Clinical trial NCT04135352
Conditions: Neoplasm Metastasis
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2019-11-04; Completion date: 2022-08-24
Enrollment: 35 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purpose of this study is to evaluate the safety, efficacy, pharmacokinetics, and V938 shedding in participants with advanced/metastatic or recurrent malignancies who receive V938 in combination with pembrolizumab (MK-3475). The primary objective is to determine the safety and tolerability and to identify a recommended Phase 2 dose (RP2D) of V938 administered in combination with pembrolizumab.

Detailed description:
Due to discontinuation of V938-001, all ongoing participants who completed V938 plus pembrolizumab treatment may be enrolled in an extension study (KN587) to continue pembrolizumab monotherapy for a total of 35 cycles since the first dose in V938-001 and to be monitored as appropriate.

Arms: arm 1: This arm will enroll participants with advanced/metastatic or recurrent solid tumors. Participants receive Dose A of V938 intratumorally in cycles 1-7. Participants also receive 200 mg of pembrolizumab intravenously once every 3 weeks (Q3W) beginning with cycle 2 for a maximum of 35 cycles. Each cycle is 21 days. arm 2: This arm will enroll participants with advanced/metastatic or recurrent solid tumors. Participants receive Dose B of V938 intratumorally in cycles 1-7. Participants also receive 200 mg of pembrolizumab intravenously Q3W beginning with cycle 2 for a maximum of 35 cycles. Each cycle is 21 days. arm 3: This arm will enroll participants with advanced/metastatic or recurrent solid tumors. Participants receive Dose C of V938 intratumorally in cycles 1-7. Participants also receive 200 mg of pembrolizumab intravenously Q3W beginning with cycle 2 for a maximum of 35 cycles. Each cycle is 21 days. arm 4: This arm will enroll participants with advanced/metastatic or recurrent solid tumors. Participants receive Dose D of V938 intratumorally in cycles 1-7. Participants also receive 200 mg of pembrolizumab intravenously Q3W beginning with cycle 2 for a maximum of 35 cycles. Each cycle is 21 days. arm 5: This arm will enroll participants with advanced/metastatic or recurrent solid tumors. Participants receive Dose B of V938 intratumorally in cycles 1-7. Participants also receive 200 mg of pembrolizumab intravenously Q3W beginning with cycle 1 for a maximum of 35 cycles. Each cycle is 21 days. arm 6: This arm will enroll participants with advanced/metastatic or recurrent solid tumors. Participants receive Dose C of V938 intratumorally in cycles 1-7. Participants also receive 200 mg of pembrolizumab intravenously Q3W beginning with cycle 1 for a maximum of 35 cycles. Each cycle is 21 days. arm 7: This arm will enroll participants with advanced/metastatic or recurrent solid tumors. Participants receive Dose D of V938 intratumorally in cycles 1-7. Participants also receive 200 mg of pembrolizumab intravenously Q3W beginning with cycle 1 for a maximum of 35 cycles. Each cycle is 21 days. arm 8: This arm will enroll only participants with with a diagnosis of stage III (unresectable) and Stage IV melanoma (any line of therapy). Participants receive V938 at the recommended Phase 2 Dose, determined by analysis of the Dose A-C arms, intratumorally in cycles 1-7. Participants also receive 200 mg of pembrolizumab intravenously Q3W beginning with cycle 1 for a maximum of 35 cycles. Each cycle is 21 days. arm 9: This arm will only enroll participants with a diagnosis of advanced/metastatic head and neck squamous cell carcinoma (HNSCC). Participants receive V938 at the recommended Phase 2 Dose, determined by analysis of the Dose A-C arms, intratumorally in cycles 1-7. Participants also receive 200 mg of pembrolizumab intravenously Q3W beginning with cycle 1 for a maximum of 35 cycles. Each cycle is 21 days.
Interventions: intervention 1: 200 mg of pembrolizumab intervention 2: V938
Intervention descriptions: intervention 1: Participants receive 200 mg of pembrolizumab intravenously Q3W for a maximum of 35 21-day cycles. intervention 2: Participants receive V938 intratumorally in cycles 1-7. Each cycle is 21 days.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 1/1b, Open-label Clinical Study of 
Intratumoral/Intralesional Administration of 
V938 in Combination with Pembrolizumab 
(MK-3475) in Participants with Advanced/
Metastatic or Recurrent Malignancies
NCT04135352
25-MAY-2022


