Clinical trial NCT03322540
Conditions: Lung Cancer
Keywords: non-small cell lung cancer programmed cell death 1 (PD-1) inhibitor indoleamine 2 3-dioxygenase 1 (IDO1) inhibitor
Sponsor: Incyte Corporation
Start date: 2017-12-15; Completion date: 2020-11-09
Enrollment: 154 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of pembrolizumab plus epacadostat compared to pembrolizumab plus placebo as first-line treatment in participants with metastatic non-small cell lung cancer (NSCLC) expressing high levels of programmed cell death ligand 1 (PD-L1).

Detailed description:

Arms: arm 1: Participants received pembrolizumab 200 mg as an intravenous (IV) infusion, every three weeks (Q3W) starting on Day 1 of each cycle for up to 35 administrations in combination with epacadostat 100 mg orally, twice daily. Epacodostat administration was discontinued after the implementation of protocol amendment 05. arm 2: Participants received pembrolizumab 200 mg by IV infusion, Q3W starting on Day 1 of each cycle for up to 35 administrations in combination with matching placebo orally, twice daily. Placebo administration was discontinued after the implementation of protocol amendment 05.
Interventions: intervention 1: Pembrolizumab intervention 2: Epacadostat intervention 3: Placebo
Intervention descriptions: intervention 1: Pembrolizumab administered intravenously every 3 weeks. intervention 2: Epacadostat administered orally twice daily. intervention 3: Matching placebo administered orally twice daily.

Protocol documents:
SAP_002.pdf: 
Official Title: 
A Phase 2, Randomized, Double-Blind Study of Pembrolizumab (MK-3475) 
Plus Epacadostat (INCB024360) Versus Pembrolizumab Plus Placebo as First-
Line Treatment in Patients With Metastatic Non-Small Cell Lung Cancer 
Expressing High Levels of PD-L1 
NCT Number: 
NCT03322540 
Document Date: 
Supplemental Statistical Analysis Plan Version 2: 04 February 2019 


PEMBROLIZUMAB - NSCLC
CLINICAL STUDY REPORT P654V01MK3475 (ECHO 305)
16.1.9
Documentation of Statistical Methods
16.1.9.1
Statistical Analysis Plan
The statistical analysis plan is found in the protocol in [16.1.1.1].
16.1.9.1.1
Supplemental Statistical Analysis Plan
(3475-ssap-654-04-amend)
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Supplemental Statistical Analysis Plan (sSAP)
1. INTRODUCTION
This supplemental SAP (sSAP) is a companion document to the protocol. In addition to the 
information presented in the protocol SAP which provides the principal features of confirmatory 
analyses for this trial, this supplemental SAP provides additional statistical analysis details/data 
derivations and documents modifications or additions to the analysis plan that are not “principal” 
in nature and result from information that was not available at the time of protocol finalization. 
Changes to 
 other non-confirmatory analyses will be updated and documented in 
this sSAP and referenced in the Clinical Study Report (CSR) for the study. 
 
 Separate analysis plans (ie, separate documents from 
the sSAP) will be developed to detail PK and biomarker analyses. 
 
   
2. SUMMARY OF CHANGES 
Section # and 
Name
Description of Change
Brief Rationale
3.1 
Statistical 
Analysis 
Plan 
Summary (Table 
1)
Updated 
stratification 
factors, 
primary 
and 
secondary 
endpoints, 
statistical methods for 
key efficacy analysis, 
interim 
analysis, 
multiplicity and sample 
size and power
To revise SAP according to Protocol Amendment 4
3.2 
Responsibility 
for Analyses/In-
House Blinding
Updated 
to 
remove 
information 
regarding 
interim analysis
To revise SAP according to Protocol Amendment 4
3.4.1 
Efficacy 
Endpoints
Updated primary and 
secondary endpoints
To revise SAP according to Protocol Amendment 4
3.6.1 Statistical 
Methods for Key 
Efficacy 
Endpoints
Updated the statistical 
methods to align with 
primary and secondary 
endpoints
To revise SAP according to Protocol Amendment 4
3.6.1.6 
Statistical 
Methods for Key 
Efficacy 
Endpoints 
(Table 4)
Updated Table 4 to align 
primary and secondary 
endpoints with Phase 2 
trial design
To revise SAP according to Protocol Amendment 4
 
 
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Section # and 
Name
Description of Change
Brief Rationale
3.7 
Interim 
Analysis
Removed Section 3.7.1 
Safety Interim Analysis 
and 
3.7.2 
Efficacy 
Interim Analysis 
To revise SAP according to Protocol Amendment 4
3.8 Multiplicity 
Removed entire section 
regarding 
interim 
analyses information 
To revise SAP according to Protocol Amendment 4
3.9 Sample Size 
and 
Power 
Calculations
Updated sample size and 
power to align with 
change to Phase 2 trial 
design
To revise SAP according to Protocol Amendment 4
3.10 
Subgroup 
Analyses
Updated 
stratification 
factors to remove ECOG 
and geographical region
To revise SAP according to Protocol Amendment 4
 
 
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3. ANALYTICAL AND METHODOLOGICAL DETAILS
3.1 STATISTICAL ANALYSIS PLAN SUMMARY
Key elements of the Statistical Analysis Plan (SAP) are summarized in Table 1. The 
comprehensive plan is provided in Sections 3.2 through 3.12. 
Table 1
Key Elements of the Statistical Analysis Plan
Study Design Overview
Phase 2 study of pembrolizumab + epacadostat vs pembrolizumab + placebo 
for first-line treatment of metastatic non-small cell lung cancer (NSCLC) in 
participants whose tumors express PD-L1 (TPS ≥50%)
Treatment Assignment
Approximately 148 participants will be randomized in a 1:1 ratio between two 
treatment arms: (1) pembrolizumab plus epacadostat and (2) pembrolizumab 
plus placebo.  
Stratification factor is predominant tumor histology(squamous vs non-
squamous) 
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary Endpoints

Objective response rate (ORR) per RECIST 1.1 based on 
BICR
Secondary Endpoints

Progression-free survival (PFS) based on RECIST 1.1 as assessed by 
BICR.

Overall survival (OS).

Duration of response (DOR) based on RECIST 1.1 as assessed by 
BICR.

Safety and tolerability.
Statistical Methods for
Key Efficacy Analyses
The primary hypothesis will be evaluated by comparing pembrolizumab plus 
epacadostat to pembrolizumab plus placebo in ORR using the stratified Miettinen 
and Nurminen method. The difference in PFS and OS will be evaluated using a
stratified Log-rank test. The hazard ratio will be estimated using a stratified 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 of safety results will follow a tiered approach.  The tiers differ with 
respect to the analyses that will be performed.  There are no events of interest that 
warrant elevation to Tier 1 events in this study.  Tier 2 parameters will be assessed 
via point estimates with 95% confidence intervals (CIs) provided for between-
group comparisons; only point estimates by treatment group are provided for Tier 
3 safety parameters.  The 95% CIs for the between-treatment differences in 
percentages will be provided using the Miettinen and Nurminen method.
Multiplicity
For this Phase 2 trial, the overall Type I error rate is strictly controlled at 5% (one-
sided) for the primary analysis of ORR.  If the primary hypothesis is rejected at 
the α=5% level (one-sided), then testing will continue to the key secondary 
hypothesis of PFS.  Nominal p-value for other endpoints will be reported, where 
applicable.
Sample Size and Power
The planned sample size is approximately 148 participants with 74 participants in 
each arm. For the ORR test, based on all patients randomized with minimum 
18 weeks of follow-up, the study has 80.4% power to detect a 20 percentage point 
difference in ORR to 70% for pembrolizumab+ epacadostat vs 50% for 
pembrolizumab+ placebo at α=5% (one-sided).
 
 
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3.2 RESPONSIBILITY FOR ANALYSES/IN-HOUSE BLINDING
The statistical analysis of the data obtained from this study will be the responsibility of the MSD 
Clinical Biostatistics department.
MSD will generate the randomized allocation schedule for study treatment assignment for this 
protocol and the randomization will be implemented in IVRS/IWRS.
An external DMC will be convened to review accumulating safety data to provide an opportunity 
to terminate the study early if there are concerns regarding safety. Treatment-level results at the 
interim analyses will be provided by the external unblinded statistician to the eDMC. The DMC 
responsibilities and review schedules will be outlined in the DMC charter. The recommendation 
of the DMC will be communicated to the Joint Executive Oversight Committee (EOC) and, in the 
event of a recommendation to halt the study early due to safety concerns, to the appropriate 
regulatory agencies. If the DMC recommends modifications to the design of the protocol or 
discontinuation of the study, the EOC and possibly other limited numbers of additional 
Sponsor/MSD personnel may be unblinded to results at the treatment level in order to act on these 
recommendations. 
Additional logistical details, revisions to the above plan, and data monitoring guidance will be 
provided in the DMC Charter.
3.3 HYPOTHESES/ESTIMATION
Objectives and hypotheses of the study are stated in protocol Section 4.0.
3.4 ANALYSIS ENDPOINTS
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below. 
3.4.1
Efficacy Endpoints
Primary
Objective Response Rate: The proportion of participants who have a confirmed CR or PR per
RECIST 1.1 based on BICR.
Secondary
Progression-free Survival: The time from randomization to the first documented PD per RECIST 
1.1 based on BICR or death due to any cause, whichever occurs first. See Section 10.6.1 for the 
definition of censoring.
Overall Survival: The time from randomization to death due to any cause. 
Duration of Response: The time from first documented evidence of CR or PR until PD per 
RECIST 1.1 as assessed by BICR or death due to any cause, whichever occurs first, in participants 
who demonstrate CR or PR.
 
 
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3.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including AEs, 
SAEs, fatal AEs, laboratory tests, and vital signs. Furthermore, specific events will be collected 
and designated as ECIs as described in protocol Section 9.3.7.
3.5 ANALYSIS POPULATIONS
3.5.1
Efficacy Analysis Populations
The analyses of primary efficacy endpoints are based on the intention-to-treat (ITT) population. 
All randomized participants will be included in this population. Participants will be analyzed in 
the treatment group to which they are randomized. Details on the approach to handling missing 
data are provided in Section 3.6.
3.5.2
Safety Analysis Populations
The all participants as treated (APaT) population will be used for the analysis of safety data in this 
study. The APaT population consists of all randomized participants who received at least one dose 
of study treatment. Participants will be analyzed in the treatment group corresponding to the study 
treatment they actually received. For most participants, this will be the treatment group to which 
they are randomized. Participants who take incorrect study treatment for the entire treatment period 
will be included in the treatment group corresponding to the study treatment actually received. 
Any participant who receives the incorrect study medication for one cycle, but receives the correct 
treatment for all other cycles, will be analyzed according to the correct treatment group and a 
narrative will be provided for any events that occur during the cycle for which the participant is 
incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 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.
 
 
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Table 2
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival
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
No PD and no death; ≥2 
consecutive 
missed 
disease assessments
Censored at last disease 
assessment
Censored at last disease 
assessment prior to ≥2 
consecutive missed visits
Censored at last disease 
assessment
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 at any time 
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
PD=progressive disease
3.6.1.3 Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test (based on the 
stratification factor defined in Section 7.3.1). A stratified Cox proportional hazard model with 
Efron's method of tie handling will be used to assess the magnitude of the treatment difference (ie, 
the HR). The HR and its 95% CI from the stratified Cox model with a single treatment covariate 
will be reported. The stratification factor (Section 7.3.1) based on tumor histology will be applied 
to both the stratified log-rank test and the stratified Cox model. Participants without documented 
death at the time of analysis will be censored at the date of last known contact. Analysis using the 
Restricted Mean Survival Time method may be conducted for OS to account for the possible non-
proportional hazards effect.
3.6.1.4 Duration of Response
For participants who demonstrate CR or PR, DOR is defined as the time from first documented 
evidence of CR or PR until disease progression or death due to any cause, whichever occurs first. 
Censoring rules for DOR are summarized in Table 3. DOR will be assessed using RECIST 1.1 by 
BICR.
For each DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided. Responses in participants who are alive, have not progressed, have 
not initiated new anti-cancer treatment, and have not been determined to be lost to follow-up are 
considered ongoing at the time of analysis. If a participant meets multiple criteria for censoring, 
the censoring criterion that occurs earliest will be applied.
 
 
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Table 3
Censoring Rules for Duration of Response
Situation
Date of 
Progression or Censoring
Outcome
No progression or death, new anti-
cancer treatment not initiated
Last adequate disease assessment
Censor
(non-event)
No progression or death, new anti-
cancer treatment initiated
Last adequate disease assessment 
before new anti-cancer therapy
initiated
Censor
(non-event)
Death 
or 
progression 
after 
≥2 
consecutive missed disease assessments
Last adequate disease assessment 
prior to the after ≥2 missed adequate 
disease assessments
Censor
(non-event)
Death or progression after ≤1 missed 
adequate disease assessments
Progressive disease or death
End of response
(Event)
Note: A missed disease assessment includes any assessment that is not obtained or is considered inadequate for evaluation 
of response.
3.6.2
Statistical Methods for Key Efficacy Endpoints
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 4.
Table 4
Analysis Methods for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses:
ORR (RECIST 1.1) 
by BICR
Testing and Estimation:
Stratified 
Miettinen 
and 
Nurminen method
ITT
Participants with missing data are 
considered non-responders
Secondary Analyses:
PFS (RECIST 1.1)
by BICR
Estimation: Stratified Cox model 
with Efron's tie handling method
Stratified Log-rank test 
ITT
Censored according to rules in
Table 2
OS
Estimation: Stratified Cox model 
with Efron's tie handling method
Stratified Log-rank test
ITT
Censored at last known alive date
DOR (RECIST 1.1) 
by BICR
Summary 
statistics 
using 
Kaplan-Meier method
All 
responders 
in ITT 
Non-responders are excluded in 
analysis
Sensitivity analyses will be performed for PFS, ORR, and DOR based on investigator's assessment.
BICR=blinded independent central review; DOR=duration of response; ITT=intent-to-treat; ORR=objective response rate; 
OS=overall survival; PFS=progression-free survival; RECIST 1.1=Response Evaluation Criteria in Solid Tumors.
 
 
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3.6.3
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including AEs, 
laboratory tests, vital signs, and ECG measurements.
The analysis of safety results will follow a tiered approach (Table 5). The tiers differ with respect 
to the analyses that will be performed. Safety parameters or AEs of special interest (AEOSI) 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% CIs provided for between-group comparisons. 
Other safety parameters will be considered Tier 2 or Tier 3. Tier 2 parameters will be assessed via 
point estimates with 95% CIs provided for between-group comparisons; only point estimates by 
treatment group are provided for Tier 3 safety parameters.
AEOSI that are immune-mediated or potentially immune-mediated are well documented and will 
be evaluated separately; however, these events have been characterized consistently throughout 
the pembrolizumab clinical development program and determination of statistical significance is 
not expected to add value to the safety evaluation. Similarly, the combination of pembrolizumab 
and epacadostat has not been associated with any new safety signals. Finally, there are no known 
AEs associated with participants with NSCLC for which determination of a p-value is expected to 
impact the safety assessment. Therefore, there are no Tier 1 events expected in this study.
Adverse experiences (specific terms as well as system organ class terms) 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 and clinical interest.  For Tier 2 events, 95% CIs will be provided for between-
treatment differences in the percentage of participants with events; these analyses will be 
performed using the Miettinen and Nurminen method.
Because many 95% CIs may be provided without adjustment for multiplicity, the CIs 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 AEs and predefined limits of 
change.
Continuous measures such as changes from baseline in laboratory, vital signs, and ECG parameters 
that are not pre-specified as Tier 1 endpoints 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.
 
 
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Table 5
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 Grade 3 to 5 AE
X
X
Any serious AE 
X
X
Any drug-related AE
X
X
Any serious and drug-related AE
X
X
Any Grade 3 to 5 and drug-related AE
X
X
Dose modification due to AE
X
X
Discontinuation due to AE
X
X
Death
X
X
Specific AEs, SOCs (including ≥4 of participants in 
one of the treatment groups)
X
X
Tier 3
Specific AEs, SOCs  (incidence <4 of participants in 
all of the treatment groups)
X
Change from baseline results (labs, ECGs, vital signs)
X
AE=adverse event; CI=confidence interval; ECG=electrocardiogram; SOC=system organ class.
 
 
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3.6.5
Summaries of Baseline Characteristics and Demographics
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 participants randomized and the primary reason for 
discontinuation will be displayed. Demographic variables (such as age) and baseline 
characteristics will be summarized by treatment either by descriptive statistics or categorical 
tables. The reasons for exclusion from the ITT population (if any) will be summarized.
 
 
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3.7 INTERIM ANALYSES
3.7.1
Safety Interim Analyses
The DMC will conduct regular safety monitoring. The timing of the safety monitoring will be 
specified in the DMC charter.
3.7.2
Efficacy Interim Analyses
No efficacy interim analysis is planned for this study. The study will be unblinded at the database 
lock for the primary analysis for ORR. 
3.8 MULTIPLICITY
The overall Type I error rate is strictly controlled at 5% (one-sided) by fixed sequence, a closed-
testing procedure. The closed testing procedure will be applied to the primary hypothesis of ORR 
first.  If the primary hypothesis is rejected at the α=5% level (one-sided), then testing will continue 
to the key secondary hypothesis of PFS. Nominal p-value for each endpoint will be reported, where 
applicable, regardless of the outcome of the closed testing procedure dictated by the multiplicity 
strategy.
3.9 SAMPLE SIZE AND POWER CALCULATIONS
3.9.1
Sample Size and Power for Efficacy Analyses
The study will randomize 148 participants in a 1:1 ratio into the pembrolizumab plus epacadostat 
and pembrolizumab plus placebo arms. ORR is a primary endpoint for the study and PFS and OS 
are secondary endpoints. 
Figure 1 summarizes power calculations for the primary hypothesis under various ORR difference 
assumptions assuming an underlying ORR of 50% in the pembrolizumab + placebo treatment 
group.
 
 
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Figure 1
Power for Primary Hypothesis under Different Effect Size Assumptions
Based on the 148 participants in the control arm and the treatment arm under comparison, the 
power of the ORR testing at the α=0.05 (one-sided) is approximately 80.4% to detect a difference 
of 20 percentage points in ORR between an underlying 50% response rate in the control arm and 
a 70% response rate in the experimental arm.
With 95 PFS events, the study will have 80% power to detect a hazard ratio of 0.6 at an alpha level 
of 5% (1-sided).
The sample size and power calculations were performed in R (package “gsDesign”).
 
 
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3.10
SUBGROUP ANALYSES AND EFFECT OF BASELINE FACTORS
To determine whether the treatment effect is consistent across various subgroups, the between-
group treatment effect for OS, PFS, and ORR (with a nominal 95% CI) will be estimated and 
plotted by treatment group within each category of the following classification variables:

Stratification factor
o
Predominant tumor histology (squamous vs non-squamous)

Geographic region (East Asia vs non-East Asia)

ECOG performance status (0 vs 1)

Age category (<65, ≥65 years)

Sex (female, male)

Race (white, non-white)

Smoking status (never vs former/current smoker)

Brain metastasis (presence vs absence) 
3.11
COMPLIANCE (MEDICATION ADHERENCE)
Drug accountability data for study treatment will be collected during the study. Any deviation from 
protocol-directed administration will be reported.
3.12
EXTENT OF EXPOSURE
Extent of exposure for a participant is defined as number of cycles in which the participant receives 
the study medication. Summary statistics will be provided on extent of exposure for the APaT 
population.
 
 
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4. REFERENCE
[Farrington, 
C. 
P. 
and 
Manning, G. 1990]
Farrington CP, Manning G. Test statistics and sample size 
formulae for comparative binomial trials with null hypothesis of 
non-zero risk difference or non-unity relative risk. Stat Med 
1990;9:1447-54.
[Maurer, W. 2013]
Maurer W, Bretz F. Multiple testing in group sequential trials 
using graphical approaches. Stat Biopharm Res 2013;5(4):311-
20.
[Miettinen, O. and Nurminen, 
M. 1985]
Miettinen O, Nurminen M. Comparative Analysis of Two Rates. 
Stat Med 1985;4:213-26.
 
