imaging will be performed per local 
standard of care and will be assessed by the investigator/site radiologist. Also, the use of 
irRECIST and iRECIST is discontinued. The following irRECIST and iRECIST language is 
no longer applicable. Participants with radiographic disease progression as determined by
RECIST 1.1 by investigator assessment will discontinue from study treatment; no
confirmatory scans are required. However, if the participant is achieving a clinically
meaningful benefit, an exception to continue with study treatment without epacadostat may 
be considered following consultation with the MSD.
Efficacy will be evaluated as an exploratory objective for ORR, DOR, PFS, and OS per 
RECIST 1.1 by the local site.  RECIST 1.1 will also be used by the local site to determine 
eligibility and irRECIST/iRECIST will be used to make treatment decisions.  
Modified RECIST for Immune related RECIST (irRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of MK-3475.  Immunotherapeutic agents such as MK-3475 may produce 
antitumor effects by potentiating endogenous cancer-specific immune responses.  The 
response patterns seen with such an approach may extend beyond the typical time course of
responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions [47].  Standard RECIST may 
not provide an accurate response assessment of immunotherapeutic agents such as MK-3475.  
Therefore, RECIST 1.1 will be used with the adaptations, in which a confirmation 
assessment of disease progression must be obtained at least 4 weeks after the initial disease 
assessment indicating progressive disease.  
Modified RECIST for Immune-based Therapeutics (iRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response seen following 
treatment with pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce antitumorveffects by potentiating endogenous cancer-specific immune responses. 
The response patterns seen with such an approach may extend beyond the typical time course 
of responses seen with cytotoxic agents, and participants treated with pembrolizumab may 
manifest a clinical response after an initial increase in tumor burden or even the appearance 
of new lesions.
Thus, standard RECIST 1.1 may not provide an accurate response assessment of
immunotherapeutic agents such as pembrolizumab. Based on an analysis of participants with
melanoma enrolled in KEYNOTE-001, 7% of evaluable participants experienced delayed or
early tumor pseudo-progression. Of note, participants who had PD by RECIST 1.1 but not by 
the immune-related response criteria [48] had longer OS than participants with PD by both 
criteria [49]. Additionally, the data suggest that RECIST 1.1 may underestimate the benefit 
of pembrolizumab in approximately 15% of participants. These findings support the need to 
 
 
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apply a modification to RECIST 1.1 that takes into account the unique patterns of atypical 
responses in immunotherapy and enables treatment beyond initial radiographic progression, 
if the participant is clinically stable.
iRECIST assessment has been developed and published by the RECIST Working Group, 
with input from leading experts from industry and academia, along with participation from 
the US Food and Drug Administration and the European Medicines Agency [50]. The 
unidimensional measurement of target lesions, qualitative assessment of non-target lesions,
and response categories are identical to RECIST 1.1, until progression is seen by RECIST 
1.1. However, if a participant is clinically stable, additional imaging may be performed to 
confirm radiographic progression. iRECIST will be used by site investigators to assess tumor 
response and progression, and make treatment decisions, as well as for exploratory efficacy 
analyses where specified.
4.2.3.3
Pharmacokinetic/Pharmacodynamic/Immunogenicity Endpoints
Blood samples will be obtained to measure pharmacokinetics of MK-3475 and INCB024360.
Plasma will be collected to assess the effects on kynurenine and tryptopohan.  The 
pharmacokinetic parameters of INCB024360 will be calculated by non-compartmental
analysis.  Subsequently, the concentration-time data to be obtained from MK-3475 serum 
assays will be used for a population PK analysis if needed.  In addition, an exploratory 
investigation on the formation of anti-MK-3475 antibody (ADA) and its effect on the 
pharmacokinetics of MK-3475 will also be evaluated for interpretation of immunogenicity 
results considering 
MK-3475 is 
a humanized monoclonal anti-PD-1 
antibody.  
Pharmacokinetics of INCB024360 will be compared between INCB024360 plus MK-3475 
dosing and INCB024360 alone dosing, and the impact of MK-3475 dosing on the 
pharmacokinetics of INCB024360 will be assessed. The sampling time points for MK-3475 
PK, PD, and ADA have been determined taking the long half-life (two to three weeks) of 
MK-3475 into account. 
4.2.3.4
Planned Exploratory Biomarker Research
Tumor biopsy analyses to evaluate IDO1 expression (+/-), PD-L1 expression (positive versus 
negative/indeterminate) in tumor tissue and immune cell infiltrate at baseline and correlate 
expression with response, PFS and/or OS.  The expression of exploratory histological 
biomarkers will also be assessed.  
Cancer immunotherapies represent an important and novel class of antitumor agents.  
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients.  Thus, to aid future patients, it is important to investigate the 
determinants of response or resistance to cancer immunotherapy, as well as determinants of 
AEs in the course of our clinical studies.  These efforts will attempt to identify predictive 
biomarkers and generate information that will better guide single-agent and combination 
therapy with immuno-oncology drugs.  
To identify biomarkers, biospecimens (ie, blood components, tumor material) will be 
collected to support analyses of cellular components (eg, protein, DNA, RNA, metabolites) 
and other circulating molecules. Whole blood, serum, and tumor tissue will be collected for 
 
 
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assessments as outlined in section 6.0 and correlated with clinical outcomes as appropriate. 
Details regarding sample processing, handling, and shipping will be provided in the 
Laboratory Manual.   Investigations may include but are not limited to:
Germline genetic analyses from blood
This research will evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation.  If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population.  Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations. DNA in blood may also be used 
to examine the T-cell receptor profile in blood to compare with the profile in the tumor. 
Microsatellite instability (MSI) may also be evaluated, as this is an important biomarker for 
some cancers.  
Genetic (DNA) analyses from tumor and blood
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability).  Key molecular changes of interest to immune-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment.  Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment.  To 
conduct the first type of research, it is important to identify tumor-specific mutations that 
occur across all genes in the tumor genome.  Thus, genome-wide approaches may be used for 
this effort.  Note that in order to understand tumor-specific mutations, it is necessary to 
compare the tumor genome with the germline genome.  Microsatellite instability may also be 
evaluated as this is an important biomarker for some cancers. If sufficient sample quantity is 
available, to conduct an assessment of T-cell clonality in tumor and in circulating T 
lymphocytes, a DNA sequencing approach may be undertaken with a specific focus on the 
analysis of diversity versus the clonality of the T-cell receptor repertoire.  
Tumor RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue may be performed to define gene expression signatures that 
correlate to clinical response to treatment with pembrolizumab or the combination of 
pembrolizumab and epacadostat.  Pembrolizumab induces a response in tumors that is 
characterized by an inflamed/immune phenotype.  Specific immune-related gene sets (ie, 
those capturing interferon-gamma transcriptional pathways) may be evaluated and new 
signatures may be identified.  Individual genes related to the immune system may also be 
evaluated (eg, IL-10).  MicroRNA profiling may also be pursued.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic device has 
been developed for use with pembrolizumab in NSCLC.  Preliminary data indicates that this 
association may also be true in additional cancer types (ie, triple negative breast cancer, head 
and neck, and gastric).  
 
 
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Additional tumor or blood-derived proteins may also correlate with response to the 
combination of pembrolizumab and epacadostat.  Therefore, tumor tissue may be subjected 
to proteomic analyses using a variety of platforms that could include but are not limited to 
immunoassays and liquid chromatography/mass spectrometry.  This approach could identify 
novel protein biomarkers that could aid in patient selection for the study treatments. Similar 
to PD-L1 expression, tumor biopsy materials may be used to assess tumor IDO1 protein or 
mRNA expression. Tumor samples may be assessed for the extent and location of immune 
infiltrate, which may include an analysis of the number and the location of CD8+ and 
FOXP3+ T-lymphocytes, macrophages, and neutrophils.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor and immune response 
derived proteins can be shed from tumor and released into the blood.  Correlation of 
expression with response to pembrolizumab or the combination of pembrolizumab and 
epacadostat may identify new approaches for predictive biomarkers in blood, representing a 
major advance from today’s reliance on assessing tumor biomarkers.  Serum analytes may 
include cytokines and other markers of inflammation and immune status, tumor markers, and 
markers of metabolism and nutritional status. If serum samples are depleted, then additional 
markers may be evaluated at the discretion of the Sponsor or MSD using remaining PK 
plasma samples. This research would serve to develop such assays for future clinical use.
4.3
Benefit/Risk
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
4.3.1
Benefit/Risk from MK-3475
The safety of MK-3475 was investigated in three controlled, randomized studies 
(KEYNOTE-002, KEYNOTE-006, and KEYNOTE-010) for the treatment of unresectable or 
metastatic melanoma or metastatic NSCLC and in an uncontrolled, open-label study 
(KEYNOTE-001) for the treatment of unresectable or metastatic melanoma or metastatic 
NSCLC. Overall, 1567 patients with melanoma (699 previously treated with ipilimumab and 
868 naïve to ipilimumab) and 1232 patients with NSCLC were treated. Safety is described 
for the pooled population of 2799 patients (studied across three doses; 2 mg/kg every 3 
weeks and 10 mg/kg every 2 or 3 weeks). The median treatment duration was 4.2 months 
(range 1 day to 30.4 months) including 1153 patients treated for greater than or equal to six 
months and 600 patients treated for greater than or equal to one year.  MK-3475 was 
discontinued for treatment-related adverse reactions in 5% of patients.
Treatment-related 
serious adverse events (SAEs) reported up to 90 days after the last dose occurred in 10% of 
patients receiving MK-3475. Of these treatment-related SAEs, the most common were 
pneumonitis, colitis, diarrhea, and pyrexia.  Immune-mediated adverse reactions are 
presented based on 2799 patients with melanoma and NSCLC. The safety profile was 
generally similar for patients with melanoma and NSCLC.  The following events were 
recognized as important identified risks for MK-3475: immune-mediated pneumonitis, colitis, 
hepatitis, nephritis, hypophysitis
(including hypopituitarism and secondary adrenal 
insufficiency), thyroid disorders (hypothyroidism, hyperthyroidism), Type I diabetes mellitus, 
 
 
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uveitis, myositis, Guillain-Barré syndrome, pancreatitis, severe skin reactions, and infusion-
related reactions, and myasthenic syndrome as a potential important risk.
4.3.2
Benefit/Risk from INCB024360
In 28-day toxicology studies, Cmax values have exceeded the IC50 for the IDO1 enzyme in 
cells (7 nM) by up to 370-fold, and the IC50 for the vasopressin 1a receptor by up to 40-fold 
(130-fold in single dose studies) in the absence of any toxicity, so the risk of unintended 
pharmacological activity is expected to be low.  In the Phase I clinical study in subjects with 
refractory solid tumors (INCB 24360-101) doses up to 700 mg BID were given without an 
MTD determined. Two DLTs occurred; 1 DLT of radiation pneumonitis at the 300 mg BID 
dose level and 1 DLT of fatigue at the 400 mg BID dose level.  INCB024360 was well 
tolerated.
Despite the substantial improvement in PFS and OS observed with pembrolizumab as 
compared to SOC platinum doublet chemotherapy in KEYNOTE-024, and the significant 
increases in ORR and PFS showed with pembrolizumab plus pemetrexed and carboplatin as 
compared to pemetrexed and carboplatin alone in KEYNOTE-021 Cohort G, there remains a 
need to investigate new treatments which offer the prospect of added benefit for this patient 
population. Details regarding specific benefits and risks of pembrolizumab treatment for 
participants in this clinical study may be found in the Investigator’s Brochure [IB Edition 13 
2017] and Informed Consent Form (ICF).
Given initial data observed in KEYNOTE-037 suggesting improved efficacy of 
pembrolizumab in combination with epacadostat and an overall safety profile comparable to 
anti-PD-1 monotherapy, this combination represents a rational and promising first-line 
therapeutic option in patients with metastatic NSCLC.
Epacadostat, as a single therapy, has a predictable PK profile and acceptable safety profile, 
but limited single-agent efficacy in participants with solid tumors in the Phase 1 study of 52
participants (INCB 24360-101). The data showing the limited efficacy in solid tumors 
support that an epacadostat monotherapy arm is not warranted.
An uncommon risk of IDO1 inhibition is an increase in serotonin levels that could precipitate 
a cluster of AEs termed serotonin syndrome (SS) when administered alone or in combination 
with other serotonergic agents. This rare syndrome has been associated with some 
monoamine oxidase inhibitors (MAOIs) and combinations of serotonergic drugs [51]. The
clinical manifestations of SS range from barely perceptible to lethal; onset is rapid (within 12
hours of drug[s] administration). Preclinical data suggest that SS is unlikely following 
treatment with either epacadostat alone or in combination with MAOIs such as linezolid [52]. 
As of 27-Feb-2017, 2 of 958 participants treated across the epacadostat program have
reported SS or symptoms of SS; both episodes were mild in severity and resolved.
Although the incidence of SS or symptoms of SS is uncommon, use of MAOIs are prohibited
during the study, and all participants will be assessed for SS symptoms at appropriate time 
points after dosing as of amendment 01. Participants will be provided with an informative 
leaflet describing the signs and symptoms of SS along with instructions to seek immediate 
medical care if any of these signs or symptoms are observed.
 
 
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Additional details regarding specific benefits and risks of epacadostat for participants in this
clinical study may be found in the accompanying Investigator’s Brochure [EPACADOSTAT
(INCB024360) – Investigators Brochure. 2017] and ICF.
4.3.3
Benefit/Risk for the Combination of MK-3475 and INCB024360
NOTE: MK-3475-654 is Phase 2 Study of Pembrolizumab ± Epacadostat in PD-L1 High 
Metastatic NSCLC. MK-3475-715 is Phase 2 Study of 
Pembrolizumab/Epacadostat/Chemotherapy in Metastatic NSCLC. The recent results 
of the final efficacy analysis of these studies indicated the below;
In KEYNOTE-654/ECHO-305 phase II study, the combination of epacadostat and 
pembrolizumab did not meet the pre-specified primary endpoint of improvement in the 
confirmed ORR compared with pembrolizumab alone based on blinded independent 
central assessment.
In KEYNOTE-715/ECHO-306 phase II study, epacadostat in combination with 
pembrolizumab and platinum-based chemotherapy also did not meet the pre-specified 
primary endpoint of improvement in the confirmed ORR compared with 
pembrolizumab combined with chemotherapy based on blinded independent central 
assessment
Subsequently, the participants’ treatment was unblinded, epacadostat was stopped, and 
the protocols were amended accordingly in those studies.
Thus, as of Amendment 02 in KN434, epacadostat/ INCB024360 has beenstopped from 
Part B. 
The combination of MK-3475 and INCB024360 has the potential to precipitate more 
frequent, more severe, and/or new immune-related toxicities as compared with each 
individually.
In the ongoing Phase I/II study (INCB 24360-202/KEYNOTE-037), combining MK-3475 
and INCB024360, the safety, efficacy, and tolerability of the combinations of epacadostat 25 
mg BID, 50 mg BID, and 100 mg BID in combination with intravenous (IV) pembrolizumab 
2 mg/kg or 200 mg Q3W were evaluated in participants including, but not limited to, Stage 
3B, IV or recurrent NSCLC, melanoma, urothelial carcinoma (UC), renal cell carcinoma 
(RCC), ovarian cancer, triple negative breast cancer (TNBC), squamous cell carcinoma of 
the head and neck (SCCHN), microsatellite-instability (MSI), colorectal cancer (CRC) and 
diffuse large B -cell lymphoma (DLBCL). In the Phase 1 dose-escalation part, oral 
epacadostat 25 mg BID, 50 mg BID and 100 mg BID with Pembrolizumab 2 mg/kg IV Q3W, 
and epacadostat 300 mg BID with pembrolizumab 200 mg IV Q3W was evaluated. Based on 
the risk for early progression during dose interruptions and dose reductions associated with 
INCB024360 300 mg BID in combination with MK-3475 200 mg IV Q3 weeks, and a PK-
pharmacodynamic model for epacadostat (Refer to section 4.2.2.1, Justification of Treatment 
Regimen), epacadostat 100 mg BID in combination with pembrolizumab 200 mg IV Q3W 
was selected as the dose for use in the Phase 2 portion of INCB 24360-202/KEYNOTE-037 
and planned phase 3 studies.
As of 27-Feb-2017, a total of 294 participants were enrolled in Phase 2 (pembrolizumab 200 
mg IV Q3W plus epacadostat 100 mg BID oral) and received ≥ 1 dose of epacadostat and 
pembrolizumab. Preliminary data show that the most common (≥10%) all-grade treatment-
 
 
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related adverse events were fatigue, rash, nausea, and pruritus. Treatment-related AEs 
≥Grade 3 were observed in 18% (most common: lipase increased [4%] and rash [3%]). There 
was one treatment- related death due to respiratory failure which was secondary to aspiration 
pneumonia [53]. 
As of 27-Feb-2017, among the 40 evaluable previously-treated participants with NSCLC, the 
ORR was 35% and DCR was 63%, which includes 2 participants with a CR.  For the 36 
participants evaluable and with 0–2 prior lines of treatment, ORR was 39% (2 CR, 12 PR) 
and DCR was 64% (9 SD).  Among these 36 participants treated with the recommended dose 
of epacadostat 100 mg BID, ORR and DCR for participants with TPS ≥50% and ≤2 prior 
treatments were 43% (3/7; all PR) and 57% (4/7; 1 SD), respectively; for participants with 
TPS <50% and ≤2 prior treatments, ORR and DCR were 33% (6/18; 1 CR) and 56% (10/18; 
4 SD), respectively. The remaining 1 CR and 4 PRs were observed among 11/36 patients 
with unknown TPS [54].
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
5.0 METHODOLOGY
5.1
Entry Criteria
5.1.1
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with advanced solid tumor at least 20 years of age will be enrolled in 
this trial.
5.1.2
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent for the trial. 
2. Be ≥ 20 years of age on day of signing informed consent.
3. Meet the following corresponding requirements for the part of the study they will 
enroll into;
Part A
Have a histologically-confirmed metastatic or locally advanced solid tumor that has 
failed to respond to standard therapy, progressed despite standard therapy, or for 
which standard therapy does not exist.
Part B
Subjects must have a histologically-confirmed or cytologically confirmed diagnosis 
of NSCLC, for stage IIIB/IV.

In cohort 1 and 2, has a histological or cytological diagnosis of non-squamous 
cancer.

Subject must be naïve to systemic therapy.
 
 
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
Have confirmation that EGFR or ALK-directed therapy is not indicated 
(documentation of absence of tumor activating EGFR mutations AND absence of 
ALK and ROS1 gene rearrangements).
a. If participant’s tumor is known to have a predominantly squamous histology,
molecular testing for EGFR mutation and ALK and ROS1 translocations will not
be required, as this is not part of current diagnostic guidelines.

