Conditions: Advanced/Metastatic Melanoma
Keywords: programmed cell death 1 (PD-1, PD1) programmed cell death ligand 1 (PD-L1, PDL1) programmed cell death ligand 2 (PD-L2, PDL2) Coxsackievirus A21 Intracellular Adhesion Molecule-1 (ICAM-1)
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 85
Healthy volunteers: no

Brief summary:
This is a Phase 2 study to assess the efficacy, safety, and tolerability of gebasaxturev administered both intratumorally (ITu) and intravenously (IV) as combination therapy with pembrolizumab (MK-3475) versus pembrolizumab alone in anti-programmed cell death ligand 1 (anti-PD-L1)-treatment-naive participants with advanced/metastatic melanoma. The primary hypothesis of the study is that gebasaxturev administered either ITu or IV in combination with pembrolizumab results in a superior objective response rate (ORR) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1) based on blinded independent central review (BICR), compared to pembrolizumab alone. This study will be terminated once all participants finish treatment with V937. Participants eligible to continue to receive pembrolizumab will be transferred to MK-3475-587 study.

Detailed description:

Arms:
arm 1: Participants receive gebasaxturev at a dose of 1 X 10\^9 TCID50 by IV infusion on Days 1, 3, 5, and 8 of Cycle 1 (28-day cycle) and Day 1 of Cycles 2-8 (21-day cycles) plus pembrolizumab 200 mg by IV infusion on Day 8 of Cycle 1 (28-day cycle) and Day 1 of each subsequent 21-day cycle. Gebasaxturev will be administered for up to 8 cycles (up to 6 months). Pembrolizumab will be administered for up to 35 cycles (up to 2 years). arm 2: Participants receive gebasaxturev at a dose of 3 X 10\^8 TCID50 by ITu injection on Days 1, 3, 5, and 8 of Cycle 1 (28-day cycle) and Day 1 of Cycles 2-8 (21-day cycles) plus pembrolizumab 200 mg by IV infusion on Day 8 of Cycle 1 (28-day cycle) and Day 1 of each subsequent 21-day cycle. Gebasaxturev will be administered for up to 8 cycles (up to 6 months). Pembrolizumab will be administered for up to 35 cycles (up to 2 years). arm 3: Participants receive pembrolizumab 200 mg by IV infusion on Day 8 of Cycle 1 (28-day cycle) and Day 1 of each subsequent 21-day cycle. Pembrolizumab will be administered for up to 35 cycles (up to 2 years).

Interventions: intervention 1: Gebasaxturev IV intervention 2: Gebasaxturev ITu intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: Administered as an IV infusion of 1 X 10\^9 TCID50 intervention 2: Administered as an ITu injection of 3 X 10\^8 TCID50 intervention 3: Administered as an IV infusion of 200 mg

Protocol document:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 2, Randomized Clinical Study of 
Intravenous or Intratumoral Administration of V937 
in Combination with Pembrolizumab (MK-3475) 
Versus Pembrolizumab Alone in Participants with 
Advanced/Metastatic Melanoma
NCT04152863
25-October-2022


