A Phase 3, Randomized, Double-blind, Active-Comparator-Controlled Clinical Study of Adjuvant MK-7684A (Vibostolimab With Pembrolizumab) Versus Adjuvant Pembrolizumab in Participants With High-risk Stage II-IV Melanoma (KEYVIBE-010)
Phase: PHASE3
Conditions: Melanoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
Protocol/Amendment No.: 010-04 A Phase 3,
Randomized, Double-blind, Active-Comparator-
Controlled Clinical Study of Adjuvant MK7684A
(Vibostolimab with Pembrolizumab) Versus
Adjuvant Pembrolizumab in Participants with
High risk Stage II IV Melanoma (KEYVIBE 010)
NCT05665595
27-Jun-2024

PRODUCT: MK-7684A
1
PROTOCOL/AMENDMENT NO.: 010-04
MK-7684A-010-04 FINAL PROTOCOL
27-JUN-2024
TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 3, Randomized, Double-blind, Active-Comparator-Controlled 
Clinical Study of Adjuvant MK-7684A (Vibostolimab with Pembrolizumab) Versus 
Adjuvant Pembrolizumab in Participants with High-risk Stage II-IV Melanoma (KEYVIBE-
010)
Protocol Number: 010-04
Compound Number: MK-7684A
Sponsor Name: Merck Sharp & Dohme LLC
(hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
NCT
05665595
EU CT
2022-501417-31
EudraCT
Not Applicable
JRCT
2031230099
WHO
Not Applicable
UTN
Not Applicable
IND
161,909
Approval Date: 27 June 2024
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
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
27-JUN-2024
Based on recommendations of the eDMC to 
discontinue the experimental arm (MK-7684A) 
following an interim review of the data 
showed no benefit over the comparator arm of 
pembrolizumab monotherapy.
Amendment 3
20-DEC-2023
To update futility analysis strategy and 
enrollment duration. The number of events 
required for IA1 has been changed to have an 
earlier futility analysis to prevent potential 
unnecessary exposure of study participants to 
study intervention (MK-7684A).
Amendment 2
15-MAR-2023
To address comments from the EU on 
inclusion of adolescents
Amendment 1
17-NOV-2022
Extended safety monitoring per Agency 
feedback
Original Protocol
15-SEP-2022
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendment:
Based on recommendations of the eDMC to discontinue the experimental arm (MK-7684A) 
following an interim review of the data showed no benefit over the comparator arm of 
pembrolizumab monotherapy.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Section 1.1, 
Synopsis
Overall Design: Text added stating per 
Amendment 04, following an interim review of 
data by eDMC that showed no benefit over the 
comparator arm (pembrolizumab monotherapy),
the experimental arm (MK-7684A) will be 
discontinued and ongoing participants will be 
offered the comparator treatment of 
pembrolizumab monotherapy, for up to 17 cycles 
of study treatment or until disease progression, 
whichever occurs first.
The experimental arm (MK-7684A) is 
discontinued based on the recommendations 
of the eDMC following an interim review of 
new data that showed no benefit over the 
comparator arm of pembrolizumab 
monotherapy.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Title Page
JRCT number added.
To provide new information.
Document History
Date for approval of Amendment 2 corrected 
from MAR 13 to MAR 15, 2023.
To correct the date for Amendment 2.
Section 1.1, 
Synopsis
Intervention Groups and Duration: Text added 
regarding the discontinuation of the experimental
arm (MK-7684A) and ongoing participants 
moved to pembrolizumab monotherapy, for up to 
17 cycles of study treatment or until disease 
progression, whichever occurs first.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Intervention Groups and Duration chart: added 
text to the Arm A heading stating discontinued as 
of Amendment 04.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Intervention Groups and Duration chart: for Arm 
B, clarified pembrolizumab monotherapy
regimen is for up to 17 cycles or until 
discontinuation, whichever occurs first.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Duration of Participation: Clarified that
pembrolizumab monotherapy will continue for 
up to 17 cycles of study treatment or until one of 
the conditions for discontinuation is met,
whichever occurs first.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Duration of Participation: Text added stating no 
data collection is required for Efficacy Follow-up 
Visit.
See rationale for Section 1.1, discontinuation 
of experimental arm.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 1.2, Schema
Text added regarding the discontinuation of the 
experimental arm (MK-7684A) following eDMC 
interim review and ongoing participants moved 
to pembrolizumab monotherapy for the 
remainder of the study.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Figure 1: Age-related symbols corrected in the 
Key Eligibility Criteria note.
To correct erroneous information.
Figure 1: Non-binding futility timings and 
number updated.
To align with current enrolment projections.
Section 1.3, 
Schedule of 
Activities
Text added regarding the discontinuation of the 
experimental arm (MK-7684A) following eDMC 
interim review and ongoing participants moved 
to pembrolizumab monotherapy for the 
remainder of the study, and added a reference to 
the new Schedule of Activities (SoA).
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 1.3.1, 
Schedule of 
Activities (Original 
Protocol to Protocol 
Amendment 03)
Added parenthetical, (Original protocol to 
Protocol Amendment 03), to section heading and 
SoA title.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Tumor Scan row: Note added to confirm imaging 
requirements for participants with primary neck 
lesions; subsequently, dashed arrow from C1 
through DMFS Follow-up removed, and X 
marker added to DMFS Follow-up column.
To confirm neck imaging is only required 
for participants with a primary lesion on the 
head or neck at all protocol-specified time 
points.
Section 1.3.2, 
Schedule of 
Activities (Protocol 
Amendment 04)
New section added to provide SoA following 
Protocol Amendment 04 approval.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 2.1, Study 
Rationale
Text added regarding the discontinuation of the 
experimental arm (MK-7684A) following eDMC 
interim review and ongoing participants moved 
to pembrolizumab monotherapy for the 
remainder of the study.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 4.1, Overall 
Design
Text added stating per Amendment 04, following 
an interim review of data by eDMC that showed 
no benefit over the comparator arm 
(pembrolizumab monotherapy), the experimental
arm (MK-7684A) will be discontinued and all 
ongoing participants on treatment will move to 
the comparator arm (Arm B: pembrolizumab 
monotherapy) for the remainder of the study.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 4.4, 
Beginning and End-
of-Study Definition
Text updated to provide maximum duration on 
study (including follow-up) and to reference
Section 1.1, Synopsis, for duration information.
To provide clear estimates for expected 
study duration.
Text added confirming the end of the study will 
be defined as when all participants have 
discontinued treatment and have completed the 
safety follow-up requirements.
See rationale for Section 1.1, discontinuation 
of experimental arm.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 4.4.1, 
Clinical Criteria for 
Early Study 
Termination
Text added stating the reason for the 
discontinuation of the experimental arm (MK-
7684A) per eDMC recommendations.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Text added confirming the end of the study will 
be defined as when all participants have 
discontinued treatment and have completed the 
safety follow-up requirements.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 6, Study 
Intervention
Text added stating that any reports of supply 
complaints or temperature excursions should be 
sent to a specified mailbox. 
To ensure study intervention issues are 
reported correctly. 
Section 6.1, Study 
Intervention(s) 
Administered
Text added regarding the discontinuation of the 
experimental arm (MK-7684A) and ongoing 
participants moved to pembrolizumab 
monotherapy, for up to 17 cycles of study 
treatment or until disease progression, whichever 
occurs first.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Table 3: Experimental Arm and Comparator Arm 
updated to reflect discontinuation of 
experimental arm and duration of pembrolizumab 
monotherapy.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Table 3: Footnote added stating that
commercially available supplies, in terms of unit 
dose strength or formulation, may vary 
depending on market availability.
To ensure compliance with local prescribing 
information for commercial supplies.
Section 6.1.1, 
Treatment
Text added regarding the discontinuation of the 
experimental arm (MK-7684A) and ongoing 
participants moved to pembrolizumab 
monotherapy, for up to 17 cycles of study 
treatment or until disease progression, whichever 
occurs first.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Text added that Sponsor should be consulted if 
the investigator wishes benefitting participants to 
continue MK-7684A treatment.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 6.3.1, 
Intervention 
Assignment
Text added regarding the discontinuation of the 
experimental arm (MK-7684A) and ongoing 
participants moved to pembrolizumab 
monotherapy, for up to 17 cycles of study 
treatment or until disease progression, whichever 
occurs first.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Text added that Sponsor should be consulted if 
the investigator wishes benefitting participants to 
continue MK-7684A treatment.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 6.3.3, 
Blinding
Text added to state that following eDMC interim 
review of data, all participants have been 
unblinded.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 6.5, 
Concomitant 
Therapy
Removed repetitive text.
See rationale for Section 1.2, Key Eligibility 
Criteria footnote.
Section 7.1, 
Discontinuation of 
Study Intervention
Text added regarding the discontinuation of the 
experimental arm (MK-7684A) and ongoing 
participants moving to pembrolizumab 
monotherapy with a reference to Section 1.3.2 
(SoA).
See rationale for Section 1.1, discontinuation 
of experimental arm.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 7.2, 
Participant 
Withdrawal From 
the Study
Text added stating that participants who complete 
or discontinue study intervention and have 
completed safety follow-up will be considered to 
have completed the study. This also applies to 
participants in efficacy follow-up.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.1.9, Study 
Intervention 
Administration
Text added regarding the discontinuation of the 
experimental arm (MK-7684A) and ongoing 
participants moved to pembrolizumab 
monotherapy for the remainder of the study (a 
total of 17 cycles of study treatment or until 
disease progression, whichever occurs first).
See rationale for Section 1.1, discontinuation 
of experimental arm.
Text added that Sponsor should be consulted if 
the investigator wishes benefitting participants to 
continue MK-7684A treatment.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.1.9.1, 
Timing of Dose 
Administration
Text added referencing Section 1.3.2 (SoA).
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.1.10, 
Discontinuation and 
Withdrawal
Text added referencing Section 1.3.2 (SoA).
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.1.11, 
Participant 
Blinding/Unblinding
Text added stating that the treatment arms have 
been unblinded, per the eDMC recommendation 
to discontinue the experimental arm (MK-
7684A).
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.2.1, 
Tumor Imaging and 
Assessment of 
Disease
Text added to confirm imaging requirements for 
participants with primary neck lesions.
See rationale for Section 1.3, Tumor Scans 
for neck imaging.
Text added to reference to Section 1.3.2 (SoA).
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.2.1.2, 
Tumor Scans 
During the Study
Text added to reference Section 1.3.2 (SoA) and 
state that no further scans are required in follow-
up.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.2.1.3, 
End-of-treatment
and Follow-up 
Tumor Scans
Text added to reference Section 1.3.2 (SoA) and 
state that no further scans are required in follow-
up.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.2.2, 
Patient-reported 
Outcomes
Text added to reference Section 1.3.2 (SoA) and 
state that no further PROs are required.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.3, Safety 
Assessments
Text added to reference Section 1.3.2 (SoA).
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.4.3, 
Follow-up of AE, 
SAE, and Other 
Reportable Safety 
Event Information
Text revised to state that all nonserious AEs are 
not required to be followed until the outcome of 
the event is known but every effort should be 
made to capture this information.
To provide flexibility to investigators when a 
patient has withdrawn consent or has been 
lost to follow-up.
Section 8.4.4, 
Regulatory 
Reporting 
Requirements for 
SAE
Text added to align with EU requirements for 
reporting SUSARs.
To comply with EU regulatory requirements.
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Section Number 
and Name
Description of Change
Brief Rationale
Section 8.6, 
Pharmacokinetics
Text added to reference Section 1.3.2 (SoA) and 
state that no further PK/ADA samples are 
required.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.8, 
Biomarkers
Text added to reference Section 1.3.2 (SoA) and 
state that no further biomarker samples are 
required.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.11.4.2, 
Efficacy Follow-up 
Visits
Text added to reference Section 1.3.2 (SoA) and 
state that no further Efficacy Follow-up Visits are 
required.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.11.4.3, 
DMFS Follow-up 
Visits
Text added to reference Section 1.3.2 (SoA) and 
state that no further DMFS Follow-up Visits are 
required.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 8.11.4.4, 
Survival Follow-up 
Contacts
Text added to reference Section 1.3.2 (SoA) and 
state that no further Survival Follow-up Contact 
are required.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 9, Statistical 
Analysis Plan 
Text added regarding the discontinuation of the 
experimental arm (MK-7684A) following eDMC 
interim review and ongoing participants moved 
to pembrolizumab monotherapy for the 
remainder of the study.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 9.1, 
Statistical Analysis 
Plan Summary
Text updated with approximate timings on IA2, 
IA3, IA4, IA5, and FA. Statistical assumptions 
were not changed.
See rationale for Section 1.2, futility timing.
Section 9.2, 
Responsibility for 
Analyses/In-house 
Blinding
Text added to state that following eDMC review 
of the data at IA1, no additional efficacy and 
PRO data analysis will be conducted at 
subsequent IAs and that information regarding 
planned IAs in Section 9 is being retained for 
historical purposes.
See rationale for Section 1.1, discontinuation 
of experimental arm.
Section 9.7.1, 
Interim Analyses
Table 11 updated with approximate timings on 
IA2, IA3, IA4, IA5, and FA. Statistical 
assumptions were not changed.
See rationale for Section 1.2, futility timing.
Section 10.1.1, 
Code of Conduct for 
Clinical Trials
Text added to reference to EU 536/2014 
regulation.
See rationale for Section 8.4.4.
Section 10.1.3, Data 
Protection
Text added regarding EU global privacy 
statement.
See rationale for Section 8.4.4.
Section 10.7.6, Italy
Section removed as requirements for Italy are 
stated in Section 10.7.11 (previously 10.7.12).
To remove duplicate text.
Throughout 
document
Treatment arm has been changed to experimental 
arm.
To be consistent with updated treatment 
arms listed in Study Interventions table.
Minor administrative, formatting, grammatical, 
and/or typographical changes were made 
throughout the document.
To ensure clarity and accurate interpretation 
of the intent of the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................18
1.1
Synopsis.................................................................................................................18
1.2
Schema ..................................................................................................................23
1.3
Schedule of Activities...........................................................................................24
1.3.1
Schedule of Activities (Original Protocol through Protocol 
Amendment 03) ...........................................................................................24
1.3.2
Schedule of Activities (Protocol Amendment 04).......................................31
2
INTRODUCTION..........................................................................................................33
2.1
Study Rationale....................................................................................................33
2.1.1
Preliminary Data for Coformulation of Vibostolimab with 
Pembrolizumab (MK-7684A) in Melanoma................................................34
2.1.1.1
Substudy KEYMAKER-02B.............................................................34
2.1.1.2
Substudy KEYMAKER-02C.............................................................34
2.2
Background ..........................................................................................................35
2.2.1
Pharmaceutical and Therapeutic Background .............................................35
2.2.1.1
MK-7684A.........................................................................................35
2.2.1.2
Pembrolizumab ..................................................................................36
2.3
Benefit/Risk Assessment......................................................................................37
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................38
4
STUDY DESIGN............................................................................................................40
4.1
Overall Design......................................................................................................40
4.2
Scientific Rationale for Study Design.................................................................41
4.2.1
Rationale for Endpoints ...............................................................................41
4.2.1.1
Efficacy Endpoints.............................................................................41
4.2.1.2
Safety Endpoints................................................................................41
4.2.1.3
Patient-reported Outcomes.................................................................41
4.2.1.4
EORTC QLQ-C30 .............................................................................42
4.2.1.5
EQ-5D-5L ..........................................................................................42
4.2.1.6
Planned Exploratory Biomarker Research.........................................42
4.2.1.7
Future Biomedical Research..............................................................44
4.2.2
Rationale for the Use of Comparator...........................................................44
4.3
Justification for Dose...........................................................................................44
4.3.1
MK-7684A...................................................................................................44
4.3.1.1
MK-7684A Dosing in Adolescents....................................................46
4.3.2
Pembrolizumab ............................................................................................47
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4.4
Beginning and End-of-Study Definition ............................................................47
4.4.1
Clinical Criteria for Early Study Termination .............................................48
5
STUDY POPULATION ................................................................................................49
5.1
Inclusion Criteria.................................................................................................49
5.2
Exclusion Criteria................................................................................................53
5.3
Lifestyle Considerations......................................................................................54
5.3.1
Meals and Dietary Restrictions....................................................................54
5.4
Screen Failures.....................................................................................................54
5.5
Participant Replacement Strategy......................................................................55
6
STUDY INTERVENTION............................................................................................56
6.1
Study Intervention(s) Administered...................................................................56
6.1.1
Treatment .....................................................................................................58
6.2
Preparation/Handling/Storage/Accountability .................................................58
6.2.1
Dose Preparation..........................................................................................58
6.2.2
Handling, Storage, and Accountability........................................................58
6.3
Measures to Minimize Bias: Randomization and Blinding..............................59
6.3.1
Intervention Assignment..............................................................................59
6.3.2
Stratification.................................................................................................59
6.3.3
Blinding........................................................................................................60
6.4
Study Intervention Compliance..........................................................................60
6.5
Concomitant Therapy..........................................................................................60
6.5.1
Rescue Medications and Supportive Care ...................................................62
6.6
Dose Modification ................................................................................................62
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................62
6.7
Intervention After the End of the Study............................................................68
6.8
Clinical Supplies Disclosure................................................................................68
6.9
Standard Policies..................................................................................................69
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................70
7.1
Discontinuation of Study Intervention...............................................................70
7.2
Participant Withdrawal From the Study...........................................................71
7.3
Lost to Follow-up .................................................................................................71
8
STUDY ASSESSMENTS AND PROCEDURES........................................................73
8.1
Administrative and General Procedures ...........................................................73
8.1.1
Informed Consent.........................................................................................73
8.1.1.1
General Informed Consent.................................................................73
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................74
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8.1.2
Inclusion/Exclusion Criteria ........................................................................74
8.1.3
Participant Identification Card.....................................................................74
8.1.4
Medical History ...........................................................................................74
8.1.5
Melanoma Disease History..........................................................................75
8.1.6
Prior and Concomitant Medications Review...............................................75
8.1.6.1
Prior Medications...............................................................................75
8.1.6.2
Concomitant Medications..................................................................75
8.1.7
Assignment of Screening Number...............................................................75
8.1.8
Assignment of Treatment/Randomization Number.....................................75
8.1.9
Study Intervention Administration ..............................................................76
8.1.9.1
Timing of Dose Administration.........................................................76
8.1.10
Discontinuation and Withdrawal .................................................................76
8.1.10.1
Withdrawal From Future Biomedical Research ................................77
8.1.11
Participant Blinding/Unblinding..................................................................77
8.1.12
Calibration of Equipment.............................................................................78
8.1.13
Tumor Tissue for Biomarker Status.............................................................78
8.1.14
Elevated Transaminases With Treated HBV or HCV .................................78
8.2
Efficacy/Immunogenicity Assessments ..............................................................79
8.2.1
Tumor Imaging and Assessment of Disease................................................79
8.2.1.1
Initial Tumor Scans............................................................................79
8.2.1.2
Tumor Scans During the Study..........................................................80
8.2.1.3
End-of-treatment and Follow-up Tumor Scans .................................80
8.2.1.4
RECIST 1.1 Assessment of Disease..................................................80
8.2.2
Patient-reported Outcomes...........................................................................81
8.3
Safety Assessments...............................................................................................81
8.3.1
Physical Examinations.................................................................................81
8.3.1.1
Full Physical Examination.................................................................82
8.3.1.2
Directed Physical Examination..........................................................82
8.3.2
Vital Signs....................................................................................................82
8.3.3
Electrocardiograms ......................................................................................82
8.3.4
Clinical Safety Laboratory Assessments .....................................................82
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................83
8.3.5
Pregnancy Testing........................................................................................83
8.3.6
Performance Assessments............................................................................84
8.3.6.1
Karnofsky Performance Status ..........................................................84
8.3.6.2
Eastern Cooperative Oncology Group Performance Status...............84
8.3.6.3
Lansky Play-Performance Scale ........................................................84
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8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................84
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................85
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......87
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...87
8.4.4
Regulatory Reporting Requirements for SAE .............................................87
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................88
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................88
8.4.7
Events of Clinical Interest............................................................................88
8.5
Treatment of Overdose........................................................................................89
8.6
Pharmacokinetics.................................................................................................89
8.6.1
Blood Collection for Pharmacokinetics Analysis........................................89
8.7
Pharmacodynamics..............................................................................................89
8.8
Biomarkers ...........................................................................................................89
8.8.1
Planned Genetic Analysis Sample Collection..............................................89
8.9
Future Biomedical Research Sample Collection...............................................90
8.10
Medical Resource Utilization and Health Economics.......................................90
8.11
Visit Requirements...............................................................................................90
8.11.1
Screening......................................................................................................90
8.11.2
Treatment Period Visits ...............................................................................91
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................91
8.11.4
Posttreatment Visit.......................................................................................91
8.11.4.1
Safety Follow-up Visit.......................................................................91
8.11.4.2
Efficacy Follow-up Visits..................................................................91
8.11.4.3
DMFS Follow-up Visits.....................................................................92
8.11.4.4
Survival Follow-up Contacts .............................................................92
8.11.5
Vital Status...................................................................................................93
9
STATISTICAL ANALYSIS PLAN .............................................................................94
9.1
Statistical Analysis Plan Summary.....................................................................94
9.2
Responsibility for Analyses/In-house Blinding .................................................95
9.3
Hypotheses/Estimation ........................................................................................96
9.4
Analysis Endpoints...............................................................................................96
9.4.1
Efficacy Endpoints.......................................................................................96
9.4.1.1
Primary Efficacy Endpoint ................................................................96
9.4.1.2
Secondary Efficacy Endpoints...........................................................96
9.4.1.3
Exploratory Endpoints .......................................................................97
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9.4.2
Safety Endpoints..........................................................................................97
9.4.3
PRO Endpoints.............................................................................................97
9.5
Analysis Populations............................................................................................97
9.5.1
Efficacy Analysis Population.......................................................................97
9.5.2
Safety Analysis Population..........................................................................98
9.5.3
PRO Analysis Population ............................................................................98
9.6
Statistical Methods...............................................................................................98
9.6.1
Statistical Methods for Efficacy Analyses...................................................98
9.6.1.1
Recurrence-free Survival ...................................................................99
9.6.1.2
Distant Metastases-free Survival .....................................................100
9.6.1.3
Overall Survival...............................................................................100
9.6.1.4
Summary of Statistical Methods for Efficacy..................................100
9.6.2
Statistical Methods for Safety Analyses ....................................................101
9.6.2.1
Overall Safety Assessment ..............................................................101
9.6.2.2
Assessment of Safety Topics of Special Interest .............................102
9.6.3
Statistical Methods for Patient-Reported Outcome Analyses....................103
9.6.4
Summaries of Demographic and Baseline Characteristics ........................103
9.7
Interim Analyses ................................................................................................103
9.7.1
Efficacy Interim Analyses..........................................................................104
9.7.2
Safety Interim Analyses.............................................................................104
9.8
Multiplicity .........................................................................................................105
9.8.1
Recurrence-free Survival ...........................................................................106
9.8.2
Distant Metastases-free Survival ...............................................................107
9.8.3
Overall Survival.........................................................................................108
9.8.4
Safety Analyses..........................................................................................110
9.9
Sample Size and Power Calculations ...............................................................110
9.9.1
Recurrence-free Survival ...........................................................................110
9.9.2
Distant Metastases-free Survival ...............................................................110
9.9.3
Overall Survival.........................................................................................111
9.10
Subgroup Analyses.............................................................................................111
9.11
Compliance (Medication Adherence)...............................................................111
9.12