Subject who had disease progression >6 months after completing adjuvant 
therapy for stage I-IIIA disease are eligible, as long as no systemic therapy was 
given for the recurrent disease.
4. Have the presence of at least one measurable lesion by CT or MRI per RECIST 1.1 
criteria as determined by the local site investigator/radiology assessment.
Note: Tumor lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.  
5. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group
(ECOG) Performance Status (Section 12.2).
6. Have an anticipated life expectancy of at least 3 months.
7. Have laboratory and medical history parameters within Protocol-defined range. The 
screening laboratory tests below must be ≤10 days before treatment initiation.
a.
Absolute neutrophil count ≥ 1,500/mcL (without supportive care)
b. Platelets ≥ 100,000/mcL
c.
Hemoglobin ≥9 g/dL or ≥5.6 mmol/L (without transfusions)
d. Serum creatinine ≤ 1.5 × institutional upper limit of normal (ULN) OR 
measured or calculated creatinine clearance (glomerular filtration rate can also 
be used in place of creatinine or CrCl) ≥ 50 mL/min for subjects with 
creatinine levels > 1.5 × institutional ULN.
e.
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin 
levels >1.5 × ULN. If there is no institutional ULN, then direct bilirubin must 
be <40% of total bilirubin to be eligible. Note: In no case can the total 
bilirubin exceed 3 x ULN.
f.
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 
× ULN.
g. International normalized ratio (INR) or prothrombin time (PT) and Activated 
partial thromboplastin time (aPTT) ≤1.5 × ULN unless subject is receiving 
anticoagulant therapy as long as PT or aPTT is within therapeutic range of 
intended use of anticoagulants.
8. In Part A, Have provided tissue for PD-L1/IDO1 expression evaluation from an 
archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion 
not previously irradiated.  
 
 
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Note: Subjects will be eligible to participate regardless of the level of PD-L1/IDO1
expression.
Note: Submit an evaluable sample for analysis.  If submitting unstained cut slides, 
freshly cut slides should be submitted to the testing laboratory within 14 days from 
when the slides are cut.  See Section 7.1.2.9 in protocol for an explanation.
Note: In Part B, the submission of tissue for PD-L1/IDO1 expression evaluation is 
optional.
9. Female subjects of childbearing potential* must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required
*Subjects of child bearing potential are those who have not been surgically sterilized 
or have not been free from menses for > 1 year.
10. Female subjects of childbearing potential* must be willing to take appropriate 
precautions to avoid becoming pregnant as outlined in Section 5.7.2 – Contraception, 
for the course of the study through 120 days after the last dose of study medication.
11. Male subjects of childbearing potential must agree to take appropriate precautions to 
avoid fathering a child as outlined in Section 5.7.2 Contraception, starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.
5.1.3
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) agents (including 
ipilimumab or any other antibody/drug specifically targeting T-cell co-stimulation or 
checkpoint pathways), or IDO1 inhibitor.
2. Is currently participating or has participated in a study with an investigational 
compound or device within 4 weeks, or 5X half-life of the investigational compound, 
whichever is longer, of initial dosing on this study.
3. In Part A, Has had chemotherapy, targeted small molecule therapy, radiotherapy, 
major surgery, or biological cancer therapy (including monoclonal antibodies) within 
4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to the first dose of trial 
treatment, or who has not recovered (≤ Grade 1 or baseline) from adverse events due 
to a previously administered.  
Note: Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this 
criterion and may qualify for the study.
Note: If subject received major surgery or radiation therapy of > 30 Gy, they must 
have recovered from the toxicity and/or complications from the intervention prior to 
starting therapy.
Note: Subject who received denosumab can be included at the discretion of the 
Investigator.
 
 
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4. In Part B, Has received radiotherapy within 7 days of the first dose of trial treatment 
or radiation therapy to the lung that is > 30 Gy within 6 months of the first dose of 
trial treatment.
5. Is expected to require any other form of systemic or localized anti-neoplastic therapy 
while in study.
6. Has known active central nervous system (CNS) mets and/or carcinomatous 
meningitis.  
Note: Subjects with previously treated brain metastases and clinically stable CNS 
mets are allowed to participate (clinically stabile is defined as a period (at least 4 
weeks prior to the first dose of trial treatment) in which (1) there is no evidence of 
new or enlarging CNS mets by MRI, (2) the subject is off steroids for CNS mets at 
least two weeks prior to the first dose of trial treatment, and (3) any neurologic 
symptoms have returned to baseline).
7. Patient has symptomatic ascites or pleural effusion.  
Note: A patient who is clinically stable following treatment for these conditions is 
eligible.
8. Has an active autoimmune disease that has required systemic treatment (i.e. with use 
of disease modifying agents, corticosteroids or immunosuppressive drugs).
Note: Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.
9. Is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone 
equivalent) or any other form of immunosuppressive therapy within 1 week prior to 
the first dose of trial treatment.
10. Has an active infection requiring systemic therapy.
11. Has history of (non-infectious) pneumonitis that required systemic steroids or current 
pneumonitis/interstitial lung disease.
12. Has received a live vaccine within 4 weeks prior to the first dose of trial treatment 
(refer to Section 5.5.3 for further details).
13. Has a known hypersensitivity to the components of the trial treatment or another 
monoclonal antibody.
14. In Part B, has a known sensitivity to any component of cisplatin, carboplatin, 
paclitaxel or pemetrexed.
15. In Part B, is on chronic systemic steroids. Patients with asthma that require 
intermittent use of bronchodilators, inhaled steroids, or local steroid injections would 
not be excluded from the study.
16. In Part B cohort 1 and 2, is unable to interrupt aspirin or other nonsteroidal anti-
inflammatory drugs (NSAIDs), other than an aspirin dose ≤ 1.3 g per day, for a 5-day 
period (8-day period for long-acting agents, such as piroxicam).
 
 
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17. In Part B cohort 1 and 2, is unable or unwilling to take folic acid or vitamin B12 
supplementation.
18. Is known to be Human Immunodeficiency Virus (HIV)-positive (HIV 1/2 antibodies).
19. 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.
a.
HBV DNA must be undetectable and HBsAg negative at screening visit.
b. 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.
c.
Participants who have had definitive treatment for HCV are permitted if HCV 
RNA is undetectable at screening.
20. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
21. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the screening visit (Visit 1) through 120 
days after the last dose of trial treatment.
Subjects who stop breast-feeding prior to initiation of trial treatment and not 
expecting to resume of breast-feeding will not be excluded from the study.
22. Has received monoamine oxidase inhibitors (MAOIs) within the 3 weeks before the 
first dose of trial treatment. 
23. Anticipates receiving any melatonin supplement, any UGT1A9 inhibitor, or any of 
the prohibited medications during the current trial (refer to Section 5.5.3 for further 
details).
24. Has any history of Serotonin Syndrome after receiving serotonergic drugs.
25. Has presence of a gastrointestinal condition that may affect drug absorption.
26. Has a history or presence of an abnormal electrocardiogram (ECG) that, in the 
investigator's opinion, is clinically meaningful.  
Note: Screening QTc interval ≥480 msec is excluded (corrected by Fredericia or 
Bazett formula).  In the event that a single QTc is ≥480 milliseconds, the subject may 
enroll if the average QTc for the 3 ECGs is < 480 milliseconds. 
27. Has a history or current evidence of any condition, therapy, or lab abnormality that 
might confound the results of the study, interfere with the subject’s participation for 
the full duration of the study, or is not in the best interest of the subject to participate, 
in the opinion of the treating Investigator.
5.2
Trial Treatment(s)
The treatments to be used in this trial are outlined below in Table 1.
 
 
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Table 1
Trial Treatments
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment Period
Use
Part A
INCB024360
100 mg
BID
Oral
Daily of each cycle‡
for up to 35 times of 
administered MK-3475 
(approximately 2 years)
Experimental
MK-3475
200 mg
Every 3 
weeks 
(Q3W)
IV infusion
Cohort 1: Day 8 of Cycle 1 
and Day 1 of each 
subsequent cycle
Cohort 2: Day 1 of each 
cycle  
for up to 35 infusions 
(approximately 2 years)
Experimental
Part B*
MK-3475
200 mg
Q3W
IV infusion
Day 1 of each cycle ‡
for up to 35 infusions 
(approximately 2 years)
Experimental
Cisplatin
75 mg/m2
Q3W
IV infusion†
Day 1 of each cycle
Up to 4 cycle
combination 
therapy
Pemetrexed
500 mg/m2
Q3W
IV infusion†
Day 1 of each cycle
combination 
therapy
Carboplatin
(Cohort 2)
AUC 5
Q3W
IV infusion†
Day 1 of each cycle
Up to 4 cycle
combination 
therapy
(Cohort 3)
AUC 6
Paclitaxel
200 mg/m2
Q3W
IV infusion†
Day 1 of each cycle
Up to 4 cycle
combination 
therapy
Note: please see the allowed dose modification in Table 5.
* In Part B, chemotherapy will be administered for 4 cycles. Pemetrexed may continue as maintenance therapy 
after these 4 cycles until disease progression.
† Infusion of combination regimens and pre-medications will follow local institutional practice.
‡ Pembrolizumab to be administered prior to chemotherapy.
Trial treatment should begin on the day of allocation or as close as possible to the date on the 
day of allocation.
MK-3475 and INCB024360 indicated in Table 1 will be provided by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
5.2.1
Dose Selection/Modification
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  There are no specific calculations or evaluations required to be 
performed in order to administer the proper dose to each subject.
 
 
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5.2.1.2
Dose Modification (Escalation/Titration/Other)
5.2.1.2.1 Tolerability Evaluation Rules
NOTE: The DLT evaluation of INCB024360 in combination with MK-3475 (Part A) and 
INCB024360 and MK-3475 in combination with chemotherapy (Part B) were conducted 
according to the following as of Amendment 01. As of Amendment 02, INCB024360 is 
stopped from Part B.
Part A
DLTs observed during the DLT evaluation period [the initial 7-day (cohort 1) or 21-day
(cohort 2) of Cycle 1] will be used to determine escalation to the next dose level and the 
tolerability of the dose level using a modified Toxicity Probability Interval (TPI) method [1] 
design (Target Toxicity Rate = approximately 16.7%).  The dose escalation/tolerability 
evaluation rules are as follows:
mTPI method:  

An initial cohort of 3 subjects is enrolled.
o
If 0/3 subjects develops a DLT, the dose level will be considered to be lower than 
tolerated dose, and escalation to the next dose will occur (do not escalate from 
Dose Level 2).
o
If 1/3 subjects develops a DLT, another 3 subjects will be enrolled at this dose 
level.

If 0 of the 3 new subjects develops a DLT (for a total of 1/6 subjects with 
a DLT at this dose level), the dose level will be considered to be tolerated 
dose.

If 1 of the 3 new subjects develops a DLT (for a total of 2/6 subjects with 
a DLT at this dose level), another 3 subjects will be enrolled at this dose 
level.

If ≤1 of the 3 new subjects develops a DLT (for a total of ≤3/9 
subjects with a DLT at this dose level), the dose level will be 
considered to be tolerated dose.

If ≥2 of the 3 new subjects develop DLTs (for a total of ≥4/9 
subjects with a DLT at this dose level), the dose level will be 
determined as not-tolerated, and de-escalate to the next lower dose 
unless the next lower dose level treated 9 subjects (do not de-
escalate from Dose Level 1).

If ≥2 of the 3 new subjects develop DLTs (for a total of ≥3/6 subjects with 
a DLT at this dose level), the dose level will be determined as not-
tolerated, and de-escalate to the next lower dose unless the next lower 
dose level treated 9 subjects (do not de-escalate from Dose Level 1).
 
 
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o
If ≥2/3 subjects develop DLTs, the dose level will be determined as not-tolerated, 
and de-escalate to the next lower dose unless the next lower dose level treated 9 
subjects (do not de-escalate from Dose Level 1).
Table 2
Dose Evaluation Rules in Part A
Number of subjects treated at current dose
3
6
9
Number of
toxicities
0
E
E
E
1
S
S
S
2
DU
S
S
3
DU
DU
S
4
DU
DU
5
DU
DU
6
DU
DU
E = Evaluable
S= Stay at the same dose
DU = The current dose is unacceptably toxic, no more patients to be treated at this dose
Additional subjects will be enrolled in a cohort to achieve the minimum of 3 evaluable 
subjects if dropouts or dose interruptions or reductions occur that result in a subject being 
non-evaluable for DLTs.  When the tolerability of INCB024360 25 mg BID and/or 100 mg 
BID in combination with MK-3475 200 mg Q3W has been identified, additional subjects will 
be enrolled unless the number of tolerability identified Dose Level is less than 6 subjects.  
Subjects will continue on the initial dose provided during Cycle 1 through all subsequent 
cycles even if it is lower than the tolerated dose.  The Sponsor will decide dose escalation 
considering all the safety information including adverse events occurred in a subject being 
non-evaluable for DLTs. 
During the study, dose interruptions and/or dose decreases may be implemented based on 
toxicity as described in Section 5.2.1.2.3.  However, dose adjustments should not be made 
during the DLT observation period without discussion with the Sponsor. Intra-subject dose 
escalation is not permitted.
Part B
DLTs observed during the DLT evaluation period (21-day of Cycle 1) will be used to 
determine the tolerability of the dose level using Toxicity Profile Interval (TPI) [1] design 
(Target Toxicity Rate = approximately 30.0%).  The tolerability evaluation rules are as 
follows:

6 subjects are enrolled into each cohort based on TPI design in the combination regimen; 
(respectively parallel enrollment is allowed).
o
If 0/3 ≤2/6 subjects develop a DLT at the combination regimen, then it is 
considered to be tolerated.
o
If ≥3/6 subjects develop a DLT, the regimen will be considered to be not tolerated.
 
 
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Table 3
Dose Evaluation Rules in Part B
Number of subjects treated at 
current dose
3
6
Number of
toxicities
0
E
E
1
S
E
2
D
S
3
DU
D
4
DU
5
DU
6
DU
E = Evaluable
S= Stay at the same dose
D=De-escalate to the previous lower dose
DU = The current dose is unacceptably toxic, no more patients to 
be treated at this dose
The subject that cannot be treated with more than 90% of prescribed dosage for MK-3475
and/or chemotherapy by reason of other than DLT toxicity will be removed from the subjects
of DLT evaluation and then add the additional subjects in this cohort.
5.2.1.2.2 Definition of Dose Limiting Toxicity (DLT)
Observed DLTs for treatment period in Cycle 1 will be used for dose finding.  Subjects will 
be hospitalized and monitored for the development of DLTs during Cycle 1.  Toxicities will 
be graded in severity according to the guidelines outlined in the NCI-CTCAE version 4.0.
A DLT will be defined as the occurrence of any treatment-emergent AE in Table 4 occurring 
up to and including Study Day 7 (1-week observation period: Part A cohort 1) or Day 21 (3-
week observation period: Part A cohort 2 and Part B).  Only toxicities with a clear alternative 
explanation (eg, due to disease progression) or transient (≤72 hours), abnormal laboratory 
values without associated clinically significant signs or symptoms based on investigator 
determination can be deemed a non-DLT.
 
 
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Table 4
Criteria for Defining Dose-Limiting Toxicities (DLTs)
Hematologic Toxicities:
Part A

Any Grade 4 thrombocytopenia

Any Grade 4 neutropenia lasting > 1 week

Febrile neutropenia (irrespective of the duration)
Part B 

Any Grade 4 thrombocytopenia

Any Grade 4 neutropenia lasting > 7 days using appropriate supportive treatment

Febrile neutropenia (irrespective of the duration) if the event is considered as clinically 
significant for the patient deemed by investigator and sponsor.
Non-Hematologic Toxicities:

Any Grade 4 toxicity

Any Grade 3 laboratory abnormality lasting > 1 week

Any other Grade 3 toxicity EXCLUDING:

Nausea or vomiting controlled by medical intervention within 72 hours

Rash in the absence of desquamation, no mucosal involvement, does not require 
systemic steroids, and resolves to Grade 1 by the next scheduled dose of MK-3475 or 
14 days, whichever is longer, or not resulting in missing a MK-3475 dose or 
INCB024360 doses for 7 days

Episcleritis, uveitis, or iritis of Grade 2 or higher
General：

If subjects are unable to receive 75% of INCB024360 during the DLT observation period 
because of toxicity, even if the toxicity does not meet DLT criteria defined above (Part A 
cohort 1).

If subjects are unable to receive 75% of INCB024360 or 1 dose of MK-3475 during the 
DLT observation period because of toxicity, even if the toxicity does not meet DLT criteria 
defined above (Part A cohort 2 and Part B).

Greater than 2 week delay in initiating cycle 2 due to toxicity
The SPONSOR and the principal investigator will decide the appropriateness of the DLT,
and enrollment of additional patients in consultation with the Data and Safety Monitoring
Committee as needed.
5.2.1.2.3 Guideline for Dose Modification
NOTE: As of Amendment 02, INCB024360 is stopped from Part B.
Dose modification and toxicity management for immune-related AEs (irAEs) associated with
pembrolizumab and/or epacadostat should be managed as follows.
Adverse events (both non-serious and serious) associated with MK-3475 and INCB024360
exposure may represent an immunologic etiology.  These irAEs may occur shortly after the 
first dose or several months after the last dose of treatment and may affect more than one 
body system simultaneously. Therefore, early recognition and initiation of treatment is
critical to reduce complications. Based on existing clinical study data, most irAEs were
 
 
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reversible and could be managed with interruptions of MK-3475, administration of
corticosteroids, and/or other supportive care. For suspected irAEs, ensure adequate 
evaluation to confirm etiology or exclude other causes. Additional procedures or tests such as 
bronchoscopy, endoscopy, or skin biopsy may be included as part of the evaluation. Based on 
the severity of irAEs, withhold or permanently discontinue MK-3475 and INCB024360 and 
administer corticosteroids.
Table 5 summarizes the irAE dose modification actions for MK-3475 and INCB024360. Of 
note, participants who require dose reduction of INCB024360 due to AEs will remain at the 
lower dose, summarized in Table 6. Re-escalation of INCB024360 is not permitted.
In cases where MK-3475 dosing is held, dosing for INCB024360 must also be held until 
MK-3475 may resume. Participants are allowed, however, to receive MK-3475 monotherapy 
at the Investigator’s discretion upon improvement of the irAE to Grade 0 or 1 (eg, if the 
toxicity was considered related to the combination therapy and not MK-3475 monotherapy), 
unless discontinuation of both study treatments is specified in Table 5.
Except in cases of emergency, it is recommended that the Investigator consult with the 
medical monitor (or other representative of MSD) before temporarily interrupting therapy for 
reasons other than protocol-mandated medication hold.
 
