A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Pembrolizumab (MK-3475) in Combination With Epacadostat or Placebo in Subjects With Unresectable or Metastatic Melanoma (Keynote-252 / ECHO-301)
Phase: PHASE3
Conditions: Melanoma
Sponsor: Incyte Corporation

1
Product:  MK-3475 (SCH 900475), INCB024360 
Protocol/Amendment No.: 252-10 (INCB 
24360-301-10) / NCT02752074
MK-3475-252-10 (INCB 24360-301-10) Final Protocol
18-May-2018
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.
This study is co-funded by Incyte and MSD. 
Execution of Trial:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Contact information can be found in the Investigator Trial File Binder (or 
equivalent).
Global Sponsor of the Study:
Incyte Corporation (Referenced herein as Sponsor)
1801 Augustine Cut-Off
Wilmington, Delaware, 19803, U.S.A
TITLE:
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of Pembrolizumab (MK-
3475) in Combination With Epacadostat or Placebo in Subjects with Unresectable or 
Metastatic Melanoma (KEYNOTE-252 / ECHO-301)
IND NUMBER:  121,704
EudraCT NUMBER:  2015-004991-31
04XN7M

Product:  MK-3475 (SCH 900475), INCB024360
2
Protocol/Amendment No.: 252-10 (INCB 24360-301-10)
MK-3475-252-10 (INCB 24360-301-10) Final Protocol
18-May-2018
Confidential
TABLE OF CONTENTS
SUMMARY OF CHANGES.................................................................................................14
1.0
TRIAL SUMMARY...................................................................................................29
2.0
TRIAL DESIGN.........................................................................................................30
Trial Design ............................................................................................................30
2.1
Trial Diagram.........................................................................................................31
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES)...................................................................32
Primary Objective(s) & Hypothesis(es) ...............................................................32
3.1
Secondary Objective(s) & Hypothesis(es)............................................................32
3.2
33
4.0
BACKGROUND & RATIONALE...........................................................................34
Background ............................................................................................................34
4.1
Pharmaceutical and Therapeutic Background .....................................................34
4.1.1
4.1.1.1
Inhibition of PD-1 as a Target for Cancer ....................................................35
4.1.1.2
Inhibition of Indoleamine 2,3–Dioxygenase as a Target for Cancer ............35
4.1.1.3
Combined Immune Checkpoint Inhibition ...................................................37
4.1.1.4
Overview of Metastatic Melanoma...............................................................38
4.1.1.5
Treatment for Advanced or Metastatic Melanoma .......................................39
Pre-clinical and Clinical Trials ............................................................................41
4.1.2
Ongoing Clinical Trials........................................................................................41
4.1.3
Rationale.................................................................................................................41
4.2
Rationale for the Trial and Selected Subject Population .....................................41
4.2.1
4.2.1.1
Rationale for Combining PD-1 Inhibitor and IDO1 Inhibitor in 
Melanoma .....................................................................................................41
 
 
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Protocol/Amendment No.: 252-10 (INCB 24360-301-10)
MK-3475-252-10 (INCB 24360-301-10) Final Protocol
18-May-2018
Confidential
Rationale for Dose Selection/Regimen/Modification ..........................................42
4.2.2
4.2.2.1
Justification for Treatment Regimen ............................................................42
4.2.2.2
Rationale for a Fixed Dose of Pembrolizumab.............................................43
Rationale for Endpoints .......................................................................................44
4.2.3
4.2.3.1
Efficacy Endpoints........................................................................................44
4.2.3.1.1
Primary Efficacy Endpoints...................................................................44
4.2.3.1.2
Secondary Efficacy Endpoints...............................................................44
45
4.2.3.2
Immune-related RECIST (irRECIST) ..........................................................45
4.2.3.3
Patient Reported Outcomes...........................................................................46
4.2.3.4
Safety Endpoints ...........................................................................................46
4.2.3.5
Pharmacokinetic Endpoints ..........................................................................46
4.2.3.6
Pharmacodynamic Endpoints........................................................................46
46
47
47
47
48
48
49
Benefit/Risk ............................................................................................................49
4.3
Risks from Epacadostat........................................................................................49
4.3.1
Risks from Pembrolizumab..................................................................................51
4.3.2
Risks for the Combination of Pembrolizumab and Epacadostat..........................51
4.3.3
 
 
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18-May-2018
Confidential
5.0
METHODOLOGY ....................................................................................................52
Entry Criteria.........................................................................................................52
5.1
Diagnosis/Condition for Entry into the Trial .......................................................52
5.1.1
Subject Inclusion Criteria.....................................................................................52
5.1.2
Subject Exclusion Criteria ...................................................................................55
5.1.3
Trial Treatment(s) .................................................................................................58
5.2
Dose Selection/Modification ...............................................................................58
5.2.1
5.2.1.1
Dose Selection (Preparation) ........................................................................58
5.2.1.2
Dose Modification (Escalation/Titration/Other)...........................................58
5.2.1.3
Dose Modification and Toxicity Management of Infusion-reactions 
Related to Pembrolizumab............................................................................63
5.2.1.4
Procedures for Subjects Exhibiting Serotonin Syndrome (SS).....................65
5.2.1.5
Dose Interruptions Unrelated to Adverse Events..........................................66
Timing of Dose Administration ...........................................................................66
5.2.2
5.2.2.1
Timing of Dose Administration of Pembrolizumab .....................................66
Trial Blinding.......................................................................................................67
5.2.3
Randomization or Treatment Allocation.............................................................67
5.3
Stratification...........................................................................................................67
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited).....................68
5.5
Acceptable Concomitant Medications .................................................................68
5.5.1
Prohibited Medications and Measures .................................................................68
5.5.2
Rescue Medications & Supportive Care..............................................................69
5.6
Supportive Care Guidelines for Pembrolizumab .................................................69
5.6.1
Diet/Activity/Other Considerations......................................................................70
5.7
Diet.......................................................................................................................70
5.7.1
 
 
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Protocol/Amendment No.: 252-10 (INCB 24360-301-10)
MK-3475-252-10 (INCB 24360-301-10) Final Protocol
18-May-2018
Confidential
Contraception.......................................................................................................70
5.7.2
Pregnancy.............................................................................................................72
5.7.3
Use in Nursing Women........................................................................................73
5.7.4
Subject Withdrawal/Discontinuation Criteria....................................................73
5.8
Discontinuation of Treatment ..............................................................................73
5.8.1
Withdrawal from the Trial ...................................................................................75
5.8.2
Subject Replacement Strategy..............................................................................75
5.9
Beginning and End of the Trial ............................................................................75
5.10
Clinical Criteria for Early Trial Termination ....................................................75
5.11
6.0
TRIAL FLOW CHART ............................................................................................77
Trial Flow Chart ....................................................................................................77
6.1
7.0
TRIAL PROCEDURES ............................................................................................81
Trial Procedures ....................................................................................................81
7.1
Administrative Procedures...................................................................................81
7.1.1
7.1.1.1
Informed Consent..........................................................................................81
7.1.1.1.1
General Informed Consent.....................................................................81
82
7.1.1.2
Inclusion/Exclusion Criteria .........................................................................82
7.1.1.3
Subject Identification Card ...........................................................................82
7.1.1.4
Medical History ............................................................................................82
7.1.1.5
Prior and Concomitant Medications Review ................................................82
7.1.1.5.1
Prior Medications...................................................................................82
7.1.1.5.2
Concomitant Medications......................................................................82
7.1.1.6
Assignment of Screening Number................................................................83
 
 
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MK-3475-252-10 (INCB 24360-301-10) Final Protocol
18-May-2018
Confidential
7.1.1.7
Assignment of Treatment/Randomization Number ......................................83
7.1.1.8
Trial Compliance (Medication).....................................................................83
7.1.1.8.1
Administration of Pembrolizumab and Compliance .............................84
7.1.1.8.2
Dispensing of Pembrolizumab...............................................................84
7.1.1.8.3
Distribution of Subject Reminder Cards and Serotonin Syndrome 
(SS) Information Sheet ..........................................................................84
7.1.1.9
Poststudy Anticancer Therapy Status ...........................................................84
Clinical Procedures/Assessments.........................................................................84
7.1.2
7.1.2.1
Adverse Events .............................................................................................84
7.1.2.2
Full Physical Examination ............................................................................85
7.1.2.3
Directed Physical Examination.....................................................................85
7.1.2.4
Vital Signs.....................................................................................................85
7.1.2.5
Twelve-Lead Electrocardiograms.................................................................85
7.1.2.6
Performance and Quality of Life Assessments .............................................85
7.1.2.6.1
Eastern Cooperative Oncology Group Performance Status...................85
86
86
86
87
Tumor Biopsy/Archival Tissue Collection ..........................................................87
7.1.3
Tumor Biopsy ......................................................................................................87
7.1.4
Tumor Imaging and Assessment of Disease ........................................................87
7.1.5
7.1.5.1
Initial Tumor Imaging...................................................................................87
7.1.5.2
Tumor Imaging During the Study.................................................................88
7.1.5.2.1
End of Treatment and Follow-up Tumor Imaging.................................89
 
 
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18-May-2018
Confidential
7.1.5.3
Assessment of Disease According to irRECIST and RECIST 1.1 ...............89
7.1.5.4
Photography for Cutaneous Lesions .............................................................91
Laboratory Procedures/Assessments ...................................................................91
7.1.6
7.1.6.1
Hematology, Hemostatic Panel, Serology, Urinalysis and Endocrine 
Function Testing ...........................................................................................91
7.1.6.2
Serum Chemistry and Liver Function Tests .................................................91
7.1.6.3
Pregnancy Testing.........................................................................................92
7.1.6.4
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) ...92
7.1.6.5
Pharmacokinetic/Pharmacodynamic Evaluations .........................................93
7.1.6.5.1
Blood Sample Collection for PK of Pembrolizumab.............................94
7.1.6.5.2
Blood Sample Collection for Anti-pembrolizumab Antibodies ............94
7.1.6.5.3
Blood Sample Collection for PK of Epacadostat...................................94
7.1.6.5.4
Pharmacodynamic Assessments ............................................................95
95
Other Procedures..................................................................................................96
7.1.7
7.1.7.1
Withdrawal/Discontinuation.........................................................................96
96
7.1.7.1.2
Lost to Follow-up...................................................................................96
7.1.7.2
Blinding/Unblinding .....................................................................................97
7.1.7.3
Calibration of Equipment..............................................................................97
Visit Requirements...............................................................................................98
7.1.8
7.1.8.1
Screening Visit..............................................................................................98
7.1.8.2
Treatment Period Visit..................................................................................98
7.1.8.3
End of Treatment ..........................................................................................98
7.1.8.4
Post-Treatment Visits....................................................................................99
 
 
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18-May-2018
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7.1.8.4.1
Safety Follow-Up Visit..........................................................................99
7.1.8.4.2
Follow-Up Visits....................................................................................99
7.1.8.4.3
Survival Follow-Up .............................................................................100
7.1.8.5
Unscheduled Visits .....................................................................................100
7.1.8.6
Survival Status ............................................................................................100
Assessing and Recording Adverse Events .........................................................100
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose.........101
7.2.1
Reporting of Pregnancy and Lactation...............................................................102
7.2.2
Immediate Reporting of Adverse Events...........................................................102
7.2.3
7.2.3.1
Serious Adverse Events ..............................................................................102
7.2.3.2
Events of Clinical Interest...........................................................................103
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting ...........104
Evaluating Adverse Events ................................................................................104
7.2.4
Responsibility for Reporting Adverse Events....................................................107
7.2.5
TRIAL GOVERNANCE AND OVERSIGHT ..................................................107
7.3
Scientific Advisory Committee..........................................................................107
7.3.1
Executive Oversight Committee ........................................................................107
7.3.2
Data Monitoring Committee ..............................................................................107
7.3.3
8.0
STATISTICAL ANALYSIS PLAN .......................................................................108
Statistical Analysis Plan Summary ....................................................................108
8.1
Responsibility for Analyses/In-House Blinding ................................................110
8.2
Hypotheses/Estimation ........................................................................................110
8.3
Analysis Endpoints ..............................................................................................111
8.4
Efficacy Endpoints.............................................................................................111
8.4.1
 
 
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18-May-2018
Confidential
Safety Endpoints ................................................................................................111
8.4.2
Analysis Population .............................................................................................112
8.5
Efficacy Analysis Population.............................................................................112
8.5.1
Safety Analysis Populations ..............................................................................112
8.5.2
Statistical Methods...............................................................................................112
8.6
Statistical Methods for Efficacy Analyses .........................................................112
8.6.1
8.6.1.1
Progression-Free Survival (PFS) ................................................................112
8.6.1.2
Overall Survival (OS) .................................................................................114
8.6.1.3
Objective Response Rate (ORR) ................................................................114
Statistical Methods for Safety Analyses ............................................................115
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other Analyses ...117
8.6.3
Interim Analyses ..................................................................................................117
8.7
Efficacy Interim Analyses..................................................................................117
8.7.1
Safety Interim Analyses.....................................................................................119
8.7.2
Multiplicity ...........................................................................................................119
8.8
Sample Size and Power Calculations .................................................................120
8.9
Sample Size and Power for Efficacy Analyses ..................................................120
8.9.1
Subgroup Analyses and Effect of Baseline Factors ..........................................122
8.10
Compliance (Medication Adherence).................................................................122
8.11
Extent of Exposure...............................................................................................123
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................123
Investigational Product .......................................................................................123
9.1
Packaging and Labeling Information ................................................................123
9.2
Clinical Supplies Disclosure................................................................................123
9.3
 
 
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18-May-2018
Confidential
Storage and Handling Requirements.................................................................124
9.4
Discard/Destruction/Returns and Reconciliation .............................................124
9.5
Standard Policies..................................................................................................125
9.6
10.0
ADMINISTRATIVE AND REGULATORY DETAILS......................................125
Confidentiality......................................................................................................125
10.1
Confidentiality of Data ......................................................................................125
10.1.1
Confidentiality of Subject Records ....................................................................125
10.1.2
Confidentiality of Investigator Information.......................................................126
10.1.3
Confidentiality of IRB/IEC Information............................................................126
10.1.4
Compliance with Financial Disclosure Requirements......................................126
10.2
Compliance with Law, Audit and Debarment ..................................................127
10.3
Compliance with Trial Registration and Results Posting Requirements .......129
10.4
Quality Management System..............................................................................129
10.5
Data Management................................................................................................129
10.6
Publications ..........................................................................................................129
10.7
11.0
LIST OF REFERENCES........................................................................................130
12.0
APPENDICES..........................................................................................................135
Merck Code of Conduct for Clinical Trials.......................................................135
12.1
138
143
Eastern Cooperative Oncology Group Performance Status............................152
12.4
Prohibited Monoamine Oxidase Inhibitors and Drugs Associated with 
12.5
Significant Monoamine Oxidase Inhibitory Activity........................................153
Common Terminology Criteria for Adverse Events v4.0 ................................154
12.6
 
 
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18-May-2018
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 ........................155
12.7
Publication on Serotonin Syndrome ..................................................................156
12.8
List of Abbreviations ...........................................................................................165
12.9
R Code for Calculations of Sample Size and Monitoring Boundaries for 
12.10
Progression-Free Survival...................................................................................168
13.0
SIGNATURES..........................................................................................................170
Sponsor's Representative ....................................................................................170
13.1
Investigator...........................................................................................................170
13.2
 
 
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Protocol/Amendment No.: 252-10 (INCB 24360-301-10)
MK-3475-252-10 (INCB 24360-301-10) Final Protocol
18-May-2018
Confidential
LIST OF TABLES
Table 1
Trial Treatment ......................................................................................................58
Table 2
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab....................................................................60
Table 3
Infusion Reaction Treatment Guidelines ...............................................................63
Table 4
Sign and Symptoms of Serotonin Syndrome.........................................................66
Table 5
Imaging and Treatment after First Radiographic Evidence of Progressive 
Disease...................................................................................................................90
Table 6
Laboratory Tests ....................................................................................................92
Table 7
Sample Collection Time Windows for Pharmacokinetic Assessments for 
Epacadostat or Matching Placebo at SELECT Centers ONLY.............................95
Table 8
Sample Collection Time Windows for Pharmacokinetic Assessments for 
Epacadostat or Matching Placebo at ALL Centers................................................95
Table 9
Plasma Samples for Pharmacodynamic Assessment.............................................95
Table 10
Evaluating Adverse Events..................................................................................105
Table 11
Censoring Rules for Primary and Sensitivity Analyses of PFS...........................113
Table 12
Analysis Strategy for Key Efficacy Variables.....................................................115
Table 13
Analysis Strategy for Safety Parameters..............................................................116
Table 14
Summary of Interim Analysis Strategy................................................................118
Table 15
Decision Guidance at IA1 and IA2 PFS Analyses and Each OS Analysis 
under a Hypothetical Timings of Interim Analyses and Initially Assigned 
Alpha....................................................................................................................118
Table 16
Product Descriptions............................................................................................123
 
 
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Protocol/Amendment No.: 252-10 (INCB 24360-301-10)
MK-3475-252-10 (INCB 24360-301-10) Final Protocol
18-May-2018
Confidential
LIST OF FIGURES
          
Figure 1
Original Study Design..........................................................................................31
Figure 2
Study Design as of Amendment 10 .....................................................................31
Figure 3
Graphical Display of Testing Strategy...............................................................120
 
 
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Protocol/Amendment No.: 252-10 (INCB 24360-301-10)
MK-3475-252-10 (INCB 24360-301-10) Final Protocol
18-May-2018
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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 
Trial Summary
Addition of notes to clarify the removal of 
epacadostat and placebo from the trial and that all 
subjects remaining in the trial will receive open-
label pembrolizumab only as of Amendment 10.
An interim review of the data 
indicated no benefit of epacadostat 
over placebo when combined with 
pembrolizumab. The external Data 
Monitoring 
Committee 
(DMC) 
recommended that all subjects be 
unblinded and all epacadostat and 
placebo administration stop.
The 
study will remain open so that 
subjects still on study will have 
continued 
access 
to 
pembrolizumab.
All references to epacadostat and 
placebo, as well as assessments/ 
procedures 
specific 
to 
these 
treatments, are removed from the 
protocol. Where deletion of text 
could cause confusion, due to the 
design of the study to date, the text 
has been left unchanged and a note 
has been added.
2.1
Trial Design
Addition of a note to describe the removal of 
epacadostat and placebo and that all subjects 
remaining in the trial will receive open-label 
pembrolizumab only as of Amendment 10.
Addition 
of 
text 
summarizing 
the 
DMC 
recommendations.
2.2
Trial Diagram
Figure 2  Study Design as 
of Amendment 10
New Figure 2 showing the updated study design.
4.1
4.2
4.3
Background
Rationale
Benefit/Risk
Addition of notes to clarify which sections and text 
are no longer applicable due to removal of 
epacadostat and placebo.
5.2
Trial Treatment(s)
Addition of note that only pembrolizumab will be 
administered. 
Other treatments (prior to this 
amendment) are deleted.
5.2
Trial Treatment(s)
Table 1  Trial Treatment
Deletion of epacadostat and placebo.
 
 
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.1.2
Dose Modification 
(Escalation/Titration/Other)
Deletion of text relating to dose modification of 
epacadostat.
5.2.1.2
Dose Modification 
(Escalation/Titration/Other)
Table 2  Dose Modification 
and Toxicity Management 
Guidelines for Immune-
related AEs Associated 
with Pembrolizumab
The dose modification table has been reverted to 
the standard table for pembrolizumab alone.
5.2.1.2
Dose Modification 
(Escalation/Titration/Other)
Table 3  Dose Level 
Adjustment of Epacadostat 
or Matching Placebo
Deletion of table.
5.2.3.2
Timing of Dose 
Administration of 
Epacadostat
Deletion of section.
5.6.2
Supportive Care Guidelines 
for Epacadostat or 
Matching Placebo
Deletion of section.
6.1
Trial Flow Chart
Deletion of rows for epacadostat and placebo 
administration and dispensing. Deletion of row for 
subject reminder card.
7.1.1.8
Trial Compliance 
(Medication)
Deletion of text and subsections relating to 
epacadostat/placebo compliance.
 
 
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18-May-2018
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
7.2.1
Definition of an Overdose 
for This Protocol and 
Reporting of Overdose
Deletion of the definition of overdose for 
epacadostat.
9.1
Investigational Product
Deletion 
of 
information 
relating 
to 
epacadostat/placebo.
9.2
Packaging and Labeling 
Information
Deletion 
of 
information 
relating 
to 
epacadostat/placebo.
1.0
Trial Summary
Deletion of text relating to Second Course.
Given the findings of the study, 
subjects 
will 
be 
provided 
pembrolizumab monotherapy up to 
a total of 35 cycles, the Second 
Course of treatment will not be 
offered, and data collection will be 
limited.
5.2.2
Second 
Course 
Phase 
(Retreatment Period)
Deletion of section.
5.8
Subject 
Withdrawal/ 
Discontinuation criteria
Deletion of text relating to retreatment.
5.8.1
Discontinuation 
of 
Treatment
Deletion of text relating to Second Course 
(retreatment).
6.2
Trial Flow Chart – Second 
Course 
Phase 
(Retreatment)
Deletion of Flow Chart.
7.1.1.5.2
Concomitant Medications
Deletion of text relating to Second Course.
7.1.5.2.2
Second 
Course 
(Retreatment) 
Tumor 
Imaging
Deletion of section.
7.1.6
Laboratory 
Procedures/Assessments
Deletion of text relating to laboratory procedures 
for Second Course.
 