Extent of Exposure.............................................................................................112
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................113
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......113
10.1.1
Code of Conduct for Clinical Trials...........................................................113
10.1.2
Financial Disclosure...................................................................................116
10.1.3
Data Protection...........................................................................................117
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10.1.3.1
Confidentiality of Data ....................................................................117
10.1.3.2
Confidentiality of Participant Records.............................................117
10.1.3.3
Confidentiality of IRB/IEC Information..........................................118
10.1.4
Committees Structure.................................................................................118
10.1.4.1
Executive Oversight Committee......................................................118
10.1.4.2
External Data Monitoring Committee .............................................118
10.1.4.3
Scientific Advisory Committee (SAC)............................................118
10.1.5
Publication Policy......................................................................................119
10.1.6
Compliance with Study Registration and Results Posting Requirements .119
10.1.7
Compliance with Law, Audit, and Debarment ..........................................119
10.1.8
Data Quality Assurance .............................................................................120
10.1.9
Source Documents .....................................................................................121
10.1.10
Study and Site Closure...............................................................................121
10.2
Appendix 2: Clinical Laboratory Tests............................................................122
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................124
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................124
10.3.2
Definition of AE ........................................................................................124
10.3.3
Definition of SAE ......................................................................................125
10.3.4
Additional Events Reported.......................................................................126
10.3.5
Recording AE and SAE .............................................................................126
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................129
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................131
10.5
Appendix 5: Contraceptive Guidance..............................................................132
10.5.1
Definitions..................................................................................................132
10.5.2
Contraceptive Requirements......................................................................133
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................134
10.7
Appendix 7: Country-specific Requirements..................................................138
10.7.1
Argentina....................................................................................................138
10.7.2
Austria........................................................................................................138
10.7.3
Belgium......................................................................................................138
10.7.4
France.........................................................................................................138
10.7.5
United Kingdom.........................................................................................138
10.7.6
Ireland ........................................................................................................139
10.7.7
Germany.....................................................................................................139
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10.7.8
Poland ........................................................................................................140
10.7.9
Romania.....................................................................................................140
10.7.10
Spain ..........................................................................................................140
10.7.11
Sweden.......................................................................................................141
10.7.12
Italy ............................................................................................................142
10.7.13
South Africa...............................................................................................142
10.7.14
China..........................................................................................................142
10.7.15
Peru ............................................................................................................143
10.7.16
Brazil..........................................................................................................143
10.8
Appendix 8: Melanoma Staging .......................................................................144
10.9
Appendix 9: Guidance for Distinguishing Primary Cutaneous Melanomas 
from Cutaneous Metastases of Melanoma.......................................................149
10.10 Appendix 10: Surgical Considerations ............................................................150
10.11 Appendix 11: Abbreviations .............................................................................152
11
REFERENCES.............................................................................................................156
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LIST OF TABLES
Table 1
Schedule of Activities (Original protocol through Protocol 
Amendment 03)...........................................................................................24
Table 2
Schedule of Activities (Protocol Amendment 04) ......................................31
Table 3
Adequate Organ Function Laboratory Values.............................................52
Table 4
Study Interventions......................................................................................57
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated With Pembrolizumab Monotherapy, 
Coformulations, or IO Combinations..........................................................64
Table 6
Pembrolizumab Monotherapy, Coformulations (MK-7684A), or IO 
Combinations Infusion Reaction Dose Modification and Treatment 
Guidelines....................................................................................................67
Table 7
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events ............................................................................86
Table 8
Censoring Rules for Primary and Sensitivity Analyses of Recurrence-
free Survival ................................................................................................99
Table 9
Analysis Strategy for Key Efficacy Endpoints..........................................101
Table 10
Analysis Strategy for Safety Parameters...................................................102
Table 11
Analyses Planned, Endpoints Evaluated, and Drivers of Timing .............104
Table 12
Probability of Continuing Study Based on Different Assumptions for 
True HR of RFS at IA1 .............................................................................106
Table 13
Boundary Properties for Planned Analyses of the RFS Analyses Based 
on α = 0.025...............................................................................................107
Table 14
Efficacy Boundaries and Properties for the DMFS Analyses ...................108
Table 15
Efficacy Boundaries and Properties for the OS Analyses.........................109
Table 16
Protocol-required Safety Laboratory Assessments ...................................122
Table 17
Melanoma T Category Definition .............................................................144
Table 18
Melanoma N Category Definition.............................................................145
Table 19
Melanoma M Category Definition ............................................................146
Table 20
AJCC Pathological (pTNM) Staging Groups............................................147
Table 21
AJCC Clinical Prognostic (cTNM) Staging Groups.................................148
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LIST OF FIGURES
Figure 1
Study Design ...............................................................................................23
Figure 2
Multiplicity Graph for Type-I Error Control of Study Hypotheses ..........105
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 3, Randomized, Double-blind, Active-Comparator-Controlled 
Clinical Study of Adjuvant MK-7684A (Vibostolimab with Pembrolizumab) Versus 
Adjuvant Pembrolizumab in Participants with High-risk Stage II-IV Melanoma (KEYVIBE-
010)
Short Title: Adjuvant MK-7684A vs Pembrolizumab for Resected High-Risk Melanoma
Acronym: KEYVIBE-010
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In individuals with high-risk resected Stage IIB, IIC, III or IV melanoma:
Primary Objective
Primary Endpoint
To compare MK-7684A to pembrolizumab 
with respect to RFS
Hypothesis (H1): MK-7684A is superior to 
pembrolizumab with respect to RFS as 
assessed by investigator.
RFS: time from randomization to any 
recurrence (local, locoregional, regional or 
distant) as assessed by investigator, or death 
due to any cause, whichever occurs first.
Secondary Objectives
Secondary Endpoints
To compare MK-7684A to pembrolizumab 
with respect to DMFS.
Hypothesis (H2): MK-7684A is superior to 
pembrolizumab with respect to DMFS as 
assessed by investigator.
DMFS: The time from randomization to 
appearance of a distant metastasis as 
assessed by investigator or death due to any 
cause, whichever occurs first. A distant 
metastasis refers to cancer that has spread 
from the original (primary) tumor to distant 
organs or distant lymph nodes.
To compare MK-7684A to pembrolizumab 
with respect to OS.
Hypothesis (H3): MK-7684A is superior to 
pembrolizumab with respect to overall 
survival.
OS: The time from randomization to death 
due to any cause.
To evaluate the safety and tolerability of 
MK-7684A and pembrolizumab
Adverse event
Study intervention discontinuation due to 
AEs
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To evaluate MK-7684A to pembrolizumab 
with respect to mean change from baseline 
in global health status/QoL, physical 
functioning, and role functioning using the 
EORTC QLQ-C30
Change in score from baseline evaluated by:
Global health status/QoL score (Items 29 
and 30)
Physical functioning score (Items 1-5)
Role functioning score (Items 6 and 7)
Overall Design:
Protocol Amendment 04 implementation: based on recommendations of the eDMC following 
an interim review of the data that showed no benefit over the comparator arm of 
pembrolizumab monotherapy, the experimental arm (Arm A: MK-7684A) will be 
discontinued and all ongoing participants on treatment will move to the comparator arm 
(Arm B: pembrolizumab monotherapy) for the remainder of the study (a total of 17 cycles of 
study treatment or until disease progression, whichever occurs first).
Study Phase
Phase 3
Primary Purpose
Treatment
Indication
Malignant melanoma
Population
Adult and adolescent participants (≥12 
years old and ≥40 kg) with high-risk (Stage 
IIb-IV) resected melanoma
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
Active Control Without Placebo
Study Blinding
Double-blind with in-house blinding
Blinding Roles
Participants or Subjects
Investigator
Sponsor
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 8 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 1,560 participants will be randomized in the study.
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Intervention Groups and Duration:
Protocol Amendment 04 implementation: All active participants in the experimental arm 
(Arm A: MK-7684A) will be moved to the comparator arm (Arm B: pembrolizumab 
monotherapy) for the remainder of the study (a total of 17 cycles of study treatment or until 
disease progression, whichever occurs first).
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Arm A 
(Protocol 
Amendment 
04: Arm A 
discontinued) 
MK-7684A
MK-7684
200 mg +
pembrolizumab
200 mg/ 20 mL
vial
200 mg / 
200 mg
IV Infusion
Q3W (Day 1 of 
each cycle) for 
17 cycles or 
until discon-
tinuation 
criteria are met
Test Product
Arm B
Pembrolizumab
25 mg/mL
Adults: 
200 mg
Adolescents 
≥40 kg: 
2 mg/kg (up to 
max of 
200 mg)
IV Infusion
Q3W (Day 1 of 
each cycle) for 
17 cycles or 
until discon-
tinuation 
criteria are met, 
whichever 
occurs first
Comparator
IV=intravenous; Q3W=every 3 weeks. 
MK-7684A is a coformulation of vibostolimab (MK-7684) with pembrolizumab.
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Total Number of Intervention Groups/Arms
2
Duration of Participation
Each participant will participate in the study 
from the time the participant provides 
documented informed consent through the 
final protocol-specified contact.
After a screening phase of up to 28 days, 
each participant will be assigned to receive 
study intervention for up to 17 cycles or 
until one of the conditions for 
discontinuation of study intervention is met, 
whichever occurs first.
After the end of treatment, each participant 
will be followed for the occurrence of AEs 
and spontaneously reported pregnancy.
Participants who discontinue for reasons 
other than disease recurrence will have 
posttreatment follow-up for disease status 
until any of the conditions for 
discontinuation of Efficacy Follow-up are 
met. 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 examination with subsequent 
biopsy). Participants who initiate a 
nonstudy anticancer treatment for 
melanoma will have posttreatment DMFS 
follow-up until metastatic disease 
recurrence is documented.
All participants will be followed for OS 
until death, withdrawal of consent, or the 
end of the study.
Protocol Amendment 04 implementation: 
no data collection for efficacy follow-up 
will be required.
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Study Governance Committees:
Executive Oversight Committee
Yes
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 11.
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1.2
Schema
The study design is depicted in Figure 1. Protocol Amendment 04 implementation: 
Following eDMC interim review of the data, the experimental arm (Arm A: MK-7684A) will 
be discontinued and all ongoing participants will move to the comparator arm (Arm B: 
pembrolizumab monotherapy) for the remainder of the study.
Figure 1
Study Design
DMFS=distant metastasis-free survival; ECOG=Eastern Cooperative Oncology Group; IA=Interim Analysis; 
INV=investigator; KPS=Karnofsky performance status; LPS=Lansky play-performance scale; OS=overall survival; 
QoL=quality of life; RFS=recurrence-free survival; ROW=rest of world.
CCI
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1.3
Schedule of Activities
See Appendix 7 for country-specific requirements. Table 1 documents the Schedule of Activities up to Protocol Amendment 03.
Protocol Amendment 04 implementation: Following eDMC interim review of the data, the experimental arm (Arm A: MK-7684A) 
will be discontinued and all ongoing participants will move to the comparator arm (Arm B: pembrolizumab monotherapy) for the 
remainder of the study. Refer to Table 2 for Schedule of Activities to be implement following approval of Protocol Amendment 04.
1.3.1
Schedule of Activities (Original Protocol through Protocol Amendment 03)
Table 1
Schedule of Activities (Original protocol through Protocol Amendment 03)
Study Period
Screening
Treatment
(3-Week Cycles for up 
to 17 Cycles)
EOT
Posttreatment
Notes
Visit Number/Title
Screening
C1
C2 and 
Even # 
Cycles
C3 and 
Odd # 
Cycles
Discon
Safety 
Follow-up
Efficacy 
Follow-
up 
DMFS 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
before treatment administration unless 
otherwise indicated.
Cycle Day
Up to 28 
days 
before first 
dose
1
1
1
At 
Discon
30 days 
and
90 days 
from last 
dose
Per 
Imaging 
Schedule 
Per 
Imaging 
Schedule 
Q12W
Scheduled Days
-28 to -1
+3
±3
±3
+7
+7
±14
Administrative Procedures
Informed Consent/Assent
X
Informed Consent/Assent for 
FBR
X
Participant may participate in main study 
without providing FBR consent.
For country-specific criteria, refer to 
Appendix 7.
Inclusion/Exclusion Criteria
X
Participant ID Card Issued
X
X
Add the randomization number at the time 
of randomization.
Medical History and 
Demographics
X
Disease History
X
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Study Period
Screening
Treatment
(3-Week Cycles for up 
to 17 Cycles)
EOT
Posttreatment
Notes
Visit Number/Title
Screening
C1
C2 and 
Even # 
Cycles
C3 and 
Odd # 
Cycles
Discon
Safety 
Follow-up
Efficacy 
Follow-
up 
DMFS 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
before treatment administration unless 
otherwise indicated.
Cycle Day
Up to 28 
days 
before first 
dose
1
1
1
At 
Discon
30 days 
and
90 days 
from last 
dose
Per 
Imaging 
Schedule 
Per 
Imaging 
Schedule 
Q12W
Scheduled Days
-28 to -1
+3
±3
±3
+7
+7
±14
Prior/Concomitant Medication 
Review
X
X
X
X
X
X
Record medication(s) administered within 
28 days before the start of study 
intervention, during the study, and through 
the Safety Follow-up Visit. Concomitant 
medications for an SAE administered after 
the Safety Follow-up Visit should be 
recorded.
Randomization
X
Poststudy Anticancer Therapy 
Status
X
X
X
X
Vital Status
X
On Sponsor request, participants may be 
contacted for survival information at any 
time during the study.
Study Intervention 
Administration
Blinded Study Intervention 
Administration (MK-7684A or 
pembrolizumab)
X
X
X
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Study Period
Screening
Treatment
(3-Week Cycles for up 
to 17 Cycles)
EOT
Posttreatment
Notes
Visit Number/Title
Screening
C1
C2 and 
Even # 
Cycles
C3 and 
Odd # 
Cycles
Discon
Safety 
Follow-up
Efficacy 
Follow-
up 
DMFS 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
before treatment administration unless 
otherwise indicated.
Cycle Day
Up to 28 
days 
before first 
dose
1
1
1
At 
Discon
30 days 
and
90 days 
from last 
dose
Per 
Imaging 
Schedule 
Per 
Imaging 
Schedule 
Q12W
Scheduled Days
-28 to -1
+3
±3
±3
+7
+7
±14
Efficacy Procedures
Tumor Scan (Neck, Chest, 
Abdomen, and Pelvis) 
X
X
X*
Perform at the EOT Visit and 12 weeks (±7 
days) from date of randomization, then 
Q12W (±7 days) for 2 years after 
randomization, then Q6M (±14 days)
through Year 4, then once at 5 years (±28 
days) after date of randomization. 
NECK CT is required only for participants 
with primary tumors of the head and neck 
and during the study if clinically indicated.
* Radiographic imaging in Survival Follow-
up may be performed as clinically indicated, 
per local standard of care, or following new 
anticancer therapy imaging schedule. 
Refer to the Site Imaging Manual for 
details.
Brain Scan
X
As clinically indicated
Bone Scan
As clinically indicated
Pathology Report
X
Recurrence only
Lesion Photograph
Recurrence only
Submit diagnostic photograph for cutaneous 
recurrence if possible.
Safety Procedures
Full Physical Examination
X
X
Height
X
X*
X*
X*
X*
X*
*Pediatric participants only.
Weight
X
X
X
X
X
X
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Study Period
Screening
Treatment
(3-Week Cycles for up 
to 17 Cycles)
EOT
Posttreatment
Notes
Visit Number/Title
Screening
C1
C2 and 
Even # 
Cycles
C3 and 
Odd # 
Cycles
Discon
Safety 
Follow-up
Efficacy 
Follow-
up 
DMFS 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
before treatment administration unless 
otherwise indicated.
Cycle Day
Up to 28 
days 
before first 
dose
1
1
1
At 
Discon
30 days 
and
90 days 
from last 
dose
Per 
Imaging 
Schedule 
Per 
Imaging 
Schedule 
Q12W
Scheduled Days
-28 to -1
+3
±3
±3
+7
+7
±14
Directed Physical Examination
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.
*During follow-up, if a clinic visit is not 
feasible, a physical examination will not be 
collected.
Vital Signs (temperature, heart 
rate, respiratory rate, and blood 
pressure)
X
X
X
X
X
X
12-lead ECG
X
A 6-lead ECG is allowed per institutional 
standard.
Age-appropriate Performance 
Scale (Lansky/Karnofsky/ECOG)
X*
X
X
X
X
*Screening assessment to be performed 
within 7 days of C1D1.
≤16 years of age: Lansky; 
>16 to <18 years of age: Karnofsky; 
≥18 years of age: ECOG
AE/SAE Review
X
X
X
X
X
X
Refer to Section 8.4.1 for the duration of AE 
reporting.
Laboratory Assessments
Laboratory samples should be taken and 
reviewed pre-dose at each time point 
indicated.
Hematology/Chemistry
X
X
X
X
X
Screening samples to be taken within 7 days 
of first dose of study intervention. See 
Appendix 2 for further details.
Urine Testing (urinalysis or 
dipstick)
X
X
X
X
Screening samples to be taken within 7 days 
of first dose of study intervention. See 
Appendix 2 for further details.
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Study Period
Screening
Treatment
(3-Week Cycles for up 
to 17 Cycles)
EOT
Posttreatment
Notes
Visit Number/Title
Screening
C1
C2 and 
Even # 
Cycles
C3 and 
Odd # 
Cycles
Discon
Safety 
Follow-up
Efficacy 
Follow-
up 
DMFS 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
before treatment administration unless 
otherwise indicated.
Cycle Day
Up to 28 
days 
before first 
dose
1
1
1
At 
Discon
30 days 
and
90 days 
from last 
dose
Per 
Imaging 
Schedule 
Per 
Imaging 
Schedule 
Q12W
Scheduled Days
-28 to -1
+3
±3
±3
+7
+7
±14
Coagulation Tests (PT/INR and 
aPTT/PTT)
X
Perform within 7 days before first dose of 
study intervention.
Consider more frequent testing for 
participants receiving anticoagulants. See 
Appendix 2 for further details.
T3/T4/TSH
X
X
X
X
Screening samples to be taken within 7 days 
of first dose of study intervention. See 
Appendix 2 for further details.
LDH
X
Recurrence only
Screening samples to be taken within 7 days 
of first dose of study intervention. See 
Appendix 2 for further details.
Urine or Serum Pregnancy Test 
(WOCBP only)
X
X
X
X
X
X*
WOCBP require a negative test within 24 
hours (for a urine test) or 72 hours (for a 
serum test) within C1D1 and before each 
subsequent dose of study intervention.
*Repeat at 120 days from last dose of study 
intervention.
See Section 8.3.5 for pregnancy testing 
requirements.
HIV, Hepatitis B and Hepatitis C 
Testing
X*
*Only if required per Section 5.1 and/or 
Appendix 7. See Appendix 2 for further 
details.
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Study Period
Screening
Treatment
(3-Week Cycles for up 
to 17 Cycles)
EOT
Posttreatment
Notes
Visit Number/Title
Screening
C1
C2 and 
Even # 
Cycles
C3 and 
Odd # 
Cycles
Discon
Safety 
Follow-up
Efficacy 
Follow-
up 
DMFS 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
before treatment administration unless 
otherwise indicated.
Cycle Day
Up to 28 
days 
before first 
dose
1
1
1
At 
Discon
30 days 
and
90 days 
from last 
dose
Per 
Imaging 
Schedule 
Per 
Imaging 
Schedule 
Q12W
Scheduled Days
-28 to -1
+3
±3
±3
+7
+7
±14
Patient-reported Outcomes 
Assessments
Administer PROs in the order shown before 
performing any other procedures, 
assessments, or treatment.
EORTC QLQ-C30
X
X*
X
X
X#
X#
*Cycles 5, 9, 13, and 17
Administered to adults (≥18 years of age at 
screening) only.
#During follow-up, if a clinic visit is not 
feasible, PROs will not be collected
EQ-5D-5L
X
X*
X
X
X#
X#
*Cycles 5, 9, 13, and 17
# During follow-up, if a clinic visit is not 
feasible, PRO will not be collected
Pharmacokinetics/ 
Pharmacodynamics/ 
Biomarkers
Blood collection for PK
X
X
X
Predose (within 24 hours before study 
intervention infusion): Cycles 1, 2, 4, 8, 12 
and 16
Postdose (within 10 minutes after end of 
infusion): Cycles 1 and 8
Blood collection for ADA
X
X
X
Predose (within 24 hours before study 
intervention infusion): Cycles 1, 2, 4, 8, 12 
and 16
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Study Period
Screening
Treatment
(3-Week Cycles for up 
to 17 Cycles)
EOT
Posttreatment
Notes
Visit Number/Title
Screening
C1
C2 and 
Even # 
Cycles
C3 and 
Odd # 
Cycles
Discon
Safety 
Follow-up
Efficacy 
Follow-
up 
DMFS 
Follow-
up
Survival 
Follow-
up
All assessments should be performed 
before treatment administration unless 
otherwise indicated.
Cycle Day
Up to 28 
days 
before first 
dose
1
1
1
At 
Discon
30 days 
and
90 days 
from last 
dose
Per 
Imaging 
Schedule 
Per 
Imaging 
Schedule 
Q12W
Scheduled Days
-28 to -1
+3
±3
±3
+7
+7
±14
Archival and/or Newly Obtained 
Tissue Collection
X
Submission of tumor tissue is optional for recurrence
At Screening: Submit archival or fresh 
tumor sample if sufficient tumor tissue is 
available. 
At Recurrence (optional): Submit fresh 
tumor sample.
See Procedure Manual for details.
Blood for Genetic Analysis
X
Collect predose. See Section 8.8.1 for 
additional information.
Blood for ctDNA Analysis
X
X*
X**
X
X***
X***
Collect predose on C1D1.
*Collect predose on Day 1 for even cycles: 
C2 and C4
**Collect predose on Day 1 for odd cycles: 
C3, C5, C9, C13, and C17
***During follow-up, if a clinic visit is not 
feasible, blood for ctDNA will not be 
collected.
ADA=antidrug antibodies; AE=adverse event; aPTT=activated partial thromboplastin time; C=cycle; ctDNA=circulating tumor DNA; D=day; Discon=discontinuation; 
DMFS=distant metastasis-free survival; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ=European Organization for Research and 
Treatment of Cancer Quality of Life Questionnaire; EOT=end of treatment; EQ-5D-5L=EuroQoL 5 dimensions-5 levels; FBR=future biomedical research; HIV=human 
immunodeficiency virus; ID=identification; LDH=lactate dehydrogenase; PK=pharmacokinetics; PRO=patient-reported outcome; PT/INR=prothrombin time/international 
normalized ratio; PTT=partial thromboplastin time; Q12W=every 12 weeks; Q6M=every 6 months; SAE=serious adverse event; T3=triiodothyronine; T4=thyroxine; 
TSH=thyroid-stimulating hormone; WOCBP=woman of childbearing potential.
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1.3.2
Schedule of Activities (Protocol Amendment 04)
Table 2
Schedule of Activities (Protocol Amendment 04)
Study Period
Treatment
(3-Week Cycles for up to 
17 Cycles)
EOT
Posttreatment
Notes
Visit Number/Title C2 and Even 
# Cycles
C3 and Odd 
# Cycles
Discon
Safety Follow-up
All assessments should be performed before treatment 
administration unless otherwise indicated.
Participants who complete or discontinue study intervention 
and have completed safety follow-up will be considered to 
have completed the study. This also applies to participants in 
efficacy follow-up.
Cycle Day
1
1
At Discon
30 days and
90 days from last dose
Scheduled Days
±3
±3
+7
+7
Administrative Procedures
Informed Consent/Assent
X
Reconsent with revised informed consent form.
Prior/Concomitant Medication 
Review
X
X
X
X
Record medication(s) administered through to the Safety 
Follow-up Visit. Concomitant medications for an SAE 
administered after the Safety Follow-up Visit should be 
recorded.
Study Intervention Administration
Pembrolizumab administration
X
X
Participants may receive a total of 17 cycles of study treatment.
Efficacy Procedures
Tumor Scan (Neck, Chest, Abdomen, 
and Pelvis)
Q12W or per local standard-
of-care
NECK CT is required only for participants with primary tumors 
of the head and neck and during the study if clinically indicated.
On-treatment scans required to confirm if recurrence occurs 
(treatment discontinuation criteria).
Safety Procedures
Full Physical Examination
X
Weight
X
X
X
X
Vital Signs (temperature, heart rate, 
respiratory rate, and blood pressure)
X
X
X
X
12-lead ECG
A 6-lead ECG is allowed per institutional standard.
Age-appropriate Performance Scale 
(Lansky/Karnofsky/ECOG)
X
X
X
X
≤16 years of age: Lansky; 
>16 to <18 years of age: Karnofsky; 
≥18 years of age: ECOG
AE/SAE Review
X
X
X
X
Refer to Section 8.4.1 for the duration of AE reporting.
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Study Period
Treatment
(3-Week Cycles for up to 
17 Cycles)
EOT
Posttreatment
Notes
Visit Number/Title C2 and Even 
# Cycles
C3 and Odd 
# Cycles
Discon
Safety Follow-up
All assessments should be performed before treatment 
administration unless otherwise indicated.
Participants who complete or discontinue study intervention 
and have completed safety follow-up will be considered to 
have completed the study. This also applies to participants in 
efficacy follow-up.
Cycle Day
1
1
At Discon
30 days and
90 days from last dose
Scheduled Days
±3
±3
+7
+7
Laboratory Assessments
Laboratory samples should be taken and reviewed pre-dose at 
each time point indicated.
Hematology/Chemistry
X
X
X
X
See Appendix 2 for further details.
Urine Testing (urinalysis or dipstick)
X
X
X
See Appendix 2 for further details.
T3/T4/TSH
X
X
X
See Appendix 2 for further details.
Urine or Serum Pregnancy Test 
(WOCBP only)
X
X
X
X*
*Repeat at 120 days from last dose of study intervention.
See Section 8.3.5 for pregnancy testing requirements.
AE=adverse event; C=cycle; D=day; Discon=discontinuation; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=end of treatment; Q12W=every 12 
weeks; SAE=serious adverse event; SOC=standard-of-care; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WOCBP=woman of childbearing potential.
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2
INTRODUCTION
2.1
Study Rationale
Melanoma is a malignant tumor that arises from melanocytes that accounts for less than 2% 
of skin cancers, though 90% of deaths due to cutaneous tumors are associated with 
melanoma [Garbe, C., et al 2012] [American Cancer Society 2014]. Worldwide, about 
324,635 individuals were diagnosed with melanoma in 2021, and in the US an estimated 
99,780 new cases of melanoma will be diagnosed and 7,650 will die of their melanoma in 
2022. The risk of melanoma increases with age, with the median age of diagnosis of 61 years 
[American Cancer Society 2014]. However, melanoma is not uncommon among individuals 
younger than 30 years and is the second most diagnosed cancer (after lymphomas) among 
adolescents and young adults [Weir, H. K., et al 2011]. Most patients with melanoma (84%) 
are initially diagnosed with localized disease, whereas 9% have regional disease, and 4% 
have metastatic disease at diagnosis [National Cancer Institute 2017].
Standard treatment for localized melanoma is surgical resection. For patients with Stage III 
or IV resectable disease, systemic adjuvant therapy has been established as a standard of care 
option for appropriate patients after resection, with NCCN-recommended regimens including 
nivolumab, pembrolizumab, and dabrafenib/trametinib (for melanoma with BRAF 
V600-activating mutation). For patients with Stage IIB or IIC disease, systemic therapy with 
pembrolizumab is an accepted standard of care option. For patients with Stage I and IIA 
disease, standard of care management after resection is observation [National Comprehensive 
Cancer Network 2022]. 
The US FDA, EMA and other worldwide health authorities have approved the use of 
pembrolizumab for the adjuvant treatment of adult and pediatric (12 years and older) patients 
with Stage IIB, IIC, or III melanoma following complete resection. KEYNOTE-054 showed 
that adjuvant pembrolizumab treatment of patients with Stage III disease resulted in a 
statistically significant and clinically meaningful improvement in RFS compared with 
placebo (HR=0.57 [98.4% CI: 0.43, 0.74]; p<0.0001) with a median duration of follow-up of 
15 months. KEYNOTE-716 further established the role of pembrolizumab therapy in the 
treatment of adjuvant melanoma by demonstrating that in patients with Stage IIB and IIC 
melanoma in the adjuvant setting, pembrolizumab provided a statistically significant and 
clinically meaningful 35% reduction in the risk of disease recurrence or death in the 
pembrolizumab group compared with the placebo group (HR=0.65 [95% CI: 0.46, 0.92]; 
p=0.00658). KEYNOTE-716 also showed that adjuvant pembrolizumab significantly 
improved DMFS compared with placebo (HR=0.64 [95% CI: 0.47, 0.88]) [Long, G. V., et al 
2022]. 
Before the approval of adjuvant anti-PD-1 therapies, the 5-year survival rate for patients with 
localized disease at diagnosis was 99% (~ 83% for Stage IIB and IIC), regional disease was 
63% and distant disease was 20%, demonstrating an unmet need for new therapeutic options 
[National Cancer Institute 2017] [Gershenwald, J. E., et al 2017]. While adjuvant anti-PD-1 
monotherapies have showed an improvement in RFS and DMFS in patients with high-risk 
disease, anti-PD-1 based combination therapies may be able to further improve these 
outcomes.
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Protocol Amendment 04 implementation: Following eDMC interim review of the data, the 
experimental arm (Arm A: MK-7684A) will be discontinued and all ongoing participants will 
move to the comparator arm (Arm B: pembrolizumab monotherapy) for the remainder of the 
study. 
2.1.1
Preliminary Data for Coformulation of Vibostolimab with Pembrolizumab 
(MK-7684A) in Melanoma
The combination of vibostolimab (MK-7684) with pembrolizumab as a fixed dose 
coformulation (MK-7684A) is under evaluation in several ongoing studies, including studies 
in participants with melanoma.
KEYMAKER-U02 is an ongoing platform study evaluating investigational agents with or 
without pembrolizumab and pembrolizumab alone in participants with melanoma. 
A summary of the existing efficacy and safety data from the KEYMAKER-U02 substudies 
evaluating MK-7684 with pembrolizumab (either sequentially administered or as 
MK-7684A) in participants with melanoma (substudies KEYMAKER-02B and 
KEYMAKER-02C) is provided below. Together, these studies show proof-of-concept for the 
evaluation of MK-7684A in this Phase 3 study.
2.1.1.1
Substudy KEYMAKER-02B
Substudy KEYMAKER-02B is evaluating various agents combined with pembrolizumab 
(including vibostolimab with pembrolizumab) compared with pembrolizumab alone in 
participants with first-line advanced melanoma. 
 