PRODUCT: V938  
1
PROTOCOL/AMENDMENT NO.: 001-08
V938-001-08 FINAL PROTOCOL
25-MAY-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 1/1b, Open-label Clinical Study of Intratumoral/Intralesional 
Administration of V938 in Combination with Pembrolizumab (MK-3475) in Participants 
with Advanced/Metastatic or Recurrent Malignancies
Protocol Number: 001-08
Compound Number: V938
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
19161
EudraCT
2020-003431-25
Approval Date: 25 May 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 8
25-MAY-2022
V938-001 is going to be discontinued due to sponsor’s development decision. The 
overall rationale for this amendment is to allow eligible participants who are still 
ongoing with the study treatment after Cycle 7 Day 1 to continue receiving 
pembrolizumab monotherapy for up to 35 cycles in a pembrolizumab extension study.
Amendment 7
22-JUN-2021
To clarify or update: collection times for shedding analysis; lesion requirements; and 
update the dose modification and toxicity management guidelines for irAEs for 
pembrolizumab.
Amendment 6
04-JAN-2021
The overall rationale for this amendment is to add a CRS grading system and to update 
the dose range for the 89Zr Df-IAB22M2C tracer.
Amendment 5
22-OCT-2020
To add new cohorts under dose escalation to evaluate combination of V938 and 
pembrolizumab with pembrolizumab starting on C1D1.
To modify dose toxicity criteria for V938 to allow dose reduction, and to provide 
general guidance on managing cytokine release syndrome.
Amendment 4
04-JUN-2020
The overall rationale for this amendment is to add Cohort 4 to dose escalation at a dose 
of V938 of 5×108 PFU.
Amendment 3
21-FEB-2020
To add a CD8 PET imaging study to be conducted at preapproved study sites
Amendment 2
27-AUG-2019
To implement revisions requested by the US FDA.
Amendment 1
26-JUN-2019
To remove an arm of the study in the Dose-confirmation Phase.
Original protocol
03-APR-2019
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 08
Overall Rationale for the Amendments:
V938-001 is going to be discontinued due to sponsor’s development decision. The overall rationale for this amendment is to allow 
eligible participants who are still ongoing with the study treatment after Cycle 7 Day 1 to continue receiving pembrolizumab 
monotherapy for up to 35 cycles in a pembrolizumab extension study.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1  Synopsis – Duration of 
Participation
1.2  Schema
4.4  Beginning and End of 
Study Definition
Language was added to allow eligible 
participants who are still ongoing in the 
study to continue to receive treatment for 
up to 35 cycles of treatment with 
pembrolizumab or be followed for survival 
through enrollment in a pembrolizumab 
extension study. Schema was updated to 
reflect changes to the study.
These changes will allow this study to be closed.
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Section # and Name
Description of Change 
Brief Rationale 
1.3.2  Schedule of Activities 
for the Treatment Period
1.3.3  Schedule of Activities 
for the End-of-Treatment 
and Posttreatment Follow-up 
Periods
Removal of certain sample collections for 
V938 PK, neutralizing V938 antibodies, 
anti-IL-12 antibodies, pembrolizumab PK, 
anti-pembrolizumab antibodies, shedding 
analyses, blood for RNA biomarker 
analyses and ctDNA, and serum for 
cytokine/chemokine analyses.
Removal of sample collections for 
pembrolizumab PK, anti-pembrolizumab 
antibodies, neutralizing V938 antibodies 
and anti-IL-12 antibodies, NDV RNA 
(V938 PK), shedding analyses, blood for 
RNA biomarker analyses and ctDNA 
analysis, and serum for 
cytokine/chemokine analyses.
Changes due to study closure.
1.3.2  Schedule of Activities 
for the Treatment Period
Changed the timeframe for injection of the 
PET tracer prior to tumor biopsy in the 
PET imaging study.
Change to the PET imaging study due to study closure.
8.1.9.1  Withdrawal from 
Future Biomedical Research
Appendix 6: Collection and 
Management of Specimens 
for Future Biomedical 
Research  
Updated e-mail address to 
clinical.specimen.management@MSD.com
Correction.
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Section # and Name
Description of Change 
Brief Rationale 
8.6  Pharmacokinetics
Added that blood samples for PK and 
antidrug antibodies may be stored, 
collection reduced, or collection 
discontinued, and any changes will be 
communicated by an administrative memo.
To allow for flexibility for collection and analyses of 
these samples.
Title Page
Section 10.1.1  Code of 
Conduct for Clinical Trials
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.
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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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................16
1.1
Synopsis.................................................................................................................16
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities (SoA)................................................................................21
1.3.1
Schedule of Activities for Screening ...........................................................21
1.3.2
Schedule of Activities for the Treatment Period..........................................23
1.3.3
Schedule of Activities for the End-of-Treatment and Posttreatment 
Follow-up Periods........................................................................................33
2
INTRODUCTION..........................................................................................................35
2.1
Study Rationale....................................................................................................35
2.2
Background ..........................................................................................................38
2.2.1
Pharmaceutical and Therapeutic Background .............................................38
2.2.1.1
V938 Pharmaceutical and Therapeutic Background..........................38
2.2.1.2
Mechanism of Action.........................................................................38
2.2.1.3
Preclinical Studies of V938 ...............................................................38
2.2.1.4
Pembrolizumab Pharmaceutical and Therapeutic Background .........38
2.2.2
Information on Other Study-related Therapy ..............................................39
2.3
Benefit/Risk Assessment......................................................................................39
2.3.1
Ongoing Clinical Studies.............................................................................40
2.3.1.1
V938 Clinical Studies ........................................................................40
2.3.1.2
Pembrolizumab Clinical Studies........................................................40
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................40
4
STUDY DESIGN............................................................................................................42
4.1
Overall Design......................................................................................................42
4.1.1
Dose-escalation Phase..................................................................................42
4.1.2
Cohort Expansion Phase ..............................................................................44
4.2
Scientific Rationale for Study Design.................................................................45
4.2.1
Rationale for Endpoints ...............................................................................45
4.2.1.1
Efficacy Endpoints.............................................................................45
4.2.1.1.1
Response Rate Assessed by RECIST Version 1.1...................45
4.2.1.1.2
Response Rate Assessed by Modified Response Evaluation 
Criteria in Solid Tumors 1.1 for Immune-based 
Therapeutics (iRECIST) ..........................................................46
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4.2.1.2
Safety Endpoints................................................................................46
4.2.1.3
Pharmacokinetic Endpoints ...............................................................47
4.2.1.4
Pharmacodynamic Endpoints.............................................................47
4.2.1.4.1
Target Engagement ..................................................................47
4.2.1.5
Anti-drug Antibodies (ADA).............................................................47
4.2.1.6
Serum Cytokines................................................................................47
4.2.1.7
Planned Exploratory Biomarker Research.........................................48
4.2.1.8
Future Biomedical Research..............................................................49
4.2.2
Rationale for Selection of Expansion Cohorts.............................................50
4.3
Justification for Dose...........................................................................................50
4.3.1
Starting and Maximum Dose of V938 and Rationale..................................50
4.3.2
Rationale for Dose Interval and Escalation Increments...............................51
4.3.3
Dose Finding Using a Modified Toxicity Probability Interval Design........51
4.3.4
Dose Escalation, Stay or De-escalation Decision for Cohorts 2a, 3a and 
4a..................................................................................................................53
4.4
Beginning and End of Study Definition .............................................................54
4.4.1
Clinical Criteria for Early Study Termination .............................................55
5
STUDY POPULATION ................................................................................................55
5.1
Inclusion Criteria.................................................................................................55
5.2
Exclusion Criteria................................................................................................60
5.3
Lifestyle Considerations......................................................................................62
5.3.1
Meals and Dietary Restrictions....................................................................62
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................62
5.3.3
Activity Restrictions ....................................................................................62
5.4
Screen Failures.....................................................................................................62
5.5
Participant Replacement Strategy in Dose Escalation .....................................63
6
STUDY INTERVENTION............................................................................................63
6.1
Study Intervention(s) Administered...................................................................63
6.1.1
Intratumoral Injection ..................................................................................65
6.2
Preparation/Handling/Storage/Accountability .................................................66
6.2.1
Dose Preparation..........................................................................................66
6.2.2
Handling, Storage, and Accountability........................................................66
6.3
Measures to Minimize Bias: Randomization and Blinding..............................67
6.3.1
Intervention Assignment..............................................................................67
6.3.2
Stratification.................................................................................................67
6.3.3
Blinding........................................................................................................67
6.4
Study Intervention Compliance..........................................................................67
6.5
Concomitant Therapy..........................................................................................67
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6.5.1
Acceptable Concomitant Medications .........................................................67
6.5.2
Prohibited Concomitant Medications ..........................................................68
6.5.3
Supportive Care ...........................................................................................69
6.5.3.1
V938 Supportive Care........................................................................69
6.5.3.2
Pembrolizumab Supportive Care.......................................................69
6.6
Dose Modification (Escalation/Titration/Other)...............................................69
6.6.1
Dose Administration/Escalation ..................................................................69
6.6.2
Definition of Dose-limiting Toxicity...........................................................69
6.6.3
Timing of Dose Administration...................................................................71
6.6.4
Guidelines for Dose Modification due to Adverse Events ..........................71
6.6.4.1
Dose Modification and Management for V938 .................................71
6.6.4.1.1
Management of Cytokine Release Syndrome..........................74
6.6.4.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................78
6.6.4.2.1
Dose Modification and Toxicity Management of Infusion 
Reactions Related to Pembrolizumab......................................83
6.6.4.2.2
Other Allowed Dose Interruption(s) for Pembrolizumab ........85
6.7
Intervention After the End of the Study............................................................85
6.8
Clinical Supplies Disclosure................................................................................85
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................85
7.1
Discontinuation of Study Intervention...............................................................85
7.2
Participant Withdrawal From the Study...........................................................86
7.3
Lost to Follow-up .................................................................................................87
8
STUDY ASSESSMENTS AND PROCEDURES........................................................87
8.1
Administrative and General Procedures ...........................................................88
8.1.1
Informed Consent.........................................................................................88
8.1.1.1
General Informed Consent.................................................................88
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................89
8.1.2
Inclusion/Exclusion Criteria ........................................................................89
8.1.3
Participant Identification Card.....................................................................89
8.1.4
Medical History ...........................................................................................89
8.1.5
Disease Details.............................................................................................89
8.1.6
Prior Oncology Treatment History ..............................................................89
8.1.7
Eastern Cooperative Oncology Group Performance Status.........................90
8.1.8
Prior and Concomitant Medications Review...............................................90
8.1.8.1
Prior Medications...............................................................................90
8.1.8.2
Concomitant Medications..................................................................90
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8.1.9
Assignment of Screening Number...............................................................91
8.1.10
Assignment of Treatment/Randomization Number.....................................91
8.1.11
Study Intervention Administration ..............................................................91
8.1.11.1
Timing of Dose Administration.........................................................91
8.1.12
Discontinuation and Withdrawal .................................................................91
8.1.12.1
Withdrawal From Future Biomedical Research ................................92
8.1.13
Participant Blinding/Unblinding..................................................................92
8.1.14
Domiciling ...................................................................................................92
8.1.15
Calibration of Equipment.............................................................................92
8.2
Efficacy/Immunogenicity Assessments ..............................................................93
8.2.1
Tumor Imaging and Medical Photography..................................................93
8.2.2
Initial Tumor Imaging..................................................................................93
8.2.3
Brain Imaging ..............................................................................................94
8.2.4
Imaging for Bone Metastases.......................................................................95
8.2.5
Tumor Imaging During the Study................................................................95
8.2.6
End-of-Treatment and Follow-up Tumor Imaging......................................96
8.2.7
Response Assessment ..................................................................................96
8.2.7.1
iRECIST 1.1 Assessment of Disease.................................................96
8.2.7.2
itRECIST..........................................................................................101
8.2.8
Eastern Cooperative Oncology Group Performance Scale........................101
8.3
Safety Assessments.............................................................................................101
8.3.1
Physical Examinations...............................................................................101
8.3.1.1
Full Physical Examination...............................................................101
8.3.1.2
Directed Physical Examination........................................................102
8.3.2
Vital Signs..................................................................................................102
8.3.3
Electrocardiograms ....................................................................................102
8.3.4
Clinical Safety Laboratory Assessments ...................................................102
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)........................................................................................103
8.3.4.2
Pregnancy Test.................................................................................103
8.3.5
Viral Shedding ...........................................................................................103
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ..................................................................................103
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................104
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....105
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.106
8.4.4
Regulatory Reporting Requirements for SAE ...........................................106
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8.4.5
Pregnancy and Exposure During Breastfeeding ........................................106
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................106
8.4.7
Events of Clinical Interest (ECIs)..............................................................107
8.5
Treatment of Overdose......................................................................................107
8.6
Pharmacokinetics...............................................................................................107
8.6.1
Blood Collection for Pembrolizumab and V938 PK .................................108
8.6.2
Viral Shedding ...........................................................................................108
8.7
Pharmacodynamics............................................................................................108
8.7.1
Blood for Pharmacodynamic Markers.......................................................108
8.7.2
Tumor Biopsy ............................................................................................108
8.8
Future Biomedical Research Sample Collection.............................................109
8.9
Planned Genetic Analysis Sample Collection..................................................109
8.10
Biomarkers .........................................................................................................109
8.10.1
Blood Collection for Anti-drug Antibodies...............................................110
8.11
Visit Requirements.............................................................................................110
8.11.1
Screening....................................................................................................110
8.11.2
Treatment Period/Vaccination Visit ..........................................................110
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ........111
8.11.4
Posttreatment Visits ...................................................................................111
8.11.4.1
Safety Follow-up Visit.....................................................................111
8.11.4.2
Imaging Follow-up Visits ................................................................111
8.11.4.3
Survival Follow-up Visits................................................................112
8.12
CD8 Tracer PET Imaging (ONLY at Preapproved Sites in the US) ............112
9
STATISTICAL ANALYSIS PLAN ...........................................................................113
9.1
Statistical Analysis Plan Summary...................................................................113
9.2
Responsibility for Analyses/In-house Blinding ...............................................114
9.3
Hypotheses/Estimation ......................................................................................114
9.4
Analysis Endpoints.............................................................................................114
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints............................114
9.4.2
Safety Endpoints........................................................................................114
9.5
Analysis Populations..........................................................................................115
9.5.1
Safety Analysis Populations ......................................................................115
9.5.2
Pharmacokinetic Analysis Populations......................................................115
9.5.3
Efficacy Analysis Populations...................................................................115
9.6
Statistical Methods.............................................................................................115
9.6.1
Statistical Methods for Efficacy Analysis..................................................116
9.6.2
Statistical Methods for Safety Analysis.....................................................116
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9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................116
9.6.3.1
Demographic and Baseline Characteristics .....................................116
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis..........116
9.7
Interim Analyses ................................................................................................117
9.8
Multiplicity .........................................................................................................117
9.9
Sample Size and Power Calculations ...............................................................117
9.10
Subgroup Analyses.............................................................................................119
9.11
Compliance (Medication Adherence)...............................................................119
9.12
Extent of Exposure.............................................................................................119
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................120
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......120
10.1.1
Code of Conduct for Clinical Trials...........................................................120
10.1.2
Financial Disclosure...................................................................................122
10.1.3
Data Protection...........................................................................................122
10.1.3.1
Confidentiality of Data ....................................................................123
10.1.3.2
Confidentiality of Participant Records.............................................123
10.1.3.3
Confidentiality of IRB/IEC Information..........................................123
10.1.4
Committees Structure.................................................................................123
10.1.4.1
Internal Medical Monitoring Team..................................................123
10.1.5
Publication Policy......................................................................................125
10.1.6
Compliance with Study Registration and Results Posting Requirements .125
10.1.7
Compliance with Law, Audit, and Debarment ..........................................126
10.1.8
Data Quality Assurance .............................................................................126
10.1.9
Source Documents .....................................................................................127
10.1.10
Study and Site Closure...............................................................................128
10.2
Appendix 2: Clinical Laboratory Tests............................................................129
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................131
10.3.1
Definition of AE ........................................................................................131
10.3.2
Definition of SAE ......................................................................................132
10.3.3
Additional Events Reported in the Same Manner as SAE.........................133
10.3.4
Recording AE and SAE .............................................................................134
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................137
