Conditions: Neoplasm Metastasis
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1)
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 76
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety, tolerability, and efficacy in participants with advanced/metastatic or recurrent malignancies who receive gebasaxturev (V937) in combination with pembrolizumab (MK-3475). The primary objective for Part 1 is to evaluate the objective response rate, and the primary objective for Part 2 is to determine the safety and tolerability of gebasaxturev administered in combination with pembrolizumab. With Amendment 4, this study will be terminated once all participants who have completed or discontinued gebasaxturev 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 V937-013.

Detailed description:

Arms:
arm 1: This arm will enroll participants with triple-negative breast cancer (TNBC) solid tumors. Participants receive 3 X 10\^8 50% tissue culture infectious dose (TCID50) of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. arm 2: This arm will enroll participants with head and neck squamous cell carcinoma (HNSCC) solid tumors. Participants receive 3 X 10\^8 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. arm 3: This arm will enroll participants with cutaneous squamous cell carcinoma (cSCC) solid tumors. Participants receive 3 X 10\^8 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. arm 4: This arm will enroll participants with solid tumors with liver metastases. Participants receive 3 X 10\^7 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. arm 5: This arm will enroll participants with solid tumors with liver metastases. Participants receive 1 X 10\^8 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. arm 6: This arm will enroll participants with solid tumors with liver metastases. Participants receive 3 X 10\^8 TCID50 of gebasaxturev intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. arm 7: This arm will enroll participants with hepatocellular carcinoma (HCC) solid tumors. Participants receive the gebasaxturev recommended phase 2 dose (RP2D) intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days. arm 8: This arm will enroll participants with gastric carcinoma solid tumors. Participants receive the gebasaxturev recommended phase 2 dose (RP2D) intratumorally for 8 cycles, and pembrolizumab intravenously for a maximum of 35 cycles. Cycle 1 is 28 days, and cycles 2-35 are 21 days.

Interventions: intervention 1: Gebasaxturev intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Participants receive gebasaxturev intratumorally for 1 28-day cycle followed by 7 21-day cycles. intervention 2: Participants receive pembrolizumab intravenously for 1 28-day cycle followed by 34 21-day cycles.

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 1b/2 Clinical Study of Intratumoral
Administration of V937 in
Combination with Pembrolizumab (MK-3475) in
Participants with Advanced/Metastatic
Solid Tumors
NCT04521621
25-October-2022


PRODUCT: V937  
1
PROTOCOL/AMENDMENT NO.: 013-04
V937-013-04 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 1b/2 Clinical Study of Intratumoral Administration of V937 in 
Combination with Pembrolizumab (MK-3475) in Participants with Advanced/Metastatic 
Solid Tumors
Protocol Number: 013-04
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
2020-001908-42
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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25-OCT-2022
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 04
25-OCT-2022
V937-013 is going to be discontinued due to the Sponsor’s development decision. The 
overall rationale for this amendment is to allow ongoing patients to transfer to another 
sponsored protocol to continue receiving pembrolizumab, incorporates previously released 
Protocol Clarification Letters, and updates the Sponsor corporate name.
Amendment 03
19-APR-2021
This amendment provides clarification to address agency feedback and also provides 
updated language to the pembrolizumab dose modification portion of the study.
Amendment 02
01-DEC-2020
The overall rationale for the amendment is to clarify existing language, provide country-
specific requirements, and to remove sections that are not applicable to this study.
Amendment 01
26-MAY-2020
The IND number was updated to address Agency feedback.
Original Protocol
14-MAY-2020
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendments:
V937-013 is going to be discontinued due to the Sponsor’s development decision. The overall rationale for this amendment is to allow 
ongoing patients to transfer to another sponsored protocol to continue receiving pembrolizumab; incorporate previously released 
Protocol Clarification Letters; and updates to the Sponsor corporate name.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1.2 Schema
1.3 Schedule of Activities
4.4.1 Clinical Criteria for Early 
Study Termination
Added language to allow participants to 
enroll in another study to continue 
receiving pembrolizumab.
Allows ongoing participants deriving benefit 
from pembrolizumab the opportunity to 
transfer to another active study upon study 
closure
1.1 Synopsis
1.2 Schema
4.1.1 Arm 1: Subcutaneous Tumors
4.1.3 Arm 2 Part II: Cohort 
Expansion in Metastatic Visceral 
Lesion Tumors
9.1 Statistical Analysis Plan 
Summary
9.9 Sample Size and Power 
Calculations
Added language indicating total planned 
enrollment number may not be met.
The study may not enroll the planned 185 
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 
Treatment Phase: Arm 1 -
Participants with Subcutaneous 
Tumors
1.3.3 Schedule of Activities for 
Treatment Phase: Arm 2 Part I -
Dose Escalation in Participants with 
Visceral Tumors
1.3.4 Schedule of Activities for 
Treatment Phase: Arm 2 Part II -
Cohort Expansion
1.3.5 Schedule of Activities for End 
of Treatment/Discontinuation and 
Posttreatment Phase: Arm 1, Arm 2 
Part I Dose Escalation Phase, and 
Arm 2 Part II Expansion Phase
Removed sample collections for serum for 
V937 PK (RNA), neutralizing V937
antibodies, blood for ctDNA analysis, 
blood for RNA analyses, and blood for 
genetic analyses.
Clarified that vital signs need not be 
collected post-dose of pembrolizumab 
when V937 is not administered.
Due to early study termination, collection of 
central laboratory samples is no longer 
required.
Clarification of vital sign collection 
information and timing.
1.3.5 Schedule of Activities for End 
of Treatment/Discontinuation and 
Posttreatment Phase: Arm 1, Arm 2 
Part I Dose Escalation Phase, and 
Arm 2 Part II Expansion Phase
8.11.3.1 Safety Follow-up Visit
8.11.3.2 Imaging Follow-up Visits
8.11.3.3 Survival Follow-up 
Contacts
Removed ‘Posttreatment Phase’ visits 
including Safety Follow-up, Imaging 
Follow-up, and Survival Follow-up visits.
Due to early study termination, completion of 
the 30-day Safety Follow-up visit, post-
treatment 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
8.6.1 Blood Collection for Serum 
V937
8.6.2 Blood Collection for 
Neutralizing V937 Antibodies
8.7 Pharmacodynamics
8.8 Biomarkers
Added statement related to collection of 
samples if study is terminated early
Updated collection information, due to early 
study termination.
Title Page
10.1.1 Code of Conduct for Clinical 
Trials
Throughout
Sponsor entity name and address change.
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.
1.1 Synopsis
6.1 Study Intervention(s) 
Administered
Updated the “Use” column to “Test 
Product” and updated the “IMP or 
NIMP/AxMP” column heading.
To align with EU CTR regulations.
8.4 Adverse Events, Serious 
Adverse Events, and Other 
Reportable Safety Events
10.3.1 Definitions of Medication 
Error, Misuse, and Abuse
Added investigator requirements for 
documenting SAEs related to medication 
error, misuse, abuse, and their definition
To align with EU CTR regulations.
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Section # and Name
Description of Change 
Brief Rationale 
1.3.1 Schedule of Activities for 
Screening
8.1.1.2 Consent and Collection of 
Specimens for Future Biomedical 
Research
8.1.3 Participant Identification Card
Updated to “documented informed 
consent”.
Adherence to COVID-19 requirements.
5.1.1 Overall Inclusion Criteria
Criterion #11: Updated to documented 
informed consent
Adherence to COVID-19 requirements.
5.2.1 Overall Exclusion Criteria
Criterion # 4 Clarified language related to 
timing of malignancy.
Criterion #15 Added COVID-19 reference.
Clarification of curative treatment timing.
Adherence to COVID-19 requirements.
6.5.2 Prohibited Concomitant 
Medications
Added COVID-19 vaccine information.
Clarified acceptable uses of 
glucocorticoids.
Adherence to COVID-19 requirements.
Clarification of information related to 
glucocorticoid use.
5.1.2.2 Specific Inclusion Criteria 
for Cohort B: Advanced/Metastatic 
Head and Neck Squamous Cell 
Carcinoma
Criterion #18: added note to clarify 
reporting of HPV status.
To clarify to obtain status for participants not 
previously tested.
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Section # and Name
Description of Change 
Brief Rationale 
5.1.4.1 Specific Inclusion Criteria 
for Cohort D: Hepatocellular 
Carcinoma
8.1.1.1 General Informed Consent
8.1.1.2 Consent and Collection of 
Specimens for Future Biomedical 
Research
8.4.1 Time Period and Frequency for 
Collecting AE, SAE, and Other 
Reportable Safety Event Information
10.1.2 Financial Disclosure
10.1.3 Data Protection
10.3.5 Recording of AE and SAE
Change “he/she” to “the investigator” or 
“the participant” and “his/her” to “their”.
Adopt gender neutral language.
6.6.3 Guidance for Management of 
Hepatic Events of Clinical Interest
10.2 Appendix 2 Clinical Laboratory 
Tests
Added GGT testing as part of HECI 
workup.
Testing must be performed as part of HECI 
workup.
8.3.7 Pregnancy Test
Updated to clarify collection timing and 
procedures.
To clarify pregnancy testing requirements.
CCI
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Section # and Name
Description of Change 
Brief Rationale 
9.10 Subgroup Analyses
Added subgroup analysis plan for 
participants whose lesions are injected 
versus noninjected.
Clarification of subgroup analysis information.
10.7.3 France-specific Requirements
10.7.4 Portugal-specific 
Requirements
Added information related to pregnancy 
testing and oocyte donation requirements.
Added section with information related to 
pregnancy and HIV/Hep B/Hep C testing 
requirements.
Adherence to Health Authority requirements.
Throughout Document
Minor administrative, formatting, 
grammatical, and/or typographical changes 
were made throughout the document.
To ensure clarity and accurate interpretation of 
the intent of the protocol.
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25-OCT-2022
Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................19
1.1
Synopsis.................................................................................................................19
1.2
Schema ..................................................................................................................24
1.3
Schedule of Activities...........................................................................................26
1.3.1
Schedule of Activities for Screening ...........................................................26
1.3.2
Schedule of Activities for Treatment Phase: Arm 1 - Participants with 
Subcutaneous Tumors..................................................................................29
1.3.3
Schedule of Activities for Treatment Phase: Arm 2 Part I - Dose 
Escalation in Participants with Visceral Tumors.........................................32
1.3.4
Schedule of Activities for Treatment Phase: Arm 2 Part II - Cohort 
Expansion.....................................................................................................35
1.3.5
Schedule of Activities for End of Treatment/Discontinuation and 
Posttreatment Phase: Arm 1, Arm 2 Part I Dose Escalation Phase, and 
Arm 2 Part II Expansion Phase....................................................................38
1.4
Study Rationale....................................................................................................40
1.5
Background ..........................................................................................................40
1.5.1
Pharmaceutical and Therapeutic Background .............................................41
1.5.1.1
V937 Pharmaceutical and Therapeutic Background..........................41
1.5.1.2
Pembrolizumab (MK-3475) Pharmaceutical and Therapeutic 
Background........................................................................................42
1.5.2
Preclinical and Clinical Studies ...................................................................42
1.5.3
Ongoing Clinical Studies.............................................................................42
1.6
Benefit/Risk Assessment......................................................................................43
2
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................43
3
STUDY DESIGN............................................................................................................46
3.1
Overall Design......................................................................................................46
3.1.1
Arm 1: Subcutaneous Tumors .....................................................................48
3.1.2
Arm 2 Part I: Dose Escalation in Metastatic Visceral Lesion Tumors........48
3.1.3
Arm 2 Part II: Cohort Expansion in Metastatic Visceral Lesion Tumors....49
3.2
Scientific Rationale for Study Design.................................................................49
3.2.1
Rationale for Endpoints ...............................................................................49
3.2.1.1
Efficacy Endpoints.............................................................................49
3.2.1.1.1
Response Rate Assessed by RECIST Version 1.1...................51
3.2.1.2
Safety Endpoints................................................................................51
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3.2.1.3
Pharmacokinetic Endpoints ...............................................................51
3.2.1.4
Pharmacodynamic Endpoints.............................................................51
3.2.1.4.1
Neutralizing V937 Antibodies.................................................51
3.2.1.5
Planned Exploratory Biomarker Research.........................................51
3.2.1.6
Future Biomedical Research..............................................................53
3.3
Justification for Dose...........................................................................................54
3.3.1
Starting Dose for This Study........................................................................54
3.3.1.1
Rationale for Starting and Maximum Dose of V937.........................54
3.3.1.2
Rationale for Dose Interval and Escalation Increments.....................55
3.4
Beginning and End of Study Definition .............................................................57
3.4.1
Clinical Criteria for Early Study Termination .............................................57
4
STUDY POPULATION ................................................................................................58
4.1
Inclusion Criteria.................................................................................................58
4.1.1
Overall Inclusion Criteria ............................................................................58
4.1.2
Arm 1: Subcutaneously Accessible Tumors................................................61
4.1.2.1
Specific Inclusion Criteria for Cohort A: Advanced/Metastatic 
Triple Negative Breast Cancer...........................................................62
4.1.2.2
Specific Inclusion Criteria for Cohort B: Advanced/Metastatic 
Head and Neck Squamous Cell Carcinoma.......................................62
4.1.2.3
Specific Inclusion Criteria for Cohort C: Locally-
advanced/Metastatic Cutaneous Squamous Cell Carcinoma.............63
4.1.3
Arm 2 Part I: Visceral Lesion Dose Escalation and Confirmation..............63
4.1.4
Arm 2 Part II: Visceral Cohort Expansion...................................................64
4.1.4.1
Specific Inclusion Criteria for Cohort D: Hepatocellular 
Carcinoma..........................................................................................64
4.1.4.2
Specific Inclusion Criteria for Cohort E: Gastric Carcinoma............66
4.2
Exclusion Criteria................................................................................................66
4.2.1
Overall Exclusion Criteria ...........................................................................66
4.2.2
Arm 2 Part II: Visceral Cohort Expansion...................................................68
4.2.2.1
Specific Exclusion Criteria for Cohort D: Hepatocellular 
Carcinoma..........................................................................................68
4.2.2.2
Specific Exclusion Criteria for Cohort E: Gastric Carcinoma...........68
4.3
Lifestyle Considerations......................................................................................69
4.3.1
Meals and Dietary Restrictions....................................................................69
4.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................69
4.3.3
Activity Restrictions ....................................................................................69
4.4
Screen Failures.....................................................................................................69
CCI
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4.5
Participant Replacement Strategy......................................................................69
5
STUDY INTERVENTION............................................................................................69
5.1
Study Intervention(s) Administered...................................................................69
5.1.1
Pembrolizumab Administration...................................................................72
5.1.2
V937 Administration for Arm 1 and Arm 2 ................................................72
5.1.2.1
V937 Administration in Arm 1: Subcutaneous Tumors ....................72
5.1.2.2
V937 Administration in Arm 2, Part I: Visceral Tumors ..................72
5.1.2.3
V937 Administration in Arm 2, Part II: Visceral Expansion 
Cohorts...............................................................................................72
5.1.2.4
V937 Administration in Arms 1 and 2: Target Lesion Size and
Injection Volume ...............................................................................73
5.2
Preparation/Handling/Storage/Accountability .................................................75
5.2.1
Dose Preparation..........................................................................................75
5.2.2
Handling, Storage, and Accountability........................................................75
5.3
Measures to Minimize Bias: Randomization and Blinding..............................76
5.3.1
Intervention Assignment..............................................................................76
5.3.2
Stratification.................................................................................................76
5.3.3
Blinding........................................................................................................76
5.4
Study Intervention Compliance..........................................................................76
5.5
Concomitant Therapy..........................................................................................77
5.5.1
Acceptable Concomitant Medications .........................................................77
5.5.2
Prohibited Concomitant Medications ..........................................................77
5.5.3
Supportive Care ...........................................................................................79
5.5.3.1
V937 Supportive Care........................................................................79
5.5.3.2
Pembrolizumab Supportive Care.......................................................79
5.6
Dose Modification (Escalation/Titration/Other) [Arm 1 and Arm 2 (Part I 
& II)] .....................................................................................................................79
5.6.1
Dose Modification for V937........................................................................80
5.6.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................80
5.6.2.1
Other Allowed Dose Interruption(s) for Pembrolizumab ..................86
5.6.3
Guidance for Management of Hepatic Events of Clinical Interest..............86
5.6.3.1
Diagnosis and Management of Non-overdose Hepatic ECIs ............87
5.6.4
Dose Administration/Escalation ..................................................................89
5.6.4.1
Dose Administration (Preparation)....................................................89
5.6.5
Definition of Dose‑limiting Toxicity for Arm 2 Part I (mTPI 
Escalation)....................................................................................................89
5.6.6
Guidelines for Dose Modification due to Adverse Events ..........................91
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5.6.6.1
Dose Modification for V937 and/or Pembrolizumab due to Drug-
related AEs in Arm 2 Part I................................................................91
5.7
Intervention After the End of the Study............................................................93
5.8
Clinical Supplies Disclosure................................................................................93
6
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................93
6.1
Discontinuation of Study Intervention...............................................................93
6.2
Participant Withdrawal From the Study...........................................................95
6.3
Lost to Follow-up .................................................................................................95
7
STUDY ASSESSMENTS AND PROCEDURES........................................................95
7.1
Administrative and General Procedures ...........................................................96
7.1.1
Informed Consent.........................................................................................96
7.1.1.1
General Informed Consent.................................................................96
7.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................97
7.1.2
Inclusion/Exclusion Criteria ........................................................................97
7.1.3
Participant Identification Card.....................................................................97
7.1.4
Medical History ...........................................................................................98
7.1.5
Prior and Concomitant Medications Review...............................................98
7.1.5.1
Prior Medications...............................................................................98
7.1.5.2
Concomitant Medications..................................................................98
7.1.6
Assignment of Screening Number...............................................................98
7.1.7
Assignment of Treatment/Randomization Number.....................................99
7.1.8
Study Intervention Administration ..............................................................99
7.1.8.1
Withdrawal From Future Biomedical Research ................................99
7.1.9
Participant Blinding/Unblinding................................................................100
7.1.10
Calibration of Equipment...........................................................................100
7.2
Efficacy/Immunogenicity Assessments ............................................................100
7.2.1
Tumor Imaging and Assessment of Disease..............................................100
7.2.2
Initial Tumor Imaging................................................................................101
7.2.3
Tumor Imaging During the Study..............................................................101
7.2.4
End of Treatment and Follow-up Tumor Imaging.....................................102
7.2.5
iRECIST 1.1 Assessment of Disease.........................................................102
7.2.6
Eastern Cooperative Oncology Group Performance Scale........................108
7.3
Safety Assessments.............................................................................................108
7.3.1
Physical Examinations...............................................................................109
7.3.1.1
Full Physical Examination...............................................................109
7.3.1.2
Directed Physical Examination........................................................109
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7.3.2
Vital Signs..................................................................................................109
7.3.3
Electrocardiograms ....................................................................................109
7.3.4
Endoscopy: Required for Arm 2 Part II, Cohort D only............................109
7.3.5
Child-Pugh Score: Required for Arm 2 Part II, Cohort D only.................109
7.3.6
Clinical Safety Laboratory Assessments ...................................................110
7.3.6.1
Laboratory Safety Evaluations (Hematology and Chemistry).........110
7.3.7
Pregnancy Test...........................................................................................111
7.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................111
7.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................112
7.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....113
7.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.114
7.4.4
Regulatory Reporting Requirements for SAE ...........................................114
7.4.5
Pregnancy and Exposure During Breastfeeding ........................................114
7.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................114
7.4.7
Events of Clinical Interest..........................................................................115
7.5
Treatment of Overdose......................................................................................116
7.6
Pharmacokinetics...............................................................................................116
7.6.1
Blood Collection for Serum V937.............................................................116
7.6.2
Blood Collection for Neutralizing V937 Antibodies.................................116
7.7
Pharmacodynamics............................................................................................116
7.8
Biomarkers .........................................................................................................117
7.8.1
Planned Genetic Analysis Sample Collection............................................117
7.9
Future Biomedical Research Sample Collection.............................................117
7.10
Health Economics Medical Resource Utilization and Health Economics.....117
7.11
Visit Requirements.............................................................................................118
7.11.1
Screening....................................................................................................118
7.11.2
Treatment Period/Vaccination Visit ..........................................................118
7.11.3
Discontinued Participants Continuing to be Monitored in the Study ........118
7.11.3.1
Safety Follow-up Visit.....................................................................119
7.11.3.2
Imaging Follow-up Visits ................................................................119
7.11.3.3
Survival Follow-up Contacts ...........................................................119
8
STATISTICAL ANALYSIS PLAN ...........................................................................119
8.1
Statistical Analysis Plan Summary...................................................................119
8.2
Responsibility for Analyses/In-house Blinding ...............................................121
8.3
Hypotheses/Estimation ......................................................................................121
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8.4
Analysis Endpoints.............................................................................................122
8.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints............................122
8.4.2
Safety Endpoints........................................................................................122
8.5
Analysis Populations..........................................................................................122
8.5.1
Safety Analysis Populations ......................................................................122
8.5.3
Efficacy Analysis Populations...................................................................123
8.6
Statistical Methods.............................................................................................123
8.6.1
Statistical Methods for Efficacy Analysis..................................................123
8.6.2
Statistical Methods for Safety Analysis.....................................................123
8.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................124
8.6.3.1
Demographic and Baseline Characteristics .....................................124
8.9
Sample Size and Power Calculations ...............................................................125
8.10
Subgroup Analyses.............................................................................................126
8.11
Compliance (Medication Adherence)...............................................................126
8.12
Extent of Exposure.............................................................................................126
9
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................127
9.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......127
9.1.1
Code of Conduct for Clinical Trials...........................................................127
9.1.2
Financial Disclosure...................................................................................129
9.1.3
Data Protection...........................................................................................129
9.1.3.1
Confidentiality of Data ....................................................................130
9.1.3.2
Confidentiality of Participant Records.............................................130
9.1.3.3
Confidentiality of IRB/IEC Information..........................................130
9.1.4
Publication Policy......................................................................................130
9.1.5
Compliance with Study Registration and Results Posting Requirements .131
9.1.6
Compliance with Law, Audit, and Debarment ..........................................131
9.1.7
Data Quality Assurance .............................................................................132
9.1.8
Source Documents .....................................................................................133
9.1.9
Study and Site Closure...............................................................................133
9.2
Appendix 2: Clinical Laboratory Tests............................................................134
9.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................136
CCI
CCI
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9.3.1
Definitions of Medication Error, Misuse, and Abuse................................136
9.3.2
Definition of AE ........................................................................................136
9.3.3
Definition of SAE ......................................................................................137
9.3.4
Additional Events Reported in the Same Manner as SAE.........................139
9.3.5
Recording AE and SAE .............................................................................139
9.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................143
9.4
Appendix 4: Medical Device and Drug-device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................145
9.5
Appendix 5: Contraceptive Guidance..............................................................146
9.5.1
Definitions..................................................................................................146
9.5.2
Contraception Requirements......................................................................147
9.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................148
9.7
Appendix 7: Country-specific Requirements..................................................153
9.7.1
Japan-specific Requirements .....................................................................153
9.7.2
Norway-specific Requirements..................................................................157
9.7.3
France-specific Requirements....................................................................158
9.7.4
Portugal-specific Requirements.................................................................158
9.8
Appendix 8: Abbreviations ...............................................................................159
9.9
Appendix 9: Child-Pugh Score .........................................................................163
10
REFERENCES.............................................................................................................165
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LIST OF TABLES
Table 1
Schedule of Activities for Screening .........................................................26
Table 2
Schedule of Activities for Treatment Phase: Arm 1 - Participants with 
Subcutaneous Tumors................................................................................29
Table 3
Schedule of Activities for Treatment Phase: Arm 2 Part I - Dose 
Escalation in Participants with Visceral Tumors.......................................32
Table 4
Schedule of Activities for Treatment Phase: Arm 2 Part II - Cohort 
Expansion...................................................................................................35
Table 5
Schedule of Activities for End of Treatment/Discontinuation and 
Posttreatment Phase: Arm 1, Arm 2 Part I Dose Escalation Phase, and 
Arm 2 Part II Expansion Phase..................................................................38
Table 6
Dose-finding Rules per mTPI Design........................................................56
Table 7
Adequate Organ Function Laboratory Values for Non-HCC Population..59
Table 8
Adequate Organ Function Laboratory Values for HCC Population..........65
Table 9
Study Interventions....................................................................................70
Table 10
Maximum Total Volume of V937 Administered in Arm 1 Scaled to 
Lesion Size.................................................................................................74
Table 11
Maximum Total Volume of V937 Administered in Arm 2 (Parts I and 
II) Scaled to Lesion Size............................................................................74
Table 12
Maximum Total Dose of V937 Possible per Participant as Well as 
Total Dose of V937 per mL of Injectate Given (Arm 1)...........................74
Table 13
Maximum Total Dose of V937 Possible per Participant at Prespecified 
Dose Levels per mTPI Design (Arm 2 Part I) ...........................................75
Table 14
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .........................................................81
Table 15
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................85
Table 16
Management of Hepatic ECIs....................................................................88
Table 17
V937 Dose Modification and Treatment Discontinuation Guidelines 
for Drug-related Adverse Events in Arm 2, Part I (mTPI) ........................92
Table 18
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease.....................................................................................................107
Table 19
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events...............................................................113
Table 20
Estimate and 95% CI of ORR (N=30).....................................................125
Table 21
Protocol-required Safety Laboratory Assessments..................................135
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LIST OF FIGURES
Figure 1
High-level Study Design............................................................................24
Figure 2
Detailed Study Design ...............................................................................25
Figure 3
Imaging and Treatment for Clinically Stable Participants after First 
Radiologic Evidence of PD Assessed by the Investigator.......................108
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1b/2 Clinical Study of Intratumoral Administration of V937 in 
Combination with Pembrolizumab (MK-3475) in Participants with Advanced/Metastatic 
Solid Tumors
Short Title: Phase 1b/2 Study of ITu V937 in Combination with Pembrolizumab
Acronym: Not applicable
Hypotheses, Objectives, and Endpoints:
There is no hypothesis testing in this study.
Throughout this protocol, the term RECIST 1.1 refers to a modification to RECIST 1.1 to 
allow a maximum of 10 target lesions in total and 5 per organ. Since ITu therapy is included 
by design in the study, RECIST 1.1 is also modified to specify that ITu injection by itself 
does not render a lesion non-evaluable. Refer to Section 4.2.1.1 for further details.
In male and female participants with advanced/metastatic solid tumors who are anti-PD-(L)1-
treatment-naïve:
Arm 1: Subcutaneous Tumor Cohorts
Primary Objectives
Primary Endpoints
- To evaluate the objective response rate 
(ORR) of V937 administered in 
subcutaneous tumors in combination with 
pembrolizumab per Response Evaluation 
Criteria in Solid Tumors Version 1.1 
(RECIST 1.1) as assessed by the investigator.
- Objective response is a confirmed 
complete response (CR) or partial response 
(PR).
Secondary Objectives
Secondary Endpoints
- To determine the safety and tolerability of 
V937 administered in subcutaneous tumors 
in combination with pembrolizumab.
- Adverse event (AE)
- Discontinuing a study intervention due to 
an AE
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- To evaluate progression-free survival (PFS) 
and duration of response (DOR) of 
participants treated with V937 in 
subcutaneous tumors in combination with 
pembrolizumab per RECIST 1.1 as assessed 
by the investigator. 
- PFS is defined as the time from the first 
dose of study treatment to the first 
documented disease progression or death 
due to any cause, whichever occurs first.
- DOR is 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 PR or CR.
- To evaluate the ORR, PFS, and DOR of 
V937 administered in subcutaneous tumors 
in combination with pembrolizumab per 
RECIST 1.1 for immune-based therapeutics 
(iRECIST) criteria as assessed by the 
investigator.
- ORR
- PFS
- DOR
- To evaluate OS (overall survival) of 
participants treated with V937 in 
subcutaneous tumors in combination with 
pembrolizumab.
- OS is defined as the time from the first 
dose of study treatment to the date of death 
from any cause.
Arm 2 Part I: Visceral Dose Escalation, and
Arm 2 Part II: Visceral Tumor Expansion
Primary Objectives
Primary Endpoints
- To determine the safety and tolerability and 
to establish a preliminary recommended 
Phase 2 dose (RP2D) of V937 administered 
in visceral tumors in combination with 
pembrolizumab.
- Dose-limiting toxicity DLT
- AE
- Discontinuing a study intervention due to 
an AE
Secondary Objectives
Secondary Endpoints
- To evaluate the ORR of V937 administered 
in visceral tumors at the preliminary RP2D 
with pembrolizumab per RECIST 1.1 and 
iRECIST criteria as assessed by the 
investigator.
- ORR
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Overall Design:
Study Phase
Phase 1/Phase 2
Primary Purpose
Treatment
Indication
The treatment of participants with advanced/metastatic solid 
tumors
Population
Participants with histologically or cytologically-confirmed 
advanced/metastatic solid tumors by pathology report who 
have not received PD-(L)1 antibody treatment, talimogene 
laherparepvec (T-VEC) or other oncolytic viruses.
Study Type
Interventional
Intervention Model
Single Group
This is a multi-site study.
Type of Control
No control
Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated Duration of 
Study
The Sponsor estimates that the study will require 
approximately 5 years from the time the first participant (or 
their legally acceptable representative) provides documented 
informed consent until the last participant’s last study-related 
telephone call or visit.
Number of Participants:
Approximately 185 participants will be allocated to the following intervention arms:

Arm 1: Subcutaneous tumors (ITu V937 + IV pembrolizumab)

Arm 2 Part I: Visceral tumor dose escalation (ITu V937 + IV pembrolizumab)

Arm 2 Part II: Visceral tumor cohort expansion (ITu V937 + IV pembrolizumab) with
the RP2D defined in Arm 2 Part I.
Due to early study termination of this study, the total enrollment number may be less than 
185 participants.
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Intervention Groups and Duration:
Intervention 
Groups
Interven-
tion 
Group 
Name
Drug
Dose 
Levels
Dose 
Frequency
Route of 
Adminis-
tration
Regimen/ 
Treatment Period/ 
Vaccination 
Regimen
Use
Arm 1
V937
3 X 108
TCID50
Cycle 1
Days 1, 3, 
5 and 8
(4 doses); 
then every 
3 weeks
ITu
Injection
Days 1, 3, 5, and 8 
of Cycle 1
(28-day cycle)
Day 1 of 
Cycles 2 to 8
(21-day cycles)
Test 
Product
Pembro-
lizumab
200 mg
Every 3 
weeks
IV Infusion
Day 8 of Cycle 1 
(28-day cycle)
Day 1 of each 
subsequent 21-day 
cycle
Test 
Product
Arm 2
Part I
V937
DL1:
3 X 107,
DL2:
1 X 108,
DL3:
3 X 108
TCID50
Cycle 1, 
Days 1 and 
8 (2 
doses);
then every 
3 weeks
ITu
Injection
Days 1 and 8 of 
Cycle 1 
(28-day cycle)
Day 1 of 
Cycles 2 to 8 
(21-day cycles)
Test 
Product
Pembro-
lizumab
200 mg
Every 3 
weeks
IV Infusion
Day 8 of Cycle 1 
(28-day cycle)
Day 1 of each 
subsequent 21-day 
cycle
Test 
Product
Arm 2
Part II
V937
RP2D
DL1:
3 X 107,
DL2:
1 X 108,
or 
DL3:
3 X 108
TCID50
Cycle 1, 
Days 1 and 
8 (2
doses); 
then every 
3 weeks
ITu
Injection
Days 1 and 8 of 
Cycle 1 
(28-day cycle)
Day 1 of 
Cycles 2 to 8 
(21-day cycles)
-Test 
Product
Pembro-
lizumab
200 mg
Every 3 
weeks
IV Infusion
Day 8 of Cycle 1 
(28-day cycle)
Day 1 of each 
subsequent 21-day 
cycle
Test 
Product
Abbreviations: ITu=intratumoral; IV=intravenous; RP2D = recommended Phase 2 dose; 
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); CAV21.
Total 
Number
Total Number of Intervention Groups/Arms: 2
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Duration of 
Participation
Each participant will participate in the study from the time the participant 
provides documented informed consent through the final protocol-specified
contact.
After a screening phase of up to 28 days, each participant will be assigned 
to receive study intervention, as described above, for approximately 2 years
until disease progression is radiographically documented, confirmed by the 
site per RECIST 1.1, 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 in Arm 1 will receive up to 11 
administrations (in 8 cycles) of V937, and participants in Arm 2 will 
receive up to 9 administrations (in 8 cycles) V937 unless any of the above 
apply.
After the end of treatment, each participant will be followed for the 
occurrence of adverse events and spontaneously reported pregnancy as 
described in Section 8.4.
Participants who discontinue for reasons other than radiographic disease 
progression will have posttreatment 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, the 
start of a new anticancer 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.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
Study design is shown in the 2 figures below. Figure 1: high-level study design; Figure 2: detailed study design. Upon study 
completion or early study termination, 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 V937-013. Due to early study termination of this study, the total enrollment number may
be less than 185 participants.
Figure 1
High-level Study Design
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Figure 2
Detailed Study Design
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1.3
Schedule of Activities
See Appendix 7 for country-specific requirements.
Upon study completion or early study termination, 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 V937-013. Such participants will be monitored and follow the Schedule of 
Activities for the pembrolizumab extension study.
1.3.1
Schedule of Activities for Screening
Table 1
Schedule of Activities for Screening
Study Period:
Screening
Notes
Visit Day:
-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. 
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
Participant identification card to be updated with treatment number at the time of treatment 
assignment.
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
Clinical Procedures/Assessments
Tumor Imaging (CT or MRI as indicated) 
(RECIST 1.1, and iRECIST Response 
Assessment)
X
Baseline tumor imaging (CT or MRI as indicated) and/or medical photography of cutaneous 
lesions should be performed within 28 days prior to C1D1.
Refer to Site Imaging Manual for detailed information.
Arm 1 only:
Medical Photography (cutaneous lesions)
X
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Study Period:
Screening
Notes
Visit Day:
-28 to -1
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.
Additional Imaging 
(PET/CT, bone scan, etc.)
X
May obtain additional scans if clinically indicated.
Arm 1: HNSCC Cohort B: Include head and neck CT
Endoscopy 
X
Required for Arm 2 Part II, Cohort D only.
Participants should undergo screening for esophageal varices, unless such screening has been 
performed in the past 12 months before first dose of treatment.
Physical Examination
X
A full physical examination should be done at screening.
Child-Pugh Score
X
Required for Arm 2 Part II, Cohort D only.
If any of the hepatic ECI criteria are met, document the Child-Pugh score with each visit until 
the hepatic ECIs resolve. Class A score required.
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
Adverse Event (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 prior to C1D1 except for thyroid and 
hepatitis testing. Thyroid and hepatitis testing must be obtained within 28 days prior to C1D1.
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
AST, ALT
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
Pregnancy test for WOCBP only (urine or 
serum β 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 Screen
X
Acceptable to be based on history unless testing is required by local regulation.
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Study Period:
Screening
Notes
Visit Day:
-28 to -1
Hepatitis B and C Screen
X
Required for Arm 2 Part II, Cohort D only: Hepatitis B and C Screen.
For Arm 2 Part II, Cohort D: Include HCV antibody or HCV RNA (qualitative) and 
HBsAg.
For all other cohorts: Acceptable to be based on history unless testing is required by local 
regulation. 
HPV Status
X
Required for Arm 1 Cohort B only.
HPV testing in oropharyngeal cancer (eg, p16 IHC; multiplex NASBA or other PCR-based 
assays) should be recorded, as determined per institutional standard.
PD-L1 tumor expression
X
Required for Arm 1 Cohort B only.
HNSCC tumors must be PD-L1 positive (CPS ≥1); local testing and historical results are 
acceptable.
Laboratory Procedures/Assessments – CENTRAL
Tumor Biopsy
X
An archival tissue sample is acceptable, otherwise a new biopsy will be obtained. Exception: 
Arm 2 Part I: If tissue block is not available, participant may be enrolled if all other inclusion 
criteria are satisfied.
Instructions for tissue collection, processing, and shipment are provided in the Procedures 
Manual.
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; β hCG=β human chorionic 
gonadotropin; BRAF=proto-oncogene B-rapidly accelerated fibrosarcoma; C=Cycle; CBC=complete blood count; CPS=combined positive score; CT=computed tomography; 
D=Day; ECOG=Eastern Cooperative Oncology Group; F=free; FBR=future biomedical research; h=hour(s); HBsAg=Hepatitis B surface antigen; HCV=Hepatitis C virus; 
HIV=human immunodeficiency virus; HPV=human papillomavirus; IHC=immunohistochemistry; INR=International Normalized Ratio; MRI=magnetic resonance imaging; 
NASBA=nucleic acid sequence-based amplification; PCR=polymerase chain reaction; 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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1.3.2
Schedule of Activities for Treatment Phase: Arm 1 - Participants with Subcutaneous Tumors
Table 2
Schedule of Activities for Treatment Phase: Arm 1 - Participants with Subcutaneous Tumors
Study Period:
Treatment Period
Notes
Treatment Cycle / Visit 
Title:
Cycle 1
(28 days)
Cycles 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.
Treatment Days per 
Cycle
1
3
5
8
1
1
Scheduling/visit Window 
(Days)
± 0
± 1
± 1
± 1
+ 3
± 3
C2D1: The visit window is + 3 days.
C3D1 and subsequent cycles: The visit window is ± 3 days.
All cycles: These visit windows apply unless otherwise specified for 
individual process/procedure.
Treatment Assignment
X
Treatment assignment can occur up to 3 days prior to C1D1.
Participant ID Card
X
Participant identification card to be updated with treatment number at the 
time of treatment allocation.
Pembrolizumab 
Administration (Q3W)
X
X
X
Cycle 2: study treatment may be administered up to 3 days after the 
scheduled C2D1.
Cycle 3 and beyond: study treatments may be administered up to 3 days 
before or after the scheduled Day 1.
Cycles 2-8: V937 will be administered a maximum of 8 cycles; to be 
administered after a 200 mg dose of pembrolizumab infused over 30 
min.
For administration details, see Pharmacy Manual.
V937 Administration for 
Subcutaneous Tumors
X
X
X
X
X
Clinical Procedures/Assessments
Tumor Imaging (CT or 
MRI as indicated) 
(RECIST 1.1, and 
iRECIST Response 
Assessment)
Screening imaging should be performed within 28 days prior to C1D1. 
On-study imaging should be performed every 9 weeks (± 7 days) after 
C1D1 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 anticancer treatment.
Refer to Site Imaging Manual for detailed information on medical 
photography.
Medical Photography 
(cutaneous lesions)
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Study Period:
Treatment Period
Notes
Treatment Cycle / Visit 
Title:
Cycle 1
(28 days)
Cycles 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.
Treatment Days per 
Cycle
1
3
5
8
1
1
Scheduling/visit Window 
(Days)
± 0
± 1
± 1
± 1
+ 3
± 3
C2D1: The visit window is + 3 days.
C3D1 and subsequent cycles: The visit window is ± 3 days.
All cycles: These visit windows apply unless otherwise specified for 
individual process/procedure.
Brain imaging 
Perform at screening ONLY for participants with previously documented 
brain metastases (to confirm stability) or as clinically indicated.
On-study imaging to be performed if positive for brain metastases at
screening and clinically indicated. Perform at CR for participants who 
were positive at baseline.
Additional Imaging 
(PET/CT, bone scan, etc.)
Obtain when clinically indicated.
Arm 1: HNSCC Cohort B: Include head and neck CT
Lesion injection scan
Obtain for all injected lesions for every intratumoral injection performed. 
If imaging is used to guide injection (CT, ultrasound, fluoroscopy, etc.), 
capture images to document injected lesions. If injection by visualization 
or palpation, capture photographs with skin markers to show injected 
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
Cycle 1: Measure within 1 h (± 30 min) prior to dosing, and 2, 4, and 6 h 
(± 30 min for each timepoint) after V937 administration.
Cycle 2 to Cycle 8: Measure within 1 h (± 30 min) prior to dosing, and 2 
and 4 h (± 30 min for each timepoint) after V937 administration.
Cycle 9 and beyond: Measure within 1 h (± 30 min) prior to dosing with 
pembrolizumab on Day 1 of every cycle.
If V937 is not administered at any cycle (eg, temporary withholding or 
discontinuation), vital signs are not required to be collected post-dose for 
that visit (ie, following administration of pembrolizumab).
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
Treatment Cycle / Visit 
Title:
Cycle 1
(28 days)
Cycles 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.
Treatment Days per 
Cycle
1
3
5
8
1
1
Scheduling/visit Window 
(Days)
± 0
± 1
± 1
± 1
+ 3
± 3
C2D1: The visit window is + 3 days.
C3D1 and subsequent cycles: The visit window is ± 3 days.
All cycles: These visit windows apply unless otherwise specified for 
individual process/procedure.
Concomitant Medication
X
X
X
X
X
X
AEs
Continuous AE reporting from the time of treatment allocation.
Survival Status
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.
Blood urea nitrogen is preferred; if not available, urea may be tested. 
Thyroid function: Samples are collected every other cycle (ie, Cycles 2, 
4, 6, etc.). Total T4 and T3 are preferred over FT4 and FT3.
Chemistry Panel
X
X
X
X
PT/INR and PTT or aPTT
X
X
X
AST, ALT
X
X
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, 
TSH)
X
X
Pregnancy test for 
WOCBP only (urine or 
serum β-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.
Abbreviations: AE=adverse event; AFP=alpha-fetoprotein; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; β 
hCG=β human chorionic gonadotropin; C=cycle; CBC=complete blood count; CT=computed tomography; D=day; ECOG=Eastern Cooperative Oncology Group; F=free; 
h=hour(s); HbsAg=Hepatitis B surface antigen; HBV=Hepatitis B virus; INR=International Normalized Ratio; iRECIST=modified RECIST 1.1 for immune-based therapeutics; 
IT=intratumoral; IV=intravenous; MRI=magnetic resonance imaging; 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 Treatment Phase: Arm 2 Part I - Dose Escalation in Participants with Visceral Tumors
Table 3
Schedule of Activities for Treatment Phase: Arm 2 Part I - Dose Escalation in Participants with Visceral Tumors
Study Period:
Treatment Period
Notes
Treatment Cycle / Visit 
Title:
Cycle 1
(28 days)
Cycles 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, 9 doses) of treatment with V937.
Treatment Days per 
Cycle
1
8
1
1
Scheduling/visit Window 
(Days)
± 0
± 1
± 5
± 5
Treatment Assignment
X
Treatment assignment can occur up to 3 days prior to C1D1.
Participant ID Card
X
Participant identification card to be updated with treatment number at the 
time of treatment allocation.
Pembrolizumab 
Administration (Q3W)
X
X
X
Cycle 1, Day 1: Following the C1D1 dosing, participants must remain in 
the clinic for a minimum of 12 h for observation.
Cycle 2 and beyond: Study treatments may be administered up to 5 days 
before or after the scheduled Day 1.
Cycles 2-8: V937 will be administered after a 200 mg dose of 
pembrolizumab is infused over 30 min.
For administration details, see Pharmacy Manual.
V937 Administration
X
X
X
Clinical Procedures/Assessments
Tumor Imaging (CT or 
MRI as indicated)
(RECIST 1.1, and 
iRECIST Response 
Assessment)
Screening imaging should be performed -28 days prior to C1D1. On-study 
imaging should be performed every 9 weeks (± 7 days) after C1D1 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 anticancer treatment.
Additional Imaging
(PET/CT, bone scan, etc.)
Obtain when clinically indicated.
Brain Imaging
Perform at screening ONLY for participants with previously documented 
brain metastases (to confirm stability) or who are clinically symptomatic.
On-study imaging to be performed if positive for brain metastases at 
screening and clinically indicated. Perform at CR for participants who 
were positive at baseline.
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Study Period:
Treatment Period
Notes
Treatment Cycle / Visit 
Title:
Cycle 1
(28 days)
Cycles 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, 9 doses) of treatment with V937.
Treatment Days per 
Cycle
1
8
1
1
Scheduling/visit Window 
(Days)
± 0
± 1
± 5
± 5
Lesion injection scan
Obtain for all injected lesions for every intratumoral injection performed. 
If imaging is used to guide injection (CT, ultrasound, fluoroscopy, etc.), 
capture images to document injected lesions. If injection by visualization 
or palpation, capture photographs with skin markers to show injected 
lesions.
Physical Examination
X
X
X
X
Directed physical examinations may be performed unless a full 
examination is deemed necessary. To be performed on Days 1and 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
Cycle 1: Measure within 1 h (± 30 min) prior to dosing, and 2, 4, and 6 h 
(± 30 min for each timepoint) after V937 administration.
Cycle 2-8: Measure within 1 h (± 30 min) prior to dosing, and 2 and 4 h 
(± 30 min for each timepoint) after V937 administration.
Cycle 9 and beyond: Measure within 1 h (± 30 min) prior to dosing with 
pembrolizumab on Day 1 of every cycle.
If V937 is not administered at any cycle (eg, temporary withholding or 
discontinuation), vital signs are not required to be collected post-dose for 
that visit (ie, following administration of pembrolizumab).
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
AEs
Continuous AE reporting from the time of treatment allocation.
Survival Status
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Study Period:
Treatment Period
Notes
Treatment Cycle / Visit 
Title:
Cycle 1
(28 days)
Cycles 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, 9 doses) of treatment with V937.
Treatment Days per 
Cycle
1
8
1
1
Scheduling/visit Window 
(Days)
± 0
± 1
± 5
± 5
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 C1D1 timepoint.
For PT/INR/PTT/aPTT: PT/INR ≤6 h before every V937 ITu visceral 
administration.
Blood urea nitrogen is preferred; if not available, urea may be tested. 
Thyroid function: Samples are collected every other cycle (ie, Cycles 2, 4, 
6). Total T4 and T3 are preferred over FT4 and FT3.
Chemistry Panel
X
X
X
X
PT/INR and PTT or 
aPTT
X
X
X
Xa
AST, ALT
X
X
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, 
TSH)
X
X
Pregnancy test for 
WOCBP only (urine or 
serum β 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.
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; β hCG=β human chorionic 
gonadotropin; C=cycle; CBC=complete blood count; CT=computed tomography; D=day; ECOG=Eastern Cooperative Oncology Group; F=free; h=hour(s); INR=International 
Normalized Ratio; iRECIST=modified RECIST 1.1 for immune-based therapeutics; IT=intratumoral; IV=intravenous; min=minutes; MRI=magnetic resonance imaging; 
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.
a Participants on anticoagulant therapy should be monitored throughout the study.
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1.3.4
Schedule of Activities for Treatment Phase: Arm 2 Part II - Cohort Expansion
Table 4
Schedule of Activities for Treatment Phase: Arm 2 Part II - Cohort Expansion
Study Period:
Treatment Period
Notes