 
 
 
 
 
 
Review of the safety data as of 
15-FEB-2022 for participants treated with the combination of vibostolimab with 
pembrolizumab in KEYMAKER-02B demonstrates a well-tolerated and manageable safety 
profile generally similar to that of pembrolizumab monotherapy.
2.1.1.2
Substudy KEYMAKER-02C
Substudy KEYMAKER-02C is evaluating various agents (including vibostolimab) in the 
neoadjuvant setting followed by adjuvant pembrolizumab in participants with clinically 
detectable and resectable Stage IIIB-IIID melanoma. 
CCI
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A review of the safety data
 identified no new safety signals from 
participants treated with vibostolimab in combination with pembrolizumab in this study.
2.2
Background
Refer to the IB and approved labeling for detailed background information on MK-7684A 
and pembrolizumab.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
MK-7684A
MK-7684A is a fixed dose coformulation of vibostolimab (MK-7684) with pembrolizumab.
MK-7684 is a humanized, antagonistic IgG1 mAb that binds to the immune checkpoint 
receptor, TIGIT, and blocks the interaction between TIGIT and its ligands. TIGIT is one of 
multiple immune checkpoint molecules that maintains immune homeostasis and prevent 
uncontrolled immune activation. TIGIT competes with the activating receptor CD226 for its 
ligands, CD155/PVR/Necl5/Tage4 and CD112/PVRL-2, which are expressed on 
antigen-presenting cells. Binding of TIGIT to its ligands negatively modulates T-cell activity. 
The mechanism of TIGIT-mediated T-cell inhibition is not completely understood. Some 
reports showed that TIGIT knockdown increases T-cell proliferation and effector cytokine 
production [Zhang, T., et al 2014] and that anti TIGIT antibodies characterized as agonists 
can decrease T-cell activation [Lozano, E., et al 2012]. Some reports have also showed that 
TIGIT may inhibit T-cell activation by opposing the CD226-mediated positive signal through 
ligand competition or heterodimerization with CD226 [Levin, S. D., et al 2011] [Johnston, R. 
J., et al 2014]. Importantly, it has been shown both in vitro and in vivo, that CD226 
knockdown or blockade (with an antagonist antibody) eliminates the positive impact of 
TIGIT antagonism [Levin, S. D., et al 2011] [Johnston, R. J., et al 2014].
CCI
CCI
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In a variety of mouse and human tumor models, TIGIT is highly expressed on CD4+ and 
CD8+ TIL and its expression has been correlated with CD8+ T-cell infiltration [Johnston, R. 
J., et al 2014] [Chauvin, J. M., et al 2015]. Coordinated TIGIT and PD-1 blockade results in 
increased proliferation, cytokine production, and degranulation of CD8+ human TIL from 
melanoma [Chauvin, J. M., et al 2015].
As of 06-JAN-2022, safety data were available for a total of 462 participants treated with 
either vibostolimab monotherapy (n=68), vibostolimab in combination with pembrolizumab 
administered sequentially (n=293), or as the coformulated product, MK-7684A (n=51), 
vibostolimab, pembrolizumab, pemetrexed, and carboplatin combination therapy (n=10), or 
MK-7684, pembrolizumab, carboplatin or cisplatin, and etoposide combination therapy 
(n=40) as part of Study MK-7684-001.
Of the 462 participants treated in Study MK-7684-001, 338 (73.2%) experienced at least 
1 AE that was considered by the investigator to be related to study treatment. Of the 
338 participants who experienced DRAEs in this study, most were of Grade 1 or 2 severity; 
15.4% experienced 1 or more DRAEs of Grade 3 severity, 4.8% experienced 1 or more 
DRAEs of Grade 4 severity (decreased neutrophil count [n=13], lipase increased [n=6], 
decreased white blood cell count [n=3], and acute kidney injury, depression and neutropenia 
[n=1 each]), and 0.2% experienced 1 or more DRAEs of Grade 5 severity (pneumonitis 
[n=1]). The most common DRAEs were pruritus (21.0%), rash (18.4%), fatigue (17.1%), and 
nausea (11.9%) [IB Edition 10 2022].
2.2.1.2
Pembrolizumab
Pembrolizumab is a potent humanized IgG4 mAb 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 several indications.
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T-cells/FoxP3+ 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 
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superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling on 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 IgV–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. After 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 CD3ζ, PKCθ, and 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].
2.3
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 monotherapy has shown activity for the adjuvant treatment of Stage II-III 
melanoma and has received regulatory approvals for this indication. Pembrolizumab has also 
shown an RFS benefit in participants with Stage IV disease in the SWOG1404/
KEYNOTE-053 study, and nivolumab has shown activity in this disease stage in the 
CheckMate-238 study, which led to regulatory approval in resected Stage IV melanoma. 
Both drugs are recommended by NCCN guidelines as options for adjuvant use after 
successful metastasis-directed therapy [National Comprehensive Cancer Network 2022].
The existing data suggest that blockade of TIGIT with vibostolimab offers a new 
immunological mechanism, which has been shown to enhance the activity of pembrolizumab 
in preclinical and early clinical observations. Review of safety data for vibostolimab in 
combination with pembrolizumab has not identified any new risks not previously identified 
for pembrolizumab monotherapy, and the severity and management of immune-mediated 
events with the combination is consistent with the established profile of pembrolizumab 
monotherapy. The combination of vibostolimab and pembrolizumab (as coformulated 
MK-7684A) may achieve increased therapeutic efficacy with minimal added toxicity over 
pembrolizumab monotherapy and preliminary data observed in KEYMAKER-02B and 
KEYMAKER-02C support this.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying MK-7684A and pembrolizumab IBs and 
informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In individuals with high-risk resected Stage IIB, IIC, III or IV melanoma:
Primary Objective
Primary Endpoint
To compare MK-7684A to pembrolizumab 
with respect to RFS
Hypothesis (H1): MK-7684A is superior to 
pembrolizumab with respect to RFS as 
assessed by investigator.
RFS: time from randomization to any 
recurrence (local, locoregional, regional or 
distant) as assessed by investigator, or death 
due to any cause, whichever occurs first.
Secondary Objectives
Secondary Endpoints
To compare MK-7684A to pembrolizumab 
with respect to DMFS.
Hypothesis (H2): MK-7684A is superior to 
pembrolizumab with respect to DMFS as 
assessed by investigator.
DMFS: The time from randomization to 
appearance of a distant metastasis as 
assessed by investigator or death due to any 
cause, whichever occurs first. A distant 
metastasis refers to cancer that has spread 
from the original (primary) tumor to distant 
organs or distant lymph nodes.
To compare MK-7684A to pembrolizumab 
with respect to OS.
Hypothesis (H3): MK-7684A is superior to 
pembrolizumab with respect to overall 
survival.
OS: The time from randomization to death 
due to any cause.
To evaluate the safety and tolerability of 
MK-7684A and pembrolizumab
Adverse event
Study intervention discontinuation due to 
AEs
To evaluate MK-7684A to pembrolizumab 
with respect to mean change from baseline 
in global health status/QoL, physical 
functioning, and role functioning using the 
EORTC QLQ-C30
Change in score from baseline evaluated by:
Global health status/QoL score (Items 29 
and 30)
Physical functioning score (Items 1-5)
Role functioning score (Items 6 and 7)
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4
STUDY DESIGN
4.1
Overall Design
Protocol Amendment 04 implementation: based on recommendations of the eDMC following 
an interim review of the data that showed no benefit over the comparator arm of 
pembrolizumab monotherapy, the experimental arm (Arm A: MK-7684A) will be 
discontinued and all ongoing participants on treatment will move to the comparator arm 
(Arm B: pembrolizumab monotherapy) for the remainder of the study. 
This is a Phase 3, randomized, double-blind, active-controlled, parallel-group, multicenter, 
efficacy and safety study of adjuvant MK-7684A (Arm A) versus adjuvant pembrolizumab 
(Arm B) in approximately 1,560 participants 12 years of age and older (and weighing at least 
40 kg if <18 years of age) with resected high-risk (Stage IIB-IV per AJCC eighth edition 
including clinical Stage II) melanoma (Appendix 8). Enrollment of participants with Stage 
IIIA disease will be capped at approximately 10% of total enrollment. Participants must not 
have received any prior systemic therapy for their melanoma beyond surgical resection. 
The study design is shown in Figure 1.
Eligible participants will be randomized 1:1 to receive treatment with either MK-7684A or 
pembrolizumab. Randomization will be stratified according to the participant’s disease risk 
(IIB/IIC/clinical IIB and IIC/IIIA/IIIB vs IIIC/IIID/IV) and by geographic region (Asia vs 
ROW). Crossover from one intervention arm to the other is not permitted.
Participants will receive treatment for up to 17 cycles of either MK-7684A or 
pembrolizumab or until one of the criteria for discontinuation of study intervention is met 
(Section 7.1). Participants will undergo imaging including neck/chest/abdomen/pelvis CT 
and/or MRI when clinically indicated at the timepoints described in the SoA. Participants 
will be followed after discontinuation of study intervention for disease recurrence and 
survival as described in Section 8.11.4. Protocol Amendment 04 implementation: All active 
participants in the experimental arm (Arm A: MK-7684A) will be moved to the comparator 
arm (Arm B: pembrolizumab monotherapy) for the remainder of the study (a total of 
17 cycles of study treatment or until disease progression, whichever occurs first)
[see Section 6.3.1].
The primary endpoint of the study is RFS, and key secondary endpoints include DMFS and 
OS. Distant metastasis refers to cancer that has spread from the primary tumor and beyond 
local or nearby tissues and regional lymph nodes to distant organs or nonregional lymph 
nodes. 
Adverse events will be monitored throughout the study and graded in severity according to 
the guidelines outlined in the NCI CTCAE v5.0 (Appendix 3.5). Each participant will be 
monitored for AEs and SAEs (refer to Section 8.4.1 for details).
Results of the futility and interim analyses will be reviewed by an eDMC, which will make 
recommendations to the Sponsor to continue, modify, or end the study according with the 
plan described in Sections 4.4.1, 9.7, and 10.1.4.
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Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study is being conducted to compare the efficacy and safety of adjuvant MK-7684A 
with adjuvant pembrolizumab monotherapy in participants with high-risk Stage II-IV 
melanoma in a randomized, double blinded fashion.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
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 randomized study in 
melanoma 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 [Food 
and Drug Administration 2018]. 
Investigator-identified recurrence will be used to make treatment decisions as well as for 
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 9 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 for potential retrospective analysis.
4.2.1.2
Safety Endpoints
See Appendix 7 for country-specific requirements.
Safety parameters frequently 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/SAEs, and changes in vital signs and laboratory values. 
AEs will be assessed as defined by CTCAE, Version 5.0.
4.2.1.3
Patient-reported Outcomes
Symptomatic improvement is considered a clinical benefit and accepted by health authorities 
as additional evidence of the risk-benefit profile of any new study intervention. In this study, 
HRQoL and disease-related symptoms will be investigated via the following assessment 
tools: EORTC QLQ-C30 questionnaires. Health utilities will be evaluated using the 
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EQ-5D-5L PRO instrument. These measures are not pure efficacy or safety endpoints 
because they are affected by both disease progression and treatment tolerability.
4.2.1.4
EORTC QLQ-C30
EORTC QLQ-C30 is a psychometrically and clinically validated instrument appropriate for 
assessing HRQoL in oncology studies [Aaronson, N. K., et al 1993]. The EORTC QLQ-C30 
is the most widely used cancer-specific HRQoL 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]. For the global health status or QoL and function 
scales, a higher value indicates a better level of function; for symptom scales and items, a 
higher value indicates increased severity of symptoms. Change from baseline in global health 
status/QoL, physical functioning, and role functioning scales of the EORTC QLQ-C30, will 
be evaluated as secondary objectives.
4.2.1.5
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. and de 
Charro, F. 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].
4.2.1.6
Planned Exploratory Biomarker Research
 