 
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Table 5
Dose Modification Guidelines for Drug-Related Adverse Events for MK-3475 and INCB024360 
Immune-related 
AEs
Toxicity Grade 
or Conditions 
(CTCAEv4.0)
Study Medication
Action Taken with Study 
Medication
irAE Management with 
Corticosteroid and/or 
Other Therapies
Monitor and Follow-up
Pneumonitis 
Grade 2
Pembrolizumab
Withhold until Grade 0-1 
Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone 
or 
equivalent) 
followed 
by taper

Monitor participants for signs
and symptoms of pneumonitis

Evaluate 
participants 
with 
suspected 
pneumonitis 
with 
radiographic 
imaging 
and 
initiate corticosteroid treatment

Add prophylactic antibiotics for 
opportunistic infections
Epacadostat
Withhold until Grade 0-1
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.
Grade 3 or 4, or 
recurrent grade 2
Pembrolizumab
Permanently discontinue
Epacadostat
Permanently discontinue
Diarrhea / colitis 
Grade 2 or 3
Pembrolizumab
Withhold until Grade 0-1

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone 
or 
equivalent) 
followed 
by taper

Monitor participants for signs 
and symptoms of enterocolitis 
(ie, diarrhea, abdominal pain, 
blood or mucus in stool with or 
without fever) and of bowel 
perforation (ie, peritoneal signs 
and ileus).

Participants 
with ≥Grade 2 
diarrhea 
suspecting 
colitis 
should consider GI consultation 
and performing endoscopy to 
rule out colitis. 

Participants with diarrhea/colitis 
should be advised to drink 
liberal quantities of clear fluids. 
If sufficient oral fluid intake is 
not 
feasible, 
fluid 
and 
electrolytes 
should 
be 
substituted via IV infusion.
Epacadostat
Withhold until Grade 0-1
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.
Grade 4
Pembrolizumab
Permanently discontinue
Epacadostat
Permanently discontinue
 
 
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Immune-related 
AEs
Toxicity Grade 
or Conditions 
(CTCAEv4.0)
Study Medication
Action Taken with Study 
Medication
irAE Management with 
Corticosteroid and/or 
Other Therapies
Monitor and Follow-up
AST
/
ALT 
Elevation 
or 
Increased 
Bilirubin
Grade 2
Pembrolizumab
Withhold until Grade 0-1

Administer 
corticosteroids (initial 
dose of 0.5-1 mg/kg 
prednisone 
or 
equivalent) 
followed 
by taper

Monitor with liver function tests 
(consider 
weekly 
or 
more 
frequently until liver enzyme 
value returns to baseline or is 
stable
Epacadostat
Withhold until Grade 0-1
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.
Grade 3 or 4 
Pembrolizumab
Permanently discontinue

Administer
corticosteroids (initial 
dose of
1-2 mg/kg 
prednisone
or 
equivalent) 
followed 
by taper
Epacadostat
Permanently discontinue
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemiaa
Newly
onset 
T1DM or 
Grade 3
or 4 
hyperglycemia 
associated 
with 
evidence of -cell 
failure
Pembrolizumab
Withhold until Grade 0-1

Initiate 
insulin
replacement 
therapy 
for participants
with 
T1DM 

Administer 
anti-
hyperglycemic 
in 
participants
with 
hyperglycemia 

Monitor 
participants
for 
hyperglycemia or other signs 
and symptoms of diabetes.
Epacadostat
Withhold until Grade 0-1
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.
 
 
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Immune-related 
AEs
Toxicity Grade 
or Conditions 
(CTCAEv4.0)
Study Medication
Action Taken with Study 
Medication
irAE Management with 
Corticosteroid and/or 
Other Therapies
Monitor and Follow-up
Hypophysitis
Grade 2
Pembrolizumab
Withhold until Grade 0-1

Administer
corticosteroids 
and 
initiate 
hormonal 
replacements
as 
clinically indicated. 

Monitor 
for 
signs 
and 
symptoms 
of 
hypophysitis 
(including hypopituitarism and 
adrenal insufficiency)
Epacadostat
Withhold until Grade 0-1
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.
Grade 3 or 4 
Pembrolizumab
Withhold until Grade 0- 1 
or 
permanently 
discontinueb
Epacadostat
Withhold until Grade 0- 1 
or 
permanently 
discontinueb
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.
Hyperthyroidisma
Grade 2
Pembrolizumab
Continue

Treat 
with 
non-
selective beta-blockers 
(eg, propranolol)
or 
thionamides 
as 
appropriate 

Monitor 
for 
signs 
and 
symptoms of thyroid disorders. 
Epacadostat
Continue
Grade 3 or 4 
Pembrolizumab
Withhold until Grade 0- 1 
or 
permanently 
discontinueb
Epacadostat
Withhold until Grade 0- 1 
or 
permanently 
discontinueb
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.
 
 
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Immune-related 
AEs
Toxicity Grade 
or Conditions 
(CTCAEv4.0)
Study Medication
Action Taken with Study 
Medication
irAE Management with 
Corticosteroid and/or 
Other Therapies
Monitor and Follow-up
Hypothyroidisma
Grade 2-4
Pembrolizumab
Continue

Initiate 
thyroid 
replacement hormones 
(eg, levothyroxine or 
liothyroinine) 
per 
standard of care

Monitor 
for
signs 
and 
symptoms of thyroid disorders.
Epacadostat
Continue
Nephritis 
and 
Renal 
Dysfunction
Grade 2
Pembrolizumab
Withhold until Grade 0- 1

Administer
corticosteroids
(prednisone 1-2 mg/kg
or 
equivalent) 
followed by taper.

Monitor 
changes 
of 
renal 
function
Epacadostat
Withhold until Grade 0-1
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.
Grade 3 or 4 
Pembrolizumab
Permanently discontinue
Epacadostat
Permanently discontinue
Myocarditis
Grade 1 or 2
Pembrolizumab
Withhold

Based on severity of 
AE 
administer 
corticosteroids
•
Ensure adequate evaluation to 
confirm 
etiology 
and/or 
exclude other causes
Epacadostat
Withhold until Grade 0
Once resolved to Grade 0, 
may restart:
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.
Grade 3 or 4
Pembrolizumab
Permanently discontinue
Epacadostat
Permanently discontinue
 
 
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Immune-related 
AEs
Toxicity Grade 
or Conditions 
(CTCAEv4.0)
Study Medication
Action Taken with Study 
Medication
irAE Management with 
Corticosteroid and/or 
Other Therapies
Monitor and Follow-up
Rash
1 or 2
Pembrolizumab
Continue

Manage with topical 
steroids 
with 
or 
without 
drug 
interruption.
Epacadostat
Continue
3 c
Pembrolizumab
Withhold until Grade 0-1

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone 
or 
equivalent) 
followed 
by taper.

If toxicity does not resolve 
within 12 weeks of last dose, or 
cannot taper below 10 mg or 
less of prednisone or equivalent 
within 
12 
weeks, 
must 
permanently discontinue.

Restart epacadostat at same 
dose if rash is mild and assessed 
as Grade 3 based only on body 
surface 
area 
and 
resolves 
without oral steroids. If oral 
steroids are required, or rash is 
severe, decrease by 1 dose level 
once resolved to Grade 0-1.
Epacadostat
Withhold until Grade 0-1
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.
4
Pembrolizumab
Permanently discontinue

Administer 
corticosteroids (initial 
dose of 1-2 mg/kg 
prednisone 
or 
equivalent) 
followed 
by taper.
Epacadostat
Permanently discontinue
 
 
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Immune-related 
AEs
Toxicity Grade 
or Conditions 
(CTCAEv4.0)
Study Medication
Action Taken with Study 
Medication
irAE Management with 
Corticosteroid and/or 
Other Therapies
Monitor and Follow-up
Asymptomatic 
d
Amylase 
or 
Lipase Increased
3
Pembrolizumab
May continue treatment 
with 
medical 
monitor 
approval

Permanently 
discontinue 
if 
clinical signs and symptoms of 
pancreatitis develop (abdominal 
pain, nausea, vomiting).

If toxicity does not resolve 
within 12 weeks of last dose 
after 
an 
interruption, 
must 
permanently discontinue unless 
approved 
by 
the 
medical 
monitor to continue.

If 
Grade 
4 
lipase/amylase 
elevation is asymptomatic and 
abdominal imaging suggests no 
pathology, 
study 
drug 
administration 
dosing 
may 
continue with medical monitor 
approval.
Epacadostat
May continue treatment 
with 
medical 
monitor 
approval
4
Pembrolizumab
Withhold 
until 
toxicity 
resolves to Grade 0-1
Epacadostat
Withhold 
until
toxicity 
resolves to Grade 0-1
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.
 
 
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Immune-related 
AEs
Toxicity Grade 
or Conditions 
(CTCAEv4.0)
Study Medication
Action Taken with Study 
Medication
irAE Management with 
Corticosteroid and/or 
Other Therapies
Monitor and Follow-up
All 
Other 
Immune-related 
AEs
Intolerable/ 
persistent Grade 
2
Pembrolizumab
Withhold until Grade 0- 1

Based on severity of 
AE 
administer
corticosteroids

Ensure adequate evaluation to 
confirm etiology or exclude 
other causes
Epacadostat
Withhold until Grade 0-1
Once resolved to Grade 
0-1, may restart:
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.
Grade 3,
Pembrolizumab
Withhold until Grade 0-1, 
or discontinue based on the 
type of event.  Events that 
require 
discontinuation 
include and not limited to: 
Guillain-Barre Syndrome, 
encephalitis
Epacadostat
Withhold until Grade 0-1
Once resolved to Grade 0-
1, may restart:
Related: Reduce by 1 dose 
level.
Not Related: Same dose 
level.  
Events 
that 
require 
discontinuation 
include 
and 
not 
limited 
to:  
Guillain-Barre 
Syndrome 
encephalitis
Grade 
4 
or 
recurrent Grade 3 
Pembrolizumab
Permanently discontinue
Epacadostat
Permanently discontinue
 
 
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Immune-related 
AEs
Toxicity Grade 
or Conditions 
(CTCAEv4.0)
Study Medication
Action Taken with Study 
Medication
irAE Management with 
Corticosteroid and/or 
Other Therapies
Monitor and Follow-up
General Instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab and epacadostat have been withheld, pembrolizumab and epacadostat can be resumed after AE has been reduced to 
Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab and epacadostat should be permanently discontinued if AE does not resolve within 12 
weeks of last dose or corticosteroids cannot be reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be
initiated if irAEs cannot be controlled by corticosteroids.
4.
If the same AE that required epacadostat dose reductions to dose level -2 re-occurs, regardless of the causality to epacadostat, epacadostat should be 
discontinued.  If a participant who is being treated at dose level -2 has a different AE that is considered unrelated to epacadostat by the Investigator, the 
participant may resume study treatment at dose level -2 after discussion with MSD Clinical Director.
NOTES: 
a.
For participants with Grade 3 or 4 immune-related endocrinopathy where withholding of pembrolizumab and epacadostat is required, pembrolizumab 
and epacadostat may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in
case of T1DM)
b.
Withhold OR permanently discontinue pembrolizumab + epacadostat at the discretion of the investigator
c.
Participants with Grade 3 rash in the absence of desquamation, no mucosal involvement, does not require systemic steroids, and resolves to Grade 1 
within 14 days does not have to hold study medication
d.
If Grade 4 lipase/amylase elevation is asymptomatic and abdominal imaging suggests no pathology, study drug administration dosing may continue 
(with or without dose reduction) with medical monitor approval.
AE=adverse events; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
GI=gastrointestinal; IV=intravenous; irAE=immune-related adverse events; T1DM= Type 1 diabetes mellitus.
 
 
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Table 6
Dose Level Adjustments of INCB024360
Chemotherapy
In Part B, Dose modification of cytotoxic chemotherapy will conform to the site’s standards 
procedures. Dose modification of chemotherapy will not be permitted in DLT evaluation 
period.
Reduction of one chemotherapy agent and not the other agent is appropriate if, in the opinion 
of the Investigator, the toxicity is clearly related to one of the treatments. If, in the opinion of 
the Investigator, the toxicity is related to the combination of both chemotherapy agents, both 
drugs should be reduced according to recommended dose modifications. Subjects may have 
chemotherapy discontinued and continue on pembrolizumab. Similarly subjects may 
discontinue pembrolizumab and continue on chemotherapy if appropriate. Chemotherapy 
may be reduced, interrupted, or discontinued at the Investigator’s discretion per the approved 
product labels and local regulations.
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be 
used to grade the severity of adverse events. All dose modifications should be based on the 
AE requiring the greatest dose modification.
5.2.1.2.4 Infusion Reaction Dose Modifications
Pembrolizumab may cause severe or life threatening infusion-reactions, including severe
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after
drug infusion and generally resolve completely within 24 hours of completion of infusion.  
Dose modification and toxicity management guidelines on pembrolizumab-associated
infusion reaction are provided in Table 7.
Dose of INCB024360 
Dose Level -1
Dose Level -2
First Reduction of 
INCB024360
Second Reduction of 
INCB024360
25 mg BID
Discontinue treatment
―
100 mg BID
50 mg BID
25 mg BID
 
 
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Table 7
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
Grade 1
Mild 
reaction; 
infusion 
interruption 
not 
indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires infusion interruption 
but 
responds 
promptly 
to 
symptomatic 
treatment 
(e.g., 
antihistamines, 
NSAIDS, 
narcotics, 
IV 
fluids); 
prophylactic 
medications 
indicated for < =24 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original 
infusion rate (e.g., from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held 
until symptoms resolve and the subject 
should be premedicated for the next 
scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration.
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of MK-3475 with:
Diphenhydramine 50 mg po 
(or 
equivalent 
dose 
of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic).
Grades 3 or 4
Grade 3:
Prolonged 
(i.e., 
not 
rapidly 
responsive 
to 
symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence 
of 
symptoms 
following initial improvement; 
hospitalization 
indicated 
for 
other clinical sequelae (e.g., 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor 
or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued 
from 
further 
trial 
treatment 
administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration.
 
 
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5.2.1.2.5 Procedures for Subjects Exhibiting Serotonin Syndrome (SS)
NOTE: As of Amendment 02, this section has been updated to reflect the removal of
INCB024360 from Part B and updated information regarding the risks of SS with the use of 
INCB024360. 
There is a rare chance that INCB024360 could cause an increase in serotonin levels in the 
brain that might trigger Serotonin Syndrome (SS) [49], (Section 12.5) when administered in 
combination with other serotonergic agents.  Selective serotonin reuptake inhibitors (SSRIs) 
and selective serotonin/norepinephrine reuptake inhibitors (SNRIs), and MAOIs are 
permitted in the study. Due to the results of a preclinical study specifically evaluating the
effect of epacadostat on the brain ECF concentrations of serotonin with linezolid, and the 
clinical experience with related medications (eg, SSRIs/SNRIs) that suggest that SS is low 
risk, the use of MAOIs is not prohibited in the current study.
The following procedures will be implemented if subjects exhibit the signs/symptoms of SS 
described in Table 8, including tremor; hyperreflexia; spontaneous, ocular, or inducible 
clonus; together with agitation, fever, diaphoresis, or muscle rigidity:

Immediately interrupt INCB024360 administration.  Administration of MK-3475 may 
continue.

Immediately interrupt any SSRI, SNRI or MAOI administration.

Provide appropriate medical management of the subject until all signs/symptoms are 
resolved (e.g., IV fluids and/or sympathomimetic amines for hypotension,
benzodiazepines for agitation, administration of 5-hydroxytryptamine antagonists 
such as cyproheptadine).

If subject chooses to withdraw from the study, or must restart treatment with SSRI,
SNRI or MAOI, the subject should be scheduled for a follow-up visit.  Treatment 
with SSRI, SNRI or MAOI may be initiated 2 weeks after resolution of signs and 
symptoms of SS.
 
 
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Table 8
Sign and Symptoms of Serotonin Syndrome
Seriousness
Autonomic signs
Neurological signs
Mental status
Other
Mild
Afebrile
or
low-
grade fever
Tachycardia
Mydriasis
Diaphoresis or shivering
Intermittent
tremor
Akathisia
Myoclonus
Mild hyperreflexia
Restlessness
Anxiety
Moderate
Increased
tachycardia
Fever (up to 41°C)
Diarrhea
with
hyperactive
bowel
sounds
Diaphoresis
with
normal skin color
Hyperreflexia
Inducible clonus
Ocular clonus (slow
continuous
lateral
eye movements)
Myoclonus
Easily startled
Increased
confusion
Agitation and
hypervigilance
Rhabdomyolysis
Metabolic
acidosis
Renal
failure
Disseminated
intravascular
coagulopathy
(secondary to
Severe
Temperature often more
than 41°C (Secondary
to increased tone)
Increased muscle tone
(lower limb > upper)
Spontaneous clonus
Substantial
myoclonus
or
hyperreflexia
Delirium
Coma
As above
Source: [Boyer EW, Shannon M. 2005]
5.2.2
Timing of Dose Administration
NOTE: As of Amendment 02, INCB024360 is stopped from Part B. This section has been 
updated accordingly.
MK-3475
Trial treatment with MK-3475 in cohort 1 should be administered on Day 8 of Cycle 1 (in 4-
week cycle) and on Day 1 of each subsequent cycle (in 3-week cycles) after all 
procedures/assessments have been completed as detailed in the Trial Flow Chart (Section 
6.0).  Trial treatment with MK-3475 in Part A cohort 2 and Part B should be administered on 
Day 1 of each cycle (in 3-week cycles). In subsequent cycles, all study treatments will be 
administered on an outpatient basis.  Trial treatment of MK-3475 may be administered up to 
3 days before or after the scheduled Day 1 of each cycle due to administrative reasons except 
for Cycle 1 Day 8 of cohort 1.
MK-3475 will be administered as a dose of 200 mg using a 30-minute IV infusion.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes -5 min/+10 min). 
The Procedures Manual contains specific instructions for MK-3475 dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
 
 
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INCB024360 (Part A)
Subjects will take their dose of INCB024360 in the morning and evening, approximately 12 
hours apart without regard to food.  Subjects will self-administer INCB024360 except on 
C1D1, C1D5, C1D12 and C2D5 of cohort 1 and C1D1, C1D5, and C2D5 of Part A cohort 2
and Part B, when the morning dose will be given at the study site clinic for PK sampling.  On 
days when INCB024360 is administered in the clinic, subjects will take INCB024360 and 
then begin infusion of MK-3475.
Chemotherapy (Part B)
Pre-medications will follow local institutional practice.
•
Cisplatin
Cisplatin 75mg/m2 should be infused approximately 30 minutes after the pemetrexed 
infusion for the first 4 cycles and administered according to local practice and labels.
•
Pemetrexed
Pemetrexed 500 mg/m2 will be administered as an IV infusion over 10 minutes Q3W until 
progression or unacceptable toxicity. All subjects should receive the appropriate 
supplementation of vitamin B12 and folic acid and corticosteroid prophylaxis as listed below 
(or as per local label):

Folic Acid 350-1000 μg oral: at least 5 doses of folic acid must be taken during the 7 
days preceding the first dose of pemetrexed, and folic acid dosing must continue during 
the full course of therapy and for 21 days after the last dose of pemetrexed.