 
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
7.1.8.4.1.1 
(now 
Section 
7.1.8.4.1)
Safety Follow-up Visit
Deletion of text relating to eligibility for Second 
Course treatment.
1.0
Trial Summary
Addition of note that the last trial visit is the Safety 
Follow-up Visit.
Given the findings of the study, the
study will close once all subjects 
complete 
treatment 
of
pembrolizumab (up to a total of 
35 cycles). 
The final visit in the study will be 
the Safety Follow-up Visit. There 
will be no follow-up for survival 
status.  Subjects currently in 
follow-up or in survival follow-up 
are considered to have completed 
the study.  However, standard 
safety reporting should continue, as 
applicable.
2.1
Trial Design
Deletion of text relating to follow-up of subjects 
who discontinue for reasons other than disease 
progression.
5.8
Subject 
Withdrawal/ 
Discontinuation criteria
Deletion of text relating to follow-up of subjects 
for survival data.
5.8.1
Discontinuation 
of 
Treatment
Deletion of text relating to follow-up of subjects 
after treatment discontinuation.
6.1
Trial Flow Chart
Deletion of columns for Follow-up and Survival 
Follow-up. 
Deletion of row for survival status 
assessment.
7.1.1.9
Poststudy 
Anticancer 
Therapy Status
Assessment of poststudy anticancer therapy will 
end at the Safety Follow-up Visit.
7.1.5.2.1
End 
of 
Treatment 
and 
Follow-up Tumor Imaging
Deletion of text relating to follow-up of subjects 
after treatment discontinuation.
 
 
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
7.1.7.1
Withdrawal/ 
Discontinuation
Deletion of text indicating that 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.  Subjects are considered to 
have completed the study after attending the Safety 
Follow-up Visit.
7.1.7.1.2
Lost to Follow-up
Addition of a note that this is no longer applicable. 
There will be no additional efforts to contact 
subjects who are lost to follow-up.
7.1.8.4.1.1 
(now 
Section 
7.1.8.4.1)
Safety Follow-up Visit
Addition of note that the last trial visit is the Safety 
Follow-up Visit. 
Addition of clarification that 
subjects currently in follow-up or in survival 
follow-up are considered to have completed the 
study; these subjects are not required to attend any 
further visits.  Assessment and recording of AEs 
will be performed as per Section 7.2.
Deletion of text about follow-up of AEs that is 
covered in Section 7.2.
7.1.8.4.1.2 
(now 
Section 
7.1.8.4.2)
Follow-up Visits
Addition of a note that this section is no longer 
applicable.  A subject will be considered to have 
completed this study once they have attended the 
Safety Follow-up Visit.  Subjects currently in 
follow-up are considered to have completed the 
study; these subjects are not required to attend any 
further visits.  Assessment and recording of AEs 
will be performed as per Section 7.2.
 
 
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
7.1.8.4.1.3 
(now 
Section 
7.1.8.4.3)
Survival Follow-up
Addition of a note that this section is no longer 
applicable.
Subjects 
currently 
in 
survival 
follow-up are considered to have completed the 
study; these subjects will no longer be contacted 
for survival information.  Assessment and 
recording of AEs will be performed as per 
Section 7.2.
7.1.8.6
Survival Status
Addition of a note that this section is no longer 
applicable. 
 
Subjects 
currently 
in 
survival 
follow-up are considered to have completed the 
study; these subjects will no longer be contacted 
for survival information.  Assessment and 
recording of AEs will be performed as per 
Section 7.2.
3.2
Secondary Objectives
Addition of a note that pharmacokinetic (PK) and 
antidrug antibodies (ADA) samples will no longer 
be collected.
Further collection of samples in 
subjects receiving pembrolizumab 
alone is not required.
Blood 
samples for PK and ADA may be 
stored. Analysis will be performed 
if required.
4.2.3.5
Pharmacokinetic Endpoints
Addition of a note that PK and ADA samples will 
no longer be collected.
6.1
Trial Flow Chart
Deletion of rows for samples collection for PK and 
ADA, and associated footnote.
7.1.6.5 and 
subsections
Pharmacokinetic/
Pharmacodynamic 
Evaluations
Addition of a note that
this section (and 
subsections) is no longer applicable.
 
 
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18-May-2018
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.1.4
Procedures 
for 
Subjects 
Exhibiting 
Serotonin 
Syndrome (SS)
Addition of a note that this section is no longer 
applicable.
Subjects 
will 
no 
longer 
be 
receiving epacadostat, so activities 
and procedures relating to serotonin 
syndrome (an expected adverse 
reaction for epacadostat, but not for 
pembrolizumab) management and 
reporting is no longer needed.
6.1
Trial Flow Chart
Deletion 
of 
row 
for 
serotonin 
syndrome 
information sheet.
7.2.3.2
Events of Clinical Interest
Deletion of text for serotonin syndrome.
12.8
Publication on Serotonin 
Syndrome
Addition of a note that this section is no longer 
applicable.
5.2.4 (now 
Section 
5.2.3)
Trial Blinding
Addition of a note that blinding is no longer 
applicable – all subjects will receive open-label 
pembrolizumab alone.
Based on DMC recommendation, 
all 
subjects 
stopped 
receiving 
blinded epacadostat/placebo. 
All 
subjects remaining in the trial will 
continue 
on 
open-label 
pembrolizumab alone.
7.1.7.2
Blinding/Unblinding
Addition of a note that blinding is no longer 
applicable – all subjects will receive open-label 
pembrolizumab alone.
9.3
Clinical 
Supplies 
Disclosure
Deletion of text relating to treatment blinding.
 
 
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18-May-2018
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.5.2
Restricted Medications and 
Measures
Deletion of section.
Subjects 
will 
no 
longer 
be 
receiving epacadostat, so restricted 
concomitant 
medications 
and 
prohibited medications related to 
epacadostat are no longer needed.
5.5.3 (now 
Section 
5.5.2)
Prohibited Medications and 
Measures
Removal of bullets for monoamine oxidase 
inhibitors and UGT1A9 inhibitors (or analogs).
12.5
Prohibited 
Monoamine 
Oxidase 
Inhibitors 
and 
Drugs 
Associated 
with 
Significant 
Monoamine 
Oxidase Inhibitory Activity
Addition of a note that this section is no longer 
applicable.
5.7.2
5.7.3
5.7.4
Contraception
Pregnancy
Use in nursing women
Text relating to epacadostat in these sections is no 
longer applicable and has been deleted.
Text relating to contraception, 
pregnancy 
and 
nursing 
requirements in subjects receiving 
epacadostat is no longer applicable. 
Pregnancy testing will revert to 
standard of care
for subjects 
receiving pembrolizumab.
6.1
Trial Flow Chart
Pregnancy testing is changed to monthly per local 
regulations, as applicable.
7.1.6.3
Pregnancy Testing
Pregnancy testing is changed to monthly per local 
regulations, as applicable.
 
 
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18-May-2018
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
7.2
Assessing and Recording 
Adverse Events
Adverse events (AEs) will be reported from the 
time of treatment allocation/randomization through 
30 days following cessation of treatment or if the 
subject initiates new anticancer therapy, whichever 
is earlier.
By the time Amendment 10 is 
approved
and 
implemented, 
subjects will have been off of 
epacadostat for >~90 days.  Thus, 
AE reporting will change to the 
pembrolizumab 
monotherapy 
standard.
7.2.3.1
Serious Adverse Events
Serious adverse events (SAEs) will be reported 
from treatment allocation/randomization through 
90 days following cessation of treatment, or 
30 days following cessation of trial treatment if the 
subject initiates new anticancer therapy, whichever 
is earlier.
7.2.4
Evaluating Adverse Events
Deletion of text stating that, 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.
As 
pembrolizumab 
is 
now 
administered as single agent (ie, not 
in combination), this text is no 
longer applicable.
4.2.3.1.1
Primary Efficacy Endpoints
Addition of a note that central imaging vendor 
assessment will no longer be required.
As all subjects are now receiving 
pembrolizumab, study procedures 
are reduced to the minimum 
requirement 
for 
investigational 
pembrolizumab administration to 
minimize 
subject 
assessment 
burden.
4.2.3.3
Patient Reported Outcomes
Addition of a note that ePRO assessments are no 
longer being collected.
6.1
Trial Flow Chart (including 
footnotes)
Change of full physical examination to directed 
physical examination, per standard of care or as 
clinically indicated, at End of Treatment (EOT) 
and Safety Follow-up Visit.
Change of ECG at EOT visit to be per standard of 
care or as clinically indicated.
 
 
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18-May-2018
Confidential
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
Deletion of patient reported outcome (PRO) 
assessments and associated footnote.
Change of laboratory assessments (including 
thyroid function and coagulation factors) from 
Cycle 4 onwards to be per standard of care or as 
clinically indicated.
Deletion of the optional request for tumor biopsy 
at Weeks 12, 24, and disease progression.
Change of tumor imaging timing to standard of 
care.  Removal of the requirement to send tumor 
imaging to the central imaging vendor.  A repeat 
scan is not required if the investigator opts to 
discontinue the subject at the initial PD.
Deletion of digital photography assessment and 
associated footnote.
Addition of poststudy anticancer therapy status 
assessment at EOT and at Safety Follow-up Visit.
 
 
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18-May-2018
Confidential
Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
7.1.2.2
7.1.2.3
Full Physical Examination
Directed 
Physical 
Examination
Update to reflect the change from full physical 
examination to directed physical examination, per 
standard of care or as clinically indicated, at EOT 
and Safety Follow-up Visit.
Study procedures are reduced to the 
minimum 
requirement 
for 
investigational 
pembrolizumab 
administration to minimize subject 
assessment burden.
7.1.2.6.2
Patient Reported Outcomes
Addition of a note that this section (and 
subsections) is no longer applicable.
7.1.4
Tumor Biopsy
Deletion of optional tumor biopsy collection at 
Week 12, Week 24, and at disease progression.
7.1.5
Tumor 
Imaging 
and 
Assessment of Disease
Addition of a note that central imaging vendor 
assessment is no longer required.  Disease 
assessments will be performed by the site 
investigator/radiology assessment, per standard of 
care.
Amendment of subsections to remove specific 
timing of assessments; timing should follow the 
site’s standard of care for oncologic tumor 
assessment until initial PD per RECIST 1.1.  A 
repeat scan is not required if the investigator opts 
to discontinue the subject at the initial PD.  
Removal of text regarding repeat imaging to 
confirm PR and CR.
7.1.5.4
Photography for Cutaneous 
Lesions
Addition of a note that this section is no longer 
applicable.
 
 
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18-May-2018
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Section 
Number (s)
Section Title(s)
Description of Change (s)
Rationale
After their review of the second 
interim analysis (IA) results, the 
DMC indicated that the comparison 
of PFS by randomized treatment 
assignment did not reach the 
protocol specified criterion for 
statistical significance and further 
the co-primary endpoint OS was 
unlikely 
to 
reach 
statistical 
significance 
for 
the 
study.  
Therefore, the DMC recommended 
that the study will stop further 
efficacy analyses.  Due to the 
current status of the study, the 
statistical analysis may be modified 
and will be reported in the CSR.
8.1
Statistical Analysis Plan 
Summary
Addition of a note that, based on recommendation 
from DMC at IA2, all subjects stopped oral therapy 
(epacadostat/placebo) and only selected analyses 
will be performed after study completion.
 
 
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Protocol/Amendment No.: 252-10 (INCB 24360-301-10)
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18-May-2018
Confidential
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.2.1.2
Dose 
Modification 
(Escalation/Titration/Other)
Minor language change in paragraph 2.
To clarify the language.
5.2.1.2
Dose 
Modification 
(Escalation/Titration/Other)
Table 2  Dose Modification 
and Toxicity Management 
Guidelines for Immune-
related 
AEs 
Associated 
with Pembrolizumab
Added that, in case of recurrent Grade 3 colitis, 
subjects will permanently discontinue treatment.
To 
align 
with
KEYTRUDA® 
Summary of Product Characteristics
and the Company Core Data Sheet.
5.2.1.5
Dose 
Interruptions 
Unrelated 
to 
Adverse 
Events
New text added.
To clarify the language.
5.5.3 
(now 
Section 
5.5.2)
Prohibited Medications and 
Measures
Bullet 2 split out into 3 separate bullets.
To clarify the language.
5.8.1
Discontinuation 
of 
Treatment
Addition of a note to bullet “Any progression or 
recurrence of any malignancy, or any occurrence 
of another malignancy that requires active 
treatment” that, for France only, a subject 
experiencing this condition must be discontinued 
from the trial.
French Health Authority (ANSM) 
requested to clarify that in the case 
of 
occurrence 
of 
another 
malignancy during the trial, the 
subject must discontinue the trial.
5.8.1
Discontinuation 
of 
Treatment
Minor language change in bullet 7.
To clarify the language.
 
 
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18-May-2018
Confidential
Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.8.2
Withdrawal from the Trial
Added:  For France only: A subject must be 
discontinued from the trial for the following 
reason:
- Any progression or recurrence of another 
malignancy, or any occurrence of another 
malignancy that requires active treatment.
ANSM requested to clarify that in 
the case of occurrence of another 
malignancy during the trial, the 
subject must discontinue the trial.
7.1.6.2
Serum Chemistry and Liver 
Function Tests
Deletion of duplicated sentence about liver 
function tests being done by local laboratories.
Correction.
Deletion of text relating to the frequency/ duration 
of liver function monitoring in case of persistent 
low-grade abnormalities.
Instructions for monitoring of liver 
function abnormalities are included 
in Table 2 in Section 5.2.1.2.
7.1.8.4.1.1 
(now 
Section 
7.1.8.4.1)
Safety Follow-up Visit
Heading level changed from Level 6 to Level 5
Correction.
7.1.8.4.1.2 
(now 
Section 
7.1.8.4.2)
Follow-up Visits
7.1.8.4.1.3 
(now 
Section 
7.1.8.4.3)
Survival Follow-up
 
 
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18-May-2018
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Section 
Number (s)
Section Title (s)
Description of Change (s)
Rationale
8.6.2
Statistical 
Methods 
for 
Safety Analyses
Deletion of phrase for clarification, “Continuous 
measures such as changes …and ECG parameters 
that are pre-specified as Tier-1 endpoints will be 
…” 
Clarification.
Throughout
Minor typographical and formatting errors were 
corrected.
 
 
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Product:  MK-3475 (SCH 900475), INCB024360
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Protocol/Amendment No.: 252-10 (INCB 24360-301-10)
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18-May-2018
Confidential
1.0 TRIAL SUMMARY
Abbreviated Title
Phase 3 Study of Epacadostat and Pembrolizumab in Melanoma
Product Identifiers
MK-3475, INCB024360
Pembrolizumab, epacadostat
NOTE: As of Amendment 10, epacadostat is removed.
Trial Phase
Phase III
Clinical Indication
Unresectable or metastatic melanoma
Trial Type
Interventional
Type of control
Placebo
NOTE: As of Amendment 10, placebo is removed.
Route of administration
Intravenous, Oral
NOTE: As of Amendment 10, epacadostat (oral administration) 
is removed.
Trial Blinding
Unblinded Open-label
Treatment Groups
pembrolizumab +  epacadostat, pembrolizumab  +  placebo
NOTE: As of Amendment 10, epacadostat and placebo are 
removed. All subjects remaining in the trial receive open-label 
pembrolizumab only.
Number of trial subjects
Approximately 700 subjects will be enrolled.
Estimated duration of trial
The Trial is estimated to require approximately 48 months from the 
time the first subject signs the informed consent until the last 
subject’s last study-related phone call or visit.
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 28 days, each subject will be assigned to 
receive trial treatment until radiographically confirmed disease 
progression is confirmed by the site per immune related Response 
Evaluation Criteria in Solid Tumors (irRECIST), unacceptable adverse 
event(s), intercurrent illness that prevents further administration of 
treatment, 
investigator’s 
decision 
to 
withdraw 
the 
subject, 
noncompliance with trial treatment or procedures requirements or 
administrative reasons requiring cessation of treatment, or until the 
subject 
has 
received 
35 
administrations 
of 
pembrolizumab 
(approximately 2 years). 
After the end of treatment, each subject will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy 
as described under Section 7.2
of the protocol.  As of 
Amendment 10, the last trial visit is the Safety Follow-up Visit.
A list of abbreviations used in this document can be found in Section 12.9.
Randomization Ratio
1:1
 
 
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18-May-2018
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2.0 TRIAL DESIGN
Trial Design
2.1
NOTE: As of Amendment 10, the epacadostat/placebo combination therapy is removed 
from both treatment groups. 
All subjects remaining in the trial continue on 
pembrolizumab alone in an open-label fashion. The Second Course retreatment phase 
is removed. The last trial visit is the Safety Follow-up Visit.
This is a randomized, placebo-controlled, parallel-group, multi-site, double-blind trial of 
pembrolizumab and epacadostat in subjects with unresectable or metastatic melanoma to be 
conducted in conformance with Good Clinical Practices.  This Phase 3 study will be 
conducted in subjects with unresectable or metastatic melanoma. Subjects will be stratified 
by 
programed 
cell 
death 
ligand 1 
(PD-L1)
expression 
(positive 
versus 
negative/indeterminate) and BRAF mutation status (BRAF mutant and received prior BRAF 
directed treatment, BRAF mutant with no prior BRAF directed treatment and BRAF wild 
type) and then be randomized 1:1 (active:placebo) to Treatment A (pembrolizumab + 
epacadostat) or Treatment B (pembrolizumab + placebo).  No treatment crossover is planned. 
The treatment period with the combination therapy will continue every 21 days for up to 
35 cycles (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. 
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.
This trial will use an adaptive design based on pre-specified criteria, using an independent, 
external Data Monitoring Committee (DMC) to monitor safety and efficacy. There will be 2 
interim analyses, as stated in Section 8.7.
Results of the interim analysis will be reviewed by the external DMC, which will make 
recommendations to continue, modify or end the trial according to the plan described in 
detail in Section 8.0 - Statistical Analysis Plan.
An interim review of the data indicated no benefit of epacadostat over placebo when 
combined with pembrolizumab.
The external DMC recommended that all subjects be 
unblinded and all epacadostat and placebo administration stop. The study will remain open 
so that subjects still on study will have continued access to pembrolizumab.
 
 
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18-May-2018
Confidential
Trial Diagram
2.2
The original trial design is depicted in Figure 1.
The revised trial design as of 
Amendment 10 is depicted in Figure 2.
Figure 1
Original Study Design
Figure 2
Study Design as of Amendment 10
 
 
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18-May-2018
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
3.1
In all randomized male/female subjects with histologically confirmed diagnosis of melanoma 
with unresectable or metastatic melanoma of at least 18 years of age:
1) Objective: To compare the progression-free survival (PFS) of the combination of 
pembrolizumab and epacadostat versus pembrolizumab and placebo (i.e. 2 treatment 
groups) based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by 
independent central review.
Hypothesis (H1): The combination of pembrolizumab and epacadostat prolongs PFS 
based on RECIST 1.1 by independent central review compared to pembrolizumab and 
placebo. 
2) Objective: To compare overall survival (OS) of the 2 treatment groups.
Hypothesis (H2): The combination of pembrolizumab and epacadostat prolongs OS 
compared to pembrolizumab and placebo. 
This study is considered to have met its study objective if pembrolizumab and epacadostat is 
superior to pembrolizumab and placebo in either PFS or OS.
Secondary Objective(s) & Hypothesis(es)
3.2
In all randomized male/female subjects with histologically confirmed diagnosis of melanoma 
with unresectable or metastatic melanoma of at least 18 years of age:
1) Objective: To compare the objective response rate (ORR) of the 2 treatment groups 
based on RECIST 1.1 by independent central review.
Hypothesis (H1): The combination of pembrolizumab and epacadostat increases 
ORR based on RECIST 1.1
by independent central review compared to 
pembrolizumab and placebo.
2) Objective: To evaluate the safety and tolerability of the 2 treatment groups.
3) Objective: To evaluate the duration of response (DOR) of the 2 treatment groups
based on RECIST 1.1 by independent central review.
4) Objective:
To evaluate the pharmacokinetics (PK)
and
anti-pembrolizumab 
antibodies of pembrolizumab and epacadostat administered concomitantly.
NOTE: As of Amendment 10, samples for PK and antidrug antibody (ADA)
assessments are no longer being collected.
 
 
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4.0 BACKGROUND & RATIONALE
Background
4.1
NOTE: As of Amendment 10, all text in this section relating to epacadostat is no longer 
applicable.
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies.  KEYTRUDA™ (pembrolizumab) is indicated for the treatment of 
patients across a number of indications.  For more details on specific indications refer to the 
Investigator brochure.
Epacadostat (formerly INCB024360) 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).  Pembrolizumab is a potent and highly selective humanized 
monoclonal antibody of the immunoglobulin (Ig) G4/kappa isotype directed against 
programmed death receptor 1 (PD-1).
Refer to the respective Investigator’s Brochure (IB) for detailed background information on
pembrolizumab and epacadostat.
Pharmaceutical and Therapeutic Background
4.1.1
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  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 [2], [3].  Histologic evaluation of many human cancers shows
extensive infiltration by inflammatory and immune cells [4], 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. 
 