 
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5. APPENDIX
 
 
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Prot_001.pdf: 
Product:  MK-3475/INCB024360 
1
Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
Title Page
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.
Protocol Title: A Phase 2, Randomized, Double-Blind Study of Pembrolizumab (MK-3475) 
plus Epacadostat (INCB024360) Versus Pembrolizumab plus Placebo as First-Line 
Treatment in Patients with Metastatic Non-Small Cell Lung Cancer Expressing High Levels 
of PD-L1
Protocol Number: 654-05/ECHO-305-05 / NCT03322540
Compound Number: MK-3475/INCB024360
This study is co-funded by Incyte and MSD.
Execution of Study:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(Referenced herein as MSD)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Global Sponsor of the Study:
Incyte Corporation (Referenced herein as Sponsor)
1801 Augustine Cut-Off
Wilmington, Delaware, 19803, U.S.A.
Regulatory Agency Identifying Number(s):
IND NUMBER: 134,459
EudraCT NUMBER: 2017-001841-28
Approval Date:  04-March-2019
055WCH


Product:  MK-3475/INCB024360 
2
Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
MSD Signatory
Typed Name:
Title:
Date
Protocol-specific MSD contact information can be found in the Investigator Trial File 
Binder (or equivalent). 
Investigator Signatory
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.
Typed Name:
Title:
Date
 
 
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Product:  MK-3475/INCB024360 
3
Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
3475-654-06
04-MAR-2019
Data from the final analysis of KEYNOTE-654/ECHO-305 (data cutoff: 10-JAN-2019) 
indicated that the study did not meet the pre-specified endpoint of improvement in objective 
response rate (ORR) for the combination of pembrolizumab plus epacadostat compared with 
pembrolizumab plus placebo. Based upon these data from the final analysis, the Sponsor and 
MSD implemented this Amendment 05 to direct that all epacadostat and placebo 
administration stop, and to reflect that the study is no longer blinded. The study will remain 
open so participants still on study will have continued access to pembrolizumab.
3475-654-04
31-MAY-2018
Updated Phase 3 design to Phase 2 design, title of protocol, primary and secondary 
endpoints.
3475-654-03
05-APR-2018
To align with regulatory requirements at French sites to exclude participants on coumarin-
based anticoagulants and prohibit coumarin based anticoagulant treatment for participants 
receiving epacadostat. In addition, to provide specific dose modification and toxicity 
management guidelines for myocarditis.
3475-654-02
6-MAR-2018
To align HIV and pregnancy testing with regulatory requirements at German sites.
3475-654-01
3-NOV-2017
To provide specific dose modification and toxicity management guidelines for myocarditis.
3475-654-00
06-JUN-2017
Initial protocol
 
 
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Product:  MK-3475/INCB024360 
4
Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 05
Overall Rationale for the Amendment:
Data from the final analysis of KEYNOTE-654/ECHO-305 (data cutoff: 10-JAN-2019) indicated that the study did not meet the pre-
specified endpoint of improvement in objective response rate (ORR) for the combination of pembrolizumab plus epacadostat 
compared with pembrolizumab plus placebo. Based upon these data from the final analysis, the Sponsor and MSD implemented this 
Amendment 05 to direct that all epacadostat and placebo administration stop, and to reflect that the study is no longer blinded. The 
study will remain open so participants still on study will have continued access to pembrolizumab.
Summary of Changes Table:
Section # 
and Name
Description of Change
Brief Rationale
1. Synopsis
2.1 Initial 
Treatment Phase 
SoA
Revised text and added notes to clarify the removal of 
epacadostat and placebo treatments from the study; 
participants may choose to discontinue from the study or 
continue on study and receive open-label 
pembrolizumab monotherapy as per protocol. Updated 
the duration of participation to reflect the removal of the 
Second Course Phase, Survival Follow-up visits, and 
post-treatment follow-up imaging as endpoints will no 
longer be collected.
Epacadostat and matching placebo are removed from 
the study and procedures for participants remaining in 
study are simplified where possible. Second Course 
Phase, Follow-up visits, and Survival Follow-up are 
removed. There are no required tumor imaging 
assessments during the treatment phase or at EOT; 
rather, all imaging is to be performed per local standard 
of care (note, data will not be collected).
In accordance with the overall rationale for the 
amendment provided above, all references to 
epacadostat and placebo, as well as 
assessments/procedures specific to these treatments, are 
removed from the protocol. Participants remaining in 
the study will be treated according to the site’s standard 
of care. The final visit of the study will be the Safety 
Follow-up Visit and there will be no follow-up for 
survival status. Participants currently in follow-up or in 
survival follow-up are considered to have completed 
the study. However, standard safety reporting should 
continue, as applicable. 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.
 
 
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Product:  MK-3475/INCB024360 
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Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
Section # 
and Name
Description of Change
Brief Rationale
2.2 Second 
Course Phase
The Second Course Phase is removed from the protocol; 
thus, this schedule of activities has been deleted.
3.3 Benefit/Risk 
Assessment
Addition of notes to clarify that the benefit/risk 
assessment of epacadostat and placebo in this section is 
no longer applicable and has been deleted.
Epacadostat has been removed from the study; thus, 
benefit:risk assessment for treatment arms containing 
epacadostat is no longer relevant.
4.0 
Objectives/Hypot
heses and 
Endpoints
Addition of a note to clarify that efficacy endpoints will 
no longer be collected and 
 may 
not be further pursued.
As the study did not meet the pre-specified endpoint 
for ORR, the scope of the study is reduced and further 
collection of efficacy data is not required.
 
 
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Product:  MK-3475/INCB024360 
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Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
Section # 
and Name
Description of Change
Brief Rationale
5.1 Overall 
Design
5.1.1 Data 
Monitoring 
Committee
5.1.2 Study 
Diagram
Addition of a note and revised text to address the 
following points: 

Removal of epacadostat and placebo from study 
treatment groups and continuation of participants 
on pembrolizumab monotherapy only on study.

Removal of Second Course Phase, Follow-up, 
and Survival Status Follow-up.

Removal of central radiologist review of 
imaging and required schedule of imaging.
Clarification that all imaging going forward is to 
be performed per local standard of care and 
assessed by the investigator for PD per RECIST 
1.1. The use of iRECIST is discontinued.

Addition of text clarifying the results of the final 
analysis and rationale behind the changes in 
study design.

Clarification that no further DMC reviews will 
be conducted.
An additional study diagram as of Amendment 05 is 
provided.
In accordance with the overall rationale for the 
amendment, removal of epacadostat and matching
placebo, and reduced overall scope of the study.
Participants may choose to discontinue from the study 
and be treated as per standard of care, or continue on 
study and receive pembrolizumab monotherapy as per 
protocol, if they will have access issues to standard of 
care outside the protocol.
 
 
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Product:  MK-3475/INCB024360 
7
Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
Section # 
and Name
Description of Change
Brief Rationale
5.2 Number of 
Participants
9.9.1 Screening
Addition of a note that enrollment was completed as of 
05-SEP-2018.
To clarify the current study status.
5.4.1 Rationale 
for Endpoints
Addition of notes to clarify which sections and text are 
no longer applicable since efficacy endpoints and 
 
data will no longer be collected, and central review of 
imaging and the use of iRECIST for treatment decisions 
are discontinued.
In accordance with the overall rationale for the 
amendment, the removal of epacadostat and matching 
placebo from the study, and the reduced scope of the 
study, further collection of efficacy endpoints and 
 central review of imaging is 
no longer warranted. All imaging and treatment 
decisions are per local standard of care based on 
investigator assessment per RECIST 1.1.
5.4.2 Rationale 
for the Use of 
Comparator/Place
bo
5.5.2 Rationale 
for Dose and 
Regimen of 
Epacadostat in 
Combination with 
Pembrolizumab
Addition of a note clarifying that this section is no 
longer applicable with the removal of epacadostat and 
matching placebo from the study.
Epacadostat and matching placebo have been removed 
from the study.
 
 
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Product:  MK-3475/INCB024360 
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Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
Section # 
and Name
Description of Change
Brief Rationale
7.1 Treatments 
Administered
Removal of epacadostat and matching placebo from the 
table of study treatments and clarification of the 
treatments to be administered to participants continuing 
in the study in each study arm.
Epacadostat and matching placebo have been removed 
from the study.
7.2.1 Dose 
Modification for 
Immune-related 
AEs
Removal of all text relating to dose modification of 
epacadostat/matching placebo and updates to text where 
appropriate to reflect the removal of 
epacadostat/matching placebo from the study. Table 3 
(Dose Modification Guidelines) has been replaced with
the current guidelines for pembrolizumab alone.
7.2.3 Procedures 
for Participants 
Exhibiting 
Serotonin 
Syndrome
Text updated to reflect the removal of 
epacadostat/matching placebo from the study. Updated 
information regarding the risks of SS with the use of 
epacadostat is provided. Text is revised to clarify that 
the use of MAOIs is no longer prohibited in the study
To align with current practices across the epacadostat 
development program as supported in the current 
version of the epacadostat IB.
7.4 Blinding
9.1.11 Participant 
Blinding/Unblindi
ng
Note that all text related to study treatment blinding is 
no longer applicable. 
Deletion of text related to blinding of 
epacadostat/matching placebo and emergency 
unblinding procedures.
As of Amendment 05, epacadostat and matching 
placebo are removed from the study and all study 
treatment is open-label.
 
 
055WCH


Product:  MK-3475/INCB024360 
9
Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
Section # 
and Name
Description of Change
Brief Rationale
7.5.1 Dose 
Preparation
Text updated to reflect the removal of 
epacadostat/matching placebo from the study.
Epacadostat and matching placebo have been removed
from the study.
7.6.2 
Administration 
and Compliance 
of Oral Study 
Treatment 
(Epacadostat or 
Matching 
Placebo)
Addition of a note clarifying that this section is no 
longer applicable with the removal of epacadostat and 
matching placebo from the study. All text in this section 
is deleted.
7.7.1 Acceptable 
Concomitant 
Therapies
Text updated to reflect the proper time frame for 
collection of concomitant medications following the 
removal of the Second Course Phase.
The Second Course Phase has been removed in
accordance with the reduced scope of the study.
7.7.2 Prohibited 
Concomitant 
Therapies
Text updated to remove UGT1A9 inhibitors and MAOIs 
as prohibited concomitant therapy.
Sentence about the Post-Treatment Follow-up Phase 
was deleted.
Per the latest IB for epacadostat, the use of MAOIs and 
UGT1A9 inhibitors are no longer prohibited with the 
100 mg BID dose of epacadostat.
The Follow-up Phase and Survival Follow-up are 
removed due to the reduced scope of the study.
7.7.3 Restricted 
Medications
Note added to clarify that as of Amendment 05, this 
section is no longer applicable to participants who were 
previously randomized to epacadostat/placebo and has 
been deleted. 
There are no restricted medications for participants 
receiving pembrolizumab.
 
 
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Product:  MK-3475/INCB024360 
10
Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
Section # 
and Name
Description of Change
Brief Rationale
7.9 Clinical 
Supplies 
Disclosure
Note added to clarify that emergency unblinding 
procedures are no longer applicable.
With the discontinuation of epacadostat and matching 
placebo, all study treatments in the study are open-
label.
8.1 
Discontinuation 
of Study 
Treatment
Note added to clarify the text is updated to reflect the 
following:

Discontinuation of BICR confirmation of 
imaging assessments. 

Treatment unblinding is no longer a reason for 
treatment discontinuation.
With the unblinding of the study and discontinuation of 
BICR verification of imaging assessments, treatment 
discontinuation criteria are updated accordingly.
8.1.1 Second 
Course Phase
Note added to clarify that the Second Course Phase is 
removed; all text is no longer applicable and has been
deleted.
The Second Course Phase, Follow-up Phase, and 
Survival Follow-up are removed due to the reduced 
scope of the study.
8.2 Withdrawal 
from the Study
9.1.10 
Withdrawal/Disco
ntinuation
9.9.3.1 Safety 
Follow-up Visit
Section updated to reflect the removal of the Follow-up 
Phase and/or Survival Follow-up as applicable.
9.1.1.1 General 
Informed Consent
Text added to clarify that re-consent of participants who 
continue on study treatment after initial disease 
progression is required.
Program-wide change to comply with FDA request in 
alignment with PDUFA VI.
 
 
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Product:  MK-3475/INCB024360 
11
Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
Section # 
and Name
Description of Change
Brief Rationale
9.1.6.2 
Concomitant 
Medications
Section updated to reflect the removal of the Second 
Course Phase.
The Second Course Phase has been removed in 
accordance with the reduced scope of the study.
9.1.9 Treatment 
Administration
9.1.9.1.2 Timing 
of Dose 
Administration of 
Epacadostat or 
Matching Placebo
Section updated to reflect the removal of 
epacadostat/matching placebo from the study.
Epacadostat and matching placebo have been removed 
from the study.
9.2.1 Tumor 
Imaging and 
Assessment of 
Disease
Note added clarifying that as of Amendment 05, BICR 
and iRECIST are no longer applicable. All disease 
assessments will be performed by the site investigator 
per local standard of care. All text related to submission 
of images to BICR and use of iRECIST for treatment 
decisions has been deleted.
In accordance with the reduced scope of the study, 
further collection of efficacy endpoints is not required 
and central review of imaging and the use of iRECIST 
is no longer warranted. All imaging and treatment 
decisions are per local standard of care based on 
investigator assessment per RECIST 1.1.
9.2.1.2 Tumor 
Imaging During 
the Study
Note added clarifying that as of Amendment 05, BICR 
and iRECIST are no longer applicable. All disease 
assessments will be performed by the site investigator 
per local standard of care, but this data will not be 
collected and no on-study imaging schedule is mandated 
during the treatment phase or at EOT. All text related to 
submission of images to BICR, the use of iRECIST for 
treatment decisions, and required timing of imaging 
assessments has been deleted.
 
 
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Product:  MK-3475/INCB024360 
12
Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
Section # 
and Name
Description of Change
Brief Rationale
9.2.1.3 End of 
Treatment and 
Follow-Up 
Imaging
Note added clarifying that as of Amendment 05, there is 
no protocol-specified imaging at end of treatment and 
no follow-up imaging is required. All text in this section 
has been deleted.
9.2.1.4 Second 
Course Phase 
Tumor Imaging
Note added clarifying that as of Amendment 05, the 
Second Course Phase is eliminated and this section is no
longer applicable. All text in this section has been 
deleted.
The Second Course Phase has been removed in 
accordance with the reduced scope of the study.
9.2.1.5 RECIST 
1.1 Assessment of 
Disease
Note added clarifying that BICR is no longer applicable 
and all imaging is to be performed as per local standard 
of care guidelines. Text relating to BICR verification of 
disease progression has been deleted.
In accordance with the reduced scope of the study, 
further collection of efficacy endpoints is not required 
and central review of imaging and the use of iRECIST 
is no longer warranted. All imaging and treatment 
decisions are per local standard of care based on 
investigator assessment per RECIST 1.1.
9.2.1.6 iRECIST 
Assessment of 
Disease
Note added clarifying that iRECIST is no longer 
applicable and all imaging should be performed per 
local standard of care guidelines and assessed per 
RECIST 1.1. All text is deleted from the section.
9.2.2 Patient 
Reported 
Outcomes
Note added clarifying that as of Amendment 05, PROs 
will no longer be collected. All text in this section has 
been deleted.
In accordance with the reduced scope of the study, 
PROs are no longer required.
9.4 Treatment of 
Overdose
Note added that epacadostat is removed from the study.
Epacadostat has been removed from the study.
 
 
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Product:  MK-3475/INCB024360 
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Protocol/Amendment No.: 654-05/ECHO-305-05
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04-Mar-2019
Confidential
Section # 
and Name
Description of Change
Brief Rationale
9.5.1.1 Full 
Physical Exam
Requirement to perform a full physical exam at the 
discontinuation visit, Second Course Cycle 1, and 
Second Course discontinuation visit has been removed.
To reflect the removal of the Second Course Phase and 
to simplify study procedures in consideration of the 
reduced scope of the study.
9.5.3 
Electrocardiogra
ms
The requirement to obtain ECGs at EOT is removed. 
ECGs are to be obtained at screening; thereafter, ECGs 
may be performed according to local standard of care or 
as clinically indicated.
Simplification of study procedures due to reduced 
scope of the study.
9.9.2 Treatment 
Phase
This section has been updated to remove information 
regarding dosing of epacadostat and matching placebo.
Epacadostat and matching placebo have been removed 
from the study.
9.9.3.1 Safety 
Follow up Visit
Notes added clarifying that the Safety Follow-up Visit 
will be the last visit in the study and that recording of 
AEs will be performed as per Section 9.3.
Removal of text detailed in Section 9.3. 
The Second Course Phase, Follow-up Phase, and 
Survival Follow-up are removed due to the reduced 
scope of the study.
Removes conflict in reporting of AE/SAEs for 
pembrolizumab.
9.9.3.2 Follow-up 
Visits
9.9.3.3 Survival
Follow-up
9.9.3.4 Survival 
Status
9.9.4 Second 
Course Phase
Notes added clarifying that the Follow-up Visits, 
Survival Follow-up, and Second Course Phase have 
been removed from the study. Participants currently in 
Follow-up or Survival Follow-up as of Amendment 05
are considered to have completed the study once they 
have attended the Safety Follow-Up Visit. All other text 
in these sections has been deleted.
The Second Course Phase, Follow-up Phase, and 
Survival Follow-up are removed due to the reduced 
scope of the study.
 
 
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Product:  MK-3475/INCB024360 
14
Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
Section # 
and Name
Description of Change
Brief Rationale
10.0 Statistical 
Analysis Plan
Note added to clarify that the final analysis has been 
performed, and, as the study did not meet the pre-
specified primary endpoint, efficacy data will no longer 
be collected in the study, including central review of 
imaging. Thus, only selected analyses detailed in all 
subsections of Section 10 will be performed at study 
completion.
In accordance with the reduced scope of the study and 
discontinuation of efficacy data collection.
10.6.2 Statistical 
Methods for 
Safety Analyses
Methods for safety analyses were revised to reflect 
changes in objectives and endpoints. 
As the study did not meet the pre-specified endpoint 
for ORR, the scope of the study is reduced.
12.2 Appendix 2: 
Clinical 
Laboratory Tests
Text regarding reporting of laboratory analyte results 
that could unblind the study has been deleted.
As of Amendment 05, the study is unblinded.
Nonsubstantive editorial and grammatical changes were made throughout the document.
 
 
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Product:  MK-3475/INCB024360 
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Protocol/Amendment No.: 654-05/ECHO-305-05
MK-3475-654-05 (INCB 24360-305-05) Final Protocol
04-Mar-2019
Confidential
Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
Synopsis.......................................................................................................................24
Schedule of Activities (SoA)......................................................................................27
Initial Treatment Phase..........................................................................................27
Introduction................................................................................................................31
Study Rationale .......................................................................................................31
Background..............................................................................................................32
Pharmaceutical and Therapeutic Background .....................................................32
Completed Clinical Studies..................................................................................35
Ongoing Clinical Studies .....................................................................................37
Benefit/Risk Assessment.........................................................................................38
Objectives/Hypotheses and Endpoints.....................................................................39
Study Design...............................................................................................................41
Overall Design .........................................................................................................41
Data Monitoring Committee and Interim Analyses.............................................42
Study Diagram .....................................................................................................42
Number of Participants ..........................................................................................43
Beginning and End of Study Definition ................................................................43
Clinical Criteria for Early Trial Termination.......................................................43
Scientific Rationale for Study Design....................................................................43
Rationale for Endpoints .......................................................................................43
Efficacy Endpoints........................................................................................43
RECIST 1.1............................................................................................44
Modified RECIST for Immune-based Therapeutics (iRECIST) ...........44
Safety Endpoints...........................................................................................45
45
 
 
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Product:  MK-3475/INCB024360 
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Protocol/Amendment No.: 654-05/ECHO-305-05
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04-Mar-2019
Confidential
45
46
46
46
46
47
48
Rationale for the Use of Comparator/Placebo .....................................................49
Justification for Dose ..............................................................................................49
Rationale for Dose and Regimen of Pembrolizumab...........................................49
Rationale for Dose and Regimen of Epacadostat in Combination with 
Pembrolizumab ....................................................................................................50
Study Population........................................................................................................51
Inclusion Criteria....................................................................................................51
Exclusion Criteria ...................................................................................................54
Lifestyle Restrictions...............................................................................................57
Meals and Dietary Restrictions............................................................................57
Contraception.......................................................................................................57
Pregnancy.............................................................................................................57
Use in Nursing Women........................................................................................58
Screen Failures ........................................................................................................58
Participant Replacement Strategy.........................................................................58
Treatments..................................................................................................................58
Treatments Administered.......................................................................................58
Dose Modification (Escalation/Titration/Other)..................................................59
Dose Modification for Immune-related AEs .......................................................59
Infusion Reaction Dose Modifications ................................................................63
Procedures for Participants Exhibiting Serotonin Syndrome ..............................64
Interruptions Unrelated to Adverse Events..........................................................66
Method of Treatment Assignment.........................................................................66
Stratification.........................................................................................................66
 
 
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Product:  MK-3475/INCB024360 
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Protocol/Amendment No.: 654-05/ECHO-305-05
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04-Mar-2019
Confidential
Blinding....................................................................................................................66
Preparation/Handling/Storage/Accountability ....................................................66
Dose Preparation..................................................................................................66
Handling, Storage and Accountability.................................................................67
Treatment Compliance...........................................................................................67
Administration and Compliance of Pembrolizumab............................................67
Administration and Compliance of Epacadostat or Matching Placebo ...............67
Concomitant Therapy.............................................................................................68
Acceptable Concomitant Therapies .....................................................................68
Prohibited Concomitant Therapies.......................................................................68
Restricted Medications.........................................................................................69
Rescue Medications & Supportive Care..............................................................69
Systemic Corticosteroid Use.........................................................................69
Treatment After the End of the Study ..................................................................70
Clinical Supplies Disclosure...................................................................................70
Standard Policies.....................................................................................................70
Discontinuation/Withdrawal Criteria......................................................................70
Discontinuation of Study Treatment.....................................................................70
Second Course Phase ...........................................................................................71
Withdrawal from the Study ...................................................................................71
Lost to Follow Up....................................................................................................72
Study Assessments and Procedures..........................................................................72
Administrative and General Procedures ..............................................................72
Informed Consent.................................................................................................72
General Informed Consent............................................................................73
Inclusion/Exclusion Criteria ................................................................................73
Participant Identification Card.............................................................................73
Serotonin Syndrome Information Card................................................................73
Medical History ...................................................................................................74
Prior and Concomitant Medications Review .......................................................74
Prior Medications..........................................................................................74
 