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................139
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................140
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10.5.1
Definitions..................................................................................................140
10.5.2
Contraception Requirements......................................................................141
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................142
10.7
Appendix 7: Country-specific Requirements..................................................147
10.8
Appendix 8: itRECIST Supplementary Figures.............................................148
10.9
Appendix 9: Abbreviations ...............................................................................153
11
REFERENCES.............................................................................................................156
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25-MAY-2022
LIST OF TABLES
Table 1
Dose-finding Rules per mTPI Design........................................................53
Table 2
Adequate Organ Function Laboratory Values ...........................................57
Table 3
Study Interventions....................................................................................64
Table 4
Estimation of Total Injected V938 Volume Based on Estimated 
Combined Lesion Size for Lesions to be Injected at Each V938 
Treatment Visit ..........................................................................................65
Table 5
V938 Dose Modification and Treatment Discontinuation Guidelines 
for Drug-related Adverse Events ...............................................................72
Table 6
CRS Grading, Adapted From ASTCT CRS Consensus Grading ..............75
Table 7
Dose Modification and Management Guideline for Treatment-related 
CRS............................................................................................................76
Table 8
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .........................................................79
Table 9
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................84
Table 10
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease.....................................................................................................100
Table 11
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events...............................................................105
Table 12
Probability of Continuing Study (Interim at N=20), by True ORR and 
Futility Bar...............................................................................................117
Table 13
Estimate and 95% CI of ORR (N=20).....................................................118
Table 14
Estimate and 95% CI of ORR (N=40).....................................................118
Table 15
Protocol-required Safety Laboratory Assessments..................................130
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PRODUCT: V938  
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PROTOCOL/AMENDMENT NO.: 001-08
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LIST OF FIGURES
Figure 1
Study Schema.............................................................................................20
Figure 2
Algorithm for Classification of Lesions at Baseline................................148
Figure 3
Reclassification of Noninjected Lesions..................................................149
Figure 4
Overall Response Assessment Until Disease Progression.......................150
Figure 5
Example of Iterative Assessment of Injected Lesion Response During 
Treatment .................................................................................................151
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PRODUCT: V938  
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1/1b, Open-label Clinical Study of Intratumoral/Intralesional 
Administration of V938 in Combination with Pembrolizumab (MK-3475) in Participants 
with Advanced/Metastatic or Recurrent Malignancies
Short Title: Phase 1/1b Open-label Study of V938 plus pembrolizumab for advanced solid 
tumors
Acronym: Not applicable.
Hypotheses, Objectives, and Endpoints:
In male/female participants with advanced/metastatic solid tumors:
Primary Objectives
Primary Endpoints
- Objective: To determine the safety and 
tolerability and to identify a recommended 
Phase 2 dose (RP2D) of V938 administered 
in combination with pembrolizumab
- Dose-limiting toxicity (DLT)
- Adverse events (AEs)
- Discontinuing study intervention due to 
an AE
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate the objective 
response rate (ORR), as assessed by the 
investigator, of V938 administered in 
combination with pembrolizumab. 
Assessment will be based on Response 
Evaluation Criteria in Solid Tumors Version 
1.1 (RECIST 1.1) and modified RECIST 1.1 
for immune-based therapeutics (iRECIST). 
- Objective response is a confirmed 
complete response (CR) or partial response 
(PR)
- Objective: To evaluate the 
pharmacokinetics (PK) of V938 administered 
alone and in combination with 
pembrolizumab.
- PK parameters of V938, including area 
under the curve (AUC) and maximum 
concentration (Cmax) of Newcastle 
Disease Virus (NDV) RNA
- Objective: To assess environmental V938 
shedding
- NDV in excretory tissue samples
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PRODUCT: V938  
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
The treatment of participants with advanced/metastatic 
or recurrent solid tumors.
Population
Participants with histologically or cytologically
confirmed advanced/metastatic solid tumor.
Study Type
Interventional
Intervention Model
Sequential
This is a multi-site study.
Type of Control
No treatment control
Study Blinding
Unblinded Open-label
Masking
No Masking
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 contact.
Number of Participants:
Approximately 20 to 44 participants will be enrolled in the dose-escalation part of this study 
(3 to 6 participants/cohort [cap at 14]), and 40 participants in the initial dose-expansion part 
of the study (20 participants/cohort) with the potential for further expansion. The final 
number of participants enrolled in the study will depend on the empirical safety data 
(DLT observations and the dose at which the RP2D is identified) and the initial signal 
finding for efficacy.
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PRODUCT: V938  
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Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admin.
Regimen/ 
Treatment 
Period/ 
Vaccination 
Regimen
Use
Cohort 1
V938
1 × 107
PFU
Cycle 1 
Days 1, 3, 5, 
and 8; then 
Q3W × 
6 doses 
(Cycle 2 to 
Cycle 7) 
Intratumoral 
injection of 
cutaneous, 
subcutaneous 
and nodal 
lesions
Total of 10 
doses 
administered 
from Cycle 1 
to Cycle 7 
Experi-
mental
Cohort 2
1 × 108
PFU
Cohort 3
3 × 108
PFU
Cohort 4
5 × 108
PFU
Cohorts 1-4
Pembro-
lizumab
200 mg
Q3W
IV infusion
w beginning 
at Cycle 2
Day 1 for a 
maximum of 
35 cycles
Experi-
mental
Cohort 2a
V938
1 × 108
PFU
Cycle 1 
Days 1, 3, 5, 
and 8; then 
Q3W × 6 
doses 
(Cycle 2 to 
Cycle 7)
Intratumoral 
injection of 
cutaneous, 
subcutaneous 
and nodal 
lesions
Total 10 
doses 
administered 
from Cycle 1 
to Cycle 7
Experi-
mental
Cohort 3a
3 × 108
PFU
Cohort 4a
5 × 108
PFU
Cohorts 
2a-4a
Pembro-
lizumab
200 mg
Q3W
IV infusion
Q3W 
beginning at 
Cycle 1 Day 
1 for a 
maximum of 
35 cycles
Experi-
mental
Dose 
Expansion
Arms A and 
B
V938
RP2D
Cycle 1 
Days 1, 3, 5, 
and 8; then 
Q3W × 6 
doses
Intratumoral, 
injection of 
cutaneous, 
subcutaneous 
and nodal 
lesions 
Total 10 
doses 
administered 
from Cycle 1 
Cycle 7
Experi-
mental
Pembro-
lizumab
200 mg
Q3W
IV infusion
Q3W
beginning at 
Cycle 1 Day 
1 for a 
maximum of 
35 cycles
Experi-
mental
Note: Pembrolizumab will be administered within 8 hours after completion of intratumoral V938
when both drugs are administered on the same day. Every cycle = 21 days
Abbreviations: IV = intravenous; PFU = plaque-forming units; RP2D = Recommended Phase 2 
Dose; Q3W = every 3 weeks.
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PRODUCT: V938  
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Total 
Number
Approximately 6 or 7 cohorts in dose escalation and 2 arms in expansion
Duration of 
Participation
After a screening phase of up to 28 days, each eligible participant will be 
receive study treatments until disease progression is radiographically 
documented and, when clinically appropriate, confirmed by the site per 
iRECIST for treated participants, unacceptable AEs, intercurrent illness that 
prevents further administration of treatment, investigator’s decision to 
withdraw the participant, noncompliance with study treatment or procedure 
requirements or administrative reasons requiring cessation of treatment, or 
until the participant has received 35 doses of pembrolizumab (approximately 
2 years). 
After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy. All participants 
will be followed by telephone for OS until death, withdrawal of consent, or 
end of the study, whichever occurs first. The duration of study from the first 
participant enrolled to the last participant’s last visit is estimated to be 
approximately 5 years.
Due to discontinuation of V938-001, all ongoing participants who have 
completed C7D1 V938 plus pembrolizumab treatment may be enrolled to an 
extension study to continue pembrolizumab monotherapy for total of 35 
cycles since first dose in V938-001 and to be monitored per the extension 
study as appropriate.
Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
There are no governance committees in this study. Regulatory, ethical, and study oversight 
considerations are presented in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 9.
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PRODUCT: V938  
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PROTOCOL/AMENDMENT NO.: 001-08
V938-001-08 FINAL PROTOCOL
25-MAY-2022
1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
C=Cycle; D=Day; DLT=dose-limiting toxicity; mHNSCC=metastatic head and neck squamous cell carcinoma;
mMEL=metastatic melanoma; pembro=pembrolizumab; PFU=plaque-forming units; RP2D=recommended Phase 2 dose; 
Q3W=every 3 weeks.
Note: Due to discontinuation of V938-001, all ongoing participants who have completed C7D1 V938 plus pembrolizumab 
treatment may be enrolled to an extension study to continue pembrolizumab monotherapy for total of 35 cycles since first 
dose in V938-001 and to be monitored per the extension study as appropriate.
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PRODUCT: V938
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1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities for Screening
Study Period
Screening
Notes
Visit Days
-28 to -1
Administrative Procedures
Informed Consent
X
Documented informed consent must be obtained prior to performing any protocol-specific procedures. Tests 
performed prior to consent as part of routine clinical management are acceptable if performed within the specified 
timeframe.
Informed Consent for Future Biomedical 
Research (Optional)
X
Consent for future biomedical research is not required to participate in the study. Any leftover biomarker samples will
be stored for future biomedical research if the participant (or their legally acceptable representative) provides documented 
informed consent for future biomedical research consent. Detailed instructions for the collection and management of 
future biomedical research specimens are provided in the Laboratory Procedure Manual.
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
Participant identification card to be updated with treatment number at the time of treatment allocation.
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), by history if available, as determined by local testing results (eg, BRCA1, BRCA2, MSI, 
TP53, MMR, PDL1, BRAF, KIT, KRAS, NRAS, PIK3CA)
HPV Status
X
HPV testing results by history in HNSCC and other squamous cell carcinoma tumors (eg, p16 IHC; multiplex nucleic 
acid sequence-based amplification [NASBA] or other polymerase chain reaction [PCR]-based assays) should be 
recorded if available, as determined per institutional standard.
Prior Medication
X
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1
X
Baseline tumor imaging (CT or MRI as indicated for tumor type) and/or medical photography of cutaneous lesions 
should be performed within 28 days of enrollment. Please refer to Imaging Manual for detailed information. 
Medical Photography 
(Cutaneous Lesions)
X
Brain Imaging (Participants with Small 
Cell Lung Cancer, Thyroid Cancer, or 
Melanoma)
X
Participants with small cell lung, thyroid cancer, or melanoma must undergo brain imaging within 28 days prior to the 
first dose of study treatment, with local confirmation that no new or untreated brain metastases are present.
Physical Examination
X
A full physical examination to be performed within 72 hours prior to C1D1. 
Height
X
Weight
X
To be performed within 72 hours prior to C1D1
Vital Signs
X
To be performed within 72 hours prior to C1D1, including temperature, pulse, respiratory rate, and blood pressure.
ECOG Performance Status
X
To be performed within 72 hours prior to C1D1.
12-Lead Electrocardiogram
X
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PRODUCT: V938
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PROTOCOL/AMENDMENT NO.: 001-08
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Study Period
Screening
Notes
Visit Days
-28 to -1
Adverse Event Monitoring
X
All adverse events 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 hours prior to C1D1 with exception of thyroid and hepatitis 
testing. 
Participants on anticoagulant therapy should be monitored throughout the study.
Thyroid function: Total T4 and T3 are preferred over FT4 and FT3.
Chemistry Panel
X
PT/INR and PTT or aPTT
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
Urinalysis
X
Pregnancy Test for WOCBP Only 
(Urine or Serum hCG)
X
To be performed within 72 hours 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. See country-specific information in Appendix 7.
HIV, Hepatitis B and C Screen (per site 
SOP)
X
Acceptable to be based on history unless testing is required by local regulation. See country-specific requirements in 
Appendix 7.
Laboratory Procedures/Assessments -Central
Tumor Tissue for Biomarker Analysis
X
Dose-escalation Cohorts 2a, 3a, 4a and expansion cohorts only. Must be performed for 1 planned injected lesion only 
after participant is deemed eligible for enrollment based on all other eligibility requirements. Optional biopsy from
planned noninjected tumor lesion should also be collected if possible. Lesions for baseline biopsies should be clearly 
recorded so the on-treatment tumor biopsies could be taken from the same tumor lesion (respectively) if possible.
89Zr-Df-IAB22M2C CD8 Tracer PET 
Imaging Evaluation (Expansion Cohorts
Only)
X
For participants in the CD8 tracer PET imaging study in Part II ONLY at selected sites in the US. One to 4 days prior 
to tumor biopsy, participants will be injected with CD8 tracer and will return for CD8 tracer PET imaging 24 h (±3 h) 
and again (optional) 6 days (±1 day) later. This activity will only occur once the participant has been deemed eligible 
for enrollment based on all other criteria.
Optional 24-hour Observation Period for 
CD8 Tracer PET Imaging Evaluation 
(Expansion Cohorts Only)
X
A 24-hour observation period following PET tracer infusion is optional. The conduct of this observation will be at the 
discretion of the investigator.
Abbreviations: aPTT=activated partial thromboplastin time; BRAF=proto-oncogene B-rapidly accelerated fibrosarcoma; BRCA=breast cancer gene; C=Cycle; CBC=complete 
blood count; CD=cluster of differentiation; CT=computed tomography;; D=Day; ECOG=Eastern Cooperative Oncology Group; FT3=free triiodothyronine; FT4= free thyroxine;
HBsAG=Hepatitis B surface antigen; HCV=hepatitis C virus; HNSCC=head and neck squamous cell carcinoma; hCG=human chorionic gonadotropin; ICF=Informed Consent 
Form; INR=International Normalized Ratio; iRECIST=modified RECIST 1.1 for immune-based therapeutics; IT=intratumoral; KIT=KIT proto-oncogene; KRAS=Kirsten ras 
oncogene homolog; MMR=mismatch repair; MRI=magnetic resonance imaging; MSI=microsatellite instable; NASBA = nucleic acid sequence based amplification; 
PCR = polymerase chain reaction; NRAS=neuroblastoma ras oncogene homolog; PD-L1=programmed cell death ligand 1; PIK3CA=phosphatidylinositol-4,5-bisphosphate 3-
kinase cancer gene; 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; TP53=tumor protein p53; TSH=thyroid-stimulating hormone; WOCBP=women of childbearing potential.
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PRODUCT: V938
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1.3.2
Schedule of Activities for the Treatment Period
Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2-7
Cycles ≥8
For all cycles: Up to 35 cycles of pembrolizumab 
and up to 7 cycles (ie, 10 doses) of V938. All cycles 
are 21 days.
For Cycle 2 and 3, D8 and D15 visits including 
safety assessments can be omitted if V938 is not 
dosed for that cycle due to interruption or 
discontinuation.
Visit Day (Days)
1
3
5
8
1
8
(Cycles
2-3 only)
15
(Cycles
2-3 only)
1
Visit Window
+1
±1
±1
±1
+3
±3
±3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Pembrolizumab Administration
Cohorts 1, 2, 3, and 4
X
X
For the first 3 doses of V938 (C1D1, C1D3, and 
C1D5), time of administration between 2 doses must 
be at least 24 hours apart.
On visits when both V938 and pembrolizumab are 
administered, V938 IT injection will be 
administered prior to pembrolizumab IV infusion.
See Pharmacy Manual for more details.
Pembrolizumab Administration
Cohorts 2a, 3a, or 4a; and the Expansion
Cohorts
X
X
X
V938 Administration
X
X
X
X
X
24-hour Observation Period 
X
X
For Dose-escalation Cohorts, a 24-hour inpatient 
observation period following V938 administration 
on C1D1 and C1D3 is required for each participant. 
Observation for the remaining V938 doses will be at 
the discretion of the investigator, per local 
Institutional Review Board, Ethics Review 
Committee, and/or Health Authority mandate. 
For Expansion Cohorts, the requirement for 24-
hour inpatient observation for the first 2 doses may
be optional based on the updated safety profile.
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PRODUCT: V938
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Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2-7
Cycles ≥8
For all cycles: Up to 35 cycles of pembrolizumab 
and up to 7 cycles (ie, 10 doses) of V938. All cycles 
are 21 days.
For Cycle 2 and 3, D8 and D15 visits including 
safety assessments can be omitted if V938 is not 
dosed for that cycle due to interruption or 
discontinuation.
Visit Day (Days)
1
3
5
8
1
8
(Cycles
2-3 only)
15
(Cycles
2-3 only)
1
Visit Window
+1
±1
±1
±1
+3
±3
±3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1, iRECIST, 
and/or itRECIST Response Assessment
Tumor imaging (CT or MRI) for solid tumors and 
medical photography of cutaneous lesions should be 
performed every 9 weeks (± 7 days) after the first 
dose for the first 54 weeks then every 12 weeks 
thereafter, following calendar days, and should not 
be adjusted for delays in cycle starts. Continue 
imaging schedule until disease progression, 
discontinuation, or the start of anticancer treatment  
Please refer to Imaging Manual for detailed 
information on medical photography.
Medical Photography 
(Cutaneous Lesions)
Lesion Injection Scan
Obtain for all injected lesions for every IT injection 
performed. If imaging is used to guide injection (eg, 
CT, ultrasound, fluoroscopy), capture images to 
document injected lesions. If injection by 
visualization or palpation, it is recommended to 
capture photographs with skin markers to show 
injected lesions.
Physical Examination
X
X
X
X
X
X
X
Directed physical examinations to be performed 
unless a full examination is deemed necessary. To 
be performed on Days 3, 5, and 8 of Cycle 1; on 
Days 1, 8, and 15 of Cycle 2, and on Day 1 of every 
cycle thereafter.
Weight
X
X
X
Every other cycle (ie, Cycles 1, 3, 5, 7, 9, etc.).
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PRODUCT: V938
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25-MAY-2022
Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2-7
Cycles ≥8
For all cycles: Up to 35 cycles of pembrolizumab 
and up to 7 cycles (ie, 10 doses) of V938. All cycles 
are 21 days.
For Cycle 2 and 3, D8 and D15 visits including 
safety assessments can be omitted if V938 is not 
dosed for that cycle due to interruption or 
discontinuation.
Visit Day (Days)
1
3
5
8
1
8
(Cycles
2-3 only)
15
(Cycles
2-3 only)
1
Visit Window
+1
±1
±1
±1
+3
±3
±3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Vital Signs *
(temperature, pulse, respiratory rate,
and blood pressure)
X
X
X
X
X
X
X
X
For Cycle 1, to be measured within 1 h prior to 
dosing, and 2, 4, and 6 hours (± 30 min for each 
timepoint) after V938 administration in Cycle 1. 
For Cycle 2 to Cycle 7, to be measured within 1 h 
prior to dosing, and 2 and 4 hours (± 30 min for 
each timepoint) after V938 administration. 
In addition, for Cycles 2 and 3, to be measured on 
Day 8 and Day 15. 
For Cycle 8 and beyond, to be measured within 1 h 
prior to each dosing with pembrolizumab.
* For participants who interrupt or discontinue V938 
but continue pembrolizumab, to be measured within 
1 h prior to dosing with pembrolizumab.
ECOG Performance Status
X
X
ECOG PS may be performed up to 72 hours prior to 
dosing. 
Concomitant Medication
X
X
X
X
X
X
X
X
Adverse Events
Continuous AE reporting from the time of treatment 
allocation.
Survival Status
Upon Sponsor request, participants may be 
contacted for survival status at any time during the 
course of the study.
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PRODUCT: V938
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25-MAY-2022
Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2-7
Cycles ≥8
For all cycles: Up to 35 cycles of pembrolizumab 
and up to 7 cycles (ie, 10 doses) of V938. All cycles 
are 21 days.
For Cycle 2 and 3, D8 and D15 visits including 
safety assessments can be omitted if V938 is not 
dosed for that cycle due to interruption or 
discontinuation.
Visit Day (Days)
1
3
5
8
1
8
(Cycles
2-3 only)
15
(Cycles
2-3 only)
1
Visit Window
+1
±1
±1
±1
+3
±3
±3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Laboratory Procedures/Assessments – LOCAL
CBC with Differential
X
X
X
X
X
Perform all scheduled clinical laboratory tests 
(chemistry and hematology) within 72 hours prior 
to the start of each new cycle.
For PT/INR/PTT/aPTT: Only as clinically 
indicated Participants on anticoagulant therapy
should be monitored throughout the study. 
Thyroid function: After Cycle 1, samples are 
collected every other cycle (ie, Cycles 2, 4, 6, 
etc.). Total T4 and T3 are preferred over FT4 and 
FT3.
Chemistry Panel
X
X
X
X
X
PT/INR and PTT or aPTT
X
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
X
Urinalysis
X
X
Pregnancy test for WOCBP only (urine 
or serum hCG)
X
Perform within 72 hours 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. See 
country-specific information in Appendix 7.
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PRODUCT: V938
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25-MAY-2022
Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2-7
Cycles ≥8
For all cycles: Up to 35 cycles of pembrolizumab 
and up to 7 cycles (ie, 10 doses) of V938. All cycles 
are 21 days.
For Cycle 2 and 3, D8 and D15 visits including 
safety assessments can be omitted if V938 is not 
dosed for that cycle due to interruption or 
discontinuation.
Visit Day (Days)
1
3
5
8
1
8
(Cycles
2-3 only)
15
(Cycles
2-3 only)
1
Visit Window
+1
±1
±1
±1
+3
±3
±3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Laboratory Procedures/Assessments – CENTRAL
NDV RNA (V938 PK) 
X
X
X
X
X *
X
Collect blood for all required timepoints.
Collect predose samples 0-24 h before V938 
administration on C1D1, C1D3, C1D5, C1D8, 
C2D1, C3D1, C5D1, and predose samples 0-24 h 
before pembrolizumab administration on C8D1.
Collect postdose samples C1D1, C1D8, C2D1 at 2, 
4, and 6 h postdose. For C3D1, collect 1 sample 
between 2 to 4 h postdose. The sample window 
preference is ± 15 min.
* For participants who discontinue V938 
prematurely, collect sample an additional 30 days 
(±7 days) after the last dose of V938. This can be 
collected at the next cycle of pembrolizumab dosing 
if pembrolizumab continues or collected at 
termination/end-of-study and safety follow-up.
Pembrolizumab PK (Cohort 1-4)
X
X
Collect predose samples 0-24 h before 
pembrolizumab administration on C2D1, C3D1, 
C5D1, C8D1, and every 4 cycles thereafter.
Additional postdose samples will be collected at 
termination/end-of-study and safety follow-up.
Pembrolizumab PK (Cohort 2a, 3a, or 4a; 
and Expansion Cohorts)
X
X
X
Collect predose samples 0-24 h before 
pembrolizumab administration on C1D1, C2D1, 
C3D1, C5D1, C8D1, and every 4 cycles thereafter.
Additional postdose samples will be collected at 
termination/end-of-study and safety follow-up.
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Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2-7
Cycles ≥8
For all cycles: Up to 35 cycles of pembrolizumab 
and up to 7 cycles (ie, 10 doses) of V938. All cycles 
are 21 days.
For Cycle 2 and 3, D8 and D15 visits including 
safety assessments can be omitted if V938 is not 
dosed for that cycle due to interruption or 
discontinuation.
Visit Day (Days)
1
3
5
8
1
8
(Cycles
2-3 only)
15
(Cycles
2-3 only)
1
Visit Window
+1
±1
±1
±1
+3
±3
±3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Neutralizing V938 antibodies
X
X
X *
X *
Collect predose samples for each time point: 0-24 h 
before V938 administration on C1D1, C1D8, C2D1, 
C3D1, C5D1, and predose samples 0 to 24 h before 
pembrolizumab administration on C8D1.
* For participants who discontinue V938 
prematurely, collect additional samples 30 days 
(±7 days) and 60 days (±7 days) after the last dose 
of V938. 