 
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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) [5], [6].  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 [7], [8].  
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 [9], [10].  Expression has also been 
shown during thymic development on CD4-CD8- (double negative) T cells as well as subsets 
of macrophages and dendritic cells [11].  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 [12], [13], [14], [8].  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 [8].  Although healthy organs express little (if any) PD-
L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  
PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects with 
melanoma [15].  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
NOTE:  As of Amendment 10, this section is no longer applicable.
Recent interest has focused on the role of indoleamine 2,3–dioxygenase (IDO1) as a 
mechanism of induction of tolerance to malignancy [16].  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 
 
 
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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 [17].  Within the immune system, IDO1 activity is 
specifically induced in cells such as DCs and macrophages at localized sites of inflammation
[18].  
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
[19].  Both the reduction in local tryptophan levels and the production of tryptophan 
catabolites that are inhibitory to cell proliferation contribute to the immunosuppressive 
effects [20].  IDO1 activity also promotes the differentiation of naive T cells to cells with a 
regulatory phenotype (Treg) [21].  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 [22], 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 [23].  A critical role for IDO1 in immunomodulation has been 
confirmed in numerous animal models, including models of allograft tolerance, 
inflammation, and cancer [17].  While IDO1 inhibition can exacerbate disease in models of 
autoimmune disorders [17], IDO1 null mice show no evidence of susceptibility to developing 
spontaneous autoimmunity or alterations in immune system development [19], suggesting 
that IDO1 inhibition, in a therapeutic setting, may produce minimal side effects in subjects 
without pre-existing autoimmune conditions.
Within the context of cancer, there are several lines of evidence to suggest that IDO1 is a key 
regulator of the immunosuppressive mechanisms responsible for tumor escape from immune 
surveillance.  Several groups have demonstrated that blockade of IDO1 activity can directly 
influence the ability of tumor-bearing animals to reject tumors [24], [25].  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 [25].  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 [26], [27].  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 
 
 
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draining lymph nodes [24].  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 [28], [29], [30], [31], [32].  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
NOTE:  As of Amendment 10, this section is no longer applicable.
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 [9], [33].  Nivolumab, a fully 
human IgG4 antibody blocking PD-1, produced durable overall responses in patients with 
melanoma, renal cell cancer, and NSCLC [34], [35], [36].  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 [37].
For example, CTLA-4 and PD-1 appear to play complementary roles in regulating adaptive 
immunity.  Whereas PD-1 contributes to T-cell exhaustion in peripheral tissues, CTLA-4 
inhibits at earlier points in T-cell activation.  In preclinical models, combined blockade of 
PD-1 and CTLA-4 achieved more pronounced antitumor activity than blockade of either 
pathway alone [38], [39].
On the basis of these observations, a Phase 3 study was conducted to investigate the safety 
and efficacy of combined CTLA-4 and PD-1 blockade (with the use of ipilimumab and 
nivolumab, respectively) in patients with advanced melanoma.  The objective response rate 
(ORR; according to modified World Health Organization criteria) for all patients in the 
concurrent-regimen group was 61% among subjects with BRAF wild-type tumors versus 
11% in the ipilimumab alone group. Median duration of response had not been reached in 
either group. Median PFS had not been reached with the combination therapy and was 4.4 
months for ipilimumab monotherapy.  Grade 3 or 4 AEs occurred in 54% of subjects in the 
concurrent-regimen group and were 24% in the ipilimumab monotherapy group [40]. 
Common Grade 3 or 4 selected AEs that were related to the combination therapy included 
colitis (17%), diarrhea (11%), and an elevated alanine aminotransferase level (11%).  
Diarrhea (11%) was the most frequently reported Grade 3 or 4 AE associated with 
ipilimumab monotherapy, followed by colitis (7%).  In both regimen groups, treatment-
related AEs were manageable and generally reversible with the use of immunosuppressants 
(or hormone-replacement therapy for endocrinopathies) according to previously established 
algorithms [40].
 
 
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As described previously, 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 [41], [42].  This effect was shown to be T-cell dependent, leading 
to enhanced T-cell proliferation and interleukin-2 production within the tumor and to a 
marked increase in the effector-to-regulatory T cell ratios in the tumors.
The IDO1 inhibitor epacadostat has completed a Phase 1 study and has several ongoing 
Phase 1 and Phase 2 studies in combination with immune-targeted agents, such as anti–PD-1, 
anti–PD-L1, and anti–CTLA-4 antibodies.  In a study combining epacadostat and ipilimumab 
(INCB 24360-201) subjects received ipilimumab (3 mg/kg IV every 3 weeks for 4 cycles) 
with epacadostat at doses of 25 mg BID, 50 mg BID continuous, 50 mg BID intermittent 
(2 weeks on, 1 week off), and 75 mg (50 mg q AM/25 mg q PM). A total of 42 subjects were 
enrolled: 25 mg BID (n=8), 50 mg BID (continuous) (n=18), 50 mg BID (intermittent) (n=9), 
and 75 mg (n=7). DLTs were: 25 mg BID, Grade 3 increased AST (n=1); 50 mg BID 
(continuous), Grade 3 diarrhea, Grade 3 increased ALT/AST grade 3 colitis and grade 3 
pneumonitis (n=1 each); 50 mg BID (intermittent), Grade 3 colitis (n=1); 75 mg, Grade 3 
rash (n=1). The most common all Grade immune-related adverse events (irAEs) were rash 
(52%), pruritus (38%), diarrhea (33%), increased ALT (21%), increased AST (16%) 
hypothyroidism (12%) and colitis (10%). Grade ≥3 irAEs occurred in 23% of subjects. 
Grade ≥ 3 irAEs occurring in more than 1 subjects were increased AST and colitis (n=4 
[9.5%] each). Among 32 immunotherapy-naïve subjects, ORR was 31% (10/32) per irRC 
and 28% (9/32) per RECIST and the CR rate per both criteria was 9.4%. At data cutoff, 
responses were ongoing in 6 subjects. The disease control rate (DCR; CR+PR+SD) was 
62.5% per irRC and 53% per RECIST. Median PFS was 8.2 months by irRC and 5.3 months 
by RECIST. Among 10 subjects previously treated with immunotherapy, the DCR by both 
criteria was 30% (all SDs).  In a study combining pembrolizumab and epacadostat (INCB 
24360-202) similar efficacy and safety were also demonstrated.
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 
melanoma as well as in other cancers, including NSCLC.
4.1.1.4
Overview of Metastatic Melanoma
Melanoma is the most serious form of skin cancer and strikes adults of all ages. The 5-year 
prevalence of melanoma in the European Union (EU) is approximately 159,000 patients with 
an incidence of approximately 41,000 per year and approximately 11,000 deaths annually as 
described in the World Health Organization (WHO) Europe region [43].  Melanoma accounts 
for approximately 5% of all new cases of cancer in the United States (US). The incidence of 
melanoma continues to rise by almost 3% per year in the US. This translates to 76,000 new 
cases a year with 9,000 associated deaths. The male-to-female incidence ratio of melanoma 
 
 
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is 1.4:1, respectively [44].  The 5-year survival rate is 15% once patients have progressed to
late-stage disease [45].
4.1.1.5
Treatment for Advanced or Metastatic Melanoma
Surgical excision with wide margins is the standard of care for early-stage melanoma, and 
most patients with in situ or early-stage melanoma will be cured by primary excision alone.  
Metastatic melanoma, however, is very unlikely to be curable by surgery because of the 
likelihood of micrometastases too small to be found by CT, MRI, or PET scans [46].  
National Comprehensive Cancer Network (NCCN) guidelines (Melanoma – Version 2.2016) 
endorse adjuvant treatment, including clinical study, observation, or high-dose interferon alfa 
for node-negative Stage IIB or IIC disease. For Stage III disease, ipilimumab may also be 
considered.  Radiation therapy may have a role as adjuvant therapy after surgery for primary 
melanomas that are associated with a high rate of local recurrence despite apparently 
adequate excision, and in those with positive margins after surgical excision [48].
High-dose interleukin-2 (IL-2) was the first treatment to modify the natural history of 
patients with metastatic melanoma and may be curative for a small fraction of patients.  
However, its severe toxicity limits its application to carefully selected patients treated at 
centers with experience in managing the side effects of treatment.  More recent research led 
to the development of immunotherapy using checkpoint inhibitors such as anti-PD1 
antibodies, pembrolizumab and nivolumab, and the anti-CTLA4 antibody (ipilimumab) and 
to targeted therapy such as BRAF and/or MEK inhibition (dabrafenib and/or trametinib, 
respectively).  Both of these approaches prolong progression free and overall survival 
compared with chemotherapy [48].
Ipilimumab, an anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) blocking 
antibody, and vemurafenib, a BRAF inhibitor, were the only agents approved for advanced 
melanoma that have demonstrated overall survival (OS) benefit in randomized, comparative 
Phase 3 registration studies until just recently. In the Phase 3 study MDX010-20, ipilimumab 
monotherapy demonstrated a hazard ratio (HR) of 0.66 and a 4-month median OS benefit 
compared to gp100 in pretreated advanced melanoma subjects [58].  Grade 3 to 4 immune-
related adverse events (AEs) included colitis (5.3%), diarrhea (4.6%), endocrinopathies 
(3.8%), and rash (0.8%). In the US, 3 mg/kg of ipilimumab was approved for advanced 
melanoma based on data from MDX010-20 and without restriction to line of therapy, in part 
because of the results of an additional Phase 3 randomized ipilimumab clinical study, 
CA184024. In the CA184024 study, treatment-naïve advanced melanoma subjects treated 
with 10 mg/kg ipilimumab in combination with dacarbazine (DTIC) demonstrated an HR of 
0.72 and a 2-month median OS benefit compared with monotherapy dacarbazine [33].  In the 
EU, ipilimumab is currently approved for the treatment of advanced (unresectable and 
metastatic) melanoma in adults who have received prior therapy.
Approximately 50% of 
cutaneous melanoma cases are BRAF V600E mutation positive. Vemurafenib is approved in 
the US and in the EU for the treatment of BRAF V600E mutation-positive advanced 
melanoma subjects regardless of line of therapy [49].  In the BRIM-3 Phase 3 study, 
 
 
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vemurafenib demonstrated a 48% response rate and an increased OS benefit compared to 
dacarbazine with a HR of 0.37, but with inadequate follow-up.
First line data in advanced or metastatic melanoma with pembrolizumab versus ipilimumab 
was recently presented at the AACR 2015 meeting with an estimated 46.4% 6-month PFS 
rate for pembrolizumab 10 mg/kg every 3 weeks versus 26.5% for ipilimumab.  The ORR 
was 32.9% for pembrolizumab 2 mg/kg every 3 weeks (Q3W) versus 11.9% for ipilimumab.  
Responses were ongoing in 96.7% of subjects after a median follow-up of 7.9 months.  
Median PFS were 4.1 months for pembrolizumab versus 2.8 months for ipilimumab.  The 
hazard ratio for the disease progression for pembrolizumab every 3 weeks versus ipilimumab 
was 0.58 (95% CI, 0.47 to 0.72; p<0.001).  At the time of the data cut off for the second 
interim analysis in this study, which was driven by a minimum follow up of duration of 12 
months for all subjects, 289 deaths occurred.  One-year estimates of survival for subjects 
receiving pembrolizumab every 3 weeks were 68.4% as compared with ipilimumab 58.2% 
(HR for death as compared with ipilimumab group 0.69; 95% CI, 0.52 to 0.90; p=0.0036).  
Because the OS results were superior to those for the ipilimumab group the IDMC 
recommended stopping the study early to allow patients in the ipilimumab group the option 
of receiving pembrolizumab [50].  
Similarly, nivolumab was studied in subjects with previously untreated advanced melanoma 
compared to dacarbazine and reported a 5.1 month median PFS compared to 2.2 months for 
the dacarbazine. The objective response rates were 40% in the nivolumab group and 13.9% 
in the dacarbazine group.  At 1 year the overall rate of survival was 72.9% for the nivolumab 
group compared to 42.1% in the dacarbazine group. 
Nivolumab showed significant 
improvements in overall survival and PFS compared with dacarbazine among previously 
untreated patients who had metastatic melanoma without BRAF mutation [51].  
In 2014, the FDA approved both nivolumab and pembrolizumab, human programmed death 
receptor-1 (PD-1) blocking antibodies, for the treatment of patients with unresectable or 
metastatic melanoma and disease progression following ipilimumab and, if BRAF V600E 
mutation positive, a BRAF inhibitor.  This indication is approved under accelerated approval 
based on tumor response rate and durability of response.
Both pembrolizumab and 
nivolumab received NCCN compendia listing recommendations for use in the first line 
metastatic melanoma setting based on these data.  In November 2015, nivolumab received 
approval for first-line treatment of patients with BRAF V600 wild-type unresectable or 
metastatic melanoma.  In December 2015, the pembrolizumab label was expanded to include 
first-line treatment of patients with unresectable or metastatic melanoma regardless of BRAF 
status. The European Commission has also approved pembrolizumab and nivolumab, for 
both first-line and previously-treated patients with advanced melanoma.
 
 
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Pre-clinical and Clinical Trials
4.1.2
NOTE:  As of Amendment 10, text in this section relating to epacadostat is no longer 
applicable.
Refer to the Investigator's Brochures (IBs) for pembrolizumab and epacadostat for preclinical 
and clinical study data.
Ongoing Clinical Trials
4.1.3
NOTE:  As of Amendment 10, text in this section relating to epacadostat is no longer 
applicable.
Refer to the Investigator's Brochures (IBs) for pembrolizumab and epacadostat for preclinical 
and clinical study data.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
4.2.1.1
Rationale for Combining PD-1 Inhibitor and IDO1 Inhibitor in Melanoma
NOTE:  As of Amendment 10, this section is no longer applicable.
If the safety profile is acceptable and this combination is shown to improve PFS and/or OS, 
this study could support the regulatory approval of this combination in subjects with 
unresectable or metastatic melanoma.  
In an ongoing dose-escalation and expansion study of pembrolizumab in combination with 
epacadostat subjects with Stage IIIB, IV, or recurrent NSCLC, melanoma, transitional cell 
carcinoma (TCC), RCC, endometrial adenocarcinoma, or SCCHN are being enrolled.    
Subjects previously treated with PD-1 or CTLA-4 targeted therapies were excluded. 
Enrollment is complete in the epacadostat 25 mg BID, 50 mg BID, and 100 mg BID cohorts 
with pembrolizumab 2 mg/kg IV Q3W. Phase 1 expansion cohorts of epacadostat 50 mg 
BID, 100 mg BID, and 300 mg BID with pembrolizumab 200 mg IV Q3W are enrolling. 
The Phase 2 portion of the study is ongoing in which the recommended Phase 2 dose of 
epacadostat 100 mg BID is being evaluated in combination with the fixed dose of 
pembrolizumab 200 mg IV Q3W. Tumor response is being assessed by the investigator 
using RECIST 1.1.
Among the 117 subjects that have received epacadostat 100 mg BID in combination with 
pembrolizumab, the most frequently reported (≥15%) adverse events (AEs) of any grade for 
the combined Phase 1 and Phase 2 treatment groups treated with epacadostat 100 mg BID 
were fatigue (35.0%), constipation (24.8%), diarrhea (20.5%), nausea (20.5%), vomiting 
(18.8%), pyrexia (16.2%) and dyspnea (15.4%). 
Fatigue (13.7%) and rash (11.1%) 
 
 
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(including the preferred terms rash, rash maculopapular, rash generalized, and rash macular) 
were the only treatment-related AE reported in > 10% of subjects. Treatment-related AEs of 
rash were only reported in the Phase 2 group.   
Treatment-related AEs ≥Grade 3 occurring in more than one subject in the combined 
Phase 1 and Phase 2 epacadostat 100 mg BID treatment group included rash (5 subjects, 
4.3%) and dehydration, lipase increased, AST increased and nausea (2 subjects [1.7%] each).
Based on the Phase 1 safety data of epacadostat doses ranging from 25 mg BID up to 300 mg 
BID, a dose of 100 mg BID was selected for the Phase 2 portion of Study 202 and for this 
Phase 3 study of epacadostat to be combined with pembrolizumab 200 mg IV Q3W.
ORR in 19 evaluable subjects with treatment-naïve metastatic melanoma was 58% (11/19) 
with disease control rate of 74% (14/19). Median PFS has not been reached and all 
responses are ongoing with min follow up of 31.7 weeks.
Rationale for Dose Selection/Regimen/Modification
4.2.2
4.2.2.1
Justification for Treatment Regimen
NOTE:  As of Amendment 10, this section is no longer applicable.
The dose selected for epacadostat for the current study was formed on the basis of having a 
well-tolerated safety profile as monotherapy and in combination with pembrolizumab, a 
robust objective response rate, durable disease control rates, as well as providing optimal 
target inhibition of IDO1 based on nonclinical models. Doses of epacadostat 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 pembrolizumab, nivolumab, durvalumab and atezolizumab are currently 
being evaluated in several ongoing Phase 2 studies. Doses of pembrolizumab 2 mg/kg and 
200 mg flat dose have been studied in the ongoing Phase 1/2 study of pembrolizumab in 
combination with epacadostat. Reductions in tumor burden were seen in 14 of 19 evaluable 
subjects across doses of 25 mg BID to 100 mg BID in combination with pembrolizumab 
2 mg/kg and 200 mg flat dosing. Objective responses were observed in all tumor types and 
all are ongoing and this combination has been well tolerated.
Based on a pharmacokinetic-pharmacodynamic model for epacadostat, nearly all patients’ 
Cavg exceeded the IC50, the range of active drug exposure seen in non-clinical models; further 
dose of 100 mg BID and above exceeded the IC50 at trough in nearly all patients [52].
Based on observed systemic exposures and a pharmacokinetic-pharmacodynamic model for 
epacadostat, all patients who received 100 mg BID epacadostat in combination with 
pembrolizumab had time-averaged inhibition of IDO1 activity exceeding 50%, a level of PD 
activity associated with inhibition of tumor growth seen in non-clinical models.  Dosing of 
100 mg BID and above exceeded the IC50 at trough in nearly all patients [52]; further, the 
majority of patients had trough epacadostat exposures that were above the IC 50 of IDO1 
inhibition.  Therefore, 100 mg BID was selected as the recommended Phase 2 dose for 
 
 
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epacadostat in study INCB 24360-202 because this regimen had better tolerability as 
demonstrated by the Phase 1 safety data including fewer dose modifications (suspension and 
reductions) and resulted in consistent inhibition of IDO1.
The overall experience of the 
epacadostat 100 mg BID dose in combination with pembrolizumab in study INCB 24360-202 
supports this dose selected for the Phase 3 study INCB 24360-301.
4.2.2.2
Rationale for a Fixed Dose of Pembrolizumab
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 2 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 Q3W (KEYNOTE-001 B2, KEYNOTE-001 D, KEYNOTE-002, 
KEYNOTE-010 and KEYNOTE-021), and three studies compared 10 mg/kg Q3W vs. 10 
mg/kg Q2W (KEYNOTE-001 B3, KEYNOTE-001 F2 and KEYNOTE-006). 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. 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 KEYNOTE-001 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.
 
 
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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 pembrolizumab protocols.
Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
4.2.3.1.1 Primary Efficacy Endpoints 
The dual primary endpoints are PFS and OS.

Progression-free survival, defined as the time from date of randomization until the 
earliest date of disease progression, as determined by independent central review of 
objective radiographic disease assessments per RECIST 1.1, or death from any cause, 
whichever comes first.  

Overall survival, defined as the time from date of randomization to date of death due 
to any cause.
The study is considered to have met its study objective if the combination is superior to 
pembrolizumab and placebo in either PFS or OS.
RECIST 1.1 (Section 12.7) as assessed by independent central review will be used to 
determine the dates of progression as this methodology is accepted by regulatory authorities. 
Final determination of radiologic progressive disease (PD) will be based on the central 
imaging vendor assessment of progression, rather than local site investigator/radiology 
assessment.
NOTE:  As of Amendment 10, central imaging vendor assessment will no longer be 
required.
4.2.3.1.2 Secondary Efficacy Endpoints

Objective response rate, defined as the proportion of subjects who have best response 
as complete response (CR) or partial response (PR). 
Responses are based on 
independent central review using RECIST 1.1.

Duration of response (DOR) determined by disease assessment defined as the time 
from the earliest date of qualifying response until earliest date of disease progression 
or death from any cause, whichever comes first. Response will be determined by 
independent central review using RECIST 1.1.
 
 
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4.2.3.2
Immune-related RECIST (irRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment of pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce antitumor effects by potentiating endogenous cancer-specific immune responses.  
The response patterns seen with such an approach may extend beyond the typical time course 
of responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions.  Standard RECIST 1.1 may, 
thus, not provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab. 
Based on an analysis of subjects
with melanoma enrolled in 
KEYNOTE-001, 7% of evaluable patients experienced delayed or early tumor 
pseudoprogression.  Of note, patients who had progressive disease by RECIST 1.1 but not by 
immune related Response Criteria had longer OS than patients with progressive disease by 
both criteria.  Additionally, the data suggest that RECIST 1.1 may underestimate the benefit 
of pembrolizumab in approximately 15% of patients.  These findings support the need to 
apply a modification to RECIST 1.1 that takes into account the unique patterns of atypical 
response in immunotherapy and enable treatment beyond initial radiographic progression. 
Immune-related RECIST (irRECIST) is RECIST 1.1 adapted to account for the unique tumor 
response seen with immuno-therapeutics as described in Nishino et al., CCR 2013. The 
assessment of unidimensional target lesions and response categories per irRECIST are 
identical to RECIST 1.1.  However, MSD has implemented an adaptation related to new 
lesions, non-target and tumor burden assessment in order to confirm radiographic 
progression. irRECIST will be used by local site investigators to assess tumor response and 
progression, and make treatment decisions as well as by independent central review in 
support of endpoints.
 
 
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4.2.3.4
Safety Endpoints

Safety and tolerability of the treatment regimens through assessment of AEs and 
changes in safety assessments including laboratory parameters.
4.2.3.5
Pharmacokinetic Endpoints

The PK parameters of epacadostat.  

The pharmacokinetics of pembrolizumab and formation of anti-pembrolizumab 
antibodies will be explored per existing modeling analysis plan (MAP). 
NOTE: As of Amendment 10, samples for PK and ADA assessments are no longer 
being collected.
 
 
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Benefit/Risk
4.3
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness.
Risks from Epacadostat
4.3.1
NOTE:  As of Amendment 10, this section is no longer applicable.
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 1 clinical study in subjects with 
refractory solid tumors (INCB 24360-101) doses up to 700 mg BID were given without an 
MTD determined. Epacadostat was well tolerated with a single SAE of exacerbated radiation 
pneumonitis in a subject with metastases treated at 300 mg BID, 1 report of asymptomatic 
and reversible hypopituitarism despite continued administration of epacadostat, and 1 event 
of Grade 3 fatigue determined by the investigator to be related to study drug and considered a 
DLT in the 400 mg BID dose group. 
 