 
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Product:  MK-3475/INCB024360 
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Protocol/Amendment No.: 654-05/ECHO-305-05
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04-Mar-2019
Confidential
Concomitant Medications.............................................................................74
Assignment of Screening Number.......................................................................74
Assignment of Treatment/Randomization Number.............................................74
Treatment Administration....................................................................................74
Timing of Dose Administration....................................................................75
Timing of Dose Administration of Pembrolizumab ..............................75
Timing of Dose Administration of Epacadostat or Matching 
Placebo...................................................................................................75
Withdrawal/Discontinuation................................................................................75
Participant Blinding/Unblinding..........................................................................75
Calibration of Critical Equipment........................................................................75
Efficacy Assessments...............................................................................................76
Tumor Imaging and Assessment of Disease........................................................76
Initial Tumor Imaging...................................................................................76
Tumor Imaging During the Study.................................................................77
End of Treatment and Follow-Up Imaging...................................................77
Second Course Phase Tumor Imaging..........................................................77
RECIST 1.1 Assessment of Disease.............................................................77
iRECIST Assessment of Disease..................................................................77
78
78
Adverse Events, Serious Adverse Events and Other Reportable Safety 
Events.......................................................................................................................78
Time Period and Frequency for Collecting AE, SAE and Other 
Reportable Safety Event Information ..................................................................78
Method of Detecting AE, SAE and Other Reportable Safety Events..................80
Follow-up of AE, SAE and Other Reportable Safety Event Information............80
Regulatory Reporting Requirements for SAE .....................................................80
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..................................................................................81
Pregnancy and Exposure During Breastfeeding ..................................................81
Events of Clinical Interest (ECI)..........................................................................81
Treatment of Overdose...........................................................................................82
 
 
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Product:  MK-3475/INCB024360 
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Protocol/Amendment No.: 654-05/ECHO-305-05
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04-Mar-2019
Confidential
Safety........................................................................................................................82
Physical Examinations.........................................................................................82
Full Physical Exam .......................................................................................82
Directed Physical Exam................................................................................83
Vital Signs............................................................................................................83
Electrocardiograms ..............................................................................................83
Eastern Cooperative Oncology Group (ECOG) Performance Scale ...................83
Clinical Safety Laboratory Assessments..............................................................83
Laboratory Safety Evaluations (Hematology, Chemistry, 
Urinalysis).....................................................................................................84
Pregnancy Test..............................................................................................84
84
84
85
85
85
86
86
86
86
87
87
Visit Requirements..................................................................................................87
Screening..............................................................................................................87
Treatment Phase...................................................................................................88
Discontinued Participants Continuing to be Monitored in the Study ..................88
Safety Follow-up Visit..................................................................................88
Follow-up Visits............................................................................................88
Survival Follow-up .......................................................................................89
Survival Status ..............................................................................................89
Second Course Phase ...........................................................................................89
Statistical Analysis Plan ............................................................................................89
 
 
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Statistical Analysis Plan Summary........................................................................90
Responsibility for Analyses/In-House Blinding....................................................90
Hypotheses/Estimation ...........................................................................................91
Analysis Endpoints..................................................................................................91
Efficacy Endpoints...............................................................................................91
Safety Endpoints ..................................................................................................91
Analysis Populations...............................................................................................92
Efficacy Analysis Populations .............................................................................92
Safety Analysis Populations ................................................................................92
Statistical Methods..................................................................................................92
Statistical Methods for Efficacy Analyses ...........................................................92
Objective Response Rate ..............................................................................92
Progression-free Survival..............................................................................93
Overall Survival............................................................................................94
Duration of Response....................................................................................94
Statistical Methods for Key Efficacy Endpoints...........................................95
Statistical Methods for Safety Analyses ..............................................................96
Summaries of Baseline Characteristics and Demographics.................................96
Interim Analyses .....................................................................................................96
Safety Interim Analyses.......................................................................................96
Efficacy Interim Analyses....................................................................................97
Multiplicity ..............................................................................................................97
Sample Size and Power Calculations ....................................................................97
Sample Size and Power for Efficacy Analyses....................................................97
Subgroup Analyses..................................................................................................98
Compliance (Medication Adherence)....................................................................99
Extent of Exposure..................................................................................................99
References...................................................................................................................99
Appendices................................................................................................................107
Appendix 1: Abbreviations and Trademarks.....................................................107
Appendix 2: Clinical Laboratory Tests...............................................................111
 
 
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Appendix 3: Study Governance Considerations ................................................113
Merck Code of Conduct for Clinical Trials ...................................................................113
Financial Disclosure.......................................................................................................115
Data Protection...............................................................................................................115
Confidentiality of Data ..................................................................................................115
Confidentiality of Participant Records...........................................................................115
Confidentiality of IRB/IEC Information........................................................................116
Committees Structure.....................................................................................................116
Joint Executive Oversight Committee .......................................................................116
Data Monitoring Committee......................................................................................116
Publication Policy......................................................................................................116
Compliance with Trial Registration and Results Posting Requirements.......................117
Compliance with Law, Audit and Debarment ...............................................................117
Data Quality Assurance .................................................................................................118
Source Documents .........................................................................................................118
Study and Site Closure...................................................................................................119
Appendix 4: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................120
Definition of AE ............................................................................................................120
Definition of SAE ..........................................................................................................121
Recording AE and SAE .................................................................................................122
Reporting of AE, SAE, and Other Reportable Safety Events to MSD ..........................126
Appendix 5: Contraceptive Guidance and Pregnancy Testing.........................127
Contraception Requirements..........................................................................................127
Pregnancy Testing..........................................................................................................129
Appendix 6: Eastern Cooperative Oncology Group (ECOG) 
Performance Status...............................................................................................130
 
 
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values......................................................53
Table 2
Study Treatments..................................................................................................58
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab.......................................................60
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines.............................................................................................................63
Table 5
Signs and Symptoms of Serotonin Syndrome ......................................................65
Table 6
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events......................................................................................79
 
85
 
85
Table 9
Key Elements of the Statistical Analysis Plan......................................................90
Table 10
Censoring Rules for Primary and Sensitivity Analyses of Progression-
free Survival..........................................................................................................93
Table 11
Censoring Rules for Duration of Response ..........................................................95
Table 12
Analysis Methods for Key Efficacy Endpoints ....................................................95
Table 13
Analysis Strategy for Safety Endpoints................................................................96
Table 14
Protocol-Required Safety Laboratory Assessments ...........................................111
Table 15
Highly Effective Contraception Methods...........................................................128
 
 
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LIST OF FIGURES
Figure 1
Original Study Diagram........................................................................................42
Figure 2
Study Diagram as of Amendment 05....................................................................43
Figure 3
Power for Primary Hypothesis under Different Effect Size Assumptions ...........98
 
 
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Synopsis
Protocol Title:  
A Phase 2, Randomized, Double-Blind Study of Pembrolizumab (MK-3475) plus 
Epacadostat (INCB024360) Versus Pembrolizumab plus Placebo as First-Line Treatment 
in Patients with Metastatic Non-Small Cell Lung Cancer Expressing High Levels of PD-L1
Short Title: 
Phase 2 Study of Pembrolizumab ± Epacadostat in PD-L1 High Metastatic NSCLC
Objectives/Hypotheses and Endpoints:
NOTE: As of Amendment 05, epacadostat and matching placebo are removed from the 
treatment groups. All participants remaining on study will continue on open-label 
pembrolizumab monotherapy. The study will therefore stop collecting efficacy endpoints 
and 
 may not be pursued.
In all randomized participants with treatment-naïve, stage IV non-small cell lung cancer 
(NSCLC), highly expressing PD-L1 (TPS ≥50%):
Objective/Hypothesis
Endpoint
Primary

To compare objective response rate 
(ORR) of pembrolizumab plus 
epacadostat versus pembrolizumab 
plus placebo.
Hypothesis (H1): The combination 
of pembrolizumab plus epacadostat 
has superior ORR compared to 
pembrolizumab plus placebo.

ORR is defined as the proportion of 
participants who have a confirmed complete 
response (CR) or partial response (PR) per 
RECIST 1.1 based on blinded independent 
central review (BICR).
This study will be considered to have met its success criteria if pembrolizumab plus 
epacadostat is superior to pembrolizumab plus placebo in ORR.
Secondary

To compare progression-free survival 
(PFS) of the combination of 
pembrolizumab plus epacadostat 
versus pembrolizumab plus placebo.

Hypothesis (H2): The 

PFS is defined as the time from 
randomization to the first documented 
progressive disease (PD) per RECIST 1.1 
based on blinded independent central review 
(BICR) or death due to any cause, 
whichever occurs first. 
 
 
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combination of pembrolizumab 
plus epacadostat has superior PFS 
compared to pembrolizumab plus 
placebo.

To compare overall survival (OS) of 
pembrolizumab plus epacadostat 
versus pembrolizumab plus placebo.

OS is defined as the time from 
randomization to death due to any cause.

To evaluate duration of response 
(DOR) of the combinations of 
pembrolizumab plus epacadostat and 
pembrolizumab plus placebo. 

DOR 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, per 
RECIST 1.1 based on BICR.

To evaluate the safety and tolerability 
of the combinations of 
pembrolizumab plus epacadostat and 
pembrolizumab plus placebo.

Number of participants experiencing AEs 
and number of participants discontinuing 
study drug due to AEs.
Overall Design:
Trial Phase
Phase II
Clinical 
Indication
First-line treatment of metastatic NSCLC with high PD-L1 
expression (TPS ≥50%)
Population
Adult patients with treatment-naïve metastatic NSCLC (TPS ≥50%)
Trial Type
Interventional
Type of Design
Randomized, active comparator, parallel-group, multi-site, double-
blind
NOTE: As of Amendment 05, the study is unblinded, open-label, 
single arm.
Type of Control
Active Control
NOTE: As of Amendment 05, active control/placebo is removed.
Trial Blinding
Double-blind
NOTE: As of Amendment 05, the study is unblinded.
Estimated 
Duration of Trial
The study is estimated to require approximately 3 years from the 
time the first participant signs the informed consent until the last 
participant’s last study-related phone call or visit.
 
 
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Number of Participants:
Approximately 148 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups

Pembrolizumab 200 mg IV every 3 weeks (Q3W), up 
to 35 cycles
NOTE: The original study design randomized participants 
into 2 treatment arms: pembrolizumab (open-label) plus 
epacadostat and pembrolizumab (open-label) plus 
matching placebo. As of Amendment 05, epacadostat and 
matching placebo are removed. All participants remaining 
in the study will receive pembrolizumab monotherapy as 
per protocol, unless they choose to discontinue from the 
study completely and be treated with standard of care.
Duration of 
Participation
NOTE: As of Amendment 05, this section has been 
updated.
Each participant will partake in the study from the time the 
participant signs the informed consent form through the 
final contact. 
After a screening phase of 30 days, each participant will be 
assigned to receive study treatment until disease 
progression, unacceptable AEs, intercurrent illness that 
prevents further administration of treatment, investigator’s 
decision to withdraw the participant, noncompliance with 
study treatment or procedure requirements or 
administrative reasons requiring cessation of treatment, 
withdrawal of consent, or until the participant has received 
35 administrations of pembrolizumab (approximately 2 
years). 
After the end of treatment, each participant will be 
followed for the occurrence of AEs and spontaneously 
reported pregnancy as described under Section 9.3.
Study governance considerations are outlined in Appendix 3. A list of abbreviations used in 
this document can be found in Appendix 1.
 
 
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Schedule of Activities (SoA)
Initial Treatment Phase
NOTE: As of Amendment 05, epacadostat and matching placebo administration are stopped and all participants remaining in 
the study will receive open-label pembrolizumab monotherapy. The final study visit will be the Safety Follow-up Visit and 
there will be no follow-up for survival status. For participants who were in Follow-up or Survival Follow-up, participation in 
the study is considered complete and no further visits are required. For those participants remaining in the study, procedures 
are simplified. The SoA has been amended and assessments no longer required have been deleted.
Study Period
Screen.
Phase
Treatment Cycles
(3-Week Cycles)
EOT
Post 
Treatment
Notes
Participants who discontinue study treatment for whatever 
reason will proceed directly to EOT and Safety Follow-up.
Treatment Cycle
Screen.
(V 1)
1
2
3
4
5
6 to 35
DC
Safety 
Follow-up1
Scheduling Window 
(Days):
-30
to -1
+3
±3
±3
±3
±3
±3
At DC 
(+3)
30 Days Post-
DC (+14)
Administrative Procedures
Informed Consent Form
X
Re-consent of participants is required at disease progression for 
participants continuing on treatment.
Inclusion/Exclusion Criteria
X
Participant ID Card
X
Demographics and Medical 
History
X
Prior/Concomitant Meds
X
X
X
X
X
X
X
X
X
NSCLC Disease Details and 
Prior Treatment
X
Serotonin Syndrome 
Information Card
X
Subsequent Anti-neoplastic 
Therapy Status
X
X
Clinical Procedures / Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
Report non-serious AEs occurring within 30 days after the last 
dose of study treatment. Report SAEs occurring within 90 days 
after the last dose of study treatment, or 30 days after the last 
dose of study treatment if a new anti-cancer therapy is initiated, 
whichever is earlier.
 
 
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Study Period
Screen.
Phase
Treatment Cycles
(3-Week Cycles)
EOT
Post 
Treatment
Notes
Participants who discontinue study treatment for whatever 
reason will proceed directly to EOT and Safety Follow-up.
Treatment Cycle
Screen.
(V 1)
1
2
3
4
5
6 to 35
DC
Safety 
Follow-up1
Scheduling Window 
(Days):
-30
to -1
+3
±3
±3
±3
±3
±3
At DC 
(+3)
30 Days Post-
DC (+14)
Full Physical Exam
X
Directed Physical Exam
X
X
X
X
X
X
X
X
Vital Signs, Height, and 
Weight
X
X
X
X
X
X
X
X
X
Height at screening only
12-Lead ECG with QTc 
Measurement
X
X
X
*
At screening for all participants. At select centers, also perform 
on C1D1 and C2D1 at predose and 120 min (±15 min) after 
morning dose of epacadostat/placebo. * At EOT, perform ECG 
per SOC or as clinically indicated.
ECOG Performance Status
X
X
X
X
X
X
X
X
X
At screening, perform within 7 days prior to Cycle 1 but before 
randomization.
Laboratory Procedures / Assessments: Analysis Performed by Local Laboratory
Pregnancy Test - Urine or 
Serum β-HCG
X
WOCBP require negative test within 72 hours prior to Cycle 1. 
Test monthly if required by local regulations.
Hepatitis B & C Serology
X
Hepatitis B surface antigen, HBV-DNA, HCV-RNA (or HCV 
antibody if HCV-RNA is not the local SOC). May use central 
lab only if local lab is not capable. If this testing was conducted 
per SOC within 42 days prior to randomization, testing does not 
need to be repeated.
HIV Testing
X
Not required unless mandated by local health authority.
PT/INR and aPTT/PTT
X
Perform eligibility labs within 10 days prior to Cycle 1. 
Participants receiving coumarin-based anticoagulants should 
have more frequent INR monitoring (weekly for first 4 weeks
after initiation of therapy and upon DC of epacadostat/placebo). 
As of Amendment 05, testing after DC of epacadostat/placebo 
is no longer required.
CBC with Differential
X
X
X
X
X
X
X
X
Perform eligibility labs within 10 days prior to Cycle 1. After 
Cycle 1, may collect up to 3 days prior to dosing.
Chemistry Panel
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Perform within 10 days prior to Cycle 1, then every 2nd cycle 
through Cycle 6, then every 6th cycle thereafter (Cycles 2, 4, 6, 
12, 18, etc.).
 
 
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Study Period
Screen.
Phase
Treatment Cycles
(3-Week Cycles)
EOT
Post 
Treatment
Notes
Participants who discontinue study treatment for whatever 
reason will proceed directly to EOT and Safety Follow-up.
Treatment Cycle
Screen.
(V 1)
1
2
3
4
5
6 to 35
DC
Safety 
Follow-up1
Scheduling Window 
(Days):
-30
to -1
+3
±3
±3
±3
±3
±3
At DC 
(+3)
30 Days Post-
DC (+14)
T3/FT3, FT4, and TSH
X
X
X
X
X
X
Perform within 10 days prior to Cycle 1, then every 2nd cycle 
(Cycles 2, 4, 6, 8, etc.). May use central lab only if local lab is 
not capable.
Efficacy Measurements
Tumor Imaging
X
X
The timing of imaging during the treatment phase is according 
to the site’s SOC for tumor assessment until PD or initiation of 
a new anticancer regimen.
Brain MRI
X
Perform only if required by local SOC.
Perform at time of CR in participants with brain metastasis at 
Screening.
 
 
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Study Period
Screen.
Phase
Treatment Cycles
(3-Week Cycles)
EOT
Post 
Treatment
Notes
Participants who discontinue study treatment for whatever 
reason will proceed directly to EOT and Safety Follow-up.
Treatment Cycle
Screen.
(V 1)
1
2
3
4
5
6 to 35
DC
Safety 
Follow-up1
Scheduling Window 
(Days):
-30
to -1
+3
±3
±3
±3
±3
±3
At DC 
(+3)
30 Days Post-
DC (+14)
Study Drug Administration – Per Randomized Assignment
Pembrolizumab
X
X
X
X
X
X
Notes:
1. If Discontinuation Visit occurs ≥30 days from last dose of study treatment, a Safety Follow-up Visit is not required. Participants will be discontinued from the study after their 
30-day Safety Follow-up Visit.
Abbreviations: AE= adverse event; aPTT= activated partial thromboplastin time; β-HCG= beta-human chorionic gonadotropin; BICR= blinded independent central (imaging) 
review; CBC= complete blood count; CR= complete response; CXDX= Cycle X Day X; d= days; DC= discontinuation; ECG= electrocardiogram; ECOG= Eastern Cooperative 
Oncology Group; EOT= end of treatment FT4= free thyroxine; H/hr= hours; HBV/HCV= hepatitis B/C virus; HIV= human immunodeficiency virus; ICF= informed consent 
form; ID= identification; INR= international normalized ratio; IRB/IEC= Institutional Review Board/Independent Ethics Committee; min= minutes; NSCLC= non-small cell 
lung cancer; PD= progressive disease;
; PT= prothrombin time; PTT=partial thromboplastin time; Q= every;; QTc= corrected QT interval; SAE= serious 
adverse event; SOC= standard of care; T3/FT3= free or total triiodothyronine; TSH= thyroid stimulating hormone; V=visit; W/wks= weeks; WOCBP= women of child-bearing 
potential.
 
 
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Introduction
Study Rationale 
The global incidence of lung cancer was 1.8 million in 2012, resulting in an estimated 1.6 
million deaths [World Health Organization 2012]. In the United States, the 2016 estimated 
incidence of new diagnoses was 224,400 and estimated number of deaths was 158,100 
[National Cancer Institute 2016]. Non-small cell lung cancer (NSCLC) represents 
approximately 80% to 85% of all lung cancers. Of the patients with NSCLC, tumor histology 
is approximately 40% to 60% adenocarcinoma, 10% to 15% squamous, 5% neuroendocrine, 
and the rest, “not otherwise specified” [Sulpher, J. A., et al 2013]. 
Approximately 70% of patients with NSCLC have advanced disease not amenable to surgical 
resection at the time of diagnosis. The 5-year relative survival for patients with any lung 
cancer overall and metastatic lung cancer specifically has been reported to be 17.7% and 
4.3%, respectively [National Cancer Institute 2016].
Pembrolizumab monotherapy is the current standard of care (SOC) for the treatment of 
patients with good Eastern Cooperative Oncology Group (ECOG) performance status 
(ECOG 0 or 1) and previously untreated, advanced, or metastatic NSCLC with a 
programmed cell death ligand 1 (PD-L1) tumor proportion score (TPS) ≥50% with no 
epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic 
tumor aberrations. Approximately 30% of patients with newly diagnosed, advanced NSCLC 
highly express PD-L1 to a TPS ≥50% [Reck, M., et al 2016].
KEYNOTE-024, a Phase 3, randomized, controlled study, compared pembrolizumab 
monotherapy to standard first-line (1L) platinum-doublet therapy in 305 previously untreated 
participants with advanced NSCLC and a PD-L1 TPS ≥50%. Results from KEYNOTE-024 
indicated a significant progression-free survival (PFS) benefit for pembrolizumab over 
platinum-doublet therapy with a hazard ratio (HR) of 0.50 (95% confidence interval [CI]
0.37-0.68, p<0.001; median PFS 10.3 months [95% CI 6.7 not reached] with pembrolizumab 
and 6.0 months [95% CI 4.2-6.2] with platinum-doublet), as well as an overall survival (OS)
benefit with an HR of 0.60 (95% CI 0.41-0.89, p=0.005; median OS was not reached in 
either treatment arm). An estimated (Kaplan-Meier) 80.2% (95% CI 72.9-85.7) of 
participants treated with pembrolizumab and 72.4% (95% CI 64.5-78.9) of participants 
treated with platinum doublet therapy were alive at 6 months. Additionally, the objective 
response rate (ORR) was higher in the pembrolizumab arm than in the platinum-doublet arm 
(44.8% vs 27.8%, respectively) [Reck, M., et al 2016].
The results from KEYNOTE-024 established pembrolizumab as 1L therapy for patients 
whose tumors have a TPS ≥50% and with no EGFR or ALK genomic tumor aberrations.
While the benefit observed in KEYNOTE-024 was substantial, with significant improvement 
in PFS and OS, the benefits may be improved further in this patient population, possibly 
through combination of pembrolizumab with other immunomodulators.
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. The presence of the tryptophan-catabolizing enzyme IDO1 inhibits T-cell-
mediated immune responses, and IDO1 expression has been shown to be elevated in many 
 
 
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human cancers; thus, IDO1 inhibition may restore an effective antitumor immune response. 
 