PRODUCT: V937  
1
PROTOCOL/AMENDMENT NO.: 011-06
V937-011-06 FINAL PROTOCOL
25-OCT-2022
Title Page
THIS PROTOCOL AMENDMENT 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 2, Randomized Clinical Study of Intravenous or Intratumoral 
Administration of V937 in Combination with Pembrolizumab (MK-3475) Versus 
Pembrolizumab Alone in Participants with Advanced/Metastatic Melanoma
Protocol Number: 011-06
Compound Number: V937
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
14547
EudraCT
2019-002034-36
Approval Date: 25 October 2022
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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 6
25-OCT-2022
V937-011 is going to be discontinued due to the Sponsor’s development decision. The 
overall rationale for this amendment is to allow eligible participants who are receiving 
pembrolizumab may be enrolled in a pembrolizumab extension study to continue receiving 
pembrolizumab monotherapy for up to 35 cycles.
Amendment 5
22-JUN-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to Merck 
Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only in an entity name 
change and update to the address.
Amendment 4
23-JUN-2021
To update the dose modification and toxicity management guidelines for irAEs.
Amendment 3
10-DEC-2020
To remove C1D1 collection of blood/serum samples from Arm 3 and all biopsies from 
Arm 3.
Amendment 2
26-AUG-2020
To remove the collection of throat swabs or sputum samples from close contacts or health 
care workers related to viral transmission of V937 from participants, to address Health 
Authority requests, and to provide additional clarifications.
Amendment 1
09-JUL-2020
The overall rationale for this amendment is to change the timing of PBMC collection to 
Day 1 of Cycle 3, and to indicate it is to be performed only at selected study site(s).
Original Protocol
19-JUN-2019
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 06
Overall Rationale for the Amendments:
V937-011 is going to be discontinued due to the Sponsor’s development decision. The overall rationale for this amendment is to allow 
eligible participants who are receiving pembrolizumab may be enrolled in a pembrolizumab extension study to continue receiving 
pembrolizumab monotherapy for up to 35 cycles.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.1 Synopsis – Duration of 
Participation
1.2 Schema
1.3 Schedule of Activities
(SoA)
6.7 Intervention After the 
End of the Study
Language was added to allow eligible 
participants who are ongoing in the study 
to continue to receive treatment for up to 
35 cycles of treatment with 
pembrolizumab or be followed for 
survival through enrollment in a 
pembrolizumab extension study.
These changes will allow this study to be closed.
1.1 Synopsis – Number of 
Participants
1.2 Schema
9.1 Statistical Analysis Plan 
Summary
9.9 Sample Size and Power 
Calculations
Added language indicating the total 
planned enrollment number may not be 
met due to early study discontinuation.
The study may not enroll the planned 135 participants 
due to early study termination.
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Section # and Name
Description of Change 
Brief Rationale 
1.3.2
Schedule of Activities 
for the Treatment Period –
Arm 1 (IV Pembro + IV 
V937)
1.3.3
Schedule of Activities 
for the Treatment Period –
Arm 2 (IV Pembro + ITu
V937)
1.3.4
Schedule of Activities 
for the Treatment Period –
Arm 3 (Pembrolizumab 
Monotherapy)
1.3.5
Schedule of Activities 
for the End of Treatment and 
Posttreatment Follow-up 
Periods
Removed sample collections for 
urinalysis, V937 PK (RNA),
pembrolizumab PK, neutralizing V937
antibodies, antipembrolizumab antibodies, 
blood for ctDNA analysis, biomarker 
analysis, blood for genetic analyses, and 
tumor biopsy.
Due to early study termination, collection of central 
laboratory samples is no longer required.
1.3.5
Schedule of Activities 
for the End of Treatment and 
Posttreatment Follow-up 
Periods
8.10.4 Posttreatment Visit
Removed survival status monitoring and 
columns corresponding to the
“Posttreatment Phase” from SoA.
Added language specifying that the Safety 
Follow-up, Imaging Follow-up and 
Survival Follow-up visits are not required 
upon early study closure.
Due to early study termination, completion of the 30-
day Safety Follow-up visit, posttreatment Imaging 
visits, and Survival Follow-up visits are no longer 
required. Participants deriving benefit from 
pembrolizumab will be given the opportunity to 
transfer to a pembrolizumab extension study, if 
available, upon study closure, and will be monitored 
following the SoA of the pembrolizumab extension 
study.
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Section # and Name
Description of Change 
Brief Rationale 
8.6 Pharmacokinetics
Added statements related to analysis of 
samples if study is terminated early
Update collection information due to early study 
termination.
1.1 Synopsis
6.1 Study Intervention(s) 
Administered
Updated Intervention Groups and 
Duration and Table 7 to reflect proper 
nomenclature for study interventions.
To align with the EU CTR
4.4 Beginning and End of 
Study Definition
New paragraph added for overall study 
end clarification and EEA on local start 
for member states.
To align with the EU CTR
8.4 Adverse Events (AEs), 
Serious Adverse Events 
(SAEs), and Other 
Reportable Safety Events
10.3.1 Definitions of 
Medication Error, Misuse, 
and Abuse
Added language related to investigator 
documenting SAEs related to medication 
error, misuse, abuse, and their definition
Added new section
To align with the EU CTR
8.5 Treatment of Overdose
Removed discontinuation statement in the 
event of overdose
Treatment interruption until AE resolution and then 
resumption is appropriate
10.7 Country-specific 
requirements
Norway
Country-specific criteria has been added 
for ‘Planned Genetic analysis Sample 
Collection’
To clarify country-specific requirement
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Section # and Name
Description of Change 
Brief Rationale 
Throughout Document
Minor administrative, formatting, 
grammatical, and 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 ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................21
1.3
Schedule of Activities (SoA)................................................................................22
1.3.1
Schedule of Activities for Screening ...........................................................22
1.3.2
Schedule of Activities for the Treatment Period – Arm 1 
(IV Pembro + IV V937)...............................................................................25
1.3.3
Schedule of Activities for the Treatment Period – Arm 2 (IV 
Pembro + ITu V937)....................................................................................29
1.3.4
Schedule of Activities for the Treatment Period – Arm 3 
(Pembrolizumab Monotherapy)...................................................................33
1.3.5
Schedule of Activities for the End of Treatment and Posttreatment 
Follow-up Periods........................................................................................36
2
INTRODUCTION..........................................................................................................37
2.1
Study Rationale....................................................................................................38
2.2
Background ..........................................................................................................39
2.2.1
V937 Pharmaceutical and Therapeutic Background....................................39
2.2.2
Pembrolizumab Pharmaceutical and Therapeutic Background ...................40
2.2.3
Preclinical and Clinical Studies ...................................................................41
2.2.4
Ongoing Clinical Studies.............................................................................41
2.2.5
Information on Other Study-related Therapy ..............................................41
2.3
Benefit/Risk Assessment......................................................................................41
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................42
4
STUDY DESIGN............................................................................................................45
4.1
Overall Design......................................................................................................45
4.2
Scientific Rationale for Study Design.................................................................45
4.2.1
Rationale for Endpoints ...............................................................................46
4.2.1.1
Efficacy Endpoints.............................................................................46
4.2.1.2
Safety Endpoints................................................................................47
4.2.1.3
Pharmacokinetic Endpoints ...............................................................47
4.2.1.4
Pharmacodynamic Endpoints.............................................................48
4.2.1.5
Anti-drug Antibodies (ADA).............................................................48
4.2.1.6
Planned Exploratory Biomarker Research.........................................48
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4.2.1.7
Future Biomedical Research..............................................................50
4.2.2
Rationale for the Use of Comparator...........................................................50
4.3
Justification for Dose...........................................................................................50
4.4
Beginning and End of Study Definition .............................................................51
4.4.1
Clinical Criteria for Early Study Termination .............................................52
5
STUDY POPULATION ................................................................................................52
5.1
Inclusion Criteria.................................................................................................52
5.2
Exclusion Criteria................................................................................................56
5.3
Lifestyle Considerations......................................................................................59
5.3.1
Meals and Dietary Restrictions....................................................................59
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................59
5.3.3
Activity Restrictions ....................................................................................59
5.3.4
Contraception...............................................................................................59
5.3.5
Pregnancy.....................................................................................................60
5.3.6
Use in Nursing Women................................................................................60
5.4
Screen Failures.....................................................................................................60
5.5
Participant Replacement Strategy......................................................................60
6
STUDY INTERVENTION............................................................................................60
6.1
Study Intervention(s) Administered...................................................................61
6.1.1
Administration of Pembrolizumab...............................................................64
6.1.2
Administration of V937 (Arms 1 and 2)......................................................64
6.1.2.1
Administration of V937 in Arm 1......................................................64
6.1.2.2
Administration of V937 in Arm 2......................................................64
6.2
Preparation/Handling/Storage/Accountability .................................................65
6.2.1
Dose Preparation..........................................................................................65
6.2.2
Handling, Storage, and Accountability........................................................66
6.3
Measures to Minimize Bias: Randomization and Blinding..............................66
6.3.1
Intervention Assignment..............................................................................66
6.3.2
Stratification.................................................................................................66
6.3.3
Blinding........................................................................................................67
6.4
Study Intervention Compliance..........................................................................67
6.5
Concomitant Therapy..........................................................................................67
6.5.1
Acceptable Concomitant Medications .........................................................67
6.5.2
Prohibited Concomitant Medications ..........................................................67
6.5.3
Rescue Medications and Supportive Care ...................................................68
6.5.3.1
V937 Supportive Care........................................................................68
6.5.3.2
Pembrolizumab Supportive Care.......................................................68
6.6
Dose Modification (Escalation/Titration/Other)...............................................69
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6.6.1
Dose Modification for V937........................................................................69
6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................70
6.7
Intervention After the End of the Study............................................................77
6.8
Clinical Supplies Disclosure................................................................................77
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................77
7.1
Discontinuation of Study Intervention...............................................................77
7.2
Participant Withdrawal From the Study...........................................................79
7.3
Lost to Follow-up .................................................................................................79
8
STUDY ASSESSMENTS AND PROCEDURES........................................................80
8.1
Administrative and General Procedures ...........................................................81
8.1.1
Informed Consent.........................................................................................81
8.1.1.1
General Informed Consent.................................................................81
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................81
8.1.2
Inclusion/Exclusion Criteria ........................................................................82
8.1.3
Participant Identification Card.....................................................................82
8.1.4
Medical History ...........................................................................................82
8.1.5
Disease Details.............................................................................................82
8.1.6
Prior Oncology Treatment History ..............................................................82
8.1.7
Prior and Concomitant Medications Review...............................................82
8.1.7.1
Prior Medications...............................................................................82
8.1.7.2
Concomitant Medications..................................................................83
8.1.8
Assignment of Screening Number...............................................................83
8.1.9
Assignment of Treatment/Randomization Number.....................................83
8.1.10
Study Intervention Administration ..............................................................84
8.1.10.1
Timing of Dose Administration.........................................................84
8.1.11
Discontinuation and Withdrawal .................................................................84
8.1.11.1
Withdrawal From Future Biomedical Research ................................85
8.1.12
Participant Blinding/Unblinding..................................................................85
8.1.13
Calibration of Equipment.............................................................................85
8.2
Efficacy/Immunogenicity Assessments ..............................................................85
8.2.1
Tumor Imaging and Assessment of Disease................................................85
8.2.1.1
Initial Tumor Imaging........................................................................86
8.2.1.2
Tumor Imaging During the Study......................................................86
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging............................87
8.2.1.4
RECIST 1.1 Assessment of Disease..................................................87
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8.2.1.5
iRECIST Assessment of Disease.......................................................87
8.2.2
Eastern Cooperative Oncology Group Performance Scale..........................90
8.3
Safety Assessments...............................................................................................90
8.3.1
Physical Examinations.................................................................................91
8.3.1.1
Full Physical Examination.................................................................91
8.3.1.2
Directed Physical Examination..........................................................91
8.3.2
Vital Signs....................................................................................................91
8.3.3
Electrocardiograms ......................................................................................91
8.3.4
Clinical Safety Laboratory Assessments .....................................................91
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)..........................................................................................92
8.3.4.2
Pregnancy Test...................................................................................92
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................92
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................93
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......95
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...95
8.4.4
Regulatory Reporting Requirements for SAE .............................................95
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................95
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................96
8.4.7
Events of Clinical Interest (ECIs)................................................................96
8.5
Treatment of Overdose........................................................................................96
8.6
Pharmacokinetics.................................................................................................97
8.6.1
Blood Collection for V937 and Pembrolizumab .........................................97
8.6.1.1
Blood Collection for PK ....................................................................97
8.6.1.2
Blood Collection for Neutralizing V937 Antibodies and 
Antipembrolizumab Antibodies.........................................................97
8.7
Pharmacodynamics..............................................................................................97
8.7.1
Blood for Pharmacodynamic Markers.........................................................97
8.7.2
Tumor Biopsy ..............................................................................................97
8.8
Biomarkers ...........................................................................................................98
8.8.1
Planned Genetic Analysis Sample Collection..............................................98
8.9
Future Biomedical Research Sample Collection...............................................98
8.10
Visit Requirements...............................................................................................99
8.10.1
Screening......................................................................................................99
8.10.2
Treatment Period/Vaccination Visit ............................................................99
8.10.3
Discontinued Participants Continuing to be Monitored in the Study ........100
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8.10.4
Posttreatment Visit.....................................................................................100
8.10.4.1
Safety Follow-up Visit.....................................................................100
8.10.4.2
Follow-up Visits...............................................................................100
8.10.4.3
Survival Follow-up Contacts ...........................................................100
8.10.5
Survival Status ...........................................................................................101
9
STATISTICAL ANALYSIS PLAN ...........................................................................101
9.1
Statistical Analysis Plan Summary...................................................................102
9.2
Responsibility for Analyses/In-house Blinding ...............................................103
9.3
Hypotheses/Estimation ......................................................................................103
9.4
Analysis Endpoints.............................................................................................103
9.4.1
Efficacy/Pharmacokinetics/Pharmacodynamic Endpoints ........................103
9.4.2
Safety Endpoints........................................................................................104
9.5
Analysis Populations..........................................................................................104
9.5.1
Efficacy Analysis Population.....................................................................104
9.5.2
Pharmacokinetic Analysis Population .......................................................104
9.5.3
Safety Analysis Population........................................................................105
9.6
Statistical Methods.............................................................................................105
9.6.1
Statistical Methods for Efficacy Analyses.................................................105
9.6.1.1
Objective Response..........................................................................105
9.6.1.2
Progression-free Survival.................................................................105
9.6.1.3
Overall Survival...............................................................................106
9.6.1.4
Duration of Response.......................................................................106
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints................................107
9.6.2
Statistical Methods for Safety Analyses ....................................................108
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analysis......................................................................................................110
9.6.3.1
Demographic and Baseline Characteristics .....................................110
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis..........110
9.7
Interim Analyses ................................................................................................110
9.8
Multiplicity .........................................................................................................111
9.9
Sample Size and Power Calculations ...............................................................111
9.10
Subgroup Analyses.............................................................................................112
9.11
Compliance (Medication Adherence)...............................................................113
9.12
Extent of Exposure.............................................................................................113
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................114
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......114
10.1.1
Code of Conduct for Clinical Trials...........................................................114
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10.1.2
Financial Disclosure...................................................................................116
10.1.3
Data Protection...........................................................................................116
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..........................................117
10.1.4
Committees Structure.................................................................................117
10.1.5
Publication Policy......................................................................................117
10.1.6
Compliance with Study Registration and Results Posting Requirements .118
10.1.7
Compliance with Law, Audit, and Debarment ..........................................118
10.1.8
Data Quality Assurance .............................................................................119
10.1.9
Source Documents .....................................................................................120
10.1.10
Study and Site Closure...............................................................................120
10.2
Appendix 2: Clinical Laboratory Tests............................................................121
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................123
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................123
10.3.2
Definition of AE ........................................................................................123
10.3.3
Definition of SAE ......................................................................................124
10.3.4
Additional Events Reported in the Same Manner as SAE.........................125
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: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................131
10.5
Appendix 5: Contraceptive Guidance..............................................................132
10.5.1
Definitions..................................................................................................132
10.5.2
Contraception Requirements......................................................................133
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................134
10.7
Appendix 7: Country-specific Requirements..................................................139
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................143
10.9
Appendix 9: Abbreviations ...............................................................................147
11
REFERENCES.............................................................................................................149
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LIST OF TABLES
Table 1
Study Schedule of Activities for Screening.....................................................22
Table 2
Study Schedule of Activities for the Treatment Period – Arm 1 (IV 
Pembro + IV V937) .........................................................................................25
Table 3
Study Schedule of Activities for the Treatment Period – Arm 2 (IV 
Pembro + ITu V937)........................................................................................29
Table 4
Study Schedule of Activities for the Treatment Period – Arm 3 (IV 
Pembro Alone).................................................................................................33
Table 5
Study Schedule of Activities for the End of Treatment and Posttreatment 
Follow-up Periods............................................................................................36
Table 6
Adequate Organ Function Laboratory Values .................................................53
Table 7
Study Interventions..........................................................................................62
Table 8
Determination of Minimum Target Lesion Diameter at Treatment 
Initiation by Dose Level...................................................................................65
Table 9
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...............................................................71
Table 10
Pembrolizumab and V937 Infusion Reaction Dose Modification and 
Treatment Guidelines.......................................................................................76
Table 11
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease.............................................................................................................89
Table 12
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................94
Table 13
Censoring Rules for Duration of Response ...................................................107
Table 14
Analysis Strategy for Key Efficacy Variables...............................................107
Table 15
Analysis Strategy for Safety Parameters........................................................109
Table 16
Power Analysis Under Varying Assumptions of ORR for Combination 
Arms...............................................................................................................112
Table 17
The 95% and 80% CI of the True ORR Under Different Scenarios of 
Response ........................................................................................................112
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PRODUCT: V937  
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LIST OF FIGURES
Figure 1
Study Schema...................................................................................................21
Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator ......................................................................................................90
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PRODUCT: V937  
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2, Randomized Clinical Study of Intravenous or Intratumoral 
Administration of V937 in Combination with Pembrolizumab (MK-3475) Versus 
Pembrolizumab Alone in Participants with Advanced/Metastatic Melanoma
Short Title: Phase 2 Randomized Study of V937 Administered IV or ITu with 
Pembrolizumab Versus Pembrolizumab Alone
Acronym: Not applicable.
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Throughout this protocol, the term RECIST 1.1 refers to modification to RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ.
In males and females with advanced/metastatic melanoma who are antiprogrammed cell 
death (ligand) 1 [anti-PD-(L)1]-treatment-naïve:
Primary Objectives
Primary Endpoints
- Objective: To evaluate the objective 
response rate (ORR) of participants 
treated with IV V937 administered in 
combination with pembrolizumab, 
ITu V937 administered in combination 
with pembrolizumab, or pembrolizumab 
alone per Response Evaluation Criteria in 
Solid Tumors Version 1.1 (RECIST 1.1) 
by blinded independent central 
review (BICR).
- Hypothesis: V937 administered either IV 
in combination with pembrolizumab or 
ITu in combination with pembrolizumab 
results in a superior ORR per RECIST 1.1 
based on BICR, compared to 
pembrolizumab alone.
- Objective response is a confirmed 
complete response (CR) or partial 
response (PR)
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PRODUCT: V937  
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Secondary Objectives
Secondary Endpoints
- To evaluate progression free 
survival (PFS), and duration of 
response (DOR) of participants treated 
with IV V937 in combination with 
pembrolizumab, ITu V937 in combination 
with pembrolizumab, or pembrolizumab 
alone per RECIST 1.1 by blinded 
independent central review (BICR).
- PFS, defined as the time from 
randomization to the first documented 
progressive disease (PD) or death from 
any cause, whichever occurs first.
- DOR, defined as the time from the first 
documented evidence of CR or PR until 
progressive disease (PD) or death due to 
any cause, whichever occurs first, in 
participants demonstrating CR or PR
- To evaluate ORR, PFS, and DOR of 
participants treated with IV V937 in 
combination with pembrolizumab, 
ITu V937 in combination with 
pembrolizumab, or pembrolizumab alone, 
per RECIST 1.1, as assessed by the 
investigator.
- Objective response
- PFS
- DOR
- To evaluate OS of participants treated with 
IV V937 in combination with 
pembrolizumab, ITu V937 in combination 
with pembrolizumab, or pembrolizumab 
alone.
- OS, defined as the time from 
randomization to the date of death from 
any cause
- Objective: To assess the safety and 
tolerability of participants treated with 
IV V937 in combination with 
pembrolizumab, ITu V937 in combination 
with pembrolizumab, or pembrolizumab 
alone. 
- Adverse events (AEs)
- Discontinuing study intervention due to an 
AE
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
The treatment of participants with advanced/metastatic
melanoma
Population
Participants with histologically or cytologically confirmed 
advanced/metastatic melanoma by pathology report who 
have not received PD-(L)1 antibody.
Study Type
Interventional
Intervention Model
Parallel
This is a multi-site study.
Type of Control
Active comparator
Study Blinding
Unblinded Open-label
Masking
No Masking
Estimated Duration of Study
The Sponsor estimates that the study will require 
approximately 3 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 135 participants will be randomly assigned in a 1:1:1 ratio to the following 
intervention arms: Arm 1 (IV pembro + IV V937); Arm 2 (IV pembro + ITu V937); Arm 3 
(IV pembro alone).
Due to early termination of this study, the total enrollment number may be less than 135 
participants.
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Intervention Groups and Duration:
Intervention 
Groups
Inter-
vention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Arm 1
V937a
1 X 109
TCID50
q2d in 
Cycle 1 
(4 doses); 
then q3w
IV infusion
Days 1, 3, 5, and 
8 of Cycle 1
(28-day cycle); 
Day 1 of 
Cycles 2-8 
(21-day cycles)
Test 
Product
pembro-
lizumab
200 mg
q3w
IV infusion
Day 8 of Cycle 1 
(28-day cycle)
Day 1 of each 
subsequent 
21-day cycle
Arm 2
V937 a
3 X 108
TCID50
q2d in
Cycle 1 
(4 doses); 
then q3w
ITu
administration via 
visual inspection 
for cutaneous 
lesions, and via 
ultrasound 
guidance for 
subcutaneous 
lesions, as needed
Days 1, 3, 5, 
and 8 of Cycle 
1 (28-day 
cycle); Day 1 
of Cycles 2-8 
(21-day cycles)
Test 
Product
pembro-
lizumab
200 mg
q3w
IV infusion
Day 8 of 
Cycle 1 
(28-day cycle)
Day 1 of each 
subsequent 
21-day cycle
Arm 3
pembro-
lizumab
200 mg
q3w
IV infusion
Day 8 of 
Cycle 1 
(28-day cycle)
Day 1 of each 
subsequent 
21-day cycle
SoC
a In Arms 1 and 2, V937 will be administered within 0.5-4 h following completion of 
pembrolizumab IV infusion.
ITu=intratumoral; IV=intravenous; q2d=every 2 days; q3w=every 3 weeks; SoC=standard of care; 
TCID50=50% tissue culture infectious dose.
Other current or former name(s) or alias(es) for study intervention(s) are as 
follows: V937: Coxsackievirus A21 (CVA21); CAVATAK®; CAV21.
Total 
Number
3 arms
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Duration of 
Participation
Each participant will participate in the study for approximately 2 years 
from the time the participant provides documented informed consent 
through the final contact. After a screening phase of up to 28 days, each 
participant will be receiving assigned intervention for up to approximately 
2 years.
Each participant will participate in the study from the time the participant 
signs the Informed Consent Form (ICF) through the final protocol-
specified contact.
After a screening phase of up to 28 days, each participant will be assigned 
to receive study intervention until disease progression is radiographically 
documented, confirmed by the site per modified Response Evaluation 
Criteria in Solid Tumors 1.1 for immune-based therapeutics (iRECIST),
when clinically appropriate, unacceptable adverse event(s) (AEs), 
intercurrent illness that prevents further administration of treatment, 
investigator’s decision to discontinue the participant, or administrative 
reasons requiring cessation of treatment, or until the participant has 
received 35 administrations of pembrolizumab (approximately 2 years). 
Participants will receive up to 8 cycles (11 administrations) of V937, 
unless any of the above apply.
After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy as described 
under Section 8.4.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status 
until disease progression is documented radiographically per RECIST 1.1,   
and when clinically appropriate, confirmed by the site per iRECIST (for 
participants treated with pembrolizumab), the start of a new anti-cancer 
treatment, withdrawal of consent, pregnancy, death, or loss to follow-up. 
All participants will be followed by telephone for overall survival until 
death, withdrawal of consent, or the end of the study.
Due to discontinuation of V937-011, participants who have completed or 
discontinued V937 treatment and are only receiving pembrolizumab may 
be enrolled in a pembrolizumab extension study, if available, to continue 
pembrolizumab monotherapy for up to 35 cycles from first pembrolizumab 
dose on V937-011 and to be monitored per the extension study as 
appropriate.
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 9.
1.2
Schema
The study design is depicted in Figure 1. Due to discontinuation of V937-011, participants 
who have completed or discontinued V937 treatment and are only receiving pembrolizumab 
may be enrolled in a pembrolizumab extension study, if available, to continue 