Vitamin B12 1000 μg IM injection in the week preceding the first dose of pemetrexed 
and once every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the 
same day as pemetrexed administration.

Dexamethasone prophylaxis 4 mg, orally twice per day (or equivalent). Taken the day 
before, day of, and day after pemetrexed administration. Higher or additional doses are 
permitted for antiemetic prophylaxis during cycles 1-4 but not to exceed doses in 
MASCC guidelines.
•
Carboplatin
Carboplatin AUC 5 or 6 will be administered as an IV infusion over 30-60 minutes on day 1 
of every three week cycle following paclitaxel or pemetrexed infusions, for a maximum of 4 
administrations. 
The dose of carboplatin will be calculated using the Calvert Formula. Carboplatin AUC 5 
and 6 do not to exceed 750mg and 900 mg.
Calvert Formula
Total Dose (mg) = (target AUC) x (CrCl + 25)
The estimated GFR used in the Calvert formula should not exceed 125 mL/min
Creatinine clearance should be calculated per institutional standard.
 
 
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•
Paclitaxel
Paclitaxel 200 mg/m2 will be administered as an IV infusion over 3 hours on day 1 of every 
three week cycle before carboplatin infusions, for a maximum of 4 administrations.
For additional details, refer to approved product labels for details regarding dose calculation, 
reconstitution, preparation of the infusion fluid, and administration for each of the standard 
of care chemotherapies.
5.2.3
Trial Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
5.3
Randomization or Treatment Allocation
Subjects participating in this trial will be allocated by non-random assignment.
5.4
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
5.5
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor.  
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the subject's primary physician.  However, the decision to continue the subject on trial 
therapy or vaccination schedule requires the mutual agreement of the investigator, the 
Sponsor and the subject.
5.5.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject's welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the eCRF, including all 
prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids.  If 
changes occur during the study period, documentation of drug dosage, frequency, route, and 
date may also be included on the eCRF (electronic Case Report Form).  If changes occur 
during the trial period, documentation of drug dosage, frequency, route, and date may also be 
included on the CRF.
All concomitant medications received within 4 weeks before the first dose of study treatment 
and 30 days after the last dose of study treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of study treatment should be 
recorded for AEs and SAEs as defined in Section 7.2.
5.5.2
Restricted Medications and Measures
NOTE: As of Amendment 02 and removal of INCB024360 from Part B, this section is
no longer applicable in Part B.
 
 
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Listed below are specific restrictions for concomitant therapy during the course of the trial:

Use of warfarin is discouraged.  Low-dose warfarin (1 mg) is acceptable; however, 
doses that increase the INR are discouraged and may require dose modification.  If an 
alternative to warfarin cannot be used, investigators should follow the guidelines in 
Table 9 and either closely monitor or closely monitor and reduce the subject's dose of 
warfarin upon initiating therapy with INCB024360.
Table 9
Warfarin Dose Adjustment Recommendation When Initiating Concurrent 
INCB024360 Treatment
Stable INR
INCB024360 Dose
≤ 100 mg BID
200 mg BID
INR ≤ 2.5
Close INR monitoring
Close INR monitoring
INR > 2.5
Close INR monitoring
Reduce warfarin by 20%-25% and
close INR monitoring
5.5.3
Prohibited Medications and Measures
NOTE: As of Amendment 02, this section is updated to reflect the removal of 
INCB024360 from Part B and current safety information for INCB024360.
Subjects are prohibited from receiving the following therapies during the screening and 
treatment phase (including retreatment for post-complete response relapse) of this study 
unless otherwise noted below:

Any investigational medication other than the trial treatment.

Any anticancer medications, including systemic chemotherapy or biologic therapy 
other than the study medications.

Any chronic immunological-suppressive treatment for any reason other than the 
management of adverse events, as described in Section 5.6.  
(NOTE:  Inhaled or topical steroids are allowed, and systemic steroids at doses 
≤10 mg/day prednisone or equivalents are allowed, as described in Section 5.6 and 
immune suppressants are allowed as prophylaxis for contrast allergy for imaging 
procedures.)

Radiation therapy or surgery
Note:  In the presence of a mixed response (some lesions improving or stable and 
other lesions progressing), radiation therapy or surgery to a symptomatic solitary 
lesion or to the brain is allowed. No MK-3475 infusions are permitted during 
radiation therapy or procedure and INCB024360 should be stopped the day treatment 
begins.  Trial treatment may be resumed as early as 1 week after treatment if the 
subject’s symptoms are improving and not requiring corticosteroids for management. 
If study medications are not resumed within 4 weeks of completing treatment, the 
subject should discontinue study treatment permanently.
 
 
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
Administration of a live attenuated vaccine within 4 weeks before the first dose of 
study treatment and while participating in the study.  Examples of live vaccines 
include, but are not limited to, the following:  measles, mumps, rubella, chicken pox, 
yellow fever, rabies, BCG, and typhoid vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed.

Any melatonin supplements. (Part A)

Melatonin receptor agonist (i.e. ramelteon) (Part A)

Any UGT1A9 inhibitor, including, but not limited to acitretin, amitriptyline, 
androsterone, cyclosporine, dasatinib, diclofenac, diflunisal, efavirenz, erlotinib,  
flutamide, gefitinib, gemfibrozil, glycyrrhetinic acid, glycyrrhizin, imatinib, 
imipramine, ketoconazole (systemic), linoleic acid supplements, mefenamic acid, 
mycophenolic acid, niflumic acid, nilotinib, phenobarbital, phenylbutazone, 
phenytoin, probenecid, propofol, quinidine, ritonavir, sorafenib, sulfinpyrazone, 
valproic acid, and verapamil. (Part A)
Note: Propofol, if administered for an on-study biopsy procedure, may be permitted. 
Administration of epacadostat on the morning of a procedure where propofol may be 
administered is permitted; however, the evening dose after the procedure should be 
held and participants may resume regular dosing the following day.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  
Subjects may receive other medications that the investigator deems to be medically necessary.
The exclusion criteria (Section 5.1.3) describe other medications that are prohibited during 
this study.  There are no prohibited therapies during the post-treatment follow-up phase.
5.6
Rescue Medications & Supportive Care
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator, including, but not limited to, the items outlined below.  Section 5.6.1 
outlines
supportive care guidelines for MK-3475
and INCB024360, respectively.  
Prophylactic medications are not allowed during Cycle 1.  However, treatment should be 
instituted for patients who develop these symptoms and pre-medication for additional cycles 
will be allowed:  
Systemic Corticosteroid Use
Systemic corticosteroids are permitted in the following situations:

To mitigate potential immune-related AEs as guided in Table 5.

As pre/post-medication to prevent AEs associated with chemotherapy or IV contrast.

Brief, limited use of systemic corticosteroids (≤7 days) are permitted where such use 
is considered SOC (eg, for COPD exacerbation).
o
Replacement doses of steroids (for example, prednisone 5 to 7.5 mg daily) are 
permitted while on study, as is the use of local steroids.
 
 
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Antiemetic Use
For participants receiving chemotherapy, antiemetic therapy should follow Multinational
Association of Supportive Care in Cancer (MASCC) or appropriate local guidelines and 
should, for the first 4 cycles, include a 5-HT3 receptor antagonist, dexamethasone (or 
equivalent), and aprepitant (or equivalent NK-1 receptor antagonist) as per the guideline 
followed.
Colony-Stimulating Factors
For participants receiving chemotherapy, the American Society of Clinical Oncology 
(ASCO) guidelines for use of colony-stimulating factors (CSFs), or local equivalent, should 
be used for patient management [55]. In Part B, G-CSF can be used in cycle 1 as an 
appropriate supportive treatment for neutropenia.
5.7
Diet/Activity/Other Considerations
5.7.1
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
5.7.2
Contraception
MK-3475 or INCB024360 may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if MK-3475 or INCB024360 has transient adverse effects on the composition of 
sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they are either: 
1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.); 
OR 
2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving trial treatment and for 120 days after 
the last dose of trial treatment by complying with use (or have their partner use) acceptable 
contraception during heterosexual activity 
 
 
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Acceptable methods of contraception are:
Single method (one of the following is acceptable):

intrauterine device (IUD)

vasectomy of a female subject’s male partner 
Combination method (requires use of two of the following):

diaphragm with spermicide

male condom

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill)
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. 
5.7.3
Pregnancy
If a subject inadvertently becomes pregnant while on treatment with MK-3475 and/or 
INCB024360, the subject will be immediately discontinued from treatment.  The site will 
contact the subject at least monthly and document the subject’s status until the pregnancy has 
been completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male subject impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 7.2.2.
5.7.4
Use in Nursing Women
It is unknown whether MK-3475 or INCB024360 is excreted in human milk.  Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions 
in the nursing infant, subjects who are breastfeeding are not eligible for enrollment.
Subjects who stop breast-feeding prior to initiation of trial treatment and not expecting to 
resume of breast-feeding will not be excluded from the study.
Refer to Package inserts for chemotherapy.
 
 
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5.8
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures are provided in Section 7.1.4 – Other 
Procedures.
In this trial, a subject may discontinue from treatment but continue in the study in the
follow-up, as long as the subject does not withdraw consent. Once a subject has 
discontinued treatment for CR or after receiving the maximum 35 infusions of MK-3475,
he/she may be eligible for retreatment if deemed medically appropriate and the subject 
meets the criteria, as outlined in Section 7.1.5.5.
A subject must be discontinued from the trial for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.

The subject is lost to follow-up.
A subject must be discontinued from treatment (but will continue to be monitored in the trial) 
for any of the following reasons:

Radiographic disease progression as assessed by the investigator per RECIST 1.1
(section 12.7. (exception if Sponsor approves treatment continuation).

Unacceptable adverse experiences as described in Section 7.2

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Non-compliance with trial treatment or procedure requirements

Administrative reasons

Completed 35 treatments with MK-3475
Note: 35 infusions (approximately. 2 years) of MK-3475 are calculated from the first 
infusion.  Subjects who stop MK-3475 after receiving 35 treatments may be eligible 
for retreatment if they progress after stopping study treatment provided they meet the 
requirements detailed in Section 7.1.5.5. For Part A, subjects who are already in 
second course as of Amendment 02 would be retreated in the Second Course Phase 
(Re-treatment) with up to 17 infusions (approximately 1 year) of MK-3475 additional 
trial treatments. New participants will not have re-treatment in Part A or Part B.
For Part A, epacadostat will be dosed BID every 12 hours (Q12H) during the treatment phase. 
Treatment may continue until the last day of the last cycle of pembrolizumab (eg, C35D21), 
unless a discontinuation criterion is met.
 
 
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The End of Treatment and Follow-up visit procedures are listed in Sections 7.1.5.3 and 
7.1.5.4.1 and the Trial Flow Chart - Section 6.0. After the end of treatment, each subject will 
be followed for a minimum of 90 days for adverse event monitoring. (Adverse events will be 
collected for up to 90 days after the end of treatment or 30 days after the end of treatment if 
the subject initiates new anticancer therapy as described in Section 7.2). 
5.8.1
Discontinuation of Study Therapy after CR
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR and have been treated for at least 8 cycles (at least 24 weeks) and had at least 2 cycles of 
the combination (2 doses of MK-3475 and at least 80% of the planned doses of 
INCB024360) beyond the date when the initial CR was declared. For Part A, subjects who 
are already in second course as of Amendment 02 would be eligible for up to 17 additional 
treatments (approximately 1 year) with MK-3475 and INCB 024360 (Second Course Phase: 
Re-treatment) at the discretion of the investigator. New participants will not have re-
treatment in Part A or Part B. Additional details are provided in Section 7.1.5.5.
5.9
Subject Replacement Strategy
If a subject discontinues from the trial, a replacement subject may be enrolled if deemed 
appropriate by the investigator and Sponsor.  The replacement subject will generally receive 
the same treatment or treatment sequence (as appropriate) as the subject being replaced. The 
replacement subject will be assigned a unique treatment/randomization number. The trial site 
should contact the Sponsor for the replacement subject’s treatment/randomization number.
5.10 Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
5.11 Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
 
 
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6.0 TRIAL FLOW CHART
6.1
Treatment Phase
6.1.1
Treatment Phase （Part A Cohort 1）
NOTE: As of Amendment 02, the final study visit will be the Safety Follow-up Visit and there will be no follow-up for survival 
status. For participants who were in Follow-up or Survival Follow-up, participation in the study is considered complete and no 
further visits are required. For those participants remaining in the study, procedures are simplified. The SoA has been 
amended and assessments no longer required have been deleted. Retreatment for new participants is no longer available.
Title Treatment: Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants who discontinue study 
treatment
for whatever reason will proceed 
directly to EOT and Safety Follow-
up.
Cycle 
(Week)
(-4)
1
(0)
2
(4)
3
(7) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
8 22)
12
28
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-1
-
-
+3
-
±3
At time of
Discon
30 (±7) days
Post Discon
Administrative Procedures
Informed Consent 4)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior/Concomitant Medication Review 5)
X
X -------------------------------------------------------------- X
X
X
Trial Treatment Administration
MK-3475 (Pembrolizumab) Administration
Q3W
X
X
X
X
INCB024360 (Epacadostat) Administration 
BID
X--------X
X----------------X
X--------X
X
Clinical Procedures/Assessments
Review Adverse Events 6)
X---------------------------------------------------------------------------------------------------- X
Full Physical Examination 7)
X
X
Directed Physical Examination 7)
X
X
X
X
Vital Signs, Height and Weight 8)
X
X
X
X
X
X
X
 
 
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Title Treatment: Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants who discontinue study 
treatment
for whatever reason will proceed 
directly to EOT and Safety Follow-
up.
Cycle 
(Week)
(-4)
1
(0)
2
(4)
3
(7) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
8 22)
12
28
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-1
-
-
+3
-
±3
At time of
Discon
30 (±7) days
Post Discon
12-Lead ECG 9)
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Arterial Blood Oxygen Saturation (SpO2)
Measurement 10)
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by local laboratory
Pregnancy Test (Urine or Serum β-HCG) 11)
X
Coagulation Parameters 12), 13), 14)
X
Hematology and Chemistry 13), 14)
X
X
X
X
X
X
Urinalysis 13), 14)
X
X
X
X
FT3, FT4 and TSH 13), 14)
X
X
X
X
KL-6, β-D glucan 14), 15)
X
Laboratory Procedures/Assessments: analysis performed by central laboratory
MK-3475 Pharmacokinetics 16)
X
X
X
Anti-MK-3475 Antibodies 16)
X
X
X
INCB024360 Pharmacokinetics 17)
X
X
X
X
INCB024360 Pharmacodynamics 17)
X
X
Blood for RNA Analyses 18)
X
X
X
X
Blood for Plasma for Biomarker Analyses 18)
X
X
X
Blood for Serum Biomarker Analyses 18)
X
X
X
Blood for Genetic Analyses 19)
X
Efficacy Measurements
Tumor Imaging
X
X
X
The timing of imaging during the 
treatment phase is according to the 
site’s SOC for tumor assessment 
until PD or initiation of a new 
anticancer regimen.
Tumor Tissue Collection 21)
X
 
 
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Title Treatment: Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants who discontinue study 
treatment
for whatever reason will proceed 
directly to EOT and Safety Follow-
up.
Cycle 
(Week)
(-4)
1
(0)
2
(4)
3
(7) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
8 22)
12
28
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-1
-
-
+3
-
±3
At time of
Discon
30 (±7) days
Post Discon
1)
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of MK-3475 for each cycle, and the window for each visit is ± 3 days unless 
otherwise specified.  Treatment cycles are 4 weeks in Cycle 1 and 3 weeks (Q3W) in subsequent cycles.
2)
Not applicable in Amendment 02.
3)
Not applicable in Amendment 02.
4)
Written consent must be obtained prior to performing any protocol specific procedure.  Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 4 weeks prior to the first dose of trial treatment).  
Screening number will be assigned when the study informed consent is signed.  
5)
Prior medications – Record all medications taken within 4 weeks of screening visit.  Concomitant medications – Enter new medications started during the trial through the 
Safety Follow-up visit.  Record all medications taken for AEs as defined in Section 7.2.
6)
Report all AEs occurring within 90 days after the last dose of trial treatment or 30 days of the end of treatment if the subject initiates new anticancer therapy, whichever is 
earlier.  Afterwards, report only SAEs that are related to trial treatment.  Adverse experiences and laboratory safety measurements will be graded per NCI CTCAE version 
4.0. All adverse experiences, whether gradable by CTCAE or not, will also be evaluated for seriousness.
7)
Perform physical examinations at predose on Day 1 of each cycle and Day 8 of Cycle 1.  A full physical examination will be performed at screening and at the 
discontinuation.
8)
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening only.
9)
ECG should be performed at predose and approximately 60 to 90 minutes after the first dose of INCB024360 for Day 1 of Cycles 1 and 2, and 30 day post-discontinuation.
10)
Arterial blood oxygen saturation (SpO2) should be measured at screening, Day 1 of each cycle, Day 8 of Cycle 1, at the discontinuation and at the safety follow-up (30 days 
post discon).
11)
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated 
if required by local guidelines.
12)
Coagulation factors should be tested as part of the screening procedures for all subjects.  Any subject receiving anticoagulant therapy should have coagulation factors 
monitored closely throughout the trial.  
13)
Laboratory tests for screening are to be performed locally within 10 days prior to the first dose of trial treatment.  After Cycle 1, lab samples can be collected up to 72 hours 
prior to MK-3475.  Urinalysis, FT3, FT4 and TSH should be performed every 2 cycles.  See Section 7.1.3 for details regarding laboratory tests.
14)
Unresolved abnormal labs that are drug related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal 
range.
15)
KL-6 and β–D glucan will be measured for pulmonary evaluation at screening (within 10 days prior to the first dose of study treatment) and thereafter if a subject develops 
suspected pneumonitis, an additional test may be performed at the descretion of the investigator.
 