 
 
 
 
 
 
 
KEYNOTE-037 (INCB 24360-202), a dose-escalation and expansion study of 
pembrolizumab in combination with epacadostat in participants with Stage IIIB, IV, or 
recurrent NSCLC, melanoma, transitional cell carcinoma, renal cell carcinoma, endometrial 
adenocarcinoma, or squamous head and neck carcinoma, is ongoing. ORR in 40 evaluable 
participants with previously-treated NSCLC was 35% (14/40) and disease control rate (DCR) 
was 60%, which includes 2 participants with a CR. Details of the results of this study thus far 
may be found in Section 3.2.3 and [Gangadhar, T. C. 2017].
Outcomes for patients evaluated in this study, with previously untreated metastatic NSCLC 
whose tumors express high levels of PD-L1 (TPS ≥50%), would be further improved if the 
safety profile of a pembrolizumab/epacadostat combination remains acceptable and is shown 
to improve outcomes compared to pembrolizumab monotherapy; thus, this study could 
support testing the hypothesis of having an improved outcome of the combination in this 
patient population.
Background
Pembrolizumab (MK-3475) is a potent and highly selective humanized monoclonal antibody 
(mAb) of the immunoglobulin (Ig)G4/kappa isotype directed against programmed cell death 
protein 1 (PD-1), thus inhibiting its interaction with PD-L1 and programmed cell death 
ligand 2 (PD-L2). Epacadostat (formerly INCB024360) represents a novel, potent, and 
selective inhibitor of the enzyme IDO1 in both human tumor cells and human dendritic cells. 
For a thorough discussion of the pharmacology of pembrolizumab and epacadostat, refer to 
the pembrolizumab Investigator's Brochure [IB Edition 15 2017] and the epacadostat 
Investigator's Brochure [Addendum 1 to IB Edition 9 2017]. 
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [Disis, M. L. 2010]. 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 [Boon, T. 1996], [Ercolini, A. M., et al 2005]. 
 
 
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Histologic evaluation of many human cancers shows extensive infiltration by inflammatory 
and immune cells [Galon, J., et al 2006], 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.
The PD-1 receptor is an immunoglobulin superfamily member shown to negatively regulate 
antigen receptor signaling upon engagement of its ligands PD-L1 and/or PD-L2 [Greenwald, 
R. J., et al 2005], [Okazaki, T., et al 2001]. The PD-1 pathway represents a major immune 
control switch, which can be exploited by tumor cells to overcome active T-cell immune 
surveillance. Expressed on the surface of activated T-cells under healthy conditions, the 
function of the PD-1 receptor is to down-modulate unwanted or excessive 
immune/autoimmune responses. A variety of cancers have been demonstrated to express 
abundant levels of PD-1 ligands, unlike healthy organs. The observed correlation of clinical 
prognosis with PD-L1 expression in multiple cancers suggests that the PD-1/PD-L1 pathway 
plays a critical role in tumor evasion and is thus an attractive target for therapeutic 
intervention.
Pembrolizumab is designed to directly block the interaction between PD-1 and its ligands 
PD-L1 and PD-L2. This blockade enhances functional activity of the target lymphocytes to 
facilitate tumor regression and ultimately immune rejection of the tumor.
Recent interest has focused on the role of IDO1 as a mechanism of induction of tolerance to 
malignancy [Godin-Ethier, J., et al 2011]. IDO1 is a heme-containing, monomeric
oxidoreductase that catalyzes the degradation of the essential amino acid tryptophan to N-
formyl-kynurenine. Kynurenine can be metabolized subsequently through a series of 
enzymatic steps to nicotinamide adenine dinucleotide. IDO1 is the first rate-limiting enzyme 
in one of the breakdown pathways of tryptophan. In another pathway, tryptophan 
hydroxylase catalysis of tryptophan leads to the formation of serotonin and melatonin.
The expression and activity profiles of IDO1 are distinct from those of tryptophan
dioxygenase, an enzyme predominantly expressed in liver that catalyzes the same enzymatic
reaction as IDO1 and maintains proper tryptophan balance in response to dietary uptake. In
contrast to tryptophan dioxygenase, IDO1 is expressed in a variety of tissues, with
particularly high levels found in areas of contact with potential sources of immune challenge
(eg, gut, respiratory tract, placenta, spleen), consistent with a role for regulating tryptophan
metabolism in a local microenvironment [Mellor, A. L. 2004]. Within the immune system, 
IDO1 activity is specifically induced in dendritic cells and macrophages at localized sites of 
inflammation [Munn, D. H. 2007].
IDO1-driven oxidation of tryptophan results in a strong inhibitory effect on the development
of T-cell-mediated responses by blocking T-cell activation and inducing T-cell apoptosis
[Mellor, A. L., et al 2003]. Both the reduction in local tryptophan levels and the production 
of tryptophan catabolites that are inhibitory to cell proliferation contribute to the 
immunosuppressive effects [Frumento, G., et al 2002]. IDO1 activity also promotes the 
differentiation of naive T-cells to cells with a regulatory phenotype (T-reg) [Fallarino, F., et 
al 2006]. Since increased T-reg activity has been shown to promote tumor growth and T-reg 
depletion has been shown to allow an otherwise ineffectual antitumor immune response to 
 
 
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occur [Zou, W. 2006], IDO1 expansion of T-regs 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 [Munn, D. H., et al 1998]. A critical role for IDO1 in 
immunomodulation has been confirmed in numerous animal models, including models of 
allograft tolerance, inflammation, and cancer [Mellor, A. L. 2004]. While IDO1 inhibition 
can exacerbate disease in models of autoimmune disorders [Mellor, A. L. 2004], IDO1 null 
mice show no evidence of susceptibility to developing spontaneous autoimmunity or 
alterations in immune system development [Mellor, A. L., et al 2003], suggesting that IDO1 
inhibition, in a therapeutic setting, may produce minimal side effects in participants without 
pre-existing autoimmune conditions.
Within the context of cancer, there are several lines of evidence to suggest that IDO1 is a key
regulator of the immunosuppressive mechanisms responsible for tumor escape from immune
surveillance. Several groups have demonstrated that blockade of IDO1 activity can directly
influence the ability of tumor-bearing animals to reject tumors [Uyttenhove, C., et al 2003], 
[Muller, A. J., et al 2005]. In addition, studies with 1-methyl-tryptophan, demonstrate that 
IDO1 inhibition dramatically increases the efficacy of various chemotherapeutic agents (eg, 
platinum compounds, taxane derivatives, cyclophosphamide) without increased toxicity 
[Muller, A. J., et al 2005]. Although the specific mechanisms responsible for this potentiation 
remain to be fully elucidated, the effects were not observed in T-cell-deficient animals, 
suggesting the disablement of immunosuppressive mechanisms that exist within the tumor
microenvironment.
Based on studies examining serum levels of tryptophan and kynurenine, IDO1 appears to be
chronically activated in participants with cancer, and IDO1 activation correlates with more
extensive disease [Huang, L., et al 2010], [Weinlich, G., et al 2007]. IDO1 has subsequently 
been found to be overexpressed by a wide variety of human tumor cell types as well as by the 
dendritic cells that localize to the TDLN [Uyttenhove, C., et al 2003]. Increased expression 
of IDO1 in tumor cells has been shown to be an independent prognostic variable for reduced 
OS in participants with melanoma, ovarian, colorectal, pancreatic, and non-small cell lung
cancers [Okamoto, A., et al 2005], [Brandacher, G., et al 2006], [Ino, K., et al 2006], 
[Nakamura, T., et al 2007], [Witkiewicz, A., et al 2008], [Hanagiri, T., et al 2014]. 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 in 
combination with chemotherapeutics and/or immunotherapy-based strategies.
As discussed above, there are a number of inhibitory mechanisms that have been identified to 
be involved in tumor-mediated immune suppression. 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. Combined inhibition of both PD-L1 and IDO1 pathways may 
therefore lead to greater enhancement of antitumor immunity and to increased efficacy.
 
 
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Completed Clinical Studies
Three completed clinical studies were conducted to evaluate the efficacy of pembrolizumab 
monotherapy in the treatment of NSCLC: KEYNOTE-001, KEYNOTE-010, and 
KEYNOTE-024.
KEYNOTE-001:
An open-label Phase 1 study (KEYNOTE-001) was conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab. The dose escalation portion of this study
evaluated three intravenous (IV) dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg administered 
every 2 weeks (Q2W), in participants with advanced solid tumors. All three dose levels were 
well tolerated and no dose-limiting toxicities were observed. Based on pharmacokinetic (PK) 
data showing a half-life of 21 days, the protocol was amended to change the dosing 
frequency in the expansion cohort to every 3 weeks (Q3W). All cohorts have completed 
enrollment.
A total of 550 NSCLC participants were treated in several dose expansion cohorts with at 
least one dose of pembrolizumab. The initial data from 495 NSCLC participants were 
published and reported. The ORR was 19.4% (18.0% in the 394 previously treated 
participants and 24.8% in the 101 previously untreated participants). The response rate (RR)
was similar regardless of dose, schedule, and histologic analysis. Current or former smokers 
had an RR of 22.5%, as compared with 10.3% among participants who had never smoked 
cigarettes.
Participants were required to submit a newly obtained tumor biopsy prior to initiating therapy 
with pembrolizumab for evaluation of PD-L1 expression. After evaluation of several 
methods for pathological assessment, in a training set, membranous PD-L1 expression in at 
least 50% of tumor cells (TPS ≥50%) was selected as the cutoff point defining PD-L1 high. 
In a validation set of 313 participants, the RR was 45.2% in the 73 participants with a TPS
≥50%, including 43.9% in previously treated participants and 50% in previously untreated 
participants, values that numerically exceeded the RR in the training group [Garon, E. B., et 
al 2015].
Pembrolizumab has been generally well tolerated. The most common treatment-related 
adverse events (AEs) were fatigue (19.4%), pruritus (10.7%), and decreased appetite 
(10.5%). Adverse events of Grade 3 or higher were reported in 47 of 495 patients (9.5%). 
The only treatment-related AEs of an inflammatory or immune-mediated nature that occurred 
in more than 2% of patients were infusion-related reactions (in 15 patients [3.0%]), 
hypothyroidism (in 34 patients [6.9%]), and pneumonitis (in 18 patients [3.6%]). One 
infusion reaction led to treatment discontinuation. All patients with hypothyroidism were 
successfully treated with medical therapy [Garon, E. B., et al 2015].
KEYNOTE-010:
KEYNOTE-010 was a randomized, adaptively designed Phase 2/3 study of pembrolizumab 
at two IV dose levels versus docetaxel in participants with NSCLC with PD-L1 positive 
tumors who had experienced disease progression after platinum-containing systemic therapy. 
Participants were randomized according to their TPS as follows: a TPS ≥50% was considered 
strongly positive and a TPS=1% to 49% was considered weakly positive. The study enrolled 
 
 
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1034 participants to examine the efficacy of pembrolizumab compared to docetaxel in an 
enriched population.
Pembrolizumab was superior to docetaxel in the strongly positive TPS ≥50% stratum 
(n=422) with regard to OS, with an HR of 0.54 (p = 0.00024) and 0.50 (p = 0.00002) for 
pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W, respectively, compared to docetaxel. 
Pembrolizumab was superior to docetaxel in the overall positive TPS ≥1% population with 
regard to OS, with an HR of 0.71 (p=0.00076) and 0.61 (p<0.00001) for pembrolizumab 
2 mg/kg Q3W and 10 mg/kg Q3W, respectively. Pembrolizumab was superior to docetaxel 
in the strongly positive TPS ≥50% stratum with regard to PFS, with an HR of 0.58 
(p=0.00009) and 0.59 (p=0.00007) for pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W, 
respectively, compared to docetaxel. Pembrolizumab also provided a numerically superior 
benefit in PFS in the overall positive TPS ≥1% population, with an HR of 0.88 and 0.79 for 
pembrolizumab 2 mg/kg Q3W and 10 mg/kg Q3W, respectively, compared to docetaxel; 
however, the differences were not statistically significant at the 0.001 level required per 
protocol.
The results of KEYNOTE-010 indicate that in previously treated participants with NSCLC 
with PD-L1 TPS ≥1%, and disease progression following platinum-containing 
chemotherapy, pembrolizumab provides a statistically significant and clinically meaningful 
OS benefit compared to standard docetaxel chemotherapy. Furthermore, the PD-L1 selection 
employed in KEYNOTE-010 identified patients more likely to benefit from pembrolizumab 
and resulted in favorable HR in OS compared to docetaxel.
Overall, the results from KEYNOTE-001 and KEYNOTE-010 demonstrated that 
pembrolizumab provided substantial, clinically meaningful benefits in OS, PFS, and ORR in 
participants with NSCLC who progressed after platinum-containing chemotherapy and 
whose tumor cells expressed PD-L1.
KEYNOTE-024:
KEYNOTE-024 was a multicenter, international, randomized, open-label, controlled study of 
IV pembrolizumab monotherapy versus the choice of multiple SOC platinum-based 
chemotherapies in participants previously untreated for their Stage IV NSCLC, whose tumors 
expressed PD-L1 at TPS ≥50%, and in whom EGFR or ALK-directed therapy is not 
indicated.
First-line treatment with pembrolizumab (n=154) significantly prolonged PFS (HR 0.50; 
95% CI: 0.37, 0.68; p<0.001) and OS (HR 0.60; 95% CI: 0.41, 0.89; p = 0.005) compared 
with SOC chemotherapy (n=151), inclusive of pemetrexed maintenance for participants with 
non-squamous tumors. In addition, pembrolizumab was associated with a higher ORR, 
including a higher complete response (CR) rate, as well as a longer duration of response 
(DOR) as compared to SOC.
Pembrolizumab was better tolerated than chemotherapy and AEs were easily managed. The 
observed safety profile of the pembrolizumab arm was consistent with the safety profile for 
pembrolizumab established to date. Based on the mechanism of action of pembrolizumab, 
immune-related AEs (irAEs), including pneumonitis, occurred at a greater frequency with 
pembrolizumab compared to chemotherapy. Most irAEs were of Grade 1 or 2 severity and 
none led to death.
 
 
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These data underscore the substantial benefit of pembrolizumab as initial therapy for
participants with previously untreated, advanced NSCLC whose tumors express high levels 
of PD-L1 (TPS ≥50%), in whom EGFR or ALK-directed therapy is not indicated.
KEYNOTE-252/ECHO-301:
KEYNOTE-252/ECHO-301 is phase 3 study evaluating epacadostat in combination with 
pembrolizumab in subjects with unresectable or metastatic melanoma. The study did not 
meet the primary endpoint of improving progression-free survival in the overall population 
compared to pembrolizumab monotherapy. Of note, based on review of the safety analysis, 
the eDMC concluded that there were no safety concerns with the treatment (pembrolizumab 
+ epacadostat) arm compared to control (pembrolizumab + placebo) arm.
Ongoing Clinical Studies
Pembrolizumab is under evaluation in patients with NSCLC as monotherapy and in 
combination with chemotherapy, immunotherapy, and targeted therapies. Epacadostat is 
undergoing studies in patients with NSCLC in combination with other immunotherapies
including various PD-1/PD-L1 targeted therapies. A full list of ongoing studies can be found 
in the respective Investigator’s Brochures of pembrolizumab [IB Edition 15 2017] and 
epacadostat [Addendum 1 to IB Edition 9 2017]. Details of the ongoing study KEYNOTE-
037 is outlined below.
KEYNOTE-037 / ECHO-202
KEYNOTE-037 (ECHO-202) is a Phase 1/2 study, with Phase 1 being a dose-escalation of 
INCB024360 in combination with MK-3475 in participants with Stage IIIB, Stage IV, or 
recurrent NSCLC, melanoma, transitional cell carcinoma of the genitourinary tract, renal cell 
carcinoma, triple negative breast cancer, adenocarcinoma of the endometrium, or squamous 
cell carcinoma of the head and neck (SCCHN) who have disease progression on at least 1 
line of therapy for advanced or metastatic cancer (except melanoma). Phase 2 is an open-
label expansion evaluating the recommended dose (from Phase I) of epacadostat 100 mg 
twice daily (BID) in combination with the fixed dose of IV pembrolizumab 200 mg Q3W in
participants with the following select tumors: NSCLC, melanoma, transitional cell carcinoma 
of the genitourinary tract, triple negative breast cancer, squamous cell carcinoma of the head 
and neck, ovarian cancer, clear cell renal cell carcinoma, microsatellite-instability high 
colorectal cancer, diffuse large B-cell lymphoma, gastric cancer, and hepatocellular 
carcinoma. There are two NSCLC cohorts in the Phase 2 expansion: one cohort with PD-L1 
high expression (≥50%) and a second cohort with low/negative or indeterminate PD-L1 
expression (<50%). Participants previously treated with PD-1 or CTLA-4 targeted therapies 
are excluded. Tumor response is being assessed by the Investigator using Response 
Evaluation Criteria in Solid Tumors (RECIST) 1.1.
As of 27-Feb-2017, a total of 294 participants were enrolled in Phase 2 and received at least 
1 dose of epacadostat + pembrolizumab.  The most frequently reported (≥ 10%) treatment-
related AEs of any grade were fatigue (29%), rash (17%), nausea (11%), and pruritus (10%).  
Rash includes the preferred terms rash, rash generalized, rash macular, rash maculopapular, 
and rash pruritic.  Treatment-related AEs Grade ≥3 were observed in 18% of participants.  
The most common treatment-related AEs Grade ≥3 were increased lipase (4%) and rash 
 
 
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(3%).  There was one treatment-related death due to respiratory failure which was secondary 
to aspiration pneumonia [Hamid, O., et al 2017].
As of 27-Feb-2017, among the 40 evaluable previously-treated participants with NSCLC, the 
ORR was 35% and DCR was 63%, which includes 2 participants with a CR. For the 36 
participants evaluable and with 0–2 prior lines of treatment, ORR was 39% (2 CR, 12 PR) 
and DCR was 64% (9 SD).  Among these 36 participants treated with the recommended dose 
of epacadostat 100 mg BID, ORR and DCR for participants with TPS ≥50% and ≤2 prior 
treatments were 43% (3/7; all PR) and 57% (4/7; 1 SD), respectively; for participants with 
TPS <50% and ≤2 prior treatments, ORR and DCR were 33% (6/18; 1 CR) and 56% (10/18; 
4 SD), respectively. The remaining 1 CR and 4 PRs were observed among 11/36 patients 
with unknown TPS [Gangadhar, T. C., et al 2017].
Benefit/Risk Assessment
NOTE: The results of the final efficacy analysis of this study indicated that the study 
did not meet the pre-specified endpoint of improvement in objective response rate 
(ORR) for the combination of pembrolizumab plus epacadostat compared with 
pembrolizumab plus placebo. As of Amendment 05, epacadostat and matching placebo 
have been removed from the study. Therefore, the benefit:risk assessment of 
epacadostat is no longer applicable and has been removed.
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Despite the substantial improvement in PFS and OS observed with pembrolizumab as 
compared to SOC platinum doublet chemotherapy in KEYNOTE-024, there remains a need
to investigate new treatments which offer the prospect of added benefit for this patient 
population. Details regarding specific benefits and risks of pembrolizumab treatment for 
participants in this clinical study may be found in the Investigator’s Brochure [IB Edition 15 
2017] and Informed Consent Form (ICF).
 
 
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Objectives/Hypotheses and Endpoints
NOTE: As of Amendment 05, epacadostat and matching placebo are removed from the 
treatment groups. All participants remaining on study will continue on open-label 
pembrolizumab monotherapy. The study will therefore stop collecting efficacy 
endpoints. 
In all randomized participants with treatment-naïve, stage IV NSCLC, highly expressing PD-
L1 (TPS ≥50%):
Objective/Hypothesis
Endpoint
Primary

To compare ORR of the combination 
of pembrolizumab plus epacadostat 
versus pembrolizumab plus placebo.

Hypothesis (H1): The 
combination of pembrolizumab 
plus epacadostat has superior 
ORR compared to 
pembrolizumab plus placebo.

ORR is defined as the proportion of 
participants who have a confirmed CR or 
PR per RECIST 1.1 based on BICR.
This study will be considered to have met its success criteria if pembrolizumab plus 
epacadostat is superior to pembrolizumab plus placebo in ORR.
Secondary

To compare PFS of the combination 
of pembrolizumab plus epacadostat 
versus pembrolizumab plus placebo.

Hypothesis (H1): The 
combination of pembrolizumab 
plus epacadostat has superior 
PFS compared to pembrolizumab 
plus placebo.

To compare OS of the combination 
of pembrolizumab plus epacadostat 
versus pembrolizumab plus placebo.

PFS is defined as the time from 
randomization to the first documented 
progressive disease (PD) per RECIST 1.1 
based on blinded independent central 
review (BICR) or death due to any cause, 
whichever occurs first. 

OS is defined as the time from 
randomization to death due to any cause.

To evaluate DOR of the 
combinations of pembrolizumab 
plus epacadostat and 
pembrolizumab plus placebo. 

DOR 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, per 
RECIST 1.1 based on BICR.
 
