Adjuvant Therapy With Pembrolizumab Versus Placebo in Resected High-risk Stage II Melanoma: A Randomized, Double-blind Phase 3 Study (KEYNOTE-716)
Phase: PHASE3
Conditions: Melanoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
Adjuvant Therapy with Pembrolizumab versus Placebo in Resected 
Highrisk Stage II Melanoma: A Randomized, Double-blind Phase 3 
Study (KEYNOTE 716)
11-May-2021
NCT03553836

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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., NJ, U.S.A.
(MSD).
Protocol Title: Adjuvant Therapy with Pembrolizumab versus Placebo in Resected High-
risk Stage II Melanoma: A Randomized, Double-blind Phase 3 Study (KEYNOTE 716)
Protocol Number: 716-04
Compound Number: MK-3475
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or MSD)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND NUMBER:   110,080
EudraCT NUMBER: 2018-000669-35
Approval Date:  11 May 2021
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical study 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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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 4
11-MAY-2021
Alignment with the USPI requirement for Pembrolizumab Dose Modifications
Amendment 3
28-SEP-2020
Clarify imaging schedule
Amendment 2
Country Specific
05-AUG-2019
Alignment with UK-specific Requirements
Amendment 1
18-MAR-2019
Conformation with FDA and other country-specific requirements
Original Protocol
17-MAY-2018
N/A
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 04
Overall Rationale for the Amendment:
Alignment with the USPI requirement for Pembrolizumab Dose Modifications
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
6.6 Immune-related Events 
and Dose Modification 
(Escalation/Titration/Other)
Updated 6.6 header. Deleted 6.6.1 
header. 
The Dose Modification and Toxicity 
Management Guidelines for irAEs and 
table were updated
The Dose Modification and Toxicity Management 
Guidelines for irAEs and table were updated to align with 
the USPI as requested by the FDA
1.1 Synopsis
4.1 Overall Design
Removed "when clinically appropriate"
Compliance with FDA request
Removed “by telephone”
Clarification of information
1.3.1 Part 1 Adjuvant 
Treatment: Pembrolizumab 
or Placebo
1.3.2 Part 1 
Crossover/Rechallenge After 
First Recurrence 8.3.1.2 
Directed Physical Exam
Added language related to inspection of 
local recurrence and palpation of 
regional lymph nodes
Clarification of Directed Physical Examination
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Section # and Name
Description of Change
Brief Rationale
4.1 Overall Design
Removed “initiating a nonstudy cancer 
treatment,"
Removed language related to the 
development of second primary 
malignancies
The efficacy assessment is based on ITT follow-up 
regardless of initiation of nonstudy cancer treatment or 
secondary primary malignancies
4.2.1.1.1 Primary Efficacy 
Endpoint
Provided reference to Appendix 12 
Guidance for Distinguishing Primary 
Cutaneous Melanomas From Cutaneous 
Metastases of Melanoma
Additional guidance for pathologist as requested by the 
FDA
4.3 Justification for Dose
PK data was summarized and a 
reference to the IB was added
Deleted reference to tumor types
Update of information
6.5.1 Specific Restrictions
Updated vaccine language
Clarification of vaccines allowed
8.2.1 Tumor Scans and 
Assessment of Disease
8.2.1.1 Initial Tumor Scans
8.2.1.2 Tumor Scans During 
the Study
8.2.1.3 End of Treatment and 
Follow-up Tumor Scans
8.2.1.4 Summary of Scans
References to images/imaging changed 
to “scan” as appropriate
Clarification of language / information.
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Section # and Name
Description of Change
Brief Rationale
8.2.1.4.1 Part 1 Adjuvant 
Treatment
8.2.1.4.2 Part 2 
Crossover/Rechallenge After 
First Recurrence
References to images/imaging changed 
to “scan” as appropriate
Clarification of language / information.
8.3 Safety Assessment
Added reference to Procedures Manual 
Text added for clarity
8.4.1 Time Period and 
Frequency for Collecting 
AE, SAE, and Other 
Reportable Safety Event 
Information
Added more language to 
pregnancy/lactation instructions to 
Table 7
Clarification of information regarding how to handle 
pregnancy/lactation exposure
8.11.3.1 Safety Follow-up 
Visit
8.11.3.2 Efficacy Follow-up 
Visits
8.11.3.3 Distant Metastases-
free Survival Follow-up
8.11.3.4 Survival Follow-up 
Contacts
8.11.4 Vital Status
Updated language to clarify visit 
information
Clarification of information
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Section # and Name
Description of Change
Brief Rationale
10.9 Appendix 9: 
Description of the iRECIST 
Process for Assessment of 
Disease Progression 
Paragraph added to align with lack of 
clinical stability used in RECIST 1.1
Alignment with FDA requirement
10.12 Appendix 12: 
Guidance for Distinguishing 
Primary Cutaneous 
Melanomas from Cutaneous 
Metastases of Melanoma
Added new appendix
Provide guidance for distinguishing primary cutaneous 
melanomas from cutaneous metastases of melanoma
Minor grammatical and typographical changes have been made throughout the document
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1.
Protocol Summary .....................................................................................................18
Synopsis....................................................................................................................18
Schema .....................................................................................................................21
Study Design........................................................................................................21
Study Flow Schema .............................................................................................22
Schedule of Activities (SoA) ...................................................................................23
Part 1 Adjuvant Treatment: Pembrolizumab or Placebo .....................................23
Part 2 Crossover/Rechallenge After First Recurrence.........................................34
Imaging Schedule.................................................................................................49
2.
Introduction................................................................................................................50
Study Rationale .......................................................................................................50
Background..............................................................................................................51
Pharmaceutical and Therapeutic Background .....................................................51
Preclinical and Clinical Studies ...........................................................................52
Ongoing Clinical Studies .....................................................................................53
Benefit/Risk Assessment.........................................................................................53
3.
Objectives/Hypotheses and Endpoints.....................................................................54
4.
Study Design...............................................................................................................55
Overall Design .........................................................................................................55
Scientific Rationale for Study Design....................................................................58
Rationale for Endpoints .......................................................................................58
Efficacy Endpoints........................................................................................58
Primary Efficacy Endpoint ....................................................................58
Secondary Efficacy Endpoints...............................................................59
Safety Endpoints...........................................................................................59
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Exploratory Endpoints ..................................................................................59
Rationale for Patient-reported Outcomes ..............................................59
EORTC QLQ-C30 .................................................................................59
EQ-5D-5L ..............................................................................................59
Pharmacokinetic Endpoints ..........................................................................60
Planned Exploratory Biomarker Research....................................................60
Future Biomedical Research.........................................................................62
Rationale for the Use of Comparator/Placebo .....................................................62
Justification for Dose ..............................................................................................62
Beginning and End of Study Definition ................................................................64
Clinical Criteria for Early Study Termination .....................................................64
5.
Study Population........................................................................................................64
Inclusion Criteria....................................................................................................64
Exclusion Criteria ...................................................................................................68
Lifestyle Considerations .........................................................................................70
Meals and Dietary Restrictions............................................................................70
Caffeine, Alcohol, and Tobacco Restrictions ......................................................70
Activity Restrictions ............................................................................................70
Pregnancy.............................................................................................................70
Screen Failures ........................................................................................................71
Participant Replacement Strategy.........................................................................71
6.
Treatments..................................................................................................................71
Treatments Administered.......................................................................................71
Preparation/Handling/Storage/Accountability ....................................................73
Dose Preparation..................................................................................................73
Handling, Storage and Accountability.................................................................73
Measures to Minimize Bias: Randomization and Blinding.................................73
Method of Treatment Assignment .......................................................................73
Stratification..................................................................................................74
Blinding................................................................................................................74
Treatment Compliance...........................................................................................74
Concomitant Therapy.............................................................................................75
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Specific Restrictions ............................................................................................75
Rescue Medications and Supportive Care ...........................................................76
Immune-related Events and Dose Modification (Withhold, Treat, 
Discontinue).............................................................................................................76
Part 2 – Crossover or Rechallenge Treatment After Recurrence ......................82
Treatment After the End of the Study ..................................................................84
Clinical Supplies Disclosure...................................................................................84
Standard Policies.....................................................................................................85
7.
Discontinuation of Study Treatment and Participant Withdrawal ......................85
Discontinuation of Study Treatment.....................................................................85
Participant Withdrawal From the Study..............................................................87
Lost to Follow-up ....................................................................................................87
8.
Study Assessments and Procedures..........................................................................88
Administrative and General Procedures ..............................................................88
Informed Consent/Assent.....................................................................................88
General Informed Consent............................................................................89
Consent/Assent and Collection of Specimens for Future 
Biomedical Research ....................................................................................89
Inclusion/Exclusion Criteria ................................................................................89
Participant Identification Card.............................................................................89
Medical History ...................................................................................................90
Prior and Concomitant Medications Review .......................................................90
Prior Medications..........................................................................................90
Concomitant Medications.............................................................................90
Assignment of Screening Number.......................................................................90
Assignment of Treatment/Randomization Number.............................................90
Treatment Administration....................................................................................91
Timing of Dose Administration....................................................................91
Part 2 Crossover/Rechallenge Therapy................................................................91
Discontinuation and Withdrawal .........................................................................91
Withdrawal From Future Biomedical Research ...........................................91
Participant Blinding/Unblinding..........................................................................92
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Calibration of Equipment.....................................................................................93
Participants Turning 18 Years of Age While on Study .......................................93
Efficacy Assessments...............................................................................................93
Tumor Scans and Assessment of Disease............................................................93
Initial Tumor Scans.......................................................................................94
Tumor Scans During the Study.....................................................................94
End of Treatment and Follow-up Tumor Scans............................................95
Summary of Scans ........................................................................................96
Part 1 Adjuvant Treatment.....................................................................96
Part 2 Crossover/Rechallenge After First Recurrence...........................97
RECIST 1.1 Assessment of Disease.............................................................98
iRECIST Assessment of Disease..................................................................99
Lactic Acid Dehydrogenase...............................................................................101
Quality of Life Assessments ..............................................................................101
Patient-reported Outcomes..........................................................................101
Safety Assessments................................................................................................102
Physical Examinations.......................................................................................102
Full Physical Exam .....................................................................................102
Directed Physical Exam..............................................................................102
Vital Signs..........................................................................................................102
Electrocardiograms ............................................................................................103
Clinical Safety Laboratory Assessments............................................................103
Pregnancy Test...................................................................................................104
Performance Assessments..................................................................................104
ECOG Performance Status .........................................................................104
Karnofsky Performance Scale.....................................................................104
Lansky Play-Performance Scale .................................................................104
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events .....................................................................................105
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ................................................................105
Method of Detecting AEs, SAEs, and Other Reportable Safety Events............107
Follow-up of AE, SAE and Other Reportable Safety Event Information..........107
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Regulatory Reporting Requirements for SAE ...................................................107
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs................................................................................108
Pregnancy and Exposure During Breastfeeding ................................................108
Events of Clinical Interest (ECIs)......................................................................108
Treatment of Overdose.........................................................................................109
Pharmacokinetics..................................................................................................109
Blood Collection for Serum MK-3475 ..............................................................109
Pharmacodynamics...............................................................................................109
Biomarkers ............................................................................................................109
Future Biomedical Research Sample Collection................................................110
Medical Resource Utilization and Health Economics........................................110
Visit Requirements................................................................................................111
Screening............................................................................................................111
Treatment Period................................................................................................111
Discontinued Participants Continuing to be Monitored in the Study ................111
Safety Follow-up Visit................................................................................111
Efficacy Follow-up Visits...........................................................................111
Distant Metastases-free Survival Follow-up...............................................111
Survival Follow-up Contacts ......................................................................112
Vital Status.........................................................................................................113
Post-study...........................................................................................................113
9.
Statistical Analysis Plan ..........................................................................................113
Statistical Analysis Plan Summary......................................................................114
Responsibility for Analyses/In-house Blinding...................................................116
Hypotheses/Estimation .........................................................................................116
Analysis Endpoints................................................................................................116
Efficacy Endpoints.............................................................................................116
Primary Efficacy Endpoint .........................................................................116
Secondary Efficacy Endpoints....................................................................116
Exploratory Endpoints ................................................................................117
Safety Endpoints ................................................................................................117
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PRO Endpoints...................................................................................................117
Analysis Populations.............................................................................................117
Efficacy Analysis Population.............................................................................117
Safety Analysis Population................................................................................118
PRO Analysis Population ..................................................................................118
Statistical Methods................................................................................................118
Statistical Methods for Efficacy Analyses.........................................................118
Recurrence-free Survival (RFS) .................................................................118
Distant Metastases-free Survival ................................................................120
Overall Survival..........................................................................................120
Summary of Statistical Methods for Efficacy.............................................121
Statistical Methods for Safety Analyses ............................................................121
Summaries of Demographic and Baseline Characteristics ................................123
Interim Analyses ...................................................................................................123
Safety Interim Analyses.....................................................................................123
Efficacy Interim Analyses..................................................................................123
Multiplicity ............................................................................................................124
Recurrence-free Survival ...................................................................................125
Distant Metastases-free Survival .......................................................................126
Overall Survival.................................................................................................127
Safety Analyses..................................................................................................128
Sample Size and Power Calculations ..................................................................128
Recurrence-free Survival ...................................................................................128
Distant Metastases-free Survival .......................................................................129
Overall Survival.................................................................................................129
Subgroup Analyses................................................................................................129
Compliance (Medication Adherence)..................................................................130
Extent of Exposure................................................................................................130
10.
Supporting Documentation and Operational Considerations.............................131
Appendix 1:  Regulatory, Ethical and Study Oversight Considerations .........131
Code of Conduct for Clinical Trials...................................................................131
Financial Disclosure...........................................................................................133
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Data Protection...................................................................................................133
Confidentiality of Data ...............................................................................133
Confidentiality of Participant Records........................................................133
Confidentiality of IRB/IEC Information.....................................................134
Committees Structure.........................................................................................134
Scientific Advisory Committee...................................................................134
Executive Oversight Committee.................................................................134
Data Monitoring Committee.......................................................................134
Publication Policy ..............................................................................................135
Compliance with Study Registration and Results Posting Requirements .........135
Compliance with Law, Audit, and Debarment ..................................................135
Data Quality Assurance .....................................................................................136
Source Documents .............................................................................................137
Study and Site Closure................................................................................137
Appendix 2:  Collection and Management of Specimens for Future 
Biomedical Research.............................................................................................138
Appendix 3:  Contraceptive Guidance and Pregnancy Testing........................142
Definitions..........................................................................................................142
Contraception Requirements..............................................................................142
Pregnancy Testing..............................................................................................144
Appendix 4: Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................145
Definition of AE ................................................................................................145
Definition of SAE ..............................................................................................146
Additional Events Reported in the Same Manner as SAE.................................147
Recording AE and SAE .....................................................................................147
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ..............................................................................................................151
Appendix 5:  Clinical Laboratory Tests..............................................................152
Appendix 6:  Country-specific Requirements ....................................................153
Germany-specific Requirements:.......................................................................153
Japan-specific Requirements: ............................................................................153
France-specific Requirements............................................................................153
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Italy-specific Requirements ...............................................................................154
Appendix 7:  Abbreviations .................................................................................155
Appendix 8: Performance Status Scales .............................................................159
ECOG Performance Scale..................................................................................159
Karnofsky Performance Scale............................................................................160
Lansky Play-Performance Scale ........................................................................161
Appendix 9: Description of the iRECIST Process for Assessment of 
Disease Progression...............................................................................................162
Appendix 10: Surgical Considerations................................................................167
Appendix 11: AJCC 8th Edition Guidelines........................................................169
Appendix 12:  Guidance for Distinguishing Primary Cutaneous 
Melanomas From Cutaneous Metastases of Melanoma....................................173
11.
References.................................................................................................................174
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values......................................................67
Table 2
Study Treatments..................................................................................................72
Table 3
Melanoma Stage Stratification Table ...................................................................74
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ....................................................................77
Table 5
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines.............................................................................................................81
Table 6
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease................................................................................................................100
Table 7
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events..........................................................................106
Table 8
Censoring Rules for Primary and Sensitivity Analyses of RFS .........................119
Table 9
Analysis Strategy for Key Efficacy Endpoints...................................................121
Table 10
Analysis Strategy for Safety Parameters ............................................................122
Table 11
Analyses Planned, Endpoints Evaluated, and Drivers of Timing.......................124
Table 12
Boundary Properties for Planned Analyses of the RFS Analyses Based 
on α = 0.025........................................................................................................126
Table 13
Efficacy Boundaries and Properties for the DMFS Analyses ............................127
Table 14
Efficacy Boundaries and Properties for the OS Analyses ..................................128
Table 15
Highly Effective Contraception Methods...........................................................143
Table 16
Protocol-required Safety Laboratory Assessments.............................................152
Table 17
Melanoma T Category Definition.......................................................................169
Table 18
Melanoma N Category Definition ......................................................................170
Table 19
Melanoma M Category Definition......................................................................171
Table 20
AJCC Pathological (pTNM) Staging Groups.....................................................172
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LIST OF FIGURES
Figure 1
Study Design.........................................................................................................21
Figure 2
Study Flow Schema..............................................................................................22
Figure 3
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator .........................................................................................................101
Figure 4
Multiplicity Graph for Type-I Error Control of Study Hypotheses....................125
Figure 5
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator .........................................................................................................166
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1. Protocol Summary
Synopsis
Protocol Title:
Adjuvant Therapy with Pembrolizumab versus Placebo in Resected High-risk Stage II 
Melanoma: A Randomized, Double-blind Phase 3 Study (KEYNOTE 716)
Short Title:
Adjuvant Therapy with Pembrolizumab versus Placebo in Resected High-risk Stage II 
Melanoma
Overall Design:
Study Phase
Phase 3
Clinical Indication
Adjuvant treatment of high-risk Stage II melanoma
Population
Participants with surgically resected high-risk Stage II 
melanoma
Study Type
Interventional
Type of Design
Randomized, Multisite, Parallel-group, with Crossover
or Rechallenge
Type of Control
Placebo
Study Blinding
Part 1 - Double-blind
Part 2 - Unblinded
Estimated Duration 
of Study
The Sponsor estimates that the study will require 
approximately 15 years from the time the first participant 
(or their legally acceptable representative) provides
documented informed consent until the last participant’s 
last study-related contact.
Number of Participants:
Approximately 954 participants will be randomized as described in Section 9.1.
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Treatment Groups and Duration:
Treatment Groups
Part 1 (Adjuvant Treatment):

Pembrolizumab (Adult: 200 mg IV Q3W or Pediatric: 2
mg/kg IV Q3W up to a maximum of 200 mg Q3W)

Placebo (saline solution IV Q3W)
Part 2 (Crossover/Rechallenge):

Pembrolizumab:
o
Adult: 200 mg IV Q3W
o
Pediatric: 2 mg/kg IV Q3W up to a maximum of 
200 mg IV Q3W
Duration of 
Participation
Each participant will participate in the study for 
approximately 15 years from the time the participant (or their 
legally acceptable representative) provides documented 
informed consent through the final contact.
After a screening phase of up to 28 days, each participant in 
Part 1 will be assigned to receive study treatment
(pembrolizumab or placebo) for 17 cycles. Participants will 
be treated with pembrolizumab or placebo unless they 
experience disease recurrence, unacceptable AEs, or 
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, or until the participant has received 
17 cycles of pembrolizumab or placebo. Disease recurrence
is confirmed by investigator radiographically and/or by 
exam/biopsy and pathologically confirmed by the site.
Participants who have recurrence of disease will be 
unblinded after Sponsor consultation and approval.  
Participants who receive placebo (Part 1 placebo arm), OR
who stop study treatment after receiving 17 cycles of 
pembrolizumab (Part 1 pembrolizumab arm), do not 
experience disease recurrence within 6 months of 
completing Part 1 treatment with pembrolizumab, and do
not stop treatment with pembrolizumab for disease 
recurrence or intolerability, may be eligible for rechallenge
(Part 2) and may receive up to 17 or 35 cycles of 
pembrolizumab therapy Q3W at recurrence per Part 2 
eligibility guidelines (Section 6.7). Disease 
recurrence/progression is confirmed by investigator 
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radiographically (with site radiologist) and/or by exam with 
subsequent biopsy. RECIST 1.1/iRECIST will be used to 
assess/confirm disease progression in participants with 
metastatic/unresectable disease identified at start of Part 2 
therapy.
After the end of treatment in Parts 1 and 2, each participant 
will be followed for the occurrence of AEs and 
spontaneously reported pregnancy as described under 
Section 8.4.  
Participants who discontinue for reasons other than 
confirmed metastatic disease recurrence will be followed 
for disease status until metastatic disease recurrence is 
confirmed (radiographically and/or by exam with 
subsequent biopsy). Participants who initiate a nonstudy 
cancer treatment will have posttreatment DMFS follow-up
until metastatic disease recurrence is documented. All 
participants will be followed for overall survival until death
or the end of the study.
Study Governance:
Study Governance 
Committees
Committee
Included in this 
study?
Steering Committee
N
Executive Oversight Committee
Y
Data Monitoring Committee
Y
Clinical Adjudication Committee
N
Study governance considerations are outlined in 
Appendix 1.
A list of abbreviations used in this document can be found in Appendix 7.
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Schema
Study Design
The study design is depicted in Figure 1.
Figure 1
Study Design
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Study Flow Schema
The study flow schema is depicted in Figure 2.
Figure 2
Study Flow Schema
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Schedule of Activities (SoA)
Part 1 Adjuvant Treatment: Pembrolizumab or Placebo
Part I Adjuvant Treatment
Trial Period
Screening
During 
Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle
(Cycle = 21 days)
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd 
# 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-
up
Follow-Up Visitsd
DMFS 
Follow-
up
Survival 
Follow-
up
30 days 
post 
last 
dose
Every 
12 
weeks
for 
the 
1st 
year
from 
EOT
Every 
6 
months 
for the 
2nd
year to 
5th
year 
from 
EOT
Yearly 
thereafter
starting 
at year 6 
from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a given 
treatment (TX) visit should 
occur on Day 1 of each cycle 
unless otherwise noted
Scheduling Window (Days):
-28 to 
-1
-10 to 
-1
+3
±3
±3
+7
±14
±14
±28
±14
±14
Administrative Procedures
Informed Consent/Assent
X
Informed Consent/Assent for Future 
Biomedical Research
X
Not mandatory for participation 
in study
Participant Identification Card
X
Eligibility Criteria
X
Demographics and Medical History
X
Prior and Concomitant Medication 
Review
X
X
X
X
X
X
X
Concomitant medications will 
be recorded beyond 30 days 
post-TX DC if related to SAE 
or ECI. 
Treatment Assignment in IRT
X
Trial Treatment Administration
Pembrolizumab/Placebo
X
X
X
Safety Procedures
Full Physical Examination
X
X
06FVJK

Product:  MK-3475 
24
Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part I Adjuvant Treatment
Trial Period
Screening
During 
Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle
(Cycle = 21 days)
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd 
# 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-
up
Follow-Up Visitsd
DMFS 
Follow-
up
Survival 
Follow-
up
30 days 
post 
last 
dose
Every 
12 
weeks
for 
the 
1st 
year
from 
EOT
Every 
6 
months 
for the 
2nd
year to 
5th
year 
from 
EOT
Yearly 
thereafter
starting 
at year 6 
from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a given 
treatment (TX) visit should 
occur on Day 1 of each cycle 
unless otherwise noted
Scheduling Window (Days):
-28 to 
-1
-10 to 
-1
+3
±3
±3
+7
±14
±14
±28
±14
±14
Directed Physical Examination
X
X
X
X
X
X
X
The investigator or qualified 
designee should conduct a 
visual inspection of local 
recurrence and palpation of 
regional lymph nodes to assess 
regional recurrence.   
Vital Signs (pulse, blood pressure, 
respiratory rate, and temperature), 
Height and Weight
X
X
X
X
X
X
X
X
X
Pediatric only – height and 
weight to be measured at every 
visit. Adult height measured at 
screening only.
12-Lead ECG
X
6 lead ECG acceptable per local 
guidelines
Age Appropriate Performance Scale 
(Lansky/Karnofsky/ECOG)
X
X
X
X
X
X
X
X
X
Evaluated prior to dosing. 
Lansky scale to be used for 
participants ≤16 years old.
Karnofsky scale to be used for 
participants >16 and <18 years 
old. ECOG to be used for 
participants ≥18 years old
06FVJK