Treatment Cycle / Visit 
Title:
Cycle 1
(28 days)
Cycles 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, 9 doses) of treatment with V937.
Treatment Days per 
Cycle
1
8
1
1
Scheduling Window 
(Days)
± 0
± 1
± 5
± 5
Treatment Assignment
X
Treatment assignment can occur up to 3 days prior to C1D1.
Participant ID Card
X
Participant identification card to be updated with treatment number at the 
time of treatment allocation.
Pembrolizumab 
Administration (Q3W)
X
X
X
Cycle 2 and beyond: study treatments may be administered up to 5 days 
before or after the scheduled Day 1. Cycles 2-8: V937 will be 
administered after a 200 mg dose of pembrolizumab is infused over 30 
min.
For administration details, see Pharmacy Manual.
V937 Administration
X
X
X
Clinical Procedures/Assessments
Tumor Imaging (CT or 
MRI as indicated)
(RECIST 1.1, and 
iRECIST Response 
Assessment)
Screening imaging should be performed 28 days prior to C1D1. On-study 
imaging should be performed every 9 weeks (± 7 days) after C1D1 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 anticancer treatment.
HCC population: Imaging must include triphasic CT/MRI for liver 
evaluation. Details are provided in the SIM
Brain Imaging
Perform at screening ONLY for participants with previously documented 
brain metastases (to confirm stability) or who are clinically symptomatic.
On-study imaging to be performed if positive for brain metastases at 
screening and clinically indicated. Perform at CR for participants who 
were positive at baseline.
Additional Imaging
(PET/CT, bone scan, 
etc.)
Obtain when clinically indicated.
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Study Period:
Treatment Period
Notes
Treatment Cycle / Visit 
Title:
Cycle 1
(28 days)
Cycles 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, 9 doses) of treatment with V937.
Treatment Days per 
Cycle
1
8
1
1
Scheduling Window 
(Days)
± 0
± 1
± 5
± 5
Lesion injection scan
Obtain for all injected lesions for every intratumoral injection performed. 
If imaging is used to guide injection (CT, ultrasound, fluoroscopy, etc.), 
capture images to document injected lesions. If injection by visualization 
or palpation, capture photographs with skin markers to show injected 
lesions.
Physical Examination
X
X
X
X
Directed physical examinations may be performed unless a full 
examination is deemed necessary. To be performed on Days 1 and 8 of 
Cycle 1; on Day 1 of every cycle thereafter
Weight
X
X
X
Every other cycle (ie, Cycles 1, 3, 5).
Vital Signs
(temperature, pulse, 
respiratory rate, and 
blood pressure)
X
X
X
X
Cycle 1: Measure within 1 h (± 30 min) prior to dosing, and 2, 4, and 6 h 
(± 30 min for each timepoint) after V937 administration.
Cycle 2 to Cycle 8: Measure within 1 h (± 30 min) prior to dosing, and 2 
and 4 h (± 30 min for each timepoint) after V937 administration.
Cycle 9 and beyond: Measure within 1 h (± 30 min) prior to dosing with 
pembrolizumab on Day 1 of every cycle.
If V937 is not administered at any cycle (eg, temporary withholding or 
discontinuation), vital signs are not required to be collected post-dose for 
that visit (ie, following administration of pembrolizumab).
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
AEs
Continuous AE reporting from the time of treatment allocation.
Survival Status
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Study Period:
Treatment Period
Notes
Treatment Cycle / Visit 
Title:
Cycle 1
(28 days)
Cycles 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, 9 doses) of treatment with V937.
Treatment Days per 
Cycle
1
8
1
1
Scheduling Window 
(Days)
± 0
± 1
± 5
± 5
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 C1D1 timepoint.
For PT/INR/PTT/aPTT: PT/INR ≤6 h before every V937 ITu visceral
administration.
Blood urea nitrogen is preferred; if not available, urea may be tested. 
Thyroid function: Samples are collected every other cycle (ie, Cycles 2, 4, 
6). Total T4 and T3 are preferred over FT4 and FT3.
Chemistry Panel
X
X
X
X
PT/INR and PTT or 
aPTT
X
X
X
Xa
AST, ALT
X
X
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, 
TSH)
X
X
Pregnancy test for 
WOCBP only (urine or 
serum β 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.
HCC (Cohort D) only:
HBsAg and HBV titers
X
X
Applicable to participants with a known history of Hepatitis B 
infections/exposure or who have a diagnosis of HCC.
Obtain predose to pembrolizumab, every 4th cycle (ie, Cycles 4, 8, 12).
HCC (Cohort D) only:
AFP
X
X
X
Obtain predose to pembrolizumab infusion
Abbreviations: AE=adverse event; AFP=alpha-fetoprotein; ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; β 
hCG=β human chorionic gonadotropin; C=Cycle; CBC=complete blood count; CT=computed tomography; D=Day; ECOG=Eastern Cooperative Oncology Group; F=free; 
h=hour(s); HbsAg=Hepatitis B surface antigen; HBV=Hepatitis B virus; INR=International Normalized Ratio; iRECIST=modified RECIST 1.1 for immune-based therapeutics; 
IT=intratumoral; IV=intravenous; min=minutes; MRI=magnetic resonance imaging; 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.
a Participants on anticoagulant therapy should be monitored throughout the study.
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1.3.5
Schedule of Activities for End of Treatment/Discontinuation and Posttreatment Phase: Arm 1, Arm 2 Part I Dose 
Escalation Phase, and Arm 2 Part II Expansion Phase
Table 5
Schedule of Activities for End of Treatment/Discontinuation and Posttreatment Phase: Arm 1, Arm 2 Part I Dose 
Escalation Phase, and Arm 2 Part II Expansion Phase
Study Period:
End of Treatment (EOT) / 
Discontinuation
Notes
Treatment Cycle / Visit Title:
Treatment Days per Cycle:
At time of treatment discontinuation
Scheduling Window (Days)
± 3
Administrative Procedures
Concomitant Medication
X
Efficacy Procedures
Tumor Imaging (CT or MRI as indicated) 
(RECIST 1.1, and iRECIST Response Assessment)
X
All imaging should be performed at the time of 
discontinuation. The evaluation window is ± 4 weeks.
Perform brain imaging if positive for brain metastases at 
Screening and as clinically indicated. Perform at CR for 
participants who were positive for metastases at baseline.
Obtain additional imaging as clinically indicated.
HNSCC Cohort B: Include head and neck CT.
Arm 1 only:
Medical Photography (cutaneous lesions)
X
Brain Imaging
X
Additional Imaging
(PET/CT, bone scan, etc.)
X
New Anticancer Therapy Status
X
Safety Assessments and Procedures
AE Monitoring
X
Full Physical Examination
X
Weight
X
Vital Signs
X
Obtain temperature, pulse, respiratory rate, and blood 
pressure.
ECOG Performance Status
X
CBC with Differential
X
See Procedures Manual for collection and management of 
laboratory samples.
Chemistry Panel
X
Abbreviations: AE=adverse event; β hCG=β human chorionic gonadotropin; CBC=complete blood count; DNA=deoxynucleic acid; ECOG=Eastern Cooperative Oncology 
Group; iRECIST=immune-based RECIST; 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 results for the treatment of a variety 
of tumors. Despite such progress, many advanced cancer patients remain unresponsive to
immunotherapy alone for reasons including, but not limited to: local immune tolerance at the 
tumor location, absence of effector T cells, and/or the development of resistance through a 
variety of adaptive mechanisms [Park, Y. J., et al 2018] [Sharma, P., et al 2017]. Efforts to 
combine preexisting and developmental therapies with anti-PD 1 agents such as conventional 
chemotherapy, dual CTLA-4, second-generation immunotherapy targets (TIGIT, LAG3, 
TIM-3, etc.), cancer vaccines, and oncolytic viruses are currently underway with the purpose 
of simultaneously targeting different hallmarks of tumor development/progression, which 
may have the potential to significantly enhance efficacy, response rates, and durability of 
clinical responses relative to single-agent first- and second-generation immunotherapies 
[Marshall, H. T. 2018].
V937 is a novel oncolytic viral therapy developed for ITu/intralesional administration to treat 
advanced cancers.
The use of oncolytic viruses to treat solid tumor malignancies has gained significant 
momentum over the last decade, with several oncolytic viruses active in Phase 2 and 3 
clinical studies [Kaufman, H. L. 2010] [Rowan, K. 2010] [Senzer, N. N., et al 2009]. The 
antitumor activity of oncolytic viruses consists of 2 distinct mechanisms of action: first, 
selective replication within neoplastic cells that results in direct lysis of tumor cells; and 
second, the induction of a systemic antitumor immunity [Kaufman, H. L., et al 2015].
The first mechanism is achieved through the combination of viral receptor cell surface
expression (ie, ICAM-1) followed by differential infectivity between normal cells and 
neoplastic cells. Although oncolytic viruses can enter both normal and cancer cells using cell 
surface receptors such as ICAM-1, abnormalities in a cancer cell’s response to stress, cell 
signaling, and homeostasis provide a selective advantage for viral replication to occur. For 
example, a normal interferon response limits the ability of viruses to replicate within, and 
spread to, adjacent cells. However, cancer cells have defective interferon responses and 
toll-like receptor signaling due to pathologic alterations in metabolic pathways. Such
deficiencies in interferon response enable oncolytic viruses to have a tumor-specific 
replication advantage [Krishnamurthy, S., et al 2006] [Stojdl, D. F., et al 2000]. Following 
viral replication, most oncolytic viruses induce cell death, which directly eliminates viable 
tumor cells, but also sets the stage for initiating a systemic immune response [Kaufman, H. 
L., et al 2015].
The second mechanism is achieved through the release of TAAs from tumor cells, which
promotes an adaptive immune response leading to tumor regression at the injected site, as 
well as distant tumor sites unexposed to virus. Tumor cells can release PAMPs, which are 
common to both viruses and bacteria. The release of viral PAMPs and additional cellular 
DAMPs promote the maturation of APCs, which then activate antigen-specific CD4+ and 
CD8+ T-cell responses. Once activated, CD8+ T cells can expand into cytotoxic effector 
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cells, which can migrate into the tumor and mediate antitumor immunity upon antigen 
recognition [Kaufman, H. L., et al 2015].
V937 is being studied for the treatment of advanced/metastatic solid tumors in combination 
with pembrolizumab. This is a Phase 1B/2 study to assess the efficacy, safety, and 
tolerability of V937 administered ITu in combination with pembrolizumab IV.
2.1
Study Rationale
There is a great unmet medical need for therapeutic agents that may enhance the efficacy of 
immunotherapy. Non-clinical studies investigating the combination of ITu or IV V937 with 
two different immunomodulatory agents demonstrated that V937 in combination with anti-
PD-1 and/or anti CTLA-4 blocking antibodies was generally well-tolerated in 
immunocompetent mouse models of melanoma and NSCLC. These studies showed that 
V937 has both antitumor activity and good tolerability in a monotherapy setting (CALM 
trial), as well as in combination with checkpoint inhibitors such as pembrolizumab and 
ipilimumab (CAPRA and MITCI trials, respectively).
In the CAPRA study, patients with advanced melanoma naïve to anti-PD-1/PD-L1 agents 
received the combination of ITu V937 and pembrolizumab. The study reported an overall 
response rate of 59% (16/27) in metastatic melanoma patients. Five Grade 3 or higher AEs 
were attributed to pembrolizumab in four participants. By contrast, few Grade 1 or 2 AEs 
were observed and attributable to V937 therapy. Thus, the combination of ITu V937 and 
pembrolizumab was generally well-tolerated among advanced melanoma patients.
In the MITCI study, patients with advanced melanoma who were naïve to checkpoint 
inhibitor therapy received the combination of ITu V937 and ipilimumab. The study reported 
an overall response rate of 50% (8/16) in metastatic melanoma patients. Additionally, a small 
number of PD-1 experienced patients were also enrolled on the trial and reported an overall 
response rate of 30% (3/10). As with the CAPRA study, patients reported AEs related to 
V937 which were largely limited to Grade 1 or 2 in severity.
The current study is intended to investigate whether ITu administration of V937 in 
combination with pembrolizumab in advanced/metastatic solid tumor malignancies can 
enhance the effectiveness of immunotherapy over immunotherapy monotherapy historical 
controls in different tumor types and metastatic lesion locations.
2.2
Background
V937 (Coxsackievirus A21; CVA21; CAVATAK®) is a non-genetically altered oncolytic 
virus derived from the Kuykendall strain of coxsackievirus A21 that has been propagated in 
cell culture. Coxsackievirus is a non-enveloped positive, single-stranded RNA virus with
4 capsid proteins which is a naturally-occurring human enterovirus. V937 has an acceptable 
preclinical safety profile and is in clinical development as an ITu/intralesional, intravesicular, 
and IV immunotherapy for advanced malignancies. For more specific details, refer to the 
V937 IB.
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Pembrolizumab is a potent, humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across several indications. For more details on specific 
indications refer to the pembrolizumab IB.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
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 there is 
literature evidence for ICAM-1 receptor expression. 
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 three major subclasses: polioviruses, echoviruses, and coxsackieviruses. The 
coxsackieviruses are further subdivided into Groups A (23 members) and B (6 members) 
[Zeichhardt, H. 2004].
Surface expression of ICAM-1 was identified as a necessary, but not entirely sufficient 
condition for successful lytic infection of 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 various other tissue types in the body.
Increased surface ICAM-1 expression levels is found on numerous malignant cells including, 
but not limited to: 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 demonstrated in metastatic human breast carcinoma cell lines [Rosette, C., et al 2005]. 
It is widely reported 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].
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2.2.1.2
Pembrolizumab (MK-3475) 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 TILs in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-
cells/FoxP3+ T-regs correlates with improved prognosis and long-term survival in solid 
malignancies, such as ovarian, colorectal, pancreatic, hepatocellular and renal cell carcinoma, 
and melanoma.
The normal function of PD-1, expressed on the cell surface of activated T-cells under healthy 
conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig superfamily member 
related to CD28 and 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 PD-1 receptor-ligand interaction is a major pathway 
hijacked by tumors to suppress immune control. 
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV-type domain responsible 
for ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. 
The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. 
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 CD3ζ, PKCθ, and ZAP70, which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010]. Consequently, the PD-1/PD-L1 pathway is an attractive target 
for therapeutic intervention in advanced/metastatic solid tumors.
2.2.2
Preclinical and Clinical Studies
Please refer to the pembrolizumab and V937 IBs for descriptions of the respective preclinical 
and clinical evaluations.
2.2.3
Ongoing Clinical Studies
Please refer to the pembrolizumab and V937 IBs for the descriptions of ongoing clinical 
studies.
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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 investigational medicines.
Potential risks associated with the administration of V937 based on clinical data may include
(but are not limited to) the following:
•
fatigue
•
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 IB and informed consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
There is no hypothesis testing in this study.
Throughout this protocol, the term RECIST 1.1 refers to a modification to RECIST 1.1 to 
allow a maximum of 10 target lesions in total and 5 per organ. Since ITu therapy is included 
by design in the study, RECIST 1.1 is also modified to specify that ITu injection by itself 
does not render a lesion non-evaluable. Refer to Section 4.2.1.1 for further details.
In male and female participants with advanced/metastatic solid tumors who are anti-PD-(L)1-
treatment-naïve:
Arm 1: Subcutaneous Tumor Cohorts
Objectives
Endpoints
Primary

To evaluate the objective response rate
(ORR) of V937 administered in 
subcutaneous tumors in combination with 
pembrolizumab per Response Evaluation 
Criteria in Solid Tumors Version 1.1 
(RECIST 1.1) as assessed by the 
investigator.

Objective response is a confirmed 
complete response (CR) or partial 
response (PR).
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Objectives
Endpoints
Secondary

To determine the safety and tolerability of 
V937 administered in subcutaneous 
tumors in combination with 
pembrolizumab.

Adverse event (AE)

Discontinuing a study intervention due 
to an AE

To evaluate progression-free survival 
(PFS) and duration of response (DOR) of 
participants treated with V937 in 
subcutaneous tumors in combination with 
pembrolizumab per RECIST 1.1 as 
assessed by the investigator.

PFS is defined as the time from the first 
dose of study treatment to the first 
documented disease progression or 
death due to any cause, whichever 
occurs first.

DOR is 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 PR 
or CR.

To evaluate the ORR, PFS, and DOR of 
V937 administered in subcutaneous 
tumors in combination with 
pembrolizumab per RECIST 1.1 for 
immune-based therapeutics (iRECIST)
criteria as assessed by the investigator.

ORR

PFS

DOR

To evaluate overall survival (OS) of 
participants treated with V937 in 
subcutaneous tumors in combination with 
pembrolizumab.