 
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Objective/Hypothesis
Endpoint

To evaluate the safety and 
tolerability of the combinations of 
pembrolizumab plus epacadostat 
and pembrolizumab plus placebo.

Number of participants experiencing AEs 
and number of participants discontinuing 
study drug due to AEs.
 
 
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Study Design 
Overall Design 
NOTE: As of Amendment 05, epacadostat and matching placebo are removed from the 
treatment groups. All participants remaining on study will continue open-label
pembrolizumab monotherapy. Participants may choose to discontinue from the study 
and be treated as per standard of care, or continue on study and receive 
pembrolizumab monotherapy as per protocol, if they will have access issues to standard 
of care outside the protocol. The Second Course Phase is removed from the study. The 
last study visit is the Safety Follow-up Visit and there will be no follow-up for survival 
status. All imaging will be performed as per local standard of care, data will not be 
collected or sent for central radiologist review (BICR). This section has been updated 
accordingly. 
This is a Phase 2 randomized, double-blind, active-controlled, parallel-group, multi-site study
conducted in participants with metastatic NSCLC who have not previously received systemic 
therapy for metastatic disease, whose tumors express PD-L1 with a TPS ≥50%, and in whom 
EGFR, ALK, or ROS1-directed therapy is not indicated. 
The original study design randomized participants into 2 treatment arms: pembrolizumab 
plus epacadostat and pembrolizumab (open-label) plus matching placebo (see Figure 1). As 
of Amendment 05, epacadostat and matching placebo are removed from the study. All 
participants remaining in the study receive open-label pembrolizumab monotherapy (see 
Figure 2).
Randomization into the original treatment arms in the study was stratified by predominant 
tumor histology (squamous vs. non-squamous).
Participants will be evaluated with radiographic imaging to assess response to treatment as 
per local standard of care until PD as assessed by the investigator/site radiologist using 
RECIST 1.1 or initiation of a new anti-cancer regimen.
Adverse event monitoring will be ongoing throughout the study and graded in severity 
according to the guidelines outlined in the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE) v4.0.
 
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Treatment with pembrolizumab will continue until 35 treatment cycles (approximately 2 
years), documented PD, unacceptable AEs, intercurrent illness that prevents further 
administration of treatment, Investigator’s decision to withdraw the participant, participant 
withdrawal of consent, pregnancy of the participant, noncompliance with study treatment or 
procedure requirements, administrative reasons, or optionally for participants with a CR who 
have received at least 8 administrations of pembrolizumab (Section 8.1).
Participants are discontinued from the study after their 30-day Safety Follow-up Visit. 
The study has no planned treatment crossover. The study will be conducted in conformance 
with Good Clinical Practices (GCP).
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure 
are provided in Section 9 – Study Assessments and Procedures.
Data Monitoring Committee and Interim Analyses
This study will use an external Data Monitoring Committee (eDMC) to monitor safety.
Details of the composition and procedures for the DMC may be found in the DMC Charter 
and Appendix 3. As of Amendment 05, no further DMC reviews will be conducted.
Study Diagram
The study design, as of Amendment 04, is depicted in Figure 1 and the study design as of 
Amendment 05 is depicted in Figure 2.
Figure 1
Original Study Diagram
 
 
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Figure 2
Study Diagram as of Amendment 05
Number of Participants
Approximately 148 participants will be randomized into the study. The study was initially 
designed to recruit 588 patients. With Amendment 04, the sample size was reduced to total 
148 participants randomized, inclusive of participants who were enrolled prior to 
Amendment 04. It was estimated that approximately 90 additional participants would be 
required to be randomized into the 2 treatment arms based on enrollment at the time 
Amendment 04 was being released. Enrollment was completed on 05-SEP-2018.
Beginning and End of Study Definition
The overall trial begins when the first participant signs the informed consent form (ICF).  
The overall trial ends when the last participant completes the last study-related phone-call or 
visit, withdraws from the trial or is lost to follow-up (i.e. the participant is unable to be 
contacted by the investigator).
Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
Scientific Rationale for Study Design 
Rationale for Endpoints
Efficacy Endpoints
NOTE: As of Amendment 05, data for efficacy endpoints, including disease assessments 
based on imaging, are no longer being collected. Imaging, performed per local standard 
of care, will be assessed by the investigator/site radiologist; data will not be collected
and transmission of images for central review is no longer required.
This study will use a primary endpoint of ORR, as outlined in Section 4.
 
 
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ORR by RECIST 1.1 criteria as assessed by BICR is considered preliminary evidence of 
efficacy and is a primary endpoint for this Phase 2 study.
OS, PFS and DOR are secondary endpoints for this study. 
OS has been recognized as the gold standard for the demonstration of superiority of a new 
antineoplastic therapy in randomized clinical studies.
PFS is an acceptable measure of clinical benefit for a late stage study that demonstrates 
superiority of a new antineoplastic therapy, especially if the magnitude of the effect is large 
and the therapy has an acceptable risk/benefit profile. The use of BICR and RECIST 1.1 to 
assess PFS is typically considered acceptable by regulatory authorities. Images will be read 
by a central imaging vendor blinded to treatment assignment to minimize bias in the response 
assessments. In addition, the final determination of radiologic progression will be based on 
the central assessment of progression, rather than a local site assessment. Real time 
determination of radiologic progression as determined by central review will be 
communicated to the site
DOR by RECIST 1.1 criteria and assessed by BICR is a commonly accepted endpoint by 
both regulatory authorities and the oncology community.
The BICR consists of a group of highly qualified radiologists contracted by the central 
imaging vendor who are otherwise not involved in the study. The methodology of the BICR 
is described in the imaging review charter.
RECIST 1.1
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the local site when determining eligibility. Although traditional RECIST 1.1 references a 
maximum of 5 target lesions in total and 2 per organ, this protocol has implemented a 
modification to RECIST 1.1 to allow a maximum of 10 target lesions in total and 5 per 
organ. This will be termed as RECIST 1.1 throughout the protocol. Further details are found 
in Section 9.2.1.5.
Modified RECIST for Immune-based Therapeutics (iRECIST)
NOTE: As of Amendment 05, the use of iRECIST is discontinued. This section is no 
longer applicable. Participants with radiographic disease progression as determined by 
RECIST 1.1 by investigator assessment will discontinue from open-label 
pembrolizumab monotherapy; no confirmatory scans are required. However, if the 
participant is achieving a clinically meaningful benefit, an exception to continue with 
pembrolizumab monotherapy may be considered following consultation with MSD.
RECIST 1.1 will be adapted to account for the unique tumor response seen following 
treatment with pembrolizumab. Immunotherapeutic agents such as pembrolizumab may 
produce 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 participants treated with pembrolizumab may 
manifest a clinical response after an initial increase in tumor burden or even the appearance 
of new lesions.
 
 
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Thus, standard RECIST 1.1 may not provide an accurate response assessment of 
immunotherapeutic agents such as pembrolizumab. Based on an analysis of participants with 
melanoma enrolled in KEYNOTE-001, 7% of evaluable participants experienced delayed or 
early tumor pseudo-progression. Of note, participants who had PD by RECIST 1.1 but not by 
the immune-related response criteria [Wolchok, J. D., et al 2009] had longer OS than 
participants with PD by both criteria [Hodi, F. S., et al 2014]. Additionally, the data suggest 
that RECIST 1.1 may underestimate the benefit of pembrolizumab in approximately 15% of 
participants. These findings support the need to apply a modification to RECIST 1.1 that 
takes into account the unique patterns of atypical responses in immunotherapy and enables
treatment beyond initial radiographic progression, if the participant is clinically stable.
iRECIST assessment has been developed and published by the RECIST Working Group, 
with input from leading experts from industry and academia, along with participation from 
the US Food and Drug Administration and the European Medicines Agency [Seymour, L., et 
al 2017]. The unidimensional measurement of target lesions, qualitative assessment of non-
target lesions, and response categories are identical to RECIST 1.1, until progression is seen 
by RECIST 1.1. However, if a participant is clinically stable, additional imaging may be 
performed to confirm radiographic progression. iRECIST will be used by site investigators to 
assess tumor response and progression, and make treatment decisions, 
 
.
Refer to Section 9.2.1.6 for details on iRECIST.
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are safety endpoints including, but not limited to, the incidence of, causality,
severity, and outcome of AEs/ SAEs; and changes in vital signs and laboratory values. AEs 
will be assessed as defined by NCI CTCAE v4.0.
 
 
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Rationale for the Use of Comparator/Placebo
NOTE: As of Amendment 05, epacadostat and matching placebo are removed from the 
study. This section is no longer applicable.
Based on the results of KEYNOTE-024, pembrolizumab monotherapy has become the SOC
for treating stage IV NSCLC in patients with PD-L1 TPS ≥50% with no EGFR or ALK
genomic tumor aberrations. The study resulted in a significant PFS benefit for 
pembrolizumab over the SOC at the time (platinum-doublet therapy), with an HR of 0.50 
(95% CI 0.37-0.68, p <0.001; median PFS 10.3 months [95% CI 6.7 not reached] with 
pembrolizumab and 6.0 months [95% CI 4.2-6.2] with platinum-doublet), as well as an OS 
benefit with an HR of 0.60 (95% CI 0.41-0.89, p=0.005; median OS was not reached in 
either treatment arm)[Reck, M., et al 2016].
The results from KEYNOTE-024 established pembrolizumab as 1L therapy for patients 
whose tumors have a TPS ≥50% and in whom EGFR or ALK-directed therapies are not 
indicated, and the regimen has received regulatory approval for this use by the FDA and 
EMA.
The use of an epacadostat matching placebo in combination with pembrolizumab will ensure 
the objectivity of the local Investigators’ treatment decision and AE causality assessments, 
while still providing participants the SOC treatment. 
Justification for Dose 
Rationale for Dose and Regimen of Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda® development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab for adults across all indications and regardless of tumor type. As outlined 
below, this dose is justified by: 

Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg Q2W, 

Clinical data showing meaningful improvement in benefit-risk including OS at 200 
mg Q3W across multiple indications, and
 
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
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically-based PK analysis) 
at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and 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 
(KN001 B2, KN001 D, KN002, KN010, and KN021), and 3 studies compared 10 mg/kg 
Q3W vs 10 mg/kg Q2W (KN001 B3, KN001 F2, and KN006). All of these studies 
demonstrated flat dose- and exposure-response relationships across the doses studied 
representing an approximate 5- to 7.5-fold difference in exposure. The 2 mg/kg (or 200 mg 
fixed-dose) Q3W provided similar responses to the highest doses studied. Subsequently, flat 
dose-/exposure-response relationships were also observed in other tumor types including 
head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumor type. These 
findings are consistent with the mechanism of action of pembrolizumab, which acts by 
interaction with immune cells, and not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in KN001 evaluating target-mediated drug disposition conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. Secondly, 
a physiologically-based PK analysis was conducted to predict tumor PD-1 saturation over a 
wide range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant 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 Dose and Regimen of Epacadostat in Combination with 
Pembrolizumab
NOTE: As of Amendment 05, this section is no longer applicable.
The dose selected for epacadostat for the current study was formed on the basis of a well-
tolerated safety profile as monotherapy and in combination with pembrolizumab, efficacy 
evidenced by robust, durable responses, and optimal target inhibition of IDO1 based on 
nonclinical models. 
The first-in-human study INCB 24360-101 evaluated the pharmacodynamic effects of 
epacadostat dose/exposure on the tryptophan pathway using an ex vivo assay optimized for 
determining the inhibition of the metabolism of tryptophan to kynurenine by IDO1. 
Epacadostat treatment produced significant dose-dependent reductions in plasma kynurenine 
levels and plasma kynurenine/tryptophan ratios at all doses and in all participants. Near-
 
 
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maximal changes were observed at doses of epacadostat ≥100 mg PO BID with >80% to 
90% inhibition of IDO1 achieved throughout the dosing period [Beatty, G. L., et al 2017]. 
In the Phase 1 portion of ECHO-202/KEYNOTE-37, epacadostat doses of 25 mg, 50 mg, and 
100 mg PO twice daily (BID) in combination with pembrolizumab 2 mg/kg IV every 3 
weeks (Q3W) and epacadostat 300 mg BID in combination with the fixed dose of 
pembrolizumab 200 mg IV Q3W were evaluated. Safety expansion cohorts also evaluated 
epacadostat doses of 50 mg, 100 mg, and 300 mg with the fixed dose of pembrolizumab 200 
mg IV Q3W.  Reductions in tumor burden were seen in 14 of 19 evaluable melanoma 
participants across doses of epacadostat 25 mg BID to 100 mg BID in combination with 
pembrolizumab 2 mg/kg and 200 mg fixed dose [Gangadhar, T. C., et al 2015]. Objective 
responses were observed in all tumor types and the majority are durable; this combination 
has been well tolerated with rates of irAEs that are similar to pembrolizumab monotherapy 
and low rates of treatment discontinuation due to irAEs [Gangadhar, T. C., et al 2017] 
[Hamid, O., et al 2017]. 
 
 
 
 
  
 
 
 
 
Study Population
Male/female participants with metastatic NSCLC, who express high levels of PD-L1 
(TPS ≥50%), have received no systemic anti-cancer therapy for their metastatic NSCLC, and
are at least 18 years of age will be enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Have a histologically or cytologically confirmed diagnosis of stage IV (AJCC version 
8 or current version as applicable) NSCLC.
2. Have confirmation that EGFR, ALK, or ROS1 directed therapy is not indicated as 
primary therapy (documentation of absence of tumor activating EGFR mutations 
 
 
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AND absence of ALK and ROS1 gene rearrangements OR presence of a KRAS
mutation). 
a.
If participant’s tumor is known to have a predominantly squamous histology, 
molecular testing for EGFR mutation and ALK and ROS1 translocations will 
not be required, as this is not part of current diagnostic guidelines.
3. Have measurable disease based on RECIST 1.1 as determined by the local site. 
a.
Lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions.
4. Tumor tissue that demonstrates PD-L1 expression in ≥50% of tumor cells (TPS 
≥50%) as assessed by IHC at a central laboratory. 
a.
Assessment of PD-L1 expression must be made from provided archival tumor 
tissue sample or newly obtained core or excisional biopsy of a tumor lesion 
not previously irradiated. Formalin-fixed, paraffin-embedded tissue blocks are 
preferred to slides. Newly obtained biopsies are preferred to archived tissue.
Demographics
5. Be ≥18 years of age on the day of signing informed consent.
6. Have a life expectancy of at least 3 months.
7. Have an ECOG performance status of 0 or 1 within 7 days prior to the first dose of 
study treatment but before randomization.
Male participants:
8. A male participant must agree to use contraception as detailed in Appendix 5 of this 
protocol during the treatment period and for at least 120 days after the last dose of 
study treatment and refrain from donating sperm during this period.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the participant.
Female participants:
9. A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
not breastfeeding, and at least one of the following conditions applies: 
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5
OR 
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during 
the treatment period and for at least 120 days after the last dose of study treatment.
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
for the participant.
Informed Consent
10. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the study.
 
 
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Laboratory Values
11. Have adequate organ function as indicated by the laboratory values in Table 1.
Specimens must be collected and reviewed within 10 days prior to the start of study 
treatment.
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematologic
Absolute neutrophil count
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/La without a red blood cell 
transfusion within 2 weeks of the screening test
Renal
Serum creatinine OR
Measured or calculated CrCl b
(GFR can also be used in place of creatinine or CrCl)
≤1.5 × ULN OR
≥30 mL/min for participants with creatinine levels 
>1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 × ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels >1.5 × ULN.
If there is no institutional ULN, then direct bilirubin 
must be < 40% of total bilirubin to be eligible. Note: 
In no case can the total bilirubin exceed 3 x ULN.
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN
Coagulation
International normalized ratio (INR) OR
prothrombin time (PT)
Activated partial thromboplastin time (aPTT) or 
partial thromboplastin time (PTT)c
≤1.5 × ULN unless the participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
Note: This table includes eligibility-defining laboratory value requirements for treatment. 
a.
Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion 
within 2 weeks of the screening test.
b.
CrCl should be calculated per institutional standard. 
c.
PTT may be performed if the local lab is unable to perform aPTT.
Abbreviations:  ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); aPTT= activated partial 
thromboplastin time; AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
CrCl=creatinine clearance; GFR=glomerular filtration rate; INR=international normalized ratio; PT= prothrombin time;
PTT=partial thromboplastin time; ULN=upper limit of normal.
 
 
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Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has known untreated central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously treated brain metastases may participate 
provided they are radiologically stable (without evidence of progression by imaging 
for at least 4 weeks prior to the first dose of study treatment), clinically stable, and 
have not required steroids for at least 14 days before first dose of study treatment.
2. Has a history of (non-infectious) pneumonitis that required systemic steroids or 
current pneumonitis/interstitial lung disease.
3. Has symptomatic ascites or pleural effusion. A participant who is clinically stable
following treatment for these conditions (including therapeutic thoraco- or
paracentesis) is eligible.
4. Has a known history of an additional malignancy, except if the participant has 
undergone potentially curative therapy with no evidence of that disease recurrence for 
5 years since initiation of that therapy.
a.
Note: The time requirement for no evidence of disease for 5 years does not 
apply to the NSCLC for which a participant is enrolled in the study. The time
requirement also does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, superficial bladder 
cancer, squamous cell carcinoma of the skin, in situ cervical cancer, or other 
in situ cancers.
5. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed. 
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(doses exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study treatment.
7. Has had an allogeneic tissue/solid organ transplant.
8. Has a known history of human immunodeficiency virus (HIV) infection. HIV testing 
is not required unless mandated by the local health authority.
9. Has known history of or is positive for active Hepatitis B (HBsAg reactive) or has 
active Hepatitis C (HCV RNA). Note: Testing must be performed to determine 
eligibility. 
a.
HBV DNA must be undetectable and HBsAg negative at screening.
b. Hepatitis C antibody testing is allowed for screening purposes in countries 
where HCV RNA is not part of SOC. In these cases, HCV antibody positive 
participants will be excluded.
 
 
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c.
Participants who have had definitive treatment for HCV are permitted if HCV 
RNA is undetectable at screening.
10. Has a history of a gastrointestinal condition or procedure that in the opinion of the 
Investigator may affect oral drug absorption.
11. 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 Fridericia or Bazett formula). In the event that a single QTc is 
>480 msec, the participant may enroll if the average QTc for 3 ECGs is <480 msec.
12. Has clinically significant cardiac disease, including unstable angina, acute myocardial 
infarction within 6 months from Day 1 of study drug administration, or New York 
Heart Association Class III or IV congestive heart failure. Medically controlled 
arrhythmia stable on medication is permitted.
13. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
14. Has an active infection requiring systemic therapy.
15. Has known psychiatric or substance abuse disorders that would interfere with the 
participant’s cooperation for the requirements of the study.
16. Previously had a severe hypersensitivity reaction to treatment with a monoclonal
antibody or has a known sensitivity to any component of epacadostat or 
pembrolizumab.
17. WOCBP who has a positive urine pregnancy test within 72 hours before the first dose 
of study treatment. If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.
a.
Note: In the event that 72 hours have elapsed between the screening 
pregnancy test and the first dose of study treatment, another pregnancy test 
(urine or serum) must be performed and must be negative in order for 
participant to start receiving study treatment.
18. 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.
Prior/Concomitant Therapy
19. Has received prior systemic chemotherapy or other targeted or biological anti-
neoplastic therapy for their metastatic NSCLC.
a.
Note: Prior treatment with chemotherapy and/or radiation as part of 
neoadjuvant/adjuvant therapy is allowed as long as therapy was completed at 
least 6 months prior to the diagnosis of metastatic NSCLC.
20. Has received prior treatment with pembrolizumab or any other anti-PD-1, anti-PD-
L1, anti-PD-L2 agent, with epacadostat or any anti-IDO1 agent, or with an agent 
directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, 
CD137, GITR). 
 
 
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21. Has received radiotherapy within 14 days before the first dose of study treatment or 
received lung radiation therapy of >30 Gy within 6 months before the first dose of 
study treatment. 
a.
Note: Participants must have recovered from all radiation-related toxicities to 
grade 1 or less, not require corticosteroids, and not have had radiation
pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 
weeks of radiotherapy) to non-CNS disease.
22. Is receiving systemic steroid therapy ≤7 days prior to the first dose of study treatment
or receiving any other form of immunosuppressive medication.
a.
Corticosteroid use after randomization is allowed for management of AEs, 
SAEs, and events of clinical interest (ECIs), as a pre-medication for IV 
contrast, or if considered necessary for a participant’s medical condition.
b. Participants who receive daily steroid replacement therapy ≤10 mg prednisone 
or equivalent are exempt.
23. Has received a live vaccine within 30 days prior to the first dose of study treatment.  
a.
Examples of live vaccines include, but are not limited to, the following:  
measles, mumps, rubella, varicella/zoster (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.
24. Has any history of Serotonin Syndrome after receiving serotonergic drugs.
25. Has received therapy with an MAOI, or UGT1A9 inhibitor within 21 days prior to 
starting treatment, or anticipates requiring one of these prohibited medications during 
the treatment phase. Examples of medications in these classes are found in Section 
7.7.2.
Prior/Concurrent Clinical Study Experience
26. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of study treatment.
a.
Note: Participants who have entered the Follow-up phase of an investigational 
study may participate as long as it has been >4 weeks after the last dose of the 
previous investigational agent.
 