 
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Title Treatment: Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants who discontinue study 
treatment
for whatever reason will proceed 
directly to EOT and Safety Follow-
up.
Cycle 
(Week)
(-4)
1
(0)
2
(4)
3
(7) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
8 22)
12
28
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-1
-
-
+3
-
±3
At time of
Discon
30 (±7) days
Post Discon
16)
Pre-dose trough PK samples for MK-3475 will be collected at Day 8 of Cycle 1, and Day 1 of Cycles 2, 4, 6 and 8 (following Cycle 8, every 4 cycles), until treatment 
discontinuation (or until the subject starts new anti-neoplastic therapy).  All pre-dose PK samples for MK-3475 should be drawn within 24 hours before infusion of
MK-3475.  The peak (post-dose) samples will be collected at Day 8 of Cycle 1 and this sample should be drawn within 30 minutes after the end of infusion. Anti-MK-
3475 antibodies should be drawn with all pre-dose trough PK samples.  Procedures for sample collection are described in the Procedures Manual. 
17)
Trough (pre-dose) and post-dose PK samples for INCB024360 will be collected at Days 1, 5, and 12 of Cycle 1, and Day 5 of Cycle 2.  All trough samples should be drawn 
before administration of INCB024360.  .  All post-dose samples should be drawn at 30 minutes, and 1, 2, 4, 6, 8 and 10 hours after the administration of INCB024360 at 
Days 1, 5 and 12 of Cycle 1. In addition, the post-dose sample should be drawn at 1 hours after the administration of INCB024360 at Day 5 of Cycle 2.  Procedures for 
sample collection are described in the Procedures Manual.  The investigator or qualified designee will remind the subject when they should not take their morning dose of 
INCB024360 on the day of full PK sampling.
18)
Blood for RNA Analyses should be collected pre-dose on Day 1 of Cycle 1, 2, and 5, or at time of discontinuation. Blood for Plasma and Serum Biomarker Analyses 
should be collected pre-dose on Day 1 of Cycle 1 and Cycle 2, or at the time of discontinuation. 
19)
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site.
20)
Not applicable in Amendment 02.
21)
Tumor tissue for biomarker analysis from an archival tissue sample or newly obtained biopsy (core or excisional: FNA/EBUS not adequate) of a tumor lesion not 
previously irradiated must be provided to the central vendor for characterization of PD-L1/IDO1 status.  These samples are not required to be obtained within 4 weeks of 
enrollment.  Detailed instructions for tissue collection, processing and shipment are provided in the Procedures Manual. 
22)
The scheduling window for Day 8 of Cycle 1 (-1 day) is applicable to Directed Physical Examination, Vital Signs and Weight, Arterial Blood Oxygen Saturation (SpO2)
Measurement and Hematology and Chemistry.
 
 
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6.1.2
Treatment Phase （Part A Cohort 2）
NOTE: As of Amendment 02, the final study visit will be the Safety Follow-up Visit and there will be no follow-up for survival 
status. For participants who were in Follow-up or Survival Follow-up, participation in the study is considered complete and no 
further visits are required. For those participants remaining in the study, procedures are simplified. The SoA has been 
amended and assessments no longer required have been deleted. Retreatment for new participants is no longer available.
Title Treatment: Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants
who discontinue study 
treatment
for whatever reason will proceed 
directly to EOT and Safety Follow-up.
Cycle 
(Week)
(-4)
1
(0)
2
(3)
3
(6) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
21
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-
+3
-
±3
At time of
Discon
30 (±7) days
Post Discon
Administrative Procedures
Informed Consent 4)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior/Concomitant Medication Review 5)
X
X-------------------------------------------------------------
X
X
X
Trial Treatment Administration
MK-3475 (Pembrolizumab) Administration
Q3W
X
X
X
INCB024360 (Epacadostat) Administration 
BID
X-----------------------------X
X-----------X
X
Clinical Procedures/Assessments
Review Adverse Events 6)
X----------------------------------------------------------------------------------------------------------X
Full Physical Examination 7)
X
X
Directed Physical Examination 7)
X
X
X
Vital Signs, Height and Weight 8)
X
X
X
X
X
X
12-Lead ECG 9)
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
Arterial Blood Oxygen Saturation (SpO2)
Measurement 10)
X
X
X
X
X
X
 
 
0574DK
05RFDK


Product:  MK-3475
73
Protocol/Amendment No.: 434-02 
MK-3475-434-02 Final Protocol
26-Apr-2019
Confidential
Title Treatment: Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants
who discontinue study 
treatment
for whatever reason will proceed 
directly to EOT and Safety Follow-up.
Cycle 
(Week)
(-4)
1
(0)
2
(3)
3
(6) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
21
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-
+3
-
±3
At time of
Discon
30 (±7) days
Post Discon
Laboratory Procedures/Assessments: analysis performed by local laboratory
Pregnancy Test (Urine or Serum β-HCG) 11)
X
Coagulation Parameters 12), 13), 14)
X
Hematology and Chemistry 13), 14)
X
X
X
X
X
Urinalysis 13), 14)
X
X
X
X
FT3, FT4 and TSH 13), 14)
X
X
X
X
KL-6, β-D glucan 14), 15)
X
Laboratory Procedures/Assessments: analysis performed by central laboratory
MK-3475 Pharmacokinetics 16)
X
X
X
Anti-MK-3475 Antibodies 16)
X
X
X
INCB024360 Pharmacokinetics 17)
X
X
X
INCB024360 Pharmacodynamics 17)
X
X
Blood for RNA Analyses 18)
X
X
X
X
Blood for Plasma for Biomarker Analyses 18)
X
X
X
Blood for Serum Biomarker Analyses 18)
X
X
X
Blood for Genetic Analyses 19)
X
Efficacy Measurements
Tumor Imaging
X
X
X
The timing of imaging during the 
treatment phase is according to the 
site’s SOC for tumor assessment until 
PD or initiation of a new anticancer 
regimen.
Tumor Tissue Collection 21)
X
1)
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of MK-3475 for each cycle, and the window for each visit is ± 3 days unless 
otherwise specified.  Treatment cycles are 3 weeks (Q3W) in each cycle.
2)
Not applicable in Amendment 02.
3)
Not applicable in Amendment 02.
4)
Written consent must be obtained prior to performing any protocol specific procedure.  Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 4 weeks prior to the first dose of trial treatment).  
Screening number will be assigned when the study informed consent is signed.  
 
 
0574DK
05RFDK


Product:  MK-3475
74
Protocol/Amendment No.: 434-02 
MK-3475-434-02 Final Protocol
26-Apr-2019
Confidential
Title Treatment: Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants
who discontinue study 
treatment
for whatever reason will proceed 
directly to EOT and Safety Follow-up.
Cycle 
(Week)
(-4)
1
(0)
2
(3)
3
(6) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
21
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-
+3
-
±3
At time of
Discon
30 (±7) days
Post Discon
5)
Prior medications – Record all medications taken within 4 weeks of screening visit.  Concomitant medications – Enter new medications started during the trial through the 
Safety Follow-up visit.  Record all medications taken for AEs as defined in Section 7.2.
6)
Report all AEs occurring within 90 days after the last dose of trial treatment or 30 days of the end of treatment if the subject initiates new anticancer therapy, whichever is 
earlier.  Afterwards, report only SAEs that are related to trial treatment.  Adverse experiences and laboratory safety measurements will be graded per NCI CTCAE version 
4.0. All adverse experiences, whether gradable by CTCAE or not, will also be evaluated for seriousness.
7)
Perform physical examinations at predose on Day 1.  A full physical examination will be performed at screening and at the discontinuation.
8)
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening only.
9)
ECG should be performed at predose and approximately 60 to 90 minutes after the first dose of INCB024360 for Day 1 of Cycles 1 and 2, and 30 day post-discontinuation.
10)
Arterial blood oxygen saturation (SpO2) should be measured at screening, Day 1 of each cycle, at the discontinuation and at the safety follow-up (30 days post discon).
11)
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines.
12)
Coagulation factors should be tested as part of the screening procedures for all subjects.  Any subject receiving anticoagulant therapy should have coagulation factors 
monitored closely throughout the trial.  
13)
Laboratory tests for screening are to be performed locally within 10 days prior to the first dose of trial treatment.  After Cycle 1, lab samples can be collected up to 72 hours 
prior to MK-3475.  Urinalysis, FT3, FT4 and TSH should be performed every 2 cycles.  See Section 7.1.3 for details regarding laboratory tests.
14)
Unresolved abnormal labs that are drug related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal 
range.
15)
KL-6 and β–D glucan will be measured for pulmonary evaluation at screening (within 10 days prior to the first dose of study treatment) and thereafter if a subject develops 
suspected pneumonitis, an additional test may be performed at the descretion of the investigator.
16)
Pre-dose trough PK samples for MK-3475 will be collected at Day 1 of Cycles 1, 2, 4, 6 and 8 (following Cycle 8, every 4 cycles) until treatment discontinuation  (or until 
the subject starts new anti-neoplastic therapy).  All pre-dose PK samples for MK-3475 should be drawn within 24 hours before infusion of MK-3475.  The peak (post-dose) 
samples will be collected at Day 1 of Cycle 1 and this sample should be drawn within 30 minutes after the end of infusion.  Anti-MK-3475 antibodies should be drawn with 
all pre-dose trough PK samples.  Procedures for sample collection are described in the Procedures Manual. 
17)
Trough (pre-dose) and post-dose PK samples for INCB024360 will be collected at Days 1 and 5 of Cycle 1, and Day 5 of Cycle 2.  All trough samples should be drawn 
before administration of INCB024360.  All post-dose samples should be drawn at 30 minutes, and 1, 2, 4, 6, 8 and 10 hours after the administration of INCB024360 at Day
5 of Cycle 1.  In addition, the post-dose sample should be drawn at 1 hours after the administration of INCB024360 at Day 5 of Cycle 2.  Procedures for sample collection 
are described in the Procedures Manual.  The investigator or qualified designee will remind the subject when they should not take their morning dose of INCB024360 on the 
day of full PK sampling.
18)
Blood for RNA Analyses should be collected pre-dose on Day 1 of Cycle 1, 2, and 5, or at time of discontinuation. Blood for Plasma and Serum Biomarker Analyses should 
be collected pre-dose on Day 1 of Cycle 1 and Cycle 2, or at the time of discontinuation.
 
 
0574DK
05RFDK


Product:  MK-3475
75
Protocol/Amendment No.: 434-02 
MK-3475-434-02 Final Protocol
26-Apr-2019
Confidential
Title Treatment: Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants
who discontinue study 
treatment
for whatever reason will proceed 
directly to EOT and Safety Follow-up.
Cycle 
(Week)
(-4)
1
(0)
2
(3)
3
(6) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
21
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-
+3
-
±3
At time of
Discon
30 (±7) days
Post Discon
19)
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site.
20)
Not applicable in Amendment 02.
21)
Tumor tissue for biomarker analysis from an archival tissue sample or newly obtained biopsy (core or excisional: FNA/EBUS not adequate) of a tumor lesion not previously 
irradiated must be provided to the central vendor for characterization of PD-L1/IDO1 status.  These samples are not required to be obtained within 4 weeks of enrollment.  
Detailed instructions for tissue collection, processing and shipment are provided in the Procedures Manual. 
 
 
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05RFDK


Product:  MK-3475
76
Protocol/Amendment No.: 434-02 
MK-3475-434-02 Final Protocol
26-Apr-2019
Confidential
6.1.3
Treatment Phase （Part B）
NOTE: As of Amendment 02, epacadostat administration is stopped and all participants remaining in the study will receive 
pembrolizumab and Chemotherapy. The final study visit will be the Safety Follow-up Visit and there will be no follow-up for 
survival status. For participants who were in Follow-up or Survival Follow-up, participation in the study is considered 
complete and no further visits are required. For those participants remaining in the study, procedures are simplified. The SoA 
has been amended and assessments no longer required have been deleted. Retreatment for participants is no longer available.
Title Treatment:
Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants
who 
discontinue 
study 
treatment
for 
whatever reason will 
proceed directly to
EOT 
and 
Safety 
Follow-up.
Cycle 
(Week)
(-4)
1
(0)
2
(3)
3
(6) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
8
15
21
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-
-
-
+3
-
±3
At time of
Discon
30 (±7)
days Post 
Discon
Administrative Procedures
Informed Consent 4)
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior/Concomitant Medication Review 5)
X
X---------------------------------------------------------------X
X
X
Trial Treatment Administration
MK-3475 (Pembrolizumab) Administration Q3W
X
X
X
Chemotherapy6)
X
X
X
Clinical Procedures/Assessments
Review Adverse Events 7)
X-------------------------------------------------------------------------------------------------------------X
Full Physical Examination 8)
X
X
Directed Physical Examination 8)
X
X
X
X
X
Vital Signs, Height and Weight 9)
X
X
X
X
X
X
X
X
12-Lead ECG 10)
X
X
X
X
 
 
0574DK
05RFDK


Product:  MK-3475
77
Protocol/Amendment No.: 434-02 
MK-3475-434-02 Final Protocol
26-Apr-2019
Confidential
Title Treatment:
Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants
who 
discontinue 
study 
treatment
for 
whatever reason will 
proceed directly to
EOT 
and 
Safety 
Follow-up.
Cycle 
(Week)
(-4)
1
(0)
2
(3)
3
(6) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
8
15
21
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-
-
-
+3
-
±3
At time of
Discon
30 (±7)
days Post 
Discon
ECOG Performance Status
X
X
X
X
X
X
Arterial Blood Oxygen Saturation (SpO2)
Measurement 11)
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by local laboratory
Pregnancy Test (Urine or Serum β-HCG) 12)
X
Coagulation Parameters 13), 14), 15)
X
Hematology and Chemistry 14), 15)
X
X
X
X
X
X
X
Urinalysis 14), 15)
X
X
X
X
FT3, FT4 and TSH 14), 15)
X
X
X
X
KL-6, SP-D, β-D glucan 15), 16)
X
X
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by central laboratory
MK-3475 Pharmacokinetics 17)
X
X
X
Anti-MK-3475 Antibodies 17)
X
X
X
INCB024360 Pharmacokinetics 18)
X
X
X
INCB024360 Pharmacodynamics 18)
X
X
Blood for RNA Analyses 19)
X
X
X
Blood for Plasma for Biomarker Analyses 19)
X
X
Blood for Serum Biomarker Analyses 19)
X
X
Blood for Genetic Analyses 20)
X
 
 
0574DK
05RFDK


Product:  MK-3475
78
Protocol/Amendment No.: 434-02 
MK-3475-434-02 Final Protocol
26-Apr-2019
Confidential
Title Treatment:
Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants
who 
discontinue 
study 
treatment
for 
whatever reason will 
proceed directly to
EOT 
and 
Safety 
Follow-up.
Cycle 
(Week)
(-4)
1
(0)
2
(3)
3
(6) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
8
15
21
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-
-
-
+3
-
±3
At time of
Discon
30 (±7)
days Post 
Discon
Efficacy Measurements
Tumor Imaging
X
X
X
The timing of imaging 
during the treatment 
phase is according to 
the site’s SOC
for 
tumor 
assessment 
until PD or initiation 
of a new anticancer 
regimen.
Tumor Tissue Collection (Optional) 22)
X
1)
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of MK-3475 for each cycle, and the window for each visit is ± 3 days unless 
otherwise specified.  Treatment cycles are 3 weeks (Q3W) in each cycle.
2)
Not applicable in Amendment 02.
3)
Not applicable in Amendment 02.
4)
Written consent must be obtained prior to performing any protocol specific procedure.  Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 4 weeks prior to the first dose of trial treatment).  
Screening number will be assigned when the study informed consent is signed.  
5)
Prior medications – Record all medications taken within 4 weeks of screening visit.  Concomitant medications – Enter new medications started during the trial through the 
Safety Follow-up visit.  Record all medications taken for AEs as defined in Section 7.2.
6)
Chemotherapy will be administered for a maximum of 4 administrations. Pemetrexed maintenance therapy can be used after 4 administrations of chemotherapy.
7)
Report all AEs occurring within 90 days after the last dose of trial treatment or 30 days of the end of treatment if the subject initiates new anticancer therapy, whichever is 
earlier. Afterwards, report only SAEs that are related to trial treatment.  Adverse experiences and laboratory safety measurements will be graded per NCI CTCAE version 
4.0. All adverse experiences, whether gradable by CTCAE or not, will also be evaluated for seriousness.
8)
Perform physical examinations at predose on Day 1 and Day 8, 15 of cycle 1.  A full physical examination will be performed at screening and at the discontinuation.
 
 
0574DK
05RFDK


Product:  MK-3475
79
Protocol/Amendment No.: 434-02 
MK-3475-434-02 Final Protocol
26-Apr-2019
Confidential
Title Treatment:
Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants
who 
discontinue 
study 
treatment
for 
whatever reason will 
proceed directly to
EOT 
and 
Safety 
Follow-up.
Cycle 
(Week)
(-4)
1
(0)
2
(3)
3
(6) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
8
15
21
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-
-
-
+3
-
±3
At time of
Discon
30 (±7)
days Post 
Discon
9)
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. However, temperature, pulse, respiratory rate and blood pressure will be performed on 
Day 8 and 15 of cycle 1. Height will be measured at screening only.
10)
ECG should be performed at predose and approximately 60 to 90 minutes after the first dose of INCB024360 for Day 1 of Cycles 1 and 2, and 30 day post-discontinuation.
11)
Arterial blood oxygen saturation (SpO2) should be measured at screening, Day 1 of each cycle, at the discontinuation and at the safety follow-up (30 days post discon).
12)
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines.
13)
Coagulation factors should be tested as part of the screening procedures for all subjects.  Any subject receiving anticoagulant therapy should have coagulation factors 
monitored closely throughout the trial.  
14)
Laboratory tests for screening are to be performed locally within 10 days prior to the first dose of trial treatment.  After Cycle 1, lab samples can be collected up to 72 hours 
prior to MK-3475.  Urinalysis, FT3, FT4 and TSH should be performed every 2 cycles.  See Section 7.1.3 for details regarding laboratory tests.
15)
Unresolved abnormal labs that are drug related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal 
range.
16)
β–D glucan will be measured for pulmonary evaluation at screening (within 10 days prior to the first dose of study treatment) and thereafter if a subject develops suspected 
pneumonitis, an additional test may be performed at the descretion of the investigator.
17)
Pre-dose trough PK samples for MK-3475 will be collected at Day 1 of Cycles 1, 2, 4, 6 and 8 (following Cycle 8, every 4 cycles) until treatment discontinuation (or until 
the subject starts new anti-neoplastic therapy).  All pre-dose PK samples for MK-3475 should be drawn within 24 hours before infusion of MK-3475.  The peak (post-dose) 
samples will be collected at Day 1 of Cycle 1 and this sample should be drawn within 30 minutes after the end of infusion.  Anti-MK-3475 antibodies should be drawn with 
all pre-dose trough PK samples.  Procedures for sample collection are described in the Procedures Manual. 
As of amendment 2, the collection for PK and ADA samples should be stopped.
18)
Trough (pre-dose) and post-dose PK samples for INCB024360 will be collected at Days 1 and 5 of Cycle 1, and Day 5 of Cycle 2.  All trough samples should be drawn 
before administration of INCB024360.  All post-dose samples should be drawn at 30 minutes, and 1, 2, 4, 6, 8 and 10 hours after the administration of INCB024360 at Day
5 of Cycle 1.  In addition, the post-dose sample should be drawn at 1 hours after the administration of INCB024360 at Day 5 of Cycle 2.  Procedures for sample collection 
are described in the Procedures Manual.  The investigator or qualified designee will remind the subject when they should not take their morning dose of INCB024360 on the 
day of full PK sampling.
 