pembrolizumab monotherapy for up to 35 cycles from first pembrolizumab dose on V937-
011 and to be monitored per the extension study as appropriate. Due to early study 
termination of this study, the total enrollment number may be less than 135 participants.
Figure 1
Study Schema
C=cycle; D=day; IV=intravenous; ORR=objective response rate; PD-(L)1=programmed cell death (ligand) 1; 
RECIST=Response Evaluation Criteria in Solid Tumors, version 1.1; TCID50=50% tissue culture infectious dose.
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1.3
Schedule of Activities (SoA)
It should be noted that there are variations to certain sections within the protocol that are based on country-specific regulations. These 
variations are organized by country and addressed in Appendix 7.
Due to discontinuation of V937-011, participants who have completed or discontinued V937 treatment and are only receiving 
pembrolizumab may be enrolled in a pembrolizumab extension study, if available, to continue pembrolizumab monotherapy for up to 
35 cycles from first pembrolizumab dose on V937-011 and to be monitored per the extension study as appropriate.
1.3.1
Schedule of Activities for Screening
Table 1
Study Schedule of Activities for Screening
Study Period
Screening
Notes
Visit Days
-28 to -1
Administrative Procedures
Informed Consent
X
Documented informed consent must be obtained prior to performing any protocol-specific procedures. Tests 
performed prior to consent as part of routine clinical management are acceptable if performed within the 
specified timeframe.
Informed Consent for Future Biomedical Research 
(FBR) (Optional)
X
Consent for FBR is not required to participate in the study. Any leftover biomarker samples will be stored for
FBR if the participant (or their legally acceptable representative) provides documented informed consent for FBR. 
Detailed instructions for the collection and management of FBR specimens are provided in the Procedures 
Laboratory Manual. This is optional for the participant.
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
Add the allocation or randomization number at the time of allocation or randomization.
Demographics and Medical History
X
Oncology Disease Status and Prior Oncology 
Treatment History
X
Mutational Status / Tumor Genetic
Alteration(s)
X
Tumor genetic alteration(s) per standard of care, by history if available, as determined by local testing 
results.
Prior Medication
X
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Study Period
Screening
Notes
Visit Days
-28 to -1
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1 Response Assessment
X
Baseline tumor imaging (CT or MRI as indicated for tumor type) and/or medical photography of cutaneous 
lesions should be performed within 28 days of enrollment. Please refer to Imaging Manual for detailed 
information. 
Medical Photography (Cutaneous Lesions)
X
Brain Imaging
X
Participants with previously treated brain metastases must undergo brain imaging within 28 days prior to the 
first dose of study treatment, with local confirmation that no new or untreated brain metastases are present.
Physical Examination
X
A full physical examination should be done at screening. 
Height
X
Weight
X
Vital Signs
X
Includes temperature, pulse, respiratory rate, and blood pressure.
ECOG Performance Status
X
To be performed within 72 h prior to dosing.
12-Lead Electrocardiogram
X
AE Monitoring
X
All AEs that occur after the consent form is signed but before treatment allocation must be reported by the 
investigator if the event causes the participant to be excluded from the study or is the result of a 
protocol-specified intervention. There is to be continuous AE reporting from the time of treatment 
allocation.
Laboratory Procedures/Assessments - LOCAL
CBC with Differential
X
Perform all screening clinical laboratory tests within 72 h of treatment initiation with the exception of
thyroid and hepatitis testing.
Participants on anticoagulant therapy should be monitored throughout the study.
Thyroid function: Total T4 and T3 are preferred over FT4 and FT3.
Chemistry Panel
X
PT/INR and PTT or aPTT
X
LDH, AST, ALT
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
Urinalysis
X
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Study Period
Screening
Notes
Visit Days
-28 to -1
Pregnancy test for WOCBP only (urine or serum hCG)
X
Perform within 72 h prior to C1D1. Urine pregnancy test to be performed as indicated; if test is positive or 
cannot be confirmed as negative, a serum pregnancy test is required. Additional pregnancy testing can be 
conducted if required by local regulations or if clinically indicated.
HIV, Hepatitis B and C Screen
X
Acceptable to be based on history unless testing is required by local regulation. Include HCV antibody or 
HCV RNA (qualitative) and HBsAg. No testing for Hepatitis B and Hepatitis C is required unless mandated 
by local health authority.
AE=adverse event; aPTT=activated partial thromboplastin time; ALT=alanine aminotransferase; AST=aspartate aminotransferase; C=Cycle; CBC=complete blood count; 
CT=computed tomography; D=Day; ECOG=Eastern Cooperative Oncology Group; FBR=future biomedical research; F=free; HBsAg=hepatitis B surface antigen; hCG=human 
chorionic gonadotropin; HCV=hepatitis C virus; HIV=human immunodeficiency virus; INR=International Normalized Ratio; LDH=lactate dehydrogenase; MRI=magnetic 
resonance imaging; PT=prothrombin time; PTT=partial thromboplastin time; RECIST 1.1=Response Evaluation Criteria in Solid Tumors, version 1.1; RNA=ribonucleic acid; 
T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential.
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PRODUCT: V937  
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1.3.2
Schedule of Activities for the Treatment Period – Arm 1 (IV Pembro + IV V937)
Table 2
Study Schedule of Activities for the Treatment Period – Arm 1 (IV Pembro + IV V937)
Study Period
Treatment Period
Notes
Visit Timing
Cycle 1
(28 days)
Cycle 2-8
(21 days)
Cycles ≥9
(21 days)
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 8 cycles (ie, 11 doses) of 
treatment with V937. Cycle 1 is 28 days and all 
subsequent cycles are 21 days.
Visit Day (Days)
1
3
5
8
1
1
Visit Window
±0
±1
±1
±1
+3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Intervention Randomization
X
Randomization can occur up to 3 days prior to 
C1D1. 
Participant Identification Card
X
Participant identification card to be updated with 
treatment number at the time of treatment 
randomization.
Pembrolizumab Administration
X
X
X
For the first 4 doses of V937, a window of 24 h for 
dosing will be allowed to accommodate weekends.
In Cycle 2, study treatment may be administered up 
to 3 days after the scheduled Day 1. Beginning in 
Cycle 3, study treatments may be administered up 
to 3 days before or after the scheduled Day 1. For 
Cycles 2-8, V937 will be infused IV over 30 min at 
0.5 to 4 h after a 200-mg dose of pembrolizumab 
infused over 30 min. For administration details, see 
Pharmacy Manual.
V937 Administration
X
X
X
X
X
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Study Period
Treatment Period
Notes
Visit Timing
Cycle 1
(28 days)
Cycle 2-8
(21 days)
Cycles ≥9
(21 days)
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 8 cycles (ie, 11 doses) of 
treatment with V937. Cycle 1 is 28 days and all 
subsequent cycles are 21 days.
Visit Day (Days)
1
3
5
8
1
1
Visit Window
±0
±1
±1
±1
+3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1, and 
iRECIST Response Assessment
Tumor imaging (CT or MRI) as indicated for tumor 
type and/or medical photography of cutaneous 
lesions should be performed every 9 weeks 
(± 7 days) after the first dose of pembrolizumab for 
the first 54 weeks then every 12 weeks thereafter, 
following calendar days, and should not be 
adjusted for delays in cycle starts. Continue 
imaging schedule until disease progression, 
discontinuation, or the start of new anticancer 
treatment.
Please refer to Imaging Manual for detailed 
information on medical photography.
Medical Photography (Cutaneous Lesions)
Physical Examination
X
X
X
X
X
X
Directed physical examinations may be performed 
unless a full examination is deemed necessary. To 
be performed on Days 1, 3, 5, and 8 of Cycle 1; on 
Day 1 of every cycle thereafter.
Weight
X
X
X
Every other cycle (ie, Cycles 1, 3, 5, 7, 9, etc.).
Vital Signs
(temperature, pulse, respiratory rate, 
and blood pressure)
X
X
X
X
X
X
To be measured within 1 h (± 30 min) prior to 
dosing of V937, and 2, 4, and 6 h (± 30 min for 
each timepoint) after V937 administration in 
Cycle 1. For Cycle 2 to Cycle 8, to be measured 
within 1 h (± 30 min) prior to dosing of V937, and 
2 and 4 h (± 30 min for each timepoint) after V937 
administration. For Cycle 9 and beyond, to be 
measured within 1 h (± 30 min) prior to dosing with 
pembrolizumab on Day 1 of every cycle.
ECOG Performance Status
X
X
X
Performed within 72 h prior to V937 dosing on 
Day 1 of each cycle.
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Study Period
Treatment Period
Notes
Visit Timing
Cycle 1
(28 days)
Cycle 2-8
(21 days)
Cycles ≥9
(21 days)
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 8 cycles (ie, 11 doses) of 
treatment with V937. Cycle 1 is 28 days and all 
subsequent cycles are 21 days.
Visit Day (Days)
1
3
5
8
1
1
Visit Window
±0
±1
±1
±1
+3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Concomitant Medication
X
X
X
X
X
X
AEs
Continuous AE reporting from the time of treatment 
allocation.
Survival Status
Upon Sponsor request, participants may be 
contacted for survival status at any time during the 
course of the study.
Laboratory Procedures/Assessments – LOCAL
CBC with Differential
X
X
X
X
Perform all scheduled clinical laboratory tests 
within 72 h prior to the start of each cycle. 
Screening procedures/sample collections done 
within this time frame do not need to be repeated 
for the Cycle 1, Day 1 timepoint.
For PT/INR/PTT/aPTT: Only as clinically indicated 
Participants on anticoagulant therapy should be 
monitored throughout the study. 
Thyroid function: After Cycle 1, samples are 
collected every other cycle (ie, Cycles 2, 4, 6, etc.). 
Total T4 and T3 are preferred over FT4 and FT3.
The participant may be dosed while thyroid 
function tests are pending.
Chemistry Panel
X
X
X
X
PT/INR and PTT or aPTT
X
X
X
LDH, AST, ALT
X
X
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
X
X
PBMC Collection
X
Optional collection on C3D1 to be performed at 
selected study site(s) in the US only.
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Study Period
Treatment Period
Notes
Visit Timing
Cycle 1
(28 days)
Cycle 2-8
(21 days)
Cycles ≥9
(21 days)
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 8 cycles (ie, 11 doses) of 
treatment with V937. Cycle 1 is 28 days and all 
subsequent cycles are 21 days.
Visit Day (Days)
1
3
5
8
1
1
Visit Window
±0
±1
±1
±1
+3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Pregnancy test for WOCBP only (urine or 
serum hCG)
X
X
Perform within 72 h prior to C1D1. Urine 
pregnancy test to be performed as indicated; if test 
is positive or cannot be confirmed as negative, a 
serum pregnancy test is required. Additional 
pregnancy testing can be conducted if required by 
local regulations or clinically indicated.
AE=adverse event; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; C=Cycle; CBC=complete blood count;
CT=computed tomography; Ctrough=trough concentration; D=Day; ECOG=Eastern Cooperative Oncology Group; F=free; hCG=human chorionic gonadotropin; INR=International 
Normalized Ratio; iRECIST=modified RECIST 1.1 for immune-based therapeutics; IV=intravenous; LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; 
PBMC=peripheral blood mononuclear cells; PT=prothrombin time; PTT=partial thromboplastin time; RECIST 1.1=Response Evaluation Criteria in Solid Tumors, version 1.1; 
T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential.
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1.3.3
Schedule of Activities for the Treatment Period – Arm 2 (IV Pembro + ITu V937)
Table 3
Study Schedule of Activities for the Treatment Period – Arm 2 (IV Pembro + ITu V937)
Study Period
Treatment Period
Notes
Visit Timing
Cycle 1
(28 days)
Cycle 2-8
(21 days)
Cycles ≥9
(21 days)
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 8 cycles (ie, 11 doses) of 
treatment with V937. Cycle 1 is 28 days and all 
subsequent cycles are 21 days.
Visit Day (Days)
1
3
5
8
1
1
Visit Window
±0
±1
±1
±1
+3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Intervention Randomization
X
Randomization can occur up to 3 days prior to 
C1D1.
Participant Identification Card
X
Participant identification card to be updated with 
treatment number at the time of treatment 
randomization.
Pembrolizumab Administration
X
X
X
For the first 4 doses of V937, a window of 24 h for 
dosing will be allowed to accommodate weekends.
In Cycle 2, study treatment may be administered up 
to 3 days after the scheduled Day 1. Beginning in 
Cycle 3, study treatments may be administered up 
to 3 days before or after the scheduled Day 1. For 
Cycles 2-8, V937 will be injected ITu 0.5 to 4 h
after a 200-mg dose of pembrolizumab infused over 
30 min. For administration details, see Pharmacy 
Manual.
V937 Administration
X
X
X
X
X
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Study Period
Treatment Period
Notes
Visit Timing
Cycle 1
(28 days)
Cycle 2-8
(21 days)
Cycles ≥9
(21 days)
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 8 cycles (ie, 11 doses) of 
treatment with V937. Cycle 1 is 28 days and all 
subsequent cycles are 21 days.
Visit Day (Days)
1
3
5
8
1
1
Visit Window
±0
±1
±1
±1
+3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1, and 
iRECIST Response Assessment
Tumor imaging (CT or MRI) as indicated for tumor 
type and/or medical photography of cutaneous 
lesions should be performed every 9 weeks 
(± 7 days) after the first dose of pembrolizumab for 
the first 54 weeks then every 12 weeks thereafter, 
following calendar days, and should not be 
adjusted for delays in cycle starts. Continue 
imaging schedule until disease progression, 
discontinuation, or the start of new anticancer 
treatment.
Please refer to Imaging Manual for detailed 
information on medical photography.
Medical Photography (Cutaneous Lesions)
Physical Examination
X
X
X
X
X
X
Directed physical examinations may be performed 
unless a full examination is deemed necessary. To 
be performed on Days 1, 3, 5, and 8 of Cycle 1; on 
Day 1 of every cycle thereafter.
Weight
X
X
X
Every other cycle (ie, Cycles 1, 3, 5, 7, 9, etc.).
Vital Signs
(temperature, pulse, respiratory rate, 
and blood pressure)
X
X
X
X
X
X
To be measured within 1 h (± 30 min) prior to 
dosing of V937, and 2, 4, and 6 h (± 30 min for 
each time point) after V937 administration in 
Cycle 1. For Cycle 2 to Cycle 8, to be measured 
within 1 h (± 30 min) prior to dosing of V937, and 
2 and 4 h (± 30 min for each time point) after V937 
administration. For Cycle 9 and beyond, to be 
measured within 1 h (± 30 min) prior to dosing 
with pembrolizumab on Day 1 of every cycle.
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Study Period
Treatment Period
Notes
Visit Timing
Cycle 1
(28 days)
Cycle 2-8
(21 days)
Cycles ≥9
(21 days)
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 8 cycles (ie, 11 doses) of 
treatment with V937. Cycle 1 is 28 days and all 
subsequent cycles are 21 days.
Visit Day (Days)
1
3
5
8
1
1
Visit Window
±0
±1
±1
±1
+3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
ECOG Performance Status
X
X
X
Performed within 72 h prior to V937 dosing on 
Day 1 of each cycle.
Concomitant Medication
X
X
X
X
X
X
AEs
Continuous AE reporting from the time of 
treatment allocation.
Survival Status
Upon Sponsor request, participants may be 
contacted for survival status at any time during the 
course of the study.
Laboratory Procedures/Assessments – LOCAL
CBC with Differential
X
X
X
X
Perform all scheduled clinical laboratory tests 
within 72 h prior to the start of each cycle. 
Screening procedures/sample collections done 
within this time frame do not need to be repeated 
for the Cycle 1, Day 1 timepoint.
For PT/INR/PTT/aPTT: Only as clinically 
indicated Participants on anticoagulant therapy
should be monitored throughout the study. 
Thyroid function: After Cycle 1, samples are 
collected every other cycle (ie, Cycles 2, 4, 6, 
etc.). Total T4 and T3 are preferred over FT4 and 
FT3. The participant may be dosed while thyroid 
function tests are pending.
Chemistry Panel
X
X
X
X
PT/INR and PTT or aPTT
X
X
X
LDH, AST, ALT
X
X
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
X
X
PBMC Collection
X
Optional collection on C3D1 to be performed at 
selected study site(s) in the US only.
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Study Period
Treatment Period
Notes
Visit Timing
Cycle 1
(28 days)
Cycle 2-8
(21 days)
Cycles ≥9
(21 days)
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 8 cycles (ie, 11 doses) of 
treatment with V937. Cycle 1 is 28 days and all 
subsequent cycles are 21 days.
Visit Day (Days)
1
3
5
8
1
1
Visit Window
±0
±1
±1
±1
+3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Pregnancy test for WOCBP only (urine or 
serum hCG)
X
Perform within 72 h prior to C1D1. Urine 
pregnancy test to be performed as indicated; if test 
is positive or cannot be confirmed as negative, a 
serum pregnancy test is required. Additional 
pregnancy testing can be conducted if required by 
local regulations or clinically indicated.
AE=adverse event; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; C=Cycle; CBC=complete blood count; 
CT=computed tomography; Ctrough=trough concentration; D=Day; ECOG=Eastern Cooperative Oncology Group; F=free; hCG=human chorionic gonadotropin; INR=International 
Normalized Ratio; iRECIST=modified RECIST 1.1 for immune-based therapeutics; ITu=intratumoral; IV=intravenous; LDH=lactate dehydrogenase; MRI=magnetic resonance 
imaging; PBMC=peripheral blood mononuclear cells; PT=prothrombin time; PTT=partial thromboplastin time; RECIST 1.1=Response Evaluation Criteria in Solid Tumors, 
version 1.1; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential.
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1.3.4
Schedule of Activities for the Treatment Period – Arm 3 (Pembrolizumab Monotherapy)
Table 4
Study Schedule of Activities for the Treatment Period – Arm 3 (IV Pembro Alone)
Study Period
Treatment Period
Notes
Visit Timing
Cycle 1
(28 days)
Cycles 2-8
(21 days)
Cycles ≥9
(21 days)
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab. Cycle 1 is 28 days and all 
subsequent cycles are 21 days.
Visit Day (Days)
1
3
5
8
1
1
Visit Window
±0
±1
±1
±1
+3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Intervention Randomization
X
Randomization can occur up to 3 days prior to 
C1D1.
Participant Identification Card
X
Participant identification card to be updated with 
treatment number at the time of treatment 
randomization.
Pembrolizumab Administration
X
X
X
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1, and 
iRECIST Response Assessment
Tumor imaging (CT or MRI) and/or medical 
photography of cutaneous lesions should be 
performed every 9 weeks (± 7 days) after the first 
dose for the first 54 weeks then every 12 weeks 
thereafter, following calendar days, and should not 
be adjusted for delays in cycle starts. Continue 
imaging schedule until disease progression, 
discontinuation, or the start of new anticancer 
treatment.
Please refer to Imaging Manual for detailed 
information on medical photography.
Medical Photography (Cutaneous Lesions)
Physical Examination
X
X
X
Directed physical examinations may be performed 
unless a full examination is deemed necessary. To 
be performed on Day 8 of Cycle 1 and Day 1 of 
every cycle thereafter.
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Study Period
Treatment Period
Notes
Visit Timing
Cycle 1
(28 days)
Cycles 2-8
(21 days)
Cycles ≥9
(21 days)
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab. Cycle 1 is 28 days and all 
subsequent cycles are 21 days.
Visit Day (Days)
1
3
5
8
1
1
Visit Window
±0
±1
±1
±1
+3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Weight
X
X
X
Every other cycle (ie, Cycles 1, 3, 5, 7, 9, etc.).
Vital Signs
(temperature, pulse, respiratory rate, 
and blood pressure)
X
X
X
To be measured within 1 h (± 30 min) prior to 
dosing with pembrolizumab on C1D8 and Day 1 of 
each subsequent cycle.
ECOG Performance Status
X
X
X
Performed within 72 h prior to dosing with 
pembrolizumab on C1D8 and Day 1 of each 
subsequent cycle.
Concomitant Medication
X
X
X
X
AEs
Continuous AE reporting from the time of treatment 
allocation.
Survival Status
Upon Sponsor request, participants may be 
contacted for survival status at any time during the 
course of the study.
Laboratory Procedures/Assessments - LOCAL
CBC with Differential
X
X
X
Perform all scheduled clinical laboratory tests within 
72 h prior to the start of dosing in each cycle. 
Screening procedures/sample collections done 
within this time frame do not need to be repeated for 
the Cycle 1, Day 8 time point.
Chemistry Panel
X
X
X
PT/INR and PTT or aPTT
X
X
X
LDH, AST, ALT
X
X
X
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Study Period
Treatment Period
Notes
Visit Timing
Cycle 1
(28 days)
Cycles 2-8
(21 days)
Cycles ≥9
(21 days)
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab. Cycle 1 is 28 days and all 
subsequent cycles are 21 days.
Visit Day (Days)
1
3
5
8
1
1
Visit Window
±0
±1
±1
±1
+3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
X
X
For PT/INR/PTT/aPTT: Only as clinically indicated 
Participants on anticoagulant therapy should be 
monitored throughout the study. 
Thyroid function: After Cycle 1, samples are 
collected every other cycle (ie, Cycles 2, 4, 6, etc.). 
Total T4 and T3 are preferred over FT4 and FT3.
The participant may be dosed while thyroid 
function tests are pending.
PBMC Collection
X
Optional collection on C3D1 to be performed at 
selected study site(s) in the US only.
Pregnancy test for WOCBP only (urine or 
serum hCG)
X
Perform within 72 h prior to C1D8. Urine pregnancy 
test to be performed as indicated; if test is positive 
or cannot be confirmed as negative, a serum 
pregnancy test is required. Additional pregnancy 
testing can be conducted if required by local 
regulations or clinically indicated.
AE=adverse event; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; C=Cycle; CBC=complete blood count; 
CT=computed tomography; Ctrough=trough concentration; D=Day; ECOG=Eastern Cooperative Oncology Group; F=free; hCG=human chorionic gonadotropin; 
INR=International Normalized Ratio; iRECIST IV=intravenous; LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; PBMC=peripheral blood mononuclear cells; 
PT=prothrombin time; PTT=partial thromboplastin time; RECIST 1.1=Response Evaluation Criteria in Solid Tumors, version 1.1; T3=triiodothyronine; T4=thyroxine; 
TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential.
Samples to be collected on C1D1 “predose” and “postdose” are to be calculated relative to an arbitrary timepoint as there is no dosing of pembrolizumab on C1D1. Samples will 
provide an untreated, controlled set to assess variability without treatment.
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1.3.5
Schedule of Activities for the End of Treatment and Posttreatment Follow-up Periods
Table 5
Study Schedule of Activities for the End of Treatment and Posttreatment Follow-up Periods
Study Period
End of Treatment/ 
Discontinuation
Notes
Visit Timing
Visit Window (Days)
±7
Administrative Procedures
Concomitant Medication
X
Efficacy Procedures
See Imaging Manual – All imaging visits have a ± 7-day window
Tumor Imaging, RECIST 1.1, and iRECIST Response Assessment 
X
Medical Photography (Cutaneous Lesions) 
X
New Anticancer Therapy Status
X
Safety Assessments and Procedures
See Procedures Manual for collection and management of samples.
AE Monitoring
X
Full Physical Examination 
X
Weight
X
Vital Signs
X
Temperature, pulse, respiratory rate, and blood pressure
ECOG Performance Status 
X
CBC with Differential 
X
Chemistry Panel 
X
AE=adverse event; CBC=complete blood count; ECOG=Eastern Cooperative Oncology Group; iRECIST=immune-based RECIST; LDH=lactate dehydrogenase; RECIST 
1.1=Response Evaluation Criteria In Solid Tumors version 1.1; 
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2
INTRODUCTION
Significant progress has been made in the field of immunotherapy to treat cancer. Antibodies 
targeting immune checkpoints have yielded impressive improvements in clinical outcomes 
for a range of tumor types. Despite this however, many advanced cancer patients do not 
respond to immunotherapy alone, due to local immune tolerance at the tumor, absence of 
effector cells, and/or the development of resistance through a variety of adaptive mechanisms 
[Park, Y. J., et al 2018] [Sharma, P., et al 2017]. Various combinations in clinical studies, 
such as with conventional chemotherapy, dual T-cell checkpoint blockade (CTLA-4), 
second-generation immunotherapy targets (TIGIT, LAG3, TIM-3, etc.), cancer vaccines, and 
oncolytic viruses, simultaneously targeting different components of tumor 
development/progression have the potential to significantly enhance efficacy, response rates, 
and durability relative to single-agent first- and second-generation immunotherapies 
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6115503/). 
V937 is a novel oncolytic viral therapy and is being developed for 
intratumoral (ITu)/intralesional, intravesicular, and intravenous (IV) administration to treat 
advanced cancers.
The use of oncolytic viruses for the treatment of cancer gained significant momentum, with 
several oncolytic viruses in Phase 2 and Phase 3 clinical evaluations [Kaufman, H. L. 2010] 
[Rowan, K. 2010] [Senzer, N. N., et al 2009], reinforcing the potential of this novel method 
for the treatment of malignancy. 
Essential to the rationale for the use of an oncolytic virus is a differential infectivity between 
normal cells and neoplastic cells. An oncolytic virus may accomplish this by different 
mechanisms, including the capacity to employ an intracellular selective process to replicate 
in a cancer cell with an inability to replicate in normal cells, as is the case with reovirus 
[Forsyth, P., et al 2008] [Harrington, K. J., et al 2010] and genetically altered vaccinia [Liu, 
T. C., et al 2008] [Merrick, A. E., et al 2009] and herpes simplex viruses [Senzer, N. N., et al 
2009].
A second mechanism by which oncolytic viruses may achieve this destructive targeting of 
cancer cells compared to normal cells is based on the interplay with innate as well as 
adaptive immune responses. It is essential for the control of a viral infection to have both 
innate and adaptive immune responses functioning. It is well documented that cancer cells 
have abnormal interferon responses due to unique metabolic pathways. A normal interferon 
response limits the ability of viruses to replicate as well as spread to adjacent cells. This 
interferon-governed response is deficient in cancer cells, giving the oncolytic virus an 
advantage in growth and spread when infecting cancer cells [Krishnamurthy, S., et al 2006] 
[Stojdl, D. F., et al 2000]. 
A third mechanism by which an oncolytic virus can achieve this differential in killing cancer 
cells, and the mechanism primarily utilized by coxsackievirus A21, is based on viral receptor 
surface expression. By targeting a viral receptor or receptor complex that is present or 
over-expressed on the surface of cancer cells compared to being absent or under-expressed 
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on normal cells, degrees of selective cell destruction can, in principle, be achieved 
[Anderson, B. D., et al 2004].
While the primary mode of action of oncolytic viruses is the direct lytic infection of the 
target cancer cell, there is increasing evidence that suggests a viral infection within a tumor 
will cause a migration into the tumor of immune modulating cells and an inflammatory 
response. Such an inflammatory response in the tumor, involving dendritic cells and 
cytotoxic T cells, may stimulate a cell-based immune response against a patient’s cancer.
V937 is under study for the treatment of solid tumors as monotherapy and as combination 
therapy with pembrolizumab and other immune checkpoint inhibitors. This is a Phase 2 study 
to assess the efficacy, safety, and tolerability of V937 administered both ITu and IV as 
combination therapy with pembrolizumab versus pembrolizumab alone.
2.1
Study Rationale
Advanced/metastatic melanoma cause significant morbidity and mortality. Melanoma is the 
most serious form of skin cancer and strikes adults of all ages. In 2008, the 5-year prevalence 
of melanoma in the European Union (EU) is approximately 159,000 patients with an 
incidence of approximately 41,000 per year and approximately 11,000 deaths annually as 
described in the World Health Organization (WHO) Europe region [Ferlay, J., et al 2010]. 
Melanoma accounts for approximately 5% of all new cases of cancer in the United States 
(US), and the incidence of melanoma continues to rise by almost 3% per year in the US. This 
translates to 76,000 new cases a year with 9000 associated deaths. The male-to-female 
incidence ratio of melanoma is 1.4:1, respectively [Siegel, R., et al 2012]. The 5-year 
survival rate is 15% once patients have progressed to late-stage disease [American Cancer 
Society 2012].
There is a great unmet medical need for therapeutic agents that can enhance the effect of 
immunotherapy. Nonclinical studies investigating the coadministration of ITu or IV V937
with 2 different immunostimulatory antibodies showed that, regardless of the method of 
administration, V937 used in combination with antiprogrammed cell death (PD)-1 and/or 
anti-CTLA-4 blocking antibodies was generally well tolerated in immunocompetent mouse 
models of melanoma and NSCLC, with gross observations not revealing AEs relating to the 
agents tested. These studies were the basis for subsequent clinical studies assessing V937 in 
combination with different checkpoint inhibitors. 
Previous clinical studies have demonstrated that V937 has antitumor activity and good 
tolerability in both monotherapy (CALM study) and in combination with checkpoint 
inhibitor such as pembrolizumab for both ITu and IV settings (CAPRA and 
STORM [KN200] studies).
In the CAPRA study, patients with advanced melanoma who were naïve to prior checkpoint 
inhibitor exposure received the combination of ITu V937 and pembrolizumab. Although the 
study is ongoing, an overall response rate of 59% (16/27) has been observed. Five Grade 3 or 
greater AEs related to pembrolizumab were reported in 4 participants, with AEs related to 
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V937 limited to Grade 1 or 2 in severity. In summary, the combination of ITu V937 and 
pembrolizumab was well tolerated.
In the STORM study (KN200), V937 administered IV as monotherapy can induce viral 
replication in NSCLC, metastatic bladder carcinoma, and melanoma. When given in 
combination with pembrolizumab, tumor responses were observed in the NSCLC and 
metastatic bladder cancer expansion cohorts. No DLTs were noted, and AEs related to V937
or pembrolizumab were mainly Grade 1 or 2 in severity. Four Grade 3 events related to V937
were reported in 3 participants, or 4% (3/85) of participants treated. Nineteen Grade 3 AEs
related to pembrolizumab were reported in 9 participants, or 11% (9/85) of treated 
participants. The ability to administer V937 systemically via IV infusion would make 
possible treatment for patients with cancers that are not accessible for ITu therapy.
The current study is a randomized study to assess whether ITu and/or IV administration of 
V937 in combination with pembrolizumab is superior to pembrolizumab alone in
anti-PD-(L)1-treatment-naive patients with melanoma (with accessible tumors).
2.2
Background
V937 (coxsackievirus A21 [CVA21]; CAVATAK; CAV21) is a live oncolytic virus 
preparation derived from the non-genetically altered prototype Kuykendall strain of 
coxsackievirus A21 that has been propagated in cell cultures. Coxsackievirus is a 
nonenveloped virus with positive single-stranded RNA and 4 capsid proteins and is a 
naturally occurring human enterovirus. V937 has an acceptable preclinical safety profile and 
is in clinical development as an intratumoral (ITu), intravesicular, and IV immunotherapy for 
advanced malignancies. For more details on specific refer to the V937 Investigator’s
Brochure (IB).
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the PD-1 receptor, thus inhibiting its interaction 
with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). 
Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1. Pembrolizumab has an acceptable preclinical safety profile and is 
in clinical development as an IV immunotherapy for advanced malignancies. Keytruda®
(pembrolizumab) is indicated for the treatment of patients across a number of indications. For 
more details on specific indications refer to the pembrolizumab IB.
2.2.1
V937 Pharmaceutical and Therapeutic Background
The primary focus of the V937 development program is to assess the safety and efficacy of 
the virus in the treatment of advanced solid tumor and other malignancies where 
ICAM-1/ DAF receptor expression occurs. Coxsackievirus A21 is a naturally occurring 
enterovirus that can cause the common cold [Zeichhardt, H. 2004]. V937 used in the current 
nonclinical and clinical studies is the prototype Kuykendall strain, which has not been 
genetically modified. 
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Coxsackievirus A21 belongs to the Enterovirus genus of the Picornaviridae family, which 
consists of more than 70 serologically distinguishable strains of virus that are otherwise 
structurally and morphologically indistinguishable. The enteroviruses are conventionally 
subdivided into 3 major subclasses: polioviruses, echoviruses, and coxsackieviruses. The 
coxsackieviruses are further subdivided into Groups A (23 members) and B (6 members) 
[Zeichhardt, H. 2004]. 
Surface-expressed ICAM-1 (CD54) was identified to be the virus uptake receptor for a 
number of human enteroviruses [Shafren, D.R., et al 1997] [Shafren, D. R. 1998] [Shafren, 
D. R., et al 2000]. The most exhaustively studied agents belong to the coxsackievirus A 
subgroup of the human enteroviruses, of which coxsackievirus A21 is a member.
For many years it has been known that moderate levels of ICAM-1 are expressed on nasal 
epithelium and can be used as a receptor by the major group of rhinoviruses, conferring 
susceptibility to common colds [Staunton, D. E., et al 1989]. ICAM-1 is also expressed on 
endothelium and used by leucocytes as a ligand by which they can transmigrate, particularly 
in response to local inflammatory mediators [Shaw, S. K., et al 2004]. 
High-level surface ICAM-1 expression is found on numerous malignant cells including 
breast cancer, head and neck cancer, prostate cancer, and melanoma [Anichini, A., et al
1990] [Berry, L.J., et al 2008] [Georgolios, A., et al 2006] [Kageshita, T., et al 1993] [Lang, 
S., et al 1999] [Si, Z. 1994] [Skelding KA, Barry RD, Shafren DR. 2009]. Several 
laboratories have shown that there is an association between the level of expression of 
ICAM-1 and the ability of melanoma cells to undergo metastasis [Anastassiou, G., et al
2000] [Anichini, A., et al 1990] [Bergelson, J. M., et al 1994] [Hakansson, A., et al 1999] 
[Johnson, J. P. 1991] [Pandolfi, F., et al 1992]. Upregulated ICAM-1 expression has also 
been implicated by study of metastatic human breast carcinoma cell lines [Rosette, C., et al 
2005]. Surface-expressed ICAM-1 enables tumor cells to interact with circulating 
lymphocytes by way of integrin receptors including LFA-1 and Mac 1, thus potentially 
providing a means by which tumors undergo metastatic spread. It is widely accepted that 
ICAM-1 is expressed at much higher levels on melanoma metastases than on primary tumors 
or precancerous lesions, and this phenomenon can be used as an indicator of cancer 
progression [Kageshita, T., et al 1993].
2.2.2
Pembrolizumab Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
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+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
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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 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (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. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in advanced/metastatic melanoma.
2.2.3
Preclinical and Clinical Studies
Please refer to the pembrolizumab and V937 IBs for descriptions of the respective preclinical 
and clinical evaluations.
2.2.4
Ongoing Clinical Studies
Please refer to the pembrolizumab and V937 IBs for descriptions of ongoing clinical studies.
2.2.5
Information on Other Study-related Therapy
Not applicable.
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.
Potential risks associated with the administration of V937 based on clinical data may include 
the following:
•
Fatigue
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•
Chills
•
Injection site pain
•
Pyrexia
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying V937 and pembrolizumab IBs and 
informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
Throughout this protocol, the term RECIST 1.1 refers to modification to RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Refer 
to Section 4.2.1.1 for further details.
In males and females with advanced/metastatic melanoma who are anti-PD-(L)1-treatment-
naïve:
Objectives
Endpoints
Primary