Product:  MK-3475 
25
Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part I Adjuvant Treatment
Trial Period
Screening
During 
Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle
(Cycle = 21 days)
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd 
# 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-
up
Follow-Up Visitsd
DMFS 
Follow-
up
Survival 
Follow-
up
30 days 
post 
last 
dose
Every 
12 
weeks
for 
the 
1st 
year
from 
EOT
Every 
6 
months 
for the 
2nd
year to 
5th
year 
from 
EOT
Yearly 
thereafter
starting 
at year 6 
from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a given 
treatment (TX) visit should 
occur on Day 1 of each cycle 
unless otherwise noted
Scheduling Window (Days):
-28 to 
-1
-10 to 
-1
+3
±3
±3
+7
±14
±14
±28
±14
±14
HIV, Hepatitis B and C determination
X
No testing for HIV, Hepatitis B 
and C is required unless 
mandated by local health 
authority. Refer to Appendix 6 
for country-specific 
requirements.
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
Submit Follow-up DMFS Imaging to 
Central Vendor
X
Site investigator must collect 
and review copy of clinical 
notes/reports, imaging reports, 
photographs and/or pathology 
reports (including imaging and 
biopsy/pathology assessment 
done external to site) to update 
disease status. A central 
imaging vendor will be used to 
collect, clean, and hold tumor 
imaging obtained during the 
DMFS phase of the study.
06FVJK

Product:  MK-3475 
26
Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part I Adjuvant Treatment
Trial Period
Screening
During 
Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle
(Cycle = 21 days)
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd 
# 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-
up
Follow-Up Visitsd
DMFS 
Follow-
up
Survival 
Follow-
up
30 days 
post 
last 
dose
Every 
12 
weeks
for 
the 
1st 
year
from 
EOT
Every 
6 
months 
for the 
2nd
year to 
5th
year 
from 
EOT
Yearly 
thereafter
starting 
at year 6 
from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a given 
treatment (TX) visit should 
occur on Day 1 of each cycle 
unless otherwise noted
Scheduling Window (Days):
-28 to 
-1
-10 to 
-1
+3
±3
±3
+7
±14
±14
±28
±14
±14
Submit Follow-up SFU Imaging to 
Central Vendor
X
Site investigator must collect 
and review copy of clinical 
notes/reports, imaging reports, 
photographs and/or pathology 
reports (including imaging and 
biopsy/pathology assessment 
done external to site) to update 
disease status if it is available. 
A central imaging vendor will 
be used to collect, clean, and 
hold submitted tumor imaging 
obtained during the SFU phase 
of the study.
Poststudy Anticancer Therapy Status
X
X
X
X
X
X
Survival Status
After investigator determined 
recurrence or start of new 
anticancer TX. Upon Sponsor 
request, participants may be 
contacted for survival status at 
any time during the study.
06FVJK

Product:  MK-3475 
27
Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part I Adjuvant Treatment
Trial Period
Screening
During 
Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle
(Cycle = 21 days)
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd 
# 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-
up
Follow-Up Visitsd
DMFS 
Follow-
up
Survival 
Follow-
up
30 days 
post 
last 
dose
Every 
12 
weeks
for 
the 
1st 
year
from 
EOT
Every 
6 
months 
for the 
2nd
year to 
5th
year 
from 
EOT
Yearly 
thereafter
starting 
at year 6 
from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a given 
treatment (TX) visit should 
occur on Day 1 of each cycle 
unless otherwise noted
Scheduling Window (Days):
-28 to 
-1
-10 to 
-1
+3
±3
±3
+7
±14
±14
±28
±14
±14
Lab Procedures/Assessments
Pregnancy Test – Urine or Serum
X
X
X
X
X
For women of childbearing
potential, a urine pregnancy test 
should be performed within 72 
hours prior to 1st dose of study 
TX. If urine pregnancy results 
cannot be confirmed as 
negative, a serum pregnancy 
test performed by the local 
study site laboratory is
required.
PT/INR and aPTT
X
aPTT/PT/INR is mandatory at 
screening. PT/INR should be 
tested subsequently as needed 
for participants on warfarin 
based anticoagulation therapy.
CBC with Differential
X
X
X
X
06FVJK

Product:  MK-3475 
28
Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part I Adjuvant Treatment
Trial Period
Screening
During 
Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle
(Cycle = 21 days)
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd 
# 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-
up
Follow-Up Visitsd
DMFS 
Follow-
up
Survival 
Follow-
up
30 days 
post 
last 
dose
Every 
12 
weeks
for 
the 
1st 
year
from 
EOT
Every 
6 
months 
for the 
2nd
year to 
5th
year 
from 
EOT
Yearly 
thereafter
starting 
at year 6 
from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a given 
treatment (TX) visit should 
occur on Day 1 of each cycle 
unless otherwise noted
Scheduling Window (Days):
-28 to 
-1
-10 to 
-1
+3
±3
±3
+7
±14
±14
±28
±14
±14
Comprehensive Chemistry Panel
X
X
X
X
Every 6 weeks (at the start of 
even # cycles) during treatment.
Screening laboratory tests that 
cannot be done -10 to -1 day 
prior to C1D1 can be done on 
the day of C1D1 (before first 
dose in Part 1) if results are 
available for investigator’s 
review before dosing
Urinalysis
X
X
X
Prior to first dose and then C4, 
C8, C12, C16 and 30 days after 
last study treatment.
T3(or Free T3), FT4 and TSH
X
X
X
After C1, retrospective review 
of thyroid function testing is 
allowed when results are not 
available prior to dosing
LDH
Recurrence only
Only required when recurrence 
is identified
06FVJK

Product:  MK-3475 
29
Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part I Adjuvant Treatment
Trial Period
Screening
During 
Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle
(Cycle = 21 days)
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd 
# 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-
up
Follow-Up Visitsd
DMFS 
Follow-
up
Survival 
Follow-
up
30 days 
post 
last 
dose
Every 
12 
weeks
for 
the 
1st 
year
from 
EOT
Every 
6 
months 
for the 
2nd
year to 
5th
year 
from 
EOT
Yearly 
thereafter
starting 
at year 6 
from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a given 
treatment (TX) visit should 
occur on Day 1 of each cycle 
unless otherwise noted
Scheduling Window (Days):
-28 to 
-1
-10 to 
-1
+3
±3
±3
+7
±14
±14
±28
±14
±14
Disease Evaluation
Tumor Imaging
(See Site Imaging Manual for more 
details)
Xa
Xa
Xa
Xa
Imaging timing should follow 
calendar days and should not be 
adjusted for delays in cycle 
starts. CT is preferred imaging 
modality for neck, chest, 
abdomen, and pelvis. CT 
portion of PET-CT may be used 
in place of stand-alone CT if it 
is of diagnostic quality per Site 
Imaging Manual. In the case of 
DC due to recurrence, scan date 
is the reference date for 
scheduling future scans. MRI 
of the brain may be performed 
as per site’s SOC practice.
Pathology Report
X
Recurrence Only
See Appendix 10 
Lesion Photograph
Recurrence Only
Submit diagnostic photograph
for cutaneous recurrence if 
possible
06FVJK

Product:  MK-3475 
30
Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part I Adjuvant Treatment
Trial Period
Screening
During 
Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle
(Cycle = 21 days)
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd 
# 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-
up
Follow-Up Visitsd
DMFS 
Follow-
up
Survival 
Follow-
up
30 days 
post 
last 
dose
Every 
12 
weeks
for 
the 
1st 
year
from 
EOT
Every 
6 
months 
for the 
2nd
year to 
5th
year 
from 
EOT
Yearly 
thereafter
starting 
at year 6 
from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a given 
treatment (TX) visit should 
occur on Day 1 of each cycle 
unless otherwise noted
Scheduling Window (Days):
-28 to 
-1
-10 to 
-1
+3
±3
±3
+7
±14
±14
±28
±14
±14
Pharmacokinetics
Blood for Serum pembrolizumab PK
Xb
Xb
Xb
Pediatric Only (Less than 18 
years old)
Blood for ADA
Xb
Xb
Xb
Translational Research/Biomarkers
Archival Tumor Tissue 
X
Submit archival tumor sample 
at screening if sufficient tumor 
tissue is available. See 
Procedure Manual for details.
Fresh Tumor Tissue Biopsy
Recurrence Only
Obtain and submit at recurrence
if sufficient tumor tissue is 
available. See Procedure 
Manual for details.
Genetics/Gene Expression/Mutation 
Assessments
X
Recurrence Only
Information collected and 
recorded on eCRF only if 
available from standard of care 
testing completed by site
Blood for Genetic Analyses
X
Collect predose on Day 1 of 
C1.
Blood for RNA Analysis
X
X
X
X
Recurrence Only
Collect predose on Day 1 of 
C1, C2, C5, DC, and at 
recurrence.
Blood for Plasma Biomarker Analyses
X
X
X
X
Recurrence Only
Blood for Serum Biomarker Analyses
X
X
X
X
Recurrence Only
06FVJK

Product:  MK-3475 
31
Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part I Adjuvant Treatment
Trial Period
Screening
During 
Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle
(Cycle = 21 days)
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd 
# 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-
up
Follow-Up Visitsd
DMFS 
Follow-
up
Survival 
Follow-
up
30 days 
post 
last 
dose
Every 
12 
weeks
for 
the 
1st 
year
from 
EOT
Every 
6 
months 
for the 
2nd
year to 
5th
year 
from 
EOT
Yearly 
thereafter
starting 
at year 6 
from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a given 
treatment (TX) visit should 
occur on Day 1 of each cycle 
unless otherwise noted
Scheduling Window (Days):
-28 to 
-1
-10 to 
-1
+3
±3
±3
+7
±14
±14
±28
±14
±14
Stool for Biomarker Analysis
X
X
X
X
Recurrence Onlyd
Collection at home within 1 
week prior to specified visit and 
brought into site on Day 1 of 
C1, C2, C5, DC, and disease 
recurrence
Blood for ctDNA
X
X
X
X
X
X
X
X
Collect predose on Day 1 of 
C1, C2, C3, subsequent odd 
cycles, DC, Safety Follow-up,
every visit during Follow-up, 
and any unscheduled visit 
where there is a clinical 
suspicion of recurrence.
06FVJK

Product:  MK-3475 
32
Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part I Adjuvant Treatment
Trial Period
Screening
During 
Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle
(Cycle = 21 days)
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd 
# 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-
up
Follow-Up Visitsd
DMFS 
Follow-
up
Survival 
Follow-
up
30 days 
post 
last 
dose
Every 
12 
weeks
for 
the 
1st 
year
from 
EOT
Every 
6 
months 
for the 
2nd
year to 
5th
year 
from 
EOT
Yearly 
thereafter
starting 
at year 6 
from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a given 
treatment (TX) visit should 
occur on Day 1 of each cycle 
unless otherwise noted
Scheduling Window (Days):
-28 to 
-1
-10 to 
-1
+3
±3
±3
+7
±14
±14
±28
±14
±14
Patient-reported Outcomes
EuroQoL EQ-5D-5L and EORTC 
QLQ-C30
Xc
Xc
Xc
Xc
Xc
Xc
PROs must be collected 
regardless of 
recurrence/progression 
status/treatment completion, 
unless participant withdraws
from this portion of the study. 
PROs are administered prior to 
drug administration, AE 
evaluation, disease status 
evaluation and all 
procedures/assessments. If 
participant does not complete 
the PRO at designated time, the 
reason must be captured.  
ADA = Antidrug Antibodies; aPTT = activated partial thromboplastin time; C1 = Cycle 1, etc.; CT = computed tomography; ctDNA = circulating tumor 
deoxyribonucleic acid; DC = discontinuation; DMFS = distant metastasis-free survival; ECG = electrocardiogram; ECI = event of clinical interest; ECOG = Eastern 
Cooperative Oncology Group; EOT = end of treatment; EORTC QLQ = European Organization for Research and Treatment of Cancer Quality of Life Questionnaire; 
IRT = Interactive Response Technology; LDH = Lactic Acid Dehydrogenase; MRI = magnetic resonance imaging; PET-CT = positron emission tomography -computed 
tomography; PK = Pharmacokinetic; PRO = patient-reported outcome; PT/INR = prothrombin time/international normalized ratio; RNA = ribonucleic acid;
SAE = serious adverse event; SFU = survival follow-up; TSH = thyroid-stimulating hormone; TX = Treatment; WNL = Within normal ;imits.
06FVJK

Product:  MK-3475 
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Protocol/Amendment No.: 716-04 
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11-May-2021
Confidential
a.
See Section 8.2.1.4 and the Site Imaging Manual for more information. CT chest, abdomen, and pelvis, or CT chest with MRI abdomen and pelvis. Neck CT and/or MRI for head and neck 
primaries. MRI brain and spine only as clinically needed. A CT scan of the extremity where the primary melanoma was diagnosed (or MRI if CT scan is contraindicated) should be performed 
at the investigator’s discretion or when clinically indicated.
b.
PK/ADA (pediatric participants only):  Predose trough PK and anti-pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, 8 and every 4 cycles thereafter, and 30 days after 
discontinuation of study drug or until the participant starts new anticancer therapy whichever is earlier. All predose trough samples should be drawn within 24 hours before infusion of study 
drug from all pediatric participants. If Discontinuation Visit and 30-Day Safety Visit occur at the same visit refer to the data entry guidelines for required procedures. PK only:  Additional 
postdose peak PK samples will be drawn within 30 minutes after end of study drug infusion at Cycles 1 and 8. An additional single PK sample should be drawn in Cycle 1 between 72 to 168 
hours (Day 4 to Day 8) postdose and Cycle 1 at 264 to 408 hours (Day 12 to Day 18). Once a participant reaches the age of 18, PK/ADA samples should not be collected.
c.
Patient-reported Outcomes (PROs) EuroQoL (EQ)-5D-5L and EORTC QLQ-C30 should be completed at baseline (Cycle 1), during treatment in year one (at Cycle 5, 9, 13, 17), every 12 
weeks during year 2 (Week 60, 72, 84, and 96 from baseline), and every 6 months during year 3 (month 30 and 36 from baseline), at treatment discontinuation visit and the 30-day follow-up 
visit. PROs are administered in the following order: EQ-5D-5L, EORTC QLQ-C30. The EORTC QLQ-C30 will be administered only to adults (≥18 years of age at baseline) since the 
questionnaire is not validated in pediatric populations. The EQ-5D-5L will be administered to all study participants, since it is considered acceptable to use for persons 12 years and older.
d.
The clinic visit at which imaging (or exam/biopsy) is performed to confirm suspected recurrence or the next scheduled or unscheduled visit at site if procedures performed at nonsite facility.
06FVJK

Product:  MK-3475 
34
Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
Administrative Procedures
Informed Consent/Assent
X
Ensure that participants 
are re-consented with 
the most up-to-date IC 
within 14 days 
(+3 days) prior to the 
first dose in Part 2.
Eligibility Criteria
X
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
Concomitant 
medications taken will 
be recorded 28 days 
prior to C1D1 and 
beyond 30 days post-
TX DC if related to 
SAE or ECI. 
06FVJK

Product:  MK-3475 
35
Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
Trial Treatment Administration
Pembrolizumab 
X
X
X
Approximately 1 year
(17 cycles) for 
local/distant recurrence 
following surgical 
resection.
Approximately 2 years
(up to 35 cycles) for 
unresectable disease; 
Participants with distant 
recurrence surgically
resected will be treated 
for 17 cycles with 
pembrolizumab in part 
2 and investigator may 
request Sponsor to 
approve up to 35 cycles
total treatment in 
Part 2.
06FVJK

Product:  MK-3475 
36
Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
Safety Procedures
Full Physical Examination
Xa
X
Directed Physical Exam
X
X
X
X
X
X
The investigator or 
qualified designee 
should conduct a visual 
inspection of local 
recurrence and 
palpation of regional 
lymph nodes to assess 
regional recurrence.   
Vital Signs (pulse, blood 
pressure, respiratory rate,
and temperature), Height, 
Weight
Xa
X
X
X
X
X
X
X
Pediatric only – height 
and weight measured at 
every visit. Adult height 
measured at Part 1 
screening only.
12-lead ECG
X
6 lead ECG acceptable 
per local guidelines
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Product:  MK-3475 
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Protocol/Amendment No.: 716-04 
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Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
Age Appropriate 
Performance Scale 
(Lansky/Karnofsky/
ECOG)
Xa
X
X
X
X
X
X
X
Evaluated prior to 
dosing. Lansky scale to 
be used for participants 
≤16 years old. 
Karnofsky scale to be 
used for participants 
>16 and <18 years old. 
ECOG to be used for 
participants ≥18 years 
old
Review Adverse Events
X
X
X
X
X
X
X
X
Poststudy Anticancer 
Therapy Status
X
X
X
X
X
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Product:  MK-3475 
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Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
Submit Follow-up DMFS
Imaging to Central Vendor
X
Site investigator must 
collect and review copy 
of clinical notes/reports, 
imaging reports, 
photographs and/or 
pathology reports 
(including imaging and 
biopsy/pathology 
assessment done 
external to site) to 
update disease status if 
it is available. A central
imaging vendor will be 
used to collect, clean, 
and hold submitted 
tumor imaging obtained 
during the DMFS phase 
of the study.
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Product:  MK-3475 
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Protocol/Amendment No.: 716-04 
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11-May-2021
Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
Submit Follow-up SFU 
Imaging to Central Vendor
X
Site investigator must 
collect and review copy 
of clinical notes/reports, 
imaging reports, 
photographs and/or 
pathology reports 
(including imaging and 
biopsy/pathology 
assessment done 
external to site) to 
update disease status if 
it is available. A central
imaging vendor will be 
used to collect, clean, 
and hold submitted 
tumor imaging obtained 
during the SFU phase 
of the study.
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Product:  MK-3475 
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Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
Survival Status
1) After investigator 
determined recurrence
or start of new 
anticancer TX. Upon
Sponsor request, pts 
may be contacted for 
survival status at any 
time during the study.
2) When follow-up 
visits are spaced to 
every 6 months or 
yearly, pts will be 
contacted every 12 
weeks between visits.
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Product:  MK-3475 
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Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
Laboratory Procedures/Assessments
Pregnancy Test – Urine or 
Serum
X
X
X
X
X
For women of 
childbearing potential, a 
urine pregnancy test 
should be performed 
within 72 hours prior to 
1st dose of study TX. If 
urine pregnancy results 
cannot be confirmed as 
negative, a serum 
pregnancy test
performed by the local 
study site laboratory is 
required.
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Product:  MK-3475 
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Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
PT/INR and aPTT
Xa
aPTT/PT/INR is 
mandatory at Part 2 
screening. PT/INR 
should be tested 
subsequently as needed 
for participants on 
warfarin based 
anticoagulation therapy.
CBC with Differential
Xa
X
X
X
Every 6 weeks (at the 
start of even # cycles)
during treatment. 
Comprehensive Chemistry 
Panel
Xa
X
X
X
Urinalysis
Xa
X
X
Prior to 1st dose and 
then C4, C8, C12, C16 
and 30 days after last 
dose of study treatment.
Pts receiving 2 years of 
treatment will provide 
urine samples at C20, 
C24, C28 and C32.
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Product:  MK-3475 
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Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
T3 (or Free T3), FT4 and 
TSH
Xa
X
X
After C1, retrospective 
review of thyroid 
function testing is 
allowed when results 
are not available prior 
to dosing.
LDH
Xa
X
X
06FVJK

Product:  MK-3475 
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Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
Disease Evaluation
Tumor Imaging