 
0574DK
05RFDK


Product:  MK-3475
80
Protocol/Amendment No.: 434-02 
MK-3475-434-02 Final Protocol
26-Apr-2019
Confidential
Title Treatment:
Screening
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants
who 
discontinue 
study 
treatment
for 
whatever reason will 
proceed directly to
EOT 
and 
Safety 
Follow-up.
Cycle 
(Week)
(-4)
1
(0)
2
(3)
3
(6) and 
beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1
5
8
15
21
1
2-21
1-21
Scheduling Window (Days):
-28
-
-
-
-
-
+3
-
±3
At time of
Discon
30 (±7)
days Post 
Discon
19)
Blood for RNA Analyses should be collected pre-dose on Day 1 of Cycle 1, 2, and 5. Blood for Plasma and Serum Biomarker Analyses should be collected pre-dose on Day 
1 of Cycle 1 and Cycle 2.
20)
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. 
21)
Not applicable in Amendment 02.
22)
Tumor tissue for biomarker analysis from an archival tissue sample or newly obtained biopsy (core or excisional: FNA/EBUS not adequate) of a tumor lesion not previously 
irradiated can be optionally provided to the central vendor for characterization of PD-L1/IDO1 status.  These samples are not required to be obtained within 4 weeks of 
enrollment.  Detailed instructions for tissue collection, processing and shipment are provided in the Procedures Manual. 
 
 
0574DK
05RFDK


Product:  MK-3475
81
Protocol/Amendment No.: 434-02 
MK-3475-434-02 Final Protocol
26-Apr-2019
Confidential
6.2
Second Course Phase (Retreatment ONLY)
Note: For Part A, subjects who are already in second course as of Amendment 02 would be eligible to receive trial treatment 
for up to 17 additional administrations of INCB024360 + MK-3475 (approximately one year). Retreatment for new 
participants in Part A, or any participants in Part B will no longer be available.
Title Treatment:
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants
who 
discontinue 
study 
treatment
for 
whatever 
reason 
will 
proceed 
directly to EOT and Safety 
Follow-up.
Cycle 
(Week)
1
(0)
2
(3)
3
(6) and beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1-21
1-21
1-21
Scheduling Window (Days):
-
±3
±3
At time of
Discon
30 (±7) days 
Post Discon
Administrative Procedures
Eligibility Criteria
X
Concomitant Medication Review 4)
X
X
X
X
X
Trial Treatment Administration
MK-3475 
(Pembrolizumab)
Administration
Q3W
X
X
X
INCB024360 (Epacadostat) Administration BID
X------------X
X------------X
X------------X
Clinical Procedures/Assessments
Review Adverse Events 5)
X---------------------------------------------------------------------------------------------------------X
Full Physical Examination 6)
X
X
Directed Physical Examination 6)
X
X
Vital Signs and Weight 7)
X
X
X
X
X
12-Lead ECG 8)
X
X
X
X
ECOG Performance Status
X
X
X
X
X
Arterial Blood Oxygen
Saturation
(SpO2)
Measurement 10)
X
X
X
X
X
Laboratory Procedures/Assessments: analysis performed by local laboratory
Pregnancy Test (Urine or Serum β-HCG) 10)
X
Coagulation Parameters 11), 12), 13)
X
Hematology and Chemistry 12) 13)
X
X
X
X
X
Urinalysis 12) 13)
X
X
X
X
FT3, FT4 and TSH 12) 13)
X
X
X
X
 
 
0574DK
05RFDK


Product:  MK-3475
82
Protocol/Amendment No.: 434-02 
MK-3475-434-02 Final Protocol
26-Apr-2019
Confidential
Title Treatment:
Treatment Cycles 1)
End of
Treatment
Post-
Treatment
Notes
Participants
who 
discontinue 
study 
treatment
for 
whatever 
reason 
will 
proceed 
directly to EOT and Safety 
Follow-up.
Cycle 
(Week)
1
(0)
2
(3)
3
(6) and beyond
Discon
Safety
Follow-up
Relative Day in Cycle (on Day)
1-21
1-21
1-21
Scheduling Window (Days):
-
±3
±3
At time of
Discon
30 (±7) days 
Post Discon
KL-6, β-D glucan 13), 14)
X
Efficacy Measurements
Tumor Imaging
X
X
X
The timing of imaging 
during the treatment phase 
is according to the site’s 
SOC for tumor assessment 
until PD or initiation of a
new anticancer regimen.
1)
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of MK-3475 for each cycle, and the window for each visit is ± 3 days unless otherwise 
specified.  Treatment cycles are 3 weeks (Q3W).
2)
Not applicable in Amendment 02.
3)
Not applicable in Amendment 02.
4)
Concomitant medications – Enter new medications started during the trial through the Safety Follow-up visit.  Record all medications taken for AEs as defined in Section 7.2.
5)
Report all AEs occurring within 90 days after the last dose of trial treatment or 30 days of the end of treatment if the subject initiates new anticancer therapy, whichever is earlier.  
Afterwards, report only SAEs that are related to trial treatment.  Adverse experiences and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All adverse 
experiences, whether gradable by CTCAE or not, will also be evaluated for seriousness.
6)
Perform physical examinations at predose on Day 1.  A full physical examination will be performed at Cycle 1 and at the discontinuation.
7)
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. 
8)
ECG should be performed at predose and approximately 60 to 90 minutes after the first dose of INCB024360 for Day 1 of Cycles 1 and 2, and 30 day post-discontinuation.
9)
Arterial blood oxygen saturation (SpO2) should be measured on Day 1 of each cycle, at the discontinuation and at the safety follow-up (30 days post discon).
10) For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of Second Course Phase.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if required by 
local guidelines.
11) Coagulation factors should be monitored closely throughout the trial for any subject receiving anticoagulant therapy.  
12) Laboratory tests for determining eligibility for Second Course Phase are to be performed locally within 10 days prior to the first dose of Second Course Phase.  After Cycle 1, lab 
samples can be collected up to 72 hours prior to the scheduled time point.  Urinalysis, FT3, FT4 and TSH should be performed every 2 cycles.  See Section 7.1.3 for details regarding 
laboratory tests.
13) Unresolved abnormal labs that are drug related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal range.
14) KL-6 and β–D glucan will be measured if a subject develops suspected pneumonitis; an additional test may be performed at the discretion of the investigator.
15)
Not applicable in Amendment 02.
 
 
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7.0 TRIAL PROCEDURES
7.1
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
7.1.1
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial. If there are changes to the subject’s status during the trial (e.g., health or age of majority 
requirements), the investigator or qualified designee must ensure the appropriate consent is in 
place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent. At the time of treatment allocation/randomization, site 
personnel will add the treatment/randomization number to the Subject Identification Card.
Subjects will also be given a serotonin syndrome (SS) information sheet for signs and 
symptoms of SS prior to the first dose of INCB024360.  This information sheet also instructs 
subjects to seek immediate medical care if any of these symptoms are observed.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator. 
Disease details regarding the subject’s cancer other than the cancer under study will be
recorded separately even if diagnosed greater than 10 years prior to the first dose of trial 
medication and not listed as medical history.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 4 weeks before the first dose of trial medication.  
In addition, the investigator will review and record all prior cancer treatments including 
systemic treatments, radiation and surgeries even if taken greater than 4 weeks prior to 
starting the trial therapy.  Prior treatments for the subject’s cancer will be recorded separately 
and not listed as a prior medication.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial from start of study treatment through the 30-day safety follow-up visit. After 
the safety follow-up visit, record all medications related to reportable AEs as defined in 
Section 7.2.
In addition, the investigator will review all new anti-neoplastic therapy initiated after the last 
dose of trial treatment.  The new cancer therapies for the subject’s cancer will be recorded 
separately and not listed as a concomitant medication.
 
 
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7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation/randomization.   Once a 
treatment/randomization number is assigned to a subject, it can never be re-assigned to 
another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
No subject randomization will occur in this study.  Eligible subjects will be assigned to each 
dose level.  The investigator examines and confirms the eligibility of the subject, and then e-
mail to the SPONSOR to register the subject including screening number, date of consent, 
allocation number/dose level or Cohort (if subject is enrolled), and date of the initial 
administration of study drug. In Part B, the investigators will inform the Sponsor of the 
chemotherapy (Cohort) that Investigators will select prior to treatment allocation. The 
SPONSOR confirms the registration of the subject.
Subjects who do not meet entry criteria will not be assigned an allocation number.  Subjects 
enrolled in one dose level cannot be re-enrolled in another dose level.  If a subject is not 
enrolled, the reason for exclusion from the study will be documented on this log (e-mail).  
The log should be kept by the investigator and the SPONSOR.
The SPONSOR will keep the investigator informed of the screening activities and enrollment 
in dose group availability.
Procedures for allocation number are described in the Procedures Manual.
7.1.1.8
Trial Compliance (Medication)
Interruptions from the protocol specified treatment plan for greater than 12 weeks between 
MK-3475 and INCB024360 doses due to toxicity require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
subject management.
The preparation and administration of cisplatin, pemetrexed, carboplatin and paclitaxel will 
be performed according to local practice and labels.
 
 
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MK-3475
Administration of MK-3475 will be witnessed by the investigator and/or trial staff.  The total 
volume of MK-3475 infused will be compared to the total volume prepared to determine 
compliance with each dose administered.  The instructions for preparing and administering 
MK-3475 will be provided in the Procedures Manual.
INCB024360
Subjects will take their dose of INCB024360 in the morning and evening, approximately 12 
hours apart without regard to food.  Subjects will self-administer INCB024360 except on 
C1D1, C1D5, C1D12 of Part A cohort 1, C1D1, C1D5 of Part A cohort 2 and Part B, and 
C2D5 of both Part A and Part B, when the morning dose will be given at the study site clinic
for PK sampling.  On days when INCB024360 is administered in the clinic, subjects will take 
INCB024360 and then begin infusion of MK-3475.  The investigator or qualified designee 
will remind the subject when they should not take their morning dose of INCB024360.
INCB024360 compliance will be calculated by the Sponsor based on the drug accountability 
documented by the site staff and monitored by the Sponsor (tablet counts).  The objective is 
100% compliance and investigators and their staff should evaluate compliance at each visit, 
and take appropriate steps to optimize compliance.
NOTE: As of Amendment 02, INCB024360 is stopped from Part B.
7.1.2
Clinical Procedures/Assessments
7.1.2.1
Adverse Event (AE) Monitoring
The investigator will assess each subject to evaluate for potential new or worsening AEs as 
specified in the Trial Flow Chart (Section 6.0) and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see Appendix 12.3).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment. 
All AEs of unknown etiology associated with MK-3475 and INCB024360 exposure should 
be evaluated to determine if it is possibly an event of a potentially immunologic etiology; see 
Section 5.6.
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.  Subjects should be assessed for possible immune-related events prior to each visit.  
Laboratory results should be evaluated and subjects should be asked for signs and symptoms 
suggestive of an immune-related event.  Subjects who develop an AE thought to be immune-
related should have additional testing to rule out other etiologic causes.  If laboratory results 
or symptoms indicate a possible immune-related AE, then additional testing should be 
performed to rule out other etiologic causes.  If no other cause is found, then it is assumed to 
be immune-related.
 
 
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7.1.2.1.1 Distribution of Serotonin Syndrome (SS) Information Sheet
NOTE: As of Amendment 02, this section is updated to reflect the removal of epacadostat 
from the study and current safety information for epacadostat. SS information sheet will no 
longer provided.
7.1.2.2
Physical Exam
The investigator will perform a full physical exam during the screening period.  Clinically 
significant abnormal findings should be recorded as medical history.  A full physical exam 
should be performed as specified in the Trial Flow Chart (Section 6.0).  For cycles that do 
not require a full physical exam per the Trial Flow Chart, the investigator will perform a 
directed physical exam as clinically indicated prior to Day 1 of each cycle and Day 8 of cycle 
1 of trial treatment administration. In Part B, the investigator will perform directed physical 
exam on Day 1 of each cycle and Day 8 and 15 of cycle 1. After the first dose of trial 
treatment new clinically significant abnormal findings should be recorded as AEs.
7.1.2.3
Vital Signs, Height and Weight
The investigator will take vital signs as specified in the Trial Flow Chart (Section 6.0).  Vital 
signs should include temperature, pulse, respiratory rate, weight and blood pressure.  
Patients must be resting in a sitting position for approximately 10 minutes prior to obtaining 
vital signs. Height will be measured at screening only.
If blood pressure is >150/100 mmHg in a patient without a history of hypertension, or 
increased >20 mmHg (diastolic) from baseline measurement in a patient with a previous 
history of hypertension, the assessment should be repeated in 10 minutes for confirmation. 
7.1.2.4
12-lead ECG
The investigator will perform a standard 12-lead ECG using local standard procedures as 
specified in the Trial Flow Chart (Section 6.0). Clinically significant abnormal findings at 
screening should be recorded as medical history. After the first dose of trial treatment new 
clinically significant abnormal findings should be recorded as AEs.
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator will assess ECOG performance status (see Section 12.2) as specified in the 
Trial Flow Chart (Section 6.0).  
7.1.2.6
Arterial Blood Oxygen Saturation (SpO2) Measurement
The investigator will measure arterial blood oxygen saturation (SpO2) as specified in the 
Trial Flow Chart (Section 6.0).
7.1.2.7
Tumor Imaging and Assessment of Disease
The process for image collection can be found in the Procedures Manual. Tumor imaging 
should be acquired by computed tomography (CT, strongly preferred). Magnetic resonance 
imaging (MRI) should be used when CT is contraindicated or for imaging in the brain. The 
same imaging technique regarding modality and use of contrast should be used in a subject 
 
 
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throughout the tri al to optimize the visualization of existing and new tumor burden.  CT or 
MRI scans should include the chest, abdomen, and pelvis. A chest CT performed for tumor 
imaging will be used for pulmonary radiographic evaluation (see Section 7.1.2.8).
Subject eligibility will be determined based on RECIST 1.1 (See Section 12.7).  
7.1.2.7.1 Initial Tumor Imaging
The tumor imaging (CT or MRI) for screening should be performed within 4 weeks prior to
the first dose of trial treatment. The site study team must review pre-trial images to confirm 
the subject has measurable disease per RECIST 1.1.  Scans performed as part of routine 
clinical management are acceptable for use as the screening scan if they are of diagnostic 
quality and performed within 4 weeks prior to the first dose of trial treatment.
Subjects with previously treated brain metastases may participate provided they have stable 
brain metastases, i.e. without evidence of progression by imaging during screening
(confirmed by MRI if MRI was used at prior imaging, or confirmed by CT imaging if CT 
used at prior imaging). Any neurologic symptoms must have returned to baseline and 
subjects must have no evidence of new or enlarging brain metastases, and have not used 
steroids for brain metastases for at least 14 days prior to trial initiation as per local site 
assessment. This exception does not include carcinomatous meningitis, as subjects with 
carcinomatous meningitis are excluded regardless of clinical stability.
7.1.2.7.2 Tumor Imaging During the Study
NOTE: As of Amendment 02, the use of irRECIST and iRECIST is discontinued. This 
section is no longer applicable. Participants with radiographic disease progression as 
determined by RECIST 1.1 by investigator assessment will discontinue from 
pembrolizumab monotherapy; no confirmatory scans are required. However, if the
participant is achieving a clinically meaningful benefit, an exception to continue with 
pembrolizumab monotherapy may be considered following consultation with MSD.
7.1.2.7.3 End of Treatment and Follow-up Tumor Imaging
NOTE: As of Amendment 02, there is no protocol-specified imaging at end of treatment
and no follow-up imaging is required. This section is no longer applicable and has been
deleted.
7.1.2.7.4 Second Course (Retreatment) Tumor Imaging
(Part A for ongoing 
participants only; not for new participants in Part A and all participants in 
Part B)
NOTE: As of Amendment 02, there is no protocol-specified imaging at second course of 
treatment is required. This section is no longer applicable and has been deleted.
7.1.2.8
Pulmonary Radiographic Evaluation for MK-3475-Induced Pneumonitis
Pulmonary radiographic imaging is used in a diagnosis of MK-3475-induced pneumonitis. A
chest CT performed for tumor imaging may be used for pulmonary radiographic evaluation.  
For a subject with suspected pneumonitis based on respiratory symptoms, other clinical
findings or laboratory findings, a chest CT should be performed immediately. If a finding on
 
 
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pneumonitis is observed, the subject should be followed every month with chest imaging to
monitor the pneumonitis.
Pulmonary radiographic evaluation will be performed according to the table in Section 6.0.  
The investigator will judge whether the variation after the trial treatment administration is an 
adverse experience or not and record it in the Case Report Form.
7.1.2.9
Tumor Tissue Collection
Participation in this trial will require submitting tumor sample for PD-L1 and IDO1 
expression evaluation at central laboratories in Part A.  These samples are not required to be 
obtained within 4 weeks of enrollment.  Expression status of PD-L1 and IDO1 will not be 
reported until the end of the study.  Subjects can be enrolled in this trial regardless of 
expression status of PD-1 and IDO1.
Note: Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are 
preferred; if submitting unstained slides, the slides should be freshly cut and submitted to the 
testing laboratory per the specifications in the Procedures Manual.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual. 
7.1.3
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  The total amount of blood/tissue to be drawn/collected over the course of 
the trial, including approximate blood/tissue volumes drawn/collected by visit and by sample 
type per subject can be found in the Procedure Manual.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 10.
 
 
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Table 10
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)
Platelet count
Alanine aminotransferase (ALT)
Protein
aPTT
WBC (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Free triiodothyronine (FT3)
Red 
Blood 
Cell 
Count
Lactate dehydrogenase (LDH)
Microscopic exam, if 
abnormal 
results 
are 
noted
Free thyroxine (FT4)
Absolute 
Neutrophil Count
Creatinine
Urine pregnancy test*
Thyroid 
stimulating 
hormone (TSH)
Absolute 
Lymphocyte Count
CRP
HIV antibody**
Uric Acid
HBsAg**
Calcium
HCV RNA**
Chloride
KL-6
Glucose
β-D glucan
Phosphorus
Tumor 
Markers
(as 
appropriate)
Potassium
SP-D***
Sodium
Magnesium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood Urea Nitrogen
* Perform on women of childbearing potential only.  If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required.  
** For screening visit only.
*** Part B only.
Laboratory tests (hematology, serum chemistry, urinalysis, coagulation parameters, thyroid 
function, KL-6, SP-D (Part B) and β-D glucan) for screening or entry into the Second Course 
Phase (Part A) should be performed locally within 10 days prior to the first dose of treatment.  
From Cycle 2, pre-dose laboratory procedures can be conducted up to 72 hours prior to 
dosing.  Results must be reviewed by the investigator and found to be acceptable prior to Day 
1 of each cycle.
 