If pembrolizumab is continued after the last 
dose of V938, neutralizing V938 antibody 
samples can be collected at the next 
3 pembrolizumab treatment cycles 
(ie, approximately 21, 42, and 64 days after 
the last dose of V938).
Anti-IL-12 antibodies
X
X
X *
X *
Collect predose samples for each time point: 0-24 h 
before V938 administration on C1D1, C1D8, C2D1, 
C3D1, C5D1, and predose samples 0-24 h before 
pembrolizumab administration on C8D1.
* For participants who discontinue V938 
prematurely, collect additional samples 30 days 
(±7 days) and 60 days (±7 days) after the last dose 
of V938. 

If pembrolizumab is continued after the last 
dose of V938, anti-IL-12 antibody samples 
can be collected at the next 3 pembrolizumab 
treatment cycles (ie, approximately 21, 42, and 
64 days after the last dose of V938).
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Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2-7
Cycles ≥8
For all cycles: Up to 35 cycles of pembrolizumab 
and up to 7 cycles (ie, 10 doses) of V938. All cycles 
are 21 days.
For Cycle 2 and 3, D8 and D15 visits including 
safety assessments can be omitted if V938 is not 
dosed for that cycle due to interruption or 
discontinuation.
Visit Day (Days)
1
3
5
8
1
8
(Cycles
2-3 only)
15
(Cycles
2-3 only)
1
Visit Window
+1
±1
±1
±1
+3
±3
±3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Anti-pembrolizumab antibodies
(Cohort 1-4)
X
X
Collect predose samples 0-24 h before 
pembrolizumab administration C2D1, C3D1, C5D1,
and C8D1.
Additional postdose samples will be collected at 
termination/end-of-study and safety follow-up.
Anti-pembrolizumab antibodies 
(Cohort 2a, 3a, or 4a; and 
Expansion Cohort)
X
X
X
Collect predose samples 0-24 h before 
pembrolizumab administration C1D1, C2D1, C3D1, 
C5D1, and C8D1.
Additional postdose samples will be collected at 
termination/end-of-study and safety follow-up.
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Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2-7
Cycles ≥8
For all cycles: Up to 35 cycles of pembrolizumab 
and up to 7 cycles (ie, 10 doses) of V938. All cycles 
are 21 days.
For Cycle 2 and 3, D8 and D15 visits including 
safety assessments can be omitted if V938 is not 
dosed for that cycle due to interruption or 
discontinuation.
Visit Day (Days)
1
3
5
8
1
8
(Cycles
2-3 only)
15
(Cycles
2-3 only)
1
Visit Window
+1
±1
±1
±1
+3
±3
±3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Shedding Analysis 1 (NDV by PCR)
X
X
X
X *
X *
Collect samples from each: oral cavity/throat, urine, 
injection site, and anal swab.
Collect predose samples 0-24 h prior to V938 on
C1D1, C1D3, C1D8, C3D1, C5D1 and predose
samples 0-24 h before pembrolizumab
administration on C8D1.
Collect postdose samples on C1D1 at 2 and 4-6 h
post dose. The sample window preference is 
± 15 min. 
* For participants who discontinue V938 
prematurely, collect shedding samples 
30 days (±7 days) and 60 days (±7 days) after the 
last dose of V938.