(See Site Imaging 
Manual for more 
details)
Xb
Xb
Xb
Xb
Imaging timing should 
follow calendar days 
and should not be 
adjusted for delays in 
cycle starts. CT is 
preferred imaging 
modality for neck, 
chest, abdomen, and 
pelvis. CT portion of 
PET-CT may be used in 
place of stand-alone CT 
if it is of diagnostic 
quality per Site Imaging 
Manual. In the case of 
DC due to recurrence, 
scan date is the 
reference date for 
scheduling future scans.
Pathology Report
Xa
Recurrence or Progression of Melanoma
See Appendix 10
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Product:  MK-3475 
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Protocol/Amendment No.: 716-04 
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Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
Lesion Photograph
Xa
Recurrence or Progression of Melanoma 
Submit diagnostic 
photograph for 
cutaneous recurrence if 
possible
Translational Research/Biomarkers
Obtain Fresh Tumor Tissue 
Biopsy
Xa
Recurrence or Progression of Melanoma
Obtain and submit at 
recurrence or 
progression if sufficient 
tumor tissue is 
available. See 
Procedure Manual for 
details.
Genetics/Gene 
Expression/Mutation 
Assessments
X
Recurrence or Progression of Melanoma
Information collected 
and recorded on eCRF 
only if available from 
standard of care testing 
completed by site
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Product:  MK-3475 
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Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
Blood for ctDNA
X
X
X
X
X
X
X
Collect predose on Day 
1 of C1, C2, C3, 
subsequent odd cycles, 
DC, Safety Follow-up, 
and every visit during 
Follow-up, and any 
unscheduled visit where 
there is a clinical 
suspicion of recurrence 
or progression
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Product:  MK-3475 
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Protocol/Amendment No.: 716-04 
MK-3475-716-04 Final Protocol
11-May-2021
Confidential
Part 2 Crossover/Rechallenge After First Recurrence
Trial Period
Screening
During Treatment
End of 
Treatment
Posttreatment
Notes
Treatment Cycle:
Prior to 
1st dose in 
Part 2
1
2
and 
every 
even 
# 
cycle
3
and 
every 
odd # 
cycle
At time of 
treatment 
discontinuation
Safety 
Follow-up
Follow-up Visits
DMFS 
Follow-
up
Survival 
Follow-
up
30 days post 
last dose
Local 
Recurrence
Every 12 
weeks (±14 
days) for 1st
year, every 6 
months (±14 
days) years 2-
5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Distant 
Recurrence
Every 12 
weeks (±14 
days) for 2
years, then 
every 6 
months (±14 
days) during 
year 3 through 
year 5, then 
annually (±28 
days) starting 
year 6 from 
EOT
Every 
12 
weeks
Every 
12 
weeks
Procedures within a 
given treatment visit 
should occur on Day 1
of each cycle unless 
otherwise noted.
Scheduling Window 
(Days):
-14 to -1
+3
±3
±3
+7
±14
±14
Patient-reported Outcomes
EuroQoL (EQ)-5D-5L
Xc
Xc
Xc
Xc
PROs must be collected 
regardless of 
recurrence/progression 
status/TX completion, 
unless participant 
withdraws from study. 
PROs are to be 
administered prior to 
drug administration, AE
evaluation, disease 
status evaluation and all 
procedures/assessments. 
If participant does not 
complete the PRO at 
designated time, the 
reason must be 
captured.  
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Confidential
C1 = Cycle 1, etc.; DC = Discontinuation; EOT = End of Treatment; ICF = Informed Consent Form; Q3W = every 3 weeks; TX= Treatment; WNL = Within normal limits.
a.
Screening laboratory tests and full physical examination are required only if they did not occur within 14 days of start of Part 2 study treatment. Tumor biopsy, lesion photography and 
pathology report must be completed within 4 weeks prior to first dose in Part 2. Sponsor consultation and approval is required prior to entry into Part 2. Screening laboratory tests that cannot 
be done -14 to -1 day prior to C1D1 can be done on the day of C1D1 (before first dose in Part 2) if results are available for investigator’s review before dosing.
b.
See Section 8.2.1.4 and the Site Imaging Manual for more information. CT chest, abdomen, and pelvis, or CT chest with MRI abdomen and pelvis. Neck CT and/or MRI for head and neck 
primaries. MRI brain: If no metastatic disease found, repeat only as clinically needed. If disease present, reimage Q12W with other staging scans. MRI spine as clinically needed. A CT scan 
of the extremity where the primary melanoma was diagnosed (or MRI if CT scan is contraindicated) should be performed at the investigator’s discretion or when clinically indicated.
c.
EuroQoL 5 Dimension Questionnaire (EQ-5D-5L) should be completed during this phase at baseline (Cycle 1), during treatment at Cycles 9, 17 and 35, and at 24 and 48 weeks during first 
year off treatment. The EuroQoL EQ-5D-5L will be administered to all study participants, since it is considered acceptable to use for persons 12 years and older.
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Imaging Schedule
C1D1= Cycle 1 Day 1 of Part 2 Treatment 
Note: For participants who stop Part 1 or Part 2 without documented recurrence/progression. Every effort should be made to capture imaging based on Part 1 and Part 2 SoA 
instructions.
*  Participants who enter Part 2 with history of Stage IV melanoma and have no evidence of disease may be treated for up to 35 cycles and will have year 2 of imaging while on 
treatment.
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2. Introduction
Study Rationale 
Recent clinical studies in melanoma have focused on treating high-risk Stage III patients with 
programmed cell death inhibitor-1 (PD-1) inhibitors and combination BRAF and MEK 
inhibitors in the adjuvant setting to decrease the risk of recurrence and improve Distant 
Metastasis-free Survival (DMFS) and Overall Survival (OS) (S1404/KN053, 
EORTC1325/KN054, CheckMate 238, COMBI-AD). Adult patients with Stage III A, B, C
melanoma who received 18 doses (~1 year) of pembrolizumab postresection in
EORTC1325/KN054 had a significantly longer recurrence-free survival (RFS) than placebo 
[hazard ratio (HR)=0.57; 98.4% confidence interval (CI), 0.43-0.74; p<0.0001] [Eggermont, 
A. M. M. 2017]. In CheckMate 238, resected Stage IIIB, IIIC and IV melanoma patients 
have improved RFS and fewer Grade 3 and 4 AEs after 1 year of adjuvant treatment with 
nivolumab compared to patients treated with ipilimumab, which was previously approved by 
the Food and Drug Administration as adjuvant therapy [Weber, J., et al 2017]. COMBI-AD 
has shown RFS benefit with 1 year of adjuvant treatment using dabrafenib and trametinib in
patients whose tumors harbor BRAF V600E or V600K mutations with Stage IIIA, B, and C 
melanoma [Long, G. V., et al 2017]. 
All Stage II patients are at risk of recurrence after complete surgical resection, which is 
considered standard of care in this patient population. IFN alpha as adjuvant therapy in 
melanoma has shown modest results at best [consistent effect on RFS with a maintained HR 
of 0.86 and approximately a 3% absolute survival advantage at 5 years] [Ives, N. J., et al 
2017]. IFN alpha is a regimen with well described significant toxicities, particularly at high-
dose, and these can profoundly affect quality of life and can even be life-threatening. With 
high-dose IFN, approximately 40% of patients have treatment-related AEs that lead to dose 
delays or reductions [Trinh, V. A., et al 2017]. Adjuvant IFN offers a reduction in RFS but is 
not universally recommended because of the significant toxicity associated with treatment 
that can affect quality of life [Garbe, C., et al 2012]. Pegylated IFN alpha 2b was approved 
by the Food and Drug Administration on 29-MAR-2011 for adjuvant therapy. Today IFN 
alpha has a limited role in adjuvant treatment of melanoma and is now recommended only to 
patients with ulcerated primary melanomas and to patients without access to more modern 
treatments [Eggermont, A. M. M. 2017].  
Some patients with Stage II melanoma have MSS outcomes similar to Stage III patients. Data 
from the American Joint Committee on Cancer suggest that 94% of Stage IIA, 87% of Stage 
IIB, and 82% of Stage IIC patients will be alive at 5 years and by 10 years 88, 82, and 75% 
respectively. Stage IIIB 5-year MSS rate of 83% is comparable to Stage IIC OS at 5 years 
(82%). Similarly, Stage IIIA (88%) and IIIB (77%) MSS at 10 years are comparable to Stage 
IIA (88%) and IIC (75%) MSS rate at 10 years, respectively [Gershenwald, J. E., et al 2017]. 
These data clearly show that survival outcomes can be as dismal for some Stage II patients as 
for Stage III patients. This population thus has an unmet medical need for adjuvant therapy 
with the goal of preventing disease recurrence and increasing survival by providing treatment 
with adjuvant pembrolizumab that now has a proven therapeutic benefit in Stage III and IV 
patients.
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EORTC1325/KN054 is currently investigating whether there is a benefit in rechallenging 
Stage III patients who experience disease recurrence, resectable or unresectable disease, at 
least 6 months from their last dose of pembrolizumab. The purpose of rechallenge is to
identify patients with an immune system that has already been primed to respond to treatment 
of melanoma with pembrolizumab and determine whether pembrolizumab is able to prevent 
recurrence in the treatment time period and for at least an additional 6 months after treatment 
is completed by mounting a response during rechallenge. As no data is currently available 
from EORTC1325/KN054 on rechallenge, KN716 will offer patients the opportunity for 
rechallenge with pembrolizumab in the event of disease recurrence.
Stage II melanoma also affects the pediatric population. KN051 is currently investigating the 
safety of pembrolizumab in the pediatric population and has established safe dosing 
guidelines (2 mg/kg dose IV Q3W with maximum dose administered of 200 mg Q3W). Data 
is currently not available on efficacy of pembrolizumab in advanced pediatric melanoma but 
pembrolizumab has shown efficacy in other pediatric cancers and is currently approved for 
treatment of classical Hodgkin lymphoma and microsatellite instability-high tumors. 
Pembrolizumab has been well tolerated in the pediatric populations studied in KN051
[Geoerger, B., et al 2017]. Patients who are naïve to intensive therapeutic regimens are 
expected to tolerate pembrolizumab well. 
Adjuvant pembrolizumab PK data has been collected from EORTC1325/KN054 and 
S1404/KN053 patients in the adjuvant treatment setting. Adult PK data will not be collected 
and analyzed in KN716. Pediatric adjuvant PK data has not been collected in prior studies
and will be collected in Part 1 of this study.
In summary, this study will examine whether the benefits achieved with pembrolizumab 
adjuvant therapy seen in Stage III and IV melanoma translates to the adult (≥18 years of age)
and pediatric (age 12 and older) High-Risk Stage II melanoma populations, and leads to 
improved RFS, DMFS and OS, while identifying biomarker correlates. Tolerable AEs are 
expected in an otherwise untreated population, making this an ideal design in which to 
include pediatric and adult participants. Upon recurrence, this study will explore whether
rechallenge with pembrolizumab after adjuvant therapy decreases the risk of another 
recurrence or disease progression.
Background
Pembrolizumab is a potent humanized IgG4 monoclonal antibody with high specificity of 
binding to the PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on 
preclinical in vitro data, pembrolizumab has high affinity and potent receptor blocking 
activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an IV immunotherapy for advanced malignancies. KEYTRUDA®
(pembrolizumab) is indicated for the treatment of patients across a number of indications. 
Refer to IB and approved product labeling for specific indications and detailed background 
information on pembrolizumab.
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
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shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of cluster of differentiation 8+ 
(CD8+) T-cells and the ratio of CD8+ effector T-cells/FoxP3+ regulatory T-cells (T-regs) 
correlates with improved prognosis and long-term survival in solid malignancies, such as 
ovarian, colorectal, and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; 
and renal cell carcinoma. Tumor-infiltrating lymphocytes can be expanded ex vivo and 
reinfused, inducing durable objective tumor responses in cancers such as melanoma [Dudley, 
M. E., et al 2005] [Hunder, N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and cytotoxic T-lymphocyte-associated protein 4 
(CTLA-4) that has been 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 structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type-I transmembrane glycoproteins containing an Ig-variable–type domain 
responsible for ligand binding and a cytoplasmic tail responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010].  
As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in patients with melanoma.
Preclinical and Clinical Studies
KEYNOTE protocols 001, 002, and 006 have led to the approval of pembrolizumab for the 
treatment of unresectable or metastatic melanoma in both pretreated and untreated patients.
As noted above, clinical studies such as S1404/KN053, EORTC1325/KN054, CheckMate 
238, and COMBI-AD are currently exploring the role of adjuvant therapy in Stage III and 
Stage IV resected melanoma, trying to improve RFS, DMFS, and OS for patients by 
providing therapy earlier when patients have been deemed free from disease by surgical 
resection. Benefits of adjuvant therapy have been reported in 3 of these studies so far.
KN051 is currently investigating the safety of pembrolizumab in the pediatric population and 
has established safe dosing guidelines. Data are currently not available on efficacy of 
pembrolizumab in advanced pediatric melanoma but this drug has shown efficacy in other 
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pediatric cancers and is currently approved for treatment of classical Hodgkin lymphoma and 
microsatellite instability-high tumors [Geoerger, B., et al 2017]. 
Refer to the IB and approved product labeling for more details on preclinical and clinical 
studies of pembrolizumab.
Ongoing Clinical Studies
Clinical development of pembrolizumab is ongoing in a number of advanced solid tumor 
indications, including advanced melanoma, NSCLC, bladder cancer, head and neck 
squamous cell carcinoma, other solid tumors, and hematologic malignancies, such as HL.
For study details please refer to the IB.
Benefit/Risk Assessment
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.
Pembrolizumab has shown activity in adult patients with melanoma, NSCLC, cHL, and head 
and neck cancer and may have similar effects in pediatric patients. Pembrolizumab has been 
approved in the United States for the treatment of unresectable or metastatic melanoma in 
adults and is currently under study in the pediatric population. Recent results from 
EORTC1325/KN054 show adult patients with Stage III melanoma who receive postresection 
therapy with pembrolizumab have a significantly longer recurrence-free survival than 
placebo) making study of adjuvant pembrolizumab in the high-risk Stage II population to 
improve RFS, DMFS, and OS a natural choice in the adult population (internal Merck data).
Some high-risk Stage II patients have MSS rates similar to Stage III patients. 
Based on current evidence, no difference in mechanism of action and activity are expected in 
melanoma between children and adults or between the adjuvant and relapsed/refractory 
settings. Thus, pembrolizumab has the potential to provide therapeutic benefit to adult and 
pediatric patients with newly diagnosed and resected high-risk Stage II melanoma. In 
addition, based on clinical data accrued to date, the safety profile of pembrolizumab in 
pediatric patients was similar to that seen in adults; therefore, pembrolizumab has the 
potential to offer children adjuvant therapy for melanoma that is expected to be well tolerated
and expected to lead to decreased risk of recurrence, improved DMFS, and OS.
Pembrolizumab appears generally well tolerated at all doses and schedules evaluated to date. 
These considerations support a favorable benefit-risk assessment for the study of adjuvant 
pembrolizumab in adult and pediatric participants with high-risk Stage II melanoma.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and Informed Consent documents.
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3. Objectives/Hypotheses and Endpoints
In participants 12 years of age and older with surgically resected High-Risk Stage II 
melanoma:
Objective/Hypothesis
Endpoint
Primary

To compare Recurrence-free Survival 
(RFS) between treatment arms.
Hypothesis (H1): Pembrolizumab is 
superior to placebo with respect to RFS
as assessed by the site investigator.

RFS: time from randomization to (1) 
any recurrence (local or regional 
[including invasive ipsilateral tumor and 
invasive loco-regional tumor], or 
distant) as assessed by the investigator,
or (2) death due to any cause (both 
cancer and noncancer causes of death)
Secondary

Objective: To compare DMFS between 
treatment arms.
Hypothesis (H2): Pembrolizumab is 
superior to placebo with respect to
DMFS as assessed by the site 
investigator.

DMFS: The time from randomization to 
appearance of a distant metastasis as 
assessed by the investigator. A distant 
metastasis refers to cancer that has 
spread from the original (primary) 
tumor to distant organs or distant lymph 
nodes.

Objective:  To compare OS between 
treatment arms.
Hypothesis (H3):  Pembrolizumab is 
superior to placebo with respect to OS.

OS: The time from randomization to 
death due to any cause. 

Objective:  To assess the safety and 
tolerability of pembrolizumab compared 
to placebo in the proportion of AEs.

AEs.

Discontinuation of study treatment due 
to AEs.
Tertiary/Exploratory

Objective:  To compare average change 
from baseline during the adjuvant 
treatment period (up to 21 days after last 
administration) in global quality of life 
between the 2 treatment arms using the 
European Organization for Research and 
Treatment of Cancer Quality of Life 
Questionnaire (EORTC QLQ-C30) 
global health status/QoL scale

EORTC QLQ-C30 global health 
status/QoL scale.
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Objective/Hypothesis
Endpoint

Objective:  To compare average change 
from baseline after the adjuvant period 
(from 21 days after last administration) 
in global quality of life between the 2
treatment arms using the EORTC QLQ-
C30 global health status/QoL scale

EORTC QLQ-C30 global health 
status/QoL scale.

Objective:  To characterize health 
utilities using the EuroQoL-5 
Dimension Questionnaire (EQ-5D-5L)
healthy utility scores.

EQ-5D-5L health utility score.

Objective: to compare the time to 
subsequent therapy (TTST) between 
treatment arms

TTST: The time from randomization to 
the date of first subsequent therapy (eg,
surgery, radiation therapy, 
antineoplastic therapy) or death 
(whatever the cause), whichever occurs 
first. 
Objective: to compare 
Progression/recurrence-free Survival 2
(PRFS2) between treatment arms
PRFS2: Time from randomization to the 
earliest of the following: (1) date of 1st
disease progression per RECIST 1.1 
beyond the initial unresectable disease 
recurrence; (2) date of 2nd recurrence in 
patients without evidence of disease after 
surgery of a resectable 1st recurrence; (3)
death.

Objective:  To identify molecular 
(genomic, metabolic, and/or proteomic) 
biomarkers that may be indicative of 
clinical response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of pembrolizumab.

Germline genetic variation, genetic 
deoxyribonucleic acid (DNA) mutations 
from tumor, tumor and blood RNA 
variation, proteomics and 
immunohistochemistry (IHC), and other 
biomarkers.
4. Study Design 
Overall Design 
This is a randomized, placebo-controlled, parallel-group, crossover/rechallenge, multicenter
study of adjuvant pembrolizumab in participants 12 years of age and older with resected 
Stage IIB or IIC cutaneous melanoma. Stage IIB and IIC cutaneous melanoma are defined as 
T category T3b, T4a, or T4b (Table 3), with negative sentinel lymph node (SLN) biopsy,
no regional metastases and no evidence of distant metastasis per AJCC 8th edition
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(Appendix 11) [Gershenwald, J. E., et al 2017]. The study design is depicted in Figure 1
(Section 1.2). Treatment regimens are described in Section 8.
Approximately 954 participants will be enrolled in the study. Eligible participants must have 
newly diagnosed, pathologically confirmed, completely resected melanoma with negative 
margins and had a negative SLN biopsy (Appendix 10). Participants cannot have received 
prior systemic therapy for Stage II melanoma. Participants will be randomized in a 1:1 ratio
to 1 of the 2 treatment groups.
In Part 1, participants with High-Risk Stage IIB or IIC melanoma will receive the 
pembrolizumab adult (≥18 years of age) dose of 200 mg IV or the pediatric (≥12 years old 
and <18 years old) dose of 2 mg/kg IV up to a maximum of 200 mg every 3 weeks, or saline 
placebo IV every 3 weeks for 17 cycles.
A participant randomized to receive pembrolizumab who is under 18 years of age at the 
beginning of Part 1 or Part 2 of the study will receive and remain on the pediatric dose of 
pembrolizumab (2 mg/kg up to 200 mg Q3W) throughout Part 1 or Part 2 respectively. Any 
participant who begins Part 2 as an adult will adhere to the fixed adult dose of 
pembrolizumab (200 mg Q3W) regardless of their Part 1 dosing regimen.
Participants will undergo imaging including chest/abdomen/pelvis computed tomography 
(CT) and/or magnetic resonance imaging (MRI), and neck CT and/or MRI for head and neck 
primaries, and other CT and/or MRI when clinically indicated every 6 months during 
treatment to be assessed by site radiologist and investigator for disease recurrence. PET alone 
will not be used for disease assessment but the CT component of PET will be allowed if of 
diagnostic quality per the Site Imaging Manual. Other images of acceptable diagnostic 
quality may be obtained at the discretion of the investigator.
Participants will be stratified in Part 1 as follows: one stratum for pediatric participants (≥12 
years of age and <18 years of age) and 3 strata for adult participants (≥18 years of age) based 
on T-stage tumor thickness and ulceration (T3b, T4a, T4b). In Part 1, study treatment must 
begin within 12 weeks of complete surgical resection. PK/antidrug antibody (ADA) data will 
be collected during Part 1 for pediatric participants. Disease recurrence is confirmed by 
investigator radiographically and/or by exam/biopsy and confirmed by the site via pathology. 
All participants will be unblinded after Sponsor consultation and approval at recurrence prior 
to crossover/rechallenge.
In Part 2, participants may receive up to 17 cycles or 35 cycles of pembrolizumab as adjuvant 
therapy per Part 2 eligibility guidelines (Section 6.7). Participants will receive 17 cycles of 
pembrolizumab Q3W after resection of recurrent disease if feasible (local recurrence, 
including local metastatic lymph nodes, or distant metastasis). Participants will receive up to 
35 cycles Q3W for unresectable disease recurrence [unresectable local (regional metastatic 
lymph nodes, in-transit, satellite, and/or microsatellite metastases) or unresectable distant 
recurrence]. Participants with distant metastasis who undergo complete resection should 
receive 17 cycles but with Sponsor approval may receive 35 cycles. Participants who achieve 
a complete response (CR) per RECIST 1.1 may discontinue pembrolizumab after at least 
8 administrations of treatment, including 2 doses beyond the date when the initial CR was 
declared. Participants receiving 35 cycles of therapy in Part 2 with partial response (PR) or 
stable disease (SD) per RECIST 1.1 or iPR or iSD per iRECIST should complete all 35 
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cycles of therapy. Participants are not eligible for further treatment with pembrolizumab 
beyond 35 cycles within the confines of the study. Participants will not be treated beyond 
true progression confirmed by iRECIST (see Section 8.2.1.6 for additional details).
The imaging schedule for participants with local, surgically resected recurrence will be every 
12 weeks during treatment. Investigators will assess recurrence radiographically (with site 
radiologist) and/or by examination with subsequent biopsy during treatment and follow-up. 
Lesions identified by physical examination should be photographed and submitted to the 
imaging vendor. For participants with unresectable local (regional metastatic lymph nodes, 
in-transit, satellite, and/or microsatellite metastases) or distant recurrence imaging will also 
be every 12 weeks during treatment. Investigators will use RECIST 1.1/iRECIST to assess 
disease response/progression for participants entering Part 2 therapy with 
unresectable/metastatic disease. 
Follow-up visits and imaging schedules will be scheduled in Part 1 and Part 2 per the SoA 
(Section 1.3). 
Detailed information on Parts 1 and 2 is found in Section 8.
The primary endpoint of the study is RFS. Secondary endpoints include DMFS and OS.
Distant metastasis refers to cancer that has spread from the original (primary) tumor and 
beyond local or nearby tissues and lymph nodes to distant organs or distant lymph nodes. 
This study will also examine the safety and tolerability of adult or pediatric pembrolizumab
doses administered every 3 weeks for 17 cycles and at recurrence for 17 or 35 cycles as a 
secondary endpoint. Safety evaluations will include AE monitoring, physical examinations, 
clinical laboratory parameters (hematology and chemistry), vital signs, and assessment of 
ECOG, KPS or LPS (Appendix 8: Performance Status Scales). Adverse events will be 
monitored throughout the study and graded in severity according to the guidelines outlined in 
the NCI CTCAE Version 4.0.  
Patient-reported outcomes (PROs) are an exploratory endpoint evaluating any clinically 
relevant differences between the 2 treatment arms in global quality of life. Differences will 
only be considered clinically relevant if they exceed the 10-point threshold on the 100-point 
QLQ-C30 scale. Health utilities will be described using the EQ-5D-5L. Other exploratory 
endpoints include identification of molecular biomarkers that may be indicative of clinical 
response/resistance, safety, pharmacodynamic activity, and/or the mechanism of action of 
pembrolizumab. Blood samples will be obtained to measure the pharmacokinetics (PK) of 
serum pembrolizumab in pediatric participants. The pembrolizumab serum minimum 
concentration (Ctrough) at planned visits and times will be summarized.
Treatment in Part 1 and Part 2 of the study will continue until documented disease 
recurrence, unacceptable AEs, intercurrent illness that prevents further administration of 
treatment, investigator’s decision to withdraw the participant, participant withdraws consent, 
participant requests to discontinue study treatment, pregnancy of the participant, 
noncompliance with study treatment or procedure requirement, completion of 17 cycles of 
pembrolizumab or placebo in Part 1, completion of 17 or 35 cycles of pembrolizumab in 
Part 2, or administrative reasons requiring cessation of treatment (Section 6.3.1).
After the end of study treatment, participants will be followed for 30 days for AE monitoring 
(SAEs and events of clinical interest (ECIs) will be collected for 90 days after the end of 
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study treatment). Participants who discontinue treatment for reasons other than disease 
recurrence will have posttreatment follow-up for disease status until metastatic disease 
recurrence, withdrawing consent, or they become lost to follow-up (see Section 7.1 for 
additional details). Thereafter, participants will be followed for OS every 12 weeks (±7 days) 
or more frequently as needed until death, withdrawal of consent, or the end of the study, 
whichever comes first.
This study will be conducted in conformance with Good Clinical Practices.
Five interim efficacy analyses are planned for this study to determine RFS, DMFS, and OS
as identified in Section 9.
Results of the interim analyses will be reviewed by an external Data Monitoring Committee 
(eDMC), which will make recommendations to the Sponsor to continue, modify or end the 
study according to the plan described briefly in Section 4.4.1 and in detail in Section 9. All 
participants will have been randomized into the study before the first interim analysis will 
be conducted.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Schedule of Activities (SoA), Section 1.3. 
Details of each procedure are provided in Section 8.
Scientific Rationale for Study Design 
Rationale for Endpoints
Efficacy Endpoints
Primary Efficacy Endpoint
This study will use RFS based on recurrence as assessed by the investigator as the primary 
endpoint. RFS 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.
Investigator identified recurrence will be used to make treatment decisions as well as for 
exploratory efficacy analyses where specified.
New incident cases of melanoma will be distinguished from recurrences by a local 
pathologist. A pathologist will review skin lesion biopsy specimens and resection samples to 
identify if an intraepidermal component exists in the sample. If an intraepidermal component 
does exist, it is consistent with a new primary melanoma as opposed to a regional (in-transit) 
or distant metastatic recurrence. Refer to Appendix 12 for details regarding Guidance for 
Distinguishing Primary Cutaneous Melanomas from Cutaneous Metastases of Melanoma.
New incident cases of melanoma and second cancer diagnoses are not counted as events for 
recurrence-free survival. A central imaging vendor will be used to collect, clean, and hold 
tumor imaging.
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Secondary Efficacy Endpoints
The secondary efficacy objectives of this study are to compare DMFS (time between the date 
of randomization and the date of 1st distant metastasis) and OS (time from the date of 
randomization to the date of death) between the 2 treatment arms in this study.
Safety Endpoints
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints including, but not limited to, the incidence of, 
causality, and outcome of AEs/serious adverse events (SAEs), and changes in vital signs and 
laboratory values. Adverse events will be assessed as defined by CTCAE, Version 4.0. 
Exploratory Endpoints
Exploratory endpoints for this study include patient-reported outcomes (Section 4.2.1.3.1) 
and biomarker studies (Section 4.2.1.5).
Rationale for Patient-reported Outcomes
The EORTC QLQ-C30 and EuroQoL-5D (EQ-5D) patient-reported outcomes (PROs) are not 
pure efficacy or safety endpoints because they are affected by both disease progression and 
treatment tolerability. 
EORTC QLQ-C30
EORTC QLQ-C30 is the most widely used cancer specific health-related quality of life 
(QoL) instrument, which contains 30 items and measures 5 functional dimensions (physical, 
role, emotional, cognitive, and social), 3 symptom items (fatigue, nausea/vomiting, and pain), 
6 single items (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea, and financial 
impact), and a global health and QoL scale [Aaronson, N. K., et al 1993]. The EORTC QLQ-
C30 is a psychometrically and clinically validated instrument appropriate for assessing QoL 
in oncology studies [Aaronson, N. K., et al 1993].
Note: The use of EORTC QLQ-C30 is restricted to adult participants.
EQ-5D-5L
The EQ-5D-5L is a standardized instrument for use as a measure of health outcome and will 
provide data to develop health utilities for use in health economic analyses [Rabin, R. 2001]. 
The 5 health state dimensions in the EQ-5D-5L include the following: mobility, self-care, 
usual activities, pain/discomfort, and anxiety/depression. Each dimension is rated on a 5-
point scale from 1 (no problem) to 5 (unable to/extreme problems). The EQ-5D-5L also 
includes a graded (0 to 100) vertical visual analog scale on which the participant rates his or 
her general state of health at the time of the assessment. This instrument has been used 
extensively in cancer studies and published results from these studies support its validity and 
reliability [Pickard, A. S., et al 2007].
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Pharmacokinetic Endpoints
Blood samples will be obtained to measure the PK of serum pembrolizumab in all pediatric
participants. The pembrolizumab serum minimum concentration (Ctrough) at planned visits 
and times will be summarized.
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or adverse events, the data might inform optimal use of therapies in the 
patient population. Furthermore, it is important to evaluate germline DNA variation across 
the genome in order to interpret tumor-specific DNA mutations.  Finally, microsatellite 
instability (MSI) may be evaluated as this is an important biomarker for some cancers (ie, 
colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Thus, genome-wide approaches may be used for this 
effort. Note that in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer). Circulating tumor 
DNA and/or RNA may also be evaluated from blood samples.
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Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with immunotherapies and/or other treatments 
administered. Immunotherapies induce a response in tumors that likely reflects an 
inflamed/immune phenotype. Specific immune-related gene sets (ie, those capturing 
interferon-gamma transcriptional pathways) may be evaluated and new signatures may be 
identified. Individual genes related to the immune system may also be evaluated (eg, IL-10).
MicroRNA profiling may also be pursued as well as exosomal profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to immunotherapy in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with immunotherapy in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to immunotherapy. Therefore, tumor tissue may be subjected to proteomic 
analyses using a variety of platforms that could include but are not limited to immunoassays 
and liquid chromatography/mass spectrometry. This approach could identify novel protein 
biomarkers that could aid in patient selection for immunotherapy and/or treatments.
Other biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as enzyme-linked immunoassay 
(ELISA) that measure proteins may also be evaluated from blood samples. Correlation of 
these biomarkers with response to immunotherapy and/or treatments may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers. This research would serve to develop such assays for 
future clinical use. 
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
Biomarker Research using Stool
Landmark studies have demonstrated that the gut microbiome can shape anti-tumor 
immunity and responses to immune checkpoint blockade in mouse models, and that 
modulation of the gut microbiome may enhance responses to immune checkpoint blockade. 
This has also been studied in patients on immune checkpoint blockade (anti-CTLA-4 and 
anti-PD-1), with evidence that differential bacterial signatures exist in responders versus non-
responders to therapy (with responders having higher diversity of the gut microbiome and 
differential composition compared with non-responders). Importantly, these differences in 
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the gut microbiome are associated with differential immune signatures in the tumor 
microenvironment [Lynch, S. V. 2016].
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma) 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research are presented in Appendix 2.
Rationale for the Use of Comparator/Placebo
In this study, participants will be will randomized at enrollment to the pembrolizumab or 
placebo treatment groups and are expected to be treated for 17 cycles in Part 1. Placebo will 
be normal saline solution prepared by the local unblinded pharmacist, dosed and 
administered in the same manner as the investigational product. Placebo is being used to 
allow for a blinded study thereby limiting bias and providing a comparator arm that is 
consistent with standard of care for patients with Stage II melanoma (ie, surgical resection).
Justification for Dose 
The planned dose of pembrolizumab for this study in adults 18 years of age and older 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. As outlined below, this dose is justified by:

Clinical data from 8 randomized studies in melanoma and NSCLC indications
demonstrating flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg every 2 weeks, representing an approximate 5 to 7.5-fold exposure range 
(refer to IB, Section 5.2.2)

Population PK analysis showing that both fixed-dosing and weight-based dosing 
provides similar control of PK variability with considerable overlap in the 
distributions of exposures, supporting suitability of 200 mg Q3W

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg Q3W across multiple indications, and
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
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically
based PK [PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and nonsmall cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 2 
mg/kg Q3W versus 10 mg/kg Q3W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, 
and KN021), and 3 studies compared 10 mg/kg Q3W versus 10 mg/kg every 2 weeks
(KN001 Cohort B3, KN001 Cohort 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 (TMDD) conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
Q3W. Second, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression. This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other 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.
A model-based PK bridging analysis, which included available pediatric PK data from the
pembrolizumab pediatric study KN051, was conducted to determine the pediatric dose based
on the approach of exposure matching with adults. This analysis showed that a dose of 2 
mg/kg (up to 200 mg) Q3W in pediatric participants provided PK exposures similar to those 
achieved at 2 mg/kg (or 200 mg) Q3W in adults, and served as the basis for approval of a 
pediatric indication in cHL as well as MSI-H cancers in the US at a dose of 2 mg/kg (up to
200 mg) Q3W. In addition, the safety of this dose in pediatric participants is established
based on data from KN051 [Geoerger, B., et al 2017]. The incidence of positive 
immunogenicity status after pembrolizumab treatment in pediatric participants (2.8%) was 
comparable with that in adults (2.1%) and had no impact on pembrolizumab exposure. Based 
on these results, the pediatric dose for evaluation in this study is 2 mg/kg Q3W (up to a 
maximum of 200 mg Q3W).
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Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
Clinical Criteria for Early Study Termination
The clinical study 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 study population 
as a whole is unacceptable. In addition, further recruitment in the study or at (a) particular 
study site(s) may be stopped due to insufficient compliance with the protocol, Good Clinical 
Practice (GCP) and/or other applicable regulatory requirements, procedure-related problems 
or the number of discontinuations for administrative reasons is too high.
5. Study Population
Male/Female participants with Stage IIB or IIC cutaneous melanoma of at least 12 years of 
age will be enrolled in this study.
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 Part 1 of the study only if all of the following 
criteria apply (See Section 6.7 for inclusion criteria for Part 2):
Type of Participant and Disease Characteristics
1. Male/female participants who are ≥12 years of age on the day of providing 
documented informed consent/assent [unless local regulations and/or institutional 
policies do not allow for participants <18 years of age to participate; for those sites, 
the eligible population is ≥18 years of age] with surgically resected and 
histologically/pathologically confirmed new diagnosis of Stage IIB or IIC cutaneous 
melanoma per AJCC 8th edition guidelines.
Note: Participants must have T-stage of T3b, T4a, or T4b (Table 3) with 
pathologically confirmed negative SLN biopsy, and no evidence of regional (N0) or 
distant metastatic disease (M0) per AJCC 8th edition guidelines (Appendix 11).
Surgical considerations can be found in Appendix 10.
2. Participants must not have been previously treated for melanoma beyond complete 
surgical resection.
Note: Participants may not have been treated with radiation therapy for their 
melanoma prior to study entry.  
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3. No more than 12 weeks may elapse between final surgical resection and 
randomization. Treatment should start only after complete wound healing from the 
surgery. If there is a delay of 1 to 7 days exceeding 12 weeks due to unforeseen 
circumstances, the eligibility should be discussed with the Sponsor and the decision 
documented. A delay of 1 to 7 days for screening imaging requirements will be 
allowed if Sponsor has allowed 1-week extension between surgical resection and 
randomization.  
Note:  Final surgical resection is defined in this protocol as complete resection of 
melanoma and a SLN biopsy. If the wide excision is followed by the SLN biopsy (ie,
they are not performed at the same time), no more than 12 weeks may elapse between 
the 2 surgical procedures. If a second wide excision needs to be completed after SLN 
biopsy, this date will be used to calculate final surgical resection date.
4. Have no evidence of metastatic disease on imaging as determined by investigator 
assessment. All suspicious lesions amenable to biopsy should be confirmed negative 
for malignancy.
5. Have a performance status of 0 or 1 on the ECOG Performance Scale at the time of 
enrollment, LPS score ≥50 (for participants ≤16 years old.), or a KPS score ≥50 (for 
participants >16 and <18 years old). (Appendix 8: Performance Status Scales).
6. Participant must have recovered adequately from toxicity and/or complications from 
surgery prior to starting study treatment.
Male participants:
7. Removed.
Female participants:
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 

Is not a woman of childbearing potential (WOCBP)
OR 
•
Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year) or be abstinent from heterosexual intercourse as their 
preferred and usual lifestyle (abstinent on a long-term and persistent basis) as 
described in Appendix 3 during the intervention period and for at least 120 days 
after the last dose of study intervention. The investigator should evaluate the 
potential for contraceptive method failure (ie, noncompliance, recently initiated) 
in relationship to the first dose of study intervention.
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•
A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] 
as required by local regulations) within 72 hours before the first dose of study 
intervention.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention 
are located in Appendix 3.
•
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.
•
Contraceptive use by women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
Informed Consent
9. The participant (or legally acceptable representative if applicable) provides 
documented informed consent/assent for the study and agrees to DMFS and OS data 
collection until these study endpoints are reached. 
10. The participant provides consent/assent for future biomedical research. However, the 
participant may take part in the main study without participating in future biomedical 
research.
11. Have adequate organ function as defined in Table 1. Specimens must be collected 
within 10 days prior to the start of study treatment.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L
Renal
Creatinine OR
Measured or calculated2 creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant 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
AST (SGOT) and ALT (SGPT)
Part 1 ≤2.5 × ULN
AST (SGOT) and ALT (SGPT)
Part 2 ≤2.5 × ULN (<5 × ULN for participants 
with liver metastases)
Coagulation
International normalized ratio (INR) OR 
prothrombin time (PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
ALT (SGPT) = alanine aminotransferase (serum glutamic-pyruvic transaminase); AST (SGOT) = aspartate 
aminotransferase (serum glutamic-oxaloacetic transaminase); GFR = glomerular filtration rate; ULN = upper limit of 
normal.
1 Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within 
last 2 weeks.
2 Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements 
should be adapted according to local regulations and guidelines for the administration of specific chemotherapies.
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Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has a known additional malignancy that is progressing or has required active 
antineoplastic therapy (including hormonal) within the past 5 years. 
Note:  Participants with basal cell carcinoma of the skin, squamous cell carcinoma of 
the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
Note: Participants with a history of nonulcerated cutaneous/acral primary melanoma 
<1 mm in depth with no nodal involvement are allowed in this study. Participants 
with any previous melanoma that was ulcerated, ≥1 mm in depth, with nodal 
involvement, metastasis, or was treated beyond surgical resection (for example, 
radiation therapy) are not eligible for this study. Participants with synchronous 
melanomas where lesions not under study are not ulcerated and <1 mm in depth are 
allowed on the study. Participants with a history of mucosal or uveal melanoma are 
excluded from this study even if diagnosis and treatment were completed >5 years 
ago. 
2. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy 
(in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study drug.
Note: The use of inhaled or topical steroids and systemic steroids at physiologic doses 
of corticosteroids (up to 5 mg/m2/day prednisone equivalent with maximum dose of 
10 mg daily) is allowed on study.
3. If participant received major surgery, they must have recovered adequately from the 
toxicity and/or complications from the intervention prior to starting study treatment.
4. A WOCBP who has a positive urine pregnancy test within 72 hours prior to 
randomization (see Appendix 5). If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.
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 
medication.
Prior/Concomitant Therapy
5. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or 
with an agent directed to another stimulatory or coinhibitory T-cell receptor 
(eg, CTLA-4, OX-40, CD137).
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6. Has received prior systemic anticancer therapy for melanoma including
investigational agents.
7. Has received a live vaccine within 30 days prior to the first dose of study drug. 
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, and typhoid vaccine. Seasonal influenza vaccines for injection are 
generally killed virus vaccines and are allowed; however, intranasal influenza 
vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
Prior/Concurrent Clinical Study Experience
8. Is currently participating in or has participated in a study of an investigational agent 
or has used an investigational device within 4 weeks prior to the first dose of study 
treatment.
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.
Diagnostic Assessments
9. Has severe hypersensitivity (≥Grade 3) to any pembrolizumab excipients.
10. 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) is not considered a form of 
systemic treatment and is allowed.
11. Has a history of (noninfectious) pneumonitis that required steroids or has current 
pneumonitis.
12. Has an active infection requiring systemic therapy.
13. Has a known history of human immunodeficiency virus (HIV) infection. No HIV 
testing is required unless mandated by local health authority.
14. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen reactive) 
or known active Hepatitis C virus (defined as Hepatitis C virus RNA [qualitative] is 
detected) infection. No testing for Hepatitis B and Hepatitis C is required unless 
mandated by local health authority.
CCI
CCI
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15. Has a history of active tuberculosis (Bacillus tuberculosis).
16. 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 
participation 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.
17. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
18. Removed.
19. Has had an allogeneic tissue/solid organ transplant.
Lifestyle Considerations
No restrictions are required.
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
Caffeine, Alcohol, and Tobacco Restrictions
No restrictions are required.
Activity Restrictions
No restrictions are required.
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, 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 the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 8.4.6.
CCI
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Screen Failures
Screen failures are defined as participants who consent/assent 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 adverse events (AEs) or serious adverse 
events (SAEs) meeting reporting requirements as outlined in the data entry guidelines.
Participant Replacement Strategy
A participant who discontinues from study treatment or withdraws from the study will not be 
replaced.
6. 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 treatment(s) provided by the Sponsor] 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 study are outlined below in Table 2.
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Table 2
Study Treatments
Study 
Treatment 
Name
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage Level(s)
Route of 
Administration
Regimen/
Treatment 
Period
Use
IMP/
NIMP
Sourcing
Pembrolizumab 
Solution for 
infusion
25 mg/mL 
vial
2 mg/kg (max. 200 
mg) Q3W for 
pediatric participants 
(≥12 and <18 years 
old); 
200 mg Q3W for 
adults (≥18 years of 
age)
IV infusion via 
infusion pump
Part 1: 17 
cycles
Part 2: 17 or 
35 cycles
Experimental
IMP
Provided 
centrally by 
the Sponsor
Saline placebo
Solution for 
infusion
None
None
IV infusion via 
infusion pump
Part 1:
17 cycles
Placebo
IMP
Provided 
locally by the 
study site, 
subsidiary, or 
designee
Definition Investigational Medicinal Product (IMP) is based on guidance issued by the European Commission. Regional and/or Country differences of the 
definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2  will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements. Every attempt should be made to source these 
supplies from a single lot/batch number where possible (eg, not applicable in the case where 
multiple lots or batches may be required due to the length of the study, etc.).
Refer to Section 8.1.8 for details regarding administration of the study treatment.
All study treatments will be administered on an outpatient basis.
Preparation/Handling/Storage/Accountability
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual.  
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 study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
Measures to Minimize Bias: Randomization and Blinding
Method of Treatment Assignment 
Treatment allocation/randomization will occur centrally using an interactive response 
technology (IRT) system. There are 2 study treatment arms. Participants will be assigned 
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randomly in a 1:1 ratio to pembrolizumab study treatment or saline placebo study treatment
in Part 1.
Stratification
Treatment allocation/randomization will be stratified according to the following factors:
1. Melanoma T-Stage (Table 3) for adults only 
2. A separate stratum for pediatric (age 12-17) participants
Table 3
Melanoma Stage Stratification Table
Melanoma Stage
T-Stage
T-Stage Definition (thickness and ulceration status)
IIB
T3b
>2.0-4.0 mm with ulceration
IIB
T4a
>4.0 mm without ulceration
IIC
T4b
>4.0 mm with ulceration
T-stage of disease as defined by thickness and ulceration status per AJCC guidelines 8th edition
Blinding 
In Part 1 of this study a double-blinding technique will be used. Pembrolizumab and placebo
will be prepared and/or dispensed in a blinded fashion by an unblinded pharmacist or 
unblinded qualified study site personnel. The participant and the investigator who is involved 
in the study treatment administration or clinical evaluation of the participants are unaware of 
the group assignments.
Participants in Part 2 will receive pembrolizumab as open-label treatment.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
Treatment Compliance
Administration of study medication(s) will be administered by the investigator and/or study 
staff according to the specifications within the Pharmacy Manual. The total volume of study 
medication infused will be compared with the total volume prepared to determine compliance 
with each dose administered.
Participants experiencing a greater than 12-week delay between doses due to a 
pembrolizumab-related AE(s) must be discontinued from treatment.
If there are interruptions in the study intervention schedule, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record. 
Refer to Section 6.6 for dose modification and toxicity management for irAEs associated 
with pembrolizumab and for other allowed dose interruptions of pembrolizumab.
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Concomitant Therapy
Specific Restrictions
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. If there is a clinical indication for any medication specifically prohibited, 
discontinuation from study treatment may be required. The investigator should discuss any 
questions regarding this with the Sponsor. The final decision on any supportive therapy rests 
with the investigator and/or the participant's primary physician. However, the decision to 
continue the participant on study treatment requires the mutual agreement of the investigator, 
the Sponsor and the participant.
Listed below are specific restrictions or prohibitions for concomitant therapy or vaccination 
during the course of the study:

Antineoplastic systemic chemotherapy, immunotherapy or biological therapy not 
specified in this protocol 
Note: Topical 5-fluorouracil use is allowed prior to enrollment on study. Treatment of 
skin cancers other than melanoma with any topical anticancer agents may be allowed 
during follow-up.

Investigational agents other than pembrolizumab.

Radiation therapy (See exceptions noted in inclusion and exclusion criteria for Part 2 
[Section 6.7]).

Live or live attenuated vaccines within 30 days before the first dose of study 
intervention and while participating in the study. Note: Killed vaccines are allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
ECI that is suspected to have an immunologic etiology. Inhaled or topical steroids are 
allowed, and systemic steroids at doses ≤5mg/m2/day (maximum allowed 10 mg/day)
prednisone or equivalent for pediatric participants (≥12 years old and <18 years old)
and ≤10 mg/day prednisone or equivalent are allowed for adults.
Participants who in the assessment of the Investigator require the use of any of the 
aforementioned treatments for clinical management should be removed from the study unless 
otherwise specified above.  
All treatments 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. All concomitant medication will be recorded on the electronic case report form 
(eCRF) including all prescription, over-the-counter (OTC) products, herbal supplements, and 
IV medications and fluids. If changes occur during the study period, documentation of drug 
dosage, frequency, route, and date should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study treatment 
and up to 30 days after the last dose of study treatment should be recorded. Concomitant 
medications administered 30 days after the last dose of study treatment should be recorded 
for SAEs and ECIs. ECIs are defined in Section 8.4.7.
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Rescue Medications and 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 along with the dose modification guidelines in 
Section 6.6, Table 4. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional antiinflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the Investigator determines the events to be 
related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance. Refer to Section 6.6 for 
guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Immune-related Events and Dose Modification (Withhold, Treat, Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab 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, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 4. 
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Table 4
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.    Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin 
if the irAEs are not controlled by corticosteroids.
2.    Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.    The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.    If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or 
Other Therapies
Monitoring 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
Recurrent Grade 
2 or Grade 3 or 4 
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.
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or 
Other Therapies
Monitoring 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
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure
Withhold a
   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 
discontinue a
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 
discontinue a
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or 
Other Therapies
Monitoring and Follow-up
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 
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology and/or 
exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
All Other irAEs
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 b
Recurrent Grade 
3 or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; 
SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a     The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the 
investigator or treating physician. If control achieved or ≤ Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b     Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically 
important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion.
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 5. 
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Table 5
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 h
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/h to 50 
mL/h). 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 study drug treatment
Participant may be premedicated 1.5h 
(±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).
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 study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the CTCAE v4.0 at http://ctep.cancer.gov
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Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant's study record. Imaging should not be delayed for delays in cycle treatment.
Part 2 – Crossover or Rechallenge Treatment After Recurrence
The primary goal of the overall study is to compare RFS of pembrolizumab versus placebo, 
while ensuring access to pembrolizumab for all participants entering the study by allowing 
crossover/rechallenge after recurrence.
All participants will be unblinded at recurrence (Section 8.1.11) after Sponsor consultation 
and approval. The site should ensure data for disease recurrence is entered in the database 
prior to unblinding. Additionally, any AEs and/or SAEs should be reported and causality 
attributed in the database prior to unblinding. Participants will be encouraged to undergo full
resection of the new lesion(s) if they experience local recurrence or have a biopsy if they 
experience unresectable or metastatic disease. Lymph node dissection should be undertaken 
per the recommendations of treating physician and surgeon.
For participants who decide to go on to Part 2 and otherwise meet criteria for crossover or 
rechallenge, resection or biopsy of unresectable or metastatic disease will be mandatory to 
confirm diagnosis. If biopsy is clinically contraindicated investigators should seek Sponsor 
review to start participant on Part 2 therapy. Participants should start Part 2 therapy within 
4 weeks of recurrence. If participant requires longer time from surgical resection (eg, for 
recovery from surgery), Sponsor may be consulted to allow additional time before start of 
Part 2 therapy.
All participants who complete Part 1 study treatment with pembrolizumab or received 
placebo will be eligible for additional cycles of pembrolizumab if they meet Part 2 
enrollment criteria listed below. Rechallenge/crossover is optional and is at the discretion of 
the Investigator upon notification of the Sponsor.
Participants assigned in the Part 1 initial treatment phase to the placebo arm who experience 
recurrence at any point during Part 1 therapy and follow-up and meet all crossover criteria 
will be offered crossover to pembrolizumab per dosing criteria in Section 4.3. Participants on 
the pembrolizumab arm during the initial phase of treatment who are greater than 6 months 
from last dose of pembrolizumab treatment and who experience a recurrence will be offered 
rechallenge with pembrolizumab per dosing criteria outlined in Section 4.3. Participants who 
have local recurrence, including local metastatic lymph nodes or distant metastases that are 
surgically resected may receive up to 17 cycles of therapy with pembrolizumab and 
participants with an unresectable local (regional metastatic lymph nodes, in-transit, satellite, 
and/or microsatellite metastases) or an unresectable distant recurrence may receive up to 35 
cycles of therapy with pembrolizumab per Section 1.3.2.  
All participants should have screening imaging within 28 days prior to C1D1 in Part 2 
Crossover/Rechallenge phase. The Part 1 EOT scan can be used as baseline for Part 2 if done 
within 4 weeks of 1st dose in Part 2. Participants who have had surgical resection of lesion 
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captured on imaging must have a scan after surgery or radiation is complete to establish 
baseline imaging within 4 weeks prior to start of Part 2 therapy. Brain MRI must be obtained 
within 4 weeks prior to start of Part 2 treatment, unless contradicted; then CT may be 
acquired.
Disease recurrence/progression is confirmed by investigator (radiographically and/or by 
exam with subsequent biopsy) and RECIST 1.1/iRECIST will be used to identify disease 
progression in participants with metastatic/unresectable disease identified at the start of Part 
2 therapy. Local recurrence should be documented with photo image.
Radiotherapy (palliative or adjuvant) is allowed prior to Part 2 (eg, post lymph node 
dissection radiotherapy when indicated). Radiotherapy has to be completed prior to first dose 
and complete wound healing is required prior to first dose. Radiotherapy is allowed during 
treatment in Part 2 as palliative therapy (treatment of pain, impending fracture, etc.) in 
participants with unresectable recurrence or metastatic disease. If surgery or radiotherapy 
other than described above is indicated while on Part 2 therapy Sponsor must be consulted.
All eligibility criteria from Part 1 Sections 5.1 and 5.2 remain valid and must be reconfirmed 
prior to enrollment into Part 2 of the study with the EXCEPTION of:

Inclusion Criteria 2, 3, 4 and 5

Exclusion Criteria 5, 6 and 11
Participants must also meet the following requirements for entry into Part 2:

Participant must have experienced an investigator determined/confirmed disease 
recurrence radiographically and/or by exam with subsequent biopsy. Local recurrence 
must be documented with photo image. Participants will only be eligible for Part 2 
treatment after the first recurrence. If a participant experiences a second recurrence, 
they will not be eligible for Part 2. Participants who are less than 6 months from their 
last Part 1 pembrolizumab dose at the time of recurrence are not eligible for Part 2 
treatment.
Note: Cutaneous lesions and other superficial lesions detectable only by physical 
exam must be categorized as nontarget lesions for Part 2 of the study. 

No new anticancer treatment was administered after the last dose of Part 1 study
treatment.

Participant is continuing from Part 1 and has completed 17 cycles of pembrolizumab
or any number of cycles with placebo with no delays in treatment ≥12 weeks. If a 
≥12-week treatment delay has occurred, Sponsor approval must be obtained before 
moving into Part 2 of the study.
Note: For any participant who is not able to complete the required 17 cycles of 
pembrolizumab or have ≥12-week treatment delay on placebo arm, a notification to 
the Sponsor is required to determine if it would impact their eligibility for entry into 
Part 2.

Surgical resection or biopsy of unresectable or metastatic disease completed within 4 
weeks of first dose. 
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
Full resection of lesions or biopsy of unresectable or metastatic disease confirmed by 
site pathologist to be melanoma. 
Note: If biopsy is clinically contraindicated, investigators should seek Sponsor review 
and approval to start participant on Part 2 therapy.
If participant is identified to have a thoracic lesion or lymph node suspicious for a
recurrence (especially if solitary lesion), it is encouraged that a biopsy be performed
to confirm metastatic melanoma versus another lung primary malignancy versus a 
nonmalignant lung disease (eg, sarcoidosis).