 
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PT/INR and aPTT will be collected as coagulation parameters.
TSH, FT3, and FT4 will be measured for thyroid function test.
Testing for HIV 1/2 antibodies, HBsAg, and HCV RNA will be performed at screening. If 
results of these tests obtained within 3 months before screening are available, they can be 
used even before consent is obtained.
For women of reproductive potential, a urine/serum pregnancy test will be performed within
72 hours of the first dose. If urine pregnancy results cannot be confirmed as negative, a
serum pregnancy test will be required.
KL-6 is a lung-specific marker for pneumonitis [56]. β-D glucan is a marker for fungus
infectious disease [57], and is used for the differential diagnosis for pneumonitis. KL-6 and
In Part A, KL-6 and β-D glucan will be measured before starting the treatment courses, and 
thereafter if a subject develops suspected pneumonitis, an additional test will be performed as 
needed by investigator’s judgment. In Part B, β-D glucan will be measured before starting the 
tratment courses, and thereafter if a subject develops suspected pneumonitis, an additional 
test will be performed as needed by investigator’s judgment.
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
To further evaluate MK-3475 immunogenicity and MK-3475 and INCB024360 exposure in 
this indication, sample collections for analysis of anti-drug antibodies (ADA) and PK are 
currently planned as shown in the Trial Flowchart (Section 6.0). If ongoing ADA and/or PK 
results continue to be consistent with existing ADA and/or PK data from other MK-3475 
clinical trials, it may be decided to discontinue or reduce further sample collection in this 
study.
Pharmacokinetic data is planned to be analyzed by comparison to historical reference data in 
this patient population. Blood samples for PK and anti- pembrolizumab-antibodies collected 
may be stored only at this time. Further analysis may be performed if required. The results of 
these analyses, if performed, will be reported separately.
7.1.3.2.1 Blood Sample Collection for PK of MK-3475
Sample collection, storage and shipment instructions for samples will be provided in the 
Procedures Manual. Serum PK samples should be drawn according to the PK collection 
schedule for subjects who receive MK-3475.
Biomarker assessments may also be conducted at the discretion of the sponsor using excess 
PK samples.
7.1.3.2.2 Blood Sample Collection for Anti-MK-3475 Antibodies
Sample collection, storage and shipment instructions for samples will be provided in the 
Procedures Manual. Anti-MK-3475 antibody serum samples should be drawn according to 
the ADA collection schedule for subjects who receive MK-3475.  Simultaneous PK sampling 
is required for interpretation of ADA analysis.
 
 
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7.1.3.2.3 Blood Sample Collection for PK of INCB024360
Sample collection, storage and shipment instructions for samples will be provided in the 
Procedures Manual.  Plasma samples will be obtained at the visits indicated in the Trial Flow 
Chart (Section 6.0.).
Pharmacokinetics samples for INCB024360 will be required for all 
subjects enrolled in this study.  Subjects will arrive at clinic having withheld their morning 
dose of INCB024360.
After the predose (predose is defined as within 24 hours before administration of MK-3475 
and before administration of INCB024360) PK sample is drawn, subjects will take 
INCB024360 and then begin infusion of MK-3475.  The exact date and time of the PK blood 
draws will be recorded along with the date and time of the last dose of trial treatment and last 
meal preceding the blood draw. 
Biomarker assessments may also be conducted at the discretion of the sponsor using excess 
PK samples.
7.1.3.2.4 Blood Sample Collection for Pharmacodynamic Assessments of INCB024360
Sample collection, storage and shipment instructions for samples will be provided in the 
Procedures Manual.  Plasma samples will be obtained for pharmacodynamic assessments at 
the visits designated in the Trial Flow Chart (Section 6.0).
Plasma PD samples will be analyzed for changes in the levels of tryptophan and kynurenine 
by liquid chromatography with tandem mass spectrometry to monitor systemic activity in 
modulating the IDO1 enzyme. Protein analytes such as relevant tumor markers and markers 
of immune function may be measured by enzyme-linked immunosorbent assay, or other 
relevant methods, using these samples. 
Biomarker assessments may also be conducted at the discretion of the sponsor using excess 
PD samples.
7.1.3.2.5 Blood Collection for RNA Analyses, Biomarker Plasma Analyses, and 
Biomarker Serum Analyses
Sample Collection, storage and shipment instruction for RNA, plasma and serum samples 
will be provided in the Procedures Manual. 
7.1.3.3
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual.
7.1.4
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the end of treatment should be performed at the time of discontinuation.  Any 
 
 
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adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events and subjects who a) attain a CR or b) complete 35 administrations 
of MK-3475 (approximately 2 years) may discontinue treatment.  After discontinuing 
treatment following assessment of CR or 35 administrations of MK-3475, these subjects 
should return to the site for a Safety Follow-up Visit and then proceed with assessments (see 
Section 7.1.5.4).
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion labs and trial assessments

Imaging equipment – as required for study objective

Infusion equipment – as required to support administration of MK-3475
See protocol-specified guidance in the Administrative Binder and Procedures Manual.
7.1.5
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
Up to 4 weeks prior to enrollment, potential subjects will be evaluated to determine that they 
fulfill the entry requirements as set forth in Section 5.1.  
Written consent for the study must be obtained prior to performing any protocol specific 
procedure.  After providing consent, subjects will be assigned a screening number.  Results 
of a test performed prior to the subject signing consent as part of routine clinical management 
are acceptable in lieu of a screening test if performed within the specified time frame.  
Screening procedures are to be completed within 4 weeks prior to the first dose of trial 
treatment except for the following:

Laboratory tests (hematology, serum chemistry, urinalysis, coagulation parameters,
thyroid function test, KL-6, SP-D (Part B) and β-D glucan) are to be performed 
locally within 10 days prior to the first dose of trial treatment.

For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to the first dose of trial treatment.  If urine pregnancy results cannot be 
 
 
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confirmed as negative, a serum pregnancy test will be required (performed by the 
local study site laboratory).

If results of HIV 1/2 antibodies, HBsAg, and HCV RNA test obtained within 3 
months before screening are available, they can be used even before consent is
obtained.

Archival tumor biopsy for PD-L1/IDO1 characterization is not required to be 
obtained within 4 weeks prior to the first dose of trial treatment.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met.
7.1.5.2
Treatment Period
The treatment period with the combination therapy will continue every 21 days for up to 35 
infusions (approximately 2 years) as long as subjects are receiving benefit from treatment 
and have not had disease progression or met any criteria for study withdrawal. 
7.1.5.3
End of Treatment
If a decision is made that the subject will permanently discontinue trial treatment, the EOT 
visit should be conducted.  If the EOT visit coincides with a regular study visit, the EOT 
evaluations will supersede those of that scheduled visit.  The subject should be encouraged to 
return for the follow-up visit.
7.1.5.4
Post-Trial
7.1.5.4.1 Safety Follow-Up
NOTE: As of Amendment 02, the Safety Follow-up Visit will be the last visit in the
study. This section has been amended accordingly.
The safety follow-up phase is the interval between the EOT visit and the scheduled safety 
follow-up visit, which should occur 30 days after the EOT visit or before the initiation of a 
new antineoplastic treatment, whichever comes first.  
Subjects in Part A who are eligible for retreatment with the combination therapy (ie ongoing 
before the amendment 2 is approved) (as described in Section 7.1.5.5) may have up to 2 
safety follow-up visits, 1 after the treatment period and 1 after the second course phase (re-
treatment).
7.1.5.4.2 Follow-Up
NOTE: As of Amendment 02, the Follow-up Phase have been removed.
7.1.5.4.3 Survival Follow-Up
NOTE: As of Amendment 02, the Survival Follow-up Phase have been removed.
7.1.5.5
Second Course Phase (Retreatment Period): Part A only
Note: For Part A, subjects who are already in second course as of Amendment 02 would 
be eligible to receive trial treatment for up to 17 additional administrations of 
 
 
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INCB024360 + MK-3475 (approximately one year). No new participants in Part A or 
any participants in part B will have re-treatment (ie second course) available.
As of Amendment 01, all subjects who stop study treatment with SD or better may be 
eligible for up to one year (17 infusions) of additional MK-3475 and INCB024360 treatment 
if they progress after stopping study treatment from the initial treatment phase.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions:
•
Either 
o
Stopped initial treatment with study treatment after attaining an investigator-
determined confirmed CR according to RECIST 1.1, and

Was treated for at least 8 administrations (at least 24 weeks) with 
study treatment before discontinuing treatment

Received at least two treatments with MK-3475 beyond the date when 
the initial CR was declared
OR
o
Had SD, PR or CR and stopped study treatment after completion of 35 
administrations (approximately 2 years) of MK-3475 for reasons other than 
disease progression or intolerability
AND
•
Experienced an investigator-determined radiographic disease progression after 
stopping their initial treatment 
•
Did not receive any anti-cancer treatment since the last dose of study treatment
•
Has a performance status of 0 or 1 on the ECOG Performance Scale
•
Demonstrates adequate organ function as detailed in Section 5.1.2
•
Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.  
•
Female subject of childbearing potential* should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  *Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year. 
•
Male subject should agree to use an adequate method of contraception starting with 
the first dose of study treatment through 120 days after the last dose of study 
treatment.
•
Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator.
 
 
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Subjects who restart treatment will be retreated at the same dose as when they last received 
INCB024360. Response or progression in this Second Course Phase (Re-treatment) will not 
count towards the ORR and PFS of the primary endpoint in this trial. Visit requirements are 
outlined in Section 6.0 – Trial Flow Chart.
7.2
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, all adverse events must be reported by the 
investigator. Such events will be recorded at each examination on the Adverse Event case 
report forms/worksheets.  The reporting timeframe for adverse events meeting any serious 
criteria is described in section 7.2.3.1. The investigator will make every attempt to follow all 
subjects with non-serious adverse events for outcome.
Electronic reporting procedures can be found in the Electronic Data Capture (EDC) data 
entry guidelines. Paper reporting procedures can be found in the Investigator Trial File 
Binder (or equivalent).
7.2.1
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
NOTE: As of Amendment 02, INCB024360 is stopped from Part B, and text relating to 
overdose of INCB024360 is no longer applicable for Part B.
 
 
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In this trial, an overdose is any dose higher than ≥1000 mg (5 times the dose) of MK-3475 or 
≥1000 mg BID of INCB024360 or ≥20% of prescribed dosage for chemotherapy.  No 
specific information is available on the treatment of overdose of MK-3475 or INCB024360.  
In the event of overdose, the subject should be observed closely for signs of toxicity.  
Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
7.2.2
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them), including the pregnancy of a male subject's female partner 
that occurs during the trial.
Pregnancies and lactations of subjects and female partners of male subjects from the time the 
consent form is signed but before treatment allocation/randomization must be reported by the 
investigator if they cause the subject to be excluded from the trial, or are the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.  Pregnancies and lactations of subjects 
and female partners of male subjects that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported. All reported pregnancies must be followed to the 
completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, 
missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, 
miscarriage and stillbirth must be reported as serious events (Important Medical Events). If 
the pregnancy continues to term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
7.2.3
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
 
 
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●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 11 f or additional details regarding each of the above criteria.
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause, that occurs to any subject must be reported within 24 hours 
to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause, whether or not related to the 
Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI)  and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
 
 
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or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry 
guidelines.  Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
7.2.4
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
 
 
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Table 11
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
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7.2.5
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
7.3
TRIAL GOVERNANCE AND OVERSIGHT
7.3.1
Efficacy and Safety Evaluation Committee
The Efficacy and Safety Evaluation Committee (ESEC) will be established for the purpose of
evaluating the safety information of this study from the specialist and objective viewpoints to
ensure the safety of subjects.  Efficacy will not be reviewed by the ESEC.
The details of the ESEC are prescribed by separate instructions.
7.3.2
Independent Pulmonary Radiographic Adviser
An independent pulmonary radiographic adviser will review pulmonary radiographic
changes and its features using chest CT imaging if necessary.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If, after 
the study has begun, but prior to any final database lock, changes made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with International Conference on Harmonisation (ICH) 
Guideline E-9).  Changes to exploratory or other non-confirmatory analyses made after the 
protocol has been finalized, but prior to final database lock, will be documented in a 
supplemental statistical analysis plan (SAP [sSAP]) and referenced in the Clinical Study 
Report (CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the 
CSR.
The following analysis plan is applied to each Cohort in Part A (Cohorts 1 and 2) and Part B 
(Chemotherapy Cohorts 1, 2 and 3).
8.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized in below table. The 
comprehensive plan is provided in Sections 8.2 through 8.10.
 
 
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Study Design Overview
A Phase I Study of INCB024360 alone and in combination 
with Pembrolizumab (MK-3475) and in combination with 
Pembrolizumab (MK-3475) and Chemotherapy in Patients 
with Advanced Solid Tumors (KEYNOTE-434)
Treatment Assignment
This is an open-label study. 
Analysis Populations
All Subjects as Treated (ASaT)
Primary Endpoint(s)
Safety and tolerability of INCB024360 alone, INCB024360
in combination with MK-3475 and INCB024360 and 
Pembrolizumab in combination with Chemotherapy
Statistical Methods for 
Key Efficacy Analyses
The point estimate of ORR and 95% confidence interval 
will be provided using an exact binomial distribution.
Statistical Methods for 
Key Safety Analyses
Count and percentage of DLT in Cycle 1 and AE will be 
provided. 
Interim Analyses
DLTs observed in Cycle 1 will be used to determine 
tolerability (see Section 5.2.1.2.1).
Multiplicity
No multiplicity adjustment is planned
Sample Size and Power 
For DLT evaluation, on Part A, up to 9 patients for 
INCB024360 25 mg BID alone, 3 patients for INCB024360 
100 mg alone, and 3 to 9 subjects for each INCB024360
dose combination with MK-3475 are estimated. On Part B, 
6 subjects for each cohort are estimated. The total number 
of evaluable subjects is maximum of 60.
8.2
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
The Sponsor will generate the allocation schedule(s) for study treatment assignment for this 
protocol.
This trial is being conducted as an open-label trial (i.e. subjects, investigators, and
SPONSOR personnel will be aware of subject treatment assignments after each subject is
enrolled and treatment is assigned).
8.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0 – Objectives & Hypotheses.
8.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
8.4.1
Safety Endpoints
Primary Endpoints
The primary endpoint in this study is the incidence of DLTs observed in the DLT evaluation
period.
 
 
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Other Major Variables

Vital signs

Physical examination

ECOG performance status

12-lead ECG

Pulmonary radiographic findings

Adverse experiences

Complete blood count

Serum chemistry

Urinalysis
All toxicities will be graded and recorded according to the CTCAE version 4.0.  AEs will be 
analyzed including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes.  
8.4.2
Pharmacokinetic Endpoints
Pharmacokinetics will be evaluated as a secondary objective for MK-3475 and INCB024360. 
The serum concentrations of MK-3475 (Ctrough and Cmax) will be evaluated in combination of 
INCB024360 and in combination with INCB024360 and chemotherapy.
The pharmacokinetic profiles of INCB024360 will be assessed. Serial samples will be 
corrected alone and in combination with MK-3475 and MK-3475 in combination with
chemotherapy. Pharmacokinetic parameters (Cmax, Tmax, Ctrough, t1/2, AUC0-t) will be 
calculated from the plasma concentrations of INCB024360 for each treatment periods using a 
non-compartmental method with WinNONLIN. 
8.4.3
ADA Endpoints
The presence of ADA will be evaluated when administered concomitantly.  
8.4.4
Efficacy Endpoints
Efficacy will be evaluated as an exploratory objective for ORR, DOR, PFS, and OS per 
RECIST 1.1 by the local site.  
Objective Response Rate (ORR) – based on RECIST 1.1 as assessed by the local site  
Objective response rate is defined as the proportion of the subjects in the analysis population 
who have a complete response (CR) or partial response (PR). Responses are based on 
assessments by the local site per RECIST 1.1.
Duration of Overall Response (DOR) – based on RECIST 1.1 as assessed by the local 
site 
For subjects who demonstrate CR or PR, duration of response is defined as the time from 
first documented evidence of CR or PR until disease progression or death due to any cause, 
 
 
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whichever occurs first. Response and progression are based on assessments by the local site 
per RECIST 1.1.
Progression-free survival (PFS) – based on RECIST 1.1 as assessed by the local site 
Progression-free-survival (PFS) is defined as the time from first dose to the first documented 
disease progression per RECIST 1.1 based on assessments by the local site or death due to 
any cause, whichever occurs first. 
Overall Survival (OS)
Overall survival (OS) is defined as the time from first dose to death due to any cause. 
Subjects without documented death at the time of the analysis will be censored at the date of 
the last follow-up.
8.4.5
Exploratory Biomarker Research
Tumor biopsy analyses to evaluate IDO1 expression (+/-), PD-L1 expression (positive versus 
negative/indeterminate) in tumor tissue and immune cell infiltrate at baseline and correlate 
expression with response, PFS and/or OS.  The expression of exploratory histological 
biomarkers will also be assessed.  
8.5
Analysis Populations
8.5.1
Safety Analysis Populations
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this trial. The ASaT population consists of all allocated subjects who received at least one 
dose of trial treatment (INCB024360 administered alone or in combination with MK-3475 or 
MK-3475 in combination with chemotherapy). Subjects will be included in the dose level 
corresponding to the treatment dose they actually received for the analysis of safety data 
using the ASaT population.
At least one laboratory, 12-lead ECG or vital sign measurement obtained subsequent to at
least one dose of treatment dose is required for inclusion in the analysis of each specific
parameter. To assess change from baseline, a baseline measurement is also required.
8.5.2
PK/ADA Analysis Populations
The All Subjects who will be administered by INCB024360 alone and in combination with 
MK-3475 in advanced solid tumors (Part A) and in combination with MK-3475 and 
chemotherapy in advanced NSCLC (Part B), and will be drawn PK/ADA samples, will serve 
as the primary population for the analysis of PK/ADA data in this trial.  
8.5.3
Efficacy Analysis Populations
The All Subjects as Treated (ASaT) population will serve as the primary population for the 
analysis of efficacy data in this trial excluding:

Failure to receive at least one dose of trial treatment (INCB024360 alone or in 
combination with MK-3475 or in combination with MK-3475 and chemotherapy).
 