OS is defined as the time from the first 
dose of study treatment to the date of 
death from any cause.
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Objectives
Endpoints
Arm 2 Part I: Visceral Dose Escalation, and Arm 2 Part II: Visceral Tumor Expansion
Objectives
Endpoints
Primary

To determine the safety and tolerability 
and to establish a preliminary
recommended Phase 2 dose (RP2D) of 
V937 administered in visceral tumors in 
combination with pembrolizumab.

Dose limiting toxicity (DLT)

AE

Discontinuing a study intervention due 
to an AE
Secondary

To evaluate the ORR of V937 
administered in visceral tumors at the 
preliminary RP2D with pembrolizumab 
per RECIST 1.1 and iRECIST criteria as 
assessed by the investigator.

ORR
Tertiary/Exploratory
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Objectives
Endpoints
4
STUDY DESIGN
4.1
Overall Design
This is a multicenter, worldwide, non-randomized, open-label, Phase 1b/2 study of V937
administered ITu in combination with pembrolizumab in participants with pathologically
confirmed diagnosis of advanced/metastatic solid tumors where anti-PD1 therapy is
recommended as first-line SOC, or for tumors unresponsive to standard treatments approved 
in the particular tumor subtype.
This study will evaluate the safety, tolerability, and preliminary efficacy of V937 
administration in combination with pembrolizumab in 2 arms: Arm 1 includes
subcutaneously-accessible tumors (Arm 1; Section 4.1.1), while Arm 2 includes tumors with 
visceral metastases. There are 2 parts to Arm 2. Arm 2 Part I consists of a dose escalation
phase of V937 + pembrolizumab in solid tumors with metastatic lesions to the liver (Arm 2 
Part I; Section 4.1.2). Following determination of a RP2D, we will proceed with Arm 2 Part 
II with 2 expansion cohorts in HCC and gastric carcinoma (Arm 2 Part II; Section 4.1.3).
Participants will enroll in Arm 1 and Arm 2 Part I simultaneously. In Arm 2 Part I, dose 
escalation will follow the mTPI design (Section 4.1.2). Per mTPI, the final number of 
participants enrolled in Arm 2 Part I will depend on empiric safety observations (DLTs) and 
final RP2D, which will have an upper boundary of 3×108 TCID50 total dose per participant.
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In Arm 1, preliminary efficacy will be evaluated using OR as assessed by the investigator 
using RECIST 1.1 as a primary endpoint. Safety and tolerability, PFS, and DOR will be 
evaluated using RECIST 1.1 as secondary endpoints. OR, PFS, and DOR will be evaluated 
using iRECIST 1.1 as additional secondary endpoints in addition to evaluation of OS. 
Finally, V937 PK/pharmacodynamic and exploratory biomarkers will be evaluated as 
tertiary/exploratory endpoints.
In Arm 2 Parts I and II, safety and tolerability and establishing RP2D of ITu administered 
V937 in combination with pembrolizumab in participants with visceral tumors will be 
assessed as a primary objective. The final RP2D for future studies will be confirmed using all 
available safety information (including early and late toxicities from Arm 1). OR will be 
evaluated using RECIST 1.1 and iRECIST criteria as a secondary endpoint. Finally, PFS and
DOR will be evaluated using RECIST 1.1 and iRECIST criteria, in addition to OS, V937 
PK/pharmacodynamic and exploratory biomarkers as tertiary/exploratory endpoints.
Participants will be monitored carefully for clinical and/or radiographic evidence of disease 
progression according to RECIST 1.1. However, iRECIST may be used by the investigator 
for treatment decisions. It will be at the discretion of the treating physician whether to 
continue a participant on study intervention until repeat imaging is obtained. Participants 
may continue to receive study intervention until tumor assessment is repeated ≥4 to 8 weeks 
later in order to confirm progressive disease by iRECIST per site assessment.
AEs will be evaluated by the investigator, according to criteria outlined in the 
NCI CTCAE v5.0, to establish safety and tolerability of V937 in combination with 
pembrolizumab as primary objectives in this study for all tumor cohorts.
The definition of DLTs and criteria for dose modification of V937 are outlined in 
Section 6.6.5 and 6.6.6.1. Pembrolizumab will be administered at a fixed dose of 200 mg 
every 3 weeks, which will not be modified.
Participants may receive study intervention (8 cycles of V937 in combination with up to 
35 cycles of pembrolizumab) for approximately 2 years. Participants will be discontinued 
from the study treatment for any of the following reasons: progressive disease, unacceptable 
toxicity, cessation of treatment due to intercurrent illness, withdrawal of treatment by 
investigator, withdrawal of consent by participant, pregnancy of participant, noncompliance 
with study intervention or procedure requirements, completion of treatment, or cessation of 
treatment due to administrative reasons.
Participants who discontinue treatment for reasons other than confirmed progressive disease 
will have post-treatment follow-up for disease status (including imaging) until progressive 
disease or death, initiating a new anticancer therapy, withdrawing consent for study 
participation, Sponsor notification, or loss to follow-up.
After confirmed progressive disease, each participant will be contacted every 12 weeks 
(84 ± 7 days) for survival until withdrawal of consent, loss to follow-up, death, or end of 
study, whichever comes first.
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4.1.1
Arm 1: Subcutaneous Tumors
In Arm 1 of the study, approximately 30 participants (or less due to early study termination) 
will be enrolled into each of the following three tumor cohorts:
Cohort A: Triple negative breast cancer
Cohort B: Head and neck squamous cell carcinoma
Cohort C: Cutaneous squamous cell carcinoma
V937 will be administered at a maximum dose of 3 × 108 TCID50, administered ITu on 
Days 1, 3, 5, and 8 of Cycle 1 (28 days), then Day 1 of Cycle 2 through Cycle 8, for a 
maximum of 11 doses. V937 will be administered at a maximum dose of 3 × 108 TCID50. 
The administered dose is dependent on the volume of tumor injected (see Table 10 and
Table 11). V937 is administered ITu on Days 1, 3, 5, and 8 of Cycle 1 (28 days), then Day 1 
of Cycle 2 through Cycle 8, for a maximum of 11 doses. The dose of pembrolizumab in 
Arm 1 will remain constant at 200 mg IV every 3 weeks, for a maximum of 35 treatment 
cycles (approximately 2 years).
4.1.2
Arm 2 Part I: Dose Escalation in Metastatic Visceral Lesion Tumors
In Arm 2 Part I of the study, an mTPI design will be used to identify and confirm the RP2D
of V937. Three predetermined dose levels of V937 will be evaluated:
Dose level 1: 3 × 107 (3E7) TCID50
Dose level 2: 1 × 108 (1E8) TCID50
Dose level 3: 3 × 108 (3E8) TCID50
The number of participants enrolled per dose level during dose escalation will be based on 
the occurrence of DLTs per the mTPI design. The maximum RP2D will be capped at 3E8. 
The administered dose is dependent on the volume of tumor injected (see Table 10 and
Table 11). V937 will be administered ITu on Days 1 and 8 of Cycle 1 (28 days), then Day 1 
of Cycle 2 through Cycle 8, for a maximum of 9 doses. The dose of pembrolizumab will 
remain constant at 200 mg IV every 21 days for a maximum of 35 treatment cycles
(approximately 2 years).
In Arm 2 Part I only, each of the first 3 participants in DL1 will undergo an observation 
period of 5 days before the next participant is dosed. Subsequent participants in all other dose 
levels will not undergo a staggered enrollment. Dose-finding and confirmation in Arm 2 
Part I will end after 14 participants have been treated at any of the selected doses, per mTPI 
design. The pool-adjacent violators algorithm will be used to estimate the DLT rates across 
doses in each treatment arm under the assumption of monotonicity between DLT rates and 
dose levels [Ji, Y. and Wang, S.-J. 2013]. The dose with an estimated DLT rate closest to 
30% may be treated as a preliminary RP2D. The totality of the data will be considered before 
deciding on the dose to carry forward to Arm 2 Part II.
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4.1.3
Arm 2 Part II: Cohort Expansion in Metastatic Visceral Lesion Tumors
Arm 2 Part II supports the visceral cohort expansion phase, which will enroll 30 participants
(or less due to early study termination) into each of the below cohorts:
Cohort D: Hepatocellular carcinoma
Cohort E: Gastric carcinoma
V937 will be administered at the RP2D (defined in Arm 2 Part I). V937 will remain at a
constant dose administered ITu on Days 1 and 8 of Cycle 1 (28 days), then Day 1 of Cycle 2 
through Cycle 8, for a maximum of 9 doses. The dose of pembrolizumab will remain 
constant at 200 mg IV every 21 days for a maximum of 35 treatment cycles (approximately 
2 years).
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 two-arm, non-randomized, open-label study of ITu V937 + 
pembrolizumab IV in participants with advanced/metastatic solid tumors who have not 
received prior therapy with anti-PD-1/PD-L1 agents, T-VEC, or other oncolytic virus
therapies.
V937 infects both normal and tumor cells by binding to ICAM-1, a viral cell surface receptor
reported to be overexpressed in many different tumor types. Upon successful entry into a 
tumor cell, oncolytic viruses leverage a tumor cell’s abnormal response to cell signaling, 
homeostasis, and stress in order to propagate an infection, which ultimately leads to cell 
lysis. Once lysis occurs, a cascade of events occurs involving the release of tumor-associated 
antigens as well as recruitment of antigen-presenting and cytotoxic T cells to the tumor site
to affect an anti-tumor response [Krishnamurthy, S., et al 2006] [Stojdl, D. F., et al 2000]. 
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Depending on the trial arm, the primary endpoints in this study include: OR (Arm 1) and 
DLT, AE and discontinuation of study intervention due to AE (Arm 2 Parts I and II).
Secondary endpoints include PFS, DOR, OR by iRECIST and OS for Arm 1, and ORR by 
RECIST 1.1 and iRECIST for Arm 2 Part II. ORR is the proportion of participants with OR.
Tumor response will be assessed using RECIST 1.1 and iRECIST as assessed by investigator 
(see Section 8.2.1). Antitumor activity will be measured through such endpoints as the OR, 
PFS, and OS, which are described further in Section 9.4.1. A planned interim futility analysis 
is described in Section 9.7.
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This study will assess ORR based on RECIST 1.1 criteria as determined by the investigator.
Objective response rate is an acceptable measure of clinical benefit 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 RECIST 1.1 to assess ORR 
is typically considered acceptable by regulatory authorities.
RECIST 1.1 will be used for efficacy measures as assessed by the investigator when 
determining eligibility (Section 8.2.1). Although traditional RECIST 1.1 references a 
maximum of 5 target lesions in total and 2 per organ, this protocol has implemented a 
modification to RECIST 1.1 to allow for a maximum of 10 target lesions in total and 5 per 
organ. Furthermore, because ITu therapy is included by design in this study, RECIST 1.1 is 
also modified to specify that ITu injection itself does not render a lesion non-evaluable.
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (iRECIST, Section 8.2.5). 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 
participants 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 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 
15% of participants. These findings support the need to apply a modification to RECIST 1.1 
that takes into account the unique patterns of atypical responses in immunotherapy and 
enables treatment beyond initial radiographic progression, if the participant is clinically 
stable.
Modified 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 FDA and the EMA [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.
For further information on iRECIST, see Section 8.2.5.
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4.2.1.1.1
Response Rate Assessed by RECIST Version 1.1
RECIST 1.1 will be used to determine the objective response. Although traditional RECIST 
1.1 references a maximum of 5 target lesions in total and 2 per organ, this protocol has 
implemented a modification to RECIST 1.1 to allow a maximum of 10 target lesions in total 
and 5 per organ. Furthermore, because ITu therapy is included by design in the study, 
RECIST 1.1 is also modified to specify that ITu injection itself does not render a lesion non-
evaluable.
4.2.1.2
Safety Endpoints
In Arm 1, safety and tolerability of ITu V937 in combination with pembrolizumab is a 
secondary objective. In Arm 2, safety and tolerability of ITu V937 in combination with 
pembrolizumab is a primary objective. The primary safety analysis will be based on 
participants who experience toxicities as defined by NCI CTCAE v5.0 criteria. Safety will be 
assessed by quantifying the types and grades of toxicities experienced by participants who 
have received V937 in combination with pembrolizumab.
For AEs, attribution to drug, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. Adverse events that will be analyzed 
include, but are not limited to, DLTs, AEs, SAEs, fatal AEs, and laboratory changes.
4.2.1.3
Pharmacokinetic Endpoints
A tertiary/exploratory objective of this study is to characterize the PK profile of V937
following ITu administration in combination with pembrolizumab. The serum concentrations 
of these agents will serve as the primary readout for the PK, and these data will be used to 
derive PK parameters of V937. Furthermore, the results of these analyses will be used in 
conjunction with the pharmacodynamics, and safety and exploratory endpoint data to help 
assess future dosing strategies for V937.
4.2.1.4
Pharmacodynamic Endpoints
4.2.1.4.1
Neutralizing V937 Antibodies
Neutralizing antibody responses at the beginning of each cycle will be determined to 
understand drug exposure and safety. The incidence of neutralizing antibodies will be 
evaluated and summarized over time. Correlations between the presence/absence of 
positivity for neutralizing antibodies, PK and pharmacodynamic markers, activity, and safety 
of V937 will be explored.
4.2.1.5
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 
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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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4.2.1.6
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 (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of future biomedical research are presented in Appendix 6.
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4.3
Justification for Dose
4.3.1
Starting Dose for This Study
4.3.1.1
Rationale for Starting and Maximum Dose of V937
Participants with Subcutaneous Tumors (V937 3 × 108 TCID50, ITu + 
Pembrolizumab 200 mg IV)
The clinical development of V937 has included safety and efficacy assessments using 
3 different routes of administration: ITu, intravesical, and IV.
 
 
 
 
The ITu dose for this study comes from Phase 2 studies conducted in participants with 
advanced melanoma (CALM and CAPRA). In the CALM study, late-stage melanoma 
participants were treated with V937 at a maximum dose of 3 × 108 TCID50 and showed an 
ORR of 28%. Furthermore, in the CAPRA study, late-stage melanoma participants were 
treated with V937 at a dose of 3 × 108 TCID50 in combination with pembrolizumab and 
showed an ORR of 59% [Pandha, H. S. 2018]. Evidence for biological activity and
tolerability in the CALM and CAPRA studies supported moving forward with 3 × 108
TCID50 RP2D in this study.
The dosing schedule in this study for ITu administration in Arm 1 is based on the CAPRA 
study. A maximum total dose of 3 × 108 TCID50 will be administered on Days 1, 3, 5, 8, of 
Cycle 1, then every 3 weeks (Cycles 2-8) for a total of 11 doses.
The dose for pembrolizumab is 200 mg IV every 3 weeks. The pembrolizumab dose and 
schedule is identical to that used in the CAPRA study, which is based on the current SOC.
Please refer to the V937 IB for additional information regarding dose selection.
Participants with Visceral Tumors (V937 Dose Escalation and Cohort Expansion, ITu + 
Pembrolizumab 200 mg IV)
Injection into visceral tumors has not previously been tested with V937. Therefore, this 
regimen will employ dose escalation to determine the RP2D for visceral injections.  Injection 
into visceral tumors is technically challenging compared to subcutaneous injections. 
Therefore, frequency of injections is limited to once-per-week.
V937 doses will be escalated at three different dose levels: 3 × 107 TCID50; 1 × 108 TCID50, 
and; 3 × 108 TCID50. The total administered dose is dependent on the tumor size 
(see Table 11 and Table 13). The maximum injected doses for DL1, DL2 and DL3 of V937 
will be 3 × 107 TCID50, 1 × 108 TCID50, and then 3 × 108 TCID50. V937 is administered on
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Day 1 and Day 8 of Cycle 1, and Day 1 of Cycles 2-8 for a total of 9 doses. The initial dose 
escalation will occur in all-comer tumors metastatic to liver. Note that injections will be 
direct into metastatic liver lesions, and NOT hepatic intraarterial injections. Multiple tumor 
histologies will be allowed in the visceral dose escalation cohort (including, but not limited 
to: NSCLC, CRC, and pancreatic carcinomas). After reaching a RP2D using the mTPI dose 
escalation scheme derived from Arm 2 Part I cohort, the trial will subsequently expand into 
2 additional visceral tumor cohorts, HCC (Cohort D) and gastric carcinoma (Cohort E). 
These visceral cohorts will begin enrolling approximately 12 to 18 months following the
completion of Arm 1 Part I dose escalation.
The dose for pembrolizumab is 200 mg IV every 3 weeks, which is based on the current 
SOC.
4.3.1.2
Rationale for Dose Interval and Escalation Increments
The starting dose and dose interval of V937 is based on integrating nonclinical toxicological, 
pharmacological, and efficacy data. Dose finding will proceed 
 
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4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
4.4.1
Clinical Criteria for Early Study Termination
Recruitment in the study or at a 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.
Early study termination will be the result of the criteria specified below:
1. If the incidence and/or severity of adverse drug reactions or procedure-related 
complications suggest that the risk/benefit ratio is unfavorable to participant
2. If the incidence and/or severity of emerging effects/clinical endpoints suggest that the
risk/benefit ratio to the study population is unacceptable
3. If there are plans to either modify or discontinue development of study drug
Ample notification will be provided if Sponsor decides to terminate the supply of V937 or 
pembrolizumab.
Upon study completion or early study termination, 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 V937-013.
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5
STUDY POPULATION
Male and Female participants at least 18 years of age with advanced/metastatic solid tumors 
will be enrolled in this study. (See Appendix 7 for country-specific requirements.)
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:
5.1.1
Overall Inclusion Criteria
1. Has locally-advanced disease that is not amenable to surgery or radiation, or Stage IV 
advanced/metastatic solid tumor malignancies.
Note: Tumor-specific criteria are provided in Section 5.1.2.1 (TNBC), Section 
5.1.2.2 (HNSCC), Section 5.1.2.3 (cSCC), Section 5.1.3 (Visceral lesion dose 
escalation), Section 5.1.4.1. (HCC), and Section 5.1.4.2 (Gastric).
2. Has histologically- or cytologically-confirmed diagnosis of an advanced/metastatic solid 
tumor.
3. Has measurable disease by RECIST 1.1 criteria as assessed by investigator. Target 
lesions in a previously irradiated area will be considered measurable if progression has 
been demonstrated in such lesions.
4. Has submitted a baseline tumor sample for analysis (either de novo biopsy or an archival 
tumor block). For details on tumor tissue submission, see the Procedures Manual.
Note: Arm 2 Part I: If tissue block is not available, participant may be enrolled if 
all other inclusion criteria are satisfied.
5. Has a performance status of 0 or 1 on the ECOG Performance Scale obtained within 
72 hours prior to the first dose of study intervention.
6. If participants have known HIV-positive disease, participants must have well-controlled 
HIV on ART defined as:
a.
CD4+ T-cell count >350 cells/mm3 at the time of screening.
b. Must have achieved and maintained virologic suppression, defined as HIV RNA 
levels below 50, or LLOQ (below limits of detection), using a locally available assay 
at the time of screening.
c.
Must be on a stable regimen without any changes in drugs or dose modifications for a 
minimum of 4 weeks prior to study entry (Day 1) [Uldrick, T. S., et al 2019].
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7. Demonstrate adequate organ function as defined in Table 7. These laboratory samples 
must be collected within 72 hours prior to the first dose of study intervention.
Table 7
Adequate Organ Function Laboratory Values for Non-HCC Population
System
Laboratory Value
Hematological
Absolute neutrophil count
>1,500/mcL
Platelets
>100,000/mcL
Hemoglobin
≥8 g/dL or >5.6 mmol/La
Renal
Creatinine OR
Measured or calculatedb CrCl
(GFR can also be used in place of CrCl)
≤1.5 × ULN or
≥30 mL/min for participants with 
creatinine levels >1.5 × ULN
Hepatic
Total bilirubin (serum) 
≤1.5 × ULN or
Direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
<2.5 × ULN or ≤5 × ULN for participants 
with liver metastases
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
<1.5 × ULN (unless participant is 
receiving anticoagulant therapy, in which 
case PT/INR or aPTT should be within the 
therapeutic range of intended use of 
anticoagulants)
Abbreviations: 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; PT=prothrombin time; 
ULN = upper limit of normal.
a Criteria must be met without packed red blood cell (pRBC) 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.
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.
Refer to Section 5.1.4.1 for laboratory value requirements for the HCC population.
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Demographics
8. Is male or female, from ≥18 years of age inclusive, at the time of signing the 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.
9. Male participants are eligible to participate if they agree to the following during the 
intervention period for and for at least 120 days after the last dose of 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.
Note: For male participants on pembrolizumab only, no contraception measures 
are needed.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
10. 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 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 
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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 
located 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.
•
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
11. The participant (or legally acceptable representative) provides documented informed 
consent for the study. The participant may also provide consent for future biomedical 
research. However, the participant may participate in the main study without participating 
in future biomedical research.
5.1.2
Arm 1: Subcutaneously Accessible Tumors
12. Have at least 1 injectable lesion amenable to injection and/or biopsy. Biopsy may be 
performed via visual inspection, ultrasound guidance, or cross-sectional imaging. 
Injections for cutaneous and subcutaneous lesions may be done by visual inspection,
ultrasound guidance and/or palpation. Lesion(s) must be measurable and meet one of the 
following criteria:

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 solid tumor participants. The longest 
diameter for an injectable lesion must be ≤10 cm for both solid tumors and nodal 
lesions in solid tumor participants.