 
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Other Exclusions
27. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's ability to 
participate for the full duration of the study, or is not in the best interest of the 
participant to participate, in the opinion of the treating Investigator.
Lifestyle Restrictions
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
 
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. 
Developmental and reproductive toxicity studies have not been performed with epacadostat. 
Epacadostat should not be used by pregnant women.
Participants 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, participants of childbearing potential must adhere to the contraception 
requirements from the day of study medication initiation (or 14 days prior to the initiation of 
study medication for oral contraception) throughout the study period up to 120 days after the 
last dose of study medication. If there is any question that a participant of childbearing 
potential will not reliably comply with the requirements for contraception, that participant 
should not be entered into the study. 
Definitions of WOCBP and standards for adequate contraception are outlined in Appendix 5.
Pregnancy
If a participant becomes pregnant while on treatment with pembrolizumab or epacadostat, the 
participant will be immediately discontinued from study treatment. The site will contact the 
participant at least monthly and document the participant’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 an SAE (eg, death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn). The 
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 participant 
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 9.3.6.
 
 
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Use in Nursing Women
It is unknown whether pembrolizumab or epacadostat are 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, participants who are breastfeeding are not eligible for 
enrollment.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized.  A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards 
of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, screen failure details, 
eligibility criteria, and any AEs or SAEs meeting reporting requirements as outlined in the 
entry guidelines.
Participant Replacement Strategy
A participant who discontinues from study treatment or withdraws from the study will not be 
replaced.
Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies (study treatments provided by MSD) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
Treatments Administered
The study treatments to be used in this trial are outlined below in Table 2.
NOTE: As of Amendment 05, epacadostat and matching placebo are removed from the 
study. This section has been updated accordingly.
Table 2
Study Treatments
Drug
Dose/ 
Potency
Dose 
Frequency
Route of 
Administration
Treatment 
Period
Use
Sourcing
Pembrolizumab
25 mg/mL 
solution for 
infusion
200 mg
Q3W
IV infusion
Day 1 of each 
cycle for up to 
35
administrations
Experimental
/ Standard of 
Care
Central
IV=intravenous; Q3W=every 3 weeks.
 
 
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All supplies indicated in Table 2 will be provided per the ‘Sourcing’ column depending upon 
local country operational requirements.  Every attempt should be made to source these 
supplies from a single lot/batch number. 
Refer to Section 9.1.9 for details regarding administration of the study treatment.
Dose Modification (Escalation/Titration/Other) 
Dose Modification for Immune-related AEs
NOTE: As of Amendment 05, text in this section relating to dose modification of 
epacadostat/matching placebo is no longer applicable. This section has been updated 
accordingly.
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 
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, or 
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 3 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 3
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
NOTE: As of Amendment 05, this table has been replaced with the current guidelines for pembrolizumab.
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
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
New 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
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
 
 
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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 
All Other immune-
related AEs
Intolerable/ persistent 
Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology 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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Infusion Reaction Dose Modifications
Pembrolizumab may cause severe or life-threatening infusion-reactions, including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab-associated 
infusion reaction are provided in Table 4.
Table 4
Pembrolizumab Infusion Reaction Dose Modification and 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 participant is deemed medically stable in the 
opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hours
Stop Infusion.
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 participant is deemed medically stable in the 
opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held until symptoms resolve 
and the participant should be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further treatment with 
pembrolizumab.
Participant may be 
premedicated 1.5 hr
(± 30 minutes) prior 
to infusion of 
pembrolizumab with:
Diphenhydramine 
50 mg po (or 
equivalent dose of 
antihistamine).
Acetaminophen 
500-1000 mg po (or 
equivalent dose of 
analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
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 participant is deemed medically stable in the 
opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used 
immediately.
Participant is permanently discontinued from further 
treatment with pembrolizumab.
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 CTCAE at http://ctep.cancer.gov
CTCAE=Common Terminology Criteria for Adverse Events; IV=intravenous; NCI=National Cancer Institute; 
NSAIDs=nonsteroidal anti-inflammatory drugs; PO=oral.
Procedures for Participants Exhibiting Serotonin Syndrome
NOTE: As of Amendment 05, this section has been updated to reflect the removal of 
epacadostat from the study and updated information regarding the risks of SS with the 
use of epacadostat.
There is a rare chance that epacadostat could cause an increase in serotonin levels in the brain 
that might trigger serotonin syndrome (SS) [Boyer, E. W. 2005], when administered in 
combination with other serotonergic agents. Selective serotonin reuptake inhibitors (SSRIs),
selective serotonin/norepinephrine reuptake inhibitors (SNRIs), and MAOIs are permitted in 
the study. Due to the results of a preclinical study specifically evaluating the effect of 
epacadostat on the brain ECF concentrations of serotonin with linezolid [Zhang, Y., et al 
2016], and the clinical experience with related medications (eg, SSRIs/SNRIs) that suggest 
that SS is low risk, the use of MAOIs is not prohibited in the current study.
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 5) should be evaluated in the context of possible comorbid conditions 
as well.
The following procedures will be implemented if participants exhibit the signs/symptoms of 
SS, including tremor; hyperreflexia; spontaneous, ocular, or inducible clonus; together with 
agitation, fever, diaphoresis, or muscle rigidity:

Immediately interrupt all study treatment administration.
 
 
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
Immediately interrupt any SSRI, SNRI, or MAOI administration.

Provide appropriate medical management of the participant until all signs/symptoms 
are resolved (eg, IV fluids and/or sympathomimetic amines for hypotension, 
benzodiazepines for agitation, administration of 5-hydroxytryptamine antagonists 
such as cyproheptadine).

If etiologies other than SS are excluded, pembrolizumab administration may be 
resumed unless other AE management guidelines apply for the specific event.

If participant chooses to withdraw from the study, or must restart treatment with 
SSRI, SNRI, or MAOI, the participant should be scheduled for a Follow-up Visit. 
Treatment with SSRI, SNRI, or MAOI may be initiated 2 weeks after resolution of 
signs and symptoms of SS.

If a participant had experienced moderate or severe unconfounded SS in the opinion 
of the investigator, without concomitant SSRI, SNRI, or MAOI usage, or serotonergic 
concomitant medications, pembrolizumab administration may be resumed.
Table 5
Signs and Symptoms of Serotonin Syndrome
Seriousness
Autonomic signs
Neurological signs
Mental status
Other
Mild
Afebrile or low-grade 
fever
Tachycardia
Mydriasis
Diaphoresis or shivering
Intermittent tremor
Akathisia
Myoclonus
Mild hyperreflexia
Restlessness
Anxiety
Moderate
Increased tachycardia
Fever (up to 41°C)
Diarrhea with hyperactive 
bowel sounds
Diaphoresis with normal 
skin color
Hyperreflexia
Inducible clonus
Ocular clonus (slow 
continuous lateral eye 
movements)
Myoclonus
Easily startled
Increased 
confusion
Agitation and 
hypervigilance
Rhabdomyolysis
Metabolic 
acidosis
Renal failure
Disseminated 
intravascular 
coagulopathy 
(secondary to 
hyperthermia)
Severe
Temperature often more 
than 41 °C (Secondary to 
increased tone)
Increased muscle tone 
(lower limb > upper)
Spontaneous clonus
Substantial myoclonus 
or hyperreflexia
Delirium
Coma
As above
Source: [Boyer, E. W. 2005]
 
 
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Interruptions Unrelated to Adverse Events
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to study treatment (eg, elective surgery, unrelated medical events, participant 
vacation, and/or holidays). Participants should be placed back on study treatment within 3 
weeks of the scheduled interruption, unless otherwise discussed with MSD. The reason for
interruption should be documented in the participant’s study record.
Method of Treatment Assignment 
Treatment randomization will occur centrally using an interactive voice response 
system/integrated web response system (IVRS/IWRS). Participants will be assigned 
randomly in a 1:1 ratio to pembrolizumab + epacadostat or pembrolizumab + matching 
placebo.
Study treatment must begin as close to treatment randomization as possible but no more than 
3 days later. If this cannot occur due to an AE or other reason, please contact MSD and 
document the reason in the participant’s medical record.
Stratification
Treatment allocation/randomization will be stratified according to the following factor:

Predominant tumor histology: squamous vs non-squamous
Blinding 
NOTE: As of Amendment 05, blinding is no longer applicable as epacadostat and 
matching placebo have been removed from the study. All participants will receive open-
label study treatment. This section is no longer applicable.
A double-blinding technique with in-house blinding will be used. Epacadostat and placebo 
will be packaged identically so that the blind is maintained. The participant, the investigator,
the Sponsor, MSD study personnel, or delegates who are involved in the study treatment 
administration or clinical evaluation of the participants are unaware of the group 
assignments.
Pembrolizumab, which will be dosed to all participants in both treatment arms, will not be
blinded.
See Section 9.1.11 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
Preparation/Handling/Storage/Accountability
Dose Preparation
NOTE: As of Amendment 05, epacadostat and matching placebo are removed from the 
study. This section has been updated accordingly.
Details on preparation and administration of IV pembrolizumab are provided in the 
Pharmacy Manual.
 
 
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Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
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.
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed 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 study 
treatments in accordance with the protocol and any applicable laws and regulations.
Treatment Compliance
Interruptions from the protocol-specified treatment plan for greater than 12 weeks from the 
last dose require consultation between the Investigator and MSD and written documentation 
of the collaborative decision on participant management. 
Administration and Compliance of Pembrolizumab
Administration of IV pembrolizumab 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. Pembrolizumab will be administered on 
an out-patient basis.
Instructions for preparing and administering pembrolizumab are provided in the Pharmacy 
Manual.
Administration and Compliance of Epacadostat or Matching Placebo
NOTE: As of Amendment 05, epacadostat and matching placebo are removed from the 
study. This section is no longer applicable and has been deleted.
 
 
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Concomitant Therapy
Acceptable Concomitant Therapies
All treatments that the investigator considers necessary for a participant’s welfare may be
administered at the discretion of the investigator in keeping with the community standards of
medical care and prohibited medications in this study. All concomitant medication will be 
recorded on the case report form (CRF) 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 will also be included on the CRF.
Palliative and supportive care is permitted during the course of the study for underlying 
medical conditions and management of symptoms. Surgery for tumor control is not permitted 
during the study. Palliative radiotherapy is permitted to a limited number of lesions if 
considered medically necessary by the treating physician as long as the lesions are NOT a
RECIST 1.1-defined target lesion. Study treatment should be held during the course of 
palliative radiotherapy and should be resumed no earlier than the next scheduled 
administration of study treatment. The specifics of the radiation treatment, including the 
location, will be recorded.
All concomitant medications received within 30 days before the first dose of study treatment
through the Safety Follow-up Visit should be recorded. After the Safety Follow-up Visit, 
record all medications taken for SAEs and ECIs as defined in Section 9.3.
Prohibited Concomitant Therapies
NOTE: As of Amendment 05, this section is updated to reflect the removal of 
epacadostat from the study and current safety information for epacadostat.
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study treatment 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 participant's primary physician. However, the decision to continue the 
participant on study treatment requires the mutual agreement of the investigator, MSD, and 
the participant.
Participants are prohibited from receiving the following therapies during the Screening and
Treatment Phases of this study:

Antineoplastic systemic chemotherapy or biological therapy not specified in this
protocol.
o
Note: denosumab is permitted.

Immunotherapy not specified in this protocol.

Investigational agents other than pembrolizumab.

Oncologic surgery for tumor control.
 
 
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
Radiation therapy for disease control.
o
Note: Radiation therapy to symptomatic lesions or to the brain may be 
allowed at the Investigator’s discretion, provided the lesions were not 
previously defined by the site as target lesions.

Live vaccines within 30 days prior to the first dose of study treatment and while
participating in the study. 
o
Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, chickenpox, yellow fever, nasal seasonal flu, nasal 
H1N1 flu, rabies, BCG, and typhoid.

Prolonged therapy with systemic glucocorticoids (>7 days) for any purpose other than 
to modulate symptoms from an AE, SAE, or ECI or for use as a pre-medication in 
participants with a known history of an IV contrast allergy administered as part of 
computed tomography (CT) radiography. Brief, limited use of systemic 
corticosteroids (≤7 days) are permitted where such use is considered SOC (eg, for 
chronic obstructive pulmonary disease [COPD] exacerbation). 
o
Replacement doses of steroids (for example, prednisone 10 mg daily) are 
permitted while on study, as is the use of local steroid injections and topical 
steroids.
Participants who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from treatment but 
continue in study for assessment of disease status and survival.
The exclusion criteria describe other medications which are prohibited in this study.
Restricted Medications
NOTE: As of Amendment 05 and removal of epacadostat from the study, this section is 
no longer applicable and has been deleted.
Rescue Medications & Supportive Care
Participants 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 in Section 7.2.1.
Systemic Corticosteroid Use
Systemic corticosteroids are permitted in the following situations:

To mediate potential immune-related AEs as guided in Table 3

As pre/post-medication to prevent AEs associated with IV contrast.
 
 
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
Brief, limited use of systemic corticosteroids (≤7 days) are permitted where such use 
is considered SOC (eg, for COPD exacerbation).
o
Replacement doses of steroids (for example, prednisone 10 mg daily) are 
permitted while on study, as is the use of local steroid injections and topical 
steroids.
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
NOTE: As of Amendment 05, epacadostat and matching placebo are removed from the 
study; thus, procedures related to emergency unblinding of these treatments are no 
longer applicable and have been deleted.
Standard Policies
At the close of the trial after unblinding, a letter is to be sent by the investigator to those 
participants who received placebos in the image of the competitor’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 Corporation.”
NOTE: As of Amendment 05, epacadostat and matching placebo are removed from the 
study; thus, procedures related to emergency unblinding of these treatments are no 
longer applicable and have been deleted.
Discontinuation/Withdrawal Criteria 
Discontinuation of Study Treatment 
NOTE: As of Amendment 05, this section has been updated. Participants will be 
discontinued from the study after completing the Safety Follow-up Visit.
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the treatment period will still continue to 
participate in the study as specified in Section 2 and Section 9.9.3.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or MSD
if study treatment is inappropriate, the trial plan is violated, or for administrative and/or other 
safety reasons.  Specific details regarding procedures to be performed at study treatment 
discontinuation are provided in Section 9.1.10.
 
 
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A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
Radiographic disease progression as assessed by the investigator per RECIST 1.1, as
outlined in Section 9.2.1 (except if MSD approves treatment continuation).
o
Unacceptable adverse experiences as described in Section 7.2.1.
o
The participant interrupts study treatment administration for more than 12 consecutive
weeks, unless approved with written documentation from MSD.
o
The participant has a medical condition or personal circumstance which, in the opinion of 
the Investigator and/or MSD, placed the participant at unnecessary risk from continued 
administration of study treatment.
o
The participant has a confirmed positive serum pregnancy test.
o
Noncompliance with study treatment or procedure requirements.
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active systemic treatment.
o
Completion of 35 treatment administrations (approximately 2 years) with 
pembrolizumab.
o
Discontinuation of treatment may be considered for participants who have attained a CR 
by local Investigator assessment and have been treated for at least 8 administrations of 
pembrolizumab and received at least 2 administrations beyond the date when the initial 
CR was declared.
For participants who are discontinued from study treatment but continue to be monitored in 
the trial, see Section 2 and Section 9.9.3 for those procedures to be completed at each 
specified visit.
Second Course Phase
NOTE: As of Amendment 05, the Second Course Phase is removed and this section is 
no longer applicable and has been deleted.
Withdrawal from the Study
NOTE: As of Amendment 05, the Follow-up Phase and Survival Follow-up have been 
removed. This section has been updated accordingly.
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study including the procedures to be performed should a participant repeatedly fail to return 
 
 
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for scheduled visits and/or if the study site is unable to contact the participant are outlined in 
Section 9.1.10.
Lost to Follow Up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
o
The site must attempt to contact the participant and reschedule the missed visit.  If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
o
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, phone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
o
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant.  The amount of missing data for the participant will be 
managed via the pre-specified data handling and analysis guidelines.
Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
Administrative and General Procedures
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical trial. If there are changes to the participant’s status during the trial (eg, health or age 
of majority requirements), the investigator or qualified designee must ensure the appropriate
consent is in place. 
 
 
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General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’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 participant before 
participation in the trial.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use.  
The participant or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’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 participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature. The participant or his/her legally acceptable representative 
will be asked to sign consent if treatment is warranted to continue as per investigator at the 
point of initial radiographic disease progression.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and MSD requirements.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study.
Participant Identification Card
All participants will be given a Participant 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 participant with a Participant Identification Card 
immediately after the participant provides written informed consent. At the time of treatment 
allocation/randomization, site personnel will add the treatment/randomization number to the 
Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Serotonin Syndrome Information Card
On Cycle 1 Day 1, participants will be given a Serotonin Syndrome (SS) information card
listing signs and symptoms of SS. This information card instructs participants to seek 
immediate medical care if any of the listed symptoms are observed.
 
 
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Medical History
A medical history will be obtained by the investigator or qualified designee.
Prior and Concomitant Medications Review
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 participant 
within 30 days before the first dose of study medication. A complete history of the 
participant’s treatment of NSCLC (if any) will be recorded separately and not listed as a prior 
medication.
Concomitant Medications
The Investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit. 
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization.  Each participant 
will be assigned only one screening number.  Screening numbers must not be re-used for 
different participants.
Any participant 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 9.9.1. 
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
NOTE: As of Amendment 05, text in this section relating to epacadostat/matching 
placebo is no longer applicable and has been deleted.
Administration of pembrolizumab will be witnessed by the investigator and/or study staff.
Study treatment should begin on the day of treatment allocation/randomization or as close as 
possible to the date on which the participant is allocated/assigned.
 
 
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Timing of Dose Administration
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 SoA (Section 2). 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 C1D1, where the window is +3 days from randomization.
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 (ie, infusion time is 30 minutes -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration.
Timing of Dose Administration of Epacadostat or Matching Placebo
NOTE: As of Amendment 05, this section is no longer applicable and has been deleted.
Withdrawal/Discontinuation
NOTE: As of Amendment 05, Survival Follow-up has been discontinued. This section 
has been updated accordingly.
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the trial, all applicable activities 
scheduled for the Discontinuation Visit should be performed at the time of withdrawal.  Any 
adverse events which are present at the time of withdrawal should be followed in accordance 
with the safety requirements outlined in Section 9.3 - Adverse Events.
Participant Blinding/Unblinding
NOTE: As of Amendment 05, the study will be unblinded and study treatment will 
continue as open-label. Text related to epacadostat/matching placebo and emergency 
unblinding in this section is no longer applicable and has been deleted.
Pembrolizumab is an open-label study treatment.
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device 
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
 
 
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Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion labs and safety assessments

Imaging equipment – as required for efficacy assessments
Efficacy Assessments 
Tumor Imaging and Assessment of Disease
NOTE: As of Amendment 05, central review of imaging (BICR) and iRECIST are no 
longer applicable. Disease assessments will be performed by the site 
investigator/radiology assessment per local standard of care. This section has been 
updated accordingly.
Tumor imaging is strongly preferred to be acquired by CT. For the abdomen and pelvis, 
contrast-enhanced magnetic resonance imaging (MRI) may be used when CT with iodinated 
contrast is contraindicated or when local practice mandates it. MRI is the strongly preferred 
modality for imaging the brain. The same imaging technique regarding modality (ideally the 
same scanner) and the use of contrast should be used in a participant throughout the study to 
optimize the reproducibility of the assessment of existing and new tumor burden and improve 
the accuracy of the assessment of response or progression based on imaging.
Participant eligibility will be determined using local assessment (Investigator assessment) 
based on RECIST 1.1.
Treatment should continue until PD has been determined by investigator-assessed disease 
progression by RECIST 1.1; no confirmatory scans are required. However, if the participant 
is achieving a clinically meaningful benefit, an exception to continue with pembrolizumab 
monotherapy may be considered following consultation with the MSD.
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 30 days prior to the date of 
randomization. The site study team must review screening images to confirm the participant 
has measurable disease per RECIST 1.1. The screening images must be submitted to the 
central imaging vendor for retrospective review.
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if it is of diagnostic quality and performed within 30 days prior to 
the date of randomization and can be assessed by the central imaging vendor.
Baseline brain imaging, while not required, should be performed per the local standard of 
care, especially if the participant was previously treated for CNS metastases. If brain imaging 
is performed to document the stability of existing metastases, MRI should be used if possible. 
If MRI is medically contraindicated, CT with contrast is an acceptable alternative.
 