 
 
 
 
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4.2.1.7
Future Biomedical Research
 
 
 
 
 
 
 
 
 
4.2.2
Rationale for the Use of Comparator
Pembrolizumab has shown efficacy in Stage III melanoma in KEYNOTE-054 and in Stage 
IIB and IIC melanoma in KEYNOTE-716, and has received approval from global health 
authorities for the use in these patient populations. It is a recommended standard of care 
regimen by the NCCN guidelines [National Comprehensive Cancer Network 2022]. 
Pembrolizumab has also shown an RFS benefit in participants with Stage IV disease in the 
SWOG1404/KEYNOTE-053 study [Grossmann, K. F., et al 2021], and nivolumab has 
shown activity in this disease stage in the CheckMate-238 study, which led to regulatory 
approval in resected Stage IV melanoma. Both drugs are recommended by NCCN guidelines 
for adjuvant use after successful metastasis-directed therapy.
4.3
Justification for Dose
4.3.1
MK-7684A
MK-7684A is a single-use drug product vial containing a fixed dose combination of 200 mg 
vibostolimab and 200 mg pembrolizumab in a 20.0 mL fill volume. MK-7684A is to be 
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administered Q3W. The single coformulation vial could provide simplified preparation and 
reduced infusion times compared with separate formulations administered sequentially.
Based on the totality of available data, including preliminary clinical PK, 
pharmacodynamics, safety, and efficacy from Study MK-7684-001, the selected dose of 
vibostolimab is 200 mg Q3W.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.3.1.1
MK-7684A Dosing in Adolescents
The Sponsor proposes to use 200 mg Q3W of vibostolimab and 200 mg q3w of 
pembrolizumab in adolescent participants aged 12 to 18 years with body weight ≥40 kg, 
administered as coformulated MK-7684A. The adult recommended Phase 2 dose of 
vibostolimab is 200 mg Q3W, and 200 mg q3w is an approved dose of pembrolizumab in 
adults. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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In summary, the regimen of 200 mg vibostolimab + 200 mg pembrolizumab (given Q3W as 
coformulated MK-7684A) in adolescents >40 kg is projected to yield exposures that overlap 
significantly with adult exposures at the same dosing regimen.
4.3.2
Pembrolizumab
The planned dose of pembrolizumab for adults in this study is 200 mg Q3W. Based on the 
totality of data generated in the KEYTRUDA® development program, 200 mg Q3W is an 
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 non–small cell lung cancer 
indications
 
 
•
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
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically based PK analysis) at 200 mg 
Q3W
For adolescents ≥40 kg, the planned dose of pembrolizumab in this study is 2 mg/kg (up to a 
maximum of 200 mg).
 
 
 
 
 
 In addition, the safety of this dose in pediatric participants is established 
based on data from KEYNOTE-051 [Geoerger, B., et al 2020]. 
 