Multiple coalescing, superficial lesions which in aggregate have a longest diameter of 
≥1 cm and ≤10 cm.
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5.1.2.1
Specific Inclusion Criteria for Cohort A: Advanced/Metastatic Triple 
Negative Breast Cancer
13. Has locally-recurrent, inoperable OR metastatic breast cancer treated with or must have 
received at least 1 prior line of chemotherapy in the metastatic setting with skin 
involvement and/or subcutaneous lesions or accessible lymph nodes amenable to local 
injection.
Note: An exception would be allowed for patients who are not eligible to receive 
chemotherapy.
Chemotherapy ineligibility would be determined by a medical oncologist and may 
include reasons such as, but not limited to, comorbid medical conditions or 
lifetime chemotherapy dose. In such cases, a reasonable alternative would be 
consideration of participation in a clinical trial.
Note: For participants with prior XRT, lesion(s) in a previously irradiated filed 
must have documented progression on scan to be considered amenable to 
injection.
14. Has diagnosis of triple-negative breast cancer (estrogen receptor, progesterone receptor, 
and HER2-receptor negative status).
15. Has been treated with (neo)adjuvant anthracycline (unless anthracycline was
contraindicated based on treating physician’s medical judgment).
Refer to Section 5.1.1 for additional inclusion criteria that apply to all tumor cohorts.
5.1.2.2
Specific Inclusion Criteria for Cohort B: Advanced/Metastatic Head and 
Neck Squamous Cell Carcinoma
16. Has histologically confirmed advanced or metastatic HNSCC of the oral cavity, 
oropharynx, hypopharynx, and/or larynx considered incurable and/or treated with no 
more than 1 previous line of therapy.
17. Tumors must be PD-L1+ (CPS ≥1).
18. Has documentation of HPV status for oropharyngeal cancers only.
Note: Oral cavity, hypopharynx, and larynx cancers are exempt from requirement 
for HPV testing since these anatomical locations typically exhibit a low incidence 
of HPV positivity.
Note: If a participant has not been previously tested, then status should be 
reported as “unavailable.”
Refer to Section 5.1.1 for additional inclusion criteria that apply to all tumor cohorts.
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5.1.2.3
Specific Inclusion Criteria for Cohort C: Locally-advanced/Metastatic 
Cutaneous Squamous Cell Carcinoma
19. Has histologically confirmed cSCC as the primary site of malignancy (metastatic skin 
involvement from another primary cancer or from cancers of unknown primary are not 
eligible).
Note: Squamous cell carcinomas with primary tumor sites involving the 
anogenital region (eg, penis, scrotum, vulva, or perianal region) are not eligible.
20. Recurrent/metastatic disease only: Has metastatic disease defined as disseminated disease 
distant from the initial/primary site of diagnosis and/or with a history of locally-recurrent 
disease previously treated with surgery and/or radiotherapy, which is now incurable.
21. Locally-advanced disease only: Participants ineligible for surgical resection.
Contraindications to surgery are defined as:

cSCC recurring in the same location following two or more surgical procedures, and
not amenable to curative resection

cSCC with significant local invasion preventing total resection

cSCC in anatomically challenging locations where surgery is not feasible (ie, would 
cause severe dysfunction and disfigurement of structures such as the nose, ears, eyes, 
or limb amputation)
22. Locally-advanced disease only: Received prior XRT to the index site or deemed 
ineligible for XRT.
Refer to Section 5.1.1 for additional inclusion criteria that apply to all tumor cohorts.
5.1.3
Arm 2 Part I: Visceral Lesion Dose Escalation and Confirmation
23. Has a histologically-confirmed advanced/metastatic solid tumor that has progressed on all 
treatment known to confer clinical benefit. Solid tumors of any type are eligible for 
enrollment with exception noted below.
Note: HCC tumors are excluded from the visceral dose escalation cohort.
24. Has metastatic liver lesion(s) not exceeding one-third of the total liver volume AND has a 
minimum of one injectable liver lesion with the following criteria:

Accessible for image-guided injection and biopsy via ultrasound guidance or cross-
sectional imaging (CT/MRI)
Note: If planning use of CT fluoroscopy for visceral lesion injections, must check
that the participant has a CrCl ≥60 mL/min within 12 hours prior to procedure.
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
lesion(s) must be ≥1 cm in longest diameter and ≤10 cm in longest diameter
Refer to Section 5.1.1 for additional inclusion criteria that apply to all tumor cohorts
5.1.4
Arm 2 Part II: Visceral Cohort Expansion
5.1.4.1
Specific Inclusion Criteria for Cohort D: Hepatocellular Carcinoma
25. Has advanced HCC following progression on, or intolerance to, sorafenib or lenvatinib
with no curative options.
26. Has diagnosis of HCC confirmed by radiology, histology, or cytology (fibrolamellar and 
mixed hepatocellular/cholangiocarcinoma subtypes not eligible for enrollment).
a.
Radiologic diagnosis is defined as: evidence of liver cirrhosis and a liver mass 
measuring at least 1 cm with characteristic vascularization (intense enhancement 
in hepatic arterial-dominant phase and contrast washout in late portal venous 
phase) on triphasic CT or MRI scan.
27. Has Child-Pugh Class A score (see Appendix 9).
28. If a participant has a history of HCV infection, then the participant must have been 
successfully treated for this condition, which is defined as SVR12. Eligible participants 
must wait for a period of ≥4 weeks between achievement of SVR12 and start of study 
drug(s). (See Section 6.6.3)
29. If participant has a known history of chronic hepatitis B infection and/or exposure and 
has received treatment with anti-hepatitis B therapy. (See Section 6.6.3)
a.
Controlled (treated) hepatitis B participants will be allowed if they meet the 
following criteria: Antiviral therapy for HBV must have been given for a 
minimum of 12 weeks. HBV viral load must be less than 100 IU/mL prior to first 
dose of study intervention. Participants on active HBV therapy with viral 
loads under 100 IU/mL should stay on the same therapy throughout study 
treatment.
b. Participants who are anti-HBc (+), negative for HBsAg, negative or positive for 
anti-HBs, and who have an HBV viral load under 100 IU/mL, do not require HBV 
anti-viral prophylaxis.
Refer to Section 5.1.3 for visceral lesion dose expansion inclusion criteria.
Refer to Section 5.1.1 for additional inclusion criteria that apply to all tumor cohorts.
30. Demonstrate adequate organ function as defined in Table 8. These laboratory samples 
must be collected within 72 hours prior to the first dose of study intervention.
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Table 8
Adequate Organ Function Laboratory Values for HCC Population
System
Laboratory Value
Hematological
Absolute neutrophil count
>1,200/mcL
Platelets
>60,000/mcL
Hemoglobin
≥8 g/dL without transfusion or EPO 
dependency within 7 days.
Renal
Creatinine OR
Measured or calculateda CrCl 
(GFR can also be used in place of CrCl)
≤1.5 × ULN or 
≥30 mL/min for participants with creatinine 
levels >1.5 × ULN
≥60 mL/min required prior to CT 
fluoroscopy guided injections
Hepatic
Total bilirubin
≤2 mg/dL or
Direct bilirubin ≤ULN for participants with 
total bilirubin levels >2 mg/dL
AST (SGOT) and ALT (SGPT)
≤5 × ULN
Albumin
≥3.0 g/dL
Note: No albumin supplement (or BCAA) 
allowed within the last 14 days.
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
<1.5 × 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)
Abbreviations: ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); 
aPTT=activated partial thromboplastin time; AST (SGOT) = aspartate aminotransferase (serum 
glutamic oxaloacetic transaminase); BCAA=branched-chain amino acids; CrCl=creatinine 
clearance; CT=computed tomography; EPO=erythropoietin; GFR = glomerular filtration rate; 
INR=International Normalized Ratio; PT=prothrombin time; ULN = upper limit of normal.
a Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; 
laboratory value requirements should be adapted according to local regulations and guidelines for 
the administration of specific chemotherapies.
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5.1.4.2
Specific Inclusion Criteria for Cohort E: Gastric Carcinoma
31. Has histologically- or cytologically-confirmed diagnosis of locally-advanced, 
unresectable or metastatic gastric or GEJ adenocarcinoma:
a.
must have received at least one prior line of therapy that includes a 
platinum/fluoropyrimidine doublet or triplet regimen. Progression can be confirmed 
by CT or PET/CT scan or clinical evidence (eg, cytology report from ascites and/or
pleural fluid).
b. must have proven clinical progression 6 months following (or during) last dose of 
adjuvant or neo-adjuvant therapy provided participant previously received a 
platinum/fluoropyrimidine doublet.
32. Participants with HER2 negative status; or, those with HER2 positive status AND 
documented disease progression on a prior regimen containing trastuzumab.
Note: HER2 negative is defined as IHC (0, or 1+) or fluorescence in situ 
hybridization (FISH) negative (HER2:CEP17 ratio <2 with average HER2 copy 
number <4.0 signals/cell)
Refer to Section 5.1.3 for visceral expansion cohort inclusion criteria.
Refer to Section 5.1.1 for additional inclusion criteria that applies to all tumor cohorts.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
5.2.1
Overall Exclusion Criteria
1. Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks 
(2 weeks for palliative radiation) prior to first dose of study intervention or has not 
recovered to CTCAE Grade 1 or better.
2. If major or minor surgery was performed at/near the area being considered for injection, 
participant must be recovered from toxicity and/or complications of intervention.
3. Has had injection, or radiation therapy of >30 Gy, participant must be recovered from 
toxicity and/or complications of intervention.
4. Has a history of second malignancy, unless potentially curative treatment has been 
completed with no further evidence of disease for ≥5 years.
Note: Time requirement of ≥5 years without further evidence of disease does not 
apply to:

the tumor for which the participant is enrolled in the trial
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
participants who underwent successful definitive resection of basal cell 
carcinoma of the skin; superficial bladder cancer; in situ cervical cancer, or 
other in situ cancers
5. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
treated brain metastases may participate if lesions are radiologically stable.
Note: Repeat imaging should be done during screening with demonstration of stable 
lesions for a minimum of 4 weeks, and without need the for steroid therapy for at 
least 2 weeks prior to first dose of study intervention.
6. Has an active infection requiring therapy (exceptions: HIV criteria outlined in 
Section 5.1.1 and HBV and HCV criteria for HCC cohort as stated in Section 5.1.4.1).
7. Has a history of interstitial lung disease.
8. Has a history of noninfectious pneumonitis requiring active steroid therapy or ongoing
pneumonitis.
9. Has an active autoimmune disease that required systemic treatment in the past 2 years (ie, 
necessitating 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 (steroid use ≤10 mg 
prednisone, or its equivalent, daily) is not considered a form of systemic treatment and is 
allowed. The use of non-systemic steroids is permitted.
10. Participants with known Hepatitis B or C infections or known to be positive for 
HBsAg/HBV DNA or Hepatitis C Antibody or RNA. Active Hepatitis C is defined by a 
known positive Hep C Ab result and known quantitative HCV RNA results greater than 
the lower limits of detection of the assay.
Note: See Section 5.1.4.1 for hepatitis guidelines in HCC cohort only. (See Appendix 
7 for country-specific requirements.)
11. Participants with a history of Kaposi’s sarcoma and/or Multicentric Castleman’s Disease.
12. Has known hypersensitivity to V937 and/or pembrolizumab or any of their excipients.
(See Appendix 7 for country-specific requirements.)
13. Has known psychiatric or substance abuse disorder that significantly interferes with 
cooperation with requirements of the trial.
Prior/Concomitant Therapy
14. Has received prior therapy with anti-PD-1/PD-L1 agents, T-VEC or any other oncolytic 
virus therapies.
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15. Has received a live or live-attenuated vaccine within 30 days prior to first dose of study 
intervention. Administration of killed vaccines is allowed.
Refer to Section 6.5.2 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
16. 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 if it has been 4 weeks after the last dose of the previous 
investigational agent.
Other Exclusions
17. 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.
5.2.2
Arm 2 Part II: Visceral Cohort Expansion
5.2.2.1
Specific Exclusion Criteria for Cohort D: Hepatocellular Carcinoma
18. Has had esophageal or gastric variceal bleeding within the last 6 months. All participants 
should undergo screening for esophageal varices, unless such screening has been 
performed in the past 12 months before first dose of treatment. If varices are present, they 
should be treated according to institutional standards before receiving any study 
intervention.
19. Has Vp4, inferior vena cava, or cardia involvement from HCC based on imaging.
20. Has had clinically diagnosed hepatic encephalopathy in the 6 months prior to initiation of 
study intervention. Participants on standing rifaximin or lactulose to control hepatic 
encephalopathy are not eligible for the study.
Refer to Section 5.2.1 for additional exclusion criteria that apply to all tumor cohorts.
5.2.2.2
Specific Exclusion Criteria for Cohort E: Gastric Carcinoma
21. Has squamous cell or undifferentiated gastric cancer.
Refer to Section 5.2.1 for additional exclusion criteria that apply to all tumor cohorts.
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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
No restrictions required.
5.3.3
Activity Restrictions
No restrictions required.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Participants who fail screening may be re-screened for eligibility following consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention(s) 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 are 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.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 9.
Country-specific differences are noted in Appendix 7.
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Table 9
Study Interventions
Arm 
Name
Arm 
Type
Inter-
vention 
Name
Inter-
vention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 1
Experi
mental
V937
Biological/
Vaccine
Solution 
for 
Infusion
7.5 X 107
TCID50/
mL
3 X 108
TCID50
(assume 4 mL 
injected)
ITu Injection
Day 1, 3, 5, and 8 of 
Cycle 1 (28-day 
cycle)
Day 1 of Cycles 
2 to 8 (21-day 
cycles)
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
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 2
Part I
Experi
mental
V937
Biological/
Vaccine
Solution 
for 
Infusion
DL1, DL2, 
and DL3a: 
7.5 X 107
TCID50/
mL
DL1: 
3 X 107
DL2: 
1 X 108
DL3: 
3 X 108
TCID50
(assume 4 mL 
injected)
ITu Injection
Day 1 and 8 of 
Cycle 1 (28-day 
cycle)
Day 1 of Cycles 
2 to 8 (21-day 
cycles)
Test 
Product
IMP
Provided 
centrally 
by 
Sponsor
Arm 2
Part I
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
Inter-
vention 
Name
Inter-
vention 
Type
Dose 
Formu-
lation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Adminis-
tration
Regimen/
Treatment Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 2
Part II
Experi
mental
V937
Biological/
Vaccine
Solution 
for 
Infusion
DL1, DL2, 
and DL3: 
7.5 X 107
TCID50/
mL
RP2D
DL1: 
3 X 107,
DL2: 
1 X 108,
or
DL3: 
3 X 108
TCID50
(assume 4 mL 
injected)
ITu Injection
Days 1 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
Part II
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
Abbreviations: AxMP = Auxiliary Medicinal Product; IMP=Investigational Medicinal Product; ITu=intratumoral; IV=intravenous; NIMP=Non-Investigational Medicinal 
Product; RP2D=Recommended Phase 2 Dose; SoC=Standard of care; TCID50= 50% tissue culture infectious dose.
The classification of Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) in this table is based on guidance issued by the European 
Commission and applies to countries in the European Economic Area (EEA). Country differences with respect to the definition/classification of IMP/NIMP may exist. In these 
circumstances, local legislation is followed.
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Participants in Arm 2 Part I will be observed for 12 hours following the Cycle 1 Day 1 ITu 
administration of V937 (see Section 6.1.2.2 for additional details). All other study 
interventions will be administered on an outpatient basis. (See Appendix 7 for country-
specific requirements.)
All products indicated in Table 9 will be provided centrally by the Sponsor.
Refer to Sections 6.1.1, 6.1.2, and 8.1.8, for details regarding administration of the study 
interventions.
6.1.1
Pembrolizumab Administration
Participants in Arms 1 and 2 will receive pembrolizumab on Day 8 of Cycle 1 (28-day cycle) 
and on Day 1 of Cycles 2-35 (21-day cycles). A 200 mg IV dose of pembrolizumab will be 
infused over 30 minutes. For administration details, see the Pharmacy Manual.
6.1.2
V937 Administration for Arm 1 and Arm 2
When selecting lesions for injection during the pre-treatment period, we recommend 
designating at least 1 lesion(s) to remain noninjected for the duration of study in order to 
determine maximal treatment effect (ie, abscopal effect). However, in the event such lesions 
enlarge and/or all other lesions cannot be injected, then such pre-designated lesions may be 
injected at a later date.
6.1.2.1
V937 Administration in Arm 1: Subcutaneous Tumors
In Arm 1, V937 will be administered into subcutaneous lesions that are visible, palpable, or 
visualizable by ultrasound guidance. Participants will receive V937 on Days 1, 3, 5, and 8 
during Cycle 1 (28-day cycle), and Day 1 of Cycles 2-8 (21-day cycles). V937 administration 
will occur 0.5 to 12 hours after a 200 mg dose of pembrolizumab infused over 30 minutes. 
For administration details, see the Pharmacy Manual.
6.1.2.2
V937 Administration in Arm 2, Part I: Visceral Tumors
In Arm 2 Part I, V937 will administered into visceral tumors via image-guidance such as 
ultrasound or CT. Participants will receive V937 on Days 1 and 8 during Cycle 1 (28-day 
cycle) and Day 1 of Cycles 2-8 (21-day cycles). V937 administration will occur 0.5 to 12
hours after a 200 mg dose of pembrolizumab infused over 30 minutes. For administration 
details, see the Pharmacy Manual.
6.1.2.3
V937 Administration in Arm 2, Part II: Visceral Expansion Cohorts
In Arm 2 Part II, V937 will be administered into visceral lesions via image-guidance such as
ultrasound or CT. Participants will receive V937 on Day 8 of Cycle 1 (28-day cycle) and 
Day 1 of Cycle 2-8 (21-day cycles). V937 administration will occur 0.5 to 12 hours after a 
200 mg IV dose of pembrolizumab is infused over 30 minutes. For administration details, see 
the Pharmacy Manual.
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6.1.2.4
V937 Administration in Arms 1 and 2: Target Lesion Size and Injection 
Volume
Each participant will receive V937 in a volume ranging from 0.5 to 4 mL of injectate for 
Arm 1 cohorts, and 1 to 4 mL in Arm 2 cohorts. The amount of V937 received will depend 
on both the number and size of lesions planned for actual injection of drug. See Table 10 and
Table 11 for volume administration range. The amount of injectate volume delivered to each 
lesion will be determined by measuring the longest diameter of target lesion as shown in
Table 10 and Table 11 (short axis for lymph nodes). V937 should be prepared in separate 
syringes for each individual lesion injection since the actual delivered dose will depend on 
target lesion size. Not all participants or lesions will receive the same total dose of drug.
Documentation of dose volume administered per lesion will be recorded.
Prioritization of lesion(s) to be injected is as follows:

first: new or progressing lesion(s)

second: largest lesion(s)

third: injection of any additional lesions (up to a total injectate volume of 4 mL 
spread across a maximum of 5 individual lesions)
Dose administration details:

Table 10: describes the maximum total volume of V937 administered in Arm 1
(estimated maximum injectate volumes are scaled to lesion size).

Table 11: describes the maximum total volume of V937 administered in Arm 2 Parts I 
and II (estimated maximum injectate volumes are scaled to lesion size).

Table 12: describes the maximum total dose possible per participant in Arm 1 (ie, 
cohorts A, B, C), as well as total dose of V937 per mL of injectate.