Objective: To evaluate the objective 
response rate (ORR) of participants 
treated with IV V937 administered in 
combination with pembrolizumab, 
ITu V937 administered in combination 
with pembrolizumab, or pembrolizumab 
alone per Response Evaluation Criteria 
in Solid Tumors 
Version 1.1 (RECIST 1.1) by blinded 
independent central review (BICR).

Hypothesis: V937 administered either 
IV in combination with pembrolizumab
or ITu in combination with 
pembrolizumab results in a superior 
ORR per RECIST 1.1 based on BICR, 
compared to pembrolizumab alone.

Objective response is a confirmed 
complete response (CR) or partial 
response (PR)
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Objectives
Endpoints
Secondary

To evaluate progression-free 
survival (PFS), and duration of 
response (DOR) of participants treated 
with IV V937 in combination with 
pembrolizumab, ITu V937 in 
combination with pembrolizumab, or
pembrolizumab alone per RECIST 1.1
by blinded independent central 
review (BICR).

PFS, defined as the time from 
randomization to the first documented 
progressive disease (PD) or death from 
any cause, whichever occurs first.

DOR, defined as the time from the first 
documented evidence of CR or PR 
until progressive disease (PD) or death 
due to any cause, whichever occurs 
first, in participants demonstrating CR 
or PR

To evaluate ORR, PFS, and DOR of 
participants treated with IV V937 in 
combination with pembrolizumab, 
ITu V937 in combination with 
pembrolizumab, or pembrolizumab 
alone, per RECIST 1.1, as assessed by 
the investigator.

Objective response

PFS

DOR

To evaluate OS of participants treated 
with IV V937 in combination with 
pembrolizumab, ITu V937 in 
combination with pembrolizumab, or
pembrolizumab alone.

OS, defined as the time from 
randomization to the date of death from 
any cause

Objective: To assess the safety and 
tolerability of participants treated with 
IV V937 in combination with 
pembrolizumab, ITu V937 in 
combination with pembrolizumab, or
pembrolizumab alone.

Adverse events (AEs)

Discontinuing study intervention due to 
an AE
Tertiary/Exploratory
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Objectives
Endpoints
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4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active-controlled, parallel-group, multisite, open-label, Phase 2 study 
of pembrolizumab in combination with V937 administered IV (Arm 1=IV pembro 
+ IV V937) or ITu (Arm 2=IV pembro + ITu V937) versus pembrolizumab alone 
(Arm 3=IV pembro alone) in participants with a histologically or cytologically confirmed 
diagnosis of Stage III or IV melanoma. The study will enroll participants with 
advanced/metastatic melanoma with cutaneous, subcutaneous, or nodal lesions that are 
amenable to ITu injection by visual inspection, palpation, or ultrasound guidance. 
Participants need to have 1 measurable lesion that is amenable to ITu injection and biopsy, as 
well as 1 measurable discrete and/or distant lesion (bystander lesion) that is amenable to 
biopsy to evaluate any abscopal effect.
This study will evaluate the efficacy, safety, and tolerability, of V937 in combination with 
pembrolizumab versus pembrolizumab alone. Figure 1 depicts a summary of the study 
design.
After a screening period of up to 28 days, participants will be randomized to: 
Arm 1: IV pembro + IV V937; Arm 2: IV pembro + ITu V937; or Arm 3: IV pembro alone. 
The first treatment cycle is 28 days, and each subsequent treatment cycle is 3 weeks. 
Participants will be treated for up to 35 cycles (approximately 2 years) after initiation of 
treatment with pembrolizumab alone or in combination with V937. V937 will be given for a 
total of 8 cycles. Discontinuation Follow-Up will be 30 days after the last dose.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
This study design is a 3-arm randomized study in participants with PD-1-naïve melanoma, 
comparing: (1) IV pembro + IV V937 to IV pembro alone and (2) IV pembro + ITu V937 to 
IV pembro alone. The choice of melanoma is due to the observation of single-agent V937 
activity when administered ITu, as well as evidence of viral replication in melanoma tumors 
when V937 is administered IV (Refer to the V937 IB).
Prior studies examining V937 combinations with pembrolizumab (eg, CAPRA for ITu and 
STORM [KN-200] for IV) were single-arm studies, and thus efficacy comparisons are 
limited to historic controls. The current study will be randomized to allow for a more 
rigorous evaluation of the impact of adding V937 to pembrolizumab, which is a standard of
care treatment for advanced melanoma.
The current study is randomized but is not blinded due to the desire not to subject all 
participants to sham ITu injections or sham IV infusions. BICR will be used for primary 
endpoints to minimize bias in objective response rate (ORR) and PFS determinations. An 
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interim futility analysis, after 25 participants on each arm are enrolled and have at least 
1 postbaseline scan, will be performed so as to limit the number of participants if the addition 
of V937 to pembrolizumab is deemed futile.
AJCC V8, divides metastatic melanoma is divided into 4 subsets, M1a, M1b, M1c, and M1d. 
These subgroups are characterized by their metastases: (M1a), nonvisceral (distant 
cutaneous, subcutaneous, nodal); (M1b), lung; (M1c), noncentral nervous system (CNS) 
visceral; and a new (M1d) designation for metastases involving the CNS. M1c no longer 
includes CNS metastasis. M1c and M1d have substantially different prognosis when 
compared to M1a and M1b, which provides a basis for stratification of this study [Dickson, 
P. V. 2011].
The current study combination dosing regimens are the same as that used in the 
nonrandomized CAPRA and STORM studies. Initial V937 dosing on Days 1, 3, 5, and 8 
maximizes V937 exposure prior to the development of V937 neutralizing antibodies, which 
appear after Day 3 and peak ≥ Day 8. See the V937 IB for further information. An
underlying hypothesis in these studies is that V937 given before (Days 1, 3, 5) administration 
of pembrolizumab (Day 8) would expand the T-cell repertoire for melanoma antigens and 
subsequent pembrolizumab may increase the lifespan and activity of these melanoma-
specific T cells.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary efficacy endpoint in this study is ORR (defined as the proportion of participants 
who have achieved confirmed CR or PR). Secondary endpoints include PFS, OS, and DOR. 
Tumor response will be assessed using RECIST 1.1 by BICR, RECIST 1.1 and iRECIST as 
assessed by investigator (see Section 8.2.1). Antitumor activity will be measured through 
such endpoints as the ORR, PFS, and OS, which are described further in Section 9.4.1. A 
planned interim futility analysis is described in Section 9.7.
This study will use ORR based on RECIST 1.1 criteria as assessed by BICR as the primary 
endpoint. Objective response rate is an acceptable measure of clinical benefit for a late -stage 
study that demonstrates superiority of a new antineoplastic therapy, especially if the 
magnitude of the effect is large and the therapy has an acceptable risk/benefit profile. The use 
of BICR and RECIST 1.1 to assess ORR is typically considered acceptable by regulatory 
authorities. Images will be submitted to an iCRO and read by an independent central review 
blinded to treatment assignment to minimize bias in the response assessments. 
OS has been recognized as the gold standard for the demonstration of superiority of a new 
antineoplastic therapy in randomized clinical studies.
RECIST 1.1 will be used by the BICR when assessing images for efficacy measures and by 
the local site when determining eligibility (Section 8.2.1.4). Although traditional RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, this protocol has 
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implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in total 
and 5 per organ.
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (iRECIST, Section 8.2.1.5). Immunotherapeutic 
agents such as pembrolizumab may produce antitumor effects by potentiating endogenous 
cancer-specific immune responses. The response patterns seen with such an approach may 
extend beyond the typical time course of responses seen with cytotoxic agents, and patients 
treated with pembrolizumab may manifest a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions. Thus, standard RECIST 1.1 may not 
provide an accurate response assessment of immunotherapeutic agents such as 
pembrolizumab. Based on an analysis of participants with melanoma enrolled in KEYNOTE-
001 (KN001), 7% of evaluable participants experienced delayed or early tumor pseudo-
progression. Of note, participants who had progressive disease (PD) by RECIST 1.1 but not 
by the immune-related response criteria [Wolchok, J. D., et al 2009] had longer overall 
survival than participants with PD by both criteria [Hodi, F. S., et al 2014]. Additionally, the 
data suggest that RECIST 1.1 may underestimate the benefit of pembrolizumab in 
approximately 10% of participants. These findings support the need to apply a modification 
to RECIST 1.1 that takes into account the unique patterns of atypical responses in 
immunotherapy and enables treatment beyond initial radiographic progression, if the 
participant is clinically stable.
Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US Food and Drug 
Administration and the European Medicines Agency [Seymour, L., et al 2017]. The 
unidimensional measurement of target lesions, qualitative assessment of nontarget lesions, 
and response categories are identical to RECIST 1.1, until progression is seen by RECIST 
1.1. However, if a participant is clinically stable, additional imaging may be performed to 
confirm radiographic progression. iRECIST will be used by investigators to assess tumor 
response and progression and make treatment decisions.
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 adverse events (AEs)/serious adverse events (SAEs); and changes 
in vital signs and laboratory values. AEs will be assessed as defined by CTCAE, Version 5.0.
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4.2.1.4
Pharmacodynamic Endpoints
There is no direct target engagement biomarker. Downstream exploratory pharmacodynamic 
biomarkers in tumor tissue and blood will be assessed for pathway activation.
4.2.1.5
Anti-drug Antibodies (ADA)
Antibodies against V937 and pembrolizumab (eg, neutralizing antibodies and ADA) can 
potentially confound drug exposures at therapeutic doses and prime for subsequent 
infusion-related toxicity. Neutralizing and ADA responses at the beginning of each cycle will 
be determined to understand drug exposure and safety. The incidence of neutralizing 
antibodies and ADA will be evaluated and summarized over time. Correlations between the 
presence/absence of positivity for neutralizing antibodies and ADA and PK and 
pharmacodynamic markers, activity, and safety of V937 will be explored.
4.2.1.6
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
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4.2.1.7
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
FBR.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this FBR research are presented in Appendix 6.
4.2.2
Rationale for the Use of Comparator
Preclinical and clinical studies have shown that V937, when combined with checkpoint 
inhibitor such as pembrolizumab, may provide improved efficacy versus V937 monotherapy 
or pembrolizumab alone. Thus far, the combination studies have all been non-randomized 
single-arm studies. Pembrolizumab has been approved as a frontline treatment for patients 
with advanced/metastatic melanoma. To confirm that adding V937 to pembrolizumab
provides clinical benefit, a pembrolizumab alone arm will be used as a comparator in this 
randomized study.
4.3
Justification for Dose
The clinical development of V937 has assessed safety and efficacy signals using 3 different 
routes of administration: ITu, intravesicular, and IV.
 