Participants with focal or multifocal brain metastasis who are asymptomatic and do 
not require supraphysiologic steroid therapy per Section 5.2 are allowed in Part 2 of 
the study and may receive concurrent radiation to these lesions. Participants with 
leptomeningeal disease are not allowed to proceed to Part 2 of the study. A brain MRI 
is required to confirm presence of brain metastasis and evaluate for leptomeningeal 
disease prior to start of Part 2 treatment and if contraindicated a CT may then be used. 
Brain lesions are not to be recorded as target lesions but should be followed as 
nontarget lesions.

ECOG performance status 0-2 in participants ≥18 years of age, LPS ≥50 for children 
up to and including 16 years of age, or KPS ≥50 for participants >16 and <18 years of 
age (Appendix 8).

For Part 2 of the study, any participant who developed a severe hypersensitivity 
(≥Grade 3) to any pembrolizumab excipients or pembrolizumab during Part 1 of the 
study will not be eligible for Part 2 therapy, as treatment in Part 1 was stopped 
secondary to an unacceptable AE.
Participants who discontinued study treatment during Part 1 due to documented disease 
recurrence on the pembrolizumab arm, unacceptable AEs, intercurrent illness that 
prevents further administration of treatment, investigator’s decision to withdraw the 
participant, participant withdraws consent, participant requests to discontinue study 
treatment, pregnancy of the participant, noncompliance with study treatment, procedure 
requirements, or administrative reasons, are not eligible for Part 2.
Treatment After the End of the Study 
The participant may be enrolled in an extension study upon completion of this study to 
continue protocol-defined assessments and treatment.
Clinical Supplies Disclosure
The emergency unblinding call center will use the treatment/randomization schedule for the 
study to unblind participants and to unmask study treatment identity during Part 1 of this 
study. The emergency unblinding call center should only be used in cases of emergency (see 
Section 8.1.11). In the event that the emergency unblinding call center is not available for a 
given site in this study, the central electronic treatment allocation/randomization system 
(IRT) should be used in order to unblind participants and to unmask study treatment identity. 
The Sponsor will not provide random code/disclosure envelopes or lists with the clinical 
supplies.
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Part 2 of the study is open-label; therefore, the participant, the study site personnel, the 
Sponsor and/or designee are not blinded. Study treatment (name, strength or potency) is 
included in the label text; random code/disclosure envelopes or lists are not provided.
See Section 8.1.11 for a description of the method of unblinding a participant during the 
study, should such action be warranted.
Standard Policies
At the close of the study 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 study conducted by the Sponsor. This is to advise you that you 
were among those who received a look-alike infusion provided locally by the clinical site to 
resemble the drug Keytruda (pembrolizumab) as much as possible. You did not receive the 
active drug Keytruda (pembrolizumab) as manufactured by Merck.”
7. Discontinuation of Study Treatment and Participant Withdrawal
Discontinuation of Study Treatment 
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 protocol-specified treatment period
will still continue to participate in the study as specified in Section 1.3 and Section 8.11.3.
Participants may discontinue study treatment at any time for any reason or be discontinued
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 the Sponsor if study treatment is inappropriate, the study 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 8.1.10.
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
The participant’s treatment assignment has been purposely unblinded by the investigator, 
MSD subsidiary or through the emergency unblinding call center during Part 1 prior to 
recurrence. 
o
Interruptions from the protocol-specified treatment plan for greater than or equal to
12 weeks between pembrolizumab doses for nondrug-related or administrative reasons 
require consultation between the investigator and the Sponsor and written documentation 
of the collaborative decision on participant management.
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o
A ≥12-week break in pembrolizumab treatment due to a drug-related AE.
o
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment.
o
The participant has a confirmed positive serum pregnancy test.
o
Participant with confirmed disease recurrence radiographically and/or by exam with 
subsequent biopsy while on Part 1 treatment with pembrolizumab or placebo must stop 
Part 1 study treatment. Participants on Part 1 treatment with placebo can be screened for 
Part 2 therapy with pembrolizumab.
o
Confirmed disease recurrence identified by investigator (radiographically and/or by exam
with subsequent biopsy) or confirmed progression per iRECIST if clinically stable during 
Part 2 treatment outlined in Section 8.11 (exception if the Sponsor approves treatment 
continuation).
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment (hormonal and/or antineoplastic therapy).
o
Exceptions to secondary malignancy include basal cell carcinoma of the skin, 
squamous cell carcinoma of the skin, new nonulcerated primary melanoma <1mm 
in depth with no nodal involvement, or carcinoma in situ (eg, breast carcinoma, 
cervical cancer in situ) that have undergone potentially curative therapy.
Exceptions should be discussed with the Sponsor prior to continuing therapy or 
remaining in follow-up.
o
Diagnosis of a new primary melanoma >1mm or <1mm with ulceration will result 
in discontinuation of therapy in Part 1 or Part 2 and make participant no longer 
eligible for Part 2 therapy.
o
Investigator may submit a Sponsor consultation form to request a participant be 
unblinded if the participant develops a second malignancy including a new 
primary melanoma >1mm or <1mm with ulceration.
o
Noncompliance with study treatment or procedure requirements.
o
Discontinuation of treatment may be considered for participants who have attained a 
confirmed CR and have been treated for at least 8 cycles (at least 24 weeks), receiving at 
least 2 doses of pembrolizumab beyond the date when the initial CR was declared.
o
Recurrent Grade 2 pneumonitis.
o
Completion of 17 cycles during Part 1 therapy.
Note: Participants who complete Part 1 therapy are still eligible for Part 2 therapy if they 
meet Part 2 eligibility guidelines. For any participant who is not able to complete the 
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required 17 cycles, a notification to the Sponsor is required to determine if it would 
impact eligibility for entry into Part 2.
o
Completion of 17 cycles or 35 cycles with pembrolizumab as assigned in Part 2.
Note: The number of treatments is calculated starting with the first dose.  
o
Withdrawal of consent by participant to continue on study.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
Participant Withdrawal From the Study
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, as well as specific details regarding withdrawal from future biomedical research are 
outlined in Section 8.1.10.1. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant
are outlined in Section 7.3.
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:
●
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.
●
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone 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.
●
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant. The missing data for the participant will be managed 
via the prespecified statistical data handling and analysis guidelines.
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8. 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.
●
The investigator is responsible for assuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
●
All study-related medical decisions must be made by an investigator who is a 
qualified physician.
●
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.
●
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent, and assent if 
applicable, be obtained from the participant. In these cases, such evaluations/testing 
will be performed in accordance with those regulations.
The maximum amount of blood collected from each pediatric participant will not exceed 
approximately 51 mL per cycle. The amount for adult participants will not exceed
approximately 42 mL per cycle.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
Administrative and General Procedures
Informed Consent/Assent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant or their legally 
acceptable representative prior to participating in this clinical study or future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent/assent is in place. 
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General Informed Consent
Informed consent/assent given by the participant or their legally acceptable representative 
must be documented on a consent/assent form. The form must include the trial protocol 
number, trial protocol title, dated signature, and /agreement of the participant (or his/her 
legally acceptable representative) and of the person conducting the consent/assent discussion.
A copy of the signed and dated informed consent/assent form should be given to the 
participant (or their legally acceptable representative) before participation in the study.
The initial informed consent/assent form, any subsequent revised informed consent/assent 
form, and any written information provided to the participant must receive the IRB/IEC’s 
approval/favorable opinion in advance of use.  The communication of this information will 
be provided and documented via a revised consent/assent form or addendum to the original 
consent/assent form that captures the participant’s or the participant’s legally acceptable 
representative’s dated signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
written documented informed consent/assent.
Participants must be re-consented with the current informed consent/assent form before 
entering Part 2 of the study.
Specifics about the study and the study population are to be included in the study informed 
consent/assent form. 
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. The assent as applicable will adhere to IRB/IEC requirements, 
applicable laws and regulations and Sponsor requirements.
Consent/Assent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent/assent to the participant, or the participant’s legally acceptable representative, answer 
all of his/her questions, and obtain documented informed consent/assent before performing 
any procedure related to future biomedical research. A copy of the informed consent/assent
will be given to the participant before performing any procedure related to future biomedical 
research.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator who is a qualified 
physician 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 study. The card will contain study 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 documented informed consent/assent. At the time of treatment 
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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.
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator. Details regarding the disease 
for which the participant has enrolled in this study will be recorded separately and not listed 
as medical history.
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 28 days before starting the study.
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. In addition, new medications started 
during Part 2 through the Part 2 Safety visit should be recorded. All medications related to 
reportable SAEs and ECIs should be recorded.
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 8.11.1. 
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.
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Treatment Administration
Study medication will be administered by the investigator and/or study staff according to the 
specifications within the Pharmacy Manual.
After ensuring participants meet study-related inclusion/exclusion criteria, study personnel 
will access IRT to obtain treatment number.
First study treatment should be administered within 3 calendar days of treatment number 
assignment in IRT.  
Timing of Dose Administration
Cycle 1 treatment should be administered starting with Day 1 of the first treatment cycle after
all procedures/assessments have been completed as detailed on the SoA (Section 1.3). Study 
treatment may be administered up to 3 days before or after the scheduled day of
administration due to administrative reasons. Participants may continue on treatment until
disease progression or until meeting other discontinuation criteria outlines in Section 7.1.
Part 2 Crossover/Rechallenge Therapy
See Section 6.7 for details on the Part 2 Crossover/Rechallenge therapy.
Discontinuation and Withdrawal
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 study, all applicable activities
scheduled for the final study visit should be performed (at the time of withdrawal). Any AEs
which are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4 -Adverse Events.
Withdrawal From Future Biomedical Research
A Participant’s consent for future biomedical research may be withdrawn by the participant 
or the participant’s legally acceptable representative (as appropriate) and their specimens and 
all derivatives destroyed.  A participant’s consent may be withdrawn at any time by 
contacting the principal investigator for the main study. If medical records for the main 
study are still available, the investigator will contact the Sponsor using the designated 
mailbox (clinical.specimen.management@merck.com). Subsequently, the participant's 
consent for future biomedical research will be withdrawn. A letter will be sent from the 
Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
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the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
Participant Blinding/Unblinding
STUDY TREATMENT IDENTIFICATION INFORMATION IS TO BE UNMASKED 
DURING PART 1 ONLY IF NECESSARY FOR THE WELFARE OF THE 
PARTICIPANT. EVERY EFFORT SHOULD BE MADE NOT TO UNBLIND. 
For emergency situations where the investigator or medically qualified designee (consistent 
with local requirements) needs to identify the drug used by a participant and/or the dosage 
administered, he/she will contact the emergency unblinding call center by telephone and 
make a request for emergency unblinding. As requested by the investigator or medically 
qualified designee the emergency unblinding call center will provide the information to 
him/her promptly and report unblinding to the Sponsor. Prior to contacting the emergency 
unblinding call center to request unblinding of a participant’s treatment assignment, the 
investigator who is a qualified physician should make reasonable attempts to enter the 
toxicity grade of the AEs observed, the relation to study drug, the reason thereof, etc., in the 
medical chart. If it is not possible to record this assessment in the chart prior to the 
unblinding, the unblinding should not be delayed.
In the event that unblinding has occurred, the circumstances around the unblinding (eg, date, 
reason and person performing the unblinding) must be documented promptly, and the 
Sponsor notified as soon as possible. 
Once an emergency unblinding has taken place, the principal investigator, site personnel, and 
Sponsor personnel (with the exception of the blinded study statisticians) may be unblinded so 
that the appropriate follow-up medical care can be provided to the participant.
For studies that require non-emergency unblinding as part of the study design (eg, disease 
progression) to support treatment decisions, instructions in Procedure Manual should be 
followed. The emergency unblinding center should not be used for this purpose.
Once a non-emergency unblinding has taken place (ie, after first recurrence), the principal 
investigator, site personnel, and Sponsor personnel (with the exception of the study blinded 
statisticians) may be unblinded to the participant’s data so that the appropriate follow-up 
medical care can be provided to the participant.
Participants whose treatment assignment has been unblinded by the investigator/delegate 
and/or nonstudy treating physician should continue to be monitored. Participants who qualify 
for Part 2 per the eligibility criteria in Section 6.7 may continue on the study.
The process for nonemergent unblinding at the time of disease recurrence in Part 1 requires 
the investigator to submit a Sponsor consultation form to the study clinical team requesting
authorization for official unblinding upon disease recurrence and consideration to proceed 
into Part 2 of the study (Crossover/Rechallenge treatment). After unblinding is complete, the 
site will assess the participant’s eligibility for Part 2 of the study and notify the Sponsor prior 
to beginning Part 2. The entry criteria for Part 2 are detailed in Section 6.7.  
During the study, all data should be entered as soon as possible after a protocol visit or 
procedure is conducted. Upon first recurrence, every effort must be made to have all pending 
data entered into the eCRFs within 1 business day or before the site is unblinded to the 
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participant’s treatment assignment. The site should ensure data for disease recurrence is 
entered in the database prior to unblinding. Additionally, any AEs and/or SAEs should be 
reported and causality attributed in the database prior to unblinding.
The study will be considered unblinded once the RFS endpoint has been achieved and has 
been reviewed by the eDMC. The Sponsor will identify to the sites the specific unblinding 
procedures to be followed.
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Participants Turning 18 Years of Age While on Study
For participants turning 18 years of age while on study, the following adjustments are to be 
observed:

Performance Assessment – The original performance assessment scale 
(Lansky/Karnofsky/ECOG) assigned to the participant will be used throughout Part 1. 
A participant will be assigned the appropriate age-related performance scale when 
entering Part 2.

Pharmacokinetics (PK and ADA Samples) – Sample collection will cease once a 
participant turns 18 years of age.

Height – Height is not collected for adults entering Part 1 or Part 2 other than at Part 1
screening. A participant below the age of 18 entering Part 1 or Part 2 will continue to 
have their height collected regardless of age.

Pembrolizumab dosing – A participant randomized to receive pembrolizumab who is 
under 18 years of age at the beginning of Part 1 or Part 2 of the study will receive and 
remain on the pediatric dose of pembrolizumab (2 mg/kg up to 200 mg Q3W) 
throughout Part 1 or Part 2 respectively. Any participant who begins Part 2 as an adult 
will adhere to the fixed adult dose of pembrolizumab (200 mg Q3W) regardless of 
their Part 1 dosing regimen.
Efficacy Assessments 
Tumor Scans and Assessment of Disease
Throughout this section, the term 'scan' refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
Tumor imaging is strongly preferred to be acquired by CT. For the abdomen and pelvis, 
contrast-enhanced MRI may be used when CT with iodinated contrast is contraindicated, or 
when mandated by local practice. Magnetic resonance imaging is the strongly preferred 
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modality for imaging the brain. A CT scan of the extremity where the primary melanoma was 
diagnosed (or MRI if CT scan is contraindicated) should be performed at the investigator’s 
discretion or when clinically indicated. The same scan 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 scans. Note: for 
the purposes of assessing tumor scans, the term “investigator” refers to the local investigator 
at the site and/or the radiological reviewer located at the site or at an offsite facility.
Initial Tumor Scans 
Initial tumor scans at Screening must be performed within 28 days prior to the date of 
randomization. The site study team must review screening scans to confirm the participant 
has no evidence of disease at study entry into Part 1. Exceptions can be made if screening 
scan performed outside of 28-day screening period. Sponsor approval must be obtained prior 
to randomization.
Tumor Scans During the Study
For Part 1 the first on-study scan time point will be performed 6 months (26 weeks ± 7 days)
from date of randomization. Subsequent tumor scans should be performed every 6 months 
(26 weeks ±7 days) while on treatment, at end of treatment, every 6 months (26 weeks ±14 
days) from years 2 to 4 from randomization, and then once in year 5 (365 ±28 days) from 
randomization or until recurrence, whichever comes first. More frequent scans may occur if 
clinically indicated.
Participants entering Part 2 who have resection of lesion captured on scans should have 
repeat scans after surgery or radiation to establish baseline imaging within 4 weeks prior to 
start of Part 2 therapy. For all Part 2 participants the first on-study scan assessment should be 
performed at 12 weeks (84 ±7 days) after first dose of pembrolizumab in Part 2 (C1D1). For 
participants with local recurrence including local metastatic lymph nodes surgically resected 
and distant metastasis surgically resected, subsequent tumor scan should be performed every 
12 weeks (84 ±7 days) for 1 year from C1D1 while on treatment, at end of treatment, every 
12 weeks (84 ±7 days) in year 2 from C1D1, every 6 months (26 weeks ±14 days) from years 
3-5 from C1D1 and yearly thereafter (365 days ±28 days) or until recurrence.  
For participants entering Part 2 who have unresectable disease, the first on-study scan
assessment should be performed at 12 weeks (84 ±7 days) after first dose of pembrolizumab 
(C1D1) in Part 2. Subsequent tumor scans should be performed every 12 weeks (84 ±7 days) 
for 2 years from C1D1 while on treatment, at end of treatment, every 12 weeks (84 ±7 days)
in year 3 from C1D1, every 6 months for years 4-5 (26 weeks ±14 days) from C1D1 and 
yearly thereafter (365 days ±28 days) or until recurrence.
Scans will be performed more frequently if clinically indicated. Scan timing should follow 
calendar days and should not be adjusted for delays in cycle starts.
Scans should continue to be performed until one of the following occurs:

Metastatic disease recurrence is identified by the investigator or 

Progression in Part 2 is assessed by investigator using RECIST 1.1/iRECIST criteria
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
Participant enters DMFS follow-up

Participant enters Survival Follow-up

Withdrawal of consent

Death 

End of study. 
Objective response should be confirmed by a repeat scan assessment. Tumor scans to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled scans, starting with 
the next scheduled scan time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor scan if it is less than 4 weeks 
later; tumor scans may resume at the subsequent scheduled imaging time point. 
Response assessment in Part 2 will be based on RECIST 1.1/ iRECIST as assessed by 
investigator/local radiology review. Objective response to confirm PR/CR is based on 
RECIST 1.1, and iRECIST will be used to confirm PD after initial site-assessed radiologic 
PD per RECIST 1.1 in clinically stable participants. Per iRECIST (Section 8.2.1.5), disease 
progression should be confirmed by the site 4 to 8 weeks after site-assessed first radiologic 
evidence of PD in clinically stable participants. Participants with unconfirmed disease 
progression may continue on treatment at the discretion of the investigator until disease 
progression is confirmed by the site, provided they have met the conditions detailed in 
Section 8.2.1.5. Participants who receive confirmatory scans do not need to undergo the next 
scheduled tumor scan if it is less than 4 weeks later; tumor scans may resume at the 
subsequent scheduled scan time point, if clinically stable. Participants with confirmed disease 
progression by iRECIST, as assessed by the site, will discontinue study treatment. 
Exceptions are detailed in Section 8.2.1.5.
A central imaging vendor will be used to collect, clean, and hold tumor scans. Images will be 
collected for possible analysis by BICR. The same scan technique should be used at each 
time point and the schedule of disease assessment should not be adjusted for delays, if any, in 
cycle starts of disease assessment. The process for scan collection and transmission to the 
central imaging vendor can be found in the Site Imaging Manual (SIM).
End of Treatment and Follow-up Tumor Scans
For participants who discontinue study treatment, tumor scans should be performed at the 
time of treatment discontinuation (± 4 week window). If previous scan was obtained within 4 
weeks prior to the date of discontinuation, then the scan at treatment discontinuation is not 
mandatory. If study required interval imaging is due within 4 weeks of EOT, interval scans
are not mandatory if all required scans have been obtained at EOT.
For participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor scans using the 
same scan schedule used while on treatment until metastatic disease recurrence disease 
progression, death, withdrawal of consent, or the end of the study, whichever occurs first.
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Summary of Scans
Part 1 Adjuvant Treatment

Tumor scans at Screening must be performed within 28 days prior to randomization. 
Exceptions can be made if screening scan is performed outside of the 28-day 
screening period. Sponsor approval must be obtained prior to randomization.  

The first on-study scan time point will be performed 6 months (26 weeks ±7 days) 
from the date of randomization.

All consecutive scans are to be performed every 6 months (26 weeks ±7 days) from 
randomization, at EOT (±7 days), every 6 months (26 weeks ±14 days) during years 2 
to 4 from randomization, and once in year 5 from randomization (365 ±28 days; ie, 5 
years from the date of randomization) or until disease recurrence. Imaging schedule 
may or may not coincide with visit schedule.

Scan timing should follow calendar days and should not be adjusted for delays in 
cycle starts.

DMFS follow-up and SFU scan collection is per local standard of care or scan
requirements for new anticancer therapy.

Participants who had the last scan performed in the preceding 4 weeks of planned 
EOT visit may have EOT scan omitted at the discretion of the investigator. For 
participants who discontinue study treatment without documented recurrence, every 
effort should be made to continue monitoring disease status every 6 months (26 
weeks ±7 days) from randomization, at EOT (±7 days), every 6 months (26 weeks 
±14 days) during years 2 to 4 from randomization, and once in year 5 from 
randomization (365 ±28 days; ie, 5 years from the date of randomization) or until 
disease recurrence. Scan schedule may or may not coincide with visit schedule.

If study required interval scans are due within 4 weeks of EOT, interval scans are not 
mandatory if all required scans have been obtained at EOT.

All scan assessments performed in Part 1 must be scheduled based on date of 
randomization.

Scans of any anatomy that show disease after screening or in subsequent evaluations 
will be required and should be submitted to the Central Imaging Vendor.

Brain CT may be acquired if MRI is contraindicated.  

Site investigator must collect and review copy of scans and reports (including scans
done external to site), photographs and pathology reports to update disease status. A
central imaging vendor will be used to collect, clean, and hold tumor scans obtained 
during the DMFS phase of the study. A central imaging vendor will be used to 
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collect, clean, and hold tumor scans obtained during the SFU phase of the study if 
scans are available.

Scan schedule may or may not coincide with visit schedule.
Part 2 Crossover/Rechallenge After First Recurrence

The EOT scan from Part 1 can be used as baseline for Part 2 if done within 4 weeks 
of 1st dose in Part 2. If the EOT scan (from Part 1) cannot be used as the screening 
scan for Part 2, the latest scan date should be within 4 weeks prior to first dose in Part 
2. Participants who have resection or radiation of lesion captured on scan should have 
a repeat scan after surgery or radiation is complete to establish baseline imaging 
within 4 weeks prior to start of Part 2 therapy.

All scans performed while on treatment and during the follow-up phase of Part 2 must 
be scheduled based on C1D1 of treatment in Part 2.

EOT scan in Part 2 should be obtained at EOT (± 4 weeks).

During Part 2 treatment phase (ie, in the absence of a second recurrence on-study), 
participants who had the last scan performed in the preceding 4 weeks of the planned 
Part 2 EOT visit may have Part 2 EOT scan omitted at the discretion of the 
investigator.

For participants with local recurrence including local metastatic lymph nodes 
surgically resected, scan assessment should be done every 12 weeks (84 ±7 days) for 
1 year from C1D1, at EOT (±7 days), every 12 weeks in year 2 from C1D1 (84 ±7 
days), every 6 months (26 weeks ±14 days) from years 3-5 from C1D1, and yearly 
(365 days ±28 days) thereafter until recurrence or end of study, whichever comes 
first.

For participants with local recurrence including local metastatic lymph nodes 
surgically resected who discontinue study treatment without documented recurrence, 
every effort should be made to continue monitoring disease status by tumor scan
every 12 weeks (84 ±7 days) for 1 year from C1D1, every 12 weeks (84 ±7 days) in 
year 2 from C1D1, every 6 months in years 3-5 (26 weeks ±14 days) from C1D1, and 
yearly thereafter (365 ±28 days) until recurrence or end of study, whichever comes 
first.  

For participants with distant metastatic disease who have undergone complete 
surgical resection, scan assessments should be done every 12 weeks (84 ±7 days) for 
1 year from C1D1, at EOT (±7 days), every 12 weeks (84 ±14 days) in year 2 from 
C1D1, every 6 months in years 3-5 (26 weeks ±14 days) from C1D1, and yearly 
thereafter (365 days ±28 days) until recurrence or end of study, whichever comes 
first.
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
For participants with resectable distant recurrence who discontinue study treatment 
without documented recurrence every effort should be made to continue monitoring 
disease status by tumor scan every 12 weeks (84 ±7 days) for the first year from 
C1D1, every 12 weeks (84 ±7 days) in year 2 from C1D1, every 6 months (26 weeks 
±14 days) in years 3-5 from C1D1, and yearly thereafter (365 days ±28 days) or until 
recurrence/progression or end of study, whichever comes first. 