Table 13: describes the maximum total dose possible per participant in Arm 2 Part I 
(visceral dose escalation) in each of 3 predefined dose levels per mTPI design (DL1, 
DL2, DL3).
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Table 10
Maximum Total Volume of V937 Administered in Arm 1 Scaled to Lesion Size
Lesion size (longest diameter in cm)a
Estimated max injection capacity (mL)
>5
4
>2.5 to 5
2
>1.5 to 2.5
1
≥0.5 to 1.5
0.5
a.
Shortest axis should be used if lesion is a lymph node
Final dose administered for Arm 1, Cohorts A, B, and C depends on the designated lesion 
volume (see Table 10).
Table 11
Maximum Total Volume of V937 Administered in Arm 2 (Parts I and II) Scaled 
to Lesion Size
Lesion size (longest diameter in cm)a
Estimated max injection capacity (mL)
>5
4
>2.5 to 5
2
≥1.0 to 2.5
1
a.
Shortest axis should be used if lesion is a lymph node
Final dose administered for Arm 2, Parts I and II depends on the designated lesion volume 
(see Table 11).
Table 12
Maximum Total Dose of V937 Possible per Participant as Well as Total Dose of 
V937 per mL of Injectate Given (Arm 1)
Dose level
Maximum dose per participant
(assuming 4 mL volume limit)
Concentration of V937
administered per mL
Subcutaneous
3 × 108 TCID50
7.5 × 107 TCID50
Abbreviations: TCID50= 50% tissue culture infectious dose.
Final administered dose is dependent on injected tumor volume (see Table 10 and 
Table 11).
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Table 13
Maximum Total Dose of V937 Possible per Participant at Prespecified Dose 
Levels per mTPI Design (Arm 2 Part I)
Dose level
Maximum dose per participant
(assuming 4 mL volume limit)
Concentration of V937 
administered per mL
Visceral DL1
3 × 107 TCID50
7.5 × 106 TCID50
Visceral DL2
1 × 108 TCID50
2.5 × 107 TCID50
Visceral DL3
3 × 108 TCID50
7.5 × 107 TCID50
Abbreviations: TCID50= 50% tissue culture infectious dose.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on the preparation and administration of V937 and pembrolizumab are provided in 
the respective Pharmacy Manual.
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 4.3.1.1.
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.
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The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation will occur centrally using an IVRS/IWRS. Participants will be 
assigned to 1 of 2 treatment arms.
Study intervention will be allocated by nonrandom assignment in both treatment arms. Arm 1 
and Arm 2 Part I will undergo simultaneous enrollment. Investigator assessment of eligibility 
and tumor type will guide participant allocation to Arm1 or Arm 2 Part I. In Arm 2 Part I
only, each of the first 3 participants in DL1 will undergo an observation period of 5 days
before the next participant is dosed. All other participants enrolled (Arm 1; Arm 2 Part I 
participant 4 and greater; Arm 2 Part I dose levels 2 and 3; Arm 2 Part II) will not be 
staggered. Each new dose level will open for enrollment without delay once the 28-day DLT 
observation period of the previous dose level is completed and a dose escalation decision is 
made.
Arm 2 Part II will begin enrollment once the participants in Arm 2 Part I complete the DLT 
evaluation and a RP2D decision has been made; IVRS/IWRS will assign participants to 1 of 
2 cohorts by tumor type.
6.3.2
Stratification
No stratification will be used in the study.
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
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant identification will be confirmed at the 
time of dosing by a member of the study site staff other than the person administering the 
study intervention.
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Interruptions from the protocol-specified treatment plan for >6 weeks between 
pembrolizumab doses for non-drug-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 >6 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 vaccines 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 intervention may be required. The 
investigator should discuss any questions regarding this with the Sponsor’s Clinical Director. 
The final decision on any supportive therapy rests with the investigator and/or the 
participant's primary physician. However, the decision to continue the participant on-study 
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 CRF including all prescription, 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 30 days before the first dose of study 
intervention and 30 days after the last dose of study intervention should be recorded. 
Concomitant medications administered after 30 days after the last dose of study intervention 
should be recorded for SAEs and 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: (See Appendix 7 for country-specific requirements.)
•
Antineoplastic systemic chemotherapy or biological therapy
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than pembrolizumab
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•
Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the investigator’s discretion after the DLT observation period for the 
participant to be considered evaluable for DLT.
Note: Palliative radiation to non-target lesion(s) for symptomatic relief is 
permitted at the investigator’s discretion. However, the participant must have 
clear, measurable disease outside the irradiated field. Palliative radiation to target
lesion(s) will render those lesions as clinically progressed, and non-evaluable for 
the remainder of trial.
•
Live or live-attenuated vaccines within 30 days prior to the first dose of study 
intervention and while participating in the study. Administration of killed vaccines are 
allowed.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a 
particular country is allowed in the study as long as they are mRNA vaccines, 
replication-incompetent adenoviral vaccines, or inactivated vaccines. These 
vaccines will be treated just as any other concomitant therapy.
Investigational vaccines (ie, those not licensed or approved for Emergency Use) 
are not allowed.
•
Systemic glucocorticoids except when used for the following purposes:
-
To modulate symptoms of an AE that is suspected to have an immunologic etiology
-
For the prevention of emesis
-
To premedicate for IV contrast allergies
-
To treat asthma or COPD exacerbations (only short-term oral or IV use in doses >10 
mg/day prednisone equivalent)
-
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent

Other glucocorticoid use except when used for the following purposes:
-
For topical use or ocular use
-
Intraarticular joint use
-
For inhalation in the management of asthma or chronic obstructive pulmonary disease
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6.5.3
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 14. 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.
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 14 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) [Arm 1 and Arm 2 (Part I & II)]
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 v5.0 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 14.
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.
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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 are fatigue, 
chills, pyrexia and influenza-like illness. These events are mainly Grade 1 or 2 in severity, 
transient, and easily managed.
Treatment-related AEs specific to V937 ITu administration include injection site pain, 
erythema, pruritis, discharge and edema reactions. These AEs are largely risks associated 
with performing an intralesional injection procedure and have not been reported when V937 
has been administered via IV or intravesicular routes. These symptoms have been largely 
mild in their severity (ie, Grade 1 or 2).
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 3 AEs reoccur in the same participants or are 
> Grade 3. For other instances in which dose interruption(s) may be required, discuss with 
Sponsor.
Within-participant dose escalation is not permitted.
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 14.(See Appendix 7 for country-specific requirements.)
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Table 14
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
Diarrhea/Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus)

Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased Bilirubin
Grade 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
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
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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
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
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
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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
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
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 15.
Table 15
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent 
Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator
None
Grade 2
Requires therapy or infusion 
interruption, but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 h
Stop Infusion
Additional appropriate medical therapy may 
include, but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of 
the original infusion rate (eg, from 100 mL/h to 50 
mL/h). Otherwise dosing will be held until 
symptoms resolve and the participant should be 
premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug 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
Abbreviations: IV=intravenous; NCI=National Cancer Institute; NSAID=nonsteroidal anti-inflammatory drugs; 
PO=taken orally, by mouth.
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
6.6.2.1
Other Allowed Dose Interruption(s) for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical/surgical events or logistical reasons not related to study intervention. 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.
6.6.3
Guidance for Management of Hepatic Events of Clinical Interest
HECIs are described in Section 8.4.7. All of these HECIs will require holding study 
intervention and notification to the Sponsor within 24 hours. All cases of retreatment after 
interruption of study intervention for HECI must be reported to the Sponsor and recorded in 
the database. As per Section 8.4.7, HECIs are not the result of disease progression or ITu 
liver lesion injection complications; and therefore, the following evaluations are not required 
for these etiologies.
Immediate assessment in case of HECI:
All Participants

All participants should be considered for evaluation according to the directions below 
within 72 hours of the alert for a non-overdose ECI.
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
Procedures:
o
Consider obtaining a consultation with a hepatologist
o
Obtain a work-up for hepatitis if there is no underlying hepatitis, including 
hepatitis A, B, C, D, E, Epstein-Barr virus, and cytomegalovirus
o
Assess for ingestion of drugs/supplements with hepatotoxic potential
o
Assess for alcohol ingestion
o
Assess for potential bacterial infection, biliary obstruction, or occult
gastrointestinal bleeding
o
Repeat ALT, AST, Tbil, Dbil, ALP, INR, and CBC with differential; GGT testing 
must be performed as part of the HECI workup
o
Measure HCV RNA viral load (applies only for participants who have current 
active HCV infection or had infection in the past)
o
HBV DNA, HBsAg, HBeAg, anti-HBc (total and IgM), anti-HBe, and anti-HBs 
regardless of prior HBV status (Note: participants should be questioned about 
compliance with the use of antiviral agents)
o
Other laboratories or imaging studies as clinically indicated
o
Consider liver biopsy if indicated
6.6.3.1
Diagnosis and Management of Non-overdose Hepatic ECIs
HCC participants are at risk for a range of complications that can cause hepatic laboratory 
abnormalities with or without clinical decompensation. Those with a history of chronic HCV 
or HBV infection also have the potential to experience virologic flares. Immune-related 
hepatitis has been observed in approximately 1% of participants who received 
pembrolizumab.
For dose interval modification, refer to Sections 6.6.1 and 6.6.2. Guidance related to the 
diagnosis and management of hepatic ECIs is located in Table 16.
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Table 16
Management of Hepatic ECIs
Event
Diagnosis
Management
Hepatitis B 
consider flare or 
change in HBV 
immunologic 
status
Rapid elevation of ALT to >5 ×
ULN and/or >3 × baseline
Interrupt intervention for up to 12 weeks.
Start antiviral therapy or check for compliance if HBV is 
detectable.
Measure safety labs for AST, ALT, ALP, Tbil, Dbil, and 
INR on weekly basis.
Measure HBsAg and HBV DNA on weekly basis (if 
detected at the time of onset of ECI).
Evaluate the following every 2 to 3 weeks:

anti-HBe, HBe antigen, anti-HBs, and HBV DNA 
levels (if not detected at the onset of ECI)
Restart intervention only if ALT returns to normal or Grade 
1 (if normal at baseline), or to baseline grade (if Grade 2 at 
baseline) within 12 weeks, and the participant is clinically 
stable; otherwise, the participant should be permanently 
discontinued.
Hepatitis C 
exacerbation in 
participants with 
HCV RNA 
positive
Rapid elevation of ALT to 
>5×ULN and/or >3x baseline 
Interrupt intervention for up to 12 weeks.
Assess use of injection or inhalation drugs.
Recheck HCV genotype at the time of relapse of HCV RNA 
to rule out new infection.
Measure safety labs for AST, ALT, ALP, Tbil, Dbil, and 
INR on weekly basis.
Measure HCV RNA levels every 2 weeks.
Please discuss risk benefit with Sponsor prior to starting 
HCV antiviral therapy.
Restart intervention only if ALT returns to normal or 
Grade 1 (if normal at baseline), or to baseline grade (if 
Grade 2 at baseline) within 12 weeks, and the participant is 
clinically stable; otherwise, the participant should be 
permanently discontinued.
Relapse of HCV 
infection for 
participants with 
successfully 
treated or new 
HCV infection 
If HCV RNA was TND at baseline, 
and now has confirmed detectable 
HCV RNA (2 specimens, 1 week 
apart)
Interrupt intervention for up to 12 weeks.
Assess use of injection or inhalation drugs.
Recheck HCV genotype at the time of relapse of HCV RNA 
to rule out new infection.
Measure safety labs for AST, ALT, ALP, Tbil, Dbil, and 
INR on weekly basis.
Measure HCV RNA levels every 2 weeks.
Please discuss risk benefit with Sponsor prior to starting 
HCV antiviral therapy.
Restart intervention only if ALT returns to normal or 
Grade 1 (if normal at baseline), or to baseline grade (if 
Grade 2 at baseline) within 12 weeks, and the participant is 
clinically stable; otherwise, the participant should be 
permanently discontinued.
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Event
Diagnosis
Management
Immune-related 
Hepatitis
If any of the HECI criteria are met 
as defined in the protocol Section 
8.4.7
Note:
Immune-related hepatitis is a 
diagnosis made after excluding 
other possible etiologies such as 
viral flare, biliary or vascular 
obstruction, infection, medications, 
and alcohol use usually immune-
related hepatitis response to 
dechallenge and/or steroids and re-
occurs with rechallenge.
Interrupt intervention for up to 12 weeks.
Start IV corticosteroid 60 mg/day of prednisone or 
equivalent followed by oral corticosteroid.
Monitor with biweekly laboratory tests, including AST, 
ALT, Tbil, Dbil, ALP, and INR.
Restart intervention only if:

Abnormal laboratory values resolve to Grade ≤1 or 
baseline (if abnormal at baseline)

Taper steroid over 28 days

Steroid treatment is tapered to prednisone <10 mg/day 
or equivalent
Permanently Discontinue intervention if:
o
Laboratory abnormalities do not resolve within 3 
weeks
o
Steroids cannot be lowered to ≤10 mg/day (or 
prednisone equivalent) within 12 weeks
o
Decompensation to CP-C status
Other Causes
Rule out infection with blood, 
urine, and ascites culture –
antibiotics should be started if 
infection is found.
If total bilirubin is elevated, 
imaging should be obtained to rule 
out vascular compromise, biliary 
obstruction, and/or tumor 
progression by imaging.
Ruled out alcohol use and 
hepatotoxic drugs including herbal 
and alternative medications.
Restart intervention only if laboratory values have returned 
to Grade 1 or baseline (if normal or Grade 1 at start) or to 
baseline grade within 3 weeks.
If biliary obstruction is present, consultation with a 
gastroenterologist and/or an interventional radiologist 
should be obtained to see if the obstruction may be relieved.
Abbreviations: ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; CP-
C=Child-Pugh Grade C; Dbil=direct bilirubin; DNA=deoxyribonucleic acid; HBs=hepatitis B surface; HBeAg=hepatitis 
B e antigen, HBV=hepatitis B virus; INR=international normalized ratio; IV=intravenous; Tbil=total bilirubin; 
TND=target not detected.
6.6.4
Dose Administration/Escalation
6.6.4.1
Dose Administration (Preparation)
Details on preparation and administration of V937 (and pembrolizumab) are provided in the 
appropriate Pharmacy/Procedures Manual.
6.6.5
Definition of Dose‑limiting Toxicity for Arm 2 Part I (mTPI Escalation)
Dose-limiting toxicities are used in Arm 2 Part I to guide dose escalation and de-escalation 
decisions for the mTPI design (see Section 4.3.1.3). The DLT window of observation will be 
during Cycle 1.
All toxicities will be graded using NCI-CTCAE v5.0 based on the investigator assessment.
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The occurrence of any of the following toxicities during Cycle 1 will be considered a DLT, if 
assessed by the investigator to be possibly, probably, or definitely related to study 
intervention administration.
1.
Grade 4 nonhematologic toxicity (not laboratory).
2.
Grade 4 hematologic toxicity lasting ≥7 days except for thrombocytopenia or febrile 
neutropenia:
•
≥Grade 3 thrombocytopenia associated with clinically significant bleeding of any 
duration, or
•
Any grade of febrile neutropenia
3.
Any nonhematologic AE ≥Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤3 days; Grade 3 diarrhea, nausea, or 
vomiting without use of anti-emetics or anti-diarrheals per SOC; clinically 
asymptomatic Grade 3 elevations of amylase or lipase without any imaging evidence 
suggestive of possible/probable etiology; Grade 3 rash without use of corticosteroids 
or anti-inflammatory agents per SOC.
4.
Any Grade 3 or Grade 4 nonhematologic laboratory value if:
•
Clinically significant medical intervention is required to treat the participant, or
•
The abnormality leads to hospitalization, or
•
The abnormality persists for >1 week, or
•
The abnormality results in a DILI (see Section 8.4.7 for criteria).
Exceptions: Clinically nonsignificant, treatable, or reversible laboratory 
abnormalities including liver function tests, uric acid, etc.
5.
Prolonged delay (>2 weeks) in initiating Cycle 2 due to intervention-related toxicity.
6.
Any intervention-related toxicity that causes the participant to discontinue 
intervention during Cycle 1.
7.
Missing the following number of ITu V937 doses as a result of drug-related AE(s) 
during the first cycle:
•
Visceral tumor, dose escalation: missing 1 dose of V937
8.
Grade 5 toxicity.
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6.6.6
Guidelines for Dose Modification due to Adverse Events
6.6.6.1
Dose Modification for V937 and/or Pembrolizumab due to Drug-related 
AEs in Arm 2 Part I
The CTCAE v5.0 must be used to grade the severity of AEs. The investigator may attribute 
toxicity events to the combination of V937 and pembrolizumab (since one may not be able to 
separate individual drug effects in every circumstance) and modify the dose according to 
Table 17. If a dose modification for toxicity occurs with V937, the dose may not be re-
escalated to the dose that preceded the dose modification. Dose modifications are always 
based on the previous cycle.
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, if 
V937 is held due to an AE attributed to that drug, then pembrolizumab may continue to be 
administered. Appropriate documentation is required regarding to which drug the 
investigator is attributing the adverse event. 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.
The dose of V937 may be decreased during Arm 2, Part I (as described in Table 17).
Participants may receive up to 2 dose modifications of V937 during the dose escalation 
phase, provided this reduction is not lower than that specified in DL1 (Table 13). If a dose 
reduction is needed from DL1, then V937 treatment should be discontinued. If further
toxicity occurs, or criteria for resuming treatment are not met, then the participant must also 
be discontinued from study. If a participant experiences several toxicities which result in
conflicting therapeutic regimens, then the treating physician should adhere to the most 
conservative dose adjustment recommended (ie, adjustment based on the severest AE 
reported). There will be no V937 dose reductions in Arm 1 or Arm 2, Part II.
Exceptional circumstances to the dose modification tables may be considered after 
consultation with the Sponsor.
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Table 17
V937 Dose Modification and Treatment Discontinuation Guidelines for Drug-
related Adverse Events in Arm 2, Part I (mTPI)
Toxicity
Hold 
Treatment
Criteria for 
Restarting 
Treatment
V937 Dose for 
Restarting 
Treatment
Criteria for Discontinuation 
after Consultation with 
Sponsor
Hematological toxicities:
Any Grade 1 
hematological toxicity
No
N/A
N/A
N/A
Any Grade 2 
hematological 
toxicity, or Grade 3 
toxicity that persists 
for ≤5 days
Per medical 
assessment of 
the 
investigator
If treatment held, 
may be restarted 
when AE 
resolves back to 
baseline or to 
Grade 1.
Per medical 
assessment of the 
investigator: may 
decrease dose by 1 
dose level.
If AE persists for 12 weeks 
without resolution following 
reduction in dose
Any Grade 3 
hematologic toxicity 
that persists for 
>5 days, or Grade 4 
hematological toxicity
Febrile neutropenia
Grade 3 
thrombocytopenia of 
any duration if 
associated with 
bleeding
Yes
Treatment may 
be restarted when 
AE resolves back 
to baseline or to 
Grade 1.
Decrease dose by 1 
dose level.
If AE persists for 12 weeks 
without resolution following 
reduction in dosing schedule.
Permanent discontinuation 
should be considered for any 
severe or life-threatening 
event
Nonhematological toxicities:
Any Grade 1 
nonhematological 
toxicity
Grade 2 alopecia
Grade 2 fatigue
No 
N/A
N/A
N/A
Any Grade 2 
nonhematological 
toxicity except Grade 
2 alopecia and Grade 
2 fatigue
Per medical 
assessment of 
the 
investigator
If treatment held, 
may be restarted 
when AE 
resolves back to 
baseline or to 
Grade 1.
Per medical 
assessment of the 
investigator: may 
decrease dose by 1 
dose level.
If AE persists for 12 weeks 
without resolution following 
reduction in dose.
Any Grade 3 or 4
nonhematological 
toxicity (not including 
laboratory, unless 
clinically significant 
medical intervention 
is required to treat the 
participant, or the 
abnormality leads to 
hospitalization, or the 
abnormality persists 
for >1 week)
Yes
Treatment may 
be restarted when 
AE resolves back 
to baseline or to 
Grade 1.
Decrease dose by 1 
dose level.
If AE persists for 12 weeks 
without resolution following 
reduction in dose.
Permanent discontinuation 
should be considered for any 
severe or life-threatening 
event
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last intervention, V937
should be discontinued after consultation with the Sponsor.
With investigator and Sponsor agreement, participants with a laboratory AE still at Grade 2 
after 12 weeks may continue intervention in the study only if asymptomatic and controlled.
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After any Grade 4, drug-related AE, participants should not restart study intervention without 
consultation with the Sponsor. Toxicity must have resolved to Grade 0-1 or baseline prior to 
restarting.
Pembrolizumab treatment will be modified for the irAEs described in Section 6.6.2.
6.7
Intervention After the End of the Study
There is no study-specified intervention following the end of the study.
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.
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 participate in the study as specified in Section 1.3 and Section 
8.11.3.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.8.
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 6 consecutive 
weeks. Participants may continue on study upon consultation with Sponsor.
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•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Confirmed radiographic disease progression outlined in Section 8.2.3 (exception if the 
Sponsor approves treatment continuation).
•
Unacceptable adverse experiences as described in Section 8.4.
•
Progression or recurrence of any malignancy, or any occurrence of another malignancy 
that requires active treatment.
•
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
•
Investigator’s decision to discontinue treatment.
•
Use of prohibited concomitant medications as described in Section 6.5.2.
•
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.
•
Completion of 35 treatments with pembrolizumab.
Note: 35 cycles (approximately 2 years) are calculated from the first dose.
•
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)

Participant has any of the following non-overdose HECIs:
o
ALT >20 × ULN
o
Child-Pugh score of ≥9 points
o
Gastrointestinal bleeding suggestive of portal hypertension (eg, esophageal or gastric 
varices)
o
New onset of clinically detectable ascites
o
Hepatic encephalopathy
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o
Recurrence of a severe or life-threatening event, or of any of the laboratory 
abnormalities listed above, that are presumed to be immune-related
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.
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 8.1.8.1. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant 
are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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.
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•
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 (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
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.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a 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 study protocol number, study 
protocol title, dated signature, and agreement of the participant (or their legally acceptable 
representative) and of the person conducting the consent discussion.
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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.
The participant or their legally acceptable representative will be asked to sign consent at the 
point of initial radiographic disease progression.
Specifics about the study and the study population are to be included in the study informed 
consent form.
The 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 participants's leagally acceptable representative, answer all 
of their 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 future biomedical research.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention allocation,
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.
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8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator. Details regarding the disease 
for which the participant has enrolled in the study will be recorded separately and not listed 
as medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before first dose of study intervention.
8.1.5.2
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.
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study and through the Safety Follow-up visit.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 8.4.
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.
8.1.6
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 intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
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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 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Administration of study intervention will be witnessed by the investigator and/or study staff. 
The total volume of study intervention infused will be compared to the total volume prepared 
to determine compliance with each dose administered.
Study intervention for V937 should begin within 3 days of treatment allocation (for Arms 1
and 2).
See Section 6.1.1 for pembrolizumab and Section 6.1.2 for V937 ITu for details related to the 
timing of dose administration.
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 
Sections 1.3 and 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Sections 8.4 and 8.11.3.
8.1.8.1
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.
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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.
8.1.9
Participant Blinding/Unblinding
This is an open-label study. 
8.1.10
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
The process for image collection and transmission to the central imaging vendor can be
found in the SIM. Tumor imaging is as follows:

Chest, abdomen, and pelvis scans are required for all participants. CT with IV and 
oral contrast is preferred or non-contrast CT of the chest and MRI of the abdomen 
and pelvis with IV gadolinium for participants in whom iodinated contrast is 
contraindicated, or when mandated by local practice.