 
Previous ongoing/completed studies examined V937 monotherapy as well as pembrolizumab 
combinations in ITu and IV settings. The highest doses (1 x 109 TCID50 in IV and 3 x 108
TCID50 in ITu) were tested, alone and in combination with pembrolizumab. These doses
were well tolerated, and the evidence of biological activity has been demonstrated at the 
proposed recommended Phase 2 dose (RP2D). In late-stage melanoma participants treated 
with monotherapy ITu V937 a 28% ORR was observed (CALM study). In the CAPRA study,
V937 in combination with pembrolizumab (CAPRA study) a 59% ORR was observed (11th
International Oncolytic Virotherapy Conference held April 2018, in Oxford, UK). These 
responses were seen in lesions that had been injected with V937, but also in distant and 
noninjected lesions, both for surface melanoma lesions as well as visceral organs (lung and 
liver). In the STORM V937 IV study (KN200), viral RNA was detected in tumor biopsies 
obtained at Day 8 in subjects with advanced melanoma, bladder or NSCLC, indicating that 
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viral replication had occurred. Similarly, in the CALM monotherapy V937 ITu study, viral 
replication was observed in the tumor microenvironment from biopsies obtained at Day 8 in 
subjects with advanced melanoma. These samples also indicated upregulation of a number of 
interferon response and immune checkpoint inhibitory genes in injected melanoma lesions, 
including PD-L1.
The evidence of biological activity (antitumor and viral replication) as well as tolerability in 
the CALM, CAPRA, and STORM studies supports moving the previously determined RP2D 
forward into this study.
For V937 ITu administration, a total dose of 3 X 108 TCID50 will be administered. In the 
cases of ITu administration, the dose may be divided among several lesions. Doses are 
administered on Days 1, 3, 5, 8, of Cycle 1, and then every 3 weeks (Cycles 2-8) for a total of 
11 doses.
For V937 IV administration, the total dose is 1 X 109 TCID50, administered on Days 1, 3, 5, 8
of Cycle 1, and then every 3 weeks (Cycles 2-8) for a total of 11 doses.
The dose for pembrolizumab is 200 mg every 3 weeks.
The dose of V937 and the dosing schedule in this study for the IV and ITu arms are based on 
the STORM and CAPRA studies, respectively. The IV dose being used in this study was 
found to be free of DLTs in the dose-escalation portion of the STORM study, when
administered as monotherapy or in combination with pembrolizumab. The dosing schedule is 
the same. The ITu dose selected for this study is the same that has been used in several 
earlier studies in patients with advanced melanoma (CALM, MITCI, and CAPRA). The 
dosing schedule is the same, with the exception that the number of doses is limited to 
11 doses, to be equivalent to that being used in the IV study arm.
The pembrolizumab dose and schedule used in this study is identical to that used in the 
CAPRA study, which is based on the current standard of care.
Please refer to the V937 IB for additional information regarding dose selection.     
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 (ie, the 
participant is unable to be contacted by the investigator).
For purposes of analysis and reporting, the overall study ends when the 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.
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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.
5
STUDY POPULATION
Male/female participants ≥18 years of age with advanced/metastatic melanoma will be 
enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
1. Has histologically or cytologically confirmed diagnosis of advanced/metastatic 
melanoma
2. Has Stage III (unresectable) or Stage IV melanoma
3. Participants must be naive to anti-PD-(L)1 treatment, TVEC and other oncolytic viruses.
4. Has 2 lesions as defined below:
1. Lesion 1: Has at least 1 cutaneous or subcutaneous lesion amenable to ITu injection
and biopsy. The injectable lesion must be measurable and meet 1 of the following 
criteria (per RECIST 1.1 for solid tumors):

A cutaneous or subcutaneous lesion ≥1 cm in longest diameter for solid tumors, 
or ≥1.5 cm in short axis for a nodal lesion in participants with solid tumor. The
longest diameter for an injectable lesion must be ≤10 cm for both solid tumors 
and nodal lesions in participants with solid tumor.

Multiple coalescing, superficial lesions that in aggregate have a longest diameter 
of ≥1 cm and ≤10 cm.
2. Lesion 2: Have at least 1 measurable, distant and/or discrete noninjected lesion that is 
amenable to biopsy via visual inspection or amenable to biopsy via image guidance, 
such as ultrasound or computed tomography (CT)/magnetic resonance imaging 
(MRI). The lesion must be measurable and meet 1 of the above mentioned criteria per 
RECIST 1.1.
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5. Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) 
Performance Scale.
6. Demonstrates adequate organ function as defined in Table 6. These laboratory samples 
must be collected within 72 hours prior to the start of study treatment.
Table 6
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
>1,500/mcL (>1,000/mcL for lymphoma 
participants)
Platelets
>100,000/mcL (>75,000/mcL for lymphoma 
participants)
Hemoglobin
>9 g/dL or >5.6 mmol/La (>8 g/dL or 
>5.0 mmol/L for lymphoma participants)
Renal
Serum Creatinine or 
Creatinine Clearance (CrCl) (measured 
or calculated)b or
Glomerular Filtration Rate (GFR) in 
place of CrCl
≤1.5 X ULN or 
>30 mL/min for participants with creatinine 
levels >1.5 X ULN
Hepatic
Total bilirubin (serum) 
≤1.5 X ULN or 
Direct bilirubin <ULN for participants with 
total bilirubin levels >1.5 X ULN
AST (SGOT) and ALT (SGPT)
<2.5 X ULN or ≤5 × ULN for participants with 
liver metastases
Lactate dehydrogenase (LDH)
≤2.5 X ULN
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
<1.5 X ULN (unless participant is receiving 
anticoagulant therapy, in which case PT/INR 
or aPTT should be within the therapeutic range 
of intended use of anticoagulants)
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System
Laboratory Value
aPTT=activated partial thromboplastin time; ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic 
transaminase); AST (SGOT)=aspartate aminotransferase (serum glutamic oxaloacetic transaminase); CrCl=creatinine 
clearance; GFR=glomerular filtration rate; INR=International Normalized Ratio; LDH=lactate dehydrogenase; 
PT=prothrombin time; ULN=upper limit of normal.
a Criteria must be met without packed red blood cell (pRBC) and platelet transfusion within the prior 2 weeks. 
Participants can be on stable dose of erythropoietin (≥ approximately 3 months).
b Creatinine clearance (CrCl) should be calculated per institutional standard. If no local guideline is available, CrCl 
should be calculated using the Cockcroft-Gault Method: CrCl=[(140-age)*weight(kg)*(0.85 for females 
only)]/(72*serum creatinine).
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.
Demographics
7. Is male or female, from ≥18 years of age, at the time of providing documented informed 
consent.
Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
8. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 120 days:
-
Refrain from donating sperm
PLUS either:
-
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent
OR
-
Must agree to use contraception unless confirmed to be azoospermic (vasectomized 
or secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male condom 
during each episode of penile-vaginal penetration.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
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9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:

Is not a woman of childbearing potential (WOCBP)
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long term and persistent basis), as described in 
Appendix 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.

A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 72 hours before the first dose of study 
intervention.

If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.

Additional requirements for pregnancy testing during and after study intervention are 
in Appendix 2.

The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
10. The participant (or legally acceptable representative if applicable) provides documented
informed consent for the study. The participant must consent to screening and 
on-treatment biopsies. The participant may also provide consent for future biomedical 
research (FBR). However, the participant may participate in the main study without 
participating in FBR.
Additional Categories
11. Has measurable disease per RECIST 1.1 as assessed by the local site 
investigator/radiology. Lesions situated in a previously irradiated area are considered 
measurable if progression has been demonstrated in such lesions.
12. Is able to provide newly obtained core or excisional biopsy of a tumor lesion not 
previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are 
preferred to slides. Note: If submitting unstained cut slides, newly cut slides should be 
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submitted to the testing laboratory within 14 days from the date slides are cut (details 
pertaining to tumor tissue submission can be found in the Procedures Manual).
13. HIV-infected participants must have well controlled HIV on antiretroviral 
therapy (ART), defined as:
a.
Participants on ART must have a CD4+ T-cell count 350 cells/mm3 at time of 
screening.
b. Participants on ART must have achieved and maintained virologic suppression 
defined as confirmed HIV RNA level below 50 or the LLOQ (the lower limit of 
quantitation) using the locally available assay at the time of screening and for at least 
12 weeks prior to screening.
c.
Participants on ART must have been on a stable regimen, without changes in drugs or 
dose modification, for at least 4 weeks prior to study entry (Day 1).
d. The combination ART regimen must not contain any antiretroviral medications other 
than: abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, or 
tenofovir.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has had chemotherapy, definitive radiation, or biological cancer therapy or an 
investigational agent or investigational device within 4 weeks (2 weeks for palliative 
radiation) prior to the first dose of study intervention or has not recovered to Common 
Terminology Criteria for Adverse Events (CTCAE) Grade 1 or better (except alopecia)
from any AEs that were due to cancer therapeutics administered more than 4 weeks 
earlier (this includes participants with previous immunomodulatory therapy with residual 
immune-related AEs). If the participant had major surgery or radiation therapy of 
>30 Gy, they must have recovered adequately from the procedure and/or any 
complications from the surgery prior to starting study intervention. Participants receiving 
ongoing replacement hormone therapy for endocrine immune-related AEs will not be 
excluded from participation in this study.
2. Has ocular melanoma.
3. Has radiographic evidence of major blood vessel invasion/infiltration. The degree of 
tumor invasion/infiltration of major blood vessels should be considered because of the 
potential risk of severe hemorrhage associated with tumor shrinkage/necrosis.
4. Has clinically significant hemoptysis or tumor bleeding within 2 weeks prior to the first 
dose of study drug.
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5. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) 
except vitiligo or resolved childhood asthma/atopy. Replacement therapy, such as 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, is not considered a form of systemic treatment and is allowed. 
6. HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric 
Castleman’s Disease.
7. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
8. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 
5 years.
Note: Participants who have had a transplant greater than 5 years ago are eligible as long 
as there are no symptoms of graft-versus-host disease (GVHD).
9. Has not fully recovered from any effects of major surgery without significant detectable 
infection. Surgeries that required general anesthesia must be completed at least 2 weeks 
before first study intervention administration. Surgery requiring regional/epidural 
anesthesia must be completed at least 72 hours before first study intervention 
administration and participants should be recovered.
10. Clinically significant (ie, active) cardiovascular disease: cerebral vascular accident/stroke 
(<6 months prior to enrollment), myocardial infarction (<6 months prior to enrollment), 
unstable angina, congestive heart failure (New York Heart Association Classification 
Class ≥ II), or serious cardiac arrhythmia requiring medication.
11. A woman of childbearing potential (WOCBP) who has a positive urine pregnancy test 
within 72 hours prior to randomization or treatment allocation (see Appendix 5). If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required.
Note: In the event that 72 hours have elapsed between the screening pregnancy test and 
the first dose of study intervention, another pregnancy test (urine or serum) must be 
performed and must be negative in order for participant to start receiving study 
medication.
Prior/Concomitant Therapy
12. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137).
13. Has received a live vaccine within 30 days prior to the first dose of study drug. Examples 
of live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), 
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and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.
Prior/Concurrent Clinical Study Experience
14. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent.
Diagnostic Assessments
15. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy in 
excess of replacement doses (in dosing exceeding 10 mg daily of prednisone equivalent) 
or any other form of immunosuppressive therapy within 7 days prior the first dose of 
study drug. Use of nonsystemic steroids is permitted.
16. Has a known additional malignancy that is progressing or has required active treatment 
within the past 2 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
17. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note 
that the repeat imaging should be performed during study screening), clinically stable and 
without requirement of steroid treatment for at least 14 days prior to first dose of study 
intervention.
18. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients.
19. Has severe hypersensitivity (≥Grade 3) to V937 or any of its excipients.
20. Has a history of (noninfectious) pneumonitis that required steroids or has current 
pneumonitis.
21. Has an active infection requiring systemic therapy.
22. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection.
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Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority.
23. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
Other Exclusions
24. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of study intervention.
25. Has had an allogenic tissue/solid organ transplant.
5.3
Lifestyle Considerations
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.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
None.
5.3.3
Activity Restrictions
None.
5.3.4
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Refer to Appendix 5 for 
approved methods of contraception.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, participants of childbearing potential must adhere to the contraception 
requirement (Appendix 5) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 
120 days after the last dose of study medication. If there is any question that a participant of 
childbearing potential will not reliably comply with the requirements for contraception, that 
participant should not be entered into the study.
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5.3.5
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study intervention. The site will contact 
the participant at least monthly and document the participant’s status until the pregnancy has 
been completed or terminated. The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study Investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 8.4.
5.3.6
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, participants who are breastfeeding are not eligible for enrollment.
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 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines. Re-screening is allowed in the study 
(see Section 8.1.9).
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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 of V937 and pembrolizumab provided by the Sponsor)
will be packaged to support enrollment. Clinical supplies will be affixed with a clinical label 
in accordance with regulatory requirements.
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6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 7.
Country-specific differences are noted in Appendix 7.
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Table 7
Study Interventions
Arm 
Name
Arm 
Type
Interven-
tion Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 1
Experi-
mental
Pembro-
lizumab
Biological/
Vaccine
Solution 
for 
Infusion
25 mg/mL
200 mg
IV 
Infusion
Day 8 of 
Cycle 1 
(28-day cycle)
Day 1 of each 
subsequent 
21-day cycle
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
Arm 1
Experi-
mental
V937
Biological/
Vaccine
Solution 
for 
Infusion
7.5 X 10^7
TCID50/
mL
1 X 10^9 
TCID50
IV 
Infusion
Days 1, 3, 5, 
and 8 of 
Cycle 1 
(28-day cycle) 
Day 1 of 
Cycles 2-8 
(21-day 
cycles)
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
Arm 2
Experi-
mental
Pembro-
lizumab
Biological/
Vaccine
Solution 
for 
Infusion
25 mg/mL
200 mg
IV 
Infusion
Day 8 of 
Cycle 1 
(28-day cycle)
Day 1 of each 
subsequent 
21-day cycle
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
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Arm 
Name
Arm 
Type
Interven-
tion Name
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Admin-
istration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 2
Experi-
mental
V937
Biological/
Vaccine
Solution 
for 
Injection
7.5 X 10^7
TCID50/
mL
3 X 10^8 
TCID50
Intra-
tumoral
Days 1, 3, 5, 
and 8 of 
Cycle 1 
(28-day cycle)
Day 1 of 
Cycles 2-8 
(21-day 
cycles)
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
Arm 3
Experi-
mental
Pembro-
lizumab
Biological/
Vaccine
Solution 
for 
Infusion
25 mg/mL
200 mg
IV 
Infusion
Day 8 of 
Cycle 1 
(28-day cycle)
Day 1 of each 
subsequent 
21-day cycle
SoC
IMP
Provided 
centrally 
by 
Sponsor
Note: V937 will be administered 0.5 to 4 h after pembrolizumab infusion (as appropriate).
The classification of IMP and NIMP/AxMP is based on guidance issued by the European Commission and applies to countries in the EEA. Regional and/or 
Country differences of the definition of IMP and NIMP/AxMP may exist. In these circumstances, local legislation is followed.
EEA=European Economic Area; IMP=Investigational Medicinal Product; IV=intravenous; NIMP/AxMP=Noninvestigational/Auxiliary Medicinal Product; 
SoC=standard of care; TCID50=50% tissue culture infectious dose.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 7 will be provided centrally by the Sponsor.
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 8.1.10 for details regarding administration of the study intervention.
6.1.1
Administration of Pembrolizumab
A 200-mg dose of pembrolizumab will be infused over 30 minutes. In Arms 1 and 2, 
pembrolizumab administration will be 0.5 to 4 hours prior to V937 administration. For
administration details, see Pharmacy Manual.
6.1.2
Administration of V937 (Arms 1 and 2)
6.1.2.1
Administration of V937 in Arm 1
In Arm 1, V937 will be infused IV over 30 minutes. For Cycles 2-8, V937 administration 
will occur 0.5 to 4 hours after a 200-mg dose of pembrolizumab infused over 30 minutes. For 
administration details, see the Pharmacy Manual.
6.1.2.2
Administration of V937 in Arm 2
In Arm 2 of the study, V937 will be administered by ITu injection into cutaneous, 
subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound 
guidance. V937 will be administered with a total maximal volume of injectate of 4 mL per 
treatment visit for all injected lesions combined. A maximum of 5 lesions can be injected 
per visit.
V937 administration will occur 0.5 to 4 hours after a 200-mg dose of pembrolizumab infused 
over 30 minutes.
Each participant will receive V937 in a volume of 0.5 to 4 mL of injectate. The amount of 
V937 administered will depend on the number of lesions injected and the size of those 
lesions. See Table 8 for dose-level range. The volume of injectate delivered to each lesion 
will be based on the longest dimension of the target lesion as shown in Table 8 (short axis 
diameter in the case of lymph nodes), and on the number of lesions injected. Documentation 
of dose volume administered per lesion will be obtained.
Prioritization of lesions to be injected should include consideration of the following order:
First: New or progressing lesion(s)
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Second: The largest lesion(s)
If multiple lesions exist, a new or progressing lesion should be considered for injection first, 
followed by injection of the largest lesion, then injection of any additional lesions, up to a 
total volume of injectate of 4 mL and a maximum number of 5 lesions.
The total volume administered to all lesions can range from 0.5 to 4 mL per participant, per 
visit. Distant lesion(s) assessed for the “abscopal” response should not be injected, unless 
approved by the Sponsor.
Table 8
Determination of Minimum Target Lesion Diameter at Treatment Initiation by 
Dose Level
Target Lesion Size (longest dimension)
Injection Volume a
>2.5 cm
2 mL
1.5 to 2.5 cm
1 mL
0.5 to <1.5 cm
0.5 mL
a Volumes are estimates; total volume injected per visit for all tumor lesions combined = 4 mL.
Details on dose calculation, preparation, and administration of V937 are provided in the 
Procedures Manual.
Injected tumor area should consist of vital tumor tissue (avoid injection into areas with 
significant necrosis, if feasible). The injected, single, sufficiently-sized target lesion at 
treatment initiation should be the same lesion that underwent pretreatment biopsy.
If at any time after treatment initiation a dose cannot be fully injected into the single target 
lesion identified at the start of treatment (eg, due to tissue induration or tumor shrinkage), the 
dose may be split and the remaining amount of V937 may be injected into another accessible 
target lesion(s). Documentation of dose volume administered per target lesion should be 
obtained. If no other target lesion is accessible for injection or lesions are no longer visible, 
the remaining amount may alternatively be injected subcutaneously into the tissue 
immediately surrounding the target lesion, if assessed feasible by the treating physician. Site 
and volume for each injection must be documented in the electronic case report form (eCRF).
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of V937 and pembrolizumab are provided in the 
Pharmacy Manual. 
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There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided 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.
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
Participants will be randomized centrally using an interactive voice response 
system/integrated web response system (IVRS/IWRS). Participants will be randomly
assigned in a 1:1:1 ratio to the following intervention arms: Arm 1 (IV pembro + IV V937); 
Arm 2 (IV pembro + ITu V937); Arm 3 (IV pembro alone).
6.3.2
Stratification
Intervention allocation/randomization will be stratified according to the following factor:
(M1c+M1d) versus others, according to AJCC Cancer Staging Manual, Eighth Edition
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6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan for more than 12 weeks between 
pembrolizumab doses for nondrug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
Interruptions from the protocol-specified treatment plan for >12 weeks between V937 doses
require consultation between the investigator and the Sponsor and written documentation of 
the collaborative decision on participant management.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required. 
The investigator should 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, the 
Sponsor, and the participant.
6.5.1
Acceptable Concomitant Medications
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 except for those that are prohibited as described in Section 6.5.2. All 
concomitant medication will be recorded on the eCRF including all prescription, 
over-the-counter (OTC), herbal supplements, and IV medications and fluids. If changes occur 
during the study period, documentation of drug dosage, frequency, route, and date may also 
be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and 30 days after the last dose of study intervention should be recorded. If 
participants experience an SAE or ECI, all concomitant medications administered after 
30 days after the last dose of study intervention are to be recorded for SAEs and events of 
clinical interest (ECIs) as defined in Section 8.4.7.
6.5.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phases of this study:

Antineoplastic systemic chemotherapy or biological therapy
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
Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion.