 
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The exploratory Biomarker analyses will be based on subjects who have evaluable 
Biomarker measurements. No explicit imputation was made for missing data.
8.6
Statistical Methods
8.6.1
Statistical Methods for Safety Analyses
Frequencies of DLTs during the DLT evaluation period [the first 1 week (Part A: cohort 1) 
and 3 weeks (Part A: cohort 2 and Part B) after initiation of study treatment] will be 
summarized by tabulating by dose level. If data is available, tables of summary statistics 
(mean, standard deviation, median, and range) for time to onset and duration of the first 
grade DLT AEs will be provided. All adverse events occur during and after cycle 1 will also 
be summarized. Laboratory assessments will be summarized. Adverse events will be 
summarized by tabulating the number (%) of subjects experiencing at least one adverse event 
within each system organ class and within each preferred term. Complete blood count, 
chemistry panel, urinalysis, pulmonary radiographic change findings, adverse events, 
electrocardiogram, vital signs, physical examination and ECOG PS will be summarized.
8.6.2
Statistical Methods for Pharmacokinetic Analyses
Descriptive statistics of the pharmacokinetic parameters of MK-3475 and INCB024360 will 
be calculated. The pharmacokinetic parameters of INCB024360 will be compared 
INCB024360 mono-therapy versus INCB024360+MK-3475 combo-therapy and versus 
INCB024360+MK-3475 + chemotherapy combo-therapy. 
8.6.3
Statistical Methods for Efficacy Analyses
The point estimate of ORR and 95% confidence interval (as determined by the upper and 
lower 97.5% one-sided confidence bounds) will be provided using an exact binomial 
distribution.  Response categories for target and non-target lesions for subjects with advanced 
solid tumors (complete response, partial response, progressive disease, and stable disease), 
DOR, PFS and OS will be tabulated across the various doses levels and will be summarized 
descriptively using Kaplan-Meier method. The Kaplan-Meier graphs will also be provided.
An exploratory analysis of a potential correlation between IDO1 expression (+/-), PD-L1 
expression levels and tumor response will be performed as appropriate.
8.7
Interim Analyses
No interim analysis is planned.
8.8
Multiplicity
Since the primary objective of this trial is to estimate safety and tolerability of INCB024360 
alone and in combination with MK-3475 and MK-3475 in combination with chemotherapy, 
no statistical hypotheses are tested, so no multiplicity adjustments will be applied to any p-
values generated or confidence intervals calculated.
No adjustment for multiplicity is 
planned.
 
 
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8.9
Sample Size and Power Calculations
The primary objective for the study is to evaluate the tolerability and safety profile of
INCB024360 alone and in combination with MK-3475 in advanced solid tumors (Part A) and  
MK-3475 in combination with chemotherapy in advanced NSCLC (Part B). The primary 
endpoints for the study are DLT rate. A mTPI (modified toxicity probability interval) design
suggested by Ji et al [1] targeting a 16.7% DLT rate for Part A and 30% for Part B will be
employed in safety assessment. Dose escalation/tolerability evaluation rules were described 
in 5.2.1.2. For DLT evaluation, on Part A, up to 9 patients for INCB024360 25 mg BID alone, 
3 patients for INCB024360 100 mg alone, and 3 to 9 subjects for each INCB024360 dose 
combination with MK-3475 are estimated. On Part B, 6 subjects for each cohort are 
estimated. The total number of evaluable subjects is maximum of 60.
8.10 Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study.  Any 
deviation from protocol-directed administration will be reported. 
MK-3475:  Compliance with protocol-directed MK-3475 will be measured by subjects: (1) 
receiving unscheduled study agent infusions/injections, (2) missing an infusion/injection, (3) 
receiving incorrect study agent dose, and (4) receiving an infusion at rate greater than 10 
mL/min. Numbers and percentages of subjects and infusion/injection visits with any 
deviation in these measures will be reported for the ASaT population.
INCB024360:  In this study, as part of the routine recording of the amount of study treatment 
taken by each subject will be counted, reviewed, and recorded at regular intervals.  These 
results will be used to calculate subject compliance.
Chemotherapy: In this study, as part of the routine recording of the amount of study 
treatment taken by each subject will be counted, reviewed, and recorded at regular intervals.  
These results will be used to calculate patient compliance.
For a subject who is followed for the entire study period, the “Number of INCB024360
Doses Should be on Therapy” is the total number of protocol specified doses from first
treatment day to the last scheduled day for treatment administration for that subject.  For a 
subject who discontinued from the study permanently, the “Number of INCB024360 Doses 
Should be on Therapy” is the total number of doses from first treatment day to the date the 
subject discontinued from the study.
For each subject, percent compliance will then be calculated using the following formula:
Summary statistics will be provided on percent compliance by treatment group for the ASaT
population.
 
 
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9.0 LABELING,
PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
9.1
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 12.  
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 12
Product Descriptions
Product Name & 
Potency
Dosage Form
Source/Additional Information
MK-3475 100 mg/ 4 mL
(pembrolizumab)
Solution for Infusion
Provided centrally by the Sponsor
INCB024360 25 mg
(epacadostat)
Tablet
Provided centrally by the Sponsor
INCB024360 100 mg
(epacadostat)
Tablet
Provided centrally by the Sponsor
9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive bottles of INCB024360 to satisfy patient treatment for one cycle.  No 
kitting is required for INCB024360.  MK-3475 will be provided as a kitted supply (2
vials/kit).
9.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
9.4
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
 
 
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Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
9.5
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for 
drug accountability and return, or local discard and destruction if appropriate.   Where local 
discard and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Confidentiality
10.1.1 Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
10.1.2 Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
10.1.3 Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
 
 
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2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
10.1.4 Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.2 Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.3 Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
 
 
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all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local laws, 
rules and regulations; and, for each subject participating in the trial, provide all data, and, 
upon completion or termination of the clinical trial, submit any other reports to the Sponsor 
as required by this protocol or as otherwise required pursuant to any agreement with the 
Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
 
 
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ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national regulations.  
For a single-center trial, the Protocol CI is the principal investigator.  In addition, the Sponsor 
must designate a principal or coordinating investigator to review the trial report that 
summarizes the trial results and confirm that, to the best of his/her knowledge, the report 
accurately describes the conduct and results of the trial [Clinical Study Report (CSR) CI].  
The Sponsor may consider one or more factors in the selection of the individual to serve as 
the Protocol CI and or CSR CI (e.g., availability of the CI during the anticipated review 
process, thorough understanding of clinical trial methods, appropriate enrollment of subject 
cohort, timely achievement of trial milestones).  The Protocol CI must be a participating trial 
investigator.
10.4 Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
10.5 Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
 
 
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functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
10.6 Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
10.7 Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
 
 
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due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
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11) Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet Oncol 
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positive selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191:891-897.
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is expressed by tumor-infiltrating immune cells and is associated with poor outcome for 
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22) Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan 
catabolism. Nat Rev Immunol 2004;4:762-774.
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Clin Invest 2007;117:1147-1154.
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expression in dendritic cell subsets suppresses T cell clonal expansion. J Immunol 
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25) Frumento G, Rotondo R, Tonetti M, et al.  Tryptophan-derived catabolites are 
responsible for inhibition of T and natural killer cell proliferation induced by 
indoleamine 2,3-dioxygenase. J Exp Med 2002;196:459-468.
 
 
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26) Fallarino F, Grohmann U, You S, et al. The combined effects of tryptophan starvation 
and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a 
regulatory phenotype in naive T cells. J Immunol 2006;176:6752-6761.
27) Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 
2006;6:295-307.
28) Munn DH, Zhou M, Attwood JT, et al. Prevention of allogeneic fetal rejection by 
tryptophan catabolism. Science 1998;281:1191-1193.
29) Uyttenhove C, Pilotte L, Théate I, et al. Evidence for a tumoral immune resistance 
mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med 
2003;9):1269-1274.
30) Muller AJ, DuHadaway JB, Donover PS, Sutanto-Ward E, Prendergast GC. Inhibition 
of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression 
gene Bin1, potentiates cancer chemotherapy. Nat Med 2005;11:312-319.
31) Huang L, Baban b, Johnson BA, Mellor AL. Dendritic cells, indoleamine 2,3 
dioxygenase and acquired immune privilege. Int Rev Immunol 2010;29:133-155.
32) Weinlich G, Murr C, Richardsen L, Winkler C, Fuchs D. Decreased serum tryptophan 
concentration predicts poor prognosis in malignant melanoma patients. Dermatology 
2007;214:8-14.
33) Okamoto A, Nikaido T, Ochiai K, et al. Indoleamine 2,3-dioxygenase serves as a 
marker of poor prognosis in gene expression profiles of serous ovarian cancer cells. 
Clin Cancer Res 2005;11:6030-6039.
34) Brandacher G, Perathoner A, Ladurner R, et al. Prognostic value of indoleamine 2,3-
dioxygenase expression in colorectal cancer: effect of tumor infiltrating T cells. Clin 
Cancer Res 2006;12:1144-1151.
35) Ino K, Yoshida N, Kajiyama H, et al. Indoleamine 2,3-dioxygenase is a novel 
prognostic indicator for endometrial cancer. Br J Cancer 2006;95:1555-1561.
36) Nakamura T, Shima T, Saeki A, et al. Expression of indoleamine 2, 3-dioxygenase and 
the recruitment of Foxp3-expressing regulatory T cells in the development and 
progression of uterine cervical cancer. Cancer Sci 2007;98:874-881.
37) Witkiewicz A, Williams TK, Cozzitorto J, et al. Expression of indoleamine 2,3-
dioxygenase in metastatic pancreatic ductal adenocarcinoma recruits regulatory T cells 
to avoid immune detection. J Am Coll Surg 2008;206:849-854.
38) Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma. N Engl J Med 2011;364:2517-2526. 
39) Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of 
Anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-2454.
40) Hamid O, Rober C, Daud A, et al. Safety and tumor responses with lambrolizumab 
(Anti-PD-1) in melanoma. N Engl J Med 2013;369:134-144.
41) Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced 
melanoma. N Engl J Med 2013;369:122-133.
 
 
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42) Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host 
immune response against cancer. Br J Cancer 2013;108:1560-1565.
43) Holmgaard RB, Zamarin D, Munn DH, Wolchok JD, Allison JP. Indoleamine 2,3-
dioxygenase is a critical resistance mechanism in antitumor T cell immunotherapy 
targeting CTLA-4. J Exp Med 2013;210:1389-1402.
44) Spranger S, Spaapen RM, Zha Y, Williams J, Meng Y, Ha TT, Gajewski TF. Up-
regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is 
driven by CD8(+) T cells. Sci Transl Med 2013;5:200ra116.
45) Gangadhar TC, Schneider BJ, Bauer TM, Wasser JS, Spira AI, Patel SP, et al. Efficacy 
and safety of epacadostat plus pembrolizumb treatment of NSCLC: Preliminary phase 
I/II results of ECHO-202/KEYNOTE-037 [abstract]. J Clin Oncol. 2017;35(15 Suppl). 
Abstract no. 9014.
46) Beatty GL, O'Dwyer PJ, Clark J, et al. First-in-Human Phase I Study of the Oral
Inhibitor of Indoleamine 2,3-Dioxygenase-1 Epacadostat (INCB024360) in Patients 
with Advanced Solid Malignancies. Clin Cancer Res. 2017 Jul 1;23(13):3269-3276.
47) Wolchok JD, Hoos A, O’Day S, Weber JS, Hamid O, Lebbe C, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. 
Clin Cancer Res 2009; 15: 7412-7420.
48) Wolchok JD, Hoos A, O'Day S, Weber JS, Hamid O, LebbéC, et al. Guidelines for the 
evaluation of immune therapy activity in solid tumors: immune-related response criteria. 
Clin Cancer Res 2009;15(23):7412-20.
49) Hodi FS, Ribas A, Daud A, Hamid O, Robert C, kefford R, et al. Evaluation of 
immune-related response criteria (irRC) in patients (pts) with advanced melanoma 
(MEL) treated with the anti-PD-1 monoclonal antibody MK-3475 [abstract]. Abstracts 
of the 2014 ASCO Annual Meeting; 2014 May 29 - Jun 2; Chicago, IL: ASCO; 2014. p. 
2.
50) Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet 
Oncol. 2017 Mar;18(3):e143-e152.
51) Boyer EW, Shannon M. The Serotonin Syndrome. N Engl J Med 2005;352:1112-20
52) Zhang Y, Bowman K, Diamond S, Yeleswaram S. Effects of Epacadostat with co-
administration of Linezolid on brain extracellular fluid concentrations of Serotonin. 
Poster session presented at: 2016 AAPS Annual Meeting And Exposition; 2016 Nov 
13-17; Denver, US.
53) Hamid O, Bauer TM, Spira AI, Smith DC, Olszanski AJ, Tarhini AA, et al. Safety of 
Epacadostat 100 mg BID Plus Pembrolizumab 200 mg Q3W in advanced solid tumors: 
Phase 2 data from ECHO 202/KEYNOTE-037. Poster session presented at: 53rd 
Annual Meeting of the American Society of Clinical Oncology; 2017 June 2–6; 
Chicago, IL.
 
 
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54) Gangadhar TC, Schneider BJ, Bauer TM, Wasser JS, Spira AI, Patel SP, et al. Efficacy 
and safety of epacadostat plus pembrolizumab treatment of NSCLC: preliminary phase 
1/2 results of ECHO-202/KEYNOTE-037. Poster session presented at: 53rd Annual 
Meeting of the American Society of Clinical Oncology (ASCO), 2017 June 2-6; 
Chicago, IL.
55) Smith TJ, Bohlke K, Lyman GH, Carson KR, Crawford J, Cross SJ, et al. 
Recommendations for the Use of WBC Growth Factors: American Society of Clinical 
Oncology Clinical Practice Guideline Update. J Cli.
56) Kohno N, Awaya Y, Oyama T, Yamakido M, Akiyama M, Inoue Y, et al. KL-6, a 
mucin-like glycoprotein, in bronchoalveolar lavage fluid from patients with interstitial 
lung disease. Am Rev Respir Dis. 1993; 148:637-42.
57) Obayashi T, Yoshida M, Tamura H, et al. Determination of plasma (1/3)-β-D-glucan: a 
new diagnostic aid to deep mycosis. J Med Vet Mycol. 1992; 30: 275-80.
 
 
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12.0 APPENDICES
12.1 Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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12.2 Eastern Cooperative oncology group (ECOG) Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
 
 
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12.3 Common Terminology Criteria for Adverse Events (CTCAE) v4.0
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be used for adverse event reporting 
(http://ctep.cancer.gov/reporting/ctc.html).
 
 
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12.4 Prohibited Monoamine Oxidase Inhibitors and Drugs Associated with Significant 
Monoamine Oxidase Inhibitory Activity
NOTE: As of Amendment 02, this section is updated to reflect the removal of
MAO inhibitors from prohibited medication list.
 
 
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12.5 Publication on Serotonin Syndrome
 
 
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12.6 Description of the iRECIST Process for Assessment of Disease Progression
NOTE: As of Amendment 02, iRECIST is no longer applicable and has been deleted
from this section. All imaging will be performed as per local standard of care guidelines
per RECIST 1.1. Participants with radiographic disease progression as determined by
RECIST 1.1 by investigator assessment will discontinue from pembrolizumab 
monotherapy; no confirmatory scans are required. However, if the participant is 
achieving a clinically meaningful benefit, an exception to continue with pembrolizumab 
monotherapy may be considered following consultation with the MSD.
 
 
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12.7 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 Criteria For 
Evaluating Response in Solid Tumors
RECIST version 1.1* will be used in this study for assessment of tumor response. While 
either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique 
in this study.
*REFERENCE:
Eisenhauer E.A, Therasse P, Bogaerts J, Schwartz L.H, Sargent D, Ford R, Dancey J, Arbuck 
S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij 
J. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009;45:228-47.
 
 
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12.8 List of Abbreviations
Abbreviation/Term
Definition
ADA
Anti-Drug Antibodies
AE
Adverse Event
ALP
alkaline phosphatase
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
ASaT
All Subjects as Treated
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
BCG
Bacillus Calmette–Guérin vaccine
BID
twice daily
CFR
Code of Federal Regulations
CI
Confidence Interval
CNS
Central Nervous System
CR
Complete Response
CrCl
Calculated Creatinine Clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
DKA
diabetic ketoacidosis
DLT
dose-limiting toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of Response
ECG
Electrocardiogram
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EOT
end of treatment
ERC
Ethics Review Committee
FFPE
Formalin-fixed, paraffin-embedded
GCP
Good Clinical Practice
G-CSF
Granulocyte-Colony Stimulating Factors
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
 
 
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Abbreviation/Term
Definition
IB
Investigator’s Brochure
ICF
Informed Consent Form
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
ICH
International Conference on Harmonization
IDO1
indoleamine 2,3 dioxygenase-1
IEC
independent ethics committee
Ig
immunoglobulin
IHC
Immunohistochemistry
iPR
iRECIST partial response
INR
International Normalized Ratio
IRB
Institutional Review Board
iRECIST
modified RECIST for immune-related RECISTbased therapeutics
irRECIST
Immune related RECIST (Modification of RECIST 1.1)
iSD
iRECIST stable disease
IUD
Intrauterine device
iUPD
iRECIST unconfirmed progressive disease
IV
Intravenous
LDH
Lactate Dehydrogenase
mAb
Monoclonal Antibody
MAOI
monoamine oxidase inhibitors
mcL
Microliters
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
mg/kg
Milligram per Kilogram
mL
milliliter
MRI
Magnetic Resonance Imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MTD
maximum tolerated dose
NA or N/A
Not Applicable
NCI
National Cancer Institute
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival
OTC
Over-the-counter
PD
pharmacodynamic or progressive disease
PD-1
Programmed Death-1
PD-L1
Programmed Death ligand-1
PET
positron emission tomography
 
 
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Abbreviation/Term
Definition
PFS
Progression Free Survival
PI
principal investigator
PK
Pharmacokinetic
PO
Oral Administration
PR
Partial Response
PS
Performance Status
PT
Prothrombin Time
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SCCHN
squamous cell carcinoma of the head and neck
SD
Stable Disease
SNRI
serotonin/norepinephrine reuptake inhibitors
SOP
Standard Operating Procedures
SS
serotonin syndrome
sSAP
supplemental SAP
ß-HCG
Beta Human Chorionic Gonadotropin
SSRI
serotonin reuptake inhibitors
Treg
regulatory T cell
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
 
 
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12.9 Clinical Study Conduct System
Clinical study conduct system in Japan is provided in Attachment by Japanese language.
 
 
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13.0 SIGNATURES
13.1 Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
13.2 Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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