 
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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 in combination with 
other serotonergic agents.  This rare syndrome has been associated with some monoamine 
oxidase inhibitors (MAOIs) and combinations of serotonergic drugs [53].  The clinical 
manifestations of SS range from barely perceptible to lethal; onset is rapid (within 12 hours 
of drug(s) administration).  Based on preliminary studies in the rat, concentrations of 
epacadostat in the cerebrospinal fluid were below the quantifiable limit of detection (2 nM) 
after IV dosing, and total brain homogenate concentrations were approximately 15% of 
corresponding plasma concentrations.  In another preclinical study in rats, the effect of 
epacadostat on the brain extracellular fluid concentration of serotonin was evaluated either 
alone or when co-administrated with the MAO inhibitor linezolid with or without the 
Serotonin reuptake inhibitors (SSRI) fluoxetine.  Both control conditions resulted in 2-6-fold 
increases in serotonin. In contrast, neither epacadostat alone or in combination with linezolid 
had an effect on the brain extracellular serotonin levels.  These preclinical data suggest that 
SS is unlikely following treatment with either epacadostat alone or with combination with 
MAO inhibitors such as linezolid [61]. Therefore, taken together, epacadostat exhibits 
apparent limited penetration across the blood-brain barrier and is likely not associated with 
significant effects on tryptophan metabolism in the brain that might impact brain serotonin 
levels.  
As of 27-FEB-2017, 2 subjects across the epacadostat program (958 subjects treated) have 
reported serotonin syndrome or symptoms of serotonin syndrome and both were mild in their 
severity and resolved.  One subject reported shivers, increased blood pressure and 
temperature (Grade 1).  The other subject reported Grade 1 tremors and Grade 2 agitation.  
One subject from Study INCB 24360-202 reported chills, increased blood pressure, and 
temperature (CTC Grade 1) on Cycle 1 Day 1 and resolved within one week while dosing 
was stopped.  The subject was taking an SSRI and while 
 experienced mild symptoms the 
full constellation of SS was not observed nor could it be ruled out.  The SSRI was 
discontinued and subject was able to restart epacadostat about one week later at the same 
dose level of 100 mg BID without further incidents.  The other subject from Study INCB 
24360-203 reported CTC Grade 1 tremors and CTC Grade 2 agitation on Cycle 4 Day 5 and 
assessed for SS on Cycle 5 Day 1.  The subject was not on an SSRI but on a medication for 
anxiety (Alprazolam). The events resolved and the dosing with epacadostat was interrupted 
for one week.  Retreatment started with a lower dose of epacadostat of 50 mg BID PO from 
75 mg BID on Cycle 5 Day 3.
Although this incidence is uncommon, use of MAOIs will be prohibited during the study and 
all subjects will be provided with an informative subject leaflet describing the signs and 
symptoms of the syndrome along with instructions to seek immediate medical care if any of 
these signs or symptoms are observed.
 
 
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Risks from Pembrolizumab
4.3.2
An open-label Phase I study (KEYNOTE--001) is being conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab.  The dose-escalation portion of this study 
evaluated 3 dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks in 
subjects with advanced solid tumors.  All 3 dose levels were well tolerated and no DLTs 
were observed.  Based on pharmacokinetic (PK) data showing a half-life of 21 days, the 
protocol was amended to include a dosing frequency of every 3 weeks in expansion cohorts.  
Of a total of 479 subjects who have received pembrolizumab in KEYNOTE-001, 466 
(97.3%) experienced treatment-emergent AEs, of which 368 (76.8%) were considered drug-
related.  Serious AEs were reported in 30.1% of subjects, but SAEs that were attributed as 
potentially (possibly, probably, or definitely) drug-related by investigators were reported in 
6.7% of subjects overall.  Potential irAEs have been observed, including pneumonitis in both 
melanoma and NSCLC cohorts.  The most commonly reported treatment-emergent AEs 
experienced have been fatigue, nausea, cough, pruritus, diarrhea, and rash.  Most subjects 
continued treatment despite of AEs, and only 4.2% of subjects discontinued study treatment 
because of an AE that was considered related to study treatment by investigators.  Thus, the 
overall AE summary suggests that pembrolizumab is generally tolerable, and AEs are 
generally manageable in subjects.
Risks for the Combination of Pembrolizumab and Epacadostat
4.3.3
NOTE:  As of Amendment 10, this section is no longer applicable.
The combination of pembrolizumab and epacadostat has the potential to cause more frequent, 
more severe, and/or new immune-related toxicities as compared with each individually.
In the ongoing Phase 1/2 study combining pembrolizumab and epacadostat, preliminary data 
suggest that doses up to 300 mg BID of epacadostat are well tolerated with 200 mg IV of 
pembrolizumab. While 300 mg bid did not exceed the MTD, there were higher rates of dose 
holds and reductions compared to 100 mg bid supporting 100 mg bid as the Phase 2 dose (as 
is detailed later in this section). In the Phase 1 portion of the study, a DLT of Grade 3 rash 
and Grade 3 arthralgia were seen in 2/19 evaluable subjects with epacadostat 50 mg BID; 2
DLTs out of 15 evaluable subjects were seen with epacadostat 100 mg BID cohort (Grade 3 
AST and Grade 2 nervous system disorder, other - ataxia), and 4 DLTs out of 19 evaluable 
subjects were seen at 300 mg BID (Grade 1 erythema, 2 Grade 3 rashes and 1 nervous system 
disorder – other – vomiting without nausea). 
The most frequently reported (≥15%) adverse events (AEs) of any grade for the combined 
Phase 1 and Phase 2 treatment groups (n=117) treated with epacadostat 100 mg BID were 
fatigue (35.0%), constipation (24.8%), diarrhea (20.5%), nausea (20.5%), vomiting (18.8%), 
pyrexia (16.2%) and dyspnea (15.4%). Fatigue (13.7%) and rash (11.1%) (including the 
preferred terms rash, rash maculopapular, rash generalized, and rash macular) were the only 
treatment-related AE reported in > 10% of subjects.
Treatment-related AEs of rash were 
only reported in the Phase 2 group.   
 
 
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Any Grade 3/4 AEs occurring in more than 1 subjects in the combined Phase 1 and Phase 2 
epacadostat 100 mg BID group include: rash (n=5, 4.3%), dehydration (n=4 3.4%), nausea, 
vomiting and AST increased, (n= 3 each, 2.6%), diarrhea, small intestine obstruction, fatigue, 
lipase increased, hypercalcemia, hyponatremia, tumor pain, and pneumonia aspiration (n=2 
each, 1.7%).  Treatment-related AEs ≥Grade 3 occurring in more than one subject included 
rash (5 subjects, 4.3%) and dehydration, lipase increased, AST increased and nausea 
(2 subjects [1.7%] each).
In subjects receiving epacadostat 300 mg BID, there was an observable trend in increased 
adverse events of rash (total events as well as severity) and the number of required dose 
holds and dose reductions for epacadostat, compared to subjects receiving 100 mg BID.  
Although the rashes observed at the 300 mg BID dose level were reversible with dose 
interruptions and medical treatment, total dose interruptions were higher in the 300 mg BID 
group with 5/19 interrupting epacadostat and 3 requiring dose reductions due to adverse 
events compared to 1 subject in 100 mg BID requiring a dose interruption, 2 subjects in 
50 mg BID and 1 subject in 25 mg BID. Based on the risk for early progression during dose 
interruptions and dose reductions associated with epacadostat 300 mg BID in combination 
with pembrolizumab 200 mg IV Q3W, 100 mg BID was selected as the dose for use in the 
proposed Phase 3 study.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying
pembrolizumab and epacadostat
Investigators Brochures (IBs) and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Male/Female subjects with histologically confirmed diagnosis of melanoma with 
unresectable or metastatic melanoma of at least 18 years will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Have histologically or cytologically confirmed melanoma.
2. Have unresectable Stage III or Stage IV melanoma, as per American Joint Committee 
on Cancer (AJCC) staging system not amenable to local therapy.
 
 
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3. Have been untreated for advanced or metastatic disease except as follows. 
a.
BRAF V600 mutant melanoma may have received standard of care targeted 
therapy (e.g. BRAF/MEK inhibitor, alone or in combination) and be eligible 
for this study
Note: Targeted therapy is not required for eligibility.
b. Prior adjuvant or neoadjuvant melanoma therapy is permitted if it was 
completed at least 4 weeks before randomization and all related adverse 
events have either returned to baseline or stabilized (resolution of toxic 
effect(s) of the most recent prior therapy to Grade 1 or less (except alopecia).
c.
Prior adjuvant therapy containing immunotherapy such as interferon or anti-
CTLA-4 therapy will only be permitted if relapse did not occur during 
treatment or within 6 months of treatment discontinuation. 
d. Prior anti-PD-1, anti-PD-L1, or IDO1 inhibitors are excluded.
4. Have documentation of V600-activating BRAF mutation status or consent to BRAF 
V600 mutation testing during the screening period.  
5. Have laboratory parameters within Protocol-defined range. The screening laboratory 
tests below must be ≤ 7 days before treatment initiation.
a.
Absolute neutrophil count ≥ 1.5 × 109/L.
b. Platelets ≥ 100 × 109/L.
c.
Hemoglobin ≥ 9 g/dL.
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.
Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and 
bilirubin, < 2.5 × ULN.
f.
Conjugated bilirubin < 2.0 × ULN (need only be tested if total bilirubin 
exceeds ULN).
g. International normalized ratio (INR) or prothrombin time (PT) ≤1.5 × ULN 
unless subject is receiving anticoagulant therapy as long as PT or INR is 
within therapeutic range of intended use of anticoagulants.
 
 
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h. Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless subject is 
receiving anticoagulant therapy, as long as PTT is within therapeutic range of 
intended use of anticoagulants.
6. 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.  Cutaneous 
lesions and other superficial lesions are not considered measurable lesions for the 
purposes of this protocol, but may be considered as non-target lesions.
a.
If subjects have only 1 measurable lesion per RECIST 1.1, the biopsy 
specimen should be obtained from the non-target lesion or archival tissue.
b. If subjects have only 1 measurable lesion per RECIST 1.1, this lesion should 
not have been in the field of prior irradiation unless there is documented 
progression of the lesion(s).
7. Provide a baseline tumor biopsy
a.
Subjects must submit the tumor sample during screening for PD-L1 
expression testing at a central pathology laboratory.  Subjects will be eligible 
to participate regardless of the level of PD-L1 expression, but will be stratified 
by PD-L1 expression level. Subjects who do not submit a sample adequate 
for PD-L1 determination will not be randomized. The biopsy may not be 
obtained from a lone target lesion.    
b. Newly-obtained tissue is preferred (no intervening treatment [local or 
systemic] involving the site of tissue biopsy once tissue biopsy is obtained at 
time of study enrollment). The only exception to this is a sample that was 
collected prior to BRAF +/- MEK targeted treatment, where the subject 
progressed on this targeted treatment, in cases where 1) fresh tissue or 2) 
archival tissue with no intervening local or systemic therapy is not possible to 
provide.
8. Have resolution of toxic effect(s) of the most recent prior therapy to Grade 1 or less 
(except alopecia). If a subject received major surgery or radiation therapy of > 30 
Gy, they must have recovered from the toxicity and/or complications from the 
intervention.
9. Be male or female subjects, age 18 years or older on the day of signing consent.
10.
 
 
  
11. Have an Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1.
 
 
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12. If female of childbearing potential (Section 5.7.2), 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.  
13. If female of childbearing potential (Section 5.7.2), must be willing to use an adequate 
method of contraception as outlined in Section 5.7.2 – Contraception, for the course 
of the study through 120 days after the last dose of study medication.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
14. If male of childbearing potential (Section 5.7.2), must agree to use an adequate 
method of contraception as outlined in Section 5.7.2- Contraception, and not to 
donate sperm starting with the first dose of study therapy through 120 days after the 
last dose of study therapy.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the subject.
Subject Exclusion Criteria
5.1.3
The subject must be excluded from participating in the trial if the subject:
1. Has received prior systemic treatment for unresectable or metastatic melanoma 
(except BRAF directed therapy as noted in the third inclusion criteria).
2. Has received prior therapy with an antiPD-1, antiPD-L1, antiPD-L2, antiCD137, 
or IDO1 inhibitor or any other antibody or drug specifically targeting checkpoint 
pathways other than anti-CTLA-4 which is permitted in the adjuvant setting.
3. Has received prior adjuvant therapy, monoclonal antibody, chemotherapy, or an 
investigational agent or device within 4 weeks or 5 half-lives (whichever is longer) 
before administration of study drug or not recovered (≤ Grade 1 or at baseline) from 
AEs due to previously administered agents. Exception to this rule would be use of 
denosumab, which is not excluded.
Note: Subjects with ≤ Grade 2 neuropathy are an exception and may enroll.
4. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days before the first dose of study treatment.
 
 
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5. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include early stage cancers (carcinoma in situ or stage 1) treated with 
curative intent, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
in situ cervical cancer, or in situ breast cancer that has undergone potentially curative 
therapy. 
6. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. 
Subjects with previously treated brain metastases may participate 
provided they are stable (without evidence of progression by imaging for at least 4 
weeks before the first dose of study treatment and any neurologic symptoms have 
returned to baseline), have no evidence of new or enlarging brain metastases 
confirmed by repeat imaging, and have not required steroids for at least 14 days 
before study treatment.
7. Has ocular melanoma.
8. Has a known hypersensitivity to active substances or any of their excipients including 
previous clinically significant hypersensitivity reaction to treatment with another 
monoclonal antibody. For a list of excipients, refer to the respective Investigator 
Brochure (Section 3.3).
9. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.
10. Has an active infection requiring systemic therapy.
11. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
12. Has a known history of or is positive for Hepatitis B (HBsAg reactive) or Hepatitis C 
(HCV RNA [qualitative] is detected). Note: Without a known history, testing needs 
to be performed to determine eligibility.
Hepatitis C Ab testing is allowed for 
screening purposes in countries where HCV RNA is not part of SOC.
13. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
14. Has received prior radiotherapy within 2 weeks of therapy.  Subjects must have 
recovered from all radiation-related toxicities, not require corticosteroids, and not 
have had radiation pneumonitis.  A 1-week washout is permitted for palliative 
radiation (≤ 2 weeks of RT) to non-CNS disease.
 
 
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15. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days 
after the last dose of study treatment.
16. Has received live vaccine within 30 days before the first dose of study treatment. 
Examples of live vaccines include, but are not limited to, the following: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, Bacillus Calmette–Guérin (BCG), 
and typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., 
FluMist®) are live attenuated vaccines and are not allowed.
17. Has received monoamine oxidase inhibitors within 21 days prior to starting study 
treatment. 
18. Has any history of Serotonin Syndrome after receiving serotonergic drugs.
19. Has presence of a gastrointestinal condition that may affect drug absorption.
20. Has a history or presence of an abnormal electrocardiogram (ECG) that, in the 
investigator's opinion, is clinically meaningful.  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. 
21. Has clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction within 6 months from Day 1 of study drug administration, New York Heart 
Association Class III or IV congestive heart failure, and arrhythmia requiring therapy. 
Medically controlled arrhythmia would be permitted.
22. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject's participation 
for the full duration of the study, or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator.
23. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the study.
24. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigation 
device within 4 weeks of the first dose of treatment.
 
 
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Trial Treatment(s)
5.2
The treatments to be used in this trial are outlined below in Table 1.
NOTE:  As of Amendment 10, only pembrolizumab will be administered. 
Other 
treatments (prior to this amendment) have been deleted.
Table 1
Trial Treatment
Drug
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment Period
Use
pembrolizumab
200 mg
Every 3 weeks
IV infusion
Day 1 of each cycle 
for up to 35
pembrolizumab 
infusions 
(approximately 2
years)
Experimental
Trial treatment for Cycle 1 should begin within 3 days of randomization. However, every
effort should be made to begin trial treatment on day of randomization.
All supplies indicated in Table 16 will be provided centrally by MSD.
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.
Dose Selection/Modification
5.2.1
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.
5.2.1.2
Dose Modification (Escalation/Titration/Other)
NOTE:  As of Amendment 10, text in this section relating to dose modification of 
epacadostat is no longer applicable and has been deleted.
Dose modification and toxicity management for immune-related AEs (irAEs) associated with 
pembrolizumab should be managed as follows.
Adverse events (both non-serious and serious) associated with pembrolizumab 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 
 
 
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complications.  Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab, 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, 
skin biopsy may be included as part of the evaluation.  Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and administer corticosteroids.
Table 2 summarizes the irAE dose modification actions for pembrolizumab.
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 2
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
NOTE:  As of Amendment 10, this table was replaced with the guidelines for pembrolizumab alone.
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 has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab must 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.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 
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
Grade 3 or 4, or 
recurrent Grade 2
Permanently discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold

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.
Grade 4, or 
recurrent Grade 3
Permanently discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other therapies 
Monitor and follow-up 
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

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 returned to baseline or is 
stable).
Grade 3 or 4 
Permanently discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

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.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency)
Grade 3 or 4 
Withhold or permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis and 
Renal 
dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE administer 
corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently discontinue
All other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or discontinue 
based on the type of 
event.  Events that 
require discontinuation 
include and not limited 
to:  Guillain-Barre 
Syndrome, encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently discontinue
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
 
 
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5.2.1.3
Dose Modification and Toxicity Management of Infusion-reactions Related to 
Pembrolizumab
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.
Table 3 shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
Table 3
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 therapy or 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 study drug 
treatment
Subject 
may 
be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab (MK-
3475) with:
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg po (or equivalent dose 
of antipyretic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at 
subsequent dosing
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:
Epinephrine**
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
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.
**In 
cases 
of 
anaphylaxis, 
epinephrine 
should 
be 
used 
immediately.
Subject 
is 
permanently 
discontinued from further trial 
treatment administration.
No subsequent dosing.
Appropriate resuscitation equipment should be available at the bedside and a physician readily 
available during the period of drug administration
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) at http://ctep.cancer.gov
CTCAE=Common Terminology Criteria for Adverse Events, NCI=National Cancer Institute, 
NSAID=non-steroidal anti-inflammatory drug, po=oral 
 
 
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5.2.1.4
Procedures for Subjects Exhibiting Serotonin Syndrome (SS)
NOTE: As of Amendment 10, this section is no longer applicable.
There is a rare chance that epacadostat could cause an increase in serotonin levels in the brain 
that might trigger serotonin syndrome [53], (Section 12.8) when administered in combination 
with other serotonergic agents.  This syndrome has been most closely associated with use of 
MAOIs, meperidine, linezolid, or methylene blue; all of these agents are prohibited during 
the 
study
(Section 
5.5.3). 
 
Serotonin 
reuptake 
inhibitors 
(SSRIs)
and 
serotonin/norepinephrine reuptake inhibitors (SNRIs) are permitted in the study.  Serotonin 
syndrome usually manifests with autonomic changes, mental status changes, and 
neurological findings.  These mild, moderate, and severe signs and symptoms of SS 
(summarized in Table 4) should be evaluated in the context of possible comorbid conditions 
as well.
The following procedures will be implemented if subjects exhibit the signs/symptoms of SS, 
including tremor; hyperreflexia; spontaneous, ocular, or inducible clonus; together with 
agitation, fever, diaphoresis, or muscle rigidity:

Immediately 
interrupt 
epacadostat
or 
matching 
placebo
and 
pembrolizumab 
administration.  

Immediately interrupt any SSRI or SNRI 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 etiologies other than SS are excluded, pembrolizumab administration may be resumed 
unless other AE management guidelines apply for the specific event.

If subject chooses to remain in the study, restart treatment with epacadostat or matching 
placebo after the SSRI or SNRI has been discontinued, no sooner than 5 half-lives have 
elapsed for the specific SSRI or SNRI in question, and after resolution of signs/symptoms 
of SS.  The SSRI or SNRI dosing MAY NOT be restarted.

If subject chooses to withdraw from the study, or must restart treatment with SSRI or 
SNRI, the subject should be scheduled for a follow-up visit..  Treatment with SSRI or 
SNRI may be initiated 2 weeks after resolution of signs and symptoms of SS.

If a subject had experienced moderate or severe unconfounded SS in the opinion of the 
investigator, without concomitant SSRI or SNRI usage, or serotonergic concomitant 
medications, only pembrolizumab administration may be resumed; epacadostat/placebo 
treatment should be permanently discontinued.
 
 
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Table 4
Sign and Symptoms of Serotonin Syndrome
Seriousness
Autonomic signs                Neurological signs          Mental status       Other
Mild
Afebrile 
or 
low-grade 
fever
Tachycardia
Mydriasis
Diaphoresis or shivering
Intermittent tremor
Akathisia
Myoclonus
Mild hyperreflexia
Restlessness
Anxiety
Moderate
Increased tachycardia
Fever (up to 41°C)
Diarrhea with hyperactive 
bowel sounds
Diaphoresis with normal 
skin color
Hyperreflexia
Inducible clonus
Ocular 
clonus 
(slow 
continuous lateral eye 
movements)
Myoclonus
Easily startled
Increased 
confusion
Agitation 
and 
hypervigilance
Rhabdomyolysis
Metabolic acidosis
Renal failure
Disseminated 
intravascular 
coagulopathy 
(secondary 
to 
hyperthermia)
Severe
Temperature often more 
than 41°C (Secondary to 
increased tone)
Increased muscle tone 
(lower limb > upper)
Spontaneous clonus
Substantial myoclonus 
or hyperreflexia
Delirium
Coma
As above
Source: [62]
5.2.1.5
Dose Interruptions Unrelated to Adverse Events
Dosing interruptions are permitted for situations other than treatment-related AEs, such as in 
the case of medical / surgical events or logistical reasons (i.e., elective surgery, unrelated 
medical events, patient vacation, holidays) not related to study therapy.  Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with MSD.  The reason for interruption should be documented in the subject's 
study record.
Timing of Dose Administration
5.2.2
5.2.2.1
Timing of Dose Administration of Pembrolizumab
Study treatment with pembrolizumab should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed in the Trial Flow Chart (Section
6.0).  All study treatments will be administered on an outpatient basis.
Study treatment of pembrolizumab 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 1, where 
window is + 3 days from randomization.
 