For participants with unresectable local (regional metastatic lymph nodes, in-transit, 
satellite, and/or microsatellite metastases) or unresectable distant recurrence scans
should be done every 12 weeks (84 ±7 days) from C1D1 during the first 2 years from 
C1D1, at EOT (±7 days), every 12 weeks (84 ±7 days) in year 3 from C1D1, every 
6 months (26 weeks ±14 days) in years 4-5 from C1D1, and yearly thereafter (365 
days ±28 days) until recurrence/progression or end of study, whichever comes first.  

For participants with unresectable local (regional metastatic lymph nodes, in-transit, 
satellite, and/or microsatellite metastases) or unresectable distant recurrence who 
discontinue study treatment without documented recurrence/progression on Part 2, 
every effort should be made to continue monitoring disease status by tumor scan
every 12 weeks (84 ±7 days) during years 1-2 from C1D1, every 12 weeks (84 ±7 
days) in year 3 from C1D1, every 6 months (26 weeks ±14 days) in years 4-5 from 
C1D1, and yearly thereafter (365 ±28 days).until recurrence/progression or end of 
study, whichever comes first. 

All target and nontarget lesions should be followed at every scan time point.  

Scans of any anatomy that shows disease either at screening or in subsequent 
evaluations will be required and should be submitted to the Central Imaging Vendor.

Brain MRI must be obtained within 4 weeks prior to start of Part 2 TX, unless 
contraindicated; then CT may be acquired. Scan timing should follow calendar days 
and should not be adjusted for delays in cycle starts.

Site investigator must collect and review copy of scans and reports (including scans
done external to site) to update disease status. A central imaging vendor will be used 
to collect, clean, and hold tumor scans obtained during the DMFS phase of the study.
A central imaging vendor will be used to collect, clean, and hold tumor scans
obtained during the SFU phase of the study if it is available.

Scan schedule may or may not coincide with visit schedule.
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used 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.
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iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs (Appendix 9). iRECIST will be used by the investigator to 
assess tumor response and progression and make treatment decisions. When clinically stable, 
participants should not be discontinued until progression is confirmed by the investigator, 
working with local radiology. This allowance to continue treatment despite initial radiologic 
PD takes into account the observation that some participants can have a transient tumor flare 
in the first few months after the start of immunotherapy, and then experience subsequent 
disease response. This data will be captured in the clinical database.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of 
disease.
•
No decline in ECOG performance status, KPS status, or LPS status (Appendix 8).
•
No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care.
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST. If the investigator decides to continue treatment, the 
participant may continue to receive study treatment and the tumor assessment should be 
repeated 4 to 8 weeks later to confirm PD by iRECIST, per investigator assessment.
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
If a participant has confirmed radiographic progression (iCPD), study treatment should be 
discontinued; however, if the participant is achieving a clinically meaningful benefit, an 
exception to continue study treatment may be considered following consultation with the 
Sponsor. In this case, if study treatment is continued, tumor imaging should continue to be 
performed following the intervals as outlined in Section 1.3. 
A description of the adaptations and iRECIST process are found in the iRECIST publication 
[Seymour, L., et al 2017]. A summary of imaging and treatment requirements after first 
radiologic evidence of progression is provided in Table 6 and illustrated as a flowchart in 
Figure 3.
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Table 6
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic evidence 
of PD by RECIST 1.1
Repeat imaging at 4 to 
8 weeks to confirm PD.
May continue study 
treatment at the 
investigator’s discretion 
while awaiting confirmatory 
tumor imaging by site by 
iRECIST.
Repeat imaging at 4 to 
8 weeks to confirm PD 
per investigator’s 
discretion only.
Discontinue treatment.
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per 
investigator assessment.
No additional imaging 
required.
Discontinue treatment 
(exception is possible upon 
consultation with Sponsor).
No additional imaging 
required.
Not applicable.
Repeat tumor imaging 
shows iUPD by 
iRECIST per 
investigator assessment.
Repeat imaging at 4 to 
8 weeks to confirm PD. 
May occur at next 
regularly scheduled 
imaging visit.
Continue study treatment at 
the investigator’s discretion.
Repeat imaging at 4 to 
8 weeks to confirm PD 
per investigator’s 
discretion only.
Discontinue treatment.
Repeat tumor imaging 
shows iSD, iPR, or iCR 
by iRECIST per 
investigator assessment.
Continue regularly 
scheduled imaging 
assessments.
Continue study treatment at 
the investigator’s discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study treatment if 
condition has improved and/or 
clinically stable per 
investigator’s discretion. Next 
tumor imaging should occur 
according to the regular 
imaging schedule.
iCPD = iRECIST confirmed progressive disease; iCR = iRECIST complete response; iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics; iSD = iRECIST stable disease; iUPD = iRECIST unconfirmed progressive disease; PD = progressive disease; RECIST 1.1 = Response Evaluation Criteria in Solid 
Tumors 1.1; VOP = verification of progression.
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iRECIST = modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; PD = progressive 
disease; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors 1.1.
Figure 3
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the Investigator
Lactic Acid Dehydrogenase
Lactic acid dehydrogenase (LDH) will be collected at the time of recurrence in Part 1 as a 
baseline. In Part 2 LDH will be collected as per the SoA (Section 1.3) in an advanced disease 
setting.
Quality of Life Assessments
Patient-reported Outcomes
The EuroQoL EQ-5D-5L and EORTC QLQ-C30 questionnaires will be administered by 
trained site personnel and completed electronically by participants in the following order: 
EuroQoL EQ-5D first, then EORTC QLQ-C30. In Part 1, EuroQoL EQ-5D-5L and EORTC 
QLQ-C30 should be completed at baseline (Cycle 1), during treatment in year one (at Cycle 
5, 9, 13, 17), every 12 weeks during year 2 (Week 60, 72, 84, and 96 from baseline), and 
every 6 months during year 3 (month 30 and 36 from baseline). The EORTC QLQ-C30 will 
be administered only to adults (≥18 years of age at baseline) since the questionnaire is not 
validated in pediatric populations. The EuroQoL EQ-5D-5L will be administered to all study 
participants, since it is considered acceptable to use for persons 12 years and older.
In Part 2, EuroQoL EQ-5D-5L should be completed during this phase at baseline (Cycle 1), 
during treatment at Cycles 9, 17 and 35, and at 24 and 48 weeks during first year off 
treatment.  
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It is best practice and strongly recommended that electronic PROs are administered to 
randomized participants prior to drug administration, AE evaluation, and disease status 
notification. If the participant does not complete the electronic PROs at a scheduled time 
point, the MISS_MODE form must be completed to capture the reason the assessment was 
not performed.
Safety Assessments
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 prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the 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 complete physical exam 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 1.3. After the first 
dose of study treatment, new clinically significant abnormal findings should be recorded as 
AEs.
Directed Physical Exam
For cycles that do not required a full physical exam as defined in Section 1.3, 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. The investigator or qualified designee should conduct a visual inspection of 
local recurrence and palpation of regional lymph nodes to assess regional recurrence.
Photographs of new skin lesions not visualized on imaging should be obtained and submitted 
to imaging vendor.
Vital Signs

Temperature, pulse rate, respiratory rate, and blood pressure will be assessed.

Blood pressure and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 
available.

Blood pressure and pulse measurements should be preceded by at least 5 minutes of 
rest for the participant in a quiet setting without distractions.
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
Vital signs will be measured after 5 minutes rest and will include temperature, 
systolic and diastolic blood pressure, and pulse and respiratory rate. 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of study treatment and at treatment discontinuation, and in 
follow-up as specified in Section 1.3. Vital signs are to be measured immediately before the 
start of study medication administration and as needed per standard of care.
For adult participants, height will be measured only at Screening in Part 1 and Part 2. For 
pediatric participants, height will be measured at study visits as specified in Section 1.3.
Weight measurements may be conducted up to 3 days before the scheduled day of 
administration due to administrative reasons. Weight measurement is not required 
postinfusion. 
Electrocardiograms
A standard 12-lead electrocardiogram (ECG) will be performed and reviewed by an 
investigator or medically qualified designee (consistent with local requirements) at screening
in Part 1 and Part 2. Clinically significant abnormal findings should be recorded as medical 
history. Additional time points may be performed as clinically necessary.
Note: A 6-lead ECG is allowed per institutional standard.
Clinical Safety Laboratory Assessments
Refer to Appendix 5 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
●
The investigator or medically qualified designee (consistent with local requirements)
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those which are not associated with the 
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 5, must be 
conducted in accordance with the SoA.
●
If laboratory values from nonprotocol 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. 
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Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 72 hours prior to 
the first dose of study treatment in Parts 1 and 2 of the study. 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 test result. Repeated Pregnancy test should be performed 
according to the SoA (Section 1.3) and may be conducted as required by local regulations.
Performance Assessments

Use of Performance scale is dependent upon age: LPS for participants up to and 
including 16 years of age; KPS for participants >16 and <18 years of age, or ECOG
for participants ≥18 years of age. The original performance assessment scale 
(Lansky/Karnofsky/ECOG) assigned to the participant will be used throughout Part 1. 
A participant will be assigned the appropriate age-related performance scale when 
entering Part 2 and that scale will be used throughout Part 2.
ECOG Performance Status
The ECOG scale is a standard way of measuring the ability of participants to perform 
ordinary tasks, with scores ranging from 0 to 5. A lower score means the participant is better 
able to carry out daily activities. See Appendix 8 for a description of the full scale. The 
ECOG scale will be assessed as specified in the SoA (Section 1.3) in participants ≥18 years 
of age. An ECOG score of 0 or 1 is required for admission to the study.
Karnofsky Performance Scale
The KPS is a standard way of measuring the ability of cancer patients to perform ordinary 
tasks, with scores ranging from 0 to 100%. A higher score means the patient is better able to 
carry out daily activities. See Appendix 8 for a description of the full scale. The KPS will be 
assessed as specified in the SoA (Section 1.3) for participants >16 and <18 years of age. A
KPS ≥50% is required for study eligibility.
Lansky Play-Performance Scale
The LPS score is a standard way of measuring the functionality of pediatric participants up to 
and including the age of 16. The LPS is rated by parents based on their child's activity over 
the past week. Parents fill out the assessment based on the directions on the form, and the 
form is readministered over time to assess for changes in performance status. A higher score 
means the child is functioning better. See Appendix 8 for a description of the full scale. The 
LPS will be assessed as specified in the SoA (Section 1.3). An LPS ≥50% is required for 
study eligibility.
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Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events 
The definitions of an AE or 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/recurrence of the cancer under study is not considered an AE as described in
Section 8.4.5 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 and any designees are responsible for detecting, 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 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
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 participant provides 
documented informed consent/assent but before intervention allocation/randomization must 
be reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event causes 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. 
●
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.
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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 the Sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 7.
Table 7
Reporting Time Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Time Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
SPONSOR:
Consent to 
Randomization/ 
Allocation (Part 1)
Consent to Time of 
First Dose (Part 2)
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period 
(Part 1)
Time of First Dose 
Through Protocol-
specified Follow-up 
Period (Part 2)
After the 
Protocol-
specified Follow-
up Period
Non-Serious 
Adverse Event 
(NSAE) 
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant 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
- participant 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:
- participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout or 
run-in treatment 
including placebo run-
in). Exception: A 
positive pregnancy test 
at the time of initial 
screening is not a 
reportable event unless 
the participant has 
received study 
intervention.
Report all
Previously 
reported – Follow 
to 
completion/termi
nation; report 
outcome
Within 24 hours of 
learning of event
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Type of Event
Time Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
SPONSOR:
Consent to 
Randomization/ 
Allocation (Part 1)
Consent to Time of 
First Dose (Part 2)
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period 
(Part 1)
Time of First Dose 
Through Protocol-
specified Follow-up 
Period (Part 2)
After the 
Protocol-
specified Follow-
up Period
Event of 
Clinical Interest 
(require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- Potential drug-
induced liver injury 
(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 AEs, SAEs, 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 nonleading 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, events of clinical interest (ECIs), 
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 7.3). In 
addition, the investigator will make every attempt to follow all nonserious 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 the Sponsor 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 has 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 AEs will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R2) Guidelines for GCP.
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●
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy 
and forwarded to investigators as necessary.
●
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file 
it along with the IB 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 the Sponsor as described 
in Section 8.4.1. Specifically, the suspected/actual events covered in this exception include 
any event that is disease progression/recurrence of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint which upon review 
is not progression of the cancer under study will be forwarded to Global Pharmacovigilance
as an SAE within 24 hours of determination that the event is not progression/not recurrence
of the cancer under study.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
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 (ECIs)
Selected nonserious and serious adverse events are also known as ECIs and must be reported 
to the Sponsor.
Events of clinical interest for this study include: 
1. an overdose of Sponsor's product, as defined in Section 8.5, 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.*
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*
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 study site guidance 
for assessment and follow-up of these criteria can be found in the Investigator Trial 
File Binder (or equivalent).
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater, or ≥5 times the indicated dose.
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Sponsor based on the clinical evaluation of the participant.
Pharmacokinetics
To evaluate the immunogenicity and exposure of pembrolizumab in this indication in 
pediatric participants in Part I of this study, sample collections for analysis of PK and ADA
are currently planned as shown in the SoA (Section 1.3.1). Blood samples for PK and ADA 
collected will be stored. Analysis will be performed only if required. If ongoing PK and/or 
ADA sampling is deemed to be unnecessary by the Sponsor, it may be reduced or 
discontinued.
Blood Collection for Serum MK-3475
Sample collection, storage and shipment instructions for serum samples will be provided in 
the operations/laboratory manual.
Pharmacodynamics
Sample collection, storage and shipment instructions for pharmacodynamic samples will be 
provided in the Procedure Manual.
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants in this study as specified in the SoA:

Blood for Genetic Analysis

Blood for RNA Analysis

Blood for Plasma Biomarker Analysis

Blood for Serum Biomarker Analysis

Stool for Biomarker Analysis
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
Blood for circulating tumor DNA (ctDNA)

Tumor tissue 
Sample collection, storage and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.
The sample for genetic analysis should be drawn for planned exploratory biomarker research. 
This sample will not be collected at the site if there is either a local law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for 
these purposes. If leftover extracted DNA will be stored for future biomedical research if the 
participant provides documented informed consent/assent for future biomedical research. If 
the genetic sample collection is not approved, but future biomedical research is approved and 
consent/assent is given, this sample will be collected for the purpose of future biomedical 
research.
Future Biomedical Research Sample Collection 
If the participant provides documented informed consent/assent for future biomedical 
research, the following specimens will be obtained as part of future biomedical research:
Leftover biomarkers listed in Section 8.8
Medical Resource Utilization and Health Economics 
Medical resource utilization and health economics data associated with medical encounters 
will be collected in the CRF by the investigator and study site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded. 
The data collected may be used to conduct exploratory economic analyses and will include:

Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient)

Duration of hospitalization (total days or length of stay, including duration by wards
[eg, intensive care unit])

Number and type of diagnostic and therapeutic tests and procedures

Outpatient medical encounters and treatments (including physician or emergency room 
visits, tests and procedures, and medications)
All cause hospitalization and emergency room visits must be reported in the eCRF 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.
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Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
above in Section 8.
Screening
Approximately 28 days prior to treatment randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5. 
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8. Unless otherwise specified, assessments/procedures are to be 
performed prior to administration of study treatment. Unless otherwise specified, the window 
for each visit is ±3 days.
Discontinued Participants Continuing to be Monitored in the Study
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before initiation of a new anti-cancer treatment, whichever 
comes first. 
Efficacy Follow-up Visits
Participants in Part 1 and 2 who complete study treatment or discontinue study treatment for 
a reason other than disease progression will begin Efficacy Follow-up and should be assessed
per respective Part 1 and Part 2 SoA (Section 1.3) until PD to monitor disease status. Every 
effort should be made to collect information regarding disease status until disease 
progression, withdrawal of consent, pregnancy, or end of study, whichever occurs first. 
Information regarding post-study anticancer treatment will be collected if new treatment is 
initiated. 
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 6.7 will move from Efficacy Follow-up to Part 2 when they experience 
disease recurrence. Details are provided in the SoA (Section 1.3) for retreatment with 
pembrolizumab.
Distant Metastases-free Survival Follow-up
Part 1 participants who start a new anti-cancer therapy with history of local recurrence, or 
who do not qualify for or do not enter Part 2 therapy will move into DMFS Follow-up  until 
distant metastatic recurrence is identified. Part 2 participants without a history of distant 
recurrence, with a history of local recurrence who experience a second local recurrence or 
local progression, or start a new anti-cancer therapy, will move into DMFS Follow-up until 
distant metastatic recurrence is identified. These participants should be assessed or contacted 
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by telephone or at an in-person visit approximately every 12 weeks to review disease status, 
recent imaging and current therapy until participants develop distant metastatic recurrence. 
Site investigator must collect and review copy of imaging reports, photographs and 
pathology reports (including imaging and biopsy/pathology assessment done external to site) 
to update disease status. A central imaging vendor will be used to collect, clean, and hold 
tumor imaging obtained during the DMFS phase of the study. Images will be collected for 
possible analysis by BICR. In the event that a participant refuses any further contact, or if a 
participant is discontinued from the study, the participant can authorize their site investigator
to provide updated information about their tumor, anticancer treatment, well-being and 
overall status updates on their behalf. Radiographic imaging in the DMFS phase may be 
performed as clinically indicated per local standard of care or following new anticancer 
therapy imaging schedule and investigator assessments should be reported to the Sponsor.
Information regarding post-study anti-cancer treatment will be collected if new treatment is 
initiated.  
Survival Follow-up Contacts
Part 1 participants with distant metastases will move into Survival Follow-up if they do not 
qualify for or choose to not enter Part 2 of the study. Part 2 participants with a history of 
distant metastases or who develop new distant metastases during Part 2 will move into 
Survival Follow-up.
Participant Survival Follow-up status will be assessed approximately every 12 weeks until 
death, withdrawal of consent, or the end of the study, whichever occurs first. The collection 
of survival includes disease status (recurrence, progression, or new malignancy) if available 
or not already collected in imaging scans; record of further anticancer therapies and the 
outcomes in accordance with local regulations and participant consent.
The first Survival Follow-up assessment should be scheduled as described below: 
•
For participants who discontinue treatment intervention and who will not enter the 
efficacy follow-up phase, the first Survival Follow-up contact will be scheduled 12 
weeks after the discontinuation visit and/or Safety Follow-up visit (whichever is last).  
•
For participants who completed assessments in Efficacy Follow-up, the first Survival 
Follow-up contact will be scheduled 12 weeks after the last Efficacy Follow-up visit 
has been performed.
These participants should be assessed or contacted by telephone or at an in-person visit
approximately every 12 weeks to review disease status, recent imaging, and current therapy. 
Site investigator must collect and review copy of imaging reports, photographs, and 
pathology reports (including imaging and biopsy/pathology assessment done external to site) 
to update disease status if it is available. A central imaging vendor will be used to collect, 
clean, and hold submitted tumor imaging obtained during the SFU phase of the study. In the 
event that a participant refuses any further contact, or if a participant is discontinued from the 
study, the participant can authorize their site investigator to provide updated information 
about their tumor, anticancer treatment, well-being, and overall status updates on their behalf. 
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Radiographic imaging in Survival Follow-up may be performed as clinically indicated, per 
local standard of care, or following new anticancer therapy imaging schedule. Information 
regarding poststudy anticancer treatment will be collected if new treatment is initiated.  
Vital Status 
To ensure current and complete vital status for survival data is available at the time of 
database locks, updated vital status survival status may be requested during the study by the 
Sponsor. For example, updated vital status for survival data may be requested prior to but not 
limited to an eDMC review, interim analysis (IA), and/or final analysis (FA). Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their vital status for survival
data  (excluding participants that have a previously recorded death event in the collection 
tool).
Post-study
Participants will be required to return to clinic approximately 30 days after the last dose of 
study treatment for the poststudy visit. If the poststudy visit occurs less than 30 days after the 
last dose of study treatment, a subsequent follow-up telephone call should be made at 30 days 
post the last dose of study treatment to determine if any AEs have occurred since the 
poststudy clinic visit.
9. Statistical Analysis Plan 
This section outlines the statistical analysis strategy and procedures for the study. If, after the 
study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended (consistent 
with International Council for Harmonisation [ICH] Guideline E-9). Changes to exploratory 
or other nonconfirmatory analyses made after the protocol has been finalized, but prior to the 
conduct of any analysis, will be documented in a supplemental Statistical Analysis Plan 
(sSAP) and referenced in the Clinical Study Report (CSR) for the study. Separate analysis 
plans may be developed for PK/modeling analysis, biomarker analysis, and genetic data 
analysis. Post hoc exploratory analyses will be clearly identified in the CSR. The PRO 
analysis plan will also be included in the sSAP.
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Statistical Analysis Plan Summary
Key elements of the Statistical Analysis Plan (SAP) are summarized below. The 
comprehensive plan is provided in Section 9.2 – Responsibility for Analyses/In-house 
Blinding through Section 9.12 – Extent of Exposure.
Study Design 
Overview
A Randomized, Double-blind Phase 3 Study to Evaluate Pembrolizumab 
versus Placebo as Adjuvant Treatment for High-Risk Stage II melanoma
Treatment 
Assignment
Approximately 954 participants will be randomized in about 15 months
(double-blind) in a 1:1 ratio between 2 treatment arms: 
(1) Pembrolizumab as adjuvant therapy or
(2) Placebo as adjuvant therapy.  
Stratification factors are as follows: one stratum for pediatric (age 12-17) 
participants and 3strata for adult (age 18 and over) participants defined by 
T-stage (T3b, T4a, and T4b).
Analysis 
Populations
Efficacy: Intention-to-Treat Population (ITT)
Safety: All Participants as Treated (APaT) 
Primary Endpoint
Recurrence-free survival (RFS)
Key Secondary 
Endpoint(s)
1.
Distant Metastasis-free Survival (DMFS)
2.
Overall Survival (OS)
Statistical Methods 
for Key Efficacy 
Analyses
Treatment comparisons for time-to-event endpoints such as RFS, DMFS and 
OS will be evaluated using a stratified log-rank test. The hazard ratio (HR)
will be estimated using a stratified Cox model.
Statistical Methods 
for Key Safety 
Analyses
The analysis of safety will follow a tiered approach. There are no Tier 1 
events for this study. Point estimates and 95% confidence intervals (CIs) for 
between-treatment comparisons via the Miettinen and Nurminen method will 
be provided for Tier 2 safety endpoints; only point estimates by treatment 
group will be provided for Tier 3 safety endpoints [Miettinen, O. 1985]. 
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Interim Analyses
Five efficacy interim analyses (IAs) and a final analysis will be performed. 
Results will be reviewed by an external Data Monitoring Committee (eDMC). 
Details are provided in Section 9.7 –Interim Analyses. 
Efficacy IAs
IA 1 (IA1): Scheduled at ~128 observed RFS events, about 33 months 
after the first participant is randomized
o Primary purpose: First interim analysis of RFS 
IA 2 (IA2): Scheduled at ~179 observed RFS events, about 48 months 
after the first participant is randomized
o Primary purpose: Final analysis of RFS
IA 3 (IA3): Scheduled at ~146 DMFS events have been observed, about 
60 months after the first participant is randomized
o Primary purpose: First interim analysis of DMFS 
IA 4 (IA4): Scheduled at ~195 observed DMFS events, about 108 months 
after the first participant is randomized
o Primary purpose: Final analysis of DMFS 
IA 5 (IA5): Scheduled at ~154 OS events have been observed, expected at 
~120 months after the first participant is randomized
o Primary purpose: First interim analysis of OS 
Final analysis: Scheduled at ~204 OS events, 180 months after the first 
participant is randomized. 
o Primary purpose: Final analysis of OS 
Multiplicity
The overall Type-I error rate over the 1 primary and 2 secondary efficacy 
endpoints will be strongly controlled at 2.5% (one-sided).
Sample Size and 
Power 
The planned sample size is approximately 954 participants. 
The final analysis of RFS in this the study is expected to occur at ~ 48 months 
after first participant is randomized. It is estimated that approximately 179
RFS events will have been observed among all participants. 
The final analysis of DMFS in this the study is expected to occur at ~108
months after first participant is randomized. It is estimated that approximately 
195 DMFS events will have been observed among all participants. 
The final analysis of OS in this the study is expected to occur at ~180 months 
after first participant is randomized. It is estimated that approximately 204 OS 
events will have been observed among all participants. 
(1) RFS: the study has an overall ~92% power at a one-sided 2.5% alpha 
level, if the true HR is 0.60.
(2) DMFS: the study has an overall ~84% power at a one-sided 2.5% alpha 
level, if the true HR is 0.65.
(3) OS: the study has an overall ~80% power at a one-sided 2.5% alpha 
level, if the true HR is 0.67.
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Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics Department of the Sponsor.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IRT.
Part 1 of this study will be conducted as a double-blind study under in-house blinding 
procedures. Blinded Sponsor personnel will remain blinded throughout study conduct and the 
official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete. In addition, the site radiologist(s) will perform the imaging review without 
knowledge of treatment group assignment and provide their results to the site investigator. 
Blinding with respect to planned efficacy interim analyses is described in Section 9.7 –
Interim Analyses. Protocol-specified blinding to treatment assignment will be maintained at 
all investigational sites. 
Part 2 of this study is open-label, so individuals participating in Part 2 will not remain 
blinded throughout the entire conduct of the study.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3 – Objectives/Hypotheses and 
Endpoints.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
Efficacy Endpoints
Primary Efficacy Endpoint
Recurrence-free Survival (RFS)
Recurrence-free Survival is defined as the time from randomization to any of the following 
events: recurrence of melanoma at any site (local, in-transit or regional lymph nodes or 
distant recurrence) or death due to any cause. New incident cases of melanoma and second 
cancer diagnoses are not counted as events for recurrence-free survival. See Section 9.6.1 –
Statistical Methods for Efficacy Analyses for the definition of censoring. 
Secondary Efficacy Endpoints
Distant Metastasis-free Survival (DMFS)
Distant Metastasis-free Survival is defined as the time from randomization to the first 
diagnosis of a distant metastasis. Distant metastasis refers to cancer that has spread from the 
original (primary) tumor and beyond local tissues and lymph nodes to distant organs or 
distant lymph nodes.
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Overall Survival (OS)
Overall survival is defined as the time from randomization to death due to any cause.
Exploratory Endpoints  
Time to Subsequent Therapy (TTST)
Time to subsequent therapy is defined as time from randomization to the date of first 
subsequent therapy (eg, surgery, radiation therapy, antineoplastic therapy) or death (whatever 
the cause) whichever occurs first. 
Progression/Recurrence-free Survival 2 (PRFS2)
Progression/recurrence-free Survival 2 is defined as the time between the date of 
randomization and the earliest of the following:

date of 1st disease progression per RECIST1.1 beyond the initial unresectable disease 
recurrence (unresectable local-regional disease recurrence or unresectable distant 
metastatic disease recurrence); 

date of 2nd recurrence in patients without evidence of disease after surgery of a 
resectable 1st recurrence (resectable local-regional recurrences or resectable distant 
metastatic disease recurrence); 

date of death.
Safety Endpoints
Safety measurements are described in Section 4.2.1 – Rationale for Endpoints and Section 
8.3 – Safety Assessments.
PRO Endpoints
The PRO endpoints are exploratory endpoints and are assessed using the EORTC QLQ-C30
version 3 and the EQ-5D-5L utility score. The primary Health-Related Quality of Life 
endpoint that is considered relevant for this study is the EORTC QLQ-C30 global health 
status/QoL scale. The other EORTC QLQ-C30 scales will be considered secondary. 
Differences will only be considered clinically relevant if they exceed the 10-point threshold 
on the 100-point EORTC QLQ-C30 scale.
Analysis Populations
Efficacy Analysis Population
The intention-to-treat (ITT) population will serve as the population for primary efficacy 
analyses. All randomized participants will be included in this population. Participants will be 
included in the treatment group to which they are randomized.
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Details on the approach to handling missing data are provided in Section 9.6 – Statistical 
Methods.
Safety Analysis Population
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 included in the treatment group 
corresponding to the study treatment they actually received for the analysis of safety data 
using the APaT population. 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 treatment for one cycle, but 
receives the correct treatment for all other cycles, will be analyzed according to the 
randomized 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 one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
PRO Analysis Population
PRO analyses are based on the PRO Full Analysis Set (FAS) population, defined as 
participants who have at least one PRO assessment available and have received at least one 
dose of study treatment.
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to the tertiary objectives addressing PROs and other exploratory 
endpoints (eg, TTST) will be described in the sSAP.
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type-I error control strategy are described in Section 9.8 – Multiplicity. Nominal p-values 
will be computed for other efficacy analyses but should be interpreted with caution due to 
potential issues of multiplicity.
Recurrence-free Survival (RFS)
The nonparametric Kaplan-Meier method will be used to estimate the RFS curve in each 
treatment group. The treatment difference in RFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron’s method of tie handling will be 
used to assess the magnitude of the treatment difference (ie, 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. Kaplan-Meier estimates and the 
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corresponding 95% CIs at specific follow-up time points will be provided for RFS. The 
stratification factors used for randomization (see Section 6.3.1.1 – Stratification) will be 
applied to both the stratified log-rank test and the stratified Cox model. 
Since disease assessment is performed periodically, events such as disease recurrence and 
metastatic disease recurrence can occur any time in the time interval between the last 
assessment where the event was not documented and the assessment when the event is 
documented. For the primary analysis, the true date of the event will be approximated by the 
date of the first assessment at which event is objectively documented. Participants who do 
not experience a first recurrence event will be censored at the last disease assessment.   
In order to evaluate the robustness of the RFS endpoint, a sensitivity analysis with a different 
set of censoring rules will be performed. For the sensitivity analysis, the true date of the 
event will be approximated by the date of the first assessment at which event is objectively 
documented, after ≤1 missed disease assessment and before new anticancer therapy is 
initiated, if any. Participants who experience a first recurrence immediately after 
≥2 consecutive missed disease assessments or after new anticancer therapy is initiated will be 
censored at the last disease assessment prior to the earlier date of the ≥2 consecutive missed 
disease assessment or date the new anticancer therapy is initiated. Participants who do not 
experience a first recurrence event will be censored at the last disease assessment before new 
anticancer therapy is initiated, if any. The censoring rules for primary and sensitivity analyses 
of RFS are summarized in Table 8.
Table 8
Censoring Rules for Primary and Sensitivity Analyses of RFS
Situation
Primary Analysis
Sensitivity Analysis
Recurrence or death documented 
after ≤1 missed disease assessment, 
and before new anticancer therapy, 
if any
Event at earliest date of 
documented recurrence or death
Event at earliest date of 
documented recurrence or death
Recurrence or death documented 
immediately after ≥2 consecutive 
missed disease assessments or after 
new anticancer therapy, if any
Event at earliest date of 
documented recurrence or death
Censored at last disease 
assessment prior to the earlier 
date of ≥2 consecutive missed 
disease assessment and new 
anticancer therapy, if any
No recurrence and no death; and 
new anticancer treatment is not 
initiated
Censored at last disease assessment 
Censored at last disease 
assessment 
No recurrence and no death; new 
anticancer treatment is initiated
Censored at last disease assessment 
Censored at last disease 
assessment before new 
anticancer treatment 
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The proportional hazards assumption on RFS will be examined using both graphical and 
analytical methods if warranted. The log[-log] of the survival function vs. time for RFS may
be plotted for the comparison between the pembrolizumab and placebo arms. If the curves 
are not parallel, indicating that hazards are not proportional, supportive analyses may be 
conducted to account for the possible non-proportional hazards effect associated with 
immunotherapies using, for example, the Restricted Mean Survival Time method [Uno, H., et 
al 2014] or a parametric method [Odell, P. M., et al 1994].
One assumption for the stratified Cox proportional hazard model is that the treatment HR is 
constant across the strata. If strong departures from this assumption are observed (which can 
result in a notably biased and/or less powerful analysis), a sensitivity analysis may be 
performed based on a two-step weighted Cox model approach, in which the treatment effect 
is first estimated for each stratum, and then the stratum specific estimates are combined for 
overall inference using sample size weights [Mehrotra, D. V., et al 2012].
As indicated in Section 9.4.1.1, new primary melanomas will not be counted as RFS events 
for the primary RFS analysis. A sensitivity analysis to include new primary melanomas as 
RFS events will be performed to assess the robustness of the RFS endpoint.
Additional supportive unstratified analyses may also be provided. Further details of 
sensitivity analyses will be described in the sSAP.
Distant Metastases-free Survival
Nonparametric cumulative incidence curves will be used to estimate the ‘time to metastatic 
disease’ curves. The treatment difference in risk for metastatic disease will be assessed by the 
stratified log-rank test. A stratified Cox proportional hazard model with Efron’s method of tie 
handling will be used to assess the magnitude of the treatment difference (ie, the HR). The 
HR and its 95% CI from the stratified Cox model with a single treatment covariate will be 
reported. The stratification factors used for randomization (see Section 6.3.1.1 –
Stratification) will be applied, as stratification factors used for analysis, to both the stratified 
log-rank test and the stratified Cox model. Participants without documented metastatic 
disease diagnosis (and alive) will be censored at the date of their last disease assessment.
Overall Survival
The nonparametric 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. A stratified 
Cox proportional hazard model with Efron’s method of tie handling will be used to assess the 
magnitude of the treatment difference (the HR). The HR and its 95% CI from the stratified 
Cox model with a single treatment covariate will be reported. The stratification factors used 
for randomization (see Section 6.3.1.1 – Stratification) will be applied, as stratification 
factors used for analysis, to both the stratified log-rank test and the stratified Cox model. 
Kaplan-Meier estimates and the corresponding 95% CIs at specific follow-up time points will 
be provided for OS. Participants without documented death at the time of the analysis will be 
censored at the date of the last follow-up.
Additional supportive unstratified analyses may also be provided. Further details of OS 
sensitivity analyses will be described in the sSAP as needed.
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Summary of Statistical Methods for Efficacy
Table 9 summarizes the primary analysis approach for primary and secondary efficacy 
endpoints. Sensitivity analysis methods are described above for each endpoint as applicable.
Methods related to exploratory objectives (and supportive analyses including TTST and 
PRFS2) will be described in the sSAP.
The strategy to address multiplicity issues with regard to multiple efficacy endpoints, 
multiple populations, and interim analyses is described in Section 9.7 – Interim Analyses and 
in Section 9.8 – Multiplicity.
Table 9
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Method†
Analysis 
Population
Missing Data Approach
Primary Hypothesis 1
RFS 
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
See Table 8 for censoring 
rules 
Secondary Hypothesis 2
DMFS
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored at last known 
disease evaluation
Secondary Hypothesis 3
OS
Test: Stratified log-rank test
Estimation: Stratified Cox 
model with Efron’s tie 
handling method
ITT
Censored at last known 
alive date
† Statistical models are described in further details in the text. For stratified analyses, the stratification factors used for 
randomization will be used as stratification factors for analysis.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse experiences (AEs), laboratory tests and vital signs.
The analysis of safety results will follow a tiered approach as shown in Table 10. The tiers 
differ with respect to the analyses that will be performed. Adverse events (specific terms as 
well as system organ class terms) are either prespecified as “Tier 1” endpoints or will be 
classified as belonging to "Tier 2" or "Tier 3" based on the number of events observed.
Safety parameters or AEs of interest that are identified a priori constitute “Tier 1” safety 
endpoints that will be subject to inferential testing for statistical significance. There are no 
Tier 1 events for this protocol. Based on a review of historic chemotherapy data and data 
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from ongoing pembrolizumab clinical studies in gastric cancer, there are no AEs of interest 
that warrant inferential testing for comparison between treatment arms in this study.
Tier 2 parameters will be assessed via point estimates with 95% CIs provided for between-
group comparisons. 
Membership in Tier 2 requires that at least 10% of participants in any treatment group exhibit 
the event; all other adverse experiences and predefined limits of change will belong to Tier 
3. The threshold of at least 10% of participants was chosen for Tier 2 event because the 
population enrolled in this study are in critical conditions and usually experience various 
adverse events of similar types regardless of treatment, events reported less frequent than 
10% of participants would obscure the assessment of overall safety profile and add little to 
the interpretation of potentially meaningful treatment differences. In addition, the percentage 
of participants with any AE, any drug-related AE, any Grade 3-5 AE, any serious AE, any 
AE which is both drug-related and Grade 3-5, any AE which is both serious and drug-related, 
a dose modification due to AE, a discontinuation due to an AE, and death will be considered 
Tier 2 endpoints. Because many 95% confidence intervals may be provided without 
adjustment for multiplicity, the confidence intervals should be regarded as a helpful 
descriptive measure to be used in review, not a formal method for assessing the statistical 
significance of the between-group differences in adverse experiences and predefined limits of 
change. These analyses will be performed using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [Miettinen, O. 1985].
Other safety parameters including AEs occurring in <10% of participants and continuous 
measures such as changes from baseline in laboratory and vital signs will be considered Tier 
3 safety parameters. For laboratory tests and vital signs, summary statistics for baseline, on-
treatment, and change from baseline values will be provided by treatment group in table 
format.
Table 10
Analysis Strategy for Safety Parameters
Safety Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any Serious AE 
X
X
Any Grade 3-5 AE
X
X
Any Drug-related AE
X
X
Any Serious and Drug-related AE
X
X
Any Grade 3-5 and Drug-related AE
X
X 
Discontinuation due to AE
X
X
Death
AEs (≥10% of participants in one of the treatment groups)
X
X
Tier 3
AEs or PDLCs
X
Change from Baseline Results (Labs, ECGs, Vital Signs)
X
PDLC = Predefined Limit of Change; X = results will be provided.
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Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant characteristic will be assessed by 
the use of tables and/or graphs. No statistical hypothesis testing will be performed on these 
characteristics. The number and percentage of participants screened and randomized and the 
primary reasons for screening failure and discontinuation will be displayed. Demographic 
variables (eg, age) and baseline characteristics will be summarized by treatment either by 
descriptive statistics or categorical tables.
Interim Analyses
Safety Interim Analyses
The eDMC will conduct regular safety monitoring. The timing of the safety monitoring will 
be specified in the DMC charter. 
Efficacy Interim Analyses
There are 5 efficacy interim analyses and a final analysis planned for this study (see 
Table 11). Details on how the planned analyses are incorporated into establishing statistical 
significance and the boundaries with regard to efficacy are discussed further in Section 9.8, 
Multiplicity. 
Treatment level results of the efficacy interim analyses will be provided by an external 
unblinded statistician to the eDMC. 
The eDMC will serve as the primary reviewer of the results of the interim analyses and will 
make recommendations for discontinuation of the study or modification to an Executive 
Oversight Committee (EOC) of the Sponsor. Depending on the recommendation of the 
eDMC, the Sponsor may prepare a regulatory submission. Participant-level unblinding to 
support regulatory filing will be restricted to a designate team at the Sponsor, who will have 
no other responsibilities associated with the study.
If the eDMC recommends modifications to the design of the protocol or discontinuation of 
the study, this EOC may be unblinded to study results at the treatment level in order to act on 
these recommendations or facilitate regulatory filing. Limited additional Sponsor personnel 
may also be unblinded to the treatment level results of the IA(s), if required, in order to act 
on the recommendations of the eDMC or facilitate regulatory filing. The extent to which 
individuals are unblinded with respect to results of interim analyses will be documented. 
Additional logistical details, revisions to the above plan and data monitoring guidance will be 
provided in the eDMC Charter.
Prior to final study unblinding, the external unblinded statistician will not be involved in any 
discussions regarding modifications to the protocol, statistical methods, identification of 
protocol deviations, or data validation efforts after the interim analyses.
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Table 11
Analyses Planned, Endpoints Evaluated, and Drivers of Timing
Analysis
Endpoint
Criteria for Conduct of Analysis
Estimated Time 
after First 
Participant 
Randomized
Primary 
Purpose of 
Analysis
IA 1: Interim 
RFS analysis
RFS 
(1) enrollment is completed, and
(2) ~ 128 RFS events observed
~33 months
RFS IA
IA 2: Final RFS 
analysis
RFS 
~179 RFS events observed
~48 months
RFS FA
IA 3: Interim 
DMFS analysis
DMFS
~146 DMFS events observed
~60 months
DMFS IA
IA 4: Final 
DMFS analysis; 
DMFS
~195 DMFS events
~108 months
DMFS FA
IA 5: Interim OS 
analysis
OS 
~154 OS events
~120 months
OS IA
FA: Final OS 
analysis
OS
~204 OS events
~180 months
OS FA
Abbreviations: RFS = Recurrence-free Survival; DMFS = distant metastatic-free survival; FA = final 
analysis; IA = interim analysis; OS = overall survival 
Multiplicity
The multiplicity strategy specified in this section will be applied to the primary hypothesis 
and 2 secondary hypotheses. The primary hypothesis tests the superiority of pembrolizumab 
to placebo with respect to RFS. The 2 secondary hypotheses test the superiority of 
pembrolizumab to placebo with respect to DMFS and OS. The overall Type-I error among 
the 3 hypotheses is strongly controlled at 2.5% (one-sided), with 2.5% initially allocated to 
the RFS hypothesis. The study will be considered a success if RFS is demonstrated to be 
statistically significant at either an interim analysis or the final analysis under multiplicity 
control.
The study uses the graphical method of Maurer and Bretz [Maurer, W. 2013] to control 
multiplicity for multiple hypotheses as well as interim analyses. According to this approach, 
when a particular null hypothesis is rejected, the alpha allocated to that hypothesis can be 
reallocated to other hypothesis tests. 
Figure 4 shows that the initial one-sided α allocation is assigned to the RFS hypothesis. 
Should the RFS comparison be statistically significant, the 2.5% alpha will be reallocated to 
the DMFS comparison. Should the DMFS comparison be statistically significant, the 2.5% 
alpha will be reallocated to the OS comparison.
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Figure 4
Multiplicity Graph for Type-I Error Control of Study Hypotheses
Recurrence-free Survival
The study initially allocates α = 2.5%, one-sided to test RFS. Table 12 shows the boundary 
properties for the interim analyses, which were derived using a Lan-DeMets O'Brien-
Fleming approximation spending function. Note that the final row indicates the total power to 
reject the null hypothesis for RFS. If the actual number of RFS events differs from that 
specified in the table, the bounds will be adjusted using the O’Brien-Fleming alpha-spending 
function accordingly. 
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Table 12
Boundary Properties for Planned Analyses of the RFS Analyses Based on α = 0.025
Analysis
Value
Efficacy
IA 1: 71%(1)
Z(2)
2.4115
N: 954
p (1-sided)(2)
0.0079
Events: 128
HR(3) at bound
0.6522
Month: 33
P(Cross)(4) if HR=1
0.0079
P(Cross)(4) if HR=0.6
0.6717
Final (IA2)
Z
2.0029
N: 954
p (1-sided)
0.0226
Events: 179
HR at bound
0.7410
Month: 48
P(Cross) if HR=1
0.0250
P(Cross) if HR=0.6
0.9190
(1)  Percentage of total number of events expected at final analysis
(2)  Boundary values for statistical significance
(3)  HR= hazard ratio
(4)  Probability of crossing boundary for statistical significance 
Distant Metastases-free Survival
The study initially allocates α=0.0, one-sided to test DMFS. If the null hypothesis for RFS is 
rejected, α=0.025 is fully reallocated to DMFS hypothesis testing. 
Table 13 shows the boundary properties for the interim analysis (at 60 months from first 
participant enrolled) and final analysis (at 108 months), which were derived using a Lan-
DeMets O'Brien-Fleming approximation spending function. Note that the final row indicates 
the total power to reject the null hypothesis for DMFS. If the actual number of events at the 
DMFS analyses differ from those specified in the table, the bounds will be adjusted using the 
Lan-DeMets O'Brien-Fleming approximation spending function accordingly.
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Table 13
Efficacy Boundaries and Properties for the DMFS Analyses
Analysis
Value
Efficacy
IA 3: 75%
Z
2.3401
N: 954
p (1-sided)
0.0096
Events: 146
HR at bound
0.6788
Month: 60
P(Cross) if HR=1
0.0096
P(Cross) if HR=0.65
0.5987
Final (IA4)
Z
2.0117
N: 954
p (1-sided)
0.0221
Events: 195
HR at bound
0.7494
Month: 108
P(Cross) if HR=1
0.0250
P(Cross) if HR=0.65
0.8425
Overall Survival
The study initially allocates α=0, one-sided to test OS. If the null hypothesis for DMFS is 
rejected then α=0.025 is fully reallocated to OS hypothesis testing.  Table 14 shows the 
boundary properties for the planned interim analysis (at 120 months from first participant 
enrolled) and final analysis (at 180 months), which were derived using a Lan-DeMets 
O'Brien-Fleming approximation spending function. Note that the final row indicates the total 
power to reject the null hypothesis for OS. If the actual number of events at the OS analyses 
differs from that specified in the table, the bounds will be adjusted using the Lan-DeMets 
O'Brien-Fleming approximation spending function accordingly. 
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Table 14
Efficacy Boundaries and Properties for the OS Analyses
Analysis
Value
Efficacy
IA 5: 76%
Z
2.3249
N: 954
p (1-sided)
0.0100
Events: 154
HR at bound
0.6875
Month: 120
P(Cross) if HR=1
0.0100
P(Cross) if HR=0.67
0.5607
Final
Z
2.0138
N: 954
p (1-sided)
0.0220
Events: 204
HR at bound
0.7538
Month: 180
P(Cross) if HR=1
0.0250
P(Cross) if HR=0.67
0.8050
Safety Analyses
The eDMC has responsibility for assessment of overall risk/benefit. When prompted by 
safety concerns, the eDMC can request corresponding efficacy data. External DMC review of 
efficacy data to assess the overall risk/benefit to study participants will not require a 
multiplicity adjustment typically associated with a planned interim efficacy analysis; 
however, to account for any multiplicity concerns raised by the eDMC review of unplanned 
efficacy data prompted by safety concerns, a sensitivity analysis for RFS adopting a 
conservative multiplicity adjustment will be prespecified in the sSAP. This analysis will be 
performed if efficacy data is requested by the eDMC during a safety evaluation to assess risk 
/ benefit.
Sample Size and Power Calculations
The study will randomize approximately 954 participants in a 1:1 ratio between 
pembrolizumab adjuvant treatment and placebo adjuvant treatment.
Recurrence-free Survival
Recurrence-free survival is the primary endpoint. The final analysis of RFS is event-driven 
and will be conducted after approximately 179 RFS events have been observed, unless the 
study is terminated early. It may occur at ~ 48 months after the first participant is randomized 
(depending on enrollment rate and event accumulation rate).
With an alpha of 2.5% (one-sided) and sample size of 954, the study has an overall ~92% 
power for RFS, assuming the true HR (pembrolizumab vs. placebo) is 0.60. These 
calculations are based on the following assumptions: (1) RFS follows an “cure” model with a 
long-term RFS of 50% and the 60-month RFS estimated to be 68%; (2) an enrollment period 
of 16 months and at least 32 months follow-up; and (3) a yearly drop-out rate of 4.7%.  
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Distant Metastases-free Survival
Distant metastases-free survival is a secondary endpoint. The final analysis of DMFS is 
event-driven and will be conducted after approximately 195 DMFS events have been 
observed, unless the study is terminated early. It may occur at ~ 108 months after the first 
participant is randomized (depending on enrollment rate and event accumulation rate).
Should the comparisons of RFS be statistically significant, an alpha of 2.5% (one-sided) will
be available for testing DMFS. With a sample size of 954, the study has ~84% power for
DMFS, assuming the true HR (pembrolizumab vs. placebo) is 0.65. These calculations are 
based on the following assumptions: (1) DMFS follows an “cure” model with a long-term 
DMFS of 65% and the 60-month DMFS estimated to be 78%; (2) an enrollment period of 
16 months and at least 92 months follow-up; and (3) a yearly drop-out rate of 4.7%.  
Overall Survival
Overall survival is a secondary endpoint. The final analysis of OS is calendar driven and will 
be conducted at approximately 15 years after the first participant is randomized, when we 
expect to have observed ~204 OS events.
Should the comparisons of both RFS and DMFS be statistically significant, an alpha of 2.5% 
(one-sided) will be available for testing OS. With a sample size of 954, the study has ~80% 
power for OS, assuming the true HR (pembrolizumab vs. placebo) is 0.67. These calculations 
are based on the following assumptions: (1) OS follows an exponential distribution with the 
120-month OS estimated to be 75%; (2) an enrollment period of 16 months and at least 164
months follow-up; and (3) a yearly drop-out rate of 4.7%. The sample size and power 
calculations were performed in the software R (package “gsDesign”).
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for the primary 
endpoints will be estimated and plotted within each category of the following classification 
variables:
•
T-Stage (T3b versus T4a versus T4b)
•
Age (<65 years versus ≥65 years)
•
Sex (male versus female)
•
Race (white versus nonwhite)
•
ECOG performance status (0 versus 1) or equivalent KPS or LPS status
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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
The extent of exposure will be summarized as duration of treatment in number of cycles or 
administrations as appropriate.
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10. Supporting Documentation and Operational Considerations
Appendix 1: Regulatory, Ethical and Study Oversight Considerations
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A. Purpose
MSD, 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 participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (e.g., International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials which are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the full 
control of MSD.
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 MSD or comparator products. Alternatively, MSD may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial. 
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of Good 
Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified 
versus source documentation according to standard operating procedures. Per MSD policies and procedures, if 
fraud, scientific/research misconduct or serious GCP-noncompliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the extent 
scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important to 
patients, physicians, and payers. 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 such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
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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. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD 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. 
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD 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
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have access to 
confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD 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.
MSD does not pay for participant referrals. However, MSD 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 MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish 
to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted 
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices. 
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
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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 the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request. 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor 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 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 the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the 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 study 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 (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents in 
order to verify worksheet/CRF data. By providing documented informed consent, the 
participant agrees to this process. If study documents will be photocopied during the process 
of verifying worksheet/CRF information, the participant will be identified by unique code 
only; full names/initials will be masked prior to transmission to the Sponsor.
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By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Committees Structure
Scientific Advisory Committee
This study was developed in collaboration with a Scientific Advisory Committee (SAC). The 
SAC is comprised of both Sponsor and non-Sponsor scientific experts who provide input with 
respect to study design, interpretation of study results and subsequent peer-reviewed scientific 
publications.
Executive Oversight Committee
The Executive Oversight Committee (EOC) is comprised of members of Sponsor Senior 
Management. The EOC will receive and decide upon any recommendations made by the 
eDMC regarding the study.
Data Monitoring Committee
To supplement the routine study monitoring outlined in this protocol, an external DMC will 
monitor the interim data from this study. The voting members of the committee are external 
to the Sponsor. The members of the DMC must not be involved with the study in any other 
way (eg, they cannot be study investigators) and must have no competing interests that could 
affect their roles with respect to the study. 
The DMC will make recommendations to the EOC regarding steps to ensure both participant 
safety and the continued ethical integrity of the study. Also, the DMC will review interim 
study results, consider the overall risk and benefit to study participants (see Section 9.7
Interim Analyses) and recommend to the EOC whether the study should continue in 
accordance with the protocol.
Specific details regarding composition, responsibilities, and governance, including the roles 
and responsibilities of the various members and the Sponsor protocol team; meeting 
facilitation; the study 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.
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Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor 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, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor 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.
Compliance with Study 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 study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated studies. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and 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 study or its results to those 
registries.
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use of Technical Requirements for Registration of Pharmaceuticals for Human 
Use Good Clinical Practice: Consolidated Guideline and other generally accepted standards 
of GCP); and all applicable federal, state and local laws, rules and regulations relating to the 
conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the 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 study
reimbursed to the investigator by the Sponsor.
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor 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. 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor 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 participants’ documented informed consent/assent, 
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 the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
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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.
Study and Site Closure
The Sponsor or its designee 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 the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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Appendix 2: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will be 
used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
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signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons. 
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research 
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and treatment outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube. 
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
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records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens 
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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Appendix 3:  Contraceptive Guidance and Pregnancy Testing
Definitions 
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
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 level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with 2 follicle-stimulating hormone 
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 nonhormonal 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
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 5.1. 
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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
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b
○
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
●
Intrauterine hormone-releasing system (IUS)
●
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 (ie, when used 
consistently and correctly). 
b) 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.
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected; at Q3W as specified in 
the Schedule of Activities (Section 1.3), after the last dose of study treatment, and as required 
locally.
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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 (also referred to as Sponsor’s 
product) 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 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, considered clinically significant in the 
medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent preexisting 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 AE, 
the AE term should reflect the clinical symptoms or abnormal test result. An overdose 
of study treatment 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/recurrence of the cancer under study is not a reportable event. 
Refer to Section 8.4.5 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 preexisting 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 preexisting condition that has not 
worsened.
●
Refer to Section 8.4.5 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 
An 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 preexisting condition that has not 
worsened is not an SAE. A preexisting 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, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
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 AE
CRFs/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. 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 the Sponsor.
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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 Criteria for 
Adverse Events (CTCAE), version 4.0. Any AE which changes CTCAE grade over the 
course of a given episode will have each change of grade recorded on the AE
CRFs/worksheets.
●
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
●
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).
●
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
●
Grade 4: Life threatening consequences; urgent intervention indicated.
●
Grade 5: Death related to AE.
Assessment of causality
●
Did the Sponsor's product cause the AE?
●
The determination of the likelihood that the Sponsor's product caused the AE 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 AE based upon the available information
●
The following components are to be used to assess the relationship between the 
Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the 
Sponsor's product caused the AE:
●
Exposure:  Is there evidence that the participant was actually exposed to the 
Sponsor's product such as:  reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
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●
Time Course:  Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor's product? Is the time of onset of the AE 
compatible with a drug-induced effect (applies to studies 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 Sponsor's product discontinued or 
dose/exposure/frequency reduced?
●
If yes, did the AE resolve or improve?
●
If yes, this is a positive dechallenge. 
●
If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor's product; (3) the study is a single-dose drug study); or (4) Sponsor's 
product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
study?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
●
If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study); or (3) 
Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S PRODUCT, OR IF 
RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE MODIFICATION 
GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE IRB/IEC.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor's product or drug class pharmacology or toxicology?
●
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
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●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor's product is reasonable. 
The AE is more likely explained by the Sponsor's product than by another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product. (Also 
entered for a 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 the Sponsor. 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 the Sponsor.
●
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
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 Sponsor 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 the Sponsor within 24 hours of 
receipt of the information.
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Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
●
The primary mechanism for reporting to the Sponsor 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 8.4.1 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 EDC 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 EDC 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 the Sponsor via paper CRF
●
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
●
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: Clinical Laboratory Tests 