 
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).
4.4
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 
(Section 7.3). For purposes of analysis and reporting, the overall study ends when the 
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Sponsor receives the last laboratory test result or at the time of final contact with the last 
participant, whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
The Sponsor estimates that the maximum duration of the study from first participant entered 
through long-term follow-up will be 8 years (~5 years after study intervention has been 
completed) to attain the final assessment of the study (eg, to evaluate safety and/or long-term 
efficacy) for all evaluable participants. Refer to the Synopsis, Section 1.1, for the duration of 
participation of participants.
Protocol Amendment 04 implementation: The study will end when all participants 
discontinue from treatment and complete safety follow up.
4.4.1
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, GCP, and/or 
other applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
Based on recommendations of the eDMC to discontinue the experimental arm (MK-7684A) 
following an interim review of the data showed no benefit over the comparator arm of 
pembrolizumab monotherapy, the study will end when all participants discontinue from 
treatment and complete safety follow up.
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5
STUDY POPULATION
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
See Appendix 7 for country-specific requirements.
Type of Participant and Disease Characteristics
1. Has surgically resected and histologically/pathologically confirmed diagnosis of Stage 
IIB and IIC (pathological or clinical), III, or IV cutaneous melanoma per AJCC eighth 
edition guidelines (Appendix 8). Participants with BRAF-mutated melanoma are eligible 
to enroll.
•
A therapeutic lymph node dissection defined as an anatomically complete 
lymphadenectomy of the involved nodal basin for macroscopic disease (clinically, 
radiographically or sonographically [if performed] detectable lymph nodes) is required 
(Appendix 10). SLN biopsy and CLND for microscopic disease, however, are not 
required. 
•
Participants with recurrent disease who had prior resection are allowed as long as all 
current disease has been resected. 
•
Melanoma of unknown primary is eligible. 
•
Stage IIIA disease will be capped at approximately 10% of total enrollment.
2. Has not received any prior systemic therapy for their melanoma beyond surgical 
resection.
NOTE: In case of an indication for post lymph node dissection radiotherapy, this must 
have been completed within 13 weeks postsurgery and before treatment initiation. 
Radiotherapy may alter the process of wound healing. If the wound healing is not 
complete, the participant is not eligible.
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3. No more than 12 weeks have elapsed between final surgical resection and randomization. 
Treatment should start only after adequate wound healing from the surgical procedure as 
assessed by the investigator. If there is a delay of ≤2 weeks exceeding 12 weeks due to 
unforeseen circumstances, the eligibility should be discussed with the Sponsor and the 
decision documented. A delay of up to 1 week for screening imaging requirements will 
be allowed if Sponsor has allowed up to 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 feasible. 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. Has no evidence of metastatic disease on imaging after resection as determined by 
investigator assessment. All suspicious lesions amenable to biopsy should be confirmed 
negative for malignancy.
5. Has an appropriate performance status as follows assessed within 7 days of C1D1:
•
Adolescents ≤16 years of age: LPS score ≥70
•
Adolescents >16 to <18 years of age: KPS score ≥70
•
Adults ≥18 years of age: ECOG Performance Status of 0 or 1
Demographics
6. Is male or female, at least 12 years of age and weighs ≥40 kg if <18 years of age, at the 
time 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).
Male Participants
No measures.
Female Participants
7. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Not a WOCBP
OR
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•
A WOCBP and:
-
Uses 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 5 
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. Contraceptive use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
-
Has a negative highly sensitive pregnancy test within 72 hours (serum) or 24 hours 
(urine) 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 in Section 8.3.5.
-
Abstains from breastfeeding during the study intervention period and for at least 
120 days after study intervention.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
8. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study and agrees to DMFS and OS data collection until these study 
endpoints are reached (maximum follow-up of approximately 8 years). The participant
may also provide consent/assent for FBR; however, the participant may participate in the 
study without participating in FBR.
Additional Categories
9. Archival tumor tissue sample or newly obtained biopsy of a tumor lesion not previously 
irradiated has been provided. Details pertaining to tumor tissue submission can be found 
in the Laboratory Manual.
Note: If a participant does not have tumor tissue available, a participant may be eligible 
for enrollment after notifying the Sponsor via email.
10. HIV-infected participants must have well controlled HIV on ART, defined as:
a.
Having a CD4+ T-cell count ≥350 cells/mm3 at the time of screening.
b. Having achieved and maintained virologic suppression defined as confirmed HIV 
RNA level below 50 or the LLOQ (below the limit of detection) using the locally 
available assay at the time of screening and for at least 12 weeks before screening.
c.
Have not had any AIDS-defining opportunistic infections within the past 12 months.
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d. Have been on a stable ART regimen, without changes in drugs or dose modification, 
for at least 4 weeks before randomization and agree to continue ART throughout the 
study.
11. Adequate organ function as defined in the following table (Table 3). Specimens must be 
collected within 7 days before the first dose of study intervention.
Table 3
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
ANC
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/La
Renal
Measured or calculated creatinine clearance
OR
GFR
≥30 mL/min
≥30 mL/min
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN
Coagulation
INR OR PT
aPTT
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); ANC=absolute neutrophil count;
aPTT=activated partial thromboplastin time; AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase); GFR=glomerular filtration rate; INR=International normalized ratio; PT=prothrombin time; 
PTT=partial thromboplastin time; ULN=upper limit of normal.
a
Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion 
within last 2 weeks.
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.
12. Participants who are HBsAg positive are eligible if they have received HBV antiviral 
therapy for at least 4 weeks, and have undetectable HBV viral load before randomization.
Hepatitis B screening tests are not required unless:
a.
Known history of HBV infection
b. As mandated by local health authority
13. Participants with history of HCV infection are eligible if HCV viral load is undetectable 
at screening.
Note: Participants must have completed curative antiviral therapy at least 4 weeks before 
randomization.
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Hepatitis C screening tests are not required unless:
a.
Known history of HCV infection 
b. As mandated by local health authority
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
See Appendix 7 for country-specific requirements.
Medical Conditions
1. Has severe hypersensitivity (≥Grade 3) to any of the study interventions or their 
excipients.
2. Has ocular, mucosal, or conjunctival melanoma.
3. 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 medication.
Note: The use of inhaled or topical steroids and systemic steroids at physiologic doses 
(up to 5 mg/m2/day prednisone equivalent with maximum dose of 10 mg daily) is allowed 
on study.
4. Has not adequately recovered from major surgical procedure or has ongoing surgical 
complications.
Prior/Concomitant Therapy
5. Has received prior radiotherapy within 2 weeks of start of study intervention or has had a 
history of radiation pneumonitis.
NOTE: Participants must have recovered from all radiation-related toxicities and do not 
require corticosteroids. 
6. Received prior anticancer therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 or 
anti-TIGIT agent, or with an agent directed to another stimulatory or coinhibitory T-cell 
receptor (eg, CTLA-4, OX-40, CD137).
7. Received a live or live attenuated vaccine within 30 days before the first dose of study 
intervention. Administration of killed vaccines is allowed.
Refer to Section 6.5 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
8. Has received an investigational agent or has used an investigational device within 
4 weeks before study intervention administration.
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Diagnostic Assessments
9. History of (noninfectious) pneumonitis/interstitial lung disease that required steroids or 
has current pneumonitis/interstitial lung disease.
10. Known additional malignancy that is progressing or has required active treatment within 
the past 3 years.
NOTE: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have 
undergone potentially curative therapy are not excluded. Participants with low-risk 
prostate cancer (T1-T2a, Gleason score ≤6, and PSA <10 ng/mL) either treated with 
definitive intent or untreated in active surveillance are not excluded. Participants with a 
history of nonulcerated cutaneous primary melanoma <1 mm in depth with no nodal 
involvement are allowed in this study.
NOTE: Participants with a history of mucosal or uveal melanoma are excluded from this 
study.
11. History of CNS metastases and/or carcinomatous meningitis.
12. Active autoimmune disease that has required systemic treatment in the past 2 years.
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is allowed.
13. Active infection, requiring systemic therapy.
14. History or current evidence of any condition, therapy, laboratory abnormality, or other 
circumstance that might confound the results of the study or interfere with the 
participant’s participation for the full duration of the study, such that it is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
15. Known psychiatric or substance abuse disorder that would interfere with the participant’s 
ability to cooperate with the requirements of the study.
Other Exclusions
16. History of allogenic tissue/solid organ transplant.
5.3
Lifestyle Considerations
No restrictions are required.
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently randomized in the study. A minimal set of screen-failure information is 
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required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Participants who fail screening may be rescreened for eligibility after consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention or withdraws from the study will not 
be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(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 interventions provided by the Sponsor) will be packaged to support 
enrollment. Clinical supplies will be affixed with a clinical label in accordance with 
regulatory requirements.
Global clinical supply complaints and/or temperature excursions are to be reported to the 
Clinical Complaints Intake mailbox, via email to clinical.complaints.intake@MSD.com, 
within 1 business day of awareness.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 4.
Protocol Amendment 04 implementation: All active participants in the experimental arm
(Arm A: MK-7684A) will be moved to the comparator arm (Arm B: pembrolizumab 
monotherapy) for the remainder of the study (a total of 17 cycles of study treatment or until 
disease progression, whichever occurs first).
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Table 4
Study Interventions
Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm A 
(Protocol 
Amendment 
04: Arm A 
discontinued)
Experimental MK-7684A
Biological/
Vaccine
Solution
MK-7684
200 mg +
pembrolizumab
200 mg/ 20 mL
vial
200 mg / 
200 mg
IV Infusion
Q3W (Day 1 
of each 
cycle) for 17 
cycles or 
until discon-
tinuation 
criteria are 
met
Test 
Product
IMP
Centrally 
by the 
Sponsor
Arm B
Active 
Comparator
Pembrolizumab Biological/
Vaccine
Solution
25 mg/mL
Adults: 
200 mg
Adolescents 
≥40 kg: 
2 mg/kg (up 
to max of 
200 mg)
IV Infusion
Q3W (Day 1 
of each 
cycle) for 17 
cycles or 
until discon-
tinuation 
criteria are 
met, 
whichever 
occurs first
Comparator
IMP
Centrally 
by the 
Sponsor
EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; max=maximum; NIMP/AxMP=noninvestigational/auxiliary medicinal product; 
Q3W=every 3 weeks.
For commercially available supplies, the unit dose strength or formulation may vary, depending on market availability.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with 
respect to the definition/classification of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 4 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.9 for details regarding administration of the study intervention.
6.1.1
Treatment
The treatment of MK-7684A and pembrolizumab consists of up to 17 treatments 
administered Q3W or until discontinuation criteria are met. NOTE: The number of 
treatments is calculated starting with the first dose.
Protocol Amendment 04 implementation: All active participants in the experimental arm
(Arm A: MK-7684A) will be moved to the comparator arm (Arm B: pembrolizumab 
monotherapy) for the remainder of the study (a total of 17 cycles of study treatment or until 
disease progression, whichever occurs first). NOTE: For study participants who, in the 
opinion of the study investigator, are benefitting from MK-7684A, the study investigator may 
request Sponsor consultation for continuation of treatment with MK-7684A.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of MK-7684A and pembrolizumab are provided in 
the Pharmacy Manual.
The rationale for selection of doses to be used in this study is in Section 4.3.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions 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.
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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention 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 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention randomization will occur centrally using an IRT system. There are 2 study 
intervention arms. Participants will be assigned randomly in a 1:1 ratio to receive MK-7684A 
(Arm A) or pembrolizumab (Arm B), respectively.
Enrollment of participants with Stage IIIA disease will be capped at approximately 10% of 
total enrollment.
Protocol Amendment 04 implementation: All active participants in the experimental arm
(Arm A: MK-7684A) will be moved to the comparator arm (Arm B: pembrolizumab 
monotherapy) for the remainder of the study. NOTE: For study participants who, in the 
opinion of the study investigator, are benefitting from MK-7684A, the study investigator may 
request Sponsor consultation for continuation of treatment with MK-7684A.
6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. Risk-based staging (IIB/IIC/clinical IIB and IIC/IIIA/IIIB vs IIIC/IIID/IV)
2. Region (Asia vs ROW)
Stratification by risk is based on the known differences in the risk of death, RFS, and DMFS 
between these groups as shown in KEYNOTE-054, KEYNOTE-716 and by others 
[Gershenwald, J. E., et al 2017a] [Eggermont, A. M. M., et al 2018] [Eggermont, A. M. M., 
et al 2021].
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6.3.3
Blinding
A double-blinding technique with in-house blinding will be used. The participant, the 
investigator, and Sponsor personnel or delegate(s) who are involved in the study intervention 
administration or clinical evaluation of the participants are unaware of the intervention 
assignments.
Protocol Amendment 04 implementation: Following eDMC interim review of data, all 
participants have been unblinded.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Refer to Section 6.6.1 for Dose Modification and Toxicity Management Guidelines for irAEs 
associated with pembrolizumab monotherapy, coformulations, or IO combinations and for 
other allowed dose interruptions.
Interruptions from the protocol-specified treatment plan require consultation between the 
investigator and the Sponsor and written documentation of the collaborative decision on 
participant management. 
Participants will be dosed at the site, and they will receive study intervention directly from 
the investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.
6.5
Concomitant Therapy
If there is a clinical indication for any medications or vaccinations prohibited, the 
investigator must discuss any questions regarding this with the Sponsor’s Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant’s primary physician. However, the decision to continue the participant on 
study intervention requires the mutual agreement of the investigator and the Sponsor. 
The following medications and vaccinations are prohibited during the study:
•
Antineoplastic systemic therapy (including chemotherapy, biological therapy, 
immunotherapy, and targeted therapies) not specified in this protocol.
NOTE: Topical anticancer agents to treat skin lesions (eg basal cell carcinoma or 
squamous cell carcinoma) are allowed (excluding skin metastases of melanoma).
•
Investigational agents other than MK-7684A or pembrolizumab
•
Radiation therapy
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•
Live or live attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study, and for 30 days after the last dose of study 
intervention.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-incompetent 
adenoviral vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy. These vaccines should not be administered within 10 days of study 
treatment. 
Investigational vaccines (ie, those not licensed or approved for Emergency Use) are not 
allowed. 
NOTE: Seasonal flu vaccines are allowed in this study but should not be administered within 
10 days of study treatment. 
For country-specific criteria, refer to Appendix 7.
•
Systemic glucocorticoids except when used for the following purposes:
To modulate symptoms of an AE that is suspected to have an immunologic etiology
For the prevention of emesis
To premedicate for IV contrast allergies
To treat asthma or COPD exacerbations (only short-term oral or IV use in doses 
>10 mg/day prednisone equivalent)
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent for 
adults or 5 mg/m2/day (maximum of 10 mg/day) prednisone equivalent for pediatric 
participants (≥12 years old and <18 years old)
•
Other glucocorticoid use except when used for the following purposes:
For topical use or ocular use
Intraarticular joint use
For inhalation in the management of asthma or chronic obstructive pulmonary disease
If the investigator determines that a participant requires any of the following prohibited 
medications and vaccinations for any reason during the study, study intervention with 
MK-7684A or pembrolizumab must be discontinued.
Blood transfusions are allowed at any time during the study, except to meet eligibility criteria 
and in the 4 weeks before the first dose of pembrolizumab.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. 
All concomitant medication will be recorded on the eCRF including all prescription, OTC 
products, herbal supplements, and IV medications, and fluids. If changes occur during the 
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study period, documentation of drug dosage, frequency, route, and date should also be 
included on the eCRF. All concomitant medications received within 28 days before the first 
dose of study intervention and up to 90 days after the last dose of study intervention should 
be recorded. All concomitant medications administered during SAEs or ECIs are to be 
recorded. SAEs and ECIs are defined in Section 8.4.
6.5.1
Rescue Medications and Supportive Care
No rescue or supportive medications are specified for use in this study.
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.
6.6
Dose Modification
Any interruption of study intervention beyond 12 weeks, due to a non-immune AE, requires
Sponsor consultation. Further details are provided in Section 7.1.
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
AEs associated with pembrolizumab monotherapy, coformulation, or IO combination 
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 monotherapy, 
coformulation, or IO combination 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 monotherapy, coformulation, or IO 
combination 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.
Attribution of Toxicity:
When study interventions are administered in combination, attribution of an adverse event to 
a single component is likely to be difficult. Therefore, while the investigator may attribute a 
toxicity event to pembrolizumab monotherapy, coformulations, or IO combinations, 
pembrolizumab monotherapy, coformulations, or IO combinations must be held according to 
the criteria in the Dose Modification and Toxicity Management Guidelines for 
Immune-Related Adverse Events.
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Holding Study Interventions:
When study interventions are administered in combination and if the AE is considered 
immune-related, pembrolizumab monotherapy, coformulations, or IO combinations should 
be held according to recommended Dose Modification criteria.
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from pembrolizumab monotherapy, coformulations, or IO 
combinations.
Restarting Study Interventions:
Participants may restart pembrolizumab monotherapy, coformulations, or IO combinations as 
described below:
If the toxicities do resolve and conditions are aligned with what is defined in the Dose 
Modification and Toxicity Management Guidelines for irAEs, pembrolizumab monotherapy, 
coformulations, or IO combinations may be restarted at the discretion of the investigator.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 5.
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Table 5
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 
(CTCAE v5.0)
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 to 2 mg/kg prednisone or 
equivalent) followed by taper
Add prophylactic antibiotics for 
opportunistic infections
Monitor participants for signs and 
symptoms of pneumonitis
Evaluate participants with suspected 
pneumonitis with radiographic 
imaging and initiate corticosteroid 
treatment
Recurrent Grade 2, or
Grade 3 or 4
Permanently discontinue
Diarrhea/Colitis
Grade 2 or 3
Withhold
Administer corticosteroids (initial 
dose of 1 to 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 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations, or IO 
Combinations
Corticosteroid and/or Other Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased 
Bilirubin
Grade 2a
Withhold
Administer corticosteroids (initial 
dose of 0.5 to 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 3b or 4c
Permanently discontinue
Administer corticosteroids (initial 
dose of 1 to 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 -cell 
failure
Withholdd
Initiate insulin replacement therapy for 
participants with T1DM
Administer antihyperglycemic 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 
discontinued
Hyperthyroidism
Grade 2
Continue
Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate
Monitor for signs and symptoms of 
thyroid disorders
Grade 3 or 4
Withhold or permanently 
discontinued
Hypothyroidism
Grade 2
Continue
Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care
Monitor for signs and symptoms of 
thyroid disorders
Grade 3 or 4
Withhold or permanently 
discontinued
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
Administer corticosteroids (prednisone 
1 to 2 mg/kg or equivalent) followed 
by taper
Monitor changes of renal function
Grade 3 or 4
Permanently discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity of AE administer 
corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab
Monotherapy, 
Coformulations, or IO 
Combinations
Corticosteroid and/or Other Therapies
Monitoring and Follow-up
Myocarditis
Asymptomatic cardiac 
enzyme elevation with 
clinical suspicion of 
myocarditis (which 
was previously 
myocarditis Grade 1 
using CTCAE v4.0)
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
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, TEN, 
or DRESS
Withhold
Based on severity of AE administer 
corticosteroids
Ensure adequate evaluation to confirm 
etiology or exclude other causes
Confirmed SJS, TEN, 
or DRESS
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 
based on the evente
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
AST/ALT: >3.0 to 5.0 × ULN if baseline normal; >3.0 to 5.0 × baseline, if baseline abnormal;
bilirubin:>1.5 to 3.0 × ULN if baseline normal; >1.5 to 3.0 × baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 × ULN, if baseline normal; >5.0 to 20.0 × baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 × ULN if baseline normal; >3.0 to 10.0 × baseline 
if baseline abnormal
c
AST/ALT: >20.0 × ULN, if baseline normal; >20.0 × baseline, if baseline abnormal; 
bilirubin: >10.0 × ULN if baseline normal; >10.0 × baseline if baseline abnormal
d
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.
e
Events that require discontinuation include, but are not limited to encephalitis 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 Monotherapy, Coformulations (MK-7684A), or IO Combinations
Pembrolizumab monotherapy, coformulations (MK-7684A), or IO combinations 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 monotherapy, coformulations (MK-7684A), or 
IO combinations associated infusion reactions are provided in Table 6.
Table 6
Pembrolizumab Monotherapy, Coformulations (MK-7684A), or IO 
Combinations 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 intervention.
Participant may be premedicated 1.5 h (±30 
min) prior to infusion of study intervention 
with:
Diphenhydramine 50 mg po (or equivalent 
dose of antihistamine).
Acetaminophen 500 to 1000 mg po (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
after 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 intervention.
No subsequent dosing
CTCAE=Common Terminology Criteria for Adverse Events; h=hour; IV=intravenous; NCI=National Cancer Institute; 
NSAIDs=nonsteroidal anti-inflammatory drugs.
Note: 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 v5.0 at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, 
or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may be interrupted for 
situations other than treatment-related AEs such as medical or surgical events and/or 
unforeseen circumstances not related to study intervention. However, study intervention is to 
be restarted within 3 weeks (21 days) of the originally scheduled dose and within <6 weeks 
(42 days) of the previously administered dose, unless otherwise discussed with the Sponsor. 
The reason for study intervention interruption is to be documented in the participant’s study 
record.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
The emergency unblinding call center will use the intervention/randomization schedule for 
the study to unblind participants and to unmask study intervention identity. The emergency 
unblinding call center should only be used in cases of emergency (see Section 8.1.11). If the 
emergency unblinding call center is not available for a given site in this study, the central 
electronic intervention randomization system (IRT) should be used to unblind participants 
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and to unmask study intervention identity. The Sponsor will not provide random 
code/disclosure envelopes or lists with the clinical supplies.
6.9
Standard Policies
Not applicable.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention 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 intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to be monitored in this study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.11.3 unless the participant has 
withdrawn from the study (Section 7.2).
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, 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 intervention.
NOTE: See Appendix 7 for country-specific requirements.
•
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.1, require 
Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.
•
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 intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Confirmed disease recurrence identified by investigator radiographically and/or by 
examination (with subsequent biopsy).
•
Any progression or recurrence of malignancy, or any occurrence of another malignancy 
that requires active treatment.
Exceptions to secondary malignancy include basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin, new nonulcerated primary melanoma <1 mm in depth with no 
nodal involvement, or carcinoma in situ (excluding carcinoma in situ of the bladder) that 
have undergone potentially curative therapy. Exceptions should be discussed with the 
Sponsor before continuing therapy or remaining in follow-up.
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Diagnosis of a new primary melanoma ≥1 mm or <1 mm with ulceration will result in 
discontinuation of therapy.
•
Initiation of new anticancer treatment.
•
Any prohibited medication as listed in Section 6.5 is deemed necessary by the 
investigator/treating physician.
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6.
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention.
Protocol Amendment 04 implementation: due to discontinuation of the experimental arm
(Arm A: MK-7684A) and participants moving to the comparator arm (Arm B: 
pembrolizumab monotherapy), the visits and procedures outlined in Section 1.3.2 
(Amendment 04 SoA) should be followed.
7.2
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 intervention 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 FBR, are outlined in Section 8.9. 
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.
Protocol Amendment 04 implementation: Participants who complete or discontinue study 
intervention and have completed safety follow-up will be considered to have completed the 
study. This also applies to participants in efficacy follow-up.
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.
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•
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 ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) 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 providing document informed consent may be used for 
screening or baseline purposes provided the procedures meet 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), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
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 FBR. 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 is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
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The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
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.
8.1.3
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 used 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. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
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disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
8.1.5
Melanoma Disease History
A history of the participant’s melanoma will be obtained by the investigator or qualified 
designee. Details of their condition including disease stage, date of initial diagnosis, date of 
resection, date of SLN and CLND (if performed), date of any upstaging and other relevant 
information regarding their melanoma including details on any prior radiation therapy 
received will be recorded. If a participant previously underwent genomic profiling for their 
melanoma, these data may be provided.
8.1.6
Prior and Concomitant Medications Review
8.1.6.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the study. Treatment for the disease for which the participant 
has enrolled in this study will be recorded separately and not listed as a prior medication.
8.1.6.2
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. All medications related to reportable 
SAEs and ECIs should be recorded.
8.1.7
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 before randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be reused 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/rescreening visit 
requirements are in Section 8.11.1.
8.1.8
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 
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participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.9
Study Intervention Administration
Study intervention will be administered by the investigator and/or study staff according to the 
specifications within the Pharmacy Manual. All study interventions will be administered on 
an outpatient basis.
If an adolescent <18 years of age at randomization becomes ≥18 years of age during the 
study, they will continue to receive the adolescent dosing to which they were randomized for 
the duration of the study.
Protocol Amendment 04 implementation: All active participants in the experimental arm
(Arm A: MK-7684A) will be moved to the comparator arm (Arm B: pembrolizumab 
monotherapy) for the remainder of the study (a total of 17 cycles of study treatment or until 
disease progression, whichever occurs first). NOTE: For study participants who, in the 
opinion of the study investigator, are benefitting from MK-7684A, the study investigator may 
request Sponsor consultation for continuation of treatment with MK-7684A.
8.1.9.1
Timing of Dose Administration
Study intervention is to be administered at the study visits outlined in the SoA. Cycle 1 study 
intervention should begin within 3 days of randomization. For all subsequent cycles, study 
intervention may be administered up to 3 days before or after the scheduled day of 
administration. Participants will continue receiving study intervention until one of the criteria 
for treatment discontinuation are met (Section 7.1) or until they complete the entire course of 
treatment as outlined in the SoA.
Protocol Amendment 04 implementation: the visits and procedures for all active participants 
outlined in Section 1.3.2 should be followed.
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period 
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the Safety Follow-up Visit at the time of withdrawal. Any AEs that 
are present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
Protocol Amendment 04 implementation: the visits and procedures for all active participants 
outlined in Section 1.3.2 should be followed.
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8.1.10.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the study investigator. If medical records for the study are still available, 
the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant’s consent for 
FBR 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 before 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.
If the medical records for the study are no longer available (eg, if the investigator is no longer 
required by regulatory authorities to retain the 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 specimen withdrawal 
cannot be processed.
8.1.11
Participant Blinding/Unblinding
STUDY INTERVENTION IDENTIFICATION INFORMATION IS TO BE UNMASKED 
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 intervention 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. Before contacting the emergency 
unblinding call center to request unblinding of a participant’s intervention 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 intervention, the reason thereof, etc, 
in the medical record. If it is not possible to record this assessment in the medical record 
before the unblinding, the unblinding should not be delayed.
If unblinding has occurred, the circumstances around the unblinding (eg, date, reason, and 
person performing the unblinding) must be documented promptly, and the Sponsor Clinical 
Director notified as soon as possible.
Once an emergency unblinding has taken place, the investigator, site personnel, and Sponsor 
personnel may be unblinded so that the appropriate follow-up medical care can be provided 
to the participant.
Participants whose treatment assignment has been unblinded by the investigator or medically 
qualified designee and/or nonstudy treating physician should continue to be monitored in the 
study.
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Additionally, the investigator or medically qualified designee must go into the IRT system 
and perform the unblind in the IRT system to update drug disposition. If the emergency 
unblinding call center is not available for a given site in this study, the IRT system should be 
used for emergency unblinding if this is required for participant safety.
At the end of the study, random code/disclosure envelopes or lists and unblinding logs are to 
be returned to the Sponsor or designee.
Protocol Amendment 04 implementation: treatment arms have been unblinded as per the 
recommendation by the eDMC to discontinue the experimental arm (MK-7684A).
8.1.12
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 are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.1.13
Tumor Tissue for Biomarker Status
During the screening period, a tumor sample for each participant is required, if available, and 
is to be:
•
A newly obtained biopsy of a tumor lesion, which was not previously irradiated
Or
•
An archival tumor tissue sample if a new biopsy is unavailable (depending on protocol 
requirements)
At the time of recurrence, the participant may provide an optional fresh tumor sample.
FFPE tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived 
tissue.
Details pertaining to tumor tissue submission can be found in the Laboratory Manual.
See Appendix 7 for country-specific requirements.
8.1.14
Elevated Transaminases With Treated HBV or HCV
Participants who were treated for HBV or HCV, enrolled in the study, and present with 
elevated transaminases according to the criteria below should be evaluated for viral hepatitis 
exacerbation/reactivation.
•
If baseline AST/ALT <2×ULN and an increase of AST/ALT ≥5×ULN
•
If baseline AST/ALT ≥2×ULN and an increase of AST/ALT >3 × baseline level
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•
AST/ALT >500 U/L regardless of baseline
Viral load testing and additional hepatitis serologies should be included as required.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging 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.
The process for scan collection and transmission to the iCRO can be found in the SIM. 
Tumor scans by CT are strongly preferred. For the abdomen and pelvis, contrast-enhanced 
MRI may be used when CT with iodinated contrast is contraindicated, or when mandated by 
local practice. The same scan technique 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 response assessment 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 at the site or at an offsite facility. 
For participants with primary tumors of the head and neck, neck imaging is required at time
points indicated in the SoA.
If brain scans are performed, magnetic resonance imaging is preferred; however, CT imaging 
will be acceptable, if MRI is medically contraindicated.
Bone scans may be performed to evaluate bone metastases. Any supplemental scans 
performed to support a positive or negative bone scan, such as plain X-rays acquired for 
correlation, should also be submitted to the iCRO.
Participant eligibility will be determined using investigator assessment. All scheduled scans 
for each participant will be submitted to the iCRO. In addition, unscheduled scans to 
determine disease progression and scans obtained for other reasons but show disease 
recurrence are to be submitted to the iCRO.
See Appendix 7 for country-specific requirements.
Protocol Amendment 04 implementation: the visits and procedures for all active participants 
outlined in Section 1.3.2 should be followed.
8.2.1.1
Initial Tumor Scans
Initial tumor scans and brain scan at Screening must be performed within 28 days before the 
date of randomization. The investigator must review the Screening scans to confirm the 
participant has no evidence of disease at study entry.
The screening scans must be submitted to the iCRO for potential retrospective review.
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Tumor scans and brain scans performed as part of routine clinical management are 
acceptable for screening if they are of acceptable diagnostic quality and performed within 
28 days of randomization.
8.2.1.2
Tumor Scans During the Study
The first on-study scan should be performed at 12 weeks (±7 days) from the date of 
randomization. Subsequent tumor scans should be performed every 12 weeks (±7 days) or 
more frequently if clinically indicated. After 2 years, participants will have scans performed 
Q6M (±14 days) through 4 years after date of randomization, and then once at 5 years 
(±28 days) from date of randomization. Scan timing should follow calendar days and should 
not be adjusted for delays in cycle starts.
Protocol Amendment 04 implementation: the visits and procedures for all active participants 
outlined in Section 1.3.2 should be followed. No scans are required in follow-up.
8.2.1.3
End-of-treatment and Follow-up Tumor Scans
If participants discontinue study intervention, tumor scans should be performed at the time of 
discontinuation (±4 week window) unless previous scans were obtained within 4 weeks of 
discontinuation. If participants discontinue study intervention due to a documented DMFS 
event, this is the final required tumor scan.
If participants discontinue study intervention without a documented DMFS event, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of randomization (refer to Section 8.2.1.2).
Scans are to be continued until one of the following conditions are met:
•
DMFS event
•
Pregnancy
•
Participant enters Survival Follow-up
•
Death
•
Withdrawal of consent
•
The end of the study
Protocol Amendment 04 implementation: the visits and procedures for all active participants 
outlined in Section 1.3.2 should be followed. No scans are required in follow-up.
8.2.1.4
RECIST 1.1 Assessment of Disease
The principles of RECIST 1.1 regarding the development of a new lesion(s) will guide the 
radiographic determination of RFS and DMFS events as assessed by the investigator.
RECIST 1.1 will additionally be used in the assessment of tumor response for evaluation of 
PRFS2. Although RECIST 1.1 references a maximum of 5 target lesions in total and 2 per 
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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.
8.2.2
Patient-reported Outcomes
The EQ-5D-5L and EORTC QLQ-C30 questionnaires will be administered by trained site 
personnel and completed electronically by participants in the following order: EORTC 
QLQ-C30 first, then EQ-5D-5L. The questionnaires should be administered before dosing at 
the visits indicated in the SoA.
The EORTC QLQ-C30 will be administered only to adults (≥18 years of age) 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 of age 
and older.
It is best practice and strongly recommended that ePROs are administered to randomized 
participants before drug administration, AE evaluation, and disease status notification. If the 
participant does not complete the ePROs at a scheduled time point, the MISS_MODE form 
must be completed to capture the reason the assessment was not performed.
Protocol Amendment 04 implementation: the visits and procedures for all active participants 
outlined in Section 1.3.2 should be followed. No further PRO assessments are required.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. 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 Study 
Procedures Manual.
Planned time points for all safety assessments are provided in the SoA.
Protocol Amendment 04 implementation: the visits and procedures for all active participants 
outlined in Section 1.3.2 should be followed. 
8.3.1
Physical Examinations
Physical examinations will be conducted by an investigator or medically qualified designee 
(consistent with local requirements) per institutional standard. Investigators should pay 
special attention to clinical signs related to previous serious illnesses.
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.
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8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a full physical examination when 
described in the SoA. Clinically significant abnormal findings at Screening should be 
recorded as medical history. After the first dose of study intervention, new clinically 
significant abnormal findings should be recorded as AEs.
8.3.1.2
Directed Physical Examination
For all visits that do not require a full physical examination as defined in the SoA, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated. 
After the first dose of study intervention, new clinically significant abnormal findings should 
be recorded as AEs.
8.3.2
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.
Height and weight will also be recorded as indicated in the SoA. For adult participants, 
height will be measured only at Screening whereas for pediatric participants height will be 
measured at every cycle as indicated in the SoA.
8.3.3
Electrocardiograms
Single 12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) at Screening using an ECG machine that 
automatically calculates the HR and measures PR, QRS, QT, and QTc intervals. Clinically 
significant abnormal findings at Screening should be recorded as medical history. Additional 
timepoints may be performed as clinically necessary.
NOTE: A 6-lead ECG is allowed per institutional standard.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator 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 CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
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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 2, must be 
conducted in accordance with the Laboratory Manual and 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 90 days after the last dose of study intervention, 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.
Details regarding specific laboratory 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 Study 
Procedures Manual. Refer to the SoA for the timing of laboratory assessments.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Details regarding specific laboratory 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 Laboratory 
Manual. Refer to the Study Flow Chart (Section 1.3) for the timing of laboratory 
assessments.
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.5
Pregnancy Testing
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine and/or serum) should be conducted at least monthly as 
described in the SoA during study intervention.
-
Pregnancy testing (urine and/or serum) should be conducted as per the SoA for the 
time required to eliminate systemic exposure after the last dose of study intervention 
and should correspond with the time frame for participant’s contraception as noted in  
Section 5.1. The length of time required to continue pregnancy testing for each study 
intervention is: 
◦
Pembrolizumab: 120 days
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◦
MK-7684A: 120 days
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant's participation in the study.
8.3.6
Performance Assessments
8.3.6.1
Karnofsky Performance Status
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 perform daily activities. The KPS will be assessed as specified in the SoA (Section 1.3) for 
participants >16 and <18 years of age.
8.3.6.2
Eastern Cooperative Oncology Group Performance Status
The ECOG Performance Status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc) with grades 0 to 5.
The ECOG status will be assessed as specified in the SoA (Section 1.3) for participants 
≥18 years of age. 
8.3.6.3
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. The LPS will be assessed as specified in the SoA 
(Section 1.3).
8.4
Adverse Events, Serious Adverse Events, 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 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6 
and Appendix 3.
Adverse events, 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. 
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Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, 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.
8.4.1
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, but before intervention randomization, must be reported by 
the investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs, from the time of intervention randomization through 90 days after cessation of 
study intervention or 30 days after cessation of study intervention 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 intervention 
randomization through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Sections 5.1 and 8.3.5, or 120 days after cessation of 
study intervention 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 the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs 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 the investigator 
considers the event to be reasonably related to the study intervention 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.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 7
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
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
SAE
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.
Report all
Previously reported 
– Follow to 
completion/
termination; report 
outcome
Within 24 hours
of learning of 
event
ECI (requiring
regulatory reporting)
Report if:
– due to intervention
– causes exclusion
Report
– potential DILI
– requiring regulatory 
reporting
Not required
Within 24 hours
of learning of 
event
ECI (does 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
New Cancer (that is not 
the cancer under study)
Report if:
– due to intervention
– causes exclusion
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
SAE)
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Type of Event
Reporting Period:
Consent to 
Randomization/
Allocation
Reporting Period:
Randomization/
Allocation 
Through 
Protocol-specified 
Follow-up Period
Reporting 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame 
to Report 
Event and 
Follow-up 
Information to 
Sponsor
Overdose
Report if:
– receiving placebo run-
in or other run-in 
medication
Report all
Not required
Within 
5 calendar days 
of learning of 
event (unless 
SAE)
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
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. SAEs and other reportable safety events, including 
pregnancy and exposure during breastfeeding, 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). The investigator will also make every attempt to 
follow nonserious AEs that occur in randomized participants for outcome. Further 
information on follow-up procedures is given in Appendix 3.
8.4.4
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 toward the safety of participants and the 
safety of a study intervention 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 intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for 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 SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
Note: To meet EU CTR requirements, the Sponsor will report SUSARs to the Eudravigilance 
database via E2B(R3) electronic ICSR form in compliance with CTR 536/2014.
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8.4.5
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.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, 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.
8.4.6
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 of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*NOTE: These criteria are based on 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 
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assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-7684A by 3 times (ie, 300%) or the prescribed dose for pembrolizumab by 5 
times. No specific information is available on the treatment of overdose of MK-7684A or 
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.
8.6
Pharmacokinetics
Protocol Amendment 04 implementation: the visits and procedures for all active participants 
outlined in Section 1.3.2 should be followed. No further PK/ADA samples are required.
8.6.1
Blood Collection for Pharmacokinetics Analysis
Samples for PK analysis will be collected as described in the SoA. Sample collection, 
storage, and shipment instructions for PK samples will be provided in the Laboratory 
Manual.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Biomarkers
8.8.1
Planned Genetic Analysis Sample Collection
 