If pembrolizumab is continued after the last 
dose of V938, post V938 shedding samples 
can be collected at the next 3 pembrolizumab 
treatment cycles (ie, approximately 21, 42, and 
64 days after the last dose of V938).
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Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2-7
Cycles ≥8
For all cycles: Up to 35 cycles of pembrolizumab 
and up to 7 cycles (ie, 10 doses) of V938. All cycles 
are 21 days.
For Cycle 2 and 3, D8 and D15 visits including 
safety assessments can be omitted if V938 is not 
dosed for that cycle due to interruption or 
discontinuation.
Visit Day (Days)
1
3
5
8
1
8
(Cycles
2-3 only)
15
(Cycles
2-3 only)
1
Visit Window
+1
±1
±1
±1
+3
±3
±3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Shedding Analysis 2 (NDV Infectivity)
X
X
X
X *
X *
Collect samples from each: oral cavity/throat, urine, 
injection site, and anal swab.
Collect predose samples at 0-24 h prior to V938 on
C1D1, C1D3, C1D8, C3D1, C5D1 and predose
samples 0-24 h before pembrolizumab
administration on C8D1.
* For participants who discontinue V938 
prematurely, collect shedding samples 30 days (±7 
days) and 60 days (±7 days) after the last dose of 
V938.
•
If pembrolizumab is continued after the last 
dose of V938, post V938 shedding samples 
can be collected at the next 3 pembrolizumab 
treatment cycles (ie, approximately 21, 42, and 
64 days after the last dose of V938).
Collect postdose samples on C1D1 at 2 and 4-6 h 
post dose. The sample window preference is 
± 15 min. 
Blood for RNA Biomarker Analyses
X
X
X
X
Collect blood for RNA biomarker analyses -4 to 0 h 
predose, and 4-8 h postdose of V938 administration 
on C1D1, C1D3, C1D8, C2D1, and C3D1.
Serum for Cytokine/Chemokine 
Analyses
X
X
X
X
X
For dose escalation phase, collect blood samples -4 
to 0 h predose and at 2 h (±15 min), 4 h (±15 min), 
and 6 h (±15 min), postdose of V938 administration 
on C1D1, C1D3, C1D8, C2D1, and C3D1.Collect 
blood samples at predose and 2 h (±15 min) 
postdose of V938 administration on C4D1, C5D1,
C6D1, and C7D1.
If V938 is discontinued prematurely, samples will 
not be collected after V938 discontinuation.
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Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2-7
Cycles ≥8
For all cycles: Up to 35 cycles of pembrolizumab 
and up to 7 cycles (ie, 10 doses) of V938. All cycles 
are 21 days.
For Cycle 2 and 3, D8 and D15 visits including 
safety assessments can be omitted if V938 is not 
dosed for that cycle due to interruption or 
discontinuation.
Visit Day (Days)
1
3
5
8
1
8
(Cycles
2-3 only)
15
(Cycles
2-3 only)
1
Visit Window
+1
±1
±1
±1
+3
±3
±3
±3
The visit window is +3 days for C2D1 and 
±3 days for Day 1 of subsequent cycles.
Blood for Genetic Analyses
X
Collect prior to treatment on C1D1.
Tumor Tissue for Biomarker Analysis 
X
Dose escalation 2a, 3a, 4a, and cohort expansion 
phases only. Required within 10 days  prior to C3D1 
in 1 planned injected lesion. Optional biopsy of
1 planned noninjected lesion 10 days  prior to 
C3D1. Biopsy should be taken from the same tumor 
lesion(s) for baseline biopsies, respectively, if 
possible. Instructions for tissue collection, 
processing, and shipment are provided in the 
Laboratory Procedures Manual.
89Zr-Df-IAB22M2C CD8 Tracer PET 
Imaging Evaluation (Cohort Expansion
Phase Only)
X
For participants in the CD8 tracer PET imaging 
study conducted ONLY at selected sites in the US. 
One to 10 days prior to tumor biopsy, participants 
will be injected with PET tracer and return for CD8 
tracer PET imaging 24 h (± 3 h) and (optional) 
6 days (± 1 day) later.
Optional 24-hour Observation Period for 
CD8 Tracer PET Imaging Evaluation 
(Cohort Expansion Only)
X
A 24-hour observation period following CD8 tracer 
infusion is optional.  The conduct of this observation 
will be at the discretion of the investigator.
Abbreviations: aPTT=activated partial thromboplastin time; C = Cycle; CBC = complete blood count; CT = computed tomography; D = Day; ECOG = Eastern Cooperative 
Oncology Group; FT3 = free triiodothyronine; FT4 = free thyroxine; hCG = human chorionic gonadotropin; IL-12 = interleukin 12; INR = International Normalized Ratio; 
iRECIST = modified RECIST 1.1 for immune-based therapeutics; IT = intratumoral; MRI = magnetic resonance imaging; NDV = Newcastle Disease Virus; PCR = polymerase 
chain reaction; PK = pharmacokinetic(s); PT = prothrombin time; PTT = partial thromboplastin time; RECIST 1.1 = Response Evaluation Criteria in Solid Tumors, version 1.1; 
RNA = ribonucleic acid; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
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1.3.3
Schedule of Activities for the End-of-Treatment and Posttreatment Follow-up Periods
Study Period
End of 
Treatment 
(EOT)/ 
Discontinuation
Posttreatment Period
Notes
30-Day 
Safety 
Follow-up 
Visit
Imaging 
Follow-up
Survival 
Follow-up
Visit Timing
30 days 
after the
last dose
Approxi-
mately 
every 
9 weeks
Approxi-
mately 
every 
12 weeks
Visit Window (Days)
±7
+7
±7
±14
Administrative Procedures
Concomitant Medication
X
X
Efficacy Procedures
See Imaging Manual – All imaging visits have a ± 7-day 
window
Tumor Imaging, RECIST 1.1 and iRECIST 
Response Assessment 
X
X
Medical Photography (Cutaneous Lesions) 
X
X
New Anticancer Therapy Status
X
X
X
Survival Status Monitoring
Upon Sponsor request, participants may be contacted 
for survival status at any time during the course of the 
study. After confirmed disease progression, each 
participant will be contacted by telephone for survival 
until participant withdrawal of consent, becoming lost 
to follow-up, death, or the end of the study.
Safety Assessments and Procedures
See Laboratory Procedures Manual for collection 
and management of samples.
Adverse Event Monitoring
X
X
Full Physical Examination 
X
X
Weight
X
X
Vital Signs
X
X
Temperature, pulse, respiratory rate, and blood pressure
ECOG Performance Status 
X
X
CBC with Differential 
X
X
Chemistry Panel 
X
X
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Study Period
End of 
Treatment 
(EOT)/ 
Discontinuation
Posttreatment Period
Notes
30-Day 
Safety 
Follow-up 
Visit
Imaging 
Follow-up
Survival 
Follow-up
Visit Timing
30 days 
after the
last dose
Approxi-
mately 
every 
9 weeks
Approxi-
mately 
every 
12 weeks
Visit Window (Days)
±7
+7
±7
±14
Pregnancy Test for WOCBP – Urine or Serum 
hCG
X
For WOCBP, perform every 30 days during a 120-day 
period following last dose, and as required locally. If a 
urine pregnancy test cannot be confirmed as negative, a 
serum pregnancy test is required. 
Thyroid Function (TSH, T3, FT3, T4, FT4) 
X
Abbreviations: CBC = complete blood count; CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FT3 = free triiodothyronine; 
FT4 = free thyroxine; hCG = human chorionic gonadotropin; MRI = magnetic resonance imaging; NDV = Newcastle Disease Virus; PET = positron emission tomography; 
PK = pharmacokinetic(s); RNA = ribonucleic acid; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors, version 1.1; iRECIST = immune-related RECIST; RNA = 
ribonucleic acid; T3 = triiodothyronine; T4 = thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
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2
INTRODUCTION
Significant progress has been made in the field of immunotherapy to treat cancer. Antibodies 
targeting immune checkpoints have yielded impressive improvements in clinical outcomes 
for a range of tumor types. Despite this however, the majority of advanced cancer patients do 
not respond to immunotherapy alone, due to local immune tolerance at the tumor, absence of 
effector cells, and/or the development of resistance through a variety of adaptive mechanisms
[Park, Y. J., et al 2018] [Sharma, P., et al 2017]. V938 is a novel oncolytic viral therapy that 
employs recombinant NDV engineered to encode human IL-12, being developed for 
IT/intralesional injection to treat advanced cancers.
This is a Phase 1 FIH study to assess the safety, tolerability, and PK/pharmacodynamics of 
V938 in combination with pembrolizumab for the treatment of advanced solid tumors.
2.1
Study Rationale
There is a great unmet medical need for therapeutic agents that can enhance the effect of 
immunotherapy. In preclinical studies, IT V938 was shown to overcome tumor resistance to 
immunotherapy via multiple mechanisms including activation of natural killer cells, 
cytotoxic CD8+ T cells, T cells that produce type 1 cytokines, and B cells [Trinchieri, G. 
2003]. NDV is a potent inducer of immunogenic cell death [Cuadrado-Castano, S., et al 
2015] and can induce type 1 IFN responses that trigger both innate and adaptive immune 
activations [Fournier, P., et al 2012] [Fernandez-Sesma, A., et al 2006]. The key potential 
advantage of NDV over other strategies that induce a type 1 IFN antitumor response is that in 
addition to induction of IFN-α by immune cells, NDV induces immune-cell death of infected 
tumor cells that results in release of cytokines, chemokines, and viral RNA that is recognized 
by immune cells. Finally, in preclinical studies in tumor-bearing mice, NDV armed with 
IL-12 in combination with muDX400 (mouse anti-programmed cell death ligand 1) resulted 
in the longest median OS compared with other treatment groups.
The empirical rationale for combining V938 with anti-PD-1 is based on the data from 
experiments in anti-PD-1-resistant syngeneic mouse tumor models that recapitulate many 
attributes of the proposed patient population. In these models, the combination of 
NDV-IL-12 with anti-PD-1 monotherapy resulted in significant reduction in tumor volumes 
in both injected and noninjected tumors, including complete regressions in 6 of 10 injected 
and 5 out of 10 noninjected tumors, demonstrating how NDV breaks resistance to immune 
checkpoint blockade. For further details, please refer to the V938 IB. The development plan 
is to evaluate V938 in combination with KEYTRUDA® (pembrolizumab) to improve 
efficacy over pembrolizumab alone. At the current time, as the preclinical studies most 
strongly support combination treatment, there are no plans to develop V938 as monotherapy 
treatment.
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NDV possesses a number of potential immunological and safety advantages relative to other 
oncolytic agents. A summary of the immunological advantages of NDV relative to other 
DNA viruses (eg, adenovirus and herpesvirus) and other RNA viruses (eg, coxsackievirus) 
follows [Schirrmacher, V. 2016]:

NDV is an avian pathogen and serology studies indicate that approximately 96% of the 
human population is seronegative. This circumvents the problem of pre-existing human 
immunity and pathogenicity [Miller, L. T. 1971] [Charan, S., et al 1981]. Both pre-
existing immunity and pathogenicity are identified problems for vaccinia, herpes simplex 
virus (HSV)-1, adenovirus, and measles vectors.

NDV possesses strong immune-stimulatory properties through induction of type 1 IFN 
and chemokines, upregulation of major histocompatibility complex and cell adhesion 
molecules, and facilitation of adhesion of lymphocytes and antigen-presenting cells 
through expression of viral glycoproteins on the surface of infected cells [Washburn, B. 
2002]. These properties have been shown to generate effective antitumor immune 
responses, which may persist long after clearance of viral infection. In addition, by 
induction of secretion of proinflammatory cytokines and chemokines from tumor cells 
themselves, NDV potentially can convert a “cold” tumor to “hot” by recruitment of 
mediators of innate and immune responses such as NK cells, lymphocytes, and 
macrophages.

The NDV genome allows for “arming” via the incorporation and stable expression of 
foreign genes of relatively large size. NDV, with a 15 kb genome and a diameter of 100
to 500 nm, has the capacity to encode one or more transgenes [DiNapoli, J. M., et al 
2007]. This contrasts with other RNA viruses such as the picornaviruses Coxsackie, 
Seneca Valley, and Polio which are ~30 nm in diameter and do not have the capacity to 
stably encode a transgene.

The ubiquitous nature of the NDV receptor allows for utilization of the virus against a 
wide variety of cancers. The specificity of the virus for cancer cells due to their defects or 
hyporesponsiveness in antiviral and apoptotic pathways ensures viral safety and may 
obviate the need for specific tumor targeting.
Several characteristics suggest that NDV will offer potential safety advantages relative to 
other oncolytic agents currently licensed or in development:

Lack of integration with host cell DNA. NDV is an RNA virus that replicates in the 
cytoplasm. It lacks any form of a DNA intermediate; therefore, there is no possibility of 
integration of the virus in the host genome.

Mild side effects in cancer patients. The reported side effects with NDV administration 
(nonsystemic formulations) in cancer patients in various studies were Grade 1 and 2.

Replication of NDV is sensitive to IFN-based inhibition of replication; therefore, NDV is 
less likely to replicate permissively in nontumor cells/tissues in patients.
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
The LaSota strain is nonpathogenic for its natural host (avian species) and humans; 
therefore, it exhibits enhanced safety over pathogenic strains by limiting the production 
of infectious virus progeny in treated patients. The replicative capacity of NDV is 
dependent on proteolytic conversion of the prefusion protein F0 to its active F form. This 
is governed by the sequence of amino acids that constitute the cleavage site. Virulent 
velogenic and mesogenic strains contain a double-basic (B) amino acid sequence of the 
general form BB-X-Q-X-BB, which permits cleavage of the F protein by intracellular 
proteases during F protein secretion/maturation in the infected cell as the protein 
traverses through the Golgi network. An enzyme in the trans Golgi, furin, cleaves and 
thereby activates the fusion property of the F protein. The amino acid sequence of the 
LaSota F protein at the cleavage activation site is not recognized as a furin substrate; 
therefore, virions are produced that are not infectious unless extracellular proteases 
activate them. Lentogenic viruses are propagated in embryonated eggs via activation of 
the F protein by a protease present in the allantoic fluid. Replication of lentogenic viruses 
will be self-limited in patients because although the viruses will replicate in tumor cells 
and produce viral progeny; the new virions will not be infectious due to the lack of 
cleavage of the F protein by cellular proteases [Panda, A., et al 2004].
The selection of IL-12 for the arming strategy may offer a potential advantage to improve on 
efficacy over T-VEC and MEDI5395, which both encode for GM-CSF. Emerging clinical 
data with Oncosec’s ImmunoPulse® IL-12 show abscopal effects as monotherapy and in 
combination with pembrolizumab in patients with melanoma (EUROGIN 2016, ASCO-SITC 
2017, and Keystone Symposium Conference “Cancer Immunology and Immunotherapy: 
Taking a Place in Mainstream Oncology” 2017). The effects of IL-12 include stimulation of 
CD8 and CD4 T cell proliferation and effector activity, differentiation of naïve T cells 
toward a TH1 phenotype, induction of IFN-γ, and potentiation of IL-2 signaling [Gately, M. 
K., et al 1998]. Preclinical studies showed that expression of IL-12, and not GM-CSF, 
enhanced the antitumor activity of a recombinant oncolytic HSV-1/2 virus in syngeneic 
mouse prostate tumor models [Varghese, S., et al 2006]. PD-1 blockade by pembrolizumab 
can show a protective effect on newly generated immune cell effectors in the tumor 
microenvironment and prevent inhibition of immune response (refer to the V938 IB). 
Therefore, a combination of the 2 treatment strategies can potentially enhance an antitumor 
response.
For preapproved study sites in the US only, a CD8 tracer PET imaging study will be 
performed to assess the CD8 tracer 89Zr-Df-IAB22M2C. The ability to visualize CD8+ 
T cells in vivo before and after treatment would be highly valuable for the development of 
immuno-oncology treatments, and such a method has been unavailable. 89Zr-Df-IAB22M2C 
has been developed by ImaginAb for imaging CD8+ T cells in humans. ImaginAb’s initial 
clinical evaluation of 89Zr-Df-IAB22M2C demonstrated favorable properties for clinical use 
and the potential targeting of CD8+ T cells [Pandit-Taskar, N., et al 2016]. The CD8 tracer 
PET imaging study will evaluate the quantitative accuracy of 89Zr-Df-IAB22M2C for 
measuring CD8+ T cells in tumors by establishing the relationship of 89Zr-Df-IAB22M2C 
accumulation in tumors with CD8+ TIL density measured by IHC following tumor biopsy. 
The goal of this study is to establish best practices for further development of 89Zr-Df-
IAB22M2C within the Sponsor’s immuno-oncology studies.
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This Phase 1/1b multicenter, open-label, study will evaluate the safety, tolerability, and 
preliminary antitumor activity of V938 via IT injection in combination with pembrolizumab 
IV in participants with advanced or recurrent solid tumors.
The study will be performed in compliance with the protocol, ICH, GCP, and local 
regulatory requirements. Aspects of the study concerned with manufacture and labeling of 
V938 will meet the requirements of GMP.
2.2
Background
Refer to the V938 IB for detailed background information on V938 and to the 
pembrolizumab IB for detailed background information on pembrolizumab. This is an
FIH study.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
V938 Pharmaceutical and Therapeutic Background
The virus was assembled in and rescued from baby hamster kidney cells and subsequently 
propagated in embryonated chicken eggs. A fit-for-purpose production and purification 
process suitable for GMP manufacture has been developed for Phase 1. Refer to the V938 IB 
for further information.
2.2.1.2
Mechanism of Action
NDV is an enveloped, nonsegmented, negative-sense single-stranded RNA avian virus of the 
Paramyxoviridae family [Lamb, R. A. 2013]. The NDV genome allows for “arming” via the 
incorporation and stable expression of foreign genes of relatively large size [DiNapoli, J. M., 
et al 2007], allowing for the selection of human IL-12 for our arming strategy. This arming 
strategy may offer a potential advantage to improve efficacy over other oncolytic virus 
strategies, such as those that encode GM-CSF, due to its enhanced antitumor activity
[Varghese, S., et al 2006] [Choi, K. J., et al 2012]. Preclinical data support the combination 
of IT administration of V938 with an anti-PD 1 monoclonal antibody. This combination is 
hypothesized to have activity against a wide spectrum of malignancies in vivo, including the 
noninflamed cold tumors for which anti-PD-1 monotherapy has demonstrated limited 
efficacy. The key properties of NDV are tumor-selective replication and lysis and 
immunostimulatory activities. Induction of secretion of proinflammatory cytokines and 
chemokines from tumor cells potentially can convert a “cold” tumor to “hot” by recruiting 
NK cells, lymphocytes, and macrophages into the tumor.
2.2.1.3
Preclinical Studies of V938
Please refer to the V938 IB for a description of preclinical evaluations of V938.
2.2.1.4
Pembrolizumab Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
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shows a correlation between tumor infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T cells and the ratio 
of CD8+ effector T cells/FoxP3+ regulatory T cells correlates with improved prognosis and 
long-term survival in patients with solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (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 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]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in solid tumors. Please refer to the current 
pembrolizumab IB for a description of preclinical and clinical evaluations of pembrolizumab.
2.2.2
Information on Other Study-related Therapy
Not applicable.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
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Potential risks associated with the administration of V938 based on nonclinical data and 
mechanism of action may include the following:

Local reactions at the injected tumor site (swelling, induration, erythema)

Transient elevation of white blood cell count

Fevers, chills, headache, flu-like symptoms
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying V938 and pembrolizumab IBs and 
informed consent documents.
2.3.1
Ongoing Clinical Studies
2.3.1.1
V938 Clinical Studies
This is the first clinical study with V938.
2.3.1.2
Pembrolizumab Clinical Studies
Ongoing clinical studies with pembrolizumab are being conducted in multiple solid tumors. 
In addition, multiple combinations with pembrolizumab are also being investigated. Refer to 
pembrolizumab IB for study details.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Throughout this protocol, the term RECIST 1.1 refers to modification to RECIST 1.1 to 
include a maximum of 10 target lesions and a maximum of 5 target lesions per organ. Refer 
to Section 4.2.1.1.1 for further details.
In male/female participants with advanced/metastatic solid tumors:
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Objectives
Endpoints
Primary
Objective: To determine the safety and 
tolerability and to identify a recommended 
Phase 2 dose (RP2D) of V938 administered 
in combination with pembrolizumab
Dose-limiting toxicity (DLT)
Adverse events (AE)
Discontinuing study intervention due to an 
AE
Secondary
Objective: To evaluate the objective 
response rate (ORR), as assessed by the 
investigator, of V938 administered in 
combination with pembrolizumab. 
Assessment will be based on Response 
Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST 1.1) and modified 
RECIST 1.1 for immune-based therapeutics 
(iRECIST).
Objective response is a confirmed complete 
response (CR) or partial response (PR)
Objective: To evaluate the 
pharmacokinetics (PK) of V938 
administered alone and in combination with 
pembrolizumab.
PK parameters of V938, including area under 
the curve (AUC) and maximum concentration 
(Cmax) of Newcastle Disease Virus (NDV) 
RNA
Objective: To assess environmental V938 
shedding
NDV in excretory tissue samples
Tertiary/Exploratory
To evaluate overall survival (OS) and
progression-free survival (PFS) of 
participants treated with V938 in 
combination with pembrolizumab. 
Assessment will be based on RECIST 1.1 
and iRECIST. 
OS is the time from the first dose of study 
treatment to death due to any cause
PFS is the time from the first dose of study 
treatment to the first documented disease 
progression or death due to any cause, 
whichever occurs first
To identify molecular (genomic, metabolic 
and/or proteomic) biomarkers that may be 
indicative of clinical response/resistance, 
safety, pharmacodynamic activity, and/or 
the mechanism of action of V938 in 
combination with pembrolizumab.
Molecular (genomic, metabolic, and/or 
proteomic) determinants of response or 
resistance to treatments, using blood and/or 
tumor tissue.
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Objectives
Endpoints
Objective: To evaluate the PK of 
pembrolizumab administered in combination 
with V938
PK parameters of pembrolizumab including 
minimum concentration (Cmin) and Cmax
To evaluate the development of antidrug and 
neutralizing antibodies, as appropriate, 
following administration of V938 and in 
combination with pembrolizumab
Neutralizing V938, anti-IL-12, and anti-
pembrolizumab antibody levels
To evaluate performance of 
89Zr-Df-IAB22M2C (CD8) PET tracer in 
context of cancer immunotherapy
Standardized uptake value (SUV) from CD8 
PET image
CD8 immunohistochemistry (IHC) score
4
STUDY DESIGN
4.1
Overall Design
This is a FIH, multiarm, multicenter, global, open-label, Phase 1/1b study of V938 in 
combination with pembrolizumab in participants with a histologically confirmed diagnosis of 
an advanced solid tumor.
This study will evaluate the safety, tolerability, PK/pharmacodynamics, and preliminary 
efficacy of V938 in combination with pembrolizumab. Each candidate participant will have a 
screening period of up to 28 days for evaluation of eligibility and performing baseline 
assessments. Each participant must have a minimum of 1 lesion that is either cutaneous, 
subcutaneous, or nodal and is amenable to IT injection.
Eligible participants will start to receive study treatment on C1D1 and have required safety, 
efficacy, and other assessments per SoA (see Section 1.3). 
The study includes a Dose-escalation Phase and a Cohort Expansion Phase. See Figure 1 for 
the study design schema and detailed description of Dose-escalation and Cohort Expansion in 
Section 4.1.1 and Section 4.1.2, respectively.
4.1.1
Dose-escalation Phase
The primary goal for the dose-escalation phase is to evaluate safety, tolerability, and 
PK/pharmacodynamics of V938 as monotherapy and in combination with pembrolizumab, 
with an ultimate goal of determining a RP2D of V938 in combination with pembrolizumab.
V938 IT will be evaluated at 4 dose levels: 1x107 PFU (Dose Level 1, evaluated via Cohort 
1), 1x108 PFU (Dose Level 2, evaluated via Cohort 2 and possibly Cohort 2a), 3x108 PFU 
(Dose Level 3, evaluated via Cohort 3 and Cohort 3a) and 5x108 PFU (Dose Level 4, 
evaluated via Cohort 4 and Cohort 4a). The dosing schedule of V938 is the same across all 
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the cohorts with 4 doses during Cycle 1 on Days 1, Day 3, Day 5, Day 8 and 1 dose each on 
Day 1 of Cycle 2 to Cycle 7. Therefore, V938 will be dosed for a maximum of 10 doses. 
Pembrolizumab will be dosed 200 mg IV Q3W for a maximum of 35 doses (in 
approximately 24 months) across all cohorts. Pembrolizumab dosing will start on C2D1 for 
Cohorts 1-4, which allows to evaluate safety and PK/pharmacodynamics of V938 as 
monotherapy for the first cycle. Pembrolizumab dosing for Cohorts 2a-4a will start on C1D1. 
In general, dose escalation will progress using an mTPI design [Ji Y, Li Y, Bekele BN 2007]
with the goal to identify the MTD and/or maximum administered dose of V938 administered 
as combination with pembrolizumab (Figure 1). Intermediate doses of V938 may also be 
explored with additional cohorts, depending on the combined safety, PK, and 
pharmacodynamics data available at each dose level.
During dose escalation, 3 to 6 participants will be initially enrolled to each dose level starting 
with Cohort 1. Treatment assignments will be nonrandom via an interactive voice response 
system/integrated web response system (IVRS/IWRS). Enrollment at the next dose level will 
begin once all participants in the current dose level complete DLT evaluation and a dose-
escalation decision has been made. The DLT evaluation period for Cohorts 1-4 is 42 days 
(Cycle 1 + Cycle 2) to evaluate safety and PK/pharmacodynamics of 1 cycle of V938 as 
monotherapy and 1 cycle of V938 in combination with pembrolizumab; the DLT evaluation 
period for Cohorts 2a-4a is 21 days (Cycle 1 only) as pembrolizumab and V938 both start on 
C1D1. 
For each participant enrolled to the dose-escalation cohorts, a minimum 24-hour inpatient 
observation period is required (may be longer based on institutional guidance) following 
administration of V938 for the first 2 doses (C1D1 and C1D3). For each new dose cohort, 
initiation of V938 treatment will be staggered by a 7-day period for the first 3 participants at 
that dose level (ie, between the first and the second, and between the second and the third 
enrolled participants).
For Cohorts 2a-4a, each enrolled participant must have at least 1 measurable lesion amenable 
to both IT injection and biopsy. One of the planned injected lesions will undergo (mandatory) 
biopsy during the screening period, once all other eligibility has been confirmed for the 
participant and within 10 days prior to C3D1 dosing. These biopsies (baseline and C3D1 
biopsy for the same injected lesion) are mandatory unless deemed medically unsafe by the 
investigator or the lesion has completely resolved. 
Dose escalation will end after up to 14 participants have been treated at any of the selected 
doses (which may include intermediate or higher dose levels) and the decision based on 
Table 1 is to stay. Dose-finding may also stop prior to enrolling 14 participants in a given 
dose. For example, if there were 0 out of 8 DLTs observed in the highest dose level, then 
even if the next 6 participants experienced a DLT, the decision would still be to stay at the 
highest dose. The pool adjacent violators algorithm [Ji, Y. 2013] will be used to estimate the 
DLT rates across doses. The totality of the data (including safety, PK, pharmacodynamics, 
and efficacy) will be considered before deciding on the RP2D.
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The preferred V938 and pembrolizumab combination schedule is to have both V938 and 
pembrolizumab started on C1D1, hence selection of RP2D will be among Cohorts 2a, 3a, and 
4a. See Section 4.3.3 for details on dosing finding using mTPI design and algorithm for dose 
escalation, stay, or de-escalation decisions for Cohorts 2a-4a. 
4.1.2
Cohort Expansion Phase
Once a RP2D has been selected from Cohorts 2a-4a based on the totality of the data, 
including safety, efficacy, and manufacturing considerations (see Section 4.3), V938 and 
pembrolizumab combination will be further evaluated in the following tumor-specific arms 
for additional safety, preliminary efficacy, and additional PK/pharmacodynamics and 
biomarker data.

Arm A will enroll participants with metastatic melanoma who have received and 
progressed from 1 or 2 prior lines of systemic treatment for metastatic melanoma, which 
must include 1 line of treatment with a PD1 or PD-L1 inhibitor either as monotherapy or 
in combination with other anticancer agents.