 
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Tumor Imaging During the Study
NOTE: As of Amendment 05, central review of imaging (BICR) and iRECIST are no 
longer applicable. All imaging will be performed as per local standard of care 
guidelines; however, the data will not be collected. This section has been updated 
accordingly.
No on-study imaging is mandated during the treatment phase. All imaging for disease 
assessment will be performed by the site investigator/radiology assessment as per standard of 
care for the disease and local guidelines; only the date of scans performed as per standard of 
care needs to be documented in the eCRF. 
Imaging can be performed until PD is identified by the investigator, the start of new anti-
cancer treatment, withdrawal of consent for imaging, or death, whichever occurs first.
Participants who have disease progression as assessed by the investigator per RECIST 1.1
will discontinue the treatment, unless treatment beyond progression is approved by MSD.
End of Treatment and Follow-Up Imaging
NOTE: As of Amendment 05, there is no protocol-specified imaging at end of treatment 
and no follow-up imaging is required. This section is no longer applicable and has been 
deleted.
Second Course Phase Tumor Imaging
NOTE: As of Amendment 05, the Second Course Phase is eliminated. This section is no 
longer applicable and has been deleted.
RECIST 1.1 Assessment of Disease
NOTE: As of Amendment 05, central review of imaging (BICR) is no longer applicable. 
All imaging will be performed as per local standard of care guidelines; however, the 
data will not be collected. This section has been updated accordingly.
RECIST 1.1 will be applied as the primary measure for assessment of tumor response, date 
of disease progression, and as a basis for all protocol guidelines related to disease status (eg, 
discontinuation of study treatment). Although RECIST 1.1 references a maximum of 5 target 
lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions in total 
and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
iRECIST Assessment of Disease
NOTE: As of Amendment 05, iRECIST is no longer applicable and has been deleted
from this section. All imaging will be performed as per local standard of care guidelines
per RECIST 1.1. Participants with radiographic disease progression as determined by 
RECIST 1.1 by investigator assessment will discontinue from open-label 
pembrolizumab monotherapy; no confirmatory scans are required. However, if the 
participant is achieving a clinically meaningful benefit, an exception to continue with 
pembrolizumab monotherapy may be considered following consultation with the MSD.
 
 
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Adverse Events, Serious Adverse Events and Other Reportable Safety Events 
The definitions of an adverse event (AE) or serious adverse event (SAE), as well as the 
method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting AE, SAE and other reportable safety event reports can be 
found in Appendix 4.
Progression of the cancer under study is not considered an adverse event as described in 
Section 9.3.5 – Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs, and Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
Adverse events will not be collected for participants during the pre-screening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention.  If the participant requires a blood draw, fresh 
tumor biopsy etc., the participant is first required to provide consent to the main study and 
AEs will be captured according to guidelines for standard AE reporting.
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 

All AEs from the time of treatment allocation/randomization through 30 days 
following cessation of study treatment must be reported by the investigator. 
 
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
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment, or 30 days following 
cessation of study treatment if the participant initiates new anticancer therapy, 
whichever is earlier must be reported by the investigator. 

All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 
30 days following cessation of study treatment if the participant initiates new 
anticancer therapy must be reported by the investigator. 

Additionally, any SAE brought to the attention of an investigator at any time outside 
of the time period specified above must be reported immediately to the Sponsor if the 
event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify MSD.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to MSD or designee within the timeframes as indicated in Table 6. 
Table 6
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events
Type of 
Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-Specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Informatio
n to MSD:
Non-Serious 
Adverse 
Event 
(NSAE)
Report if:
- due to protocol-
specified intervention
- causes exclusion
- subject is receiving 
placebo run-in or 
other run-in treatment
Report all
Not required
Per data 
entry 
guidelines
Serious 
Adverse 
Event (SAE)
including 
Cancer and 
Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- subject is receiving 
placebo run-in or 
other run-in treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/terminati
on; report outcome
Within 24 
hours of 
learning of 
event
 
 
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Type of 
Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-Specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol 
Specified Follow-up 
Period
Timeframe 
to Report 
Event and 
Follow-up 
Informatio
n to MSD:
Event of 
Clinical 
Interest 
(require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential DILI
- Require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of 
Clinical 
Interest (Do 
not require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring regulatory 
reporting
Not required
Within 5 
calendar 
days of 
learning of 
event
Method of Detecting AE, SAE and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and non-leading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events 
including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all non-serious AEs that occur in randomized participants for 
outcome.  Further information on follow-up procedures is given in Appendix 4.
Regulatory Reporting Requirements for SAE

Prompt notification (within 24 hours) by the investigator to MSD of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants 
and the safety of a study treatment under clinical investigation are met. 

The Sponsor and MSD have a legal responsibility to notify both the local regulatory 
authority and other regulatory agencies about the safety of a study treatment under 
clinical investigation. 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.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and MSD policy and 
forwarded to investigators as necessary.
 
 
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
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from MSD will file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Efficacy endpoints as outlined in this section will not be reported to MSD as described in 
Section 9.3.1. Specifically, the suspected/actual events covered in this exception include any 
event that is disease progression of the cancer under study.
MSD will monitor unblinded aggregated efficacy endpoint events and safety data to ensure 
the safety of the participants in the study. Any suspected endpoint that upon review is not 
progression of the cancer under study will be forwarded to MSD global safety as an SAE 
within 24 hours of determination that the event is not progression of the cancer under study.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered adverse 
events, any pregnancy or infant exposure during breastfeeding in a participant (spontaneously 
reported to the investigator or their designee) that occurs during the trial are reportable to 
MSD.
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.
Events of Clinical Interest (ECI)
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to MSD.
Events of clinical interest for this trial include: 
1. an overdose of study treatment, as defined in Section 9.4 – Treatment of Overdose, 
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).
 
 
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3.  Serotonin syndrome. The signs and symptoms of serotonin syndrome are described in 
Section 7.2.3.
Treatment of Overdose
NOTE: As of Amendment 05, epacadostat is removed from the study, and text relating 
to overdose of epacadostat is no longer applicable.
In this study, an overdose is defined as any dose ≥1000 mg (5 times the dose) of
pembrolizumab or ≥1000 mg daily of epacadostat. No specific information is available on the
treatment of overdose of pembrolizumab or epacadostat. In the event of overdose, the 
participant should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated.
If an AE is associated with (“results from”) the overdose of study treatment, the AE is 
reported as an SAE, even if no other seriousness criteria are met.
If a dose of study treatment 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 ECI, using the terminology “accidental or intentional overdose without adverse 
effect.”
All reports of overdose with and without an AE must be reported by the investigator within 
24 hours to MSD either by electronic media or paper. Electronic reporting procedures can be 
found in the electronic data collection data entry guidelines. Paper reporting procedures can 
be found in the Investigator Trial File Binder (or equivalent).
Safety 
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the study (from pre-study to post-study visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Trial 
Procedures Manual.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
Full Physical Exam
The investigator or qualified designee will perform a full physical exam as per institutional 
standard during the screening period. Clinically significant abnormal findings should be 
recorded as medical history. The time points for full physical exams are described in 
Section 2. After the first dose of study treatment, new clinically significant abnormal findings 
should be recorded as AEs.
 
 
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Directed Physical Exam
For cycles that do not require a full physical exam (as specified in the SoA), the Investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to the 
administration of the study treatment. New clinically significant abnormal findings should be 
recorded as AEs.
Vital Signs
The Investigator or qualified designee will take vital signs at screening, prior to the
administration of each dose of study treatment, and during the Follow-up Period as specified 
in the SoA. Vital signs include temperature, pulse, respiratory rate, weight, and blood 
pressure. Height will be measured at screening only.
Electrocardiograms
Baseline ECGs will be obtained at screening for all participants.  Additional ECGs at EOT 
are only required if according to local standard of care or as clinically indicated. At SELECT
centers only, additional ECGs will also be obtained at C1D1 predose and approximately 2 
hours (±15 minutes) after the first dose of epacadostat, and C2D1 predose and approximately 
2 hours (±15 minutes) after administration of epacadostat. The ECG measurement should 
always be performed prior to the 
 sample blood draw if both are scheduled at the same 
nominal planned timepoint. Clinically significant abnormal findings observed prior to 
signing the ICF should be recorded as medical history. Clinically significant abnormal 
findings observed after signing the ICF 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 participant management. The decision to include or withdraw a participant 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 
Fridericia (preferred) or Bazett correction method for calculating QTc will be used and 
recorded in the electronic case report form (eCRF).
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The Investigator or qualified designee will assess ECOG status at screening (within 7 days 
prior to the first dose but before randomization), prior to the administration of each dose of 
study treatment, and during the Follow-up Period as specified in the SoA. The ECOG 
performance status scale is described in Appendix 6.
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
 
 
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underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.
●
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
●
If laboratory values from non-protocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
●
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 
treatment, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator. 
Laboratory Safety Evaluations (Hematology, Chemistry, Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2. Refer 
to the SoA for the timing of laboratory assessments.
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal (as defined in Appendix 5), must be tested for 
pregnancy within 72 hours of the first dose of study treatment. Monthly pregnancy testing 
should be conducted as per local regulations where applicable. If a urine test is positive or 
not evaluable, a serum test will be required. Participants must be excluded/discontinued from 
the study in the event of a positive or borderline-positive test result.
 
 
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Visit Requirements
Visit requirements are outlined in Section 2 – Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 – Study Assessments and 
Procedures.
Screening
Approximately 30 days prior to treatment randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Sections 6.1 and 
6.2. Screening procedures may be repeated after consultation with MSD.
Written consent must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed prior to the participant signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within approximately 30 days prior to the 
first dose of study treatment except for the following:

Laboratory tests are to be performed within 10 days prior to the first dose of study 
treatment. An exception is hepatitis testing, which may be done up to 42 days prior to 
the first dose of study treatment.

Evaluation of ECOG is to be performed within 7 days prior to the first dose of study 
treatment but before randomization.

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to the first dose of study treatment. If urine 
 
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pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required (performed by the local study site laboratory).

Archival tumor sample collection is not required to be obtained within 30 days prior 
to the first dose of study treatment. Newly obtained tumor tissue may be obtained 
within 90 days of treatment initiation.
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria are met. Participants who are rescreened will retain their original 
screening number.
NOTE: Enrollment was completed on 05-SEP-2018.
Treatment Phase
NOTE: As of Amendment 05, epacadostat and matching placebo are removed. This 
section has been updated accordingly.
Visit requirements are outlined in the SoA (Section 2). Specific procedure-related details are 
provided in Section 9.
Treatment with pembrolizumab will occur every 21 days (1 cycle) for up to 35 
administrations (approximately 2 years). The maximum duration of the treatment phase is 
specified as 35 administration of pembrolizumab (approximately 2 years). 
Discontinued Participants Continuing to be Monitored in the Study
Safety Follow-up Visit
NOTE: As of Amendment 05, the Safety Follow-up Visit will be the last visit in the 
study. This section has been amended accordingly.
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anticancer treatment, whichever 
comes first. If the participant has a Discontinuation Visit ≥30 days after the last dose of study 
treatment, the Safety Follow-up Visit is not required.
A participant will be considered to have completed this study once they have attended this 
visit. Participants currently in Follow-up or Survival Follow-up are considered to have 
completed the study; these participants are not required to attend any further visits. 
Assessment and recording of AEs will be performed as per Section 9.3.
Follow-up Visits
NOTE: As of Amendment 05, this section is no longer applicable and has been deleted. 
Participants currently in post-treatment follow-up are considered to have completed the 
study once they have attended the Safety Follow-up Visit; assessment and recording of 
AEs will be performed as per Section 9.3.
 
 
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Survival Follow-up
NOTE: As of Amendment 05, this section is no longer applicable and has been deleted.
Participants currently in Survival Follow-up are considered to have completed the 
study; these participants will no longer be contacted for survival information. 
Assessment and recording of AEs will be performed as per Section 9.3.
Survival Status
NOTE: As of Amendment 05, this section is no longer applicable and has been deleted; 
survival data is no longer being collected.
Second Course Phase
NOTE: As of Amendment 05, this section is no longer applicable and has been deleted.
Statistical Analysis Plan 
NOTE: The final analysis of the study was conducted as described below, with a data 
cutoff of 10-JAN-2019. Data from the final analysis showed the study did not meet the 
pre-specified primary endpoint of improvement in ORR for the combination of 
pembrolizumab plus epacadostat compared with pembrolizumab plus matching 
placebo. As of Amendment 05, the study will therefore stop collecting efficacy data, 
including central review of imaging. Thus, after study completion, only selected 
analyses as detailed in this section will be performed
 
This section outlines the statistical analysis strategy and procedures for the study. If changes 
are made to primary and/or key secondary hypotheses or the statistical methods related to 
those hypotheses after the study has begun, but prior to any unblinding/final database lock, 
then the protocol will be amended (consistent with ICH Guideline E9). Changes to 
 other non-confirmatory analyses made after the protocol has been finalized, 
but prior to unblinding/final database lock, will be documented in a supplemental Statistical 
Analysis Plan (sSAP) and referenced in the Clinical Study Report (CSR) for the study. 
 
 
 
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Statistical Analysis Plan Summary
Key elements of the Statistical Analysis Plan (SAP) are summarized in Table 9. The 
comprehensive plan is provided in Sections 10.2 through 10.12.
Table 9
Key Elements of the Statistical Analysis Plan
Study Design Overview
Phase 2 study of pembrolizumab + epacadostat vs pembrolizumab + placebo 
for first-line treatment of metastatic non-small cell lung cancer (NSCLC) in 
participants whose tumors express PD-L1 (TPS ≥50%)
Treatment Assignment
Approximately 148 participants will be randomized in a 1:1 ratio between 
two treatment arms: (1) pembrolizumab plus epacadostat and (2) 
pembrolizumab plus placebo.  
Stratification factor is predominant tumor histology (squamous vs non-
squamous)
Analysis Populations
Efficacy: Intention to Treat (ITT)
Safety: All Participants as Treated (APaT)
Primary Endpoints

Objective response rate (ORR) per RECIST 1.1 based on BICR
Secondary Endpoints

Progression-free survival (PFS) based on RECIST 1.1 as assessed by 
BICR.

Overall survival (OS).

Duration of response (DOR) based on RECIST 1.1 as assessed by 
BICR.

Safety and tolerability.
Statistical Methods for
Key Efficacy Analyses
The primary hypothesis will be evaluated by comparing pembrolizumab plus 
epacadostat to pembrolizumab plus placebo in ORR using the stratified 
Miettinen and Nurminen method. The difference in PFS and OS will be 
evaluated using a stratified Log-rank test. The hazard ratio will be estimated
using a stratified 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
As of Amendment 05, individual events and the broad AE categories consisting 
of the proportion of participants with any AE, a drug-related AE, a serious AE, 
an AE which is both drug-related and serious, a Grade 3-5 AE, a drug related 
Grade 3-5 AE, a fatal AE, dose interruption due to an AE and discontinuation 
due to an AE, will be summarized by counts and percentages by treatment 
group.
Multiplicity
For this Phase 2 trial, the overall Type I error rate is strictly controlled at 5% 
(one-sided) for the primary analysis of ORR.  If the primary hypothesis is 
rejected at the α=5% level (one-sided), then testing will continue to the key 
secondary hypothesis of PFS.  Nominal p-value for other endpoints will be 
reported, where applicable.
Sample Size and Power
The planned sample size is approximately 148 participants with 74 participants 
in each arm. For the ORR test, based on all patients randomized with minimum 
18 weeks of follow-up, the study has 81.7% power to detect a 20-percentage 
point difference in ORR for pembrolizumab+ epacadostat vs pembrolizumab+ 
placebo at α=5% (one-sided).
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
MSD Clinical Biostatistics department.
MSD will generate the randomized allocation schedule for study treatment assignment for 
this protocol and the randomization will be implemented in IVRS/IWRS.
 
 
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An external DMC will be convened to review accumulating safety data to provide an 
opportunity to terminate the study early if there are concerns regarding safety. Treatment-
level results of the safety analyses will be provided by the external unblinded statistician to 
the eDMC. The DMC responsibilities and review schedules will be outlined in the DMC 
charter. The recommendation of the DMC will be communicated to the Joint Executive 
Oversight Committee (EOC) and, in the event of a recommendation to halt the study early 
due to safety concerns, to the appropriate regulatory agencies. If the DMC recommends 
modifications to the design of the protocol or discontinuation of the study, the EOC and 
possibly other limited numbers of additional Sponsor/MSD personnel may be unblinded to 
results at the treatment level in order to act on these recommendations. 
Participant-level unblinding to support regulatory filing, should one occur before the end of 
the study, will be restricted to a designated Sponsor/MSD team, who will have no other 
responsibilities associated with the study. The extent to which individuals are unblinded with 
respect to the results will be documented. Additional logistical details, revisions to the above 
plan, and data monitoring guidance will be provided in the DMC Charter.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 4.0.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within- and/or between-treatment 
differences are listed below. 
Efficacy Endpoints
Primary
Objective Response Rate: The proportion of participants who have a confirmed CR or PR 
per RECIST 1.1 based on BICR.
Secondary
Progression-free Survival: The time from randomization to the first documented PD per
RECIST 1.1 based on BICR or death due to any cause, whichever occurs first. See 
Section 10.6.1 for the definition of censoring.
Overall Survival: The time from randomization to death due to any cause. 
Duration of Response: The time from first documented evidence of CR or PR until PD per 
RECIST 1.1 as assessed by BICR or death due to any cause, whichever occurs first, in 
participants who demonstrate CR or PR.
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, fatal AEs, laboratory tests, and vital signs. Furthermore, specific events will be 
collected and designated as ECIs as described in Section 9.3.7.
 
 
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Analysis Populations
Efficacy Analysis Populations
The analyses of primary efficacy endpoints are based on the intention-to-treat (ITT)
population. All randomized participants will be included in this population. Participants will 
be analyzed in the treatment group to which they are randomized. Details on the approach to 
handling missing data are provided in Section 10.6.
Safety Analysis Populations
The all participants as treated (APaT) population will be used for the analysis of safety data 
in this study. The APaT population consists of all randomized participants who received at 
least one dose of study treatment. Participants will be analyzed in the treatment group 
corresponding to the study treatment they actually received. For most participants, this will 
be the treatment group to which they are randomized. Participants who take incorrect study 
treatment for the entire treatment period will be included in the treatment group 
corresponding to the study treatment actually received. Any participant who receives the 
incorrect study medication for one cycle, but receives the correct treatment for all other 
cycles, will be analyzed according to the correct treatment group and a narrative will be 
provided for any events that occur during the cycle for which the participant is incorrectly 
dosed.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 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
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary efficacy
objectives.
 Efficacy 
results that will be deemed to be statistically significant with Type I error strictly controlled
at 5%. Nominal p-values will be computed for other efficacy analyses, but should be 
interpreted with caution due to potential issues of multiplicity.
Objective Response Rate
The stratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] will 
be used for comparison of ORR between the treatment groups. The difference in ORR and its 
95% CI from the stratified Miettinen and Nurminen method with strata weighting by sample 
size will be provided. The stratification factor (Section 7.3.1) based on tumor histology will 
be used in the analysis.
 
 
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Progression-free Survival
The non-parametric 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 (based on the stratification factors defined in Section 7.3.1). A stratified Cox proportional 
hazard model with Efron's method of tie handling will be used to assess the magnitude of the 
treatment difference (ie, the HR) between the treatment arms. The HR and its 95% CI from 
the stratified Cox model with Efron's method of tie handling and with a single treatment 
covariate will be reported. The stratification factor (Section 7.3.1) based on tumor histology
will be applied to both the stratified log-rank test and the stratified Cox model.
Since disease progression is assessed periodically, 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. For the primary analysis, for participants who have PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1 (based on BICR), regardless of discontinuation of 
study drug. Death is always considered as a confirmed PD event.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 based on BICR, two 
sensitivity analyses with a different set of censoring rules will be performed. For the first 
sensitivity analysis, participants who miss more than one disease assessment (with or without 
a subsequent death or progression) are censored at the last disease assessment prior to 
missing visits. The second sensitivity analysis handles participants who discontinue treatment 
or initiate an anticancer treatment subsequent to discontinuation of study-specified treatments 
differently from the primary analysis. The censoring rules for primary and sensitivity 
analyses are summarized in Table 10. If a participant meets multiple criteria for censoring, 
the censoring criterion that occurs earliest will be applied.
Table 10
Censoring Rules for Primary and Sensitivity Analyses of Progression-free 
Survival
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
No PD and no death; 
≥2 consecutive missed 
disease assessments
Censored at last 
disease assessment
Censored at last disease 
assessment prior to ≥2 
consecutive missed 
visits
Censored at last disease 
assessment
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
 
 
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Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death 
documented at any 
time 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
PD=progressive disease
Overall Survival
The non-parametric Kaplan-Meier method will be used to estimate the survival curves. The 
treatment difference in survival will be assessed by the stratified log-rank test (based on the 
stratification factor defined in Section 7.3.1). A stratified Cox proportional hazard model 
with Efron's method of tie handling will be used to assess the magnitude of the treatment 
difference (ie, the HR). The HR and its 95% CI from the stratified Cox model with a single 
treatment covariate will be reported. The stratification factor (Section 7.3.1) based on tumor 
histology will be applied to both the stratified log-rank test and the stratified Cox model. 
Participants without documented death at the time of analysis will be censored at the date of 
last known contact. Analysis using the Restricted Mean Survival Time method may be 
conducted for OS to account for the possible non-proportional hazards effect.
Duration of Response
For participants who demonstrate CR or PR, DOR is defined as the time from first 
documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first. Censoring rules for DOR are summarized in Table 11. DOR will be 
assessed using RECIST 1.1 by BICR.
For each DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided. Responses in participants who are alive, have not progressed, 
have not initiated new anti-cancer treatment, and have not been determined to be lost to 
follow-up are considered ongoing at the time of analysis. If a participant meets multiple 
criteria for censoring, the censoring criterion that occurs earliest will be applied.
 