Cohort B HNSCC: Include head and neck CT.

Additional imaging acquired as per standard of care or as clinically indicated, used to 
support disease progression or efficacy assessments, should be sent to the imaging 
vendor.

Brain imaging (MRI is preferred) is required at baseline and on-study for participants
with a history of brain metastasis or when clinically indicated. Brain imaging is also 
required to confirm a CR in participants who have brain metastases at baseline.

Bone imaging (eg, PET scan, bone scan) is required at baseline and on-study when 
clinically indicated for participants who are symptomatic (eg. new bone pain).

Lesion injections (eg, CT, MRI, ultrasound, etc.) with the needle inserted into 
lesion(s) are required for all study drug injection procedures.
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
Medical photography (including a scale/ruler) is required for assessment of cutaneous 
lesions at screening and on-study for Arm 1.

Images to document which lesions were injected:
o
For lesions injected under CT, MRI, or fluoroscopic guidance, collect images 
from the procedure showing the tip of the needle in the lesion.
o
For lesions injected under ultrasound guidance, collect images from the 
procedure showing the tip of the needle in the lesion, with text overlays on the 
lesions indicating the location, with anatomic landmarks if available, and 
precise anatomic descriptors otherwise.
o
For lesions injected using direct visualization or palpation for guidance, 
collect photographs with a skin marker showing the location of the lesion. 
Photographs should include both close-up views and views distant enough to 
identify the location of the lesion.
Although RECIST 1.1 references to a maximum of 5 target lesions in total and 2 per organ, 
the Sponsor allows a maximum of 10 target lesions in total and 5 per organ, if clinically 
relevant to enable a broader sampling of tumor burden. Additionally, because intratumoral 
therapy is incorporated into this study, RECIST 1.1 will be modified to specify that 
intratumoral injection of a lesion does not render the lesion non-evaluable.
8.2.2
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the date of first 
dose (C1D1) of study intervention.
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 28 days prior 
to the date of first dose (C1D1).
Participants with previously treated brain metastases must undergo brain imaging within 
28 days prior to the first dose (C1D1) of study intervention, with local confirmation that no 
new or untreated brain metastases are present.
8.2.3
Tumor Imaging During the Study
Sites will be required to send in anatomical images/medical photography of the needle into
lesions during the study drug injection procedures to a central imaging vendor, as indicated 
in the SIM.
The first on-study imaging assessment should be performed at 9 weeks (63 days ± 7 days) 
from the date of first dose (C1D1). Subsequent tumor imaging should be performed every 
9 weeks (63 days ± 7 days) or more frequently if clinically indicated. After 54 weeks, 
participants who remain on treatment will have imaging performed every 12 weeks (84 days 
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± 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, the start of new anticancer treatment, withdrawal of consent, 
death, or notification by the Sponsor, whichever occurs first.
PR and CR should be confirmed by a repeat imaging assessment. The imaging for 
confirmation of response may be performed at the earliest 4 weeks after the first indication of 
response, or at the next scheduled scan (ie, 9 weeks or 12 weeks later), whichever is 
clinically indicated. Participants will then return to regular scheduled imaging every 9 weeks 
or 12 weeks, 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.
Per iRECIST (Section 8.2.5.), disease progression should be confirmed by the site at least 
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, provided they 
have met the conditions detailed in Section 8.2.5. 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 the treatment. Exception is detailed in Section 8.2.5.
8.2.4
End of Treatment and Follow-up Tumor Imaging
In participants who discontinue study intervention, tumor imaging should be performed at the 
time of intervention discontinuation (± 4-week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at intervention 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented disease progression by RECIST 1.1, this is the final required tumor imaging if
the investigator elects to not implement iRECIST.
8.2.5
iRECIST 1.1 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 investigator/local radiology 
reviewers to assess tumor response and progression, and to make treatment decisions. When 
clinically stable, participants should not be discontinued until progression is confirmed by the 
investigator, working with local radiology, according to the rules outlined below. 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. These 
data will be collected and captured in the clinical database.
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 
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intervention until repeat imaging is obtained (using iRECIST for participant management 
(see Table 18 and Figure 3). This decision by the investigator should be based on the
participant’s overall 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 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.
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 non-target lesion(s) identified at baseline
•
Development of new lesion(s)
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 non-target 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. 
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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 initial iUPD 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 non-target lesions
◦
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
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 scan proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
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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 pseudoprogression, 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 intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention.
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 
treatment 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 the SoA and submitted to the central imaging vendor.
Detection of Progression at Visits after Pseudoprogression Resolves
After resolution of pseudoprogression (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 pseudoprogression. The nadir is always the 
smallest SOD seen during the entire study, either before or after an instance of 
pseudoprogression.
•
Non-target lesions
If non-target lesions have never shown unequivocal progression, their doing so for the first 
time results in iUPD
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If non-target lesions had 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 factors above indicate 
iUPD, the iUPD evaluation process repeats, just as on the first occurrence of iUPD. iUPD 
must be confirmed before iCPD can occur.
Additional details about iRECIST are provided in the iRECIST publication [Eisenhauer, E. 
A., et al 2009] [Seymour, L., et al 2017].
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Table 18
Imaging and Treatment after First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD 
by RECIST 1.1
Repeat imaging 
at 4 to 8 weeks 
to confirm PD
May continue study 
intervention at the 
local site 
investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST
Repeat imaging 
at 4 to 8 weeks 
to confirm PD 
per physician 
discretion only
Discontinue 
treatment
Repeat tumor 
imaging 
confirms PD 
(iCPD) by 
iRECIST per 
local 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 
local assessment
Repeat imaging 
at 4 to 8 weeks 
to confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit.
Continue study 
intervention at the 
local site 
investigator’s 
discretion
Repeat imaging 
at 4 to 8 weeks 
to confirm PD 
per physician 
discretion only
Discontinue 
treatment
Repeat tumor 
imaging shows 
iSD, iPR, or iCR 
by iRECIST per 
local assessment
Continue 
regularly 
scheduled 
imaging 
assessments
Continue study 
intervention at the 
local site 
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 image 
should occur 
according to the 
regular imaging 
schedule.
Abbreviations: iCPD=immune confirmed progressive disease; iCR=immune complete response; 
iPR=immune partial response; iRECIST=immune-related response evaluation criteria in solid tumors; 
iSD=immune stable disease; iUPD=immune unconfirmed progressive disease; PD=progressive disease; 
PFS=progression-free survival.
If progression has been centrally verified, further management by the study site, based on iRECIST. Any 
further imaging should still be submitted to the vendor, but no rapid review will occur.
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Figure 3
Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator
iRECIST= 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.
8.2.6
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.
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 during 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 Section 8.3.6.1.
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 exam during the 
Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in the SoA. 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 exam as defined in the SoA, the investigator or 
qualified designee will perform a directed physical exam 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 and blood 
pressure. Weight will be obtained as specified in the SoA. Height will be measured at
screening only.
8.3.3
Electrocardiograms
A standard 12-lead 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
Endoscopy: Required for Arm 2 Part II, Cohort D only
An endoscopy will be performed using local standard procedures at screening for esophageal 
varices, unless such screening has been performed in the past 12 months prior to C1D1.
8.3.5
Child-Pugh Score: Required for Arm 2 Part II, Cohort D only
The Child-Pugh score will be assessed at screening only. If any of the hepatic ECI criteria are 
met, document the Child-Pugh score with each visit until the hepatic ECIs resolve. The 
Class A score is required for study eligibility. (See Section 10.9 for scoring guidelines.)
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8.3.6
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
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 in 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.
8.3.6.1
Laboratory Safety Evaluations (Hematology and Chemistry)
Laboratory tests for hematology and chemistry are specified in Appendix 2.
The maximum amount of blood collected from each participant over the duration of the study 
will not exceed 950 mL (approximately 650 mL blood will be collected in Year 1 and 
300 mL blood in Year 2). See Laboratory Manual for additional details.
Laboratory tests for screening should be performed within 3 days prior to the first dose of 
study intervention. An exception is hepatitis and thyroid serologies, which may be performed 
within 28 days prior to first dose. After Cycle 1, predose laboratory safety tests can be 
conducted up to 72 hours prior to dosing unless otherwise noted on the flow charts.
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of study intervention. Unresolved 
abnormal laboratory values that are drug-related AEs should be followed until resolution. 
Laboratory tests do not need to be repeated after the end of treatment if laboratory results are 
within normal range.
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8.3.7
Pregnancy Test
Pregnancy testing ([urine or serum] as required by local regulations) should be conducted 
according to Section 1.3 (SoA) and at the end of relevant systemic exposure for all arms.
◦
Pregnancy testing requirements for study inclusion are described in Section 5.1.
◦
Pregnancy testing (urine or serum) should be conducted at monthly intervals during 
intervention, according to local regulations or if clinically indicated.
◦
Pregnancy testing (urine or serum) should be conducted for the time it takes to 
eliminate systemic exposure after the last dose of study intervention(s) as noted in 
Section 5.1, ie, 120 days following cessation of pembrolizumab.
Additional serum or urine pregnancy tests may be performed as determined necessary by the 
investigator to establish the absence of pregnancy at any time during the participant's 
participation in the study. (See Appendix 7 for country-specific requirements.)
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
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.
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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 allocation 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 allocation through 30 days following cessation of 
study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation 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
allocation 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 the investigator
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs, and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 19.
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Table 19
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:
NSAE
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
SAE including 
Cancer and 
Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
-  participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout or 
run-in treatment 
including placebo run-
in)
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (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
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
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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, 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 allocated 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 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.
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.
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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
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1.
An overdose of Sponsor's product, as defined in Section 8.5.
2.
All cohorts except HCC-specific expansion cohorts:
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
3.
HCC-specific expansion cohort, Arm 2 Part II:
Hepatic ECIs include any of the following events if the events are considered not due to 
disease progression or TACE as judged by the investigator. All of these events (if not 
associated with disease progression under study) will require holding study treatment, 
notification of the event(s) to the Sponsor within 24 hours after awareness via electronic 
media or paper.
For dose interval modification, refer to Section 6.6.1 (V937) and 6.6.2 (pembrolizumab).  For 
guidance related to the diagnosis and management of hepatic ECIs, refer to Section 6.6.3.

ALT:
o
Among participants with Baseline ALT <2 × ULN:  ALT ≥5 × ULN
o
Among participants with Baseline ALT ≥2 × ULN:  ALT >3 × the Baseline level
o
ALT >500 U/L regardless of baseline level
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
Total Bilirubin:
o
Total bilirubin >3.0 mg/dL

Regardless of laboratory values, hepatic decompensation diagnosed clinically, including:
o
New onset clinically detectable ascites requiring intervention for >3 days
o
Hepatic encephalopathy
o
Gastrointestinal bleeding suggestive of portal hypertension (eg, esophageal or gastric 
varices)
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, V937 or pembrolizumab 
should be discontinued and the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
8.6
Pharmacokinetics
PK supports evaluation of V937 immunogenicity and exposure in this indication, and 
evaluation of exposure of the proposed dosing regimen. Blood samples will be obtained to 
evaluate V937 exposures which are used to derive PK parameters (AUC and Cmax) and 
immunogenicity.
If ongoing PK and neutralizing antibody analysis is deemed to be unnecessary by the 
Sponsor, it may be reduced or discontinued.
PK sample collection is no longer required.
8.6.1
Blood Collection for Serum V937
PK sample collection is no longer required.
8.6.2
Blood Collection for Neutralizing V937 Antibodies
Neutralizing V937 antibodies sample collection is no longer required.
8.7
Pharmacodynamics
Pharmacodynamic sample collection is no longer required.
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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 in this study as specified in the SoA (collection no 
longer required):
•
Blood for genetic analysis
•
Blood for RNA analyses
•
Blood for ctDNA analyses
•
Tumor biopsy
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 future biomedical research if the participant
provides documented informed consent for future biomedical research. 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 future biomedical research, the 
following specimens will be obtained as part of future biomedical research:
•
Leftover DNA for future research
•
Leftover RNA from Blood RNA Analyses
•
Leftover plasma from Blood for ctDNA analyses
•
Leftover main study tumor biopsy
8.10
Health Economics Medical Resource Utilization and Health Economics
Not applicable to this study.
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3, Table 1, Table 2, Table 3, Table 4, and 
Table 5. Specific procedure-related details are provided in Section 8.
8.11.1
Screening
Approximately 3 days prior to treatment allocation, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in the SoA. Screening 
procedures may be repeated after consultation with the Sponsor.
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 
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.
•
Has a performance status of 0 or 1 on the ECOG Performance Scale.
•
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).
•
Archival tumor sample collection is not required to be obtained within 28 days prior to 
the first dose of study intervention. Newly obtained tumor tissue may be obtained within 
90 days of study intervention initiation.
8.11.2
Treatment Period/Vaccination Visit
The overall treatment period duration is 2 years. See Sections 4.1.1 (Arm 1), 4.1.2 (Arm 2 
Part I), and 4.1.3 (Arm 2 Part II) for treatment details.
Visit requirements are outlined in the SoA. Specific procedure-related details are provided 
above in Section 8.
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. Visit requirements are outlined in the SoA. Additional details regarding participant 
withdrawal and discontinuation are presented in Section 7.
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8.11.3.1
Safety Follow-up Visit
All AEs that occur prior to the Discontinuation 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 visit will not be required after completion of the Discontinuation Visit.
8.11.3.2
Imaging Follow-up Visits
Due to early study discontinuation, participants may be enrolled in a pembrolizumab 
extension study, if available, to continue pembrolizumab monotherapy. Imaging Follow-up 
visits will not be required.
8.11.3.3
Survival Follow-up Contacts
Due to early study discontinuation, participants may be enrolled in a pembrolizumab 
extension study, if available, to continue pembrolizumab monotherapy. Survival Follow-up 
contacts will not be required.
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study. 
 
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).
 
 
9.1
Statistical Analysis Plan Summary
This section contains a brief summary of statistical analyses for this trial. Full details are in 
the SAP, Sections 9.2 through 9.12.
Study Design 
Overview
Phase 1b/2 study of ITu administration of V937 in combination with 
pembrolizumab in participants with advanced/metastatic solid tumors. 
Arm 1 (Subcutaneous Tumors) will enroll participants with 3 tumor 
specific cohorts (Cohort A: TNBC; Cohort B: HNSCC; Cohort C: 
cSCC). Arm 2 (Visceral Tumors) Part I applies an mTPI design for 
dose escalation and confirmation of preliminary RP2Ds, followed by 
Part II expansion phase with 2 tumor-specific cohorts (Cohort D: 
HCC; Cohort E: Gastric)
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Intervention 
Assignment
Participants will be allocated centrally through IRT by nonrandom 
assignment to receive V937 in combination with pembrolizumab. In 
Arm 1, participants will be allocated to one of the 3 cohorts (TNBC, 
HNSCC, cSCC) depending on their tumor types through IWRS. In 
Arm 2 Part I, participants will be allocated to solid tumors with liver 
metastases through IWRS. In Arm 2 Part II, participants will be 
allocated to one of the 2 cohorts (HCC, gastric) depending on their 
tumor types through IWRS. The trial is open-label.
Analysis 
Populations
Safety: APaT and DLTe
Efficacy: FAS
Primary 
Endpoint(s)
Arm 1:
•
OR is a confirmed CR or PR by RECIST 1.1 assessed by the 
investigator
Arm 2:

DLT

AE

Discontinuation of study intervention due to AE
Secondary 
Endpoints
Arm 1:

AE and discontinuation study intervention due to AE

PFS and DOR per RECIST 1.1 assessed by the investigator

OR, PFS, DOR per iRECIST assessed by the investigator

OS
Arm 2 Parts I and II:

OR as evaluated by RECIST 1.1 and iRECIST criteria assessed 
by the investigator
Statistical Methods 
for Efficacy/
Immunogenicity/ 
Pharmacokinetic 
Analyses
ORR will be estimated using an exact method based on the binomial 
distribution (Clopper-Pearson interval) together with its 95% 
confidence interval.
Statistical Methods 
for Safety Analyses
Summary statistics (counts, percentages, means, standard deviations, 
etc.) will be provided for the safety endpoints as appropriate. 
 
The estimate of the DLT rate 
among participants treated at RP2D of V937 in combination with 
pembrolizumab and the 90% Bayesian credible intervals for the 
estimate will be provided.
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Sample Size and 
Power
Arm 1 will enroll 90 participants (30 each for TNBC, HNSCC, and 
cSCC cohorts) or less due to early study termination. Arm 2 Part I 
will enroll approximately 35 participants for dose escalation and 
confirmation, and Arm 2 Part II will enroll 60 participants (30 each
for HCC and gastric cohorts) or less due to early study termination. A 
target sample size of 185 participants will be used for study planning 
purposes.
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 study is open-label (ie, participants, investigators, and Sponsor personnel will be aware 
of participant intervention assignment after each participant is enrolled and treatment is 
assigned). Participants will be allocated by nonrandom assignment.
9.3
Hypotheses/Estimation
Objectives of the study are outlined in Section 3.
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9.4
Analysis Endpoints
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
OR is a confirmed CR or PR based on RECIST 1.1 by the investigator. OR is primary 
endpoint for the 3 cohorts in Arm 1 and is secondary endpoint for the 2 cohorts in Arm 2 Part 
II. ORR is the proportion of participants with OR.
PFS is defined as the time from the first dose of study treatment to the first documented PD 
based on RECIST1.1 by the investigator or death due to any cause, whichever occurs first.
PFS is secondary endpoint for the 3 cohorts in Arm1.
DOR is defined as the time from the first documented evidence of CR or PR until PD based 
on RECIST1.1 by the investigator or death due to any cause, whichever occurs first, in 
participants demonstrating PR or CR. DOR is secondary endpoint for the 3 cohorts in Arm1.
OR, PFS and DOR are also evaluated based on iRECIST by the investigator.
OS is defined as the time from the first dose of study treatment to death due to any cause. 
Participants who do not die will be censored on the date of the last study assessment or 
contact. Overall survival is a secondary endpoint for Arm 1.
9.4.2
Safety Endpoints
The safety endpoints include DLTs, AEs, and discontinuation of study intervention due to 
AE. In addition, safety and tolerability will be assessed by clinical review of all relevant 
parameters including SAEs, laboratory tests, and vital signs.
A description of safety measures is provided in Sections 8.3 and 8.4.
9.5
Analysis Populations
9.5.1
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all participants who received at least 1 dose of study intervention.
The DLT evaluable population includes APaT participants that meet the criteria for DLT 
evaluability (eg, finished Cycle 1 without a DLT or experienced a DLT in Cycle 1). See 
Section 6.6.5 for details.
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At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of
study intervention is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a baseline measurement is also required.
9.5.3
Efficacy Analysis Populations
The FAS population will be used for the analyses of efficacy data in this study. It consists of 
all participants with a baseline scan that demonstrated measurable disease by the 
investigator’s assessment, and who were administered at least 1 dose of study intervention.
The efficacy analyses for Arm 2 Part II expansion cohort will pool Part I participants who 
meet the inclusion criteria for the respective Part II tumor type and received the same dose 
level of V937 in combination with pembrolizumab.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives.
9.6.1
Statistical Methods for Efficacy Analysis
Objective response rate estimates in each treatment arm and cohort will be reported along 
with the 95% CI using the Clopper and Pearson method.
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. For PFS and OS, Kaplan-Meier curves and median estimates from 
the Kaplan-Meier curves will be provided as appropriate. Censoring rules for DOR and PFS 
will be provided in sSAP.
9.6.2
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, ECG measurements, and physical examinations.
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Adverse events will be summarized by counts and frequencies for each dose level and/or 
cohort. Laboratory tests, vital signs, and other safety endpoints will be summarized as 
appropriate.
For Arm 2 Part I,
 
 
The estimate of the DLT rate among participants treated at the RP2D and the 
90% Bayesian credible interval based on a prior distribution of Beta (1,1) for the estimate 
will be provided.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
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9.9
Sample Size and Power Calculations
The overall sample size for this Phase 1b/2 trial is expected to be 185 participants or less due 
to early study termination. This is an estimation study and there is no formal hypothesis 
testing. 
The planned sample size for Arm 1 is 90 participants (30 each for TNBC, HNSCC and cSCC 
cohorts) or less due to early study termination. The planned sample size for Arm 2 is 95 
participants (35 for Part I and 60 for Part II) or less due to early study termination
 
 
 
Approximate 35 participants will be used for study planning purposes. Part II will have 60 
participants (30 each for HCC and gastric cohorts) or less due to early study termination.
While there is no formal hypothesis testing in this study,
 
 
 
 
 