 
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8.9
Future Biomedical Research Sample Collection
8.10
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.
All-cause hospitalizations and emergency department visits must be reported in the eCRF, 
from the time of treatment randomization through 90 days after cessation of study 
intervention, or 30 days after cessation of study intervention, if the participant initiates new 
anticancer therapy, whichever is earlier.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame.
Screening procedures are to be completed within 28 days before the first dose of study 
intervention except for the following:
•
Archival tumor tissue sample should be from <5 years before Screening.
•
Laboratory tests and performance status are to be performed within 7 days before the first 
dose of study intervention.
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•
For women of childbearing potential, a urine or serum pregnancy test will be performed 
within 24 or 72 hours, respectively, before the first dose of study intervention. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required (performed by the local study-site laboratory).
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.11.2
Treatment Period Visits
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
Discontinuation of treatment does not represent withdrawal from the study.
When a participant discontinues study intervention, procedures for discontinuation will be 
performed.
The discontinuation visit should occur at the time study intervention is discontinued for any 
reason. If the discontinuation visit occurs 90 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up Visit, the discontinuation visit procedures and 
any additional safety follow-up procedures should be performed. Visit requirements are 
outlined in Section 1.3. Additional details regarding participant withdrawal and 
discontinuation are presented in Section 7.
8.11.4
Posttreatment Visit
8.11.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visits should be conducted approximately 30 days and 
90 days after the last dose of study intervention or before initiation of a new anticancer 
treatment, whichever comes first.
8.11.4.2
Efficacy Follow-up Visits
Participants who complete study intervention or who discontinue study intervention for a 
reason other than disease recurrence will begin Efficacy Follow-up and should be assessed
according to the SoA to monitor disease status. Every effort should be made to collect 
information regarding disease status until disease recurrence, pregnancy, withdrawal of 
consent, death, or the end of the study. Information regarding poststudy anticancer treatment 
will be collected if new treatment is initiated. After disease recurrence is documented, 
participants will continue to be monitored for DMFS according to the SoA.
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Protocol Amendment 04 implementation: the visits and procedures for all active participants 
outlined in Section 1.3.2 should be followed. Efficacy Follow-up Visits are not required.
8.11.4.3
DMFS Follow-up Visits
If participants discontinue study intervention without a documented DMFS event, every 
effort is to be made to monitor disease status by acquiring tumor scans using the same 
schedule calculated from the date of randomization. Participants will be assessed 
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 conducted external to site) to update disease status. A central 
imaging vendor will be used to collect, clean, and hold tumor imaging obtained during 
DMFS follow-up for possible analysis by Blinded Independent Central Review. If 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 follow-up should be performed as described in the SoA 
and investigator assessments should be reported to the Sponsor. Information regarding 
poststudy anticancer treatment will be collected if new treatment is initiated.
At the time of recurrence, the participant may provide an optional fresh tumor sample.  
Once participants complete all Efficacy Follow-up and DMFS follow-up visits and/or will 
not have further efficacy assessments, they must enter Survival Follow-up.
Protocol Amendment 04 implementation: the visits and procedures for all active participants 
outlined in Section 1.3.2 should be followed. DMFS Follow-up Visits are not required.
8.11.4.4
Survival Follow-up Contacts
Participant Survival Follow-up status will be assessed approximately every 12 weeks to 
assess for survival status 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 Efficacy 
Follow-up, 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 assessment follow-up 
visit has been performed.
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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.
Protocol Amendment 04 implementation: the visits and procedures for all active participants 
outlined in Section 1.3.2 should be followed. No Survival Follow-up Contact is required.
8.11.5
Vital Status
To ensure current and complete survival information (vital status) is available at the time of 
database locks, updated vital status may be requested during the study by the Sponsor. For 
example, updated vital status may be requested before but not limited to, an eDMC review, 
interim and/or final analysis. Upon Sponsor notification, all participants who do not/will not 
have a scheduled study visit or study contact during the Sponsor-defined period will be 
contacted for their vital status.
Protocol Amendment 04 implementation: the visits and procedures for all active participants 
outlined in Section 1.3.2 should be followed. No further contact is required for Vital Status.
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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 ICH Guideline E-9). Changes to exploratory or other nonconfirmatory analyses made 
after the protocol has been finalized, but before the conduct of any analysis, will be 
documented in a sSAP and referenced in the 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.
Protocol Amendment 04 implementation: Following eDMC interim review of the data, the 
experimental arm (Arm A: MK-7684A) will be discontinued and all ongoing participants will 
move to the comparator arm (Arm B: pembrolizumab monotherapy) for the remainder of the 
study.
9.1
Statistical Analysis Plan Summary
Key elements of the 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 Phase 3, Randomized, Double-blind, Active-Comparator-Controlled Clinical Study of 
Adjuvant MK-7684A (Vibostolimab with Pembrolizumab) Versus Adjuvant 
Pembrolizumab in Participants with High-risk Stage II-IV Melanoma (KEYVIBE-010)
Treatment 
Assignment
Approximately 1560 participants will be randomized in about 20 months (double-blind) 
in a 1:1 ratio between 2 treatment arms: 

Arm A: MK-7684A as adjuvant therapy or

Arm B: Pembrolizumab as adjuvant therapy.
Stratification factors are:

Risk-based Stage (IIB/IIC/clinical IIB and IIC/IIIA/IIIB vs IIIC/IIID/IV)

Region (Asia or ROW)
Analysis 
Populations
Efficacy: ITT 
Safety: APaT
PRO: PRO FAS
Primary Endpoint
Recurrence-free survival
Key Secondary
Endpoint(s)

DMFS

OS
Statistical 
Methods for Key 
Efficacy Analyses
The primary hypothesis (RFS) and key secondary hypothesis (DMFS and OS) will be 
evaluated by comparing MK-7684A to pembrolizumab using a stratified log-rank test. 
The HR will be estimated using a stratified Cox regression model. Event rates over time 
will be estimated within each treatment group using the Kaplan-Meier method.
Statistical 
Methods for Key 
Safety Analyses
For analyses in which 95% CIs will be provided for differences between treatment
groups in the percentage of participants with events, these analyses will be performed 
using the Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985].
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Interim Analyses
Efficacy 
Safety
The eDMC will review safety data periodically in the study. Safety analyses will also be 
performed at the time of interim efficacy analyses. Details will be specified in the DMC 
charter.
Multiplicity
Sample Size and 
Power 
The planned sample size is approximately 1560 participants.
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics Department of the Sponsor. 
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This study will be conducted as a double-blind study under in-house blinding procedures. 
The official, final database will not be unblinded until medical/scientific review has been 
performed, protocol deviations have been identified, and data have been declared final and 
complete.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in an IVRS.
Blinding issues with respect to planned IAs are described in Section 9.7 – Interim Analyses.
Protocol Amendment 04: Following eDMC review of the data at IA1, no additional efficacy 
data analysis will be conducted at subsequent IAs; information regarding planned IAs in 
Section 9 is being retained for historical purposes. No PRO analysis will be conducted.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3 – Hypotheses, Objectives, and 
Endpoints.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
9.4.1
Efficacy Endpoints
9.4.1.1
Primary Efficacy Endpoint
Recurrence-free Survival (RFS)
RFS is defined as the time from randomization to any recurrence (local, locoregional, 
regional or distant) as assessed by the investigator, or death due to any cause, whichever 
occurs first. New incident cases of melanoma and second cancer diagnoses are not counted as 
events for RFS. See Section 9.6.1 – Statistical Methods for Efficacy Analyses for the 
definition of censoring. 
9.4.1.2
Secondary Efficacy Endpoints 
Distant Metastasis-free Survival 
DMFS is defined as the time from randomization to the first diagnosis of a distant metastasis, 
or death due to any cause, whichever occurs first. 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.
Overall Survival 
OS is defined as the time from randomization to death due to any cause.
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9.4.1.3
Exploratory Endpoints
9.4.2
Safety Endpoints
Safety measurements are described in Section 4.2.1 – Rationale for Endpoints and 
Section 8.3 – Safety Assessments.
9.4.3
PRO Endpoints
The following secondary PRO endpoints will be evaluated:
•
Change from baseline in EORTC QLQ-C30 global health status/QoL score, physical 
functioning score, and role functioning score 
Exploratory PRO endpoints as described in Section 4.2.1.3 will be evaluated. Details will be 
provided in the sSAP.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The 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.
Details on the approach to handling missing data are provided in Section 9.6 – Statistical 
Methods.
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9.5.2
Safety Analysis Population
Safety analyses will be conducted in the APaT population, which consists of all randomized 
participants who received at least one dose of study intervention. 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 after 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.
9.5.3
PRO Analysis Population
The PRO analyses are based on the PRO FAS population, defined as all randomized 
participants who have at least one PRO assessment available for the specific endpoint and 
have received at least one dose of study treatment. Participants will be analyzed in the 
treatment group to which they are randomized. The PRO FAS population will be limited to 
participants ≥18 years of age for analysis of the EORTC QLQ-C30.
9.6
Statistical Methods
Statistical testing and inference for safety analyses are described in Section 9.6.2. 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. Nominal p-values may be computed for 
other efficacy analyses, but should be interpreted with caution due to potential issues of 
multiplicity, sample size, etc.
9.6.1
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 
 
 will be described in the sSAP.
The stratification factors used for randomization (see Section 6.3.2) will be applied to all 
stratified analyses, in particular, the stratified log-rank test, stratified Cox model. If there are 
small strata, for the purpose of analysis, strata will be combined to ensure sufficient number 
of participants, responses and events in each stratum. Details regarding the pooling strategy 
will be prespecified in a future sSAP amendment before the database lock for the first 
analysis when each applicable endpoint will be analyzed.
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9.6.1.1
Recurrence-free Survival 
The nonparametric Kaplan-Meier method will be used to estimate the RFS curve in each 
treatment group. 
 
 
 
 
 
 
The stratification factors used for 
randomization (see Section 6.3.2 – 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.
 
 
 
 
 
 
 
 
 
 
Table 8
Censoring Rules for Primary and Sensitivity Analyses of Recurrence-free 
Survival
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As indicated in Section 9.4.1.1, new primary melanomas will not be counted as RFS events 
for the primary
 
Additional supportive unstratified analyses may also be provided. Further details of RFS 
sensitivity analyses will be described in the sSAP.
9.6.1.2
Distant Metastases-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the survival 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 6.3.2 – 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.
Additional supportive unstratified analyses may also be provided. Further details of DMFS 
sensitivity analyses will be described in the sSAP as needed.
9.6.1.3
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 (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 6.3.2 – 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 timepoints 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.
9.6.1.4
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 
 
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Table 9
Analysis Strategy for Key Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical Methoda
Analysis 
Population
Missing Data Approach
DMFS=distant metastasis free survival; ITT=intent-to-treat: OS=overall survival; RFS=recurrence-free 
survival.
a
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.
9.6.2
Statistical Methods for Safety Analyses
9.6.2.1
Overall Safety Assessment 
The overall safety evaluation will include a summary by treatment group of the number and 
percentage of participants with at least one AE, a drug-related AE, a serious AE, a serious 
drug-related AE, a Grade 3 to 5 AE, a discontinuation from study intervention due to an AE, 
and an AE resulting in death. Point estimates and 95% CIs for the differences between 
treatment groups in the percentages of participants with the event will be provided based on 
the criteria described below.
 
 
 
 
 
 
 
 
 
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Table 10
Analysis Strategy for Safety Parameters
Analysis Part
Safety Endpoint
Descriptive Statistics
95% Between-group CI 
(Graphical Display)
Assessment of 
safety topics 
of special 
interest
Pembrolizumab AEOSI
X
-
AE=adverse event; AEOSI=adverse event(s) of special interest; CI=confidence interval; SOC=system organ class.
9.6.2.2
Assessment of Safety Topics of Special Interest 
AEs that are immune-mediated or potentially immune-mediated will be evaluated separately. 
These events have been characterized consistently throughout the pembrolizumab clinical 
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development program. Point estimates and 95% CIs for between-group difference is not 
expected to add value to the safety evaluation, and hence only number and percentage of 
participants with such pembrolizumab AEOSI will be provided, as well as the number and 
percentage of participants with corticosteroids administration to treat an AEOSI. Summary 
statistics will be provided for the analysis of time from first dose to the onset of an AEOSI.
9.6.3
Statistical Methods for Patient-Reported Outcome Analyses
The time point for the mean change from baseline will be determined based on blinded data 
review before the database lock for any PRO analysis and documented in the sSAP. 
 
 
 
 
Additional details for the PRO analyses will be described in the sSAP.
9.6.4
Summaries of Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be assessed by the use of tables and/or graphs. No statistical hypothesis 
tests will be performed on these characteristics. The number and percentage of participants 
screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. Demographic variables, baseline characteristics, primary and secondary 
diagnoses, and prior and concomitant therapies will be summarized by treatment either by 
descriptive statistics or categorical tables.
9.7
Interim Analyses
Study enrollment may be ongoing at the time of IA1 (Table 11). Blinding to treatment 
assignment will be maintained at all investigational sites. The results of IAs will not be 
shared with the investigators before the completion of the study. Participant-level unblinding 
will be restricted to an internal unblinded (or external, as appropriate) statistician and 
scientific programmer performing the IA, who will have no other responsibilities associated 
with the study.
An eDMC will serve as the primary reviewer of the results of the IA (analyses) of the study 
and will make recommendations for discontinuation of the study or protocol modifications to 
an executive committee of the Sponsor. If the eDMC recommends modifications to the 
design of the protocol or discontinuation of the study, this executive committee (and 
potentially other limited Sponsor personnel) may be unblinded to results at the treatment-
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level results to act on these recommendations. The extent to which individuals are unblinded 
with respect to results of IAs will be documented by the unblinded statistician. Additional 
logistic details will be provided in the eDMC charter.
Treatment-level results from the IA will be provided to the eDMC by the unblinded 
statistician. Before final study unblinding, the 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 IAs.
9.7.1
Efficacy Interim Analyses
 
 
 
 
 
Table 11
Analyses Planned, Endpoints Evaluated, and Drivers of Timing
Analyses
Key
Endpoints
Timing
Estimated Time After First 
Participant Randomized
Primary Purpose 
of Analysis
DMFS=distant metastasis-free survival; FA=final analysis; IA=interim analysis; OS=overall survival; RFS=recurrence-
free survival.
9.7.2
Safety Interim Analyses
The eDMC will be responsible for periodic interim safety reviews as specified in the eDMC 
charter. Interim safety analyses will also be performed at the time of interim efficacy 
analyses. Details will be specified in the DMC charter.
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9.8
Multiplicity
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9.8.1
Recurrence-free Survival
 
 
 
 
 
 
 
 
 
 
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9.8.2
Distant Metastases-free Survival
 
 
 
 
 
 
 
 
 
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9.8.3
Overall Survival
 
 
 
 
 
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9.8.4
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.
9.9
Sample Size and Power Calculations
The study will randomize approximately 1560 participants in a 1:1 ratio between MK-7684A 
adjuvant treatment and pembrolizumab adjuvant treatment. RFS is the primary endpoint for 
the study, with DMFS and OS as the key secondary endpoints.
9.9.1
Recurrence-free Survival
RFS is the primary endpoint. 
 
 
 
 
 
 
 
 
 
9.9.2
Distant Metastases-free Survival
DMFS is a secondary endpoint. 
 
 
 
 
 
 
 
 
 
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9.9.3
Overall Survival
OS is a secondary endpoint. 
 