 
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Table 11
Censoring Rules for Duration of Response
Situation
Date of 
Progression or Censoring
Outcome
No progression or death, new anti-
cancer treatment not initiated
Last adequate disease assessment
Censor
(non-event)
No progression or death, new anti-
cancer treatment initiated
Last adequate disease assessment 
before new anti-cancer therapy
initiated
Censor
(non-event)
Death or progression after ≥2 
consecutive missed disease 
assessments
Last adequate disease assessment 
prior to the after ≥2 missed 
adequate disease assessments
Censor
(non-event)
Death or progression after ≤1 missed 
adequate disease assessments
Progressive disease or death
End of response
(Event)
Note: A missed disease assessment includes any assessment that is not obtained or is considered inadequate for 
evaluation of response.
Statistical Methods for Key Efficacy Endpoints
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 12.
Table 12
Analysis Methods for Key Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses:
ORR (RECIST 1.1) 
by BICR
Testing and Estimation:
Stratified Miettinen and 
Nurminen method
ITT
Participants with missing data are 
considered non-responders
Secondary Analyses:
PFS (RECIST 1.1)
by BICR
Estimation: Stratified Cox model 
with Efron's tie handling method
Stratified Log-rank test
ITT
Censored according to rules in
Table 10
OS
Estimation: Stratified Cox model 
with Efron's tie handling method
Stratified Log-rank test
ITT
Censored at last known alive date
DOR (RECIST 1.1) 
by BICR
Summary statistics using 
Kaplan-Meier method
All 
responders 
in ITT 
Non-responders are excluded in 
analysis
Sensitivity analyses will be performed for PFS, ORR, and DOR based on investigator's assessment.
BICR=blinded independent central review; DOR=duration of response; ITT=intent-to-treat; ORR=objective response 
rate; OS=overall survival; PFS=progression-free survival; RECIST 1.1=Response Evaluation Criteria in Solid Tumors.
 
 
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Statistical Methods for Safety Analyses
As of Amendment 05, safety and tolerability will be assessed by clinical review of all 
relevant parameters including adverse experiences (AEs), laboratory tests, and vital signs.
Individual events and the broad AE categories consisting of the proportion of participants 
with any AE, a drug-related AE, a serious AE, an AE which is both drug-related and serious, 
a Grade 3-5 AE, a drug related Grade 3-5 AE, a fatal AE, dose interruption due to an AE and 
discontinuation due to an AE, will be summarized by counts and percentages by treatment 
group (Table 13).  
Table 13
Analysis Strategy for Safety Endpoints
Safety Endpoint
Descriptive Statistics
Any AE
X
Any Serious AE 
X
Any Grade 3-5 AE 
X
Any Drug-Related AE
X
Any Serious and Drug-Related AE
Any Grade 3-5 and Drug-Related AE
X
X
Dose Interruption due to AE
X
Discontinuation due to AE
X
Death
X
Specific AEs, SOCs 
X
Change from Baseline Results (Laboratory toxicity grade)
X
Summaries of Baseline Characteristics and Demographics
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 participants randomized and the primary 
reason for discontinuation will be displayed. Demographic variables (such as age) and 
baseline characteristics will be summarized by treatment either by descriptive statistics or 
categorical tables. The reasons for exclusion from the ITT population (if any) will be 
summarized.
Interim Analyses
Safety Interim Analyses
The eDMC will conduct regular safety monitoring. The timing of the first safety monitoring 
will be specified in the DMC charter. As of Amendment 05, no additional eDMCs will take 
place.
 
 
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Efficacy Interim Analyses
No efficacy interim analysis is planned for this study. The study will be unblinded at the 
database lock for the primary analysis for ORR.
Multiplicity
The overall Type I error rate is strictly controlled at 5% (one-sided) by fixed sequence, a 
closed-testing procedure. The closed testing procedure will be applied to the primary 
hypothesis of ORR first.  If the primary hypothesis is rejected at the α=5% level (one-sided), 
then testing will continue to the key secondary hypothesis of PFS.   Nominal p-value for each 
endpoint will be reported, where applicable, regardless of the outcome of the closed testing 
procedure dictated by the multiplicity strategy.
Sample Size and Power Calculations
Sample Size and Power for Efficacy Analyses
The study will randomize 148 participants in a 1:1 ratio into the pembrolizumab plus
epacadostat and pembrolizumab plus placebo arms. ORR is a primary endpoint for the study 
and PFS and OS are secondary endpoints. 
Figure 3 summarizes power calculations for the primary hypothesis under various ORR 
difference assumptions.
 
 
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Figure 3
Power for Primary Hypothesis under Different Effect Size Assumptions
Based on the 148 participants in the control arm and the treatment arm under comparison, the 
power of the ORR testing at the α=0.05 (one-sided) is approximately 81.7% to detect a 
difference of 20 percentage points in ORR between an underlying 50% response rate in the 
control arm and a 70% response rate in the experimental arm.
With 95 PFS events, the study will have 80% power to detect a hazard ratio of 0.6 at an alpha 
level of 5% (1-sided).
The sample size and power calculations were performed in R (package “gsDesign”).
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
between-group treatment effect for OS, PFS, and ORR (with a nominal 95% CI) will be 
estimated and plotted by treatment group within each category of the following classification 
variables:

Stratification factor
o
Predominant tumor histology (squamous vs non-squamous)

Geographic region (East Asia vs non-East Asia)

ECOG performance status (0 vs 1)
 
 
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
Age category (<65, ≥65 years)

Sex (female, male)

Race (white, non-white)

Smoking status (never vs former/current smoker)

Brain metastasis (presence vs absence) 
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
Extent of Exposure
Extent of exposure for a participant is defined as number of cycles in which the participant
receives the study medication. Summary statistics will be provided on extent of exposure for 
the APaT population.
References
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Meeting of the American Society of Clinical 
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2006 Dec 4;95(11):1555-61.
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Mellor AL, Baban B, Chandler P, Marshall B, 
Jhaver K, Hansen A, et al. Cutting edge: 
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Sutanto-Ward E, Prendergast GC. Inhibition 
of indoleamine 2,3-dioxygenase, an 
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chemotherapy. Nat Med. 2005 Mar;11(3):312-
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049PWD
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Munn DH, Zhou M, Attwood JT, Bondarev I, 
Conway SJ, Marshall B, et al. Prevention of 
allogeneic fetal rejection by tryptophan 
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049PWF
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Nakamura T, Shima T, Saeki A, Hidaka T, 
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of indoleamine 2, 3-dioxygenase and the 
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Okamoto A, Nikaido T, Ochiai K, Takakura S, 
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Appendices
Appendix 1: Abbreviations and Trademarks
Abbreviation
Definition
1L
first-line (therapy)
AE
adverse event
AEOSI
adverse events of special interest
ALK
anaplastic lymphoma kinase
ALT
alanine aminotransferase
APaT
all participants as treated (population)
AST
aspartate aminotransferase
BCG
Bacillus Calmette-Guérin
BICR
blinded independent central review
BID
twice daily
C1D1
Cycle 1 Day 1
C2D1
Cycle 2 Day 1
CI
confidence interval
CNS
central nervous system
COPD
chronic obstructive pulmonary disease
CR
complete response
CRF
case report form
CSR
Clinical Study Report
CT
computed tomography
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DCR
disease control rate
DMC
Data Monitoring Committee
DOR
duration of response
ECG 
electrocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EGFR
epidermal growth factor receptor
 
 
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Abbreviation
Definition
EMA
European Medicines Agency
EOC
Executive Oversight Committee
EOT
end of treatment
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
GCP
Good Clinical Practice
HBsAG
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormonal replacement therapy
IA1
interim analysis 1
ICF
informed consent form
iCPD
iRECIST confirmed progressive disease
iCR
iRECIST complete response
IDO1
indoleamine 2,3 dioxygenase-1
IEC
Independent Ethics Committee
Ig
immunoglobulin
IHC
immunohistochemistry
INR
international normalized ratio
iPR
iRECIST partial response
irAE
immune-related adverse event
IRB
Institutional review board
iRECIST
modified RECIST for immune-based therapeutics
 
 
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Abbreviation
Definition
iSD
iRECIST stable disease
ITT
intent to treat
iUPD
iRECIST unconfirmed progressive disease
IV
Intravenous
IVRS/IWRS
interactive voice response system/ integrated web response system
mAb
monoclonal antibody
MAOI
monoamine oxidase inhibitor
MRI
magnetic resonance imaging
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PFS
progression-free survival
PK
pharmacokinetic
PR
partial response
Q12H
every 12 hours
Q2W
every 2 weeks
Q3W
every 3 weeks
QoL
Quality of Life 
QTc
corrected QT interval
RECIST
Response Evaluation Criteria in Solid Tumors 1.1
RR
response rate
 
 
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Abbreviation
Definition
SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
stable disease
SNRI
serotonin-norepinephrine reuptake inhibitor
SoA
Schedule of Activities
SOC
standard of care
SS
serotonin syndrome
sSAP
supplemental Statistical Analysis Plan
SSRI
selective serotonin reuptake inhibitor
TB
tuberculosis
TDLN
tumor draining lymph nodes
TPS
tumor proportion score
T-reg
regulatory T-cell
WOCBP
woman of child bearing potential
 
 
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Appendix 2: Clinical Laboratory Tests 

The tests detailed in Table 14 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 14
Protocol-Required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
%Reticulocytes
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
PT or INR
aPTT or PTTa
Chemistry
Blood Urea Nitrogen 
(BUN) or urea (one 
or the other should be 
collected per 
institutional standard; 
both tests are not 
required)
Potassium
Aspartate 
Aminotransferase
(AST)/ Serum 
Glutamic-
Oxaloacetic 
Transaminase 
(SGOT)
Total bilirubin (and 
direct bilirubin, if 
total bilirubin is 
elevated above the 
upper limit of 
normal)
Albumin
A measure of 
carbon dioxide 
(CO2 or 
bicarbonate)b
Chloride
Phosphorous
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Total Protein
Glucose [Indicate if 
fasting, or 
nonfasting]
Calcium
Alkaline 
phosphatase
Amylase
Lipase
Routine 
Urinalysis

Specific gravity

Glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)

Pregnancy test, as needed for woman of childbearing potential (WOCBP) within 
72hrs before first dose
 
 
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Laboratory 
Assessments
Parameters
Other Tests
(performed 
locally unless 
not feasible to 
perform at the 
site)

Thyroid panel: TSH, FT4, FT3/T3

Follicle-stimulating hormone (as needed in woman of non-childbearing potential 
only)

Serum β human chorionic gonadotropin (β-hCG) pregnancy test (as needed for 
WOCBP)

Serology: 
o
Hepatitis B surface antigen, HBV-DNA
o
HCV-RNA, HCV antibody (if HCV-RNA is not the local standard of care)
o
HIV-RNA (if required by local regulations)
Abbreviations: ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = 
aspartate aminotransferase; BUN = blood urea nitrogen; DNA = deoxyribonucleic acid; FT4 = free 
thyroxine; HCV = Hepatitis C Virus; INR = international normalized ratio; MCH = mean corpuscular 
hemoglobin; MCV = mean corpuscular volume; PT = prothrombin time; PTT = partial thromboplastin time; 
RNA = ribonucleic acid; RBC = red blood cells; SGOT = serum glutamic oxaloacetic transaminase; SGPT = 
serum glutamic-pyruvic transaminase; SoC = Standard of Care; T3 = triiodothyronine; TSH = thyroid 
stimulating hormone (thyrotropin); WBC = white blood cells.
Notes:
a. PTT may be performed if the local lab is unable to perform aPTT.
b. If available as SoC in your region. The carbon dioxide may be either a measurement of CO2 or 
bicarbonate as an electrolyte.
Investigators must document their review of each laboratory safety report.
 
 
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Appendix 3: Study Governance Considerations
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participant 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 (eg, 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 
participant preferences, etc.  
The design (ie, participant population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research participants 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 participants, adequacy of 
facilities and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial 
initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Participant Protection
A. IRB/IEC review
All clinical trials will be reviewed and approved by an independent IRB/IEC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/IEC prior to implementation, except that 
changes required urgently to protect participant safety and well-being may be enacted in anticipation of IRB/IEC 
approval. For each site, the IRB/IEC and Merck will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance.  
Potential participants 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.  Participants are never denied access to 
appropriate medical care based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Participants are enrolled only after providing informed consent 
for participation.  Participants 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 participant 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 participant 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 participants 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 participant referrals.  However, Merck may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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/IEC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (eg, 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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Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is MSD’s
responsibility to determine, based on these regulations, whether a request for Financial 
Disclosure information is required.  It is the investigator's/subinvestigator's responsibility to 
comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by MSD in accordance with 21 CFR 
Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor or 
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 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
MSD. The investigator/subinvestigator(s) also consent to the transmission of this information 
to the Sponsor and MSD in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by MSD. Any participant records or datasets 
that are transferred to MSD will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor and MSD in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by MSD, by appropriate 
IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
By signing this protocol, the investigator affirms to MSD that information furnished to the 
investigator by MSD will be maintained in confidence, and such information will be divulged 
to the institutional review board, ethics review committee (IRB/IEC) 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 Participant Records
By signing this protocol, the investigator agrees that the Sponsor, MSD (or Sponsor or MSD
representative), IRB/IEC, 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 participant agrees to this process.  If trial documents will be photocopied during the 
process of verifying worksheet/case report form information, the participant will be identified 
by unique code only; full names/initials will be masked prior to transmission to MSD.
 
 
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this trial in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
MSD will record the name and address of each IRB/IEC that reviews and approves this trial.  
MSD will 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.
Committees Structure
Joint Executive Oversight Committee
The Joint 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
To supplement the routine trial monitoring outlined in this protocol, an external Data 
Monitoring Committee (DMC) will monitor the safety data from this trial.  The voting 
members of the committee are external to the Sponsor and MSD.  The members of the DMC 
must not be involved with the trial in any other way (eg, 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 participant 
safety and the continued ethical integrity of the trial.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor and MSD; meeting facilitation; 
the trial governance structure; and requirements for and proper documentation of DMC 
reports, minutes, and recommendations will be described in the DMC charter that is reviewed 
and approved by all the DMC members.
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor
and MSD will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor and MSD will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In this 
case, a coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor or MSD, the investigator agrees to 
submit all manuscripts or abstracts to the Sponsor and MSD before submission.  This allows 
the Sponsor and MSD to protect proprietary information and to provide comments.  
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
 
 
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Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are 
participant to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  The Sponsor will review this protocol 
and submit the information necessary to fulfill these requirements. Entries are not limited to 
FDAAA or the EMA clinical trial directive mandated trials.  Information posted will allow 
participants 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 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (eg, 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 sponsored or executed by MSD, is provided in 
this appendix under the Merck Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the trial 
reimbursed to the investigator by MSD.
The investigator will promptly inform MSD of any regulatory authority inspection conducted 
for this trial.
The Investigator agrees to provide MSD with relevant information from inspection 
observations/findings to allow MSD to assist in responding to any citations resulting from 
regulatory authority inspection, and will provide MSD with a copy of the proposed response 
for consultation before submission to the regulatory authority. 
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 study. 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.
 
 
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Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to MSD or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Trial documentation will be promptly and fully disclosed to MSD 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 MSD or any regulatory authorities.  
The investigator agrees to promptly take any reasonable steps that are requested by MSD or 
any regulatory authorities as a result of an audit or inspection to cure deficiencies in the trial 
documentation and worksheets/case report forms.
MSD or designee is responsible for the data management of this study, including quality 
checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of MSD. No records may be transferred to 
another location or party without written notification to MSD. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
 
 
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Study and Site Closure
MSD, in collaboration with the Sponsor, may stop the study or study site participation in the 
study for medical, safety, regulatory, administrative, or other reasons consistent with 
applicable laws, regulations, and GCP. 
In the event MSD prematurely terminates a particular trial site, MSD will promptly notify 
that trial site’s IRB/IEC.
 
 
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE Definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment includes any pharmaceutical 
product, biological product, vaccine, device, diagnostic agent or protocol specified 
procedure whether investigational (including placebo or active comparator product) 
or marketed, manufactured by, licensed by, provided by or distributed by the Sponsor
or MSD for human use in this study.
Events Meeting the AE Definition 
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in 
the medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even 
though it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated 
adverse event, the AE term should reflect the clinical symptoms or abnormal test 
result.  An overdose without any associated clinical symptoms or abnormal laboratory 
results is reported using the terminology “accidental or intentional overdose without 
adverse effect.”
●
Any new cancer (that is not a condition of the study). 
Note: Progression of the cancer under study is not a reportable event. Refer to 
Section 9.3.5 for additional details.
 
 
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Events NOT Meeting the AE Definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has 
not worsened.
●
Refer to Section 9.3.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing 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 an MSD product and is documented in the patient’s 
medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
 
 
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e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize 
the participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered 
serious.
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events reported in the same manner as SAE
Additional Events which require reporting in the same manner as SAE
●
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);
●
Is associated with an overdose.
Recording AE and SAE
AE and SAE Recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) 
related to the event.
●
The investigator will record all relevant AE/SAE information on the Adverse Event 
case report forms/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to MSD in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are 
requested by MSD. In this case, all participant identifiers, with the exception of the 
participant number, will be blinded on the copies of the medical records before 
submission to MSD.
 
 
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●
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and 
other reportable safety event) according to the NCI Common Terminology for 
Adverse Events (CTCAE), version 4. 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.
●
Grade 1: Mild; asymptomatic or mid symptoms; clinical or diagnostic 
observations only; intervention not indicated.
●
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
●
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation or hospitalization indicated; disabling; limiting 
self-care ADL.
●
Grade 4: Life threatening consequences; urgent intervention indicated.
●
Grade 5: Death related to AE.
Assessment of Causality
●
Did the study treatment cause the adverse event?
●
The determination of the likelihood that the study treatment 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 product and the adverse event based upon the available 
information
●
The following components are to be used to assess the relationship between 
the study treatment and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the 
study treatment caused the adverse event:
●
Exposure:  Is there evidence that the participant was actually exposed to the 
study treatment such as:  reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
 
 
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●
Time Course:  Did the AE follow in a reasonable temporal sequence from 
administration of the study treatment? 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
●
Dechallenge: Was the study treatment discontinued or 
dose/exposure/frequency reduced?
●
If yes, did the AE resolve or improve?
●
If yes, this is a positive dechallenge. 
●
If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of 
the study treatment; (3) the trial is a single-dose drug trial); or (4) study 
treatment(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the study treatment in this 
trial?
●
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) study 
treatment(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE STUDY 
TREATMENT, OR IF RE-EXPOSURE TO THE STUDY TREATMENT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN 
THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE MSD
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
study treatment 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.
 
 
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●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study treatment relationship).
●
Yes, there is a reasonable possibility study treatment relationship:
There is evidence of exposure to the study treatment.  The temporal sequence of 
the AE onset relative to the administration of the study treatment is reasonable.  
The AE is more likely explained by the study treatment than by another cause. 
●
No, there is not a reasonable possibility of study treatment relationship:
Participant did not receive the study treatment OR temporal sequence of the AE 
onset relative to administration of the study treatment is not reasonable OR the 
AE is more likely explained by another cause than the study treatment.  (Also 
entered for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to MSD. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to MSD.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
●
For studies in which multiple agents are administered as part of a combination 
regimen, the investigator may attribute each adverse event causality to the 
combination regimen or to a single agent of the combination.  In general, causality 
attribution should be assigned to the combination regimen (i.e., to all agents in the 
regimen). However, causality attribution may be assigned to a single agent if in the 
investigator’s opinion, there is sufficient data to support full attribution of the adverse 
event to the single agent.
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by MSD to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, 
or consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to MSD within 24 hours of receipt 
of the information.
 
 
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Reporting of AE, SAE, and Other Reportable Safety Events to MSD
AE, SAE, and Other Reportable Safety Event Reporting to MSD via Electronic 
Data Collection Tool
●
The primary mechanism for reporting to MSD will be the electronic data collection 
(EDC) tool.  
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.  
●
Reference section 9.3.1 – Time Period and Frequency for Collecting AE and 
SAE and Other Reportable Safety Event Information for reporting time 
requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
●
After the study is completed at a given site, the electronic data collection tool will be 
taken off-line to prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form or by 
telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
SAE Reporting to MSD via Paper CRF
●
If the electronic data collection tool is not operational, facsimile transmission or 
secure e-mail of the SAE paper CRF is the preferred method to transmit this 
information to MSD.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
 
 
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Appendix 5: Contraceptive Guidance and Pregnancy Testing
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
Contraception Requirements
Male Participants:
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in section 6.1: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent
●
Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in Table 15 when having penile-vaginal intercourse with a woman 
of childbearing potential who is not currently pregnant.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
 
 
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Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 15
during the protocol-defined time frame in Section 6.1. 
Table 15
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraception b, c
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b, c
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen- only contraceptive implant b, c
●
Intrauterine hormone-releasing system (IUS) b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.) 
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for participants of 
clinical studies. 
a) Typical use failure rates are higher than perfect-use failure rates (i.e. when used consistently and correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at least 
120 days after the last dose of study treatment.
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
hormonal contraceptives are limited to those which inhibit ovulation. 
 
 
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test within 72 hours of the first dose. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required. Monthly pregnancy testing should be 
conducted as per local regulations where applicable.
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected and as required locally.
  
 
 
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Appendix 6: Eastern Cooperative Oncology Group (ECOG) Performance Status
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, eg, light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited selfcare; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any selfcare; totally confined to bed or 
chair
5
Dead
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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Signature Manifest
Document Number: IC-DEV-PROT-AMEND-0456
Revision: 0
Title: INCB 24360-305 Protocol Amendment 5 (3475-654-05, ECHO-305)
All dates and times are in Eastern Standard Time.
Quick Approval
Approve Now
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Title
Date
Meaning/Reason
 
04 Mar 2019, 11:31:44 AM
Approved