For each tumor-specific cohort, with total 30 participants and the presumable number of 
responders, response rate and estimated 95% CI are stated in Table 20.
Table 20
Estimate and 95% CI of ORR (N=30)
Sample Size
Number of Responses 
(PR/CR)
Observed ORR
95% CI of ORR
30
3
10.0%
(2.1%, 26.5%)
4
13.3%
(3.8%, 30.7%)
5
16.7%
(5.6%, 34.7%)
6
20.0%
(7.7%, 38.6%)
7
23.3%
(9.9%,42.3%)
8
26.7%
(12.3%,45.9%)
9
30.0%
(14.7%,49.4%)
10
33.3%
(17.3%,52.8%)
Abbreviations: CI = confidence interval; CR = complete response; ORR = objective response rate; 
PR = partial response
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9.10
Subgroup Analyses
To determine whether the response rate is consistent across various subgroups, the estimate 
of ORR (with a nominal 90% CI) endpoint may be estimated within each category of the 
following classification variable:

Participants having at least non-injected target lesion vs without having any non-
injected target lesions.
If the number of participants in a category of a subgroup variable is less than 10% of the FAS 
population, the subgroup analysis may not be performed for this category of the subgroup 
variable. Details of other subgroup analyses, if any, will be documented in the sSAP.
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 their financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, 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
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that their personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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
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.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the 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.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Council on Harmonisation 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 Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
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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.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants' documented informed consent, 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 
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Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.8
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.
10.1.9
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
See Appendix 7 for country-specific requirements.
•
The tests detailed in Table 21 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 and correspond with the time 
frame for female participant contraception in Section 5.1.
-
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.
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Table 21
Protocol-required Safety Laboratory Assessments
Hematology
Comprehensive Chemistry Panel
Other
Hematocrit
Albumin
Pregnancy test 
Hemoglobin
Alkaline phosphatase
(serum or urine) a
Platelet count
Alanine aminotransferase
Total T3 (or Free T3 [FT3]), 
WBC (total and
Aspartate aminotransferase
Total T4 (or Free T4 [FT4]),
differential) c
Bicarbonate
and TSH b
RBC
Calcium
Anti-HCV
Absolute lymphocyte
Chloride
HCV viral load
Count c
Creatinine
HCV genotype
Absolute neutrophil
Glucose
anti-HBs
Count c
Phosphorus
HBsAg
PT/INR
Potassium
anti-HBc (total and IgM)
aPTT or PTT
Sodium
HBeAg
Total bilirubin  
anti-HBe
Direct bilirubin
HBV viral load
Total protein
Anti-HDV
Blood urea nitrogen
AFP
(or Urea) d
CD4+ T-cell count e
GGT (for HECI assessment only)
Abbreviations: AFP=alpha-fetoprotein; aPTT=activated partial thromboplastin time; FT3= Free T3; FT4=Free 
T4; GGT=gamma glutamyl transpeptidase; HBc=hepatitis B core; HBeAg=hepatitis B e antigen; 
HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; HDV= hepatitis delta 
virus; HECI= Hepatic Events of Clinical Interest; HIV=human immunodeficiency virus; IgM=immunoglobulin 
M; PTT=partial thromboplastin time; RBC=red blood cell; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-
stimulating hormone; WBC=white blood cell.
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. Total T4 is preferred; if not available, Free T4 may be 
tested.
c  Report % or absolute results per standard of practice. Report the results in the same manner throughout the 
study.
d  Blood urea nitrogen is preferred; if not available, urea may be tested.
e  For HIV-positive participants only.
Investigators 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 non-therapeutic 
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, medical device, combination product, or protocol specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), manufactured by, licensed by, provided by, or distributed by the Sponsor 
for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
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
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
Note: Congenital disorders (eg, present from birth) not detected or diagnosed prior to 
study intervention administration do not qualify for reporting as AE.

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
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b. Is life-threatening
•
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c. Requires inpatient hospitalization or prolongation of existing hospitalization
•
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not 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.
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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)
•
Is associated with an overdose
10.3.5
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
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Assessment of intensity/toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
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-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this 
study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
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•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
•
For each AE/SAE, the investigator must document in the medical notes that the 
investigator has reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each AE causality to the combination regimen or to a single agent 
of the combination. In general, causality attribution should be assigned to the combination 
regimen (ie, to all agents in the regimen). However, causality attribution may be assigned to a 
single agent if in the investigator’s opinion, there is sufficient data to support full attribution 
of the AE to the single agent.
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Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the EDC tool.
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
If the electronic system is unavailable for more than 24 hours, then the site will 
use the paper AE Reporting form.
◦
Reference Section 8.4.1 for reporting time requirements.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).

Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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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: Medical Device and Drug-device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
This section is not applicable to this study.
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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 Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
IUSc,d
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
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
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
Male condoms must be used in addition to hormonal contraception.
d
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a. Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c. Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e. RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3,4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3,4
a. Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in future 
biomedical research.
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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 participants' clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history and intervention outcomes 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 biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
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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 Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample Coding 
Categories. Available from http://www.ich.org/products/guidelines/efficacy/efficacy-
single/article/definitions-for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-
genomic-data-and-sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, Scope 
and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-
pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
Japan-specific Requirements
1. Additional procedures/assessments are included in the Schedule of Activities for Japan. 
See the corresponding tables in Section 1.3 (Schedule of Activities) for the comprehensive
schedules: Section 1.3.1, Table 1; Section 1.3.3, Table 3; Section 1.3.4, Table 4; 
Section 1.3.5, Table 5.
Table 1
Schedule of Activities for Screening
Study Period:
Screen-
ing
Notes
Visit Day:
-28 to -1
Clinical Procedures/Assessments
Pulse Oximetry (SpO2)
X
Assessments will be performed by the investigator or a 
qualified designee according to local standard procedures.
Laboratory Procedures/Assessments - LOCAL
HBsAg, anti-HBc, and anti-
HBs
X
Table 3
Schedule of Activities for Treatment Phase: Arm 2 Part I - Dose Escalation in 
Participants with Visceral Tumors
Study Period:
Treatment Period
Notes
Treatment 
Cycle / Visit 
Title:
Cycle 1
(28 days)
Cycles 
2-8
(21 
days)
Cycles 
≥9
(21 
days)
Treatment 
Days per Cycle
1
8
1
1
Scheduling / 
visit Window 
(Days)
± 0
± 1
± 5
± 5
Clinical Procedures/Assessments
Pulse Oximetry 
(SpO2)
X
X
X
X
Assessments will be performed by the 
investigator or a qualified designee according to 
local standard procedures.
Laboratory Procedures/Assessments - LOCAL
AST and ALT
X
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Table 4
Schedule of Activities for Treatment Phase: Arm 2 Part II - Cohort Expansion
Study Period:
Treatment Period
Notes
Treatment 
Cycle / Visit 
Title:
Cycle 1
(28 days)
Cycles 
2-8
(21 
days)
Cycles 
≥9
(21 
days)
Treatment 
Days per Cycle
1
8
1
1
Scheduling / 
visit Window 
(Days)
± 0
± 1
± 5
± 5
Clinical Procedures/Assessments
Pulse Oximetry 
(SpO2)
X
X
X
X
Assessments will be performed by the 
investigator or a qualified designee according to 
local standard procedures.
Table 5
Schedule of Activities for End of Treatment/Discontinuation and Posttreatment 
Phase: Arm 1, Arm 2 Part I Dose Escalation Phase, and Arm 2 Part II Expansion 
Phase
Study Period:
End of 
Treatment 
(EOT) / 
Discontinuation
Posttreatment Phase
Treatment Cycle / 
Visit Title:
Safety
Follow-
up
Imaging
Follow-
up
Survival
Follow-up
Treatment Days 
per Cycle:
At time of 
treatment 
discontinuation
30 days 
after the 
last dose
Every
9 or 12 
weeks
Approximately 
every 12 
weeks
Notes
Scheduling 
Window (Days)
± 3
± 3
± 7
± 7
Clinical Procedures/Assessments
Pulse Oximetry 
(SpO2)
X
X
Assessments will 
be performed by 
the investigator or 
a qualified 
designee according 
to local standard 
procedures.
2. Modified the language in Section 5 (Study Population) as shown by the underlined text.
Male and female, ≥20 years of age, with advanced/metastatic solid tumors will be enrolled in 
this study.
3. Modified the language for Criterion 8 in Section 5.1.1 (Overall Inclusion Criteria).
8. Male or female ≥20 years of age, at the time of signing the informed consent.
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4. Added language to Criteria 10 and 12 in Section 5.2 (Exclusion Criteria), as shown by 
the underlined text.
10. Participants with known Hepatitis B or C infections or known to be positive for 
HBsAg/HBV DNA or Hepatitis C Antibody or RNA. Active Hepatitis C is defined by 
a known positive Hep C Ab result and known quantitative HCV RNA results greater 
than the lower limits of detection of the assay.
Note: See Section 5.1.4.1 for hepatitis guidelines in HCC cohort only.
Participants who are positive for anti-HBc or anti-HBs are excluded from this study. 
If the participant is anti-HBs positive, anti-HBc negative, and has a history of HBV 
vaccination, the investigator can consider enrolling the patient in consultation with 
the Sponsor.
12. Has known hypersensitivity to V937 and/or pembrolizumab or any of their excipients, 
and/or has known history of hypersensitivity to ingredients (derived from human, 
bovine, or porcine) used in the manufacturing process of the product.
5. In Japan, V937 is designated as a Regenerative Medical Product, not ‘IMP/NIMP’ as 
shown in Table 9.
6. The language in the first paragraph following Table 9 in Section 6.1 (Study Interventions 
Administered) has been modified (see underlined text) to align with the requirement for 
participants to be hospitalization during Cycle 1, the DLT observation period.
Participants in Arm 2 Part I will be hospitalized and monitored for the duration of Cycle 1
following the Cycle 1 Day 1 ITu administration of V937 (see Section 6.1.2.2 for additional 
details). All other study interventions will be administered on an outpatient basis.
7. The following is an additional prohibited medication applicable to criteria listed in
Section 6.5.2 (Prohibited Concomitant Medications).

Transfusion therapy and hematopoietic factors such as granulocyte colony-
stimulating factor (G-CSF) as primary prophylaxis during DLT assessment
8. Section 8.3 (Safety Assessments) modifications were applied to address the collection of 
pulse oximetry assessments.
In addition to the safety assessments outlined in Section 8.3, pulse oximetry assessments will 
be performed by the investigator or a qualified designee according to local standard 
procedures. Planned timepoints for these assessments are provided in supplements to Tables 
1, 3, 4, and 5 provided at the beginning of Section 10.7.1.
9. The following statement has been added to Section 10.3.6 (Reporting of AEs, SAEs, and 
Other Reportable Safety Events to the Sponsor):
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Other reporting items related to regenerative medical products:
Since V937 is categorized as a Regenerative Medical Product in Japan, AEs meeting below 
criteria should be reported to the Sponsor in addition to recording and reporting the AE as 
described in Section 10.3.
10. The following content has been added to Section 10.3.6 (Reporting of AEs, SAEs, and 
Other Reportable Safety Events to the Sponsor) to provide information specific to 
Regenerative Medical Product:
10.3.6.1 – Definition of Regenerative Medical Product
Regenerative Medical Products (Japan-specific regulation: Act on Securing Quality, Efficacy 
and Safety of Products Including Pharmaceuticals and Medical Devices Article 2-9)
1. The following items intended for use in human or animal healthcare that are obtained 
after culturing or other processes using human or animal cells:

Reconstruction, repairing, or formation of the structure or function of the bodies 
of humans or animals

Treatment or prevention of disease in humans or animals
2. Items intended for use in the treatment of disease in humans or animals that are 
introduced into cells of humans or animals and contain genes to be expressed in their 
bodies.
The defect:
Any defect (or issue) of the regenerative medical products or generally poor conditions such 
as adverse reactions where the cells adversely affect the human body in any stages including 
manufacturing, delivery, storage or use.
Any defect (or issue) that is considered to have caused and/or may have caused SAEs.
Any defect (or issue) in the regenerative medical products concerned that cause or may cause 
death or SAEs. “The events concerned that may cause” means that there is the possibility that 
death or SAEs may occur in the participant, although these cases have not actually occurred.
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10.3.6.2 - Regenerative Medical Products – Recording and Reporting
In order to fulfill Japan regulatory reporting obligations, the issue of regenerative medical 
products information that cause or may cause SAEs due to defect should be collected. The 
defect should be reported to the Sponsor via a Japan-specific paper reporting form. 
Information on Japan-specific paper reporting form will be reported only to Japan MSD.

The SAEs that may occur due to defect should be reported within 5 calendar days to 
the Sponsor.

The SAEs that occur due to defect should be reported within 24 hours to the Sponsor.
10.7.2
Norway-specific Requirements
1. Additional procedures/assessments are included in the Schedule of Activities for Norway. 
See the corresponding section and table for the comprehensive schedule: Section 1.3.5,
Table 5.
Table 5
Schedule of Activities for End of Treatment/Discontinuation and Posttreatment 
Phase: Arm 1, Arm 2 Part I Dose Escalation Phase, and Arm 2 Part II Expansion 
Phase
Study Period:
End of 
Treatment 
(EOT) / 
Discontinuation
Posttreatment Phase
Treatment Cycle / 
Visit Title:
Safety
Follow-
up
Imaging
Follow-
up
Survival
Follow-up
Treatment Days 
per Cycle:
At time of 
treatment 
discontinuation
30 days 
after the 
last dose
Every
9 or 12
weeks
Approximately 
every 12 
weeks
Notes
Scheduling 
Window (Days)
± 3
± 3
± 7
± 7
Laboratory Procedures/Assessments - LOCAL
Pregnancy test for 
WOCBP only 
(urine or serum β 
hCG)
X
Pregnancy testing 
will be performed 
approximately 
every 30 days for 
120 days following
the last dose of 
study treatment.
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2. This guidance supplements language in Section 8.3.7 (Pregnancy Test) requiring testing 
out to 120 days from last dose of study treatment (see underlined text).
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 each 
cycle of study intervention and 30 days posttreatment. If a urine test is positive or not 
evaluable, a serum test will be required. Participants must be excluded/discontinued from the 
study in the event of a positive or borderline-positive test result. Pregnancy testing will be 
performed approximately every 30 days for 120 days past the last dose of study treatment.
3. This guidance supplements the language provided in Section 10.2, Appendix 2 (Clinical 
Laboratory Tests), indicating additional pregnancy testing.

Pregnancy Testing:
-
Pregnancy testing will be performed approximately every 30 days for 120 days 
past the last dose of study treatment.
10.7.3
France-specific Requirements
1. Section 6.6.2 provides guidance for the management of immune-related AEs associated 
with pembrolizumab. In France, refer to the Keytruda European Summary of Product 
Characteristics available on the Public Drug Database for the guidelines regarding 
withholding or discontinuing pembrolizumab for Grades 2, 3, or 4 adrenal insufficiency 
as per investigator decision.
2. Pregnancy testing must be performed prior to study intervention administration at each 
cycle during the treatment period, and 120 days after the last dose at the end of study 
intervention.
3. Oocyte donation is prohibited during treatment and at least 120 days after last dose of 
study intervention.
10.7.4
Portugal-specific Requirements
1. HIV testing is required at screening.
2. Hepatitis B and Hepatitis C testing is required at screening.
3. Pregnancy testing must be performed for all WOCBP participants at screening, prior to 
study intervention administration at each cycle during the treatment period, as well as 
before the last dose of study intervention. 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
ADA
anti-drug antibodies
AE
adverse event 
ALP
alkaline phosphatase
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
AR
adverse reaction
ART
anti-retroviral therapy
AST
aspartate aminotransferase
ATD
accelerated titration design
ATP
adenosine triphosphate
AUC
areas under the curve
BCG
Bacillus Calmette–Guérin
BDS
blood drug screen
β-hCG
β-human chorionic gonadotropin
BID
twice daily
BMI
body mass index
BP
blood pressure
CBC
complete blood count
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CI
confidence interval
Cmax
maximum concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CL
clearance
CPS
combined positive score
CrCl
creatinine clearance
CR
complete response
CRF
Case Report Form 
cSCC
cutaneous Squamous Cell Carcinoma
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE v5.0
Common Terminology Criteria for Adverse Events, Version 5.0
ctDNA
circulating tumor DNA
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DAMP
danger-associated molecular pattern
Dbil
direct bilirubin
DILI
drug-induced liver injury
DL (1, 2, 3)
dose level (1, 2, 3)
DLT
dose-limiting toxicity
DLTe
dose-limiting toxicity-evaluable
DMC
data Monitoring Committee 
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
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Abbreviation
Expanded Term
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FAS
Full Analysis Set
FFPE
formalin-fixed, paraffin embedded
FISH
fluorescence in situ hybridization
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice 
GEJ
gastroesophageal junction
GGT
Gamma-glutamyl Transferase
HBc
hepatitis B core 
HBeAg
hepatitis B e antigen
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDV
hepatitis delta virus
HECI
Hepatic Events of Clinical Interest
Hep C Ab
hepatitis C antibody
HER2
human epiderma growth factor receptor 2
HIV
human immunodeficiency virus
HNSCC
head and neck squamous cell carcinoma
HPV
human papillomavirus
HR
heart rate
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
iCPD
immune confirmed progressive disease
iCR
immune complete response
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgM
immunoglobulin M
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IND
Investigational New Drug 
INR
International Normalize Ratio
IO
immuno-oncology
iPR
immune partial response
irAEs
immune-related AEs
IRB
Institutional Review Board
iRECIST
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics
IRT
interactive response technology
iSD
immune stable disease
ITP
idiopathic thrombocytopenic purpura
ITu
intratumoral
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Abbreviation
Expanded Term
IUD
intrauterine device
iUPD
immune unconfirmed progressive disease
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IVRS
interactive voice response system
IWRS
integrated web response system
LAM
lactational amenorrhoea method
LLOQ
lower limit of quantification
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
mTPI
modified Toxicity Probability Interval
NCI
National Cancer Institute
NDA
New Drug Application 
NSCLC
non-small cell lung cancer
OPV
oral poliovirus
OR
objective response
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PAMP
pathogen-associate molecular pattern
PBPK
physiologically-based PK
PD
progressive disease
PD-1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression-free survival
PK
pharmacokinetic
PKCθ
protein kinase C-theta
PO
orally
PP
Per-protocol
PR
partial response
Q3W
every 3 weeks
RNA
ribonucleic acid
RP2D
Recommended Phase 2 Dose
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SIM
Site Imaging Manual
SoA
schedule of activities
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
SVR12
sustained virologic response; no detectable amount of HCV in blood after 12 weeks 
of treatment
TAA
tumor-associated antigens
Tbil
total bilirubin
TCID50
median tissue culture infectious dose
TILs
tumor-infiltrating lymphocytes
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Abbreviation
Expanded Term
TMDD
target-mediated drug disposition
TNBC
triple negative breast cancer
T-regs
regulatory T cells
T-VEC
talimogene laherparepvec
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
XRT
radiotherapy
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10.9
Appendix 9: Child-Pugh Score
The Child-Pugh score is used to assess the prognosis of chronic liver disease, mainly 
cirrhosis. Although it was originally used to predict mortality during surgery, it is now used 
to determine the prognosis, as well as the required strength of treatment and the necessity of 
liver transplantation.
Scoring
The score employs 5 clinical measures of liver disease. Each measure is scored from 1 to 3, 
with 3 indicating most severe derangement.
Measure
1 point
2 points
3 points
Total bilirubin1 (mg/dL)
<2.0
2.0 to 3.0
>3.0
Serum albumin (g/dL)
>3.5
2.8 to 3.5
<2.8
INR2
Or
Prothrombin time,
prolongation (seconds)
<1.7
<4.0
1.7 to 2.3
4.0-6.0
> 2.3
>6.0
Ascites
None
Mild (easily 
controlled by 
medication)
Moderate to Severe
(poorly controlled)
Hepatic encephalopathy3
None
Grade I-II (mild or 
moderate)
Grade III-IV (severe or 
coma)
1In primary sclerosing cholangitis and primary biliary cirrhosis, the bilirubin references are 
changed to reflect the fact that these diseases feature high conjugated bilirubin levels. The 
upper limit for 1 point is 68 μmol/L (4 mg/dL) and the upper limit for 2 points is 170 
μmol/L (10 mg/dL).
2 Different textbooks and publications use different measures. Some older reference works substitute 
PT prolongation for INR
3 Hepatic encephalopathy graded according to West Haven Criteria for Semi-quantitative 
Grading of Mental Status: Adapted from: Conn H, Lieberthal M. The hepatic coma 
syndromes and lactulose. Baltimore: Williams & Wilkins; 1979. 

Grade I:
Trivial lack of awareness; euphoria or anxiety; shortened attention span; 
impaired performance of addition or subtraction

Grade II:
Lethargy or apathy; minimal disorientation for time or place; subtle 
personality change; inappropriate behavior
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
Grade III: Somnolence to semi-stupor, but responsive to verbal stimuli
Confusion; Gross disorientation

Grade IV: Coma (unresponsive to verbal or noxious stimuli)
Interpretation
Chronic liver disease is classified into Child-Pugh class A to C, employing the added score 
from above.
Points
Class
One-year survival
Two-year survival
5–6
A
100%
85%
7–9
B
81%
57%
10–15
C
45%
35%
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11
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