 
 
 
 
 
 
 
 
9.10
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 and 
key secondary endpoints will be estimated and plotted within each category of the following 
classification variables: 
The consistency of the treatment effect will be assessed using descriptive statistics for each 
category of the subgroup variables listed above. If the number of participants in a category of 
a subgroup variable is less than 5% of the ITT population, the subgroup analysis will not be 
performed for this category of the subgroup variable, and this subgroup variable will not be 
displayed in the forest plot. The subgroup analyses for RFS, DMFS, and OS will be 
conducted using an unstratified Cox model.
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
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9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in number of cycles or 
administrations as appropriate. Summary statistics will be provided on the Extent of 
Exposure for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
I.
Introduction
A. Purpose
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD), through its subsidiaries, 
conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, planning, 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 and conduct of clinical trials. In all cases, MSD clinical trials will be 
conducted in compliance with MSD’s global standards, local and/or national 
regulations (including all applicable data protection laws and regulations), Regulation 
(EU) 536/2014, the International Council for Harmonisation Good Clinical Practice 
(ICH GCP) E6 and ICH General Considerations for Clinical Studies E8, 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 that 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 and shall respect the data 
protection rights of all participants, trial site staff and, where applicable, third 
parties. Input may be considered from a broad range of stakeholders, including 
patient advocacy groups/patients representing the trial population, caregivers, and 
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healthcare providers to ensure operational feasibility. Trial design also includes 
proactive identification of critical to quality factors utilizing a risk-based 
approach. Plans are then developed to assess and mitigate risks to those factors as 
appropriate during the trial. All trial protocols are and will be assessed for the 
need and capability to enroll underrepresented groups. Participants must meet 
protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in 
diverse populations, including people of varying age, race, ethnicity, gender, and 
accounting for other potential disease related factors. 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 (or 
individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial. Individuals involved in trial conduct receive training commensurate with 
their role prior to their becoming involved in the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD 
will make concerted efforts to raise awareness of clinical trial opportunities in 
various communities. MSD will seek to engage underrepresented groups and 
those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to 
those who will ultimately use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and 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 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
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 pre-specified 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.
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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 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. Regulatory Authority and Ethics Committee Review (Institutional Review Board 
[IRB]/Independent Ethics Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory 
authority acceptance/authorization prior to implementation of the trial or amendment, 
in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s 
brochure, and other relevant trial documents must be reviewed and approved by an 
IRB/IEC before being implemented at each site, in compliance with local and/or 
national regulations and ICH Guidelines. Changes to the protocol that are required 
urgently to eliminate an immediate hazard and to protect participant safety may be 
enacted in anticipation of ethics committee approval. MSD will inform regulatory 
authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
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. Trial designs include procedures and systems for 
the identification, monitoring, and reporting of safety concerns. 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.
During trial planning, the need for an independent Data Monitoring Committee 
(DMC) is assessed. DMC review of data accumulated during the conduct of the trial 
is integral to the well-being of trial participants.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
E. Trial Results
At the time of providing informed consent and in accordance with local laws and 
regulations, participants should be informed about the plans for availability of trial 
results.
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 medical record review and medical evaluation 
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.
See Appendix 7 for country-specific requirements.
10.1.2
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 
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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 their 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, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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 that would make the participant identifiable will not be transferred.
The participant must be informed that their 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 their 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.
The Sponsor has EU-approved Binding Corporate Rules since 2017, covering all aspects of 
its Global Privacy Program (Corporate Policy 20), and is self-certified pursuant to the EU-US 
Data Privacy Framework.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the 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.
10.1.3.2
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 to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
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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 before transmission to the Sponsor.
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.
10.1.3.3
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.
10.1.4
Committees Structure
10.1.4.1
Executive Oversight Committee
The EOC is comprised of members of Sponsor Senior Management. The EOC will receive 
and decide on any recommendations made by the DMC regarding the study.
10.1.4.2
External 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 (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.
10.1.4.3
Scientific Advisory Committee (SAC)
This study was developed in collaboration with a SAC. The SAC is comprised of both 
Sponsor and non-Sponsor scientific experts who provide scientific and strategic guidance on 
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various aspects of the clinical trial and/or development, which may include study design, 
interpretation of study results, and subsequent peer-reviewed scientific publications.
10.1.5
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 ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, 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, https://euclinicaltrials.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 trials 
Regulation 536/2014 mandated trials. 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 study-site 
contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials Regulation 536/2014, 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.
10.1.7
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, ICH GCP: 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.
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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.
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.
For investigators located in countries with serious breach reporting requirements, investigator 
will promptly report to the Sponsor any serious breach or suspected serious breach that 
occurs in compliance with those requirements. Unless more specifically defined in the 
applicable requirements, a serious breach is any breach of the applicable clinical trial 
regulation or of the clinical trial protocol which is likely to affect to a significant degree: (i) 
the safety or rights of a trial participant, or (ii) the reliability and robustness of the data 
generated in the clinical trial.
10.1.8
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.
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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, 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.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). 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/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
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 or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 16 will be performed by the local laboratory as indicated in the 
SoA. Results should be reviewed pre-dose at each time point indicated in the SoA.
•
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.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
Laboratory results that could unblind the study will not be reported to investigative sites or 
other blinded personnel until the study has been unblinded.
Table 16
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices:
MCV
MCH
Reticulocytes
WBC count with 
Differentiala:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUNb
Potassium
AST/SGOT
Total bilirubin (and 
direct bilirubin, if total 
bilirubin is above the 
ULN)
Albumin
Carbon Dioxide 
(CO2) or 
Bicarbonatee
Chloride
Phosphorous
Creatinine, CrClc or 
GFRd
Sodium
ALT/SGPT
Total Protein
Glucose (fasting or 
nonfasting per 
institutional 
standard)
Calcium
Alkaline 
phosphatase
Magnesium
LDH
Routine 
Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, by dipstick
•
Microscopic examination (if blood or protein is abnormal)
Pregnancy 
Testing
•
Highly sensitive serum and/or urine hCG pregnancy test (as needed for WOCBP)
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Laboratory 
Assessments
Parameters
Other Screening 
Tests
•
Coagulation: PT/INR and aPTT/PTT
•
FSH (as needed in WONCBP only)
•
Thyroid: T3, T4 and TSH
NOTE: Free T3/T4 is acceptable if total T3/T4 cannot be determined
•
Serology (HIV antibody, HBsAg and/or HBV DNA, and anti-HCV antibody 
and/or HCV RNA) if applicable (refer to Section 5.1 and Appendix 7)
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; FSH=follicle-stimulating hormone; GFR=glomerular filtration rate; hCG=human 
chorionic gonadotropin; MCH=mean corpuscular hemoglobin; MCV=mean corpuscular volume; PTT=partial 
thromboplastin time; RBC=red blood cell; SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum glutamic 
pyruvic transaminase; ULN=upper limit of normal; WOCBP=women of childbearing potential; WONCBP=women of 
nonchildbearing potential.
a
Absolute or % acceptable per institutional standard.
b
BUN is preferred, but if not available, then urea may be tested. Record either BUN or urea result, but not both.
c
Creatinine clearance should be calculated using Cockcroft-Gault:
(140-age [years]) × weight (kg) (×F)*
Serum creatinine (mg/dL) × 72
*where F = 0.85 for females and F = 1 for males
d
To individualize GFR in units of mL/min, multiply the estimate of GFR by the participant’s body surface area 
and divide by 1.73 m2.
e
Perform if considered local standard of care.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
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 intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), 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 intervention administration even 
though it may have been present before the start of the study.
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•
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 
intervention 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 
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). Progression of the cancer under 
study is not a reportable event. Refer to Section 8.4.6 for additional details.
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.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
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 participant’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.
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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) that may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
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 1 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.
10.3.4
Additional Events Reported
Additional events that require reporting
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor.
•
Is a new cancer (that is not the cancer under study) as noted in Section 8.4.1.
•
Is associated with an overdose.
10.3.5
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.
•
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.
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Assessment of intensity/toxicity
•
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 CTCAE, version 5.0. Any AE that 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 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?
-
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 IMP)?
-
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?
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◦
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 1 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 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
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 CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their 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).
-
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.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
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•
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 their 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 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by 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.
10.3.6
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 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).
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•
Contacts for SAE reporting can be found in the Investigator Study 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 Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
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
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
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 FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantc
•
IUSc,d
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This 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. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview. 
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
•
Combined (estrogen- and progestogen- containing) hormonal contraceptionc
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
•
Progestogen-only hormonal contraceptionc
-
Oral
-
Injectable
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 intervention. 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.
a   Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b  Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly)
c   If locally required, in accordance with CTFG guidelines, acceptable hormonal contraceptives are limited to 
those which inhibit ovulation.
d   IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: 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 Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
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 Research3, 4
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 their 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 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.
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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 Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ 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 sex, age, medical history, and intervention outcomes is
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 that 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 Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using 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 Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, 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, 
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if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before 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.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the 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 Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the 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 used 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 Security3, 4
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 Participants3, 4
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.
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 Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
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11. Risks Versus Benefits of Future Biomedical Research3, 4
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 emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [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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10.7
Appendix 7: Country-specific Requirements
10.7.1
Argentina
Section 1.3 – Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
10.7.2
Austria
Section 5.1 Inclusion Criteria
Pediatric participants (<18 years of age) will not be enrolled in Austria.
10.7.3
Belgium
Section 5.1 Inclusion Criteria
Pediatric participants (<18 years of age) will not be enrolled in Belgium.
10.7.4
France
Section 5.1 Inclusion Criteria
Pediatric participants (<18 years of age) will not be enrolled in France.
10.7.5
United Kingdom
Section 5.1 Inclusion Criteria
Pediatric participants (<16 years of age) will not be enrolled in the United Kingdom.  
Section 6.5 Concomitant Therapy 
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):
•
Live vaccines must not be administered for 90 days after the last dose of study 
intervention. Refer to Section 6.5 for information on COVID-19 vaccines.
NOTE: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
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10.7.6
Ireland
Section 5.1 Inclusion Criteria
Pediatric participants (<18 years of age) will not be enrolled in Ireland.  
Section 6.5 Concomitant Therapy 
Listed below are specific concomitant therapies or vaccinations that are prohibited during the 
study (exceptions noted):
•
Live vaccines must not be administered for 90 days after the last dose of study 
intervention. Refer to Section 6.5 for information on COVID-19 vaccines.
NOTE: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
10.7.7
Germany
Throughout the Protocol:
Legally Acceptable Representative
Persons of legal age, who are incapable of comprehending the nature, significance and 
implications of the clinical study and of determining their will, are generally excluded from 
the participation in a clinical study at German sites as per AMG § 40b sentence 4 and 5. 
Therefore all references to a participant’s “legally acceptable representative” in the protocol 
are not applicable for participants in Germany.
Exclusion of minors as per German Drug Law (AMG) § 40b sentence 3
In compliance with German Drug Law no patients below the legal age of 18 will be enrolled 
in the study.
Exclusion of persons who per order of court or authorities have been accommodated in 
an institution as per German Drug Law (AMG) § 40a sentence 2 
Persons, who have been committed to an institution by virtue of an order issued either by the 
judicial or the administrative authorities are excluded from participation in this clinical study 
in Germany.
Section 5.1 – Inclusion Criteria:
Inclusion Criterion 10: HIV testing is required at Screening for participants.
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Inclusion Criteria 11 and 12: Hepatitis B and C testing is required at Screening for 
participants.
Explanation concerning inclusion of persons who may be dependent on the Sponsor or 
investigator according to GCP-V §7 sentence 3 no. 3
Relatives of Sponsor or investigators are not excluded from participation in this clinical study 
according to the inclusion and exclusion criteria. The Sponsor considers it unacceptable in 
oncology studies to deny the above patient group access to study therapies that may be 
superior to current standard care.
Section 8.2.1 Tumor Imaging and Assessment of Disease
The process for scan collection and transmission to the iCRO can be found in the SIM. 
Tumor scans by CT are strongly preferred. For the abdomen and pelvis, contrast-enhanced 
MRI may be used when CT with iodinated contrast is contraindicated, or when mandated by 
local practice. The same scan technique 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 response assessment based on scans.
CLARIFICATION
Per SIM Option 4, MRI is acceptable as replacement for CT if contraindicated medically 
and/or not aligned with local practice.
10.7.8
Poland
Section 5.1 Inclusion Criteria
Pediatric participants (<18 years of age) will not be enrolled in Poland.  
10.7.9
Romania
Section 1.3 Schedule of Activities
HIV testing at screening is mandatory.
Hepatitis B and C testing at Screening is mandatory.
Section 5.1 – Inclusion Criteria
Inclusion Criteria 11 and 12: Hepatitis B and C testing is required at Screening for 
participants.
10.7.10
Spain
Section 5.1 Inclusion Criteria
Pediatric participants (<18 years of age) will not be enrolled in Spain.  
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10.7.11
Sweden
Section 4.2.1.2 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/SAEs; and changes in vital signs and laboratory values.
Adverse events will be assessed as defined by CTCAE, v5.0.
Section 5.1 Inclusion Criteria
Pediatric participants (<18 years of age) will not be enrolled in Sweden.  
Section 10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1 Code of Conduct for Clinical Trials
III. Participant Protection
A. Ethics Committee Review (IRB/IEC) and Health Authorities
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents must be submitted to and approved by the applicable Competent Authority and 
IRB/IEC before the study is initiated in accordance with EU Directive 2001/20/EC, Article 
10 (a) and/or local requirements. Any amendments to the protocol will require IRB/IEC and 
Competent Authority approval before implementation of changes made to the study design, 
except for changes necessary to eliminate an immediate hazard to study participants 
[2001/20/EC, Article 10 (c)].
•
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.
In the EU [CT-1 (2010/C 82/01)], the Sponsor must send immediate end-of-study 
notification to the national competent authority and the Ethics Committee of the Member 
State concerned. The end-of-study notification must be sent within 15 days after the study is 
halted to clearly describe the reasons and follow-up measures, if any, taken for safety 
reasons. The 15-day notification applies only for early termination of the study. Otherwise 
the time window to send end-of-study notification is 90 days in the EU.
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10.7.12
Italy
Section 1.3 – Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
Section 5.1 Inclusion Criteria
Pediatric participants (<18 years of age) will not be enrolled in Italy.  
Section 5.2 – Exclusion Criteria
•
Has a known history of HIV infection
•
History of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus 
(defined as detectable HCV RNA [qualitative]) infection
10.7.13
South Africa
Section 1.3 – Schedule of Activities
HBV, HCV, and HIV testing at screening is mandatory.
Section 5.2 – Exclusion Criteria
•
History of Hepatitis B (defined as HBsAg reactive) or known active Hepatitis C virus 
(defined as detectable HCV RNA [qualitative]) infection
10.7.14
China
Biomarker sample collection, testing and analysis as described in the following sections will 
be dependent on approval by the Human Genetic Resources Administration of China for 
participants enrolled in China:
Section 1.3 – Schedule of Activities
Section 4.2.1.6 – Planned Exploratory Biomarker Research
Section 5.1 – Inclusion Criteria 
Section 5.2 – Exclusion Criteria
Section 8.1.13 – Tumor Tissue for Biomarker Status
Section 8.8 – Biomarkers
FBR will not be conducted in China.
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10.7.15
Peru
Section 1.3 – Schedule of Activities
HBV, HCV, and HIV testing at Screening is mandatory.
10.7.16
Brazil
Section 5.1 Inclusion Criteria
Pediatric participants (<18 years of age) will not be enrolled in Brazil.  
Section 1.3 – Schedule of Activities
FBR will not be conducted in Brazil.
Section 8.8 – Biomarkers
FBR will not be conducted in Brazil.
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10.8
Appendix 8: Melanoma Staging
The AJCC has designated staging by TNM classification to define melanoma.
Staging tables are adapted from the AJCC, Eighth Edition. Refer to the AJCC guidelines for 
more information [Gershenwald, J. E., et al 2017b].
Staging tables are provided as follows:
[Table 17]
Melanoma T Category Definition
[Table 18]
Melanoma N Category Definition
[Table 19]
Melanoma M Category Definition
[Table 20]
AJCC Pathological (pTNM) Staging Groups
[Table 21]
AJCC Clinical Prognostic (cTNM) Staging Groups
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
≤1.0 mm (ulceration status unknown or unspecified)
T1a
<0.8 mm without ulceration
T1b
<0.8 mm with ulceration or
0.8-1.0 mm with or without ulceration
T2
>1.0-2.0 mm (ulceration status unknown or unspecified)
T2a
>1.0-2.0 mm without ulceration
T2b
>1.0-2.0 mm with ulceration
T3
>2.0-4.0 mm (ulceration status unknown or unspecified)
T3a
>2.0-4.0 mm without ulceration
T3b
>2.0-4.0 mm with ulceration
T4
>4.0 mm (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 Eighth 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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Table 21
AJCC Clinical Prognostic (cTNM) Staging Groups
Staging (AJCC Eighth Edition)
0
Tis
N0
M0
IA
T1a
N0
M0
IB
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
III
Any T, Tis
≥N1
M0
IV
Any T
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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10.9
Appendix 9: 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 on pathological 
examination alone. This is particularly the case for a melanoma 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:
1. The presence of rare single atypical epidermal melanocytes, 
2. Epidermal thinning with loss of rete ridges, 
3. Fibrosis and vascular proliferation in the dermis overlying the lesion, 
4. Defect in the band of superficial solar elastosis, 
5. Bandlike 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 2017b] [Scolyer, R. A., et al 2020].
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10.10 Appendix 10: Surgical Considerations
Recommendation for Surgical Management:
a.
Wide excision with a 1-2 cm 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 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.
Therapeutic lymph node dissection for macroscopic disease
For this study a therapeutic axillary lymph node dissection is required for macroscopic 
disease (ie, clinically, radiographically, sonographically [if performed] detectable nodes).
Axillary Lymphadenectomy: 
Axillary node dissection must include all involved nodes or at least 10 nodes are required for 
adequacy if this exceeds the number of involved nodes taken from Levels I and II and the 
Level III nodes. The boundaries of the dissection should include the axillary vein superiorly 
beginning at the thoracic outlet and coursing to the latissimus dorsi tendon. The lateral border 
of the dissection is the anterior edge of the latissimus dorsi muscle. The posterior boundary is 
the subscapular muscle. The anterior border of the resection is the pectoralis major group. 
The inferior boundary of the dissection should be the juncture of the latissimus dorsi and the 
serratus anterior muscles. 
The contents within these boundaries should be completely removed with the exception of 
the long thoracic nerve and the thoracodorsal nerve, which should be identified during the 
dissection and preserved throughout. As stated, the pectoralis minor muscle may be divided 
or sacrificed with the specimen at the discretion of the surgeon. Care should be exercised that 
in the superior part of the dissection, the anterior pectoral nerve is not injured. The preferable 
approach to the axilla is through a horizontal incision in the line of the skin crease, 3 or 4 cm 
below the apex of the skin fold of the axilla.
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Inguinal Lymphadenectomy: 
A superficial femoral node dissection should be performed by excising all of the nodes 
inferior to the inguinal ligament and bounded by the medical border of the sartorius muscle 
in the lateral border of the adductor magnus muscle. The fatty and lymphatic tissues should 
be dissected carefully off the femoral vessels and nerves all the way up to the inguinal canal 
and for 3 cm superior to the inguinal ligament. The saphenous vein is resected to ensure 
complete excision of the lymph nodes. Transposition of the sartorius muscle should be 
considered (but is not mandatory) to cover the femoral vessels after complete lymphatic 
excision. Ideally, this area should be entered through a curvilinear incision staring laterally 
over the inguinal ligament and curving medially and inferiorly ending over the midpoint of 
the adductor magnus muscle. A minimum of 5 nodes must be resected for adequacy if this 
exceeds the detected number of involved nodes. 
Deep Inguinal and External Iliac Node Dissection: 
Deep inguinal and external iliac node dissection can be most easily approached by incising 
the abdominal wall musculature 3 or 4 cm superior to the inguinal ligament. This incision is 
taken down through the external oblique, internal oblique and transversus muscles, and the 
surgeon at that point stays extraperitoneally as in the approach to the iliac vessels for renal 
transplantation. With this approach, the external, internal and common iliac arteries are 
exposed and the lymphatics coursing among the iliac vessels are excised. A full ilioinguinal 
(deep) inguinal node dissection is advised in case of overt inguinal node- metastasis and 
when Cloquet’s node is positive. 
(Modified) Radical Neck Dissection: 
Classic or modified radical neck dissection must be performed for patients with melanoma of 
the head and neck and involved nodes. A minimum of 15 nodes must be resected for 
adequacy if this exceeds the detected number of involved nodes. Patients with melanoma 
located on the ear and anterior scalp and face require superficial parotidectomy along with a 
radical neck procedure. The boundaries of the radical neck dissection are inferiorly the 
clavicle; the mandible, the mastoid and the tail of the parotid gland superiorly; the anterior 
border of the trapezius muscle posteriorly and the strap muscle of the larynx anteriorly. The 
sternocleidomastoid muscle may be sacrificed or preserved at the surgeon's discretion. For 
posterior nodes, the radical neck incision must be extended posteriorly or a second incision 
must be made so that the suboccipital nodal group can be resected. For posterior neck 
dissection, surgical and pathological resection of at least 5 nodes are required for adequacy if 
this exceeds the detected number of involved nodes.
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
Ab
antibody
ADA
antidrug antibodies
AE
adverse event 
AEOSI
adverse event of special interest
AJCC
American Joint Committee on Cancer
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANC
absolute neutrophil count
APaT
All Participants as Treated
ART
antiretroviral therapy
AST
aspartate aminotransferase
AUC
area under the curve
AxMP
auxiliary medicinal product
BCC
basal cell carcinoma
C
cycle
CD
cluster of differentiation
cHL
classical Hodgkin lymphoma
CI
confidence interval
CL
clearance
CLND
complete lymph node dissection
Cmax
maximum plasma concentration
CNS
central nervous system
CONSORT
Consolidated Standards of Reporting Trials
COPD
chronic obstructive pulmonary disease
COVID-19
Coronavirus Disease 2019
CrCl
creatinine clearance
(e)CRF
(electronic) Case Report Form 
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Ctrough
minimum plasma concentration
CYP
cytochrome P450
D
day
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
(e)DMC
(external) Data Monitoring Committee 
DMFS
distant metastasis-free survival
DNA
deoxyribonucleic acid 
DRAE
drug-related adverse event
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Abbreviation
Expanded Term
DRESS
drug rash with eosinophilia and systemic symptom
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
EEA
European Economic Area
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EORTC QLQ
European Organization for Research and Treatment of Cancer Quality 
of Life Questionnaire
EOT
end of treatment
EQ-5D-5L
EuroQoL 5 dimensions-5 levels
E-R
exposure response
EU
European Union
FAS
full analysis set
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Acts
FFPE
formalin-fixed, paraffin embedded
FSH
follicle-stimulating hormone 
FSR
first site ready
GCP
Good Clinical Practice 
GFR
glomerular filtration rate
GI
gastrointestinal
H
hypothesis
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HGRAC
Human Genetic Resources Administration of China
HIV
human immunodeficiency virus
HR
hazard ratio
HRT
hormone replacement therapy
HRQoL
health-related quality of life
IA(s)
interim analysis(ses)
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
iCRO
imaging CRO
IEC
Independent Ethics Committee
Ig
immunoglobulin
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Abbreviation
Expanded Term
IHC
immunohistochemistry
IL
interleukin
IMP
investigational medicinal product
IND
Investigational New Drug 
IO
immune-oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
IRT
interactive response technology
ITIM
immunoreceptor tyrosine-based inhibitory motif
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVRS
interactive voice response system
IWRS
integrated web response system
KPS
Karnofsky performance status
LLOQ
lower limit of quantitation
LPLV
last patient last visit
LPS
Lansky play-performance scale
LS
least squares
M&N
Miettinen & Nurminen
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MSI-H
microsatellite instability-high
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NIMP
noninvestigational medicinal product
NR
not reached
NSAID
nonsteroidal anti-inflammatory drug
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
pCR
pathological complete response
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PK
pharmacokinetic
pNR
pathological no response
po
orally
pPR
pathological partial response
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Abbreviation
Expanded Term
PRFS2
progression/recurrence-free survival 2
(e)PRO
(electronic) patient-reported outcome
PS
performance status
PSA
prostate-specific antigen
PVR
poliovirus receptor
QxM
every x months
QxW
every x weeks
QoL
quality of life
RECIST
Response Evaluation Criteria In Solid Tumors
RFS
recurrence-free survival
RNA
ribonucleic acid
ROW
rest of world
RP2D
recommended Phase 2 dose
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SCC
squamous cell carcinoma
SD
standard deviation
SGOT
serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SHP-1/2
Src homology region 2 domain-containing phosphatase 1/2
SIM
Site Imaging Manual
SJS
Stevens-Johnson Syndrome
SLN
sentinel lymph node
SNP
single nucleotide polymorphism
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
SWOG
Southwest Oncology Group
T1DM
type 1 diabetes mellitus
T3
triiodothyronine
T4
thyroxine
TEN
toxic epidermal necrolysis
TIGIT
T-cell immunoreceptor with Ig and ITIM domains
TIL
tumor-infiltrating lymphocyte
TSH
thyroid-stimulating hormone
TTST
time to subsequent therapy
ULN
upper limit of normal
US
United States
Vc
volume of the central compartment
VAS
Visual Analog Scale
WBC
white blood cell
WOCBP
woman/women of childbearing potential
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11
REFERENCES
[Aaronson, N. K., et al 
1993]
Aaronson NK, Ahmedzai S, Bergman B, Bullinger 
M, Cull A, Duez NJ, et al. The European 
Organization for Research and Treatment of Cancer 
QLQ-C30: a quality-of-life instrument for use in 
international clinical trials in oncology. J Natl 
Cancer Inst 1993;85(5):365-76.
[03Q3QL]
[American Cancer 
Society 2014]
American Cancer Society [Internet]. Atlanta; c2014 
[updated 2014 Sep 5]. What are the key statistics 
about melanoma skin cancer?; Available from: 
http://www.cancer.org/cancer/skincancer-
melanoma/detailedguide/melanoma-skin-cancer-
key-statistics
[0402DW]
[Bai,S., et al 2012]
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-
Beyer LA, et al. A guide to rational dosing of 
monoclonal antibodies. Clin Pharmacokinet 
2012;51(2):119-35.
[03T78B]
[Basu, S., et al 2020]
Basu S, Lien YTK, Vozmediano V, Schlender JF, 
Eissing T, Schmidt S, et al. Physiologically based 
pharmacokinetic modeling of monoclonal antibodies 
in pediatric populations using PK-Sim. Front 
Pharmacol. 2020 Jun 11;11:868.
[080SWM]
[Chauvin, J. M., et al 
2015]
Chauvin JM, Pagliano O, Fourcade J, Sun Z, Wang 
H, Sander C, et al. TIGIT and PD-1 impair tumor 
antigen-specific CD8⁺ T cells in melanoma patients. 
J Clin Invest. 2015 May;125(5):2046-58.
[04GS9H]
[Chemnitz, J. M., et al 
2004]
Chemnitz JM, Parry RV, Nichols KE, June CH, 
Riley JL. SHP-1 and SHP-2 associate with 
immunoreceptor tyrosine-based switch motif of 
programmed death 1 upon primary human T cell 
stimulation, but only receptor ligation prevents T 
cell activation. J Immunol 2004;173:945-54.
[00VMPN]
[Dirks, N. L. and 
Meibohm, B 2010]
Dirks NL, Meibohm B. Population 
pharmacokinetics of therapeutic monoclonal 
antibodies. Clin Pharmacokinet 2010;49(10):633-59.
[058SQX]
[Disis, M. L. 2010]
Disis ML. Immune regulation of cancer. J Clin 
Oncol 2010;28(29):4531-8.
[058SQL]
08M9TH