 
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Pembrolizumab 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 Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
Trial Blinding 
5.2.3
NOTE:  As of Amendment 10, blinding is no longer applicable – all subjects will receive open-
label pembrolizumab alone.
A double-blinding technique with in-house blinding will be used.  Epacadostat and matching 
placebo will be packaged identically so that blind is maintained.
The subject, the 
investigator, and Sponsor and MSD study personnel or delegate(s) who are involved in the 
administration of epacadostat or matching placebo or clinical evaluation of the subjects are 
unaware of the group assignments.
Randomization or Treatment Allocation
5.3
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS).
There are 2 treatment arms.  
Subjects will be assigned randomly in a 1:1 ratio to pembrolizumab + epacadostat or
pembrolizumab + matching placebo, respectively.  No treatment crossover is planned.  
Stratification
5.4
Subjects will be stratified by:  
o
PD-L1 expression
o
Positive (≥1% of tumor and associated immune cells displaying PD-L1 
expression as determined by immunohistochemistry)
o
Negative (<1% expression/indeterminate)
o
BRAF mutation status
o
BRAF mutant and received prior BRAF directed treatment 
o
BRAF mutant and received no prior BRAF directed treatment
o
BRAF wild type
Recently acquired or archived tumor tissue (obtained since most recent therapy) from an 
unresectable or metastatic site must be analyzed and be evaluable for PD-L1 status during 
 
 
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screening in order to be randomized.  BRAF mutation status will be determined by local 
standard of care.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
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 MSD
Clinical Director.  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 MSD Clinical Director and the subject.
Acceptable Concomitant Medications
5.5.1
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 electronic Case Report 
Form (eCRF), including all prescription, over-the-counter, 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.
All concomitant medications received within 28 days before the first dose of study treatment 
and 30 days after the last dose of study treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of study treatment should be 
recorded for SAEs and AEs as defined in Section 7.2.
Prohibited Medications and Measures
5.5.2
NOTE:  As of Amendment 10, prohibited concomitant medications that were specific to 
epacadostat administration were deleted.
Subjects are prohibited from receiving the following therapies during the screening and 
treatment phase of this study unless otherwise noted below:

Any investigational medication other than the study drugs.

Antineoplastic systemic chemotherapy or biologic therapy.

Immunotherapy not specified in this protocol.

Chemotherapy not specified in this protocol.
 
 
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
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, with MSD consultation. 
No pembrolizumab 
infusions are permitted during radiation therapy or procedure.  Study medications 
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.

Administration of a live attenuated vaccine within 30 days before the first dose of 
study treatment and while participating in the study.  Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, rubella, chicken pox, 
yellow fever, rabies, BCG, and typhoid vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
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
treatment.  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.
Rescue Medications & Supportive Care
5.6
Supportive Care Guidelines for Pembrolizumab
5.6.1
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.1.2. Where appropriate, these guidelines include the use of oral or IV treatment 
with corticosteroids as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids. Note that several courses of steroid tapering 
may be necessary as symptoms may worsen when the steroid dose is decreased. For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or
bacterial or viral infection, which might require additional supportive care. The treatment 
 
 
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guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related to pembrolizumab, the 
investigator does not need to follow the treatment guidance. Refer to Table 2 and Table 3 in 
Section 5.2.1.2 for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Diet/Activity/Other Considerations
5.7
Diet
5.7.1
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
Contraception
5.7.2
Pembrolizumab may have adverse effects on a fetus (unborn baby) in utero.  Furthermore, it 
is not known if pembrolizumab 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.
 
 
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Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:  
1) practice abstinence† from heterosexual activity; 
OR 
2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):
•
Intrauterine device (IUD)
•
Vasectomy of a female subject’s male partner 
•
Contraceptive rod implanted into the skin
Combination method (requires use of two of the following):
•
Diaphragm with spermicide (cannot be used in conjunction with cervical cap/spermicide)
•
Cervical cap with spermicide (nulliparous women only)  
•
Contraceptive sponge (nulliparous women only) 
•
Male condom or female condom (cannot be used together)
•
Hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-only 
pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous contraceptive 
injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual lifestyle and 
if considered acceptable by local regulatory agencies and ERCs/IRBs.  Periodic abstinence 
(e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are 
not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at sites in 
this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
 
 
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initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of study drugs.  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.
Below are the required contraceptions for countries where the health authority requests 
compliance with the Clinical Trial Facilitation Group (CTFG) Guidance:
Subjects should use birth control methods that can achieve a failure rate of less than 1% per 
year when used consistently and correctly and are considered as highly effective birth control 
methods. Such methods include:

Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:
o
Oral
o
Intravaginal
o
Transdermal

Progestogen-only hormonal contraception associated with inhibition of ovulation:

Oral

Injectable

Implantable
o
Intrauterine device (IUD)
o
Intrauterine hormone-releasing system (IUS)
o
Bilateral tubal occlusion
o
Vasectomised partner
o
Sexual abstinence
Pregnancy
5.7.3
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, 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 MSD 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 MSD. 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 MSD and followed as described in Section 7.2.
 
 
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Use in Nursing Women
5.7.4
It is unknown whether pembrolizumab 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.
Subject Withdrawal/Discontinuation Criteria
5.8
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 MSD 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 7.1.7 – Other Procedures.
Discontinuation of Treatment
5.8.1
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment period will still continue to participate in the trial as 
specified in Section 6.0 - Trial Flow Chart and Section 7.1.8.5 – Post-Trial.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or MSD if treatment is inappropriate, 
the trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding procedures to be performed at treatment discontinuation are provided in Section 
7.1.7 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:

The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
The subject has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or MSD, placed the subject at unnecessary risk from continued 
administration of study drug/vaccine.
o
The subject has a confirmed positive serum pregnancy test.
o
Confirmed radiographic disease progression outlined in Section 7.1.5 (exception if 
MSD approves treatment continuation).
o
Unacceptable adverse experiences as described in Section 7.2.
 
 
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o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment. Note: For France only, a subject 
experiencing this condition must be discontinued from the trial.
o
Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment.
o
Recurrent Grade 2 pneumonitis.
o
Any toxicity listed in Section 5.2.1.2, Table 2, with a requirement to permanently 
discontinue.
o
Non-compliance with trial treatment or procedure requirements.
o
Investigator’s decision to discontinue treatment.
o
Administrative reasons.
o
Completed 35 treatments with pembrolizumab.
Note: 35 cycles (approximately. 2 years) are calculated from the first dose.  
o
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 (at least 2 doses of pembrolizumab) beyond the 
date when the initial CR was declared. 
The End of Treatment and Follow-up visit procedures are listed in Sections 7.1.8.4 and the 
Trial Flow Chart - Section 6.0.  
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
see Section 6.0 – Trial Flow Chart, and Section 7.1.8.4 – Post-Trial for those procedures to 
be completed at each specified visit.
 
 
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Withdrawal from the Trial
5.8.2
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
For France only: A subject must be discontinued from the trial for the following reason:

Any progression or recurrence of another malignancy, or any occurrence of another 
malignancy that requires active treatment.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, 
 
 are outlined in Section 7.1.7
– Other Procedures.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
5.10
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).
Clinical Criteria for Early Trial Termination
5.11
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.
Early trial termination will be the result of the criteria specified below:
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the IRB or independent 
ethics committee (IEC) in writing of the study's completion or early termination, and send a 
copy of the notification to MSD or MSD designee and retain 1 copy for the site study 
regulatory file.
 
 
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MSD in collaboration with the Sponsor may terminate the study electively, if required by 
regulatory decision, or upon advice of the DMC.  If the study is terminated prematurely, the 
investigators, the IRBs and IECs, and regulatory bodies will be notified of the decision and 
reason for termination of the study.  The DMC will recommend termination of the study if 
warranted, as described in Section 8.2.
In addition, early study termination may occur based on clinical criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete;
2. Poor adherence to Protocol and regulatory requirements;
3. Incidence or severity of adverse drug reaction in this or other studies indicates a 
potential health hazard to subjects;
4. Plans to modify or discontinue the development of the study drug.
In the event of a decision to no longer supply study drug, ample notification will be provided 
so that appropriate adjustments to subject treatment can be made.
 
 
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6.0 TRIAL FLOW CHART
Trial Flow Chart
6.1
As of Amendment 10, epacadostat and placebo administration are stopped and all subjects remaining in the trial receive 
pembrolizumab alone. For those subjects remaining in the trial, procedures are simplified. The Flow Chart has been amended 
and assessments no longer required have been deleted.
Screening 
Phase
Treatment Cycles
End of Treatment 
(EOT)
Post-treatment
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4 -35
Treatment 
Discontinuation
Safety Follow-Up
At time of Treatment 
Discontinuation
30 Days Post-
discontinuation
Scheduling Window (Days)a
-28 to -1
± 3
± 3
± 3
± 5
+ 7
Administrative Procedures
Informed Consent
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Review
X
X
X
X
X
X
X
Post-study Anticancer Therapy Status
X
X
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
Full Physical Examination
X
Directed Physical Examination
X
X
X
X
Xk
Xk
 
 
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Screening 
Phase
Treatment Cycles
End of Treatment 
(EOT)
Post-treatment
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4 -35
Treatment 
Discontinuation
Safety Follow-Up
At time of Treatment 
Discontinuation
30 Days Post-
discontinuation
Scheduling Window (Days)a
-28 to -1
± 3
± 3
± 3
± 5
+ 7
Height, Weight, and Vital Signs (T,P,RR,BP)b
X
X
X
X
X
X
X
12-Lead Electrocardiogram (Local)i
X
X
X
Xk
BRAF Testing
Xj
ECOG Performance Status
Xj
X
X
X
X
X
X
Trial Treatment Administration
Pembrolizumab Administration
Xa
X
X
X
Laboratory Procedures/Assessments:  Analysis 
performed by LOCAL laboratory
Pregnancy Testd
X
X
X
X
Xk
PT/INR and aPTT
Xc
Xk
Xk
CBC with Differential
Xc
X
X
Xk
Chemistry Panel
Xc
X
X
Xk
Urinalysis
Xc
X
Xk
T3, FT4, and TSH
Xc
X
Xk
Hepatitis B and C Testingl
X
Laboratory Procedures/Assessments: Analysis 
performed by CENTRAL/REFERAL laboratory
 
 
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Screening 
Phase
Treatment Cycles
End of Treatment 
(EOT)
Post-treatment
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4 -35
Treatment 
Discontinuation
Safety Follow-Up
At time of Treatment 
Discontinuation
30 Days Post-
discontinuation
Scheduling Window (Days)a
-28 to -1
± 3
± 3
± 3
± 5
+ 7
Tumor Tissue Collection
Newly-Obtained Tumor Tissuee
X
Archival Tumor Tissuef
X
Efficacy Measurements
Tumor Imagingn
Xg
Xh
X
a.
Cycle 1 treatment must be given within 3 days of allocation. The window for each visit is ± 3 days unless otherwise noted.  
b.
Height will be measured at Visit 1 only. 
c.
ECOG Performance Status and Laboratory tests for screening are to be performed within 7 days prior to the first dose of trial treatment.  If screening laboratory testing are 
performed within 7 days of Day 1 they are not required to be evaluated on Day 1 before treatment initiation.
d.
For women of reproductive potential, monthly pregnancy testing should be conducted as per local regulations where applicable, and whenever an expected menstrual cycle 
is missed or when pregnancy is otherwise suspected.  A serum test can be done if urine is not appropriate. Additionally, if urine test is positive or is not evaluable, a serum 
test is required. Subjects must be excluded/discontinued in the event of a positive test result.  
e.
Newly-obtained tissue is preferred (no intervening treatment [local or systemic] involving the site of tissue biopsy once tissue biopsy is obtained at time of study 
enrollment). Formalin-fixed, paraffin-embedded (FFPE) block specimens are preferred to slides.
f.
Archived tissue samples obtained since last treatment may be acceptable.  Refer to Section 7.1.4 for details.
g.
Screening tumor imaging will be performed within 28 days prior to randomization.  Scans performed as part of routine clinical management prior to consent are acceptable 
for use as the screening scan if they are of diagnostic quality and performed within 28 days before randomization.  The same imaging technique should be used in a subject 
throughout the study.  Local reading (investigator assessment with site radiology reading) will be used to determine eligibility and for subject management.
h.
Imaging timing should be performed according to the site’s standard of care for tumor assessment until initial PD per RECIST 1.1. A repeat scan at least 4 weeks later per 
irRECIST is not required if the investigator opts to discontinue the subject at the initial PD.
i.
Baseline ECGs will be obtained at screening, with additional ECGs obtained at EOT, and as clinically indicated for all subjects. At select centers, additional ECGs will 
also be obtained at Cycle 1 Day 1 predose and approximately 60 to 90 minutes after the first dose of epacadostat, and Cycle 2 Day 1 predose and approximately 60 to 90 
minutes after administration of epacadostat
j.
BRAF V600 mutation analysis should be performed locally by the sites during screening in subjects without documented BRAF status. BRAF mutation status will be 
 
 
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Screening 
Phase
Treatment Cycles
End of Treatment 
(EOT)
Post-treatment
Treatment Cycle
Screening 
(Visit 1)
1
2
3
4 -35
Treatment 
Discontinuation
Safety Follow-Up
At time of Treatment 
Discontinuation
30 Days Post-
discontinuation
Scheduling Window (Days)a
-28 to -1
± 3
± 3
± 3
± 5
+ 7
determined by local standard of care. 
k.
Per standard of care or as clinically indicated.
l.
Hepatitis B and C serologies should be obtained for subjects without a known history of Hepatitis B or C.  Those with a known history are ineligible. Include HCV RNA 
(qualitative), HBsAg.  See Table 6 for list of laboratory tests.  Hepatitis C Ab testing is allowed for screening purposes in countries where HCV RNA is not part of SOC.  
Hepatitis B and C testing should be performed within the 28 day screening period.
n.
CT of C/A/P with contrast are mandatory at baseline, and at minimum, CT of known sites of disease be performed at all follow-up assessments.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
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 MSD 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.
Administrative Procedures
7.1.1
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.  
 
 
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The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations.
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.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
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 melanoma will be recorded separately 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 28 days of the first dose of trial treatment.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial through the Safety Follow-up visit.
 
 
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All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2.
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 7.1.8.1.  
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be randomly allocated 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.
The IVRS/IWRS will be contacted to obtain a subject identification number when a subject 
enters the screening phase.  Upon determining that the subject is eligible for study entry, the 
IVRS/IWRS will be contacted to obtain study drug assignment.  Additionally, the 
IVRS/IWRS will be contacted at each regular study visit to update the study drug supply.
7.1.1.8
Trial Compliance (Medication)
Administration of trial medications and compliance are provided in Sections 7.1.1.8.
NOTE:  As of Amendment 10, text in this section relating to epacadostat is no longer 
applicable and has been deleted.
Interruptions from the protocol specified treatment plan for > 12 weeks between 
pembrolizumab doses due to toxicity require consultation between the investigator and MSD
and written documentation of the collaborative decision on subject management.
Administration of pembrolizumab will be witnessed by the investigator and/or trial staff.  
 
 
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7.1.1.8.1 Administration of Pembrolizumab and Compliance
Administration of pembrolizumab (± 3 days) will be witnessed by the investigator and/or 
study staff.  The total volume of study treatment infused will be compared to the total volume 
prepared to determine compliance with each dose administered.
The instructions for preparing and administering pembrolizumab will be provided in the 
Pharmacy Manual.
7.1.1.8.2 Dispensing of Pembrolizumab 
Site staff will contact IVRS to obtain the subject study drug assignment.  The investigator or 
designee will select the assigned vials and dispense the medication.  At subsequent 
medication dispensing visits, the investigator or designee will follow the same procedures as 
described above.  Full details will be provided in the IVRS Manual.
7.1.1.8.3 Distribution of Subject Reminder Cards and Serotonin Syndrome (SS)
Information Sheet
NOTE:  As of Amendment 10, this section is no longer applicable.
Subjects will be provided with reminder cards to remind the subject when they should not 
take their morning dose of epacadostat or matching placebo.  On Cycle 1 Day 1, subjects will 
also be given a serotonin syndrome (SS) information sheet for signs and symptoms of SS.  
This information sheet also instructs subjects to seek immediate medical care if any of these 
symptoms are observed.
7.1.1.9
Poststudy Anticancer Therapy Status
The investigator or qualified designee will review all new antineoplastic therapy initiated 
after the last dose of study treatment until the Safety Follow-up Visit. 
Clinical Procedures/Assessments
7.1.2
7.1.2.1
Adverse Events
The investigator or qualified designee 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 events will be graded and recorded throughout the trial and 
during the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.6). 
Toxicities will be characterized in terms regarding seriousness, causality, toxicity grading, 
and action taken with regard to trial treatment.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of
AEs.  
 
 
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7.1.2.2
Full Physical Examination
The investigator or clinical designee will perform a complete physical exam during the 
screening period.
Clinically significant abnormal findings should be recorded as medical 
history.  After the first dose of trial treatment new clinically significant abnormal findings 
should be recorded as AEs.
7.1.2.3
Directed Physical Examination
For cycles that do not require a full physical exam per the Trial Flow Chart (Section 6.0), the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to dosing on Day 1 of each treatment cycle, then per standard of care or as 
clinically indicated at the EOT visit and 30-day Safety Follow-up Visit.  New clinically 
significant abnormal findings should be recorded as AEs.  
7.1.2.4
Vital Signs
Vital sign measurements include blood pressure, pulse, respiratory rate, body temperature, 
and weight. The investigator or qualified designee will take vital signs at screening, prior to 
the administration of each dose of trial treatment and during the follow-up period as specified 
in the Trial Flow Chart (Section 6.0).  Height will be measured at screening only.
7.1.2.5
Twelve-Lead Electrocardiograms
Baseline ECGs will be obtained at screening, with additional ECGs obtained at EOT, and as 
clinically indicated for all subjects. At select centers, additional ECGs will also be obtained 
at Cycle 1 Day 1 predose and approximately 60 to 90 minutes after the first dose of 
epacadostat, and Cycle 2 Day 1 predose and approximately 60 to 90 minutes after 
administration of epacadostat. Clinically significant abnormal findings prior to signing 
consent should be recorded as medical history. Clinically significant abnormal findings after 
signing consent should be recorded as an AE.
The 12-lead ECGs will be interpreted by the investigator at the site and will be used for 
immediate subject management. The decision to include or withdraw a subject from the 
study based on an ECG flagged as "Abnormal, Clinically Significant" is the responsibility of 
the investigator, in consultation with the MSD medical monitor, as appropriate.
The 
correction method (Fredericia or Bazett) used for calculating QTc will need to be provided in 
the eCRF.
7.1.2.6
Performance and Quality of Life Assessments
7.1.2.6.1 Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess ECOG performance status (Section 12.4) at 
screening and before the administration of each cycle of study treatment and as specified in 
the Trial Flow Chart (Section 6.0).  
 
 
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Tumor Biopsy/Archival Tissue Collection
7.1.3
Tumor Biopsy
7.1.4
NOTE:  As of Amendment 10, optional post-baseline tumor biopsy has been removed.
Fresh tumor biopsies or archived tumor sample will be required at baseline.  Newly-obtained 
tissue is preferred (no intervening treatment [local or systemic] involving the site of tissue 
biopsy once tissue biopsy is obtained at time of study enrollment).
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.     
Note: Subjects for whom newly obtained samples cannot be obtained (e.g. inaccessible or 
subject safety concern) may submit an archived specimen.
Detailed instructions for fresh tissue collection, as well as details for processing and shipping 
the archived tumor tissue samples will be provided in the Procedures Manual.
Tumor Imaging and Assessment of Disease
7.1.5
NOTE:  As of Amendment 10, central imaging vendor assessment is no longer required.
Disease assessments will be performed by the site investigator/radiology assessment, per 
standard of care.
The process for image collection and transmission to the central imaging vendor can be 
found in the Site Imaging Manual (SIM).  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 throughout the trial to 
optimize the visualization of existing and new tumor burden.  
7.1.5.1
Initial Tumor Imaging
Initial tumor imaging must be performed within 28 days before the first date of 
randomization. The site study team must review prestudy images to confirm the subject has 
measurable disease per RECIST 1.1.  The baseline imaging scan should be submitted to the 
central imaging vendor for a retrospective analysis of this eligibility criterion.
 