Live vaccines within 30 days prior to the first dose of study intervention and while 
participating in the study. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. (Refer local regulation in Appendix 7)

Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE
that is suspected to have an immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
Participants who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from treatment.
Participants may receive other medications that the investigator deems to be medically 
necessary.
6.5.3
Rescue Medications and Supportive Care
6.5.3.1
V937 Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
6.5.3.2
Pembrolizumab Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6, Table 9. Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.
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Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 9 in 
Section 6.6 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
6.6
Dose Modification (Escalation/Titration/Other)
Adverse events (both nonserious and serious) associated with V937 and pembrolizumab 
exposure may represent an immunologic etiology. These AEs may occur shortly after the 
first dose or several months after the last dose of treatment.
The CTCAE Version 5.0 must be used to grade the severity of AEs. The investigator may 
attribute each toxicity event to V937 alone, to pembrolizumab alone, or to the combination, 
and modify the dose according to Table 9. Although the investigator may attribute an AE to 
V937 alone, pembrolizumab must be held for AEs as indicated in Table 9, regardless of 
attribution.
Reduction or holding of 1 agent and not the other agent is appropriate if, in the opinion of the 
investigator, the toxicity is clearly related to 1 of the study interventions. For example, in 
combination, if V937 is held due to an AE attributed to that drug, then pembrolizumab may 
continue to be administered, and vice versa. Appropriate documentation is required regarding 
to which drug the investigator is attributing the AE. If, in the opinion of the investigator, the 
toxicity is related to the combination of 2 agents, then both drugs should be held according to 
recommended dose modifications.
Pembrolizumab or V937 may be interrupted for situations other than treatment-related AEs 
such as medical / surgical events or logistical reasons not related to study therapy. 
Participants should be placed back on study therapy within 3 weeks of the scheduled 
interruption, unless otherwise discussed with the Sponsor. The reason for interruption should 
be documented in the participant's study record.
6.6.1
Dose Modification for V937
The most common drug-related adverse reactions seen with V937 treatment continue to be 
fatigue, chills, pyrexia and influenza-like illness. These events are mainly Grade 1 or 2 in 
severity, transient, and easily managed.
In addition, a group of treatment-related AEs is specific to studies where V937 is delivered 
by ITu administration. This includes injection site pain, injection site erythema, injection site 
reaction, injection site pruritis, injection site discharge and injection site edema. These AEs
are associated with the intralesional procedure, and have not been reported when V937 has 
been given by the IV or intravesicular route. These symptoms are limited to being mild 
(Grade 1) in severity.
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As common practice, anti-inflammatory or anti-allergic agents, such as acetaminophen or 
ibuprofen, should be initiated if Grade 2 fever, chill, or site injection reaction occurs. 
Permanently discontinue V937 if these Grade 2 AEs reoccur in the same participants or are 
>Grade 2. For infusion reaction related to IV administered V937, please refer to Table 10 for 
guidance. For other instances in which dose interruption(s) may be required, discuss with 
Sponsor.
Pembrolizumab treatment will be modified for the AEs described in Section 6.6.2.
6.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 9.
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Table 9
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, 
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
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
AST or ALT 
Elevation or 
Increased Bilirubin
Grade 2 a
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 3 b or 4 c
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
Withhold d
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
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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
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
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 
discontinue d
Hypothyroidism
Grade 2, 3 or 4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of 
care
Monitor for signs and symptoms of thyroid 
disorders
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
Grade 1
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
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 event e
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
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 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if 
baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x 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
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 10. Life-threatening infusion reactions have not been 
observed with V937.
Table 10
Pembrolizumab and V937 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 hrs
Stop Infusion
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour 
of stopping drug infusion, the 
infusion may be restarted at 50% 
of the original infusion rate (eg, 
from 100 mL/hr to 50 mL/hr). 
Otherwise dosing will be held 
until symptoms resolve and the 
participant should be 
premedicated for the next 
scheduled dose.
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug intervention.
Participant may be premedicated 1.5 h (±30 
minutes) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg PO (or equivalent 
dose of antihistamine).
Acetaminophen 500-1000 mg PO (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Participant is permanently 
discontinued from further study 
drug intervention.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 
(CTCAE) at http://ctep.cancer.gov
6.7
Intervention After the End of the Study
Due to discontinuation of V937-011, participants who have completed or discontinued V937 
treatment and are only receiving pembrolizumab may be enrolled in a pembrolizumab 
extension study, if available, to continue pembrolizumab monotherapy for up to 35 cycles 
from first pembrolizumab dose on V937-011 and to be monitored per the extension study as 
appropriate.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
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.
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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 prior to 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 8.10.3 unless the participant has 
withdrawn from the study.
Participants may discontinue study intervention at any time for any reason or be dropped 
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. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.11.
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

The participant interrupts study intervention administration for more than 12 consecutive 
weeks.

The participant has a medical condition or personal circumstance that, 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.

Unacceptable adverse experiences as described in Section 8.3.

Use of prohibited concomitant medications as described in Section 6.5.2.

Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.

Investigator’s decision to discontinue treatment.

Side effects and/or concomitant medications required for treatment of HIV and/or its 
complications that are incompatible with continued study treatment (exceptions are 
permissible but should be discussed with the Sponsor).

Confirmed radiographic disease progression outlined in Section 8.2 (exception if the 
Sponsor approves treatment continuation following confirmed PD per iRECIST)
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
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment

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.

Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) and have been treated for at least 8 cycles (at least 
24 weeks), receiving at least 2 doses of pembrolizumab alone (Arm 3) or 2 cycles of the 
combination therapy (Arms 1 and 2) including 2 doses of pembrolizumab and at least 
80% of the planned doses of V937 beyond the date when the initial CR was declared.

Completion of 35 treatments (approximately 2 years) with pembrolizumab
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, 
he/she shall not be allowed to restart study intervention.
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 future biomedical research, are 
outlined in Section 8.1.11. 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.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:

The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
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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.
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 signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), 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.
The approximate amount of blood collected from each participant over the duration of the 
study is provided in the Procedures Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
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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 future biomedical 
research. If there are changes to the participant’s status during the study (eg, health or age of 
majority requirements), the investigator or medically qualified designee must ensure the 
appropriate documented informed consent 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 trial protocol number, trial 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent 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.
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.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form template at the protocol level. 
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 future biomedical research 
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 future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to FBR.
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8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria (Sections 5.1 and 5.2) 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 identification card also contains contact information for the emergency 
unblinding call center so that a healthcare 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 significant. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
8.1.5
Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
8.1.6
Prior Oncology Treatment History
The investigator or qualified designee will record all prior cancer treatments including 
systemic treatments, radiation, and surgeries.
8.1.7
Prior and Concomitant Medications Review
8.1.7.1
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 first dose of study intervention. Treatment for the disease for which the 
participant has enrolled in this study will be recorded separately and not listed as a prior 
medication.
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8.1.7.2
Concomitant Medications
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, with the exceptions of those specifically excluded (see Section 6.5.2). All
concomitant medication will be recorded on the eCRFs, including all prescription, OTC 
products, herbal supplements, and IV medications, and fluids. If changes occur during the 
study period, documentation of drug dosage, frequency, route, and date should also be 
included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
Concomitant medications administered 30 days after the last dose of study treatment should 
be recorded for SAEs and events of clinical interest (ECIs) as defined in Section 8.4.7. 
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 as defined in 
Section 8.4.7.
All new anticancer therapy initiated after the study start must be recorded in the eCRF. If a 
participant initiates another anticancer therapy other than the assigned study intervention(s), 
the study intervention(s) should be discontinued and the participant will move into the 
survival follow-up phase; if a participant initiates a new anticancer therapy within 30 days 
after the last dose of the study intervention, the 30-day Safety Follow-up Visit should occur 
before the first dose of the new therapy.
8.1.8
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit. Participants may be screened up to 2 times. Specific 
details on the screening/rescreening visit requirements are provided in Section 8.10.1.
8.1.9
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
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A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.10
Study Intervention Administration
Administration of study medication will be monitored by the investigator and/or study staff.
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the pharmacy manual.
Study intervention should begin within 3 days of randomization (for Arms 1 and 2) or C1D8 
±1 day (for Arm 3).
8.1.10.1
Timing of Dose Administration
In all arms of the study, pembrolizumab will be administered on Day 8 of Cycle 1 (28-day 
cycle) and on Day 1 of all subsequent cycles. V937 will be administered either IV (Arm 1) or 
ITu (Arm 2) on Days 1, 3, 5, and 8 of Cycle 1 (28 days); on Day 8 of Cycle 1, V937 will be 
administered 0.5 to 4 hours after a 200-mg dose of pembrolizumab infused over 30 minutes.
For Cycles 2-8, V937 will be administered IV (Arm 1) or ITu (Arm 2) on Day 1 of each 
21-day cycle, 0.5 to 4 hours after a 200-mg dose of pembrolizumab infused over 30 minutes.
Each participant may undergo up to 11 administrations of V937 and may continue treatment 
with pembrolizumab for up to a total of 35 cycles (approximately 2 years).
In Cycle 1, for the first 4 doses of V937 in Arms 1 and 2, a window of 24 hours for dosing 
will be allowed to accommodate weekends. In Cycle 2, study intervention may be 
administered up to 3 days after the scheduled Day 1. Beginning in Cycle 3, study 
intervention may be administered up to 3 days before or after the scheduled Day 1.
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
that are not related to study therapy (eg, elective surgery, unrelated medical events, 
participant vacation, and/or holidays). Participants should be placed back on study therapy 
within 3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor 
Medical Monitor or designee. The reason for interruption should be documented in the 
participant’s study record.
8.1.11
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to 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 8.10.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the End-of-Treatment Visit should be performed (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 and Section 8.10.3.
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8.1.11.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant's consent for future biomedical research will be withdrawn. A letter will be sent 
from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of the 
investigator to inform the participant of completion of withdrawal. Any analyses in progress 
at the time of request for withdrawal or already performed prior to the request being received 
by the Sponsor will continue to be used as part of the overall research study data and results. 
No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.12
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.13
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.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Assessment of Disease
In addition to survival, efficacy will be assessed based on imaging evaluation of changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
survival follow-up. The process for image collection and transmission to the iCRO for BICR 
can be found in the Site Imaging Manual. Tumor imaging is strongly preferred to be acquired 
by CT. For the abdomen and pelvis, contrast-enhanced MRI may be used when CT with 
iodinated contrast is contraindicated, or when mandated by local practice. The same imaging 
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 imaging. Note: for the purposes of assessing tumor imaging, 
the term “investigator” refers to the local investigator at the site and/or the radiological 
reviewer at the site or at an offsite facility. Tumor imaging schedule is based on calendar 
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days from the first administration of study intervention and will not be postponed due to 
delays in treatment cycles. Additional tumor imaging and medical photography may be 
performed as clinically indicated. Brain imaging is required for all participants with 
previously treated brain metastases at screening. Magnetic resonance imaging is preferred; 
however, CT imaging will be acceptable, if MRI is medically contraindicated.
Bone scans are also required for participants with a history of bone metastases and/or for 
those participants with new bone pain. Any supplemental imaging done to support a positive 
or negative bone scan, such as plain X-rays that may be acquired for correlation, should be 
submitted to the iCRO.
Other imaging modalities that may be collected, submitted to the iCRO, and included in 
response assessment include medical photography.
All scheduled imaging for all study participants will be submitted to the iCRO. In addition, 
imaging that is obtained at an unscheduled time point, for any reason (including suspicion of 
progression or other clinical reason), should also be submitted to the iCRO if it shows 
progression, or if it is used to support a response assessment. All imaging acquired within the 
protocol-specified window of time around a scheduled imaging visit can be classified as 
pertaining to that visit.
RECIST 1.1 and iRECIST assessment will be done for both injected and noninjected lesions. 
Injecting a lesion after treatment has begun will not render it “nonevaluable” for response 
assessment purposes. 
8.2.1.1
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
randomization, and the site study team must confirm that the participant has measurable 
disease as defined by RECIST 1.1 criteria to confirm eligibility. Tumor imaging performed 
as part of routine clinical management is acceptable for use as screening tumor imaging if 
they are of diagnostic quality and performed within 42 days prior to the date of 
randomization.
8.2.1.2
Tumor Imaging During the Study
The first on-study imaging assessment should be performed at 9 weeks (63 days ±7 days]) 
from the date of the first dose of pembrolizumab. Subsequent tumor imaging should be 
performed every 9 weeks (63 days ±7 days) or more frequently if clinically indicated. After
54 weeks (379 days ±7 days]), participants who remain on treatment will have imaging 
performed every 12 weeks (84 days ±7 days). Imaging timing should follow calendar days 
and should not be adjusted for delays in cycle starts. Imaging should continue to be 
performed until disease progression is identified by the investigator (unless the investigator
elects to continue treatment and follow iRECIST), the start of new anticancer treatment, 
withdrawal of consent, or death, whichever occurs first. All supplemental imaging must be 
submitted to the iCRO.
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Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of a 
response is observed. Participants will then return to regular scheduled imaging, starting with 
the next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 
4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Note: Response does not typically need to be verified in real time by the BICR.
Per iRECIST (Section 8.2.1.5), disease progression should be confirmed by the site 4 to 
8 weeks after site-assessed first radiologic evidence of PD in clinically stable participants. 
Participants who have unconfirmed disease progression may continue on treatment at the 
discretion of the investigator until progression is confirmed by the site provided they have 
met the conditions detailed in Section 8.2.1.5. Participants who receive confirmatory imaging 
do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks later; 
tumor imaging may resume at the subsequent scheduled imaging time point, if clinically 
stable. Participants who have confirmed disease progression by iRECIST, as assessed by the 
site, will discontinue study intervention. Exceptions are detailed in Section 8.2.1.5.
8.2.1.3
End-of-Treatment and Follow-up Tumor Imaging
For participants who discontinue study intervention, tumor imaging should be performed at 
the time of treatment discontinuation (±4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study intervention due to documented 
disease progression, this is the final required tumor imaging if the investigator elects not to 
implement iRECIST.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring disease status by tumor imaging using 
the same imaging schedule used while on treatment calculated from the date of first 
pembrolizumab administration (see Section 8.2.1.2) until the start of a new anticancer 
treatment, disease progression, pregnancy, death, withdrawal of consent, or the end of the 
study, whichever occurs first.
8.2.1.4
RECIST 1.1 Assessment of Disease
RECIST 1.1 will be used by BICR as the primary measure for assessment of tumor response, 
date of disease progression, and as a basis for all protocol guidelines related to disease status 
(eg, discontinuation of study intervention). Although RECIST 1.1 references a maximum of 
5 target lesions in total and 2 per organ, this protocol allows a maximum of 10 target lesions 
in total and 5 per organ, if clinically relevant to enable a broader sampling of tumor burden.
8.2.1.5
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by the investigator to assess tumor 
response and progression, and make treatment decisions. When clinically stable, participants 
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should not be discontinued until progression is confirmed by the investigator, working with 
local radiology, according to the rules outlined in Appendix 8. This allowance to continue 
treatment despite initial radiologic PD takes into account the observation that some 
participants can have a transient tumor flare in the first few months after the start of 
immunotherapy, and then experience subsequent disease response. This data will be captured 
in the clinical database.
Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of 
disease

No decline in ECOG performance status

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
iCRO for potential retrospective BICR.
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
If a participant has confirmed radiographic progression (iCPD) as defined in Appendix 8, 
study intervention should be discontinued; however, if the participant is achieving a 
clinically meaningful benefit, an exception to continue study intervention may be considered 
following consultation with the Sponsor. In this case, if study intervention is continued, 
tumor imaging should continue to be performed following the intervals as outlined in
Section 8.2.1.2 and submitted to the iCRO.
A description of the adaptations and iRECIST process is provided in Appendix 8, with 
additional details in the iRECIST publication [Seymour, L., et al 2017]. A summary of 
imaging and treatment requirements after first radiologic evidence of progression is provided 
in Table 11 and illustrated as a flowchart in Figure 2.
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Table 11
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD by 
RECIST 1.1 per 
investigator assessment
Repeat imaging 
at 4 to 8 weeks 
to confirm PD
May continue 
study treatment at 
the assessment of 
the investigator 
and after the 
participant’s 
consent
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
First radiologic 
evidence of PD by 
RECIST 1.1.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD.
May continue 
study intervention
at the 
investigator’s 
discretion while 
awaiting 
confirmatory 
tumor imaging by 
site by iRECIST.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor imaging 
confirms PD (iCPD) by 
iRECIST per 
investigator 
assessment.
No additional 
imaging 
required.
Discontinue 
treatment 
(exception is 
possible upon 
consultation with 
Sponsor).
No additional 
imaging required.
Not applicable
Repeat tumor imaging 
shows iUPD by 
iRECIST per 
investigator 
assessment.
Repeat imaging 
at 4 to 8 weeks 
to confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit.
Continue study 
intervention at the 
investigator’s 
discretion.
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
investigator’s 
discretion only.
Discontinue 
treatment
Repeat tumor imaging 
shows iSD, iPR, or 
iCR by iRECIST per 
investigator 
assessment.
Continue 
regularly 
scheduled 
imaging 
assessments.
Continue study 
intervention at the 
investigator’s 
discretion.
Continue regularly 
scheduled imaging 
assessments.
May restart study 
intervention if 
condition has 
improved and/or 
clinically stable 
per investigator’s 
discretion. Next 
tumor imaging 
should occur 
according to the 
regular imaging 
schedule.
iCPD=iRECIST confirmed progressive disease; iCR=iRECIST complete response; iRECIST=modified 
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; iSD=iRECIST stable 
disease; iUPD=iRECIST unconfirmed progressive disease; PD=progressive disease; RECIST 1.1=Response 
Evaluation Criteria in Solid Tumors 1.1; VOP=verification of progression
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Figure 2
Imaging and Treatment for Clinically Stable Participants Treated With 
Pembrolizumab After First Radiologic Evidence of PD Assessed by the 
Investigator
iRECIST=modified Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; 
PD=progressive disease; RECIST 1.1=Response Evaluation Criteria in Solid Tumors 1.1.
8.2.2
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of study intervention, and during the follow-up period as 
specified in the SoA (Section 1.3).
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 Procedures 
Manual.
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings should be recorded 
as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of study intervention and during the follow-up period as 
specified in the SoA. Vital signs include temperature, pulse, respiratory rate, weight, and 
blood pressure. Height will be measured at screening only. Weight will be measured at 
screening, at every other cycle, and in follow-up as specified in the SoA. 
8.3.3
Electrocardiograms
A standard 12-lead electrocardiogram (ECG) will be performed using local standard 
procedures. The timing of ECGs is specified in the SoA. Clinically significant abnormal 
findings should be recorded as medical history. Additional ECGs may be performed as 
clinically necessary.
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 case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
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significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.