PRODUCT: MK-7684A
157
PROTOCOL/AMENDMENT NO.: 010-04
MK-7684A-010-04 FINAL PROTOCOL
27-JUN-2024
[Dostalek,M., et al 
2012]
Dostalek M, Gardner I, Gurbaxani BM, Rose RH, 
Chetty M. Pharmacokinetics, pharmacodynamics 
and physiologically-based pharmacokinetic 
modelling of monoclonal antibodies. Clin 
Pharmacokinet 2013;52:83-124.
[03T7LF]
[Dudley, M. E., et al 
2005]
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, 
Topalian SL, Restifo NP, et al. Adoptive cell 
transfer therapy following non-myeloablative but 
lymphodepleting chemotherapy for the treatment of 
patients with refractory metastatic melanoma. J Clin 
Oncol 2005;23(10):2346-57.
[00VMPR]
[Eggermont, A. M. M., 
et al 2018]
Eggermont AMM, Blank CU, Mandala M, Long, 
GV, Atkinson V, Dalle S, et al. Adjuvant 
Pembrolizumab versus Placebo in Resected State III 
Melanoma. N Engl J Med 2018; 378:1789-801.
[04WXLF]
[Eggermont, A. M. M., 
et al 2021]
Eggermont AMM, Blank CU, Mandala M, Long 
GV, Atkinson VG, Dalle S, et al. Adjuvant 
pembrolizumab versus placebo in resected stage III 
melanoma (EORTC 1325-MG/KEYNOTE-054): 
distant metastasis-free survival results from a 
double-blind, randomised, controlled, phase 3 trial. 
Lancet Oncol. In press 2021.
[06C9F8]
[Food and Drug 
Administration 2018]
Food and Drug Administration. Clinical trial 
endpoints for the approval of cancer drugs and 
biologics: guidance for industry. Silver Spring, MD. 
Dec 2018.
[054RV4]
[Food and Drug 
Administration 2019]
Food and Drug Administration. Considerations for 
the inclusion of adolescent patients in adult 
oncology clinical trials: guidance for industry. Silver 
Spring, MD. Mar 2019.
[082NYJ]
[Francisco, L. M., et al 
2010]
Francisco LM, Sage PT, Sharpe AH. The PD-1 
pathway in tolerance and autoimmunity. Immunol 
Rev 2010;236:219-42.
[058SQP]
[Garbe, C., et al 2012]
Garbe C, Peris K, Hauschild A, Saiag P, Middleton 
M, Spatz A, et al. Diagnosis and treatment of 
melanoma. European consensus-based 
interdisciplinary guideline - update 2012. Eur J 
Cancer 2012;48:2375-90.
[03YM8V]
08M9TH

PRODUCT: MK-7684A
158
PROTOCOL/AMENDMENT NO.: 010-04
MK-7684A-010-04 FINAL PROTOCOL
27-JUN-2024
[Geoerger, B., et al 
2020]
Geoerger B, Kang HJ, Yalon-Oren M, Marshall LV, 
Vezina C, Pappo A, et al. Pembrolizumab in 
paediatric patients with advanced melanoma or a 
PD-L1-positive, advanced, relapsed, or refractory 
solid tumour or lymphoma (KEYNOTE-051): 
interim analysis of an open-label, single-arm, phase 
1-2 trial. Lancet Oncol. 2020 Jan;21:121-33.
[05DN5R]
[Gershenwald, J. E., et 
al 2017]
Gershenwald JE, Scolyer RA, Hess KR, Sondak 
VK, Long GV, Ross MI, et al. Melanoma staging: 
evidence-based changes in the American joint 
committee on cancer eighth edition cancer staging 
manual. CA Cancer J Clin. 2017 Dec;67(6):474-92.
[04VJRR]
[Gershenwald, J. E., et 
al 2017a]
Gershenwald JE, Scolyer RA, Hess KR, Sondak 
VK, Long GV, Ross MI, et al. Melanoma staging: 
evidence-based changes in the American Joint 
Committee on Cancer eighth edition Cancer Staging 
Manual. CA Cancer J Clin. 2017 Nov;67(6):474-92.
[04VHZF]
[Gershenwald, J. E., et 
al 2017b]
Gershenwald JE, Scolyer RA, Hess KR, Sondak
VK, Long GV, Ross MI, et al. Melanoma staging: 
evidence-based changes in the American Joint 
Committee on Cancer eighth edition cancer staging 
manual. CA Cancer J Clin. 2017 Nov;67(6):472-92.
[04TQYM]
[Greenwald, R. J., et al 
2005]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 
family revisited. Annu Rev Immunol 2005;23:515-
48.
[00VMQL]
[Grossmann, K. F., et 
al 2021]
Grossmann KF, Othus M, Patel SP, Tarhini AA, 
Sondak VK, Petrella TM, et al. Final analysis of 
overall survival (OS) and relapse-free-survival 
(RFS) in the intergroup S1404 phase III randomized 
trial comparing either high-dose interferon (HDI) or 
ipilimumab to pembrolizumab in patients with high-
risk resected melanoma [abstract]. Presented at: 
2021 American Society of Clinical Oncology 
(ASCO) Annual Meeting; 2021 Jun 4-8; [online 
meeting]. J Clin Oncol. 2021;39(15 suppl).
[06G8BP]
[Hendrikx, J. J. M. A., 
et al 2017]
Hendrikx JJMA, Haanen JBAG, Voest EE, 
Schellens JHM, Huitema ADR, Beijnen JH. Fixed 
dosing of monoclonal antibodies in oncology. 
Oncologist. 2017;22:1212-21.
[05JHQC]
08M9TH

PRODUCT: MK-7684A
159
PROTOCOL/AMENDMENT NO.: 010-04
MK-7684A-010-04 FINAL PROTOCOL
27-JUN-2024
[Hunder, N. N., et al 
2008]
Hunder NN, Wallen H, Cao J, Hendricks DW, 
Reilly JZ, Rodmyre R, et al. Treatment of metastatic 
melanoma with autologous CD4+ T cells against 
NY-ESO-1. N Engl J Med 2008;358(25):2698-703.
[00VMPX]
[IB Edition 10 2022]
MK-7684/7684A (Vibostolimab) Investigator's 
Brochure, Edition Number 10, 29-Jun-2022.
[07YDML]
[Johnston, R. J., et al 
2014]
Johnston RJ, Comps-Agrar L, Hackney J, Yu X, 
Huseni M, Yang Y, et al. The immunoreceptor 
TIGIT regulates antitumor and antiviral CD8(+) T 
cell effector function. Cancer Cell. 2014 Dec 
8;26(6):923-37.
[04GS9T]
[Keizer,R.J., et al 2010]
Keizer RJ, Huitema ADR, Schellens JHM, Beijnen 
JH. Clinical pharmacokinetics of therapeutic 
monoclonal antibodies. Clin Pharmacokinet 
2010;49(8):493-507.
[03T7M7]
[Levin, S. D., et al 
2011]
Levin SD, Taft DW, Brandt CS, Bucher C, Howard 
ED, Chadwick EM, et al. Vstm3 is a member of the 
CD28 family and an important modulator of T-cell 
function. Eur J Immunol. 2011 Apr;41(4):902-15.
[04GT88]
[Long, G. V., et al 
2022]
Long GV, Luke JJ, Khattak M, de la Cruz Merino L, 
Del Vecchio M, Rutkowski P, et al. Distant 
metastasis-free survival with pembrolizumab versus 
placebo as adjuvant therapy in stage IIB or IIC 
melanoma: the phase 3 KEYNOTE-716 study 
[abstract]. Oral abstract session presented at: 2022 
American Society of Clinical Oncology (ASCO) 
Annual Meeting; 2022 Jun 3-7; Chicago, IL. J Clin 
Oncol. 2022;40(17 suppl).
[0842X8]
[Lozano, E., et al 2012]
Lozano E, Dominguez-Villar M, Kuchroo V, Hafler 
DA. The TIGIT/CD226 axis regulates human T cell 
function. J Immunol. 2012 Apr 15;188(8):3869-75.
[04J3HX]
[Maurer, W. and Bretz, 
F. 2013]
Maurer W and Bretz F. Multiple testing in group 
sequential trials using graphical approaches. Stat 
Biopharm Res 2013;5(4):311-20.
[03XQVB]
[Miettinen, O. and 
Nurminen, M. 1985]
Miettinen O and Nurminen M. Comparative analysis 
of two rates. Stat Med 1985;4:213-26.
[00QHZT]
08M9TH

PRODUCT: MK-7684A
160
PROTOCOL/AMENDMENT NO.: 010-04
MK-7684A-010-04 FINAL PROTOCOL
27-JUN-2024
[Modeling and 
Simulation Report: 
Extension... 2017]
Modeling and Simulation Report: Extension of 
Population Pharmacokinetic Analysis of 
Pembrolizumab (MK 3475) to Patients with 
Hodgkin Lymphoma and Pediatric Patients, 2017.
[04LL90]
[National Cancer 
Institute 2017]
National Cancer Institute. SEER cancer stat facts: 
melanoma of the skin [Internet]. Bethesda, MD: 
National Cancer Institute; 2017. Available from 
https://seer.cancer.gov/statfacts/html/melan.html.
[04VJ0N]
[National 
Comprehensive Cancer 
Network 2022]
National Comprehensive Cancer Network. NCCN 
clinical practice guidelines in oncology: melanoma: 
cutaneous; version 3.2022. Plymouth Meeting (PA): 
National Comprehensive Cancer Network (NCCN); 
2022. 226 p.
[080D8F]
[Okazaki, T., et al 
2001]
Okazaki T, Maeda A, Nishimura H, Kurosaki T, 
Honjo T. PD-1 immunoreceptor inhibits B cell 
receptor-mediated signaling by recruiting src 
homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. Proc Natl Acad 
Sci U S A 2001;98(24):13866-71.
[00VMQ6]
[Parry, R. V., et al 
2005]
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco
AR, Braunstein I, Kobayashi SV, et al. CTLA-4 and 
PD-1 receptors inhibit T-cell activation by distinct 
mechanisms. Mol Cell Biol 2005;25(21):9543-53.
[00VMQ7]
[Pickard, A. S., et al 
2007]
Pickard AS, Neary MP, Cella D. Estimation of 
minimally important differences in EQ-5D utility 
and VAS scores in cancer. Health Qual Life 
Outcomes 2007;5:1-8.
[00W0FM]
[Rabin, R. and de 
Charro, F. 2001]
Rabin R and de Charro F. EQ-5D: a measure of 
health status from the EuroQol group. Ann Med 
2001;33:337-43.
[03QM46]
[Riley, J. L. 2009]
Riley JL. PD-1 signaling in primary T cells. 
Immunol Rev 2009;229:114-25.
[00VMQ9]
[Robbie, G. J., et al 
2012]
Robbie GJ, Zhao L, Mondick J, Losonsky G, Roskos 
LK. Population pharmacokinetics of palivizumab, a 
humanized anti-respiratory syncytial virus 
monoclonal antibody, in adults and children. 
Antimicrob Agents Chemother. 2012 
Sep;56(9):4927-36. Erratum in: Antimicrob Agents 
Chemother. 2012 Oct;56(10):5431.
[040CNK]
08M9TH

PRODUCT: MK-7684A
161
PROTOCOL/AMENDMENT NO.: 010-04
MK-7684A-010-04 FINAL PROTOCOL
27-JUN-2024
[Scolyer, R. A., et al 
2020]
Scolyer RA, Prieto VG, Elder DE, Cochran AJ, 
Mihm MC Jr. Cutaneous melanoma. 6th ed. Balch 
CM, Atkins MB, Garbe C, Gershenwald JE, Halpern 
AC, Kirkwood JM, McArthur GA, Thompson JF, 
Sober AJ, editors. Cham (Switzerland): Springer 
Nature Switzerland AG, c2020. Classification and 
histopathology of melanoma; p. 317-66.
[06CC04]
[Sheppard, K-A, et al 
2004]
Sheppard K-A, Fitz LJ, Lee JM, Benander C, 
George JA, Wooters J, et al. PD-1 inhibits T-cell 
receptor induced phosphorylation of the 
ZAP70/CD3zeta signalosome and downstream 
signaling to PKCtheta. FEBS Lett. 2004;574:37-41.
[00VMQC]
[Verbeke, G. and 
Molenberghs, G. 2009]
Verbeke G and Molenberghs G. Linear mixed 
models for longitudinal data. New York, NY: 
Springer Verlag New York, LLC; c2009. p. 578.
[084DMS]
[Weir, H. K., et al 
2011]
Weir HK, Marrett LD, Cokkinides V, Barnholtz-
Sloan J, Patel P, Tai E, et al. Melanoma in 
adolescents and young adults (ages 15-39 years): 
United States, 1999-2006. J Am Acad Dermatol 
2011;65(5 Suppl 1):S38-S49.
[00VXRJ]
[Zhang, T., et al 2014]
Zhang T, Wang J, Zhou X, Liang R, Bai Q, Yang L, 
et al. Increased expression of TIGIT on CD4+ T 
cells ameliorates immune-mediated bone marrow 
failure of aplastic anemia. J Cell Biochem. 2014 
Nov;115(11):1918-27.
[04J3J5]
[Zhang, X., et al 2004]
Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, 
Chen L, et al. Structural and functional analysis of 
the costimulatory receptor programmed death-1. 
Immunity 2004;20:337-47.
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