 
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Scans performed as part of routine clinical management are acceptable for use as the 
screening scan if they are of diagnostic quality and performed within 28 days before the first 
dose of study treatment.  The same imaging technique should be used in a subject throughout 
the study. Baseline scan must be a CT or MRI, except in circumstances where there is a 
contrast allergy or with medical monitor approval.  When the CT component of a positron 
emission tomography (PET)/CT uses higher energy and thinner slices, it may be acceptable 
(with medical monitor approval). 
A standard, full assessment for lesions should be 
conducted at baseline, including CT or MRI scans of chest, abdomen, and pelvis. The same 
modality (CT or MRI) should be used for follow-up assessments, and include radiological 
assessments of all sites of disease present at baseline.  Timing should follow the site’s 
standard of care for oncologic tumor assessment.  In addition to radiological monitoring, all 
other lesions observed at the screening visit should be followed.
For selection of target lesions, RECIST 1.1 should be followed.  For example, RECIST 
discourages selection of target lesions inside the field of prior irradiation.  Lesions situated in 
a previously irradiated area, or in an area subjected to other loco-regional therapy, are usually 
not considered measurable unless it is the solitary site of measurable disease AND there has 
been demonstrated progression in the lesion.  Also, if a subject has only 1 measurable lesion, 
this lesion should not be biopsied.
Subjects with previously treated brain metastases may participate provided they have stable 
brain metastases, i.e. without evidence of progression by imaging (confirmed by magnetic 
MRI if MRI was used at prior imaging, or confirmed by CT imaging if CT used at prior 
imaging) for at least 4 weeks prior to the first dose of trial treatment.
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.
7.1.5.2
Tumor Imaging During the Study
NOTE:  As of Amendment 10, central imaging vendor assessment is no longer required. 
Disease assessments will be performed by the site investigator/radiology assessment, per 
standard of care.
Tumor imaging may be performed by CT or MRI, but the same imaging technique should be 
used in a subject throughout the study. Scans must be a contrast CT or MRI, except in 
circumstances where there is a contrast allergy or with medical monitor approval.  When the 
CT component of a PET/CT uses higher energy and thinner slices, it may be acceptable (with 
medical monitor approval) if it was the same technique used for baseline. Imaging should 
include radiological assessments of all sites of disease present at baseline. In addition to 
radiological monitoring, all other lesions observed at the screening visit should be followed.  
Imaging should continue to be performed until documented disease progression, the start of 
new anticancer treatment, withdrawal of consent, death, or the end of the study, whichever 
 
 
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occurs first.  Disease progression should be confirmed at least 4 weeks after the first scan 
indicating progressive disease in clinically stable subjects.  Subjects who have unconfirmed 
disease progression may continue on treatment until progression is confirmed provided they 
have met the conditions detailed in Section 7.1.5.3.  A repeat scan is not required if the 
investigator opts to discontinue the subject at the initial PD.
7.1.5.2.1 End of Treatment and Follow-up Tumor Imaging
In subjects who discontinue trial treatment, tumor imaging should be performed at the time 
of treatment discontinuation (± 4 week window).  If a previous scan was obtained within 
4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is not 
mandatory.
In subjects who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
7.1.5.3
Assessment of Disease According to irRECIST and RECIST 1.1
NOTE:  As of Amendment 10, disease assessments will be performed by the site 
investigator/radiology using RECIST 1.1 and irRECIST; centralized review per 
RECIST 1.1 is no longer required.
Modifications to RECIST 1.1 Criteria (irRECIST) will be used for assessment of tumor 
response for the purposes of managing subjects on protocol treatment and decision making 
for discontinuation of study therapy due to disease progression. These disease assessments 
will be performed by the site investigator/radiology assessment. One exception is that for 
baseline tumor assessments, at least one measurable lesion according to RECIST 1.1 criteria 
must be present on a bi-dimensional imaging study (CT or MRI) at baseline. 
For the purposes of the efficacy endpoints of the study, response assessment based on 
RECIST 1.1 by independent central review will be applied as the primary measure of 
progression.
RECIST 1.1 will be adapted for defining PD as follows to account for the unique tumor 
response seen in this class of therapeutics.
If imaging shows PD, it is at the discretion of the investigator to keep a subject on study 
treatment or to stop study treatment until imaging is repeated approximately 4 weeks later in 
order to confirm PD, as described in the irRECIST recommendations.  A repeat scan is not 
required if the investigator opts to discontinue the subject at the initial PD. Subjects that are 
deemed clinically unstable or who have biopsy proven new metastatic lesions are not 
required to have repeat imaging for confirmation. This decision will be based on clinical 
judgment of a subject’s overall clinical condition, including performance status, clinical 
symptoms, and laboratory data. At a minimum, subjects must meet the following criteria for 
continued treatment on study after disease progression is identified at a tumor assessment:
Subjects may receive study treatment while waiting for confirmation of PD if they are 
clinically stable (see Table 5) as defined by the following criteria:
 
 
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
No decline in ECOG performance status

Absence of new or worsening symptoms

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., spinal cord 
compression) requiring urgent alternative medical intervention.
Table 5
Imaging and Treatment after First Radiographic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD 
Option to repeat 
imaging 
at 
≥4 
weeks to confirm 
PD 
May 
continue 
study treatment at 
the investigator's 
discretion 
while 
awaiting 
confirmatory 
imaging
Repeat imaging at 
≥ 
4 
weeks 
to 
confirm 
PD 
if 
possible 
Discontinue 
treatment 
Repeat imaging
confirms PD by 
irRECIST
No 
additional 
imaging required 
Discontinue 
treatment 
No 
additional 
imaging required 
Not applicable
Repeat imaging
shows SD, PR, 
or 
CR 
by 
irRECIST
Continue regularly 
scheduled imaging 
assessments 
per 
standard of care 
Continue 
study 
treatment at the 
investigator's 
discretion 
Continue regularly 
scheduled imaging 
assessments 
per 
standard of care
May 
restart 
study treatment 
if condition has 
improved and/or 
clinically stable 
per 
investigator's 
discretion 
CR=complete response; irRECIST=immune-related response evaluation criteria in solid tumors; 
PD=progressive disease; PFS=progression-free survival; PR=partial response; SD=stable disease
In determining whether the tumor burden has increased or decreased, investigators should 
consider all target lesions as well as non-target lesions (refer to the Site Imaging Manual). 
Subjects who are deemed clinically unstable are not required to have repeat imaging for 
confirmation.  If radiologic progression is confirmed, then the subject will be discontinued 
from study treatment as specified in the protocol, and the first radiographic evidence of PD 
should be the date of progression.  If radiologic progression is not confirmed, then the subject 
should resume/continue study treatment and have their next scan according to the Protocol-
specified schedule.  If progression is not confirmed and the subject continues on treatment, 
 
 
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the next imaging that documents disease progression (and is confirmed by a second tumor 
imaging at least 4 weeks later), will be considered the date of disease progression.
NOTE: If a subject with confirmed radiographic progression (i.e., 2 images at least 28 days 
apart demonstrating progressive disease) is clinically stable or clinically improved, and there 
is no further increase in the tumor dimensions at the confirmatory imaging, an exception may 
be considered to continue treatment upon consultation with MSD.  Clinically stable subjects 
should also have at the confirmatory scan no further increase in the target lesions, no 
unequivocal increase in non-target lesions, and no additional new lesions develop 
(nonworsening PD) to continue study treatment.
7.1.5.4
Photography for Cutaneous Lesions
NOTE:  As of Amendment 10, this section is no longer applicable.
Digital photographs documenting measureable cutaneous lesions should be obtained if the 
cutaneous lesion is included as part of the non-target lesions for disease assessment
according to RECIST 1.1. Copies of the photograph should be forwarded to the central 
imaging vendor for potential retrospective analysis. The timing for capturing cutaneous
lesion photographs should follow the same schedule as the imaging scans.
Laboratory Procedures/Assessments
7.1.6
Details regarding specific laboratory procedures/assessments to be performed in this trial 
follow. The total amount of blood/tissue to be drawn/collected over the course of the trial 
(from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the procedures 
manual.
After Cycle 1, predose laboratory procedures can be conducted up to 72 hours before study 
drug administration.  Results must be reviewed by the investigator or qualified designee and 
found to be acceptable before each dose of study treatment.
7.1.6.1
Hematology, Hemostatic Panel, Serology, Urinalysis and Endocrine Function 
Testing 
Hematology, hemostatic panel, urinalysis and endocrine function will all be analyzed by the 
site laboratory.
7.1.6.2
Serum Chemistry and Liver Function Tests
All serum chemistry testing and liver function testing as shown in the Trial Flow Chart 
(Section 6.0) will be performed by the site's local laboratory.  Throughout the protocol, LFT 
refers specifically to liver chemistry testing, and required analytes for LFTs are listed in
Table 6.
 
 
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7.1.6.3
Pregnancy Testing
Monthly pregnancy testing should be conducted as per local regulations where applicable, 
and whenever an expected menstrual cycle is missed or when pregnancy is otherwise 
suspected. If a urine test is positive or not evaluable a serum test will be required. Subjects 
must be excluded/discontinued from study treatment in the event of a positive or borderline-
positive test result.
7.1.6.4
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 6.
Table 6
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine)a
Hemoglobin
Alkaline phosphatase
Glucose
Hepatitis

Hepatitis B surface 
antigen

Hepatitis 
B 
core 
antibody

HCV-RNAf
Platelet count
Alanine 
aminotransferase 
(ALT)
Protein
Hemostatic:

PT 

aPTT

INR
WBC 
(total 
and 
differential)e
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Endocrine Monitoring:

Thyroid-stimulating 
hormone (TSH)

Free thyroxine (T4)

Total 
triiodothyronine 
(T3)d
Red blood cell count
Amylase 
Microscopic exam, if 
abnormal results are 
noted
LFT Monitoring: 

Alkaline phosphatase

ALT

AST

Total bilirubin
Differential 
count, 
including:

Basophils

Eosinophils

Lymphocytes

Monocytes

Neutrophils
Bicarbonate or Carbon 
Dioxidec
 
 
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Hematology
Chemistry
Urinalysis
Other
Blood 
Urea 
Nitrogen/Ureab
IgG - Immunoglobulin G
Calcium
C-reactive protein (CRP) 
Chloride
Creatinine
Glucose
Lactate dehydrogenase 
(LDH)
Phosphorus
Potassium
Serum lipase
Sodium
Total Bilirubin  
Direct 
Bilirubin, 
if 
total 
bilirubin 
is 
elevated 
above 
the 
upper limit of normal
Total protein
a Perform on women of childbearing potential only, 72 hours prior to Day 1 of each cycle and 30 
days post treatment.
b Blood Urea Nitrogen is preferred; if not available urea may be tested.
c If these tests are not done as part of standard of care in your region then these tests do not need to 
be performed.
d T3 is preferred; if not available free T3 may be tested. If the local laboratory is unable to perform 
either of these tests the site should submit the sample to the central laboratory for testing.  Details 
are provided in the procedures manual.  Blood draws for thyroid function tests should be done 
prior to dosing at the scheduled time point; however results can be reviewed after dosing if they 
are not available at the time of the scheduled dosing.
e Report % or absolute results per standard of practice. Report the results in the same manner 
throughout the study.
f Hepatitis C Ab testing is allowed for screening purposes in countries where HCV RNA is not part 
of SOC.
Pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing.
7.1.6.5
Pharmacokinetic/Pharmacodynamic Evaluations
NOTE:  As of Amendment 10, this section is no longer applicable.
The accumulation of robust PK and ADA data has allowed for the adequate characterization 
the clinical pharmacology of pembrolizumab across indications.  Further collection of 
samples in subjects receiving pembrolizumab alone is not required.  Blood samples for PK 
and ADA may be stored.  Analysis will be performed only if required.
To evaluate the immunogenicity and exposure of pembrolizumab and epacadostat in this 
indication, sample collections for analysis of PK and anti-pembrolizumab antibodies (ADA)
 
 
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are currently planned as shown in the Trial Flowchart (Section 6.0). Blood samples collected 
for PK and ADA may only be stored at this time. Further analysis may be performed if 
required. If ongoing PK and/or ADA sampling is deemed to be unnecessary by the Sponsor, 
it may be reduced or discontinued.
7.1.6.5.1 Blood Sample Collection for PK of Pembrolizumab
NOTE:  As of Amendment 10, this section is no longer applicable.
Sample collection, storage and shipment instructions for serum samples will be provided in
the Procedures Manual. PK samples should be drawn according to the PK collection 
schedule.
7.1.6.5.2 Blood Sample Collection for Anti-pembrolizumab Antibodies
NOTE:  As of Amendment 10, this section is no longer applicable.
Sample collection, storage and shipment instructions for serum samples will be provided in
the Procedures Manual. Anti- pembrolizumab antibody samples should be drawn according 
to the ADA collection schedule.  Simultaneous PK sampling is required for interpretation of 
ADA analysis.
7.1.6.5.3 Blood Sample Collection for PK of Epacadostat
NOTE:  As of Amendment 10, this section is no longer applicable.
Pharmacokinetics samples for epacadostat will be required for all subjects enrolled in this 
study as noted in Table 8 with sample collection times and windows shown. Subjects will 
arrive at clinic having withheld their morning dose of epacadostat or matching placebo.  
Pharmacokinetic samples will be obtained at the visits indicated in the Trial Flow Chart
(Section 6.0.)  Additional timed serial sample collection for epacadostat will be collected at 
SELECT centers for all subjects enrolled at those centers as indicated in Table 7. All sample 
times noted are required.  
After the predose (predose is defined as within 24 hours before administration of 
pembrolizumab and before administration of epacadostat) PK sample is drawn, subjects will 
take epacadostat or matching placebo and then begin infusion of pembrolizumab.  The exact 
date and time of the PK blood draws will be recorded along with the date and time of the last 
dose of study drug and last meal preceding the blood draw.  Instructions for sample 
preparation and shipping will be provided in the Laboratory Manual.  
 
 
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Table 7
Sample Collection Time Windows for Pharmacokinetic Assessments for 
Epacadostat or Matching Placebo at SELECT Centers ONLY
Study Visit
Timing of Sample Relative to Epacadostat
or Matching Placebo Administration
C1D1
Predose
1 h
± 30 min
2 h
± 30 min
4-10 h
C2D1
Predose
1 h
± 30 min
2 h
± 30 min
4-10 h
Table 8
Sample Collection Time Windows for Pharmacokinetic Assessments for 
Epacadostat or Matching Placebo at ALL Centers
Study Visit
Timing of Sample Relative to Epacadostat 
or Matching Placebo Administration
C1D1
Predose
1 h ± 30 min
C2D1
Predose
1 h ± 30 min
7.1.6.5.4 Pharmacodynamic Assessments
NOTE:  As of Amendment 10, this section is no longer applicable.
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. 
Plasma samples will be obtained for pharmacodynamic assessments at the visits designated 
in the Trial Flow Chart (Section 6.0) and Table 9 and will be collected for subjects in the 
treatment phase only (not in Second Course Phase [Retreatment]).  The plasma PD sample 
collection for epacadostat or matching placebo should occur in parallel with the predose PK 
sampling for epacadostat or matching placebo outlined in Table 8 for all centers.
Table 9
Plasma Samples for Pharmacodynamic Assessment
Study Visit
Timing of Sample Relative to Epacadostat 
or Matching Placebo Administration
C1D1
Predose
C2D1
Predose
 
 
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Other Procedures
7.1.7
7.1.7.1
Withdrawal/Discontinuation
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
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. These subjects should return to the site for the Safety Follow-Up 
visit and will then be considered to have completed the study.
7.1.7.1.2 Lost to Follow-up
NOTE: As of Amendment 10, this section is no longer applicable. There will be no 
additional efforts to contact subjects who are lost to follow-up.
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
 
 
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
The investigator or designee must make every effort to regain contact with the subject 
at each missed visit (e.g. phone calls and/or a certified letter to the subject’s last 
known mailing address or locally equivalent methods). 
These contact attempts 
should be documented in the subject’s medical record.

Note:  A subject is not considered lost to follow up until the last scheduled visit for 
the individual subject.  The amount of missing data for the subject will be managed 
via the pre-specified data handling and analysis guidelines
7.1.7.2
Blinding/Unblinding
NOTE:  As of Amendment 10, blinding is no longer applicable – all subjects will receive open-
label pembrolizumab alone.
When the investigator or sub-investigator needs to identify the drug used by a subject and the 
dosage administered in case of emergency e.g., the occurrence of serious adverse 
experiences, he/she will contact the emergency unblinding call center by telephone and make 
a request for emergency unblinding.  As requested by the investigator or sub-investigator the 
emergency unblinding call center will provide the information to him/her promptly and 
report unblinding to MSD.  The emergency unblinding call center will make a record 
promptly however, the investigator or sub-investigator must enter the toxicity grade of the 
adverse experiences observed, their relation to study drug, the reason thereof, etc., in the 
medical chart etc., before unblinding is performed.
Additionally, the investigator must go into the IVRS system and perform the unblind in the 
IVRS system to update drug disposition. In the event that the emergency unblinding call 
center is not available for a given site in this study, the IVRS/IWRS system should be used 
for emergency unblinding in the event that this is required for subject safety.
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and the 
MSD Clinical Director notified as soon as possible. Only the principal investigator or 
delegate and the respective subject’s code should be unblinded. Trial site personnel and MSD
personnel directly associated with the conduct of the trial should not be unblinded.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
At the end of the trial, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to MSD or designee.
7.1.7.3
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical trial that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
 
 
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calibrated and/or 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.
Laboratory equipment – as required for inclusion labs and trial assessments
Imaging equipment – as required for study objectives
See protocol-specified guidance in the Administrative Binder, Procedures Manual and Site 
Imaging Manual.
Visit Requirements
7.1.8
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.8.1
Screening Visit
Approximately 28 days prior to treatment allocation/randomization, potential subjects will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5.1.  
Screening procedures may be repeated after consultation with MSD.  
Screening is the interval between the signing of the inform consent form (ICF) and the day 
the subject received the first dose of treatment in the study (Cycle 1 Day 1).  Informed 
consent must be obtained before performing any study-specific procedures.  However, 
assessments done as part of standard of care prior to informed consent may be used if they 
are within the required screening period.  Screening procedures may be repeated with MSD 
consultation.  Results from the screening visit evaluations will be reviewed to confirm 
subject eligibility before randomization or the administration of study drug.  Baseline 
radiographic imaging must be performed within 28 days of study start. Subjects may be 
rescreened after initially failing to meet the inclusion/exclusion criteria.
Subjects who are rescreened will retain their original screening number.
7.1.8.2
Treatment Period Visit
Visit requirements are outlined in the Trial Flow Chart (Section 6).  Specific 
procedure-related details are provided in Section 7.1.
7.1.8.3
End of Treatment
If a decision is made that the subject will permanently discontinue study drug, 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.
 
 
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7.1.8.4
Post-Treatment Visits
7.1.8.4.1 Safety Follow-Up Visit
NOTE: As of Amendment 10, the Safety Follow-up Visit will be the last visit in the 
study. This section has been amended as appropriate.
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 after the last dose of 
study drug if the EOT visit was not performed).  A subject will be considered to have 
completed this study once they have attended this visit.  Subjects currently in follow-up or in 
survival follow-up are considered to have completed the study; these subjects are not 
required to attend any further visits. Assessment and recording of AEs will be performed as 
per Section 7.2.  If a subject initiates a new anticancer therapy within 30 days after the last 
dose of study treatment, the 30-day Safety Follow-Up visit should occur before the initiation 
of new anticancer therapy.  Reasonable efforts should be made to have the subject return for 
the follow-up visit and report any AEs that may occur prior to initiating new anticancer 
therapy. 
7.1.8.4.2 Follow-Up Visits
NOTE:  As of Amendment 10, this section is no longer applicable.  A subject will be 
considered to have completed this study once they have attended the Safety Follow-up 
Visit.  Subjects currently in follow-up are considered to have completed the study; these 
subjects are not required to attend any further visits. Assessment and recording of AEs 
will be performed as per Section 7.2.
Subjects who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 9 weeks (63  ± 7 days) from 
Week 12 up to Week 102 by radiologic imaging to monitor disease status then every 
12 weeks (84 days ± 7 days) thereafter.  Every effort should be made to collect information 
regarding disease status until the start of new anti-cancer therapy, disease progression, death, 
and end of the study, or if the subject begins retreatment as detailed in Section 7.1.8.3.  
Information regarding poststudy antineoplastic treatment will be collected if new treatment is 
initiated.
Subjects who are eligible to receive retreatment according to the criteria in Section 5.2.2 will 
move from the Follow-Up Phase to the Second Course Phase (Retreatment) when they 
experience disease progression.  Details are provided in Section 5.2.2.
MSD consultation 
will be needed prior to starting Second Course Retreatment.
 
 
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7.1.8.4.3 Survival Follow-Up
NOTE: As of Amendment 10, this section is no longer applicable.  Subjects currently in 
survival follow-up are considered to have completed the study; these subjects will no 
longer be contacted for survival information.  Assessment and recording of AEs will be 
performed as per Section 7.2.
Subjects who experience disease progression by site assessment or start a new anti-cancer
therapy will move into the Survival Follow-Up Phase and should be contacted by telephone 
approximately every 9 weeks to assess for survival status until death, withdrawal of consent, 
or the end of the study, whichever occurs first.  
7.1.8.5
Unscheduled Visits
Unscheduled study visits may occur at any time if medically warranted.  Any assessments 
performed at those visits should be recorded in the eCRF.
7.1.8.6
Survival Status
NOTE:  As of Amendment 10, this section is no longer applicable.  Subjects currently in 
survival follow-up are considered to have completed the study; these subjects will no 
longer be contacted for survival information.  Assessment and recording of AEs will be 
performed as per Section 7.2.
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by MSD.  For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis.  Upon MSD 
notification, all subjects who do not/will not have a scheduled study visit or study contact 
during MSD defined time period will be contacted for their survival status (excluding 
subjects that have a previously recorded death event in the collection tool).
Assessing and Recording Adverse Events
7.2
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 MSD’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.  
 
 
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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.
MSD'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 MSD 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.
A progression of the cancer under study is not considered an adverse event.
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 30 days following cessation of 
treatment or 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 nonserious adverse events for 
outcome.
Definition of an Overdose for This Protocol and Reporting of Overdose
7.2.1
In this trial, an overdose is any dose higher than ≥1000 mg (5 times the dose) of 
pembrolizumab.  No specific information is available on the treatment of overdose of 
pembrolizumab. 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 MSD’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 MSD’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 MSD either by electronic media or paper. Electronic reporting 
 
 
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procedures can be found in the EDC data entry guidelines. Paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation 
7.2.2
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) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the 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 that occur from the time of treatment 
allocation/randomization through 120 days following cessation of MSD’s product, or if the 
subject initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator. All reported pregnancies must be followed to the completion/termination of the 
pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to MSD 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).
Immediate Reporting of Adverse Events
7.2.3
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
MSD’s product that:
●
Results in death;
●
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 MSD in the same timeframe as 
SAEs to meet certain local requirements. Therefore, these events are considered serious by 
MSD for collection purposes.
●
Is a new cancer (that is not a condition of the study);
 
 
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●
Is associated with an overdose.
Refer to Table 10 for additional details regarding each of the above criteria.
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, other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details) that occurs to any subject must be reported within 24 
hours to MSD 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 trial 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 other than progression 
of the cancer under study (reference Section 7.2.3.3 for additional details) whether or not 
related to MSD’s product, must be reported within 24 hours to MSD 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 MSD’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 MSD.  
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 MSD.
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 MSD 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 30 days 
following cessation of treatment, any ECI, or follow up to an ECI, whether or not related to 
MSD’s product, must be reported within 24 hours to MSD, 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).
 
 
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Events of clinical interest for this trial include:
1. an overdose of MSD’s product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to MSD, 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).
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to MSD as described in 
Section 7.2.3. - Immediate Reporting of Adverse Events to MSD.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
Unblinded aggregated efficacy endpoint events and safety data will be monitored to ensure 
the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study
Evaluating Adverse Events
7.2.4
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version v4.0. 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.
 