The tests detailed in Table 16 will be performed by the local laboratory. 

Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 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 16
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Count
Hemoglobin
Hematocrit
WBC count with Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Chemistry
Blood Urea 
Nitrogen (BUN)
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
Bicarbonate or 
Carbon Dioxide*
Chloride
Phosphorus
Creatinine
Sodium
Alanine 
Aminotransferase
(ALT)/ Serum 
Glutamic-Pyruvic 
Transaminase 
(SGPT)
Magnesium
Glucose
Calcium
Alkaline phosphatase
Routine 
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones by dipstick

Microscopic examination (if blood or protein is abnormal)
Other 
Screening 
Tests

Serum or urine hCG) pregnancy test (as needed for WOCBP)

Thyroid function tests (T3/FT3, FT4, and TSH)

Coagulation panel (prothrombin time [PT]/ International Normalized Ratio [INR], 
activated partial thromboplastin time[aPTT])
Urea is acceptable if BUN is not available as per institutional standard.
T3 is preferred; if not available, free T3 may be tested.
*If these tests are not done as part of standard of care in your region then these tests do not need to be 
performed.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Laboratory/analyte results that could unblind the study will not be reported to investigative 
sites or other blinded personnel until the study has been unblinded.
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Appendix 6:  Country-specific Requirements
CCI
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CCI
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Appendix 7: Abbreviations
Abbreviation
Expanded Term
ADA
Antidrug Antibodies
ADL
Activities of daily living  
AE
Adverse event 
AJCC
American Joint Committee on Cancer
ALT
Alanine aminotransferase
APaT
All participants as treated (population)
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
CBC
Complete blood count
CD
Cluster of differentiation
CI
Confidence interval
CR
Complete response
CrCl
Creatinine clearance
CRF
Case Report Form 
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating tumor DNA
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
DMC
Data Monitoring Committee 
DMFS
Distant metastasis-free survival
DNA
Deoxyribonucleic acid 
ECG
Electrocardiogram 
ECI
Event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic data collection 
eDMC
External Data Monitoring Committee
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC
European Organisation for Research and Treatment of Cancer
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Abbreviation
Expanded Term
EORTC 
QLQ-C30
EORTC Quality of Life Questionnaire-C30
EOT
End of treatment
EQ-5D-5L
EuroQoL-5 Dimension - 5 Level Questionnaire
FA
Final analysis
FDAAA
Food and Drug Administration Amendments Act
GCP
Good Clinical Practice 
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HR
Hazard ratio
HRT
Hormone replacement therapy
IA
Interim analysis
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IFN
Interferon
Ig
Immunoglobulin 
IHC
Immunohistochemistry
IL-10
Interleukin 10
IMP
Investigational Medicinal Product
INR
International normalized ratio
irAE
Immune-related adverse event
IRB
Institutional Review Board 
iRECIST
Modified RECIST 1.1 for immune-based therapeutics
IRT
Interactive Response Technology
ITT
Intention-to-treat
IV
Intravenous
KPS
Karnofsky Performance Scale
LDH
Lactic acid dehydrogenase
LPS
Lansky Play-Performance Scale
MRI
Magnetic resonance imaging
mRNA
Messenger RNA
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Abbreviation
Expanded Term
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
MSS
Melanoma Specific Survival
MTD
Maximum tolerated dose 
NCI
National Cancer Institute
NDA
New Drug Application 
NIMP
Non-investigational Medicinal Product
OS
Overall survival
PD
Progressive disease
PD-1
Programmed cell death-1
PD-L1
Programmed cell death-ligand 1
PD-L2
Programmed cell death-ligand 2
PET
Positron emission tomography 
PK
Pharmacokinetic
PR
Partial response
PRFS2
Progression/Recurrence-free Survival 2
PRO
Patient-reported outcome(s)
PT
Prothrombin time
Q3W
Every 3 weeks
QLQ 
Quality of Life Questionnaire
QoL
Quality of life
RECIST 1.1
Response Evaluation Criteria in Solid Tumors version 1.1
RFS
Recurrence-free Survival
RNA
Ribonucleic acid
SAC
Scientific Advisory Committee
SAE
Serious adverse event 
SFU
Survival Follow-up
SLN
Sentinel lymph node
SoA
Schedule of Activities
SOP
Standard Operating Procedure
sSAP
Supplemental Statistical Analysis Plan
SUSAR
Suspected unexpected serious adverse reaction
T1DM
Type 1 Diabetes Mellitus
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Abbreviation
Expanded Term
TSH
Thyroid-stimulating hormone
TTST
Time to subsequent therapy
TX
Treatment
US
United States
WBC
White blood cells
WNL
Within normal limits
WOCBP
Woman/women of childbearing potential 
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Appendix 8: Performance Status Scales
ECOG Performance Scale
Grade
ECOG Status
0
Fully active, able to carry on all predisease 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 self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
Source: [ECOG-ACRIN Cancer Research Group 2016]
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Karnofsky Performance Scale
Score
Activity
100
Normal. No complaints. No evidence of disease.
90
Able to carry on normal activity. Minor signs or symptoms of disease.
80
Normal activity with effort. Some signs or symptoms of disease.
70
Care of self. Unable to carry on normal activity or to do active work.
60
Requires occasional assistance but is able to care for most of his needs.
50
Requires considerable assistance and frequent medical care.
40
Disabled. Requires special care and assistance.
30
Severely disabled. Hospitalization is indicated although death not imminent.
20
Hospitalization necessary, very sick active supportive treatment necessary.
10
Moribund. Fatal processes progressing rapidly.
0
Dead.
Source: [Karnofsky, D. A. 1949]
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Lansky Play-Performance Scale
Score
Activity
100
Fully active, normal
90
Minor restrictions in physically strenuous activity
80
Active, but tires more quickly
70
Both greater restriction of, and less time spent in, active play
60
Up and around, but minimal active play; keeps busy with quieter activities
50
Gets dressed, but lies around much of the day; no active play; able to 
participate in all quiet play and activities
40
Mostly in bed; participates in quiet activities
30
In bed; needs assistance even for quiet play
20
Often sleeping; play entirely limited to very passive activities
10
No play; does not get out of bed
0
Unresponsive
Source: [Lansky, S. B., et al 1987]
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Appendix 9: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and to guide decisions about changes in management.
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study treatment 
until repeat imaging is obtained using iRECIST for participant management. The decision by 
the investigator should be based on the participant’s overall clinical condition.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of 
disease
•
No decline in ECOG performance status for adults, LPS for children up to and 
including 16 years of age, or KPS for participants >16 or <18 years of age.
(Appendix 8: Performance Status Scales)
•
No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. 
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% 
and ≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements”,
but “sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.
•
Unequivocal progression of nontarget lesion(s) identified at baseline
•
Development of new lesion(s)
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iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Nontarget.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:
•
Any of the factors that were the basis for the initial iUPD show worsening
o
For target lesions, worsening is a further increase in the sum of diameters of ≥5 
mm, compared to any prior iUPD time point
o
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:
•
An increase in the new lesion sum of diameters by ≥5 mm from a prior 
iUPD time point 
•
Visible growth of new nontarget lesions 
•
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial 
PD threshold (by RECIST 1.1)
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Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered following consultation with the Sponsor. In this case, if study 
treatment is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3.
Detection of Progression at Visits after Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
•
Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-
progression. The nadir is always the smallest sum of diameters seen during the 
entire study, either before or after an instance of pseudo-progression.
•
Nontarget lesions
o
If nontarget lesions have never shown unequivocal progression, their doing so 
for the first time results in iUPD.
o
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth 
of nontarget lesions, taken as a whole.
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•
New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified nontarget lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017]. A summary of imaging and treatment requirements after first radiologic evidence of 
progression is illustrated as a flowchart in Figure 5.
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Figure 5
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the Investigator
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Appendix 10: Surgical Considerations
1. Recommendation for Surgical Management:
a) Wide excision with a 1-2cm clinical margin surrounding the primary lesion or biopsy scar 
is recommended for entry on to this protocol. If the primary melanoma is completely resected 
within the wide excision margin, the resection is acceptable. 
b) For lesions with Breslow’s thickness >2 mm, a 2 cm minimum clinical margin is 
recommended when anatomically feasible. On other body sites with limited tissue 
availability a narrower margin is acceptable to avoid excessive morbidity. 
c) For subungual melanoma, interphalangeal metacarpal/metatarsal-phalangeal amputation 
with histologically negative margins constitutes an adequate wide excision. 
d) The specimen shall be excised to include skin and all subcutaneous tissue down to the 
muscular or deep fascia. Fascia may be included at the discretion of the operating surgeon. 
e) The pathology report should report surgical margins and whether or not surgical resection 
margins are involved with the tumor, including close margin (eg, <1 mm between tumor and 
resection margin) and tumor abutting margin.
Closure of the defect (eg, primary advancement flap closure, split thickness skin graft, 
complex reconstruction) is at the discretion of the surgeon.
2. SLN Procedure: 
A SLN is defined as any lymph node(s) receiving direct lymphatic drainage from a primary 
tumor site identified during lymphoscintigraphy with radioactive and/or visible tracer. There 
may be more than one sentinel node for some primary melanoma sites. The clinical rationale 
for SLN identification and separate evaluation is based on the assumption that metastatic 
lymph node involvement will first involve the SLN(s) that receive the majority of the 
lymphatic drainage from a given primary tumor before it involves more distant lymph nodes. 
Involvement of SLN(s) increases the likelihood that other, more distant node(s) may also 
contain metastatic disease. Conversely, if sentinel nodes are negative, other regional nodes 
are less likely to contain metastasis.
a) Pathological considerations for SLNs: AJCC and CAP guidelines should be followed for 
the pathologic examination and reporting of SLN biopsy specimens.
Parameters to include in the SLN pathology report are:
•
Total number of sentinel nodes excised and submitted for pathologic review
•
Number of sentinel nodes, if any, involved by tumor
b)  Sequence of sectioning and staining in SLN protocol for melanoma
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Pathologists should examine multiple hematoxylin– eosin (H&E) and 
immunohistochemically stained sections (for one or more melanocytic markers such as S100, 
HMB45, MelanA, SOX10 and/or tyrosinase) from each SLN. When S100 or SOX10 
immunohistochemistry (IHC) is positive, a second IHC may be performed to assist in the 
interpretation of difficult cases. Any metastatic tumor cells identified within a lymph node, 
irrespective of how small they are or whether they are identified on H&E or immunostained 
sections, should be designated as a tumor-positive SLN. As per AJCC guidelines, if 
melanoma cells are identified within a lymphatic channel within or adjacent to a SLN, that 
SLN is regarded as tumor-involved. [Gershenwald, J. E., et al 2017] [College of American 
Pathologists 2018]
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Appendix 11: AJCC 8th Edition Guidelines
The AJCC has designated staging by TNM classification to define melanoma.
Staging tables (Table 17, Table 18, Table 19, Table 20) adapted from AJCC 8th edition.
Refer to AJCC guidelines for more information [Gershenwald, J. E., et al 2017].
Table 17
Melanoma T Category Definition
T-Stage
T-Stage Definition (thickness and ulceration)
TX
Primary tumor thickness cannot be assessed (ulceration status not 
applicable)
T0
No evidence of primary tumor (ulceration status not applicable)
Tis
Melanoma in situ (ulceration status not applicable)
  T1
≤1.0mm (ulceration status unknown or unspecified)
  T1a
<0.8mm without ulceration
  T1b
<0.8mm with ulceration or
0.8-1.0mm with or without ulceration
T2
>1.0-2.0mm (ulceration status unknown or unspecified)
  T2a
>1.0-2.0mm without ulceration
  T2b
>1.0-2.0mm with ulceration
T3
>2.0-4.0mm (ulceration status unknown or unspecified)
  T3a
>2.0-4.0mm without ulceration
  T3b
>2.0-4.0 mm with ulceration
T4
>4.0mm (ulceration status unknown or unspecified)
  T4a
>4.0 mm without ulceration
  T4b
>4.0 mm with ulceration
AJCC = American Joint Committee on Cancer; T = primary tumor.
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Table 18
Melanoma N Category Definition
N Category
Number of Tumor-Involved Regional Lymph 
Nodes
Presence of In-
transit, satellite, 
and/or 
microsatellite 
metastases
NX
Regional Nodes not assessed (exception: 
pathological N category not required for T1 
melanomas, use clinical N information)
No
N0
No regional metastases detected
No
N1
One tumor-involved node or any number of 
in-transit, satellite, and/or microsatellite 
metastases with no tumor-involved nodes
N1a
One clinically occult (detected by SLN
biopsy)
No
N1b
One clinically detected
No
N1c
No regional lymph node disease
Yes
N2
Two or 3 tumor-involved nodes or any 
number of in-transit, satellite, and/or 
microsatellite metastases with one tumor-
involved node
  N2a
Two or 3 clinically occult (detected by SLN
biopsy)
No
  N2b
Two or 3, at least one of which was clinically 
detected
No
  N2c
One clinically occult or clinically detected
Yes
N3
Four or more tumor-involved nodes or any 
number of in-transit, satellite, and/or 
microsatellite metastases with 2 or more 
tumor-involved nodes, or any number of 
matted nodes without or with in-transit, 
satellite, and/or microsatellite metastases
  N3a
Four or more clinically occult (detected by 
SLN biopsy)
No
  N3b
Four or more, at least one of which was 
clinically detected, or the presence of any 
number of matted nodes
No
  N3c
Two or more clinically occult or clinically 
detected and/or presence of any number of 
matted nodes
Yes
N=Regional Lymph Node
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Table 19
Melanoma M Category Definition
M Category
Anatomic Site
Lactate Dehydrogenase
Level
M0
No evidence of distant 
metastasis
Not applicable
M1
Evidence of distant 
metastasis
See below
  M1a
Distant metastasis to skin, 
soft tissue including muscle, 
and/or nonregional lymph 
node
Not recorded or unspecified
    M1a(0)
Not elevated
    M1a(1)
Elevated
  M1b
Distant metastasis to lung 
with or without M1a sites of 
disease
Not recorded or unspecified
    M1b(0)
Not elevated
    M1b(1)
Elevated
  M1c
Distant metastasis to 
noncentral nervous system 
visceral sites with or without 
M1a or M1b sites of disease
Not recorded or unspecified
    M1c(0)
Not elevated
    M1c(1)
Elevated
  M1d
Distant metastasis to CNS 
with or without M1a, M1b, 
or M1c sites of disease
Not recorded or unspecified
    M1d(0)
Not elevated
    M1d(1)
Elevated
M=Distant Metastasis
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Table 20
AJCC Pathological (pTNM) Staging Groups
Staging (AJCC 8th edition)
0
Tis
N0
M0
IA
T1a
N0
M0
IA
T1b
N0
M0
IB
T2a
N0
M0
IIA
T2b
N0
M0
IIA
T3a
N0
M0
IIB
T3b
N0
M0
IIB
T4a
N0
M0
IIC
T4b
N0
M0
IIIB
T0
N1b, N1c
M0
IIIC
T0
N2b, N2c, N3b, N3c
M0
IIIA
T1a/b-T2a
N1a or N2a
M0
IIIB
T1a/b-t2a
N1b/c or N2b
M0
IIIB
T2b/T3a
N1a-N2b
M0
IIIC
T1a-T3a
N2c or N3a/b/c
M0
IIIC
T3b/T4a
Any N≥N1
M0
IIIC
T4b
N1a-N2c
M0
IIID
T4b
N3a/b/c
M0
IV
Any T, Tis
Any N
M1
M0 = No evidence of distant metastases; N0 = No regional metastasis detected including no tumor-involved nodes and 
no in-transit, satellite, and/or microsatellite metastasis.
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Appendix 12: Guidance for Distinguishing Primary Cutaneous Melanomas 
From Cutaneous Metastases of Melanoma
If the diagnosis is made in the context of an appropriate clinical history, it is usually not 
difficult to establish a correct pathologic diagnosis of either primary cutaneous melanoma or 
cutaneous metastasis of melanoma. Occasionally it may be extremely difficult to definitively 
determine whether a melanoma is a primary tumor, or a metastasis based upon pathological 
examination alone. This is particularly the case for a melanoma located in the dermis that 
lacks an in situ component in the overlying epidermis. In many instances, such tumors 
represent a primary melanoma with regression of the superficial dermal and epidermal 
components. The pathologist should recognize this phenomenon by the presence of some 
subtle clues such as:

the presence of rare single atypical epidermal melanocytes, 

epidermal thinning with loss of rete ridges, 

fibrosis and vascular proliferation in the dermis overlying the lesion, 

defect in the band of superficial solar elastosis,

band-like lymphohistiocytic inflammatory cell infiltrate which usually includes 
numerous pigment-laden macrophages.
In cases where difficulty remains, it is prudent to examine microscopically additional tissue 
from the lesion, including further sections cut from the original and additional tissue blocks. 
In some instances, it is impossible to be certain from the pathologic features alone whether a 
melanoma is primary or metastatic. In such cases, correlation with clinical information is 
essential, as this may provide further and critical clues (eg, a history of a pigmented plaque 
that disappeared over time leaving a lump in the dermis would be strong evidence in favor of 
a primary melanoma with a regressed superficial/epidermal component). Furthermore, some 
primary melanomas may arise in the dermis without origin from the epidermis, including 
some cases of desmoplastic melanoma, melanomas arising in congenital nevi and blue nevus-
like melanoma. The presence of an associated, benign nevus component is evidence favoring 
that a lesion is a primary melanoma and not metastatic melanoma. 
Some metastatic melanomas can show prominent epidermotropism, mimicking a primary 
tumor. In most epidermotropic melanomas the overlying junctional change does not extend 
beyond the dermal component. The presence of multiple foci of intralymphatic tumor may be 
a clue to recognizing epidermotropic melanoma.
Although the presence of subtle nuclear pleomorphism, occasional mitotic figures and an 
associated lymphoid infiltrate may provide pathologic clues to the correct diagnosis, 
correlation with clinical information is, as always, essential in reaching a final diagnosis
[Gershenwald, J. E., et al 2017] [Scolyer, R. A., et al 2020].  
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