All protocol-required laboratory assessments, as defined in Appendix 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 30 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 Study Flow Chart (Section 1.3) for the timing of laboratory 
assessments.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
8.3.4.2
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 72 hours of the 
first dose of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
test result. Repeated pregnancy test (such as monthly testing) may be conducted if required 
by local regulation.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
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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. 
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 30 days following cessation 
of study intervention must be reported by the investigator.

All AEs meeting serious criteria, from the time of intervention randomization through 90 
days following cessation of study intervention or 30 days following 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 120 days following cessation of study intervention, or 30 days 
following 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 of 
the time period 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 he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
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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 12.
Table 12
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE) including 
Cancer and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- potential drug-
induced liver 
injury (DILI)
- require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
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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. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 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 towards 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 suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
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. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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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 monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that upon review is 
not progression of the cancer under study will be forwarded to Global Pharmacovigilance as 
an SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
2. An elevated AST or ALT laboratory value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin laboratory value that is greater than or 
equal to 2X the upper limit of normal and, at the same time, an alkaline phosphatase 
laboratory value that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
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 V937 by >50% of the indicated dose or a pembrolizumab dose of ≥1000 mg (≥5 
times the indicated dose). No specific information is available on the treatment of overdose 
of V937 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.
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8.6
Pharmacokinetics
PK supports evaluation of V937 and pembrolizumab immunogenicity and exposure of the 
proposed dosing regimen. Blood samples were obtained to evaluate V937 exposure which 
are used to derive PK of V937 RNA and serum pembrolizumab. PK parameters for 
pembrolizumab (eg, Ctrough) at planned visits and times will be summarized. PK parameters 
for V937 RNA (eg, AUC and Cmax) at planned visits and times will be summarized. If 
ongoing ADA and/or PK results continue to be consistent with existing ADA and/or PK data 
from other pembrolizumab clinical studies, it may be decided to discontinue or reduce further 
sample collection in this study. Should this occur, it will be communicated by an 
administrative memo.
If ongoing PK, neutralizing V937 antibodies and anti-pembrolizumab antibody analysis is 
deemed to be unnecessary by the Sponsor, it may be reduced or discontinued.
PK collection is no longer required.
8.6.1
Blood Collection for V937 and Pembrolizumab
8.6.1.1
Blood Collection for PK
PK sample collection is no longer required.
8.6.1.2
Blood Collection for Neutralizing V937 Antibodies and Antipembrolizumab 
Antibodies
Neutralizing V937 antibodies and antipembrolizumab antibody sample collection is no 
longer required.
8.7
Pharmacodynamics
8.7.1
Blood for Pharmacodynamic Markers
Sample collection is no longer required.
8.7.2
Tumor Biopsy
Participants in Arms 1 and 2 will be required to provide mandatory tumor biopsies at C1D1 
(predose) and C1D8 (predose) unless deemed medically unsafe by the investigator. A tumor
biopsy on C2D1 (predose) is optional. Tumor samples will be collected at the time points 
described in Section 1.3 – SoA.
Predose biopsy collection on above visits can be performed within 48 hour prior to dosing.
Tumor biopsies will only be performed at tumor sites that are deemed medically safe, in 
accordance with local guidelines.
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In Arm 2, for the tumor lesion intended for treatment with ITu injection of V937 and the 
distant/discrete lesion, the sample will be obtained by either punch biopsy for cutaneous 
lesions, or by ultrasound guided biopsy for subcutaneous lesions. These biopsies will be 
collected within 48 hours preceding ITu administration of V937. On-treatment biopsy site 
location may vary from baseline biopsy site location based on lesion accessibility and 
participant tolerance.
Leftover main study tissue will be stored for FBR if the participant signs the FBR consent. 
Detailed instructions for tissue collection, processing, and shipment are provided in the 
Central Laboratory Manual.
8.8
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA (collection no longer required):
•
Blood for genetic analysis
•
Blood for biomarker analyses
•
Tumor biopsy
•
Serum for biomarker analyses
•
Blood for ctDNA analysis
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but future 
biomedical research is approved and consent is given, this sample will be collected for the 
purpose of future biomedical research.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of future biomedical research:

Leftover from specimens listed in Section 8.8, Biomarkers
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8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Written consent must be obtained prior to performing any protocol-specific procedure. 
Results of a test performed prior to the participant signing consent as part of routine clinical 
management are acceptable in lieu of a screening test if performed within the specified time 
frame. Screening procedures are to be completed within 28 days prior to the first dose of 
study intervention except for the following:

Laboratory tests are to be performed within 72 hours prior to the first dose of study 
intervention. An exception is hepatitis testing which may be done up to 28 days prior to 
the first dose of study intervention.

Evaluation of ECOG is to be performed within 72 hours prior to the first dose of study 
intervention.

For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 72 hours prior to 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.
8.10.2
Treatment Period/Vaccination Visit
The treatment period in each treatment arm begins with Cycle 1 (Arms 1 and 2: Cycle 1 
Day 1 and Arm 3: Cycle 1 Day 8;) and may continue for up to 35 cycles (approximately 
2 years) from the start of treatment until disease progression, unacceptable AE(s), 
intercurrent illness that prevents further administration of treatment, investigator’s decision 
to withdraw the participant, participant withdraws consent, pregnancy of the participant, 
noncompliance with study treatment or procedure requirements, or administrative reasons
requiring cessation of treatment. Each cycle includes study drug administration and all 
associated assessments as outlined in the SoA (Section 1.3). 
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
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8.10.3
Discontinued Participants Continuing to be Monitored in the Study
Discontinuation of treatment does not represent withdrawal from the study.
The End of Treatment Visit should occur at the time study intervention is discontinued for 
any reason. If the End of Treatment Visit occurs 30 days from the last dose of study 
intervention, at the time of the mandatory Safety Follow-up Visit, the End of Treatment
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.
8.10.4
Posttreatment Visit
8.10.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
All AEs that occur prior to the Safety Follow-up Visit should be recorded (up to 30 days 
following end of treatment).
Due to early study discontinuation, participants may be enrolled in a pembrolizumab 
extension study, if available, to continue pembrolizumab monotherapy. The Safety Follow-
up will not be required for such participants.
8.10.4.2
Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for a reason other than disease progression will begin the 
Imaging Follow-up and should be assessed every 9 weeks to monitor disease status. Every 
effort should be made to collect information regarding disease status until the start of new 
anticancer therapy, disease progression, death, or the end of study, whichever occurs first.
Information regarding poststudy anticancer treatment will be collected if new treatment is 
initiated. Participants who completed all imaging assessments and/or will not have further 
efficacy assessments must enter the Survival Follow-up Phase.
Due to early study discontinuation, participants may be enrolled in a pembrolizumab 
extension study, if available, to continue pembrolizumab monotherapy. The Imaging Follow-
up will not be required for such participants.
8.10.4.3
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 including early 
study closure, whichever occurs first.
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The first survival follow-up assessment should be scheduled as described below:
•
For participants who discontinue treatment intervention and who will not enter the 
Efficacy Follow-up Phase, the first survival follow-up contact will be scheduled 12 
weeks after the discontinuation visit and/or safety follow-up visit (whichever is last).
•
For participants who completed assessments in the Efficacy Follow-up Phase, the first 
survival follow-up contact will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
Due to early study discontinuation, participants may be enrolled in a pembrolizumab 
extension study, if available, to continue pembrolizumab monotherapy. The Survival Follow-
up contact will not be required for such participants.
8.10.5
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to 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 time period will be 
contacted for their survival status (excluding participants that have a previously recorded 
death event in the collection tool).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study. Exploratory and other nonconfirmatory analyses will be 
outlined in a separate supplemental Statistical Analysis Plan (sSAP).
If, after the study has begun, changes are made to primary and/or secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other nonconfirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analyses, will be 
documented in the sSAP as needed and referenced in the Clinical Study Report (CSR) for the 
study. Separate analysis plans may be developed for PK/modeling analysis, biomarker 
analysis, and genetic data analysis. Post hoc exploratory analyses will be clearly identified in 
the CSR.
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9.1
Statistical Analysis Plan Summary
Study Design Overview
A Phase 2, randomized study of IV or ITu administration of V937 in 
combination with pembrolizumab versus pembrolizumab alone in 
participants with advanced/metastatic melanoma
Treatment Assignment
Approximately 135 participants will be randomized in a 1:1:1 ratio to Arm 1
(IV pembro + IV V937), Arm 2 (IV pembro + ITu V937) and Arm 3 (IV
pembro alone). The stratification factor is (M1c+M1d) versus others. 
Analysis Populations
Efficacy (Primary and Secondary): Intention-to-Treat (ITT)
Safety (Secondary): All-Participants-as-Treated (APaT)
Primary Endpoint(s)
Objective response (OR) is a confirmed complete response (CR) or partial 
response (PR) by RECIST 1.1 as assessed by BICR.
Secondary Endpoints

Progression-free Survival (PFS) and Duration of response (DOR) by 
RECIST 1.1 as assessed by BICR.

OR, PFS and DOR per RECIST 1.1 as assessed by investigator. 

Overall survival (OS)

Adverse events (AEs)

Discontinuing study intervention due to AE.
Statistical Methods for Key 
Efficacy
The primary hypothesis comparing Arm 1 to Arm 3, and Arm 2 to Arm 3
with regard to ORR will be evaluated using the stratified Miettinen and 
Nurminen method [Miettinen, O. and Nurminen, M. 1985]. The ORR 
between Arm 1 and Arm 2 will be compared without formal hypothesis 
testing. DOR will be summarized descriptively using Kaplan-Meier 
medians and quartiles if the sample size permits. The nonparametric 
Kaplan-Meier method will be used to estimate the PFS and OS curve in 
each treatment group. The hazard ratio for PFS and OS will be estimated 
using a stratified Cox regression model.
Statistical Methods for Key 
Safety Analyses
The analysis of safety results will follow a tiered approach for the 
comparison of Arm 1 vs Arm 3, Arm 2 vs Arm 3, and Arm 1 vs Arm 2. 
The tiers differ with respect to the analyses that will be performed. There 
is no Tier 1 safety endpoint for this study. Tier 2 parameters will be 
assessed via point estimates with 95% confidence intervals (CIs) provided
for between-arm comparisons; only point estimates by treatment arm are 
provided for Tier 3 safety parameters. The 95% CIs for the 
between -treatment differences in percentages will be provided using the 
Miettinen and Nurminen method.
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Sample Size and Power 
The planned sample size for this study is approximately 135 participants or 
less due to early study termination.
 
 
 
 
 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate a randomized allocation schedule for study treatment assignment 
for this protocol, and the randomization will be implemented in IRT.
Independent radiologists will perform the central imaging review without knowledge of 
treatment assignments.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy/Pharmacokinetics/Pharmacodynamic Endpoints
Primary Endpoint

Objective Response (OR): a confirmed complete response (CR) or partial response (PR) 
per RECIST 1.1 based on BICR. ORR is the proportion of participants with objective 
response.
Secondary Endpoints

PFS: time from randomization to the first documented PD per RECIST 1.1 based on 
BICR or death from any cause, whichever occurs first. See Section 9.6.1 for the 
definition of censoring.

DOR: time from the first documented evidence of CR or PR until PD per RECIST 1.1 as 
assessed by BICR or death due to any cause, whichever occurs first, in participants 
demonstrating CR or PR.