 
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Table 10
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 mild 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 of 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 MSD’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 MSD 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 MSD’s product to be discontinued?
Relationship to 
MSD’s product
Did MSD’s product cause the adverse event? The determination of the likelihood that MSD’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 MSD’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely MSD’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to MSD’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 
MSD’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 MSD’s 
product
(continued) 
Dechallenge
Was MSD’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 
MSD’s product; or (3) the trial is a single-dose drug trial); or (4) MSD’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to MSD’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) 
MSD’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 MSD’S PRODUCT, OR IF REEXPOSURE TO MSD’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE MSD 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 MSD’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 MSD’s product relationship).
Yes, there is a reasonable 
possibility of MSD’s product
relationship.
There is evidence of exposure to MSD’s product.  The temporal sequence of the AE onset relative to the administration of MSD’s product is 
reasonable.  The AE is more likely explained by MSD’s product than by another cause.
No, there is not a reasonable 
possibility of MSD’s product
relationship
Subject did not receive MSD’s product OR temporal sequence of the AE onset relative to administration of MSD’s product is not reasonable OR the 
AE is more likely explained by another cause than MSD’s product.  (Also entered for a subject with overdose without an associated AE.)
 
 
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Responsibility for Reporting Adverse Events
7.2.5
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.
TRIAL GOVERNANCE AND OVERSIGHT
7.3
Scientific Advisory Committee
7.3.1
The Scientific Advisory Committee (SAC) comprises both Sponsor and non-Sponsor 
scientific experts who provide input with respect to trial design, interpretation of trial results 
and subsequent peer-reviewed scientific publications.
Executive Oversight Committee
7.3.2
The Executive Oversight Committee (EOC) comprises members of Sponsor and MSD Senior 
Management.  The EOC will receive and decide upon any recommendations made by the 
Data Monitoring Committee (DMC) regarding the trial.
Data Monitoring Committee
7.3.3
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the interim data from this trial.  The voting 
members of the committee are external to the Sponsor.  The members of the DMC must not 
be involved with the trial in any other way (e.g., they cannot be trial investigators) and must 
have no competing interests that could affect their roles with respect to the trial. 
The DMC will make recommendations to the EOC regarding steps to ensure both subject 
safety and the continued ethical integrity of the trial.  Also, the DMC will review interim trial 
results, consider the overall risk and benefit to trial participants (see Section 8.7 - Interim 
Analyses) and recommend to the EOC if the trial should continue in accordance with the 
protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the protocol team; meeting facilitation; the 
trial governance structure; and requirements for and proper documentation of DMC reports, 
minutes, and recommendations will be described in a separate charter that is reviewed and 
approved by the DMC.  The DMC will monitor the trial at an appropriate frequency, as 
described in the detailed DMC charter.
A DMC recommendation will be communicated to as agreed to in the DMC charter.
 
 
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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 unblinding/final database lock, changes are made to 
primary and/or key secondary hypotheses, or the statistical methods related to those 
hypotheses, then the protocol will be amended (consistent with ICH Guideline E-9).  
 
 
 
 
 
Statistical Analysis Plan Summary
8.1
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 8.2-8.12. 
Study Design Overview
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study of 
Pembrolizumab in Combination With Epacadostat or Placebo in 
Subjects with Unresectable or Metastatic Melanoma 
Treatment Assignment
Following 
stratification 
by 
PD-L1 
expression 
(Positive; 
Negative/indeterminate) and BRAF mutation status (BRAF mutant 
and received prior BRAF directed treatment; BRAF mutant no prior 
BRAF directed treatment; BRAF wild type) patients will be 
randomized 1:1 to treatment with pembrolizumab in combination 
with either epacadostat or placebo
Analysis Populations
Efficacy: Intent to Treat (ITT)
Safety: All Subjects as Treated (ASaT)
Primary Endpoint(s)
1.
Progression-free survival (PFS)
2.
Overall survival (OS)
Key Secondary Endpoints
1.
Objective response rate (ORR)
Statistical Methods for 
Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
The primary hypotheses will be evaluated by comparing treatment 
with 
pembrolizumab 
and 
epacadostat
to 
treatment 
with 
pembrolizumab and placebo on (1) PFS and (2) OS using a stratified 
log-rank test. Estimation of the hazard ratio will be done using a 
Cox regression model. Event rates over time will be estimated 
within each treatment group using the Kaplan-Meier method. 
Statistical Methods for 
Key Safety Analyses
The analysis strategy for safety endpoints will depend upon the 
safety tier (see Section 8.6.2).  There are no Tier 1 safety endpoints.  
Descriptive statistics will be provided for the rate of Tier 2 safety 
endpoints, as well as 95% confidence intervals for the treatment 
comparisons.  
 
 
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Interim Analyses
Two interim analyses will be performed in this study.  Results will 
be reviewed by an external data monitoring committee.  These 
interim analyses are summarized below.  Details are provided in 
Section 8.7. An analysis of ORR may be conducted using data from 
interim analysis 2 (IA2). 

IA 1:
o
Timing: To be performed when approximately 331 
PFS events are observed. This analysis is expected to 
be performed about 12 months after enrollment starts.
Approximately 100 OS events are expected at IA1.
o
Testing: Inferential analyses for PFS and OS will be 
performed. 

IA 2:
o
Timing: to be performed when approximately 420 PFS 
events are observed.  This is the final PFS analysis and 
is expected to be performed about 24 months after 
enrollment starts. Approximately 200 OS events are 
expected at IA2. 
o
Testing: Inferential analyses for PFS and OS will be 
performed.  

Final analysis
o
Timing: To be performed when approximately 293 OS 
events are observed.  This is the final OS analysis and 
is expected to be performed about 45 months after 
enrollment starts. 
o
Testing: Inferential analyses for OS will be performed.
Multiplicity
The Type-I error rate over the multiple endpoints tested, as well as 
for the multiple analyses  planned, will be controlled by sequential 
interim monitoring and the methods of Maurer and Bretz [59]
Sample Size and Power 
The planned sample size was initially approximately 600 subjects.
Japan will begin enrolling late in the enrollment period, and must 
meet a minimum enrollment regulatory requirement. 
Therefore 
enrollment from Japan may continue after enrollment in other 
countries ends. 
Total enrollment is now expected to be 
approximately 700 subjects. For PFS, the trial has ~98% power to 
demonstrate that pembrolizumab and epacadostat is superior to 
pembrolizumab and placebo at an overall 1-sided 1.25% alpha-level.  
For OS, the trial has
~79% power to demonstrate that 
pembrolizumab and epacadostat is superior to pembrolizumab and 
placebo at an initial overall 1-sided 1.25% alpha-level.  Should the 
PFS comparison be statistically significant, the 1.25% alpha will be 
re-assigned to OS.  Should the OS comparison be statistically 
significant, the 2.5% alpha will be re-assigned to ORR. Should the 
total alpha assigned to OS be 2.5%, the power to demonstrate 
improved OS with the combination will be about 86%.  The 
treatment effect (true hazard rate) is assumed to be 0.65 for PFS and 
0.70 for OS.
Based on review of IA2 data, the DMC recommended that all subjects stop oral therapy 
(epacadostat/placebo).  After study completion, only selected analyses will be performed.
 
 
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Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of MSD.
This study will be conducted as a double-blind study under in-house blinding procedures.  
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Clinical Biostatistics department will generate the randomized allocation schedule(s) for 
study treatment assignment.  Randomization will be implemented in an interactive voice 
response system (IVRS).
Planned interim analyses are described in Section 8.7.  Study enrollment is expected to be 
completed at the time of any interim analyses.  Blinding to treatment assignment will be 
maintained at all investigational sites.  The results of interim analyses will not be shared with 
the investigators prior to the completion of the study.  Subject-level unblinding will be 
restricted to an external unblinded statistician and scientific programmer performing the 
interim analysis for the DMC, who will have no other responsibilities associated with the 
study.
The external Data Monitoring Committee (DMC) will serve as the primary reviewer of the 
unblinded results of the interim analyses and will make recommendations for discontinuation 
of the study or modification to an Executive Oversight Committee (EOC). Depending on the 
recommendation of the DMC, a regulatory submission may be prepared. If the DMC 
recommends modifications to the design of the protocol or discontinuation of the study, this 
EOC and limited additional personnel may be unblinded to results at the treatment level in 
order to act on these recommendations. The extent to which individuals are unblinded with 
respect to results of interim analyses will be documented. 
Additional logistical details, 
revisions to the above plan, and data monitoring guidance will be provided in the DMC 
Charter.
Prior to final study unblinding, the external unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol deviations, or data validation efforts after the interim analyses.
Hypotheses/Estimation
8.3
Objectives and hypotheses of the study are stated in Section 3.0. The study is considered to 
have met its primary objective in the study population if the combination of pembrolizumab 
and epacadostat is superior to the pembrolizumab and placebo in PFS at an interim PFS
analysis or at the final analysis (i.e., interim analysis 2) or in OS at an interim OS analysis or
at the final OS analysis.
 
 
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Analysis Endpoints
8.4
Efficacy and safety endpoints that will be evaluated for between-treatment differences are 
listed below, followed by the descriptions of the derivations of selected endpoints.
Efficacy Endpoints
8.4.1
Dual-Primary 
Progression-Free Survival – RECIST 1.1
Progression-free survival (PFS) is defined as the time from randomization to the first 
documented disease progression per RECIST 1.1 based on independent central review or 
death due to any cause, whichever occurs first.  See Section 8.6.1.1 for definition of 
censoring.
Overall Survival
Overall Survival (OS) is defined as the time from randomization to death due to any cause. 
Patients without documented death at the time of the final analysis will be censored at the 
date of the last follow-up.
Secondary
Duration of response (DOR) determined by disease assessment is defined as the time from 
the earliest date of qualifying response until earliest date of disease progression or death from 
any cause, whichever comes first based upon blinded independent radiologists’ RECIST 1.1 
assessment.
Objective response rate (ORR) is defined as the proportion of the subjects in the analysis 
population who have a confirmed complete response (CR) or partial response (PR) based on 
RECIST 1.1 by independent central review.
Safety Endpoints
8.4.2
Safety measurements are described in Section 8.6.2.
 
 
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Analysis Population
8.5
Efficacy Analysis Population
8.5.1
The Intent to Treat (ITT) population will serve as the population for the analysis of efficacy 
data in this study.  The ITT population consists of all randomized subjects.
Subjects will be included in the treatment group to which they are randomized for the 
analysis of efficacy data.  Details on the approach to handling missing data are provided in 
Section 8.6 Statistical Methods.
Safety Analysis Populations
8.5.2
The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in 
this study.  The ASaT population consists of all randomized subjects who received at least 
one dose of study treatment. Subjects will be included in the treatment group corresponding 
to the study treatment they actually received for the analysis of safety data using the ASaT 
population.  For most subjects this will be the treatment group to which they are randomized.  
Subjects who take incorrect study treatment for the entire treatment period will be included in 
the treatment group corresponding to the study treatment actually received 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Statistical Methods
8.6
Statistical testing and inference for efficacy analyses are described in 8.6.1. Efficacy results 
that will be deemed to be statistically significant after consideration of the Type I error 
control strategy are described in Section 8.8, Multiplicity.
Nominal p-values may be 
computed for other efficacy analyses, but should be interpreted with caution due to potential 
issues of multiplicity, sample size, etc.  Unless otherwise stated, all statistical tests will be 
conducted at α=0.05 (2-sided) level.
Statistical Methods for Efficacy Analyses
8.6.1
This section describes the statistical methods that address the primary and secondary 
objectives.  
 
8.6.1.1
Progression-Free Survival (PFS)
To address the primary PFS hypothesis, the Kaplan-Meier method will be used to estimate 
the PFS curve in each treatment group. The treatment difference in PFS will be assessed by 
the stratified log-rank test. A stratified Cox proportional hazard model with Efron's method 
of tie handling will be used to assess the magnitude of the treatment difference (i.e., hazard 
ratio) between the treatment groups. The hazard ratio and its 95% confidence interval from 
 
 
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the stratified Cox model with Efron's method of tie handling and with a single treatment 
covariate will be reported. The same stratification factors used for randomization (see 
Section 5.4) will be applied to both the stratified log-rank test and the stratified Cox model. 
Since disease progression is assessed periodically, progressive disease (PD) can occur any 
time in the time interval between the last assessment where PD was not documented and the 
assessment when PD is documented. In the primary analysis, for the subjects who have PD, 
the true date of disease progression will be approximated by the date of the first assessment 
at which PD is documented based on RECIST 1.1 by independent central review, regardless 
of discontinuation of study drug. Death as a first event is always considered as a confirmed 
PD event. 
In order to evaluate the robustness of the PFS endpoint, two sensitivity analyses will be 
performed, each with a different set of censoring rules. The first sensitivity analysis is the 
same as the primary analysis except that it censors at the last disease assessment without PD 
when PD or death is documented after more than one missed disease assessment. The second 
sensitivity analysis is the same as the primary analysis except that it considers 
discontinuation of treatment or initiation of new anticancer treatment, whichever occurs later, 
to be a PD event for subjects without documented PD or death. The censoring rules for 
primary and sensitivity analyses are summarized in Table 11.
Table 11
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary 
Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No PD and no death; 
new 
anticancer 
treatment 
is 
not 
initiated
Censored at last 
disease 
assessment 
Censored 
at 
last 
disease assessment 
Censored at last disease 
assessment if still on 
study therapy; progressed 
at 
treatment 
discontinuation otherwise
No PD and no death; 
new 
anticancer 
treatment is initiated
Censored at last 
disease 
assessment before 
new 
anticancer 
treatment
Censored 
at 
last 
disease 
assessment 
before 
new 
anticancer treatment
Progressed at date of new 
anticancer treatment
PD 
or 
death 
documented after ≤ 1 
missed 
disease 
assessment
Progressed at date 
of 
documented 
PD or death
Progressed at date of 
documented PD or 
death
Progressed at date of 
documented PD or death
PD 
or 
death 
documented after ≥ 2 
missed 
disease 
assessments
Progressed at date 
of 
documented 
PD or death
Censored 
at 
last 
disease 
assessment 
prior to the  ≥ 2 
missed 
disease 
assessment
Progressed at date of 
documented PD or death
 
 
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In case there is an imbalance between the treatment groups on disease assessment schedules 
or censoring patterns, the following two additional PFS sensitivity analyses may be 
performed: 1) a PFS analysis using time to scheduled tumor assessment visit from 
randomization as opposed to actual tumor assessment time; 2) Finkelstein’s likelihood-
based score test for interval-censored data [54] which modifies the Cox proportional hazard 
model for interval censored data, will be used as a supportive analysis for the PFS endpoint. 
The interval will be constructed so that the left endpoint is the date of the last disease 
assessment without documented PD and the right endpoint is the date of documented PD or 
death, whichever occurs earlier.
The proportional hazards assumption on PFS will be examined using both graphical and 
analytical methods if warranted. The log [-log] of the survival function versus time for PFS 
will be plotted for the comparison between pembrolizumab and the control group. If the
curves are not parallel, indicating that hazards are not proportional, supportive analyses 
may be conducted to account for the possible non-proportional hazards effect associated 
with immunotherapies: for example, using Restricted Mean Survival Time (RMST) method
[55], parametric method [56], comparison of PFS at fixed follow-up times (6 months; 1 
year) etc. Further details of sensitivityanalyses will be described in supplemental SAP.
8.6.1.2
Overall Survival (OS)
To address the primary OS hypothesis, the Kaplan-Meier method will be used to estimate the 
OS curves. The treatment difference in survival will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (i.e., the hazard ratio). The hazard 
ratio and its 95% confidence interval from the stratified Cox model with a single treatment 
covariate will be reported.
The same stratification factors used for randomization (see 
Section 5.4) will be applied to both the stratified log-rank test and the stratified Cox model.
8.6.1.3
Objective Response Rate (ORR)
To address the secondary ORR hypothesis, stratified Miettinen and Nurminen’s method [57]
with weighting based on group size will be used for comparison of the objective response 
rates between the treatment groups. A 95% confidence interval for the difference in response 
rates between the pembrolizumab + epacadostat regimen and the pembrolizumab + placebo 
regimen will be provided. Sensitivity analyses will be performed for ORR using Cochran-
Mantel-Haenszel test. Associated odds ratios and 95% CIs will be calculated. The same 
stratification factors used for randomization (see Section 5.4) will be applied to the analysis. 
Table 12 summarizes the key efficacy analyses.
 
 
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Table 12
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Dual Primary Hypotheses #1 and #2
Progression free-survival (per 
independent central review as 
assessed by RECIST 1.1)
Testing: Stratified Log-
rank test
Estimation: Stratified Cox 
model with Efron's tie 
handling method
ITT
Model based
Overall survival
Testing: Stratified Log-
rank test
Estimation: Stratified Cox 
model with Efron's tie 
handling method
ITT
Model based
Secondary Objectives 
ORR (per independent central review 
as assessed by RECIST 1.1)
Testing and estimation: 
Stratified Miettinen and 
Nurminen’s method
ITT
Model based
DOR (per independent central review 
as assessed by RECIST 1.1)
Testing: Stratified Log-
rank test
Estimation: Stratified Cox 
model with Model based  
Efron's tie handling 
method
ITT (responder 
subs Model 
based et)
Model based
The strategy to address multiplicity issues with regard to multiple efficacy endpoints and 
interim analyses is described in Section 8.7, Interim Analyses and in Section 8.8, 
Multiplicity.
Statistical Methods for Safety Analyses
8.6.2
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (AEs), laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 13).  The tiers differ with 
respect to the analyses that will be performed.  Safety parameters or adverse events of special 
interest that are identified a priori constitute “Tier 1” safety endpoints that will be subject to 
inferential testing for statistical significance with p-values and 95% confidence intervals 
provided for between-group comparisons.  For this protocol, there are no Tier 1 events.  
Other safety parameters will be considered Tier 2 or Tier 3.  Tier 2 parameters will be 
assessed via point estimates with 95% confidence intervals provided for between-group 
comparisons; only point estimates by treatment group are provided for Tier 3 safety 
parameters.
 
 
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Table 13
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint†
p-Value
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Serious AE
X
X
Any Drug-Related AE
X
X
Any Serious and Drug-Related AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs, or PDLCs‡ (incidence ≥4/1% of 
subjects in one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs or PDLCs‡ (incidence <4/1% of 
subjects in all of the treatment groups)
X
Change from Baseline Results (Labs, ECGs, Vital 
Signs)
X
†
Adverse Event references refer to both Clinical and Laboratory AEs.
‡
Includes only those endpoints not pre-specified as Tier 1 or not already pre-specified as Tier-2 endpoints.
Note: SOC=System Organ Class; PDLC=Pre-Defined Limit of Change; X= results will be provided.
Adverse events (specific terms as well as system organ class terms) and predefined limits of 
change in laboratory, vital signs, and ECG parameters that are not pre-specified as Tier-1 
endpoints will be classified as belonging to "Tier 2" or "Tier 3", based on the number of 
events observed.  Membership in Tier 2 requires that at least 4 subjects in any treatment 
group exhibit the event; all other adverse events and predefined limits of change will belong 
to Tier 3.
The threshold of at least 4 events was chosen because the 95% confidence interval for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. Because many 95% confidence intervals 
may be provided without adjustment for multiplicity, the confidence intervals should be 
regarded as a helpful descriptive measure to be used in review, not a formal method for 
assessing the statistical significance of the between-group differences in adverse events and 
predefined limits of change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG 
parameters will be considered Tier 3 safety parameters.  Summary statistics for baseline, on-
treatment, and change from baseline values will be provided by treatment group in table 
format.  In addition, summary statistics for the difference between treatment groups will also 
be provided, along with nominal p-values for between-group differences.  Mean change from 
baseline over time will be plotted with the corresponding standard errors.  
The broad clinical and laboratory AE categories consisting of the percentage of subjects with 
any AE, a drug related AE, a serious AE, an AE which is both drug-related and serious, and 
who discontinued due to an AE will be considered Tier 2 endpoints.  Ninety-five percent 
confidence intervals (Tier 2) will be provided for between-treatment differences in the 
 
 
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percentage of subjects with events; these analyses will be performed using the unstratified 
Miettinen and Nurminen method [57], an unconditional, asymptotic method.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs.  No statistical hypothesis tests will be performed on these 
characteristics.  The number and percentage of subjects screened, randomized, the primary 
reasons for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized by treatment either by descriptive statistics or 
categorical tables.
Interim Analyses
8.7
If the statistical criterion for success for one or more of the primary hypotheses is met at an 
interim analysis, a regulatory submission may be prepared while the trial continues, and the 
Clinical Study Report (CSR) will comprise all available data used to draw the conclusion in 
the decisive interim analysis.  The remaining data obtained afterwards (from additional visits 
and close-out visits) will be reported in a subsequent CSR. 
Efficacy Interim Analyses
8.7.1
Three analyses (two interim and one final) are planned in this trial.  Table 14 provides the 
summary of the strategy and timing of the interim and final analyses. Accrual is expected to 
be completed prior to the first interim analysis.  The final analysis of PFS will be performed 
at interim analysis 2 (IA2) scheduled to be performed at about 420 PFS events (about 24
months following the start of enrollment). The final analysis of OS will be performed at 
about 293 OS events (about 45 months following the start of enrollment).  
 