OS: time from randomization to the date of death due to any cause.
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9.4.2
Safety Endpoints
Safety endpoint is the number/proportion of participants with AEs, and who discontinue 
study treatment due to AEs. In addition, safety and tolerability will be assessed by clinical 
review of all relevant parameters including adverse events (AEs), laboratory tests, and vital 
signs.
A description of safety measures is provided in Section 8.3 – Safety Assessments.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The analyses of efficacy endpoints (ORR, PFS, OS and DOR) are based on the 
intention-to-treat (ITT) population. All randomized participants will be included in this 
population. Participants will be analyzed in the treatment arm to which they are randomized. 
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9.5.3
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who receive at least 1 dose of study 
treatment. Participants will be analyzed in the treatment arm corresponding to the study 
treatment they actually receive. For most participants, this will be the treatment group to 
which they are randomized. Participants who receive incorrect study treatment for the entire 
treatment period will be included in the treatment arm corresponding to the study treatment 
actually received. Any participant who receives incorrect study medication for 1 cycle, but 
receives the correct treatment for all other cycles, will be analyzed according to the correct 
treatment group, and a narrative will be provided for any events that occur during the cycle 
for which the participant is incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory objectives will be described in the sSAP. The final 
analyses will be performed using all data available.
9.6.1.1
Objective Response
The stratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] will 
be used for the ORR comparison (Arm 1 vs Arm 3; Arm 2 vs Arm 3). The difference in 
ORR, 90% CI and p -values from the stratified Miettinen and Nurminen method with strata 
weighted by sample size will be reported. The stratification factor used for randomization 
(Section 6.3.2) will be applied to the analysis.
The ORR difference between Arm 1 and Arm 2 will also be evaluated via stratified Miettinen 
and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. The difference in ORR and 
its 90% CI will be reported. 
9.6.1.2
Progression-free Survival
The nonparametric Kaplan-Meier method will be used to estimate the PFS curve in each 
treatment group. The treatment difference in PFS will be assessed by the stratified log-rank 
test. A stratified Cox proportional hazard model with Efron's method of tie handling will be 
used to assess the magnitude of the treatment difference (ie, the HR) between the treatment 
arms. The HR and its 95% CI from the stratified Cox model with Efron's method of tie 
handling and with a single treatment covariate will be reported. The stratification factor used 
for randomization (Section 6.3.2) will be applied to both the stratified log-rank test and the 
stratified Cox model. 
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Because disease progression is assessed periodically, PD can occur any time in the interval 
between the last assessment when PD is not documented and the assessment when PD is 
documented. For the primary analysis, for participants with PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1, based on BICR. Death is always considered as a 
confirmed PD event. Participants who do not experience a PFS event will be censored at the 
last disease assessment. Sensitivity analyses will be performed for comparison of PFS based 
on the investigator's assessment.
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 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 Cox 
model with a single treatment covariate will be reported. The stratification factors used for 
randomization (Section 6.3.2) will be applied to both the stratified log-rank test and the 
stratified Cox model. Participants without documented death at the time of analysis will be 
censored at the date of last known contact. 
9.6.1.4
Duration of Response
For participants with a CR or PR, whichever occurs first; censoring rules for DOR are 
summarized in Table 13. DOR will be assessed using RECIST 1.1 by BICR, RECIST 1.1 by 
investigator, and iRECIST by investigator.
For each DOR analysis, a corresponding summary of the reasons for which responding 
participants are censored will also be provided. Responses in participants who are alive, have 
not progressed, have not initiated new anticancer treatment, and have not been determined to 
be lost to follow-up, and who have had a disease assessment within approximately 5 months 
of the data cutoff date, are considered ongoing at the time of analysis. If a participant meets 
multiple criteria for censoring, the censoring criterion that occurs earliest will be applied.
If the sample size permits, DOR will be summarized descriptively using Kaplan-Meier 
medians and quartiles. Only the subset of participants with a confirmed CR or PR will be 
included in this analysis. 
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Table 13
Censoring Rules for Duration of Response
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new 
anticancer therapy initiated
Last adequate disease assessment 
before new anticancer therapy was 
initiated
Censor
(non-event)
Death or progression immediately 
after ≥2 consecutive missed disease 
assessments or after new anticancer 
therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥2 missed 
adequate disease assessments and 
new anticancer therapy, if any
Censor
(non-event)
Death or progression after ≤1 missed 
disease assessments and before new 
anticancer therapy, if any
Progressive disease or death
End of response
(Event)
A missed disease assessment includes any assessment that is not obtained, or is considered inadequate for 
evaluation of response.
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints
Table 14 summarizes the analysis strategy for the primary and secondary efficacy endpoints.
Table 14
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
Objective Response 
(RECIST 1.1 by 
BICR)
Test and estimation:
Stratified Miettinen and 
Nurminen method.
ITT
Participants with missing data are 
considered nonresponders
Secondary Analyses
Objective Response 
(RECIST 1.1 by 
Investigator)
Estimation:
Stratified Miettinen and 
Nurminen method.
ITT
Participants with missing data are 
considered nonresponders
PFS (RECIST 1.1 
by BICR and
RECIST 1.1 by 
investigator)
Summary statistics using 
Kaplan-Meier method
Estimation: stratified Cox model 
with Efron's tie-handling 
method
ITT
See section 9.6.1.2
DOR (RECIST 1.1
by BICR and
RECIST 1.1 by 
investigator)
Summary statistics using 
Kaplan-Meier method
All 
responders 
in ITT
Censored according to rules in
Table 13
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Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
OS
Summary statistics using 
Kaplan-Meier method
Estimation: stratified Cox model 
with Efron's tie-handling 
method
ITT
Censored at last known alive date
BICR=blinded independent central review; DOR=duration of response; ITT=intention-to-treat; 
ORR=objective response rate; OS=overall survival; PFS=progression-free survival; RECIST 1.1=Response 
Evaluation Criteria in Solid Tumors Version 1.
Note: Sensitivity analyses will be performed for PFS, ORR, and DOR based on investigator's assessment.
9.6.2
Statistical Methods for Safety Analyses
There are no safety hypotheses for this study. Safety and tolerability will be assessed by 
clinical review of all relevant parameters, including AEs, laboratory tests, and vital signs.
The analysis of safety results will follow a tiered approach (Table 15). The tiered approach 
will be used for the comparisons of Arm 1 vs Arm 3, Arm 2 vs Arm 3, and Arm 1 vs Arm 2.
The tiers differ with respect to the analyses that will be performed. Adverse Events (specific 
terms as well as system organ class terms) and events that meet pre-defined limits of change 
(PDLCs) in laboratory, vital sign, and ECG parameters are either pre-specified as Tier 1
events, or will be classified as belonging to Tier 2 or Tier 3 based on the number of events 
observed.
Tier 1 Events
Safety parameters or adverse events of special interest (AEOSIs) that are identified a priori
constitute Tier 1 safety events that will be subject to inferential testing for statistical 
significance. 
AEOSIs that are immune mediated or potentially immune mediated are well documented and 
will be evaluated separately; however, these events have been characterized consistently 
throughout the pembrolizumab clinical development program and determination of statistical 
significance is not expected to add value to the safety evaluation. The combination of 
pembrolizumab and V937 has not been associated with any new safety signals. Finally, based 
on review of historic data from ongoing V937 and pembrolizumab clinical studies, there are 
no known AEs associated with participants with melanoma for which determination of a 
p -value is expected to impact the safety assessment. Therefore, there are no Tier 1 events for 
this protocol.
Tier 2 Events
Tier 2 events will be assessed via point estimates with 95% confidence intervals provided for 
differences in the proportion of participants with events using the Miettinen and Nurminen 
method, an unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985].
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Membership in Tier 2 requires that at least 4 participants (~10%) in any treatment arm 
exhibit the event. The threshold of at least 4 events was chosen because the 95% CI for the 
between-group difference in percent incidence will always include zero when treatment 
groups of equal size each have less than 4 events and thus would add little to the 
interpretation of potentially meaningful differences. In addition, Grades 3 to 5 AEs and SAEs 
with at least 2 participants (~5%) in 1 of the treatment arms will be considered Tier 2 events. 
Because many 95% CIs may be provided without adjustment for multiplicity, the CIs should 
be regarded as a helpful descriptive measure to be used in safety review, not a formal method 
for assessing the statistical significance of the between treatment differences.
In addition to individual events that occur in 4 or more participants in any treatment group, 
the broad AE categories consisting of the proportion of participants with any AE, a drug-
related AE, a Grade 3 to 5 AE, an AE that is both Grade 3 to 5 and drug-related, a serious 
AE, an AE that is both serious and drug-related, a dose interruption(s) due to an AE, and a 
discontinuation due to an AE will be considered Tier 2 endpoints.
Tier 3 Events
Safety events that are not Tier 1 or Tier 2 events will be considered Tier 3 events. Only point 
estimates by treatment arm will be provided for Tier 3 safety parameters.
Continuous Safety Measures
For continuous measures such as changes from baseline in laboratory, vital sign, and ECG
parameters, summary statistics for baseline, on -treatment, and change from baseline values 
will be provided by treatment arm in table format.
Table 15
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE
X
X
Any serious AE 
X
X
Any Grade 3 to 5 AE
X
X
Any drug-related AE
X
X
Any serious and drug-related AE
X
X
Any Grade 3 to 5 and drug-related AE
X
X
Dose interruption(s) due to AE
X
X
Discontinuation due to AE
X
X
Specific AEs, SOCs (incidence ≥4 participants in 
one of the treatment groups)
X
X
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Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 3
Specific AEs, SOCs (incidence <4 participants in 
both treatment groups) or PDLCs
X
Change from baseline results (laboratory, vital signs)
X
AE=adverse events; CI=confidence interval; SOC=system organ class; PDLC=predefined limit of change.
Note: X = results will be provided.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analysis
9.6.3.1
Demographic and Baseline Characteristics 
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be presented in tables and/or graphs. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants randomized 
and the primary reason for discontinuation will be displayed. Demographic variables (such as 
age) and baseline characteristics will be summarized by treatment either by descriptive 
statistics or categorical tables.
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9.9
Sample Size and Power Calculations
The study will randomize approximately 135 participants or less due to early study 
termination in a 1:1:1 ratio to Arm 1 (IV pembro + IV V937),
Arm 2 (IV pembro + ITu V937), and Arm 3 (IV pembro alone).
CCI
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CCI
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9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
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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)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection regulations), and
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also 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. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the 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.
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. 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. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or 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.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review 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.
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 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
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The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
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
Not applicable.
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 
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standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated 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 directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
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, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 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 Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
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The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
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.
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.
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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 the table below will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of relevant systemic exposure.
-
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 subject's participation in the study.
Protocol-required Safety Laboratory Assessments
Hematology
Comprehensive Chemistry 
Panel
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine)a
Hemoglobin
Alkaline phosphatase
Glucose
Total T3 (or Free T3 
[FT3]), Total T4 (or Free 
T4 [FT4]), and TSHb,c
Platelet count
Alanine aminotransferase
Protein
Anti-HCV e
WBC (total and 
differential)d
Aspartate aminotransferase
Specific gravity 
HCV viral loadc, e
RBC
Carbon dioxide or bicarbonate
Microscopic examination, 
if abnormal results are 
noted
HIV Viral Load, HIV 1,2 
Antibody e, f
Absolute 
lymphocyte countd
Calcium
anti-HBsc, e
Chloride
HbsAg 
Absolute neutrophil 
countd
Creatinine
anti-HBc (total and 
IgM)c, e
PT/INR
Glucose
HbeAgc, e
PTT or aPTT
Phosphorus
anti-Hbec, e
Basophil
Potassium
HBV viral loadc, e
Eosinophil
Sodium
CD4+ T-cell count f
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Hematology
Comprehensive Chemistry 
Panel
Urinalysis
Other
Monocyte
Total bilirubin
Direct bilirubin
Total protein
Blood urea nitrogen
Urea
Lactate dehydrogenase
aPTT=activated partial thromboplastin time; HBc=hepatitis B core; HBeAg=hepatitis B e-antigen; 
HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; INR=International Normalized Ratio; PT=prothrombin time; PTT=partial 
thromboplastin time; RBC=red blood count; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating 
hormone; WBC=white blood count.
a Perform on women of childbearing potential only 72 hours prior to Day 1 of Cycle 1. Pregnancy tests must 
be repeated prior to every cycle if required or as specified per local regulatory guidance.
b T3 is preferred; if not available, Free T3 may be tested.
c If the local laboratory is unable to perform these tests, the site should submit the sample to the central 
laboratory for testing. Details are provided in the Laboratory Manual.
d Report % or absolute results per standard of practice. Report the results in the same manner throughout the 
study.
e Only collect if consistent with local requirements.
f For HIV-positive participants only
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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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 (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, 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 pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
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
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
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 considered a reportable event unless it results in hospitalization or death.
Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 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.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing 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.

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 in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.

Is a new cancer (that is not a condition of the study)
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
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.
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.
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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 investigational medicinal product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
-
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
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◦
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 his/her best clinical judgment, 
including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
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
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 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 electronic data collection 
(EDC) tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
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
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail 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: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
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 two FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception 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,d

IUSd,e

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 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,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable

Progestogen-only hormonal contraceptionc,d
-
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 contraceptive implants are limited to those 
which inhibit ovulation.
d.
Male condoms must be used in addition to female participants hormonal contraception.
e.
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 8.9 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 Research. 3,4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research
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b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at 
a study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated 
in the SoA. If delayed, present consent at next possible Participant Visit. Consent 
forms signed by the participant will be kept at the clinical study site under secure 
storage for regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be 
captured in the eCRFs. Any specimens for which such an informed consent cannot 
be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as 
outlined in the SoA. In general, if additional blood specimens are being collected 
for future biomedical research, these will usually be obtained at a time when the 
participant is having blood drawn for other study purposes.
4.
Confidential Participant Information for Future Biomedical Research3,4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. 
In fact little or no research can be conducted without connecting the clinical study data 
to the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes 
are critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers 
will appear on the specimen tube.
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5.
Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be 
performed by the Sponsor, or an additional third party (eg, a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in future biomedical research 
protocol and consent. Future biomedical research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6.
Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for future biomedical research and ask that 
their biospecimens not be used for future biomedical research. Participants may 
withdraw consent at any time by contacting the investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if 
the investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this 
situation, the request for withdrawal of consent and/or destruction cannot be processed.
7.
Retention of 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 main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped 
to the Sponsor-designated biorepository. If a central laboratory is not utilized in a 
particular study, the study site will ship directly to the Sponsor-designated 
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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.
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.
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13.
References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for 
Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and 
Sample Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
United Kingdom
Sections 1.3.2 (Table 2), 1.3.3 (Table 3), and 1.3.4 (Table 4) - Schedule of Activities for the
Treatment Period
This language replaces what is documented in the corresponding section of the referenced 
tables.
Assessment
Note
Pregnancy test for 
WOCBP only (urine or
serum hCG)
Perform within 72 h prior to C1D1. Urine pregnancy test to 
be performed as indicated; if test is positive or cannot be 
confirmed as negative, a serum pregnancy test is required. 
Thereafter, pregnancy testing should be performed 
approximately monthly.
Section 5.1 – Inclusion Criteria
This language replaces what is documented in the corresponding section of the protocol.
8. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 120 days:
•
Refrain from donating sperm (from screening to 120 days after the last study 
intervention)
                  PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long-term and persistent basis) and agree to remain abstinent
                  OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
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Section 6.5.2 – Prohibited Concomitant Medications
This language replaces what is documented in the corresponding bullet of the protocol.
•
Live vaccines within 30 days prior to the first dose of study intervention, while 
participating in the study, and for 90 days after the end of study intervention. Examples 
of live vaccines include, but are not limited to, the following: measles, mumps, rubella, 
varicella/zoster, yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and typhoid 
vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and 
are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed.
Section 8.3.4.2 – Pregnancy Testing
This language replaces what is documented in the corresponding section of the protocol.
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 72 hours of the 
first dose of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
test result. During study treatment, pregnancy testing should be repeated approximately 
monthly and then again 30 days after the last study dose of study treatment.
Appendix 2 Clinical Laboratory Tests
This language replaces what is documented in corresponding table footnote.
Footnote to the table reads: 
a.Perform on women of childbearing potential only 72 hours prior to Day 1 of Cycle 1. 
Pregnancy tests must be repeated approximately monthly.
Norway
Sections 1.3.5 (Table 1)- Schedule of Activities for the End of Treatment and Posttreatment 
Follow-up Periods
This language replaces what is documented in the corresponding section of the referenced 
tables.
Assessment
Notes
Pregnancy Test for 
WOCBP – Urine or 
Serum hCG
For WOCBP, perform as required locally. If a urine pregnancy 
test cannot be confirmed as negative, a serum pregnancy test is 
required. Monthly pregnancy testing should be conducted up to 
120 days after the last administration of pembrolizumab.
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5.2 Exclusion Criteria
This language replaces what is documented in the corresponding section of the protocol.
Exclusion criterion 21 “Has an active infection requiring systemic therapy, with the 
exception of HIV infection.”
Section 8.8.1 Planned Genetic Analysis Sample Collection
In this study, genetic analyses will be performed.
In cases where comprehensive mapping of the participant’s genomes are conducted, the 
Norwegian legislation will be adhered to.
If a significant health finding is observed in a participant during the trial, the finding will be 
assessed and the participant informed, if required, in accordance with the Norwegian 
legislation.
France
6.6.2 Dose Modification for Pembrolizumab
The following information provides additional irAEs and related details to what is stated in
Table 9.
irAEs
Toxicity grade (CTCAE v5.0)
Action with pembrolizumab
Endocrinopathies
Grade 2 adrenal insufficiency and 
hypophysitis
Withhold treatment until controlled by 
hormone replacement
Grades 3 or 4 adrenal insufficiency 
or symptomatic hypophysitis
Type 1 diabetes associated with 
Grade ≥3 hyperglycemia (glucose 
>250 mg/dL or >13.9 mmol/L) or 
associated with ketoacidosis
Hyperthyroidism Grade ≥3
Withhold until adverse reactions recover to 
Grades 0-1a
For patients with Grade 3 or Grade 4 
endocrinopathies that improved to Grade 2 or 
lower and are controlled with hormone 
replacement, if indicated, continuation of 
pembrolizumab may be considered after 
corticosteroid taper, if needed. Otherwise 
treatment should be discontinued.
Hypothyroidism
Hypothyroidism may be managed with 
replacement therapy without treatment 
interruption.
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irAEs
Toxicity grade (CTCAE v5.0)
Action with pembrolizumab
Hepatitis
Grade 2 with aspartate 
aminotransferase (AST) or alanine 
aminotransferase (ALT) >3 to 5
times ULN or total bilirubin >1.5 to 
3 times ULN
Withhold until adverse reactions recover to 
Grades 0-1a
Grade ≥3 with AST or ALT 
>5 times ULN or total bilirubin 
>3 times ULN
Permanently discontinue
In case of liver metastasis with 
baseline Grade 2 elevation of AST 
or ALT, hepatitis with AST or ALT 
increases ≥50% and lasts ≥1week
Permanently discontinue
Skin reactions
Grade 3 or suspected Stevens-
Johnson syndrome (SJS) or toxic 
epidermal necrolysis (TEN)
Withhold until adverse reactions recover to 
Grades 0-1a
Grade 4 or confirmed SJS or TEN
Permanently discontinue
a If treatment-related toxicity does not resolve to Grades 0-1 within 12 weeks after last dose of 
pembrolizumab, or if corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks, pembrolizumab should be permanently discontinued.
Italy
6.6.2 Dose Modification for Pembrolizumab
The following information provides additional irAEs and related details to what is stated in 
Table 9.
irAEs
Toxicity grade (CTCAE v5.0)
Action with pembrolizumab
Skin reactions
Grade 3 or suspected Stevens-
Johnson syndrome (SJS) or toxic 
epidermal necrolysis (TEN)
Withhold until adverse reactions recover to 
Grades 0-1a
Grade 4 or confirmed SJS or TEN
Permanently discontinue
a If treatment-related toxicity does not resolve to Grades 0-1 within 12 weeks after last dose of 
pembrolizumab, or if corticosteroid dosing cannot be reduced to ≤10 mg prednisone or equivalent per day 
within 12 weeks, pembrolizumab should be permanently discontinued.
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study 
intervention until repeat imaging 4 to 8 weeks later is obtained (using iRECIST for 
participant management (see Table 11 and Figure 2). This decision by the investigator should 
be based on the participant’s overall clinical condition.
Clinical stability is defined as the following:

Absence of symptoms and signs indicating clinically significant progression of disease

No decline in ECOG performance status

No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at   
site-assessed first radiologic evidence of PD, and is not required to have repeat tumor 
imaging for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
iCRO for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
Note: The iRECIST publication uses the terminology “sum of measurements,” but “sum 
of diameters” will be used in this protocol, consistent with the original RECIST 1.1 
terminology.

Unequivocal progression of nontarget lesion(s) identified at baseline

Development of new lesion(s)
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iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment,
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the iUPD at the previous visit show worsening
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any of these:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point
◦
Visible growth of new nontarget lesions
◦
The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
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Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold.
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset.” This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit , an exception to continue study 
intervention may be considered following consultation with the Sponsor. In this case, if study 
intervention is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3 and submitted to the iCRO.
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Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions
-
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudo-progression. The nadir 
is always the smallest sum of diameters seen during the entire study, either before or 
after an instance of pseudo-progression.

Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD.
-
If nontarget lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.

New lesions
-
New lesions appear for the first time
-
Additional new lesions appear
-
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
-
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: If new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017]. 
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibodies
ADL
activities of daily living
AE
adverse event
ALT (SGPT)
alanine aminotransferase (serum glutamic pyruvic transaminase)
aPTT
activated partial thromboplastin time
AST (SGOT)
aspartate aminotransferase (serum glutamic oxaloacetic transaminase)
AUC
area under the curve
C
Cycle
CBC
complete blood count
Cmax
maximum plasma concentration
CNS
central nervous system 
CrCl
creatinine clearance
CRF
Case Report Form 
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor deoxyribonucleic acid;
CTFG
Clinical Trial Facilitation Group 
Ctrough
trough concentration
D
Day
DILI
drug-induced liver injury
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection 
EEA
European Economic Area
EMA
European Medicines Agency
F
free
FBR
future biomedical research
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
FSR
first site ready
GCP
Good Clinical Practice 
GFR
glomerular filtration rate
HBc
hepatitis B core
HBeAg
hepatitis B e antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
INR
International Normalized Ratio
IRB
Institutional Review Board 
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Abbreviation
Expanded Term
iRECIST
modified RECIST 1.1 for immune-based therapeutics
ITu
intratumoral(ly)
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous(ly)
LDH
lactate dehydrogenase
LLOQ
lower limit of quantitation
M1a
nonvisceral (distant cutaneous, subcutaneous, nodal) metastasis
M1b
lung metastasis
M1c
non-CNS viscera metastasis
M1d
CNS metastasis
MRI
magnetic resonance imaging
NCI
National Cancer Institute
ORR
objective response rate
PBMC
peripheral blood mononuclear cells
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PD-(L)1
programmed cell death (ligand) 1
pembro
pembrolizumab
PK
pharmacokinetic(s)
PT
prothrombin time
PTT
partial thromboplastin time
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
SAE
serious adverse event 
SoA
Schedule of Activities
SUSAR
suspected unexpected serious adverse reaction
T3
triiodothyronine
T4
thyroxine
TCID50
50% tissue culture infectious dose
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
WOCBP
woman/women of childbearing potential 
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