 
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Table 14
Summary of Interim Analysis Strategy
Analysis
Key 
endpoints
Targeted number of 
events at the time of 
analysis
Expected 
approximate 
timing of analysis 
(from study start)
Primary purpose of 
analysis
IA 1
PFS
OS
Approximately 331 total 
PFS events. About 100
OS events are expected at 
IA1.
About 12 months 
First
interim analysis of 
PFS: demonstrate superiority 
of combination in PFS. First
interim 
analysis 
of
OS; 
Demonstrate superiority of 
combination in OS.
IA 2
PFS
OS
Approximately 420 total 
PFS events.  This is the 
final PFS analysis.  About 
200
OS 
events 
are 
expected at IA2.
About 24 months
Final 
analysis 
of 
PFS:
demonstrate superiority of 
combination in PFS.  
Second interim look at OS; 
Demonstrate superiority of 
combination in OS.   
Final 
OS 
Approximately 293 total 
OS events.  This is the 
final OS analysis.  
About 45 months 
Final OS analysis:
Demonstrate superiority of 
combination in OS.
Table 15 provides the details of the interim efficacy monitoring boundaries for PFS and OS.
Table 15
Decision Guidance at IA1 and IA2 PFS Analyses and Each OS Analysis under a 
Hypothetical Timings of Interim Analyses and Initially Assigned Alpha 
Analysis
Targeted 
number 
of PFS 
events
One-
sided 
PFS 
Efficacy 
boundary 
p-value
PFS 
observed 
hazard 
ratio
OS 
events
One-
sided OS 
efficacy 
boundary 
p-value
OS 
observed 
hazard 
ratio
IA 1
~331
< 0.0053
< ~0.75
~100
< 0.0001
< ~0.46
IA 2
(Final 
PFS 
analysis)
~420
< 0.0108
< ~0.80
~200
< 0.0029
< ~0.68
Final 
OS 
Analysis
Targeted 
for ~293
< 0.0115
< ~0.77
The final analysis will take place when about 293 deaths have occurred between the 
pembrolizumab + epacadostat regimen and the pembrolizumab + placebo regimen, which is 
expected to occur ~45 months after study start.  According to Table 15 the nominal alpha for 
the final OS testing is 0.0115 (one-sided) if no alpha re-use occurs. A nominal alpha 
< 0.0115 corresponds to the approximate observed hazard ratio for OS superiority < 0.77. 
The nominal alpha level for PFS and OS interim hypothesis testing will be re-calculated if 
the actual number of events available at the times of the interim analyses is different from 
those specified above. The nominal alpha level for OS interim hypothesis testing will be re-
 
 
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calculated if alpha is transferred to the OS hypothesis testing following a significant 
difference seen in PFS. A 95% confidence interval will be provided for the hazard ratios to 
characterize the PFS and OS effects in case the superiority of the combination is not 
demonstrated. 
ORR analysis: Should the definitive OS analysis be statistically significant at any interim or 
final analysis, the definitive ORR analysis will be performed using the data available at IA2.
Safety Interim Analyses
8.7.2
The external Data Monitoring Committee (DMC) will perform ongoing review of the interim 
safety data from this trial, as described in Section 7.3.3. 
Multiplicity
8.8
The multiplicity strategy specified in this section will be applied to the overall ITT 
population for the testing of primary hypotheses.
The overall type I error is strongly 
controlled at 2.5% (one-sided) for the multiple endpoints tested, as well as for the multiple 
analyses of overall survival planned using the methods of Maurer and Bretz [59], with 1.25% 
allocated up front to the PFS hypothesis and 1.25% allocated up front to the OS hypotheses.  
The trial is considered statistically positive if either PFS or OS is positive.
The superiority of PFS will be tested at 1.25% in this study. If the pembrolizumab + 
epacadostat combination regimen demonstrates superior PFS, the 0.0125 alpha will be re-
assigned to the comparison of OS.  Should the OS comparison be statistically significant, the 
alpha assigned to OS will be reassigned to the comparison of ORR.  
A graphical display of the plans for re-allocation of alpha is displayed in Figure 3.
 
 
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Figure 3
Graphical Display of Testing Strategy 
For the PFS and OS hypothesis, an exponential alpha-spending function (see Anderson and 
Clark [60]) with nu=0.75 (approximating an O’Brien-Fleming boundary) will be used.  For 
PFS the cumulative alpha will be 1.25% unless OS and ORR are statistically significant, in 
which case the 1.25% alpha associated with OS will be reallocated to PFS and testing will be 
done at 2.5% alpha.  For OS, the cumulative alpha will be 1.25% (if PFS superiority is not 
demonstrated) or 2.5% (if PFS superiority is demonstrated).  
Sample Size and Power Calculations
8.9
Sample Size and Power for Efficacy Analyses
8.9.1
The study will randomize subjects in a 1:1 ratio into the pembrolizumab + epacadostat 
regimen and the pembrolizumab + placebo regimen. The overall sample size for this study
was projected to be ~600 subjects (maximum enrollment 660).  Enrollment, excluding Japan, 
was 662 subjects, and is expected to be a total of 700 subjects after enrollment in Japan is 
completed.
The study is event driven (i.e., number of subjects and follow-up time are subject to change 
but number of events is not) and will complete after approximately 293 deaths have been 
observed between the two treatments. 
 
 
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PFS analysis: The primary PFS analysis will be carried out at the second interim analysis, 
which occurs after about 420 PFS events have been observed, expected to occur about 24
months from the start of enrollment. An initial alpha of 1.25% will be allocated to the PFS 
analysis. If the number of PFS events is exactly as specified in Table 15, the study has about 
98% power to detect a 0.65:1.00 hazard ratio favoring combination therapy. A p-value less 
than 0.0108 for PFS corresponds to an approximate observed hazard ratio < 0.80.
OS analyses: OS efficacy analyses will be performed at the first and second interim analyses.  
The final analysis will be conducted when about 293 deaths have been observed.  An initial 
alpha of 1.25% will be allocated to the OS analysis. If the comparison of PFS is not 
statistically significant, and the number of OS events is exactly as specified in Table 15, the 
study has about 79% power to detect a 0.70 hazard.  Details on the nominal alpha and the 
approximate efficacy boundary at each interim analysis are summarized in Section 8.2.9.  
The nominal alpha levels will be re-calculated based upon the actual observed number of 
deaths at each interim analysis using the alpha-spending function.  If the comparison of PFS 
is statistically significant, the 1.25% allocated to the PFS comparison will be re-allocated to 
the OS comparison.  If superiority of the combination is demonstrated for PFS, the OS 
comparison will be performed at an alpha of 2.5% and, if the final analysis is done at 293 OS 
events, the power to detect a true hazard ratio of 0.70 will be approximately 86%. If the 
accumulation of the final number of OS events (293) is substantially delayed from the 
estimated 45 months, an additional interim analysis may be added.
ORR analysis: Should the definitive OS analysis be statistically significant, the definitive 
ORR analysis will be performed using the data available at IA2.  Assuming the available 
alpha for the ORR comparison is 2.5% and an ORR of 35% for the pembrolizumab + placebo 
regimen, the study has ~97% power to detect an ORR rate for the combination regimen of 
50%.  
The above calculations are based on the following assumptions (in addition to the interim 
analysis plan in Section 8.7):  1) OS for the pembrolizumab + placebo regimen follows a 
distribution with a “cure” rate of 35%, with survival for the remaining 65% of patients 
following an exponential distribution with a median of 14 months; 2) PFS follows a 
distribution with a “cure” rate of 30%, with PFS for the remaining 70% of patients following 
an exponential distribution with a median of 4.75 months in the pembrolizumab + placebo 
regimen; 3) the hazard ratio for OS between the pembrolizumab + epacadostat combination 
and pembrolizumab + placebo is 0.7; 4) hazard ratio for PFS between the pembrolizumab + 
epacadostat combination and pembrolizumab + placebo is 0.65 and 5) an enrollment period 
of approximately 12 months. The sample size and power calculation were performed in the 
software R package gsDesign (see R code, Section 12.10).
 
 
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Subgroup Analyses and Effect of Baseline Factors
8.10
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoint will be estimated and plotted within each category of the following classification 
variables:

Age category (<65 vs. ≥65 years)

Sex (female vs. male)

Race (white vs. non-white)

Disease stage (III vs. IVM1a vs. IVM1b vs. IVM1c)

ECOG status (0 vs. 1)

BRAF mutation status (wild type vs. mutant with prior BRAF directed therapy vs. 
mutant with no prior BRAF directed therapy)

PD-L1 status (positive vs. negative [includes indeterminate])

LDH (≤ ULN vs. > ULN but < 2X ULN vs. ≥ 2X ULN)
In addition, a Forest plot will be produced, which provides the estimated point estimates and 
confidence intervals for the treatment effect across the categories of subgroups listed above.
The consistency of the treatment effect will be assessed descriptively via summary statistics 
by category for the classification variables listed above.
Compliance (Medication Adherence)
8.11
Pembrolizumab: Drug accountability data for pembrolizumab will be collected during the 
study. Compliance with protocol-directed pembrolizumab 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 ITT population.
Epacadostat: 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.

For a subject who is followed for the entire study period, the “Number of Epacadostat 
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 
Epacadostat Doses Should be on Therapy” is the total number of doses from first 
treatment day to the date the subject discontinued from the study.
 
 
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Percent compliance is defined as “the number of doses the patient received on therapy” 
divided by “the number of doses the patient should have received on therapy” multiplied by 
100.
Summary statistics will be provided on percent compliance by treatment group for the ITT 
population.
Extent of Exposure
8.12
The extent of exposure will be summarized by treatment as duration of treatment in cycles.
Dose intensity will also be summarized as appropriate.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
9.1
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 MSD as summarized in Table 16.
Table 16
Product Descriptions
Product Name & Potency
Dosage Form
pembrolizumab 100 mg/4 mL
Solution for Infusion
Packaging and Labeling Information
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Pembrolizumab (MK-3475) will be provided as a kitted supply.
Clinical Supplies Disclosure
9.3
NOTE:  As of Amendment 10, blinding is no longer applicable – all subjects will receive open-
label pembrolizumab alone.
This is a blinded trial in which the epacadostat or epacadostat placebo treatment is blinded.  
However, the pembrolizumab (MK-3475) provided for the trial is open-label; therefore, the 
subject, the trial site personnel, the Sponsor, MSD and/or designee are not blinded to the 
 
 
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MK-3475 treatment. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
The emergency unblinding call center will use the treatment/randomization schedule for the 
study to unblind subjects and to unmask epacadostat or matching placebo treatment identity 
The emergency unblinding call center should only be used in cases of emergency (see 
Section 7.1.7.2). In the event that the emergency unblinding call center is not available for a 
given site in this study, the central electronic treatment allocation/randomization system 
(IVRS/IWRS) should be used in order to unblind subjects and to unmask study treatment 
identity. MSD will not provide random code/disclosure envelopes or lists with the clinical 
supplies.
Treatment identification information is to be unmasked ONLY if necessary for the welfare of 
the subject.  Every effort should be made not to unblind the subject unless necessary. 
In the event that unblinding has occurred, the circumstances around the unblinding (e.g., 
date, reason and person performing the unblinding) must be documented promptly, and MSD
Clinical Director notified as soon as possible.  Only the principal investigator or delegate and 
the respective subject’s code should be unblinded.  Trial site personnel, MSD, and Sponsor
personnel directly associated with the conduct of the trial should not be unblinded to 
treatment assignment.
Section 5.8 outlines the criteria for allowing subjects who are discontinued from treatment to 
continue to be monitored in the trial.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
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.
Discard/Destruction/Returns and Reconciliation
9.5
The investigator is responsible for keeping accurate records of the clinical supplies received 
from MSD 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 MSD 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.
 
 
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Standard Policies
9.6
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
At the close of the trial after unblinding, a letter is to be sent by the investigator to those 
subjects who received placebos in the image of MSD’s product to provide the following 
advice: 
“You have participated in a trial conducted by MSD under the sponsorship of Incyte. This is 
to advise you that you were among those who received a look-alike tablet created by the 
Sponsor to resemble the drug epacadostat as much as possible. You did not receive the active
drug epacadostat as manufactured by Incyte.”
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
By signing this protocol, the investigator affirms that information furnished to the 
investigator 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.
Confidentiality of Subject Records
10.1.2
By signing this protocol, the investigator agrees that the Sponsor, MSD, or Sponsor or MSD 
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.
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.
 
 
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Confidentiality of Investigator Information
10.1.3
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;
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, MSD, and subsidiaries, affiliates and agents of the Sponsor or MSD, 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, an 
investigator’s name and contact information may be shared with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
10.1.4
The name and address of each IRB/IEC that reviews and approves this trial is required to be 
recorded.  There is also a requirement 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.
Compliance with Financial Disclosure Requirements
10.2
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  Financial 
Disclosure information may be requested based on these regulations.  It is the 
investigator's/subinvestigator's responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested in accordance with 21 CFR Part 54, to 
provide his/her financial interests in and/or arrangements with the Sponsor and MSD 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 provided 
Certification/Disclosure Form, commonly known as a financial disclosure form. The 
 
 
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investigator/subinvestigator(s) also consent to the transmission of this information to and 
within the United States for these purposes.  This may involve the transmission of 
information to countries that do not have laws protecting personal data.
Compliance with Law, Audit and Debarment
10.3
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 
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, 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 MSD.
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 as required 
by this protocol or as otherwise required pursuant to any agreement.
Trial documentation will be promptly and fully disclosed 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 MSD or any regulatory 
authorities.  The investigator agrees to promptly take any reasonable steps that are requested 
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, 
 
 
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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 MSD team will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  MSD will determine the minimum retention period and 
upon request, will provide guidance to the investigator when documents no longer need to be 
retained.  MSD 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 MSD prior to destroying trial and/or subject files.  
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 MSD 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 trial.  The investigator will 
immediately disclose in writing to MSD 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 a particular trial site is prematurely terminated, 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, MSD 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, MSD 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].  MSD 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.
 
 
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Compliance with Trial Registration and Results Posting Requirements
10.4
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.  The Sponsor
will review this protocol and submit the information necessary to fulfill these requirements.  
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.
Quality Management System
10.5
By signing this protocol and in contract with the Sponsor, MSD agrees to be responsible for 
implementing and maintaining a quality management system with written development 
procedures and 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.
Data Management
10.6
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.
Publications
10.7
Study results will be published in accordance with applicable local and national regulations.  
If necessary, the authorities will be notified of the investigator’s name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study 
results are contained in the agreement signed with the Sponsor and/or MSD.  A signed 
agreement will be retained by the Sponsor and/or MSD.
 
 
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54. Finkelstein, D.  A proportional hazards model for Interval-Censored Failure Time 
Data.  Biometrics 1986 Dec; 42:845-854
55. Uno H, Claggett B, Tian L, Inoue E, Gallo P, Miyata T, et al.  Moving beyond the 
hazard ratio in quantifying the between-group difference in survival analysis. J Clin 
Oncol. 2014 Aug 1;32(22):2380-5.
56. Odell PM, Anderson KM, Kannel WB. New models for predicting cardiovascular 
events. J Clin Epidemiol. 1994 Jun;47(6):583-92.
57. Miettinen OS, Nurminen M. Comparative analysis of two rates. Statistics in Medicine 
1985;4:213-226.)
58. Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in 
patients with metastatic melanoma. N Engl J Med 2010; 363:711-23.
59. Maurer W, Bretz F. Multiple Testing in Group Sequential Trials Using Graphical 
Approaches. Stat Biopharm Res. 2013 Nov; 5(4):311-320.
60. Anderson KM, Clark JB. Fitting Spending Functions. Statistics in Medicine 2010; 
29(3):321-327.
61. Zhang Y, Li Y, Diamond S, Yeleswaram S. Effects of Epacadostat with Co-
Administration of Linezolid on Brain Extracellular Fluid Concentrations of 
Serotonin: An Intracerebral Microdialysis Study in Sprague-Dawley Rats. American 
Association of Pharmaceutical Scientists 2016, abstract/poster 19M0400.  
62. Boyer EW, Shannon M. The Serotonin Syndrome. N Engl J Med 2005; 352:1112-
1120.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
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 
 
 
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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. 
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.
 
 
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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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Eastern Cooperative Oncology Group Performance Status
12.4
Grade
Performance Status
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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Prohibited Monoamine Oxidase Inhibitors and Drugs Associated with Significant 
12.5
Monoamine Oxidase Inhibitory Activity
NOTE:  As of Amendment 10, this section is no longer applicable.
Monoamine Oxidase Inhibitors
Drugs Associated With Significant 
Monoamine Oxidase Inhibitory Activity
Hydrazines (example phenelzine)
Meperidine
Caroxazone
Linezolid
Echinopsidine
Methylene blue
Furazolidone
Tranylcypromine
Brofaromine
Metralindole
Minaprine
Moclobemide
Pirlindole
Toloxatone
Lazbemide
Pargyline
Rasagiline
Selegiline
 
 
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Common Terminology Criteria for Adverse Events v4.0
12.6
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 
(https://ctep.cancer.gov/).
 
 
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Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 
12.7
RECIST 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.
* As published in the European Journal of Cancer
 
 
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Publication on Serotonin Syndrome
12.8
NOTE:  As of Amendment 10, this section is no longer applicable.
 
 
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List of Abbreviations
12.9
Abbreviation/Term
Definition
AACR
American Association for Cancer Research
ADA
Anti-Drug Antibodies
AE
Adverse Event
AJCC
American Joint Committee on Cancer
ALT
Alanine Aminotransferase
APS
Allred proportion score
aPTT
Activated Partial Thromboplastin Time
ASaT
All Subjects as Treated
AST
Aspartate Aminotransferase
BCG
Bacillus Calmette–Guérin vaccine
BID
twice daily
CBC
Complete Blood Count
CFR
Code of Federal Regulations
CI
Confidence Interval
CL
Clearance
CNS
Central Nervous System
CR
Complete Response
CRP
C-reactive protein
CrCl
Calculated Creatinine Clearance
CSR
Clinical Study Report
CT
Computed Tomography
Ctrough
serum minimum concentration 
CTCAE
Common Toxicity Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
DC
dendritic cell
DCR
disease control rate
DKA
diabetic ketoacidosis 
DLT
dose-limiting toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DOR
Duration of Response
DTIC
Dacarbazine
ECG
Electrocardiogram
ECI
Events of Clinical Interest
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
eDMC
external Data Monitoring Committee
EOC
Executive Oversight Committee
EOT
end of treatment
ERC
Ethics Review Committee
EU
European Union
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
 
 
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Abbreviation/Term
Definition
FDAMA
Food and Drug Administration Modernization Act
FFPE
Formalin-fixed, paraffin-embedded
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GI
Gastrointestinal
H&N
Head and neck
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
IA1
interim analysis 1
IA2
interim analysis 2
IA3
interim analysis 3
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IDO1
indoleamine 2,3 dioxygenase-1
IEC
independent ethics committee
Ig
immunoglobulin
IHC
Immunohistochemistry
IL-2
interleukin-2
INR
International Normalized Ratio
irAEs
Immune-related Adverse Events
IRB
Institutional Review Board
irRECIST
Immune related Response Evaluation Criteria in Solid Tumors 
(Modification of RECIST 1.1)
ITT
Intent To Treat
IUD
Intrauterine device
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVRS
Interactive Voice Response System
IWRS
Integrated Web Response System
Kg
Kilogram
LDH
Lactate Dehydrogenase
LFT
liver function test
MAOI
monoamine oxidase inhibitors
mcL
Microliters
MEL
Melanoma 
mg
Milligram
mg/kg
Milligram per Kilogram
mL
milliliter
MRI
Magnetic Resonance Imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MSI
Microsatellite Instability
MTD
maximum tolerated dose
n/a or N/A
Not Applicable
NCI
National Cancer Institute
NCCN
National Comprehensive Cancer Network 
 
 
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Abbreviation/Term
Definition
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival
PD
pharmacodynamic or progressive disease
PD-1
Programmed Death Receptor-1
PD-L1
Programmed cell Death Ligand 1
PET
positron emission tomography
PFS
Progression Free Survival
PIN
Personal Identification Number
PK
Pharmacokinetic
po
Oral Administration
PR
Partial Response
PRO
Patient Reported Outcomes
PT
Prothrombin Time
Q3W
Every 3 Weeks
Q9W
Every 9 Weeks
QALYs
quality adjusted life years
QoL
Quality of Life
RCC
Renal Cell Carcinoma
RECIST
Response Evaluation Criteria in Solid Tumors
RMST
Restricted Mean Survival Time
RNA
Ribonucleic Acid
SAC
Scientific Advisory Committee
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCC
squamous cell carcinoma
SCCHN
squamous cell carcinoma of the head and neck
SD
Stable Disease
SNP
single nucleotide polymorphism
SNRI
serotonin/norepinephrine reuptake inhibitors
SOP
Standard Operating Procedures
SS
serotonin syndrome
sSAP
supplemental Statistical Analysis Plan
SIM
Site Imaging Manual
SSRI
serotonin reuptake inhibitors
T3
Total triiodothyronine
T4
Free thyroxine
TCC
transitional cell carcinoma
TNBC
Triple negative breast cancer
Treg
regulatory T cell
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
US
United States
V
Volume of distribution
WHO
World Health Organization
 
 
 
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R Code for Calculations of Sample Size and Monitoring Boundaries for 
12.10
Progression-Free Survival
The sample size for this study is driven primarily by the enrollment and follow-up required to 
have the specified power (~98%) to detect a true hazard ratio (pembrolizumab + epacadostat 
versus pembrolizumab + placebo) for progression-free survival of 0.65:1.00.
As specified in Section 8.9, the statistical considerations assume a 12 month period for the 
600 patient protocol-specified enrollment.  PFS for the patients treated with the 
pembrolizumab + placebo regimen is assumed to follow a distribution with a “cure” rate of 
30%, with PFS for the remaining 70% of patients following an exponential distribution with 
a median of 4.75 months. The true hazard ratio under the alternative hypothesis for PFS 
between the pembrolizumab + epacadostat combination and the pembrolizumab + placebo 
regimen is assumed to be 0.65.
Similarly, OS for patients treated with the pembrolizumab + placebo regimen is assumed to 
follow a distribution with a “cure” rate of 35%, with survival for the remaining 65% of 
patients following an exponential distribution with a median of 14 months. The true hazard 
ratio under the alternative hypothesis for OS between the pembrolizumab + epacadostat 
combination and the pembrolizumab + placebo regimen is assumed to be 0.70.
For the PFS and OS hypotheses, an exponential alpha-spending function with nu=0.75 
(approximating an O’Brien-Fleming boundary) will be used.  For PFS the cumulative alpha 
will be 1.25%; for OS the cumulative alpha will be 1.25% (if PFS superiority is not 
demonstrated) or 2.5% (if PFS superiority is demonstrated).
The R code generating the monitoring specifications for PFS is specified below.  The R code 
generating the monitoring specifications for OS follows the same approach.
 
 
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R code for specification of the PFS analysis plan 
 
 
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13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
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 MSD 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
 
 
04XN7M