Arm B will enroll participants with metastatic HNSCC who have received and progressed 
from 1 or 2 prior lines of systemic treatment for metastatic HNSCC, which must include 
1 line of treatment with a PD1 or PD-L1 inhibitor either as monotherapy or in 
combination with other anticancer agents.
For each arm in the expansion cohorts, an interim analysis will be conducted once there are 
approximately 20 evaluable participants with at least 2 post-treatment tumor assessments
(~18 weeks after start of treatment). For each arm, if there is ≤2 responder among the first 
20 participants enrolled in that arm, the arm may be stopped early for futility. If 3 or more 
responders are observed from an arm, further expansion will be considered (see Section 9.7 
for more details).
The assessments and schedules for the expansion cohorts (Arm A and Arm B) will follow 
that of dose-escalation Cohorts 2a-4a including the requirement for tumor biopsy (see 
Section 1.3 for SoA and Section 4.1.1 for detailed lesion requirement for baseline and 
on-treatment tumor biopsy).
A CD8 tracer PET imaging assessment will be performed at preapproved sites only in the US 
with 7-10 participants. These participants will undergo CD8 tracer PET imaging evaluation 
during the screening period and within 10 days prior to C3D1. At each time point, 
participants will be injected with a dose of 0.5-1.5 mg, or 0.8-1.2 mCi (26-48 MBq) of 
89Zr-Df-IAB22M2C tracer (CD8 tracer) as an IV infusion over 5-10 minutes using a syringe 
pump via a peripheral vein. Participants will return for PET imaging scans, one at 24 hours 
(±3 hours) and an optional second scan at 6 days (±1 day) after tracer infusion. The 
CD8 tracer infusion will occur 1 to 4 days prior to tumor biopsy.
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.
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4.2
Scientific Rationale for Study Design
V938 is an oncolytic virus armed with a human IL-12 transgene that offers potential 
immunological and safety advantages over other oncolytic viruses. V938 is being evaluated 
in a clinical study designed to assess the safety, tolerability, PK, and pharmacodynamics of 
escalating doses of V938 when used in combination with pembrolizumab in participants with 
advanced/refractory solid tumors.
This study exposes a small number of participants to each dose of V938 in combination with 
pembrolizumab and enrolls different participants for each cohort. A low starting dose is used 
to evaluate safety with minimal risk to participants.
All safety and tolerability data will be evaluated before escalating to the next dose level in a 
new cohort.
Tumor response will also be assessed to support the secondary and exploratory objectives of 
the study.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Efficacy endpoints in this study include ORR (secondary endpoint, defined as the proportion 
of participants who have achieved confirmed CR or PR), PFS (exploratory), and 
OS (exploratory).
ORR is a commonly used endpoint in oncology studies to estimate preliminary efficacy and 
used for futility assessments. PFS and OS are also standard endpoints in oncology to further 
evaluate efficacy of tested interventions.
Tumor response in participants with solid tumors will be assessed using RECIST 1.1 and 
iRECIST (see Section 4.2.1.1.1 and Section 4.2.1.1.2) by investigator review. Antitumor 
activity will be measured through such endpoints as the ORR, PFS, and OS, which are 
described further in Section 9.4.1. A central imaging vendor will be used to collect, clean, 
and hold tumor imaging and medical photography from all patients enrolled in the study per 
the collection frequency outlined in the SoA. Images will be collected for possible analysis 
by blinded, independent central review. Instructions for collection and sending images from 
the site to the central vendor will be included in the imaging manual.
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.
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4.2.1.1.2
Response Rate Assessed by Modified Response Evaluation Criteria in 
Solid Tumors 1.1 for Immune-based Therapeutics (iRECIST)
iRECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with pembrolizumab (Section 8.2.7). 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 OS than participants with PD by both criteria [Hodi, 
F. S., et al 2014]. Additionally, the data suggest that RECIST 1.1 may underestimate the 
benefit of pembrolizumab in approximately 15% of participants. These findings support the 
need to apply a modification to RECIST 1.1 that takes into account the unique patterns of 
atypical responses in immunotherapy and enables treatment beyond initial radiographic 
progression, if the participant is clinically stable.
iRECIST assessment has been developed and published by the RECIST Working Group, 
with input from leading experts from industry and academia, along with participation from 
the US Food and Drug Administration and the 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 as well as for secondary 
and tertiary/exploratory efficacy analyses.
For further information on iRECIST, see Section 8.2.7.
4.2.1.2
Safety Endpoints
The primary objective of this study is to characterize the safety and tolerability of V938 in 
combination with pembrolizumab in participants with advanced/ metastatic solid tumors. The 
primary safety analysis will be based on participants who experience toxicities as defined by 
CTCAE Version 4.0 criteria and DLTs further defined in Section 6.6.2. Safety will be 
assessed by quantifying the toxicities and grades of toxicities experienced by participants 
who have received V938 and 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, all AEs, SAEs, fatal AEs, and laboratory changes. Viral 
shedding (including NDV PCR and infectivity) will be analyzed as an additional safety 
endpoint.
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Assessment of safety will be monitored continuously throughout this Phase 1, open-label 
exploratory study. The approach to safety includes ongoing, frequent medical monitoring of 
AEs as they occur with timely and robust discussion around any safety events. SAEs will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up. Additional approaches to safety include: 1) a stepwise 
approach to enrollment with each new dose level requiring a minimum of 3 participants to be 
enrolled and complete the DLT evaluation period before enrollment of additional 
participants, and 2) utilization of a modified toxicity probability interval in the dose-
escalation phase to determine requirements in dose adjustments and as a prerequisite to 
advance to the cohort expansion phase of the protocol. The totality of the data will be 
reviewed before deciding on the dose to carry forward to the cohort expansion phase and 
may be adjusted based on PK and emerging safety data. Additional details regarding medical 
monitoring can be found in Section 10.1.4.1.
4.2.1.3
Pharmacokinetic Endpoints
A secondary objective of this study is to characterize the PK profile of V938 following IT 
administration as a single agent, and to characterize the PK profile of V938 and 
pembrolizumab following administration as combination therapy. The RNA levels of V938 
and the serum concentrations of pembrolizumab will serve as the primary readout for the PK, 
and these data will be used to derive PK parameters (AUC and Cmax of NDV RNA) of the 
agents when administered in combination with pembrolizumab. 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 V938.
4.2.1.4
Pharmacodynamic Endpoints
4.2.1.4.1
Target Engagement
There is no direct target engagement biomarker. Downstream exploratory pharmacodynamic 
biomarkers in tumor tissue and blood will be assessed for pathway activation.
4.2.1.5
Anti-drug Antibodies (ADA)
Antibodies against V938 and pembrolizumab (eg, neutralizing antibodies and ADA) can 
potentially confound drug exposures at therapeutic doses and prime for subsequent infusion-
related toxicity. Immunogenicity will be assessed at the beginning of each cycle. The 
incidence of immunogenicity will be evaluated and summarized over time by dose. 
Correlations between the presence/absence of positivity for immunogenicity and PK and 
pharmacodynamic markers, activity, and safety of V938 will be explored.
4.2.1.6
Serum Cytokines
Because treatment with V938 can result in immune stimulation and resulting potential for 
cytokine release, serum cytokines will be collected to provide supplementary information to 
assist in the evaluation of any safety events.
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4.2.1.7
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome in order to interpret tumor-specific DNA mutations.  Finally, microsatellite 
instability (MSI) may be evaluated as this is an important biomarker for some cancers (ie, 
colorectal cancer).
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Thus, genome-wide approaches may be used for this 
effort. Note that in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer). Circulating tumor 
DNA and/or RNA may also be evaluated from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with pembrolizumab or other immunotherapies. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/immune 
phenotype. Specific immune-related gene sets (ie, those capturing interferon-gamma 
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transcriptional pathways) may be evaluated and new signatures may be identified. Individual 
genes related to the immune system may also be evaluated (eg, IL-10). MicroRNA profiling 
may also be pursued as well as exosomal profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD-L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with pembrolizumab in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to pembrolizumab. Therefore, tumor tissue may be subjected to proteomic 
analyses using a variety of platforms that could include but are not limited to immunoassays 
and liquid chromatography/mass spectrometry. This approach could identify novel protein 
biomarkers that could aid in patient selection for pembrolizumab (MK-3475) therapy.
Other blood-derived biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as enzyme-linked immunoassay 
(ELISA) measure such proteins in serum. Correlation of expression with response to 
pembrolizumab therapy may identify new approaches for predictive biomarkers in blood, 
representing a major advance from today’s reliance on assessing tumor biomarkers. This 
research would serve to develop such assays for future clinical use.
CD8 PET imaging
An experimental CD8 PET tracer (89Zr-Df-IAB22M2C) will be used to assess levels of CD8 
T cells within tumors in a sub-population of the study. The data collected from CD8 PET 
imaging with 89Zr-Df-IAB22M2C will be compared with CD8 IHC in order to establish 
details pertaining to the sensitivity of the imaging agent within tumors.
4.2.1.8
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma), 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
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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.
4.2.2
Rationale for Selection of Expansion Cohorts
PD-1 immune checkpoint inhibitors have demonstrated highly significant improvement in 
clinical efficacy for treating advanced cancers including advanced melanoma and HNSCC, 
either as single agent or in combination with chemotherapy or other immunotherapeutic 
agents and have become the new standard of care for these advanced cancers (NCCN 
guideline v4.2020 for cutaneous melanoma; NCCN guideline v2.2020). However, there are 
still a large proportion of patients who are refractory to the initial anti-PD-1 treatment, 
therefore an area with significant unmet medical need. 
As elaborated in Section 2.1, NDV is a potent inducer of immunogenic cell death that can 
trigger both innate and adaptive immune activations via type I IFN responses. IL-12 is a 
cytokine can elicit strong proinflammatory reactions such as stimulation of CD4 and CD8 
T-cell priming, proliferation, and their effector activity. In the preclinical in vivo studies, 
significant antitumor efficacy was observed with NDV-muIL-12 (murine surrogate of V938) 
in combination with muDX400, a murine anti-PD1, compared to either NDV-muIL-12 or 
muDX400 alone (see V938 IB Section 4). There is a potential that V938 can help overcome 
resistance to PD-1 inhibitor like pembrolizumab in these advanced cancers.
4.3
Justification for Dose
4.3.1
Starting and Maximum Dose of V938 and Rationale
The current projected safe starting clinical dose of V938 is 1 × 107 PFU, which is also 
expected to show clinical response. The dose projection is based on efficacy data from a 
B16F10 mouse bilateral tumor growth inhibition study, and cytokine data from 2 studies: an 
IV dose-ranging kinetic study in CD-1 mice and IT dosing study in tumor-bearing B16F10 
mice. Please refer to V938 IB (Section 4) for details.
To determine the starting dose for the FIH study, the following approaches were used: 
(1) tumor volume normalization for the efficacious dose, and (2) serum cytokine predictions, 
(ie, projected serum levels of IL-12 and IFN-γ following V938 dosing in participants). Using 
both approaches, we predict a safe and efficacious starting dose for V938 to be 1 × 107 PFU 
in a 1 cm3 human tumor.
The NOAEL dose in nonclinical rodent toxicity studies is 3 × 108 PFU given IV, which after 
normalizing to mouse body weight of 0.030 kg is 1 × 1010 PFU/kg. This NOAEL dose is 
60,000-fold higher than the planned starting clinical dose of 1.67 × 105 PFU/kg (1 × 107 PFU
normalized to 60-kg human).
A maximum clinical dose of 1 × 109 PFU is predicted to be safe and efficacious. The rodent
NOAEL dose is 600-fold higher than the planned maximum clinical dose of 
1.67 × 107 PFU/kg (1 × 109 PFU normalized to 60-kg human). This maximum dose is chosen 
based on modeling for safety and efficacy and on manufacturing complexities.
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4.3.2
Rationale for Dose Interval and Escalation Increments
The human starting dose and dosing interval of V938 are based on an integration of 
nonclinical toxicological, pharmacological, and efficacy data. To ensure early and maximum 
treatment effect after IT dosing, V938 will initially have an accelerated every-2-days dosing 
frequency followed by a Q3W dosing frequency matching pembrolizumab dosing frequency. 
The10-fold increment between dose levels 1 and 2, during dose escalation, was chosen to
ensure adequate dose differences based on in vitro activity. The development plan is to 
evaluate V938 in combination with pembrolizumab to improve efficacy over pembrolizumab 
alone. There are no plans to develop V938 as monotherapy treatment. 
Cohorts 1-4 include Cycle 1 as a V938 monotherapy cycle for evaluation of safety, PK, and 
PD of V938 monotherapy before addition of pembrolizumab on C2D1. Cohorts 2a-4a have 
pembrolizumab dosing starts on C1D1 together with V938. This schedule will allow 
PD1/PD-L1 immune checkpoint inhibition to be unleashed within the tumor 
microenvironment and get the immune system ready to respond once immune activities are 
elicited by V938 via local tumor injection. It is expected that initiation of pembrolizumab on 
C1D1 may provide better clinical efficacy than delaying pembrolizumab by 1 cycle. In the 
preclinical in vivo studies using B16F10 mice bilateral tumor model, concurrent combination 
treatment with muDX400 (mice version of PD1 inhibitor) and NDV-muIL-12 showed 
significant survival benefit compared to treatment with either agent alone (see V938 IB 
Section 4).
4.3.3
Dose Finding Using a Modified Toxicity Probability Interval Design
Dose-finding will follow the mTPI design [Ji Y, Li Y, Bekele BN 2007] with a target DLT 
rate of 30%. Dose-escalation and de-escalation decisions are based on the mTPI design and 
depend on the number of participants enrolled and number of DLTs observed at the current 
dose level. The DLT analysis includes only the dose-escalation phase of the protocol.
A minimum of 3 participants are required at each dose level. However, depending on the 
accrual rate, 3, 4, 5, or 6 participants may be enrolled. In Table 1, the columns indicate the 
numbers of participants treated at the current dose level, and the rows indicate the numbers of 
participants experiencing DLT. The entries of the table are the dose-finding decisions: E, S, 
D, and DU represent escalating the dose, staying at the same dose, de-escalating the dose, 
and excluding the dose from the study due to unacceptable toxicity, respectively. For 
example, if 0 of 3 participants at a given dose level develop a DLT, then the dose can 
escalate to the next level. However, if an additional 3 participants were then enrolled at this 
same dose level after initially observing 0 out of 3 DLTs, the dose decision would need to 
wait until the newly enrolled participants complete their DLT assessment. If 2 participants 
out of 3 develop a DLT, the dose will be de-escalated to the next lower dose level. If 3 out of 
3 participants develop a DLT, this indicates an unacceptable toxicity at this dose. The dose 
should be de-escalated, and the current dose will not be explored further. If 1 out of 
3 participants at a given dose level develop a DLT, then additional participants should be 
enrolled at that dose level following the rules below.
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When adding participants to a dose level in response to a “stay” decision, the number of 
additional participants to be enrolled is capped to minimize the exposure to a dose that may 
be unacceptably toxic (denoted as DU in Table 1). Second, to determine how many more 
participants can be enrolled at the dose level, one can count steps in diagonal direction (down 
and to the right) from the current cell to the first cell marked DU. For example, if 
1 of 3 participants have experienced a DLT at a given dose level, no more than an additional 
3 participants should be enrolled at this dose level until additional DLT data are available. 
This is because this dose level would be considered unacceptably toxic if all 3 of the 
additional participants experience a DLT (ie, 4/6 participants with DLT in Table 1). The 
same principles will be applied whether 3, 4, 5, or 6 participants are initially enrolled at that 
dose level.
A D or DU decision at the lowest dose level will stop the study. An E decision at the highest 
dose level will result in staying at that level. During dose-finding, it may be acceptable to 
de-escalate to an intermediate dose that was not predefined and not previously studied if 
evaluation of toxicity at such a dose is desired. If this approach is taken, 3 to 6 new 
participants may be enrolled at the new intermediate dose, and the aforementioned rules 
should be used to determine further enrollment at this dose level.
After 14 participants have been enrolled at any of the tested doses in the dose-escalation 
phase (including intermediate doses), dose-finding will stop if the mTPI table indicates “S” 
for staying at current dose. Otherwise, up to 14 new participants may be enrolled at a lower 
dose if “D” or “DU” is indicated, or at a higher dose if “E” is indicated. Dose-finding may 
also stop prior to enrolling 14 participants in a given dose. For example, if there were 0 out of 
8 DLTs observed in the highest dose level, then even if the next 6 participants experienced a 
DLT, the decision would still be to stay at the highest dose. In this case, dose-finding is 
complete after observing the 0 out of 8 DLTs in the highest dose. 
The pool adjacent violators algorithm [Ji, Y. 2013] will be used to estimate the DLT rates 
across doses. The dose with an estimated DLT rate closest to 30% will be treated as a 
preliminary MTD. However, the totality of the data will be considered before deciding on the 
dose(s) to carry forward to Phase 2, and the escalation schedule may be adjusted based on 
pharmacodynamics, PK, and safety data emerging throughout the study. 
Note that although 30% was the target toxicity rate used to generate the guidelines in
Table 1, the observed rates of participants with DLTs at the MTD may be slightly above or 
below 30%.
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Table 1
Dose-finding Rules per mTPI Design
Number of Participants Evaluable for DLT at Current Dose
Number of participants
with at least 1 DLT
3
4
5
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
D=De-escalate to the next lower dose; DU=The current dose is unacceptably toxic; E=Escalate to the next higher dose; 
S=Stay at the current dose.
Target toxicity rate = 30%
Flat noninformative prior Beta (1,1) is used as a prior and ε1=ε2=0.03 [Ji Y, Li Y, Bekele BN 2007] [Ji, Y. 2013] [Ji, Y., et 
al 2010]
4.3.4
Dose Escalation, Stay or De-escalation Decision for Cohorts 2a, 3a and 4a
New cohorts for evaluation of dosing schedule with both V938 and pembrolizumab starting 
on C1D1 will be included via V938-001 Amendment 05 when the dose-finding decision has 
been made for Cohort 3, according to the rules described from the mTPI design 
(Section 4.3.3). When Cohort 3a, 4a, or 2a is open, 3 to 6 participants will be enrolled 
initially to each cohort, with potential to expand up to 14 participants. It is not necessary to 
have Cohort 3 or Cohort 4 expanding to 14 participants before transition to Cohort 3a, 4a, or 
2a. The following algorithms are implemented for decision on dose-escalation, stay, or 
de-escalation for these new cohorts:

Cohort 3: 
-
If DLT evaluation indicates escalation, both Cohort 4 and Cohort 3a can be enrolled, 
with enrollment to Cohort 4 prioritized over Cohort 3a.
-
If DLT evaluation indicates stay, only Cohort 3a can be enrolled.
-
If DLT evaluation indicates de-escalation, only enroll Cohort 2a.
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
Cohort 4: 
-
If DLT evaluation indicates escalation or stay, Cohort 4a can be enrolled only if 
Cohort 3a also indicates dose escalation.
-
If DLT evaluation indicates de-escalation, wait for outcome from Cohort 3a.

Cohort 3a:
-
If DLT evaluation indicates escalation, Cohort 4a can be enrolled only if Cohort 4 
also indicates dose escalation.
-
If DLT evaluation indicates stay – expand cohort up to 14 participants.
-
If DLT evaluation indicates de-escalation, only enroll Cohort 2a.

Cohort 4a:
-
If DLT evaluation indicates escalation or stay – cohort expand up to 14 participants
-
If DLT evaluation indicates de-escalation – expand Cohort 3a up to 14 participants

Cohort 2a:
-
If DLT evaluation indicates escalation, may re-escalate to Cohort 3a.
-
If DLT evaluation indicates stay, cohort expand up to 14 participants.
-
If DLT evaluation indicates de-escalation, will end this dosing schedule.
The final selection of RP2D will be from Cohorts 2a, 3a, and 4a based on the totality of the 
available data.
4.4
Beginning and End of Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator).
Due to discontinuation of V938-001, all ongoing participants who have completed C7D1 
V938 plus pembrolizumab treatment may be enrolled to an extension study to continue 
pembrolizumab monotherapy for total of 35 cycles since first dose in V938-001 and to be 
monitored per the extension study as appropriate.
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4.4.1
Clinical Criteria for Early Study Termination
Recruitment in the study or at (a) particular study site(s) may be stopped due to insufficient 
compliance with the protocol, GCP and/or other applicable regulatory requirements, 
procedure-related problems, or the number of discontinuations for administrative reasons is 
too high.
Study recruitment/treatment will be paused if one of the following occurs:

Any death (not due to disease progression) that is possibly, probably, or definitely related 
to V938 or V938 in combination with pembrolizumab.

Two Grade 4 AEs that are possibly, probably, or definitely related to V938 or V938 in 
combination with pembrolizumab.
Early study termination will be the result of the criteria specified below:

Incidence or severity of adverse drug reactions in this or other studies suggest a potential 
health hazard to participants

Plans to modify or discontinue the development of the study medication

Quality or quantity of data recording is inaccurate or incomplete
Ample notification will be provided in the event of Sponsor decision to no longer supply 
V938 or pembrolizumab.
5
STUDY POPULATION
Male/female participants at least 18 years of age with advanced/metastatic solid tumors who 
have progressed on, been ineligible for, or refused other active therapies including targeted 
therapy based on mutation status (eg, MSI-H, BRAF) per standard of care, will be enrolled in 
this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
To be eligible for inclusion in this study, the participant must:
Type of Participant and Disease Characteristics
1. For Dose-escalation Cohorts: Have a histologically confirmed advanced/metastatic 
solid tumor and have received, been intolerant to, or been ineligible for treatments known 
to confer clinical benefit. Solid tumors of any type are eligible for enrollment. Tumor 
types of greatest interest include, but are not limited to, malignant melanoma, HNSCC, 
and breast carcinoma.
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For Arm A of Cohort Expansion: Have a histologically confirmed Stage III 
(unresectable) or Stage IV cutaneous melanoma and have received and progressed 
following 1 or 2 prior lines of systemic treatments for metastatic melanoma which must 
include 1 line of treatment with PD-1 or PD-L1 immune checkpoint inhibitor either as 
monotherapy or in combination with other therapy.
For Arm B of Cohort Expansion: Have a histologically confirmed advanced HNSCC
and have received and progressed following 1 or 2 prior lines of systemic treatments for 
metastatic HNSCC which must include 1 line of treatment with PD-1 or PD-L1 immune 
checkpoint inhibitor either as monotherapy or in combination with other therapy.
For Arms A and B of Cohort Expansion: PD-1 treatment progression is defined by 
meeting all of the following criteria:
a.
Has received at least 2 doses of an approved anti-PD-1/L1 mAb.
b. Has shown disease progression after anti-PD-1/L1 as defined by RECIST v1.1. 
The initial evidence of disease progression is to be confirmed by a second 
assessment no less than 4 weeks from the date of the first documented disease 
progression, in the absence of rapid clinical progression (as defined in 1.c).
c.
Progressive disease has been documented within 12 weeks from the last dose of 
anti-PD-1/L1 mAb.
i.
Progressive disease is determined according to iRECIST.
ii.
This determination is made by the investigator. Once disease progression 
is confirmed, the initial date of disease progression documentation will be 
considered the date of disease progression.
2. Have a performance status of 0 or 1 on the ECOG Performance Scale.
3. Show adequate organ function as defined in Table 2. These samples must be collected 
within 72 hours prior to C1D1.
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Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
≥1,500/mcL 
Platelets
≥100,000/mcL 
Hemoglobin
≥9 g/dL or >5.6 mmol/La)
Renal
Serum creatinine or 
CrCl (measured or calculated)b or
GFR 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
INR or PT
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); 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) and platelet transfusion within the prior 
2 weeks. Participants can be on stable dose of erythropoietin (≥ approximately 3 months).
b Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
Demographics
4. Are male or female, and must be at least 18 years of age 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.
5. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 120 days:
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-
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.
-
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
-
Is not a woman of childbearing potential (WOCBP)
OR
-
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long term and persistent basis), as described in
Appendix 5 during the intervention period and for at least 120 days after the last dose 
of study intervention. The investigator should evaluate the potential for contraceptive 
method failure (ie, noncompliance, recently initiated) in relationship to the first dose 
of study intervention.
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 72 hours before C1D1.
-
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.
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The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed 
consent/assent 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. See country-specific information in 
Appendix 7.
Additional Categories
8. Has well controlled HIV (for HIV-infected participants) on ART, defined as:
a.
Participants on ART must have a CD4+ T-cell count >350 cells/mm3 at time of 
screening.
b. Participants on ART must have achieved and maintained virologic suppression 
defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of 
detection) using the locally available assay at the time of screening and for at least 12 
weeks prior to screening.
c.
Participants on ART must have been on a stable regimen, without changes in drugs or 
dose modification, for at least 4 weeks prior to study entry (Day 1).
d. The combination ART regimen must not contain any antiretroviral medications other 
than: abacavir, dolutegravir, emtricitabine, lamivudine, raltegravir, rilpivirine, or 
tenofovir.
9. Have lesions as defined below:
a.
For All Participants: Have at least 1 cutaneous or subcutaneous lesion amenable to IT
injection and must be measurable and meet 1 of the following criteria (per 
RECIST 1.1):
i.
A cutaneous or subcutaneous lesion ≥1 cm in longest diameter for solid tumors, or 
≥1.5 cm in short axis for a nodal lesion in participants with solid tumor. The
longest diameter for an injectable lesion must be ≤10 cm for both solid tumors 
and nodal lesions in participants with solid tumors.
ii.
Multiple coalescing, superficial lesions that in aggregate have a longest diameter 
of ≥1 cm and ≤10 cm.
b. For Expansion Cohorts (Arms A and B) ONLY: Have at least 1 distant and/or 
discrete noninjected lesion that is measurable per RECIST 1.1 criteria.
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10. For Dose-escalation Cohorts 2a, 3a, or 4a and Expansion Cohorts (Arms A and B) 
ONLY: Have baseline biopsy performed from one of the injectable lesions that are 
planned for IT injection and with tumor tissue provided.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks 
(2 weeks for palliative radiation) prior to the first dose of study intervention or has not 
recovered to CTCAE Grade 1 or better from any AEs that were due to cancer 
therapeutics administered more than 4 weeks earlier (this includes participants with 
previous immunomodulatory therapy with residual immune-related AEs). Participants 
receiving ongoing replacement hormone therapy for endocrine immune-related AEs will 
not be excluded from participation in this study.
2. Has a history of a second malignancy, unless potentially curative treatment has been 
completed with no evidence of malignancy for 2 years.
Note: The time requirement does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, superficial bladder cancer or in 
situ cervical cancer, or other in-situ cancers.
3. Has clinically active central nervous system metastases and/or carcinomatous meningitis. 
Participants with previously treated brain or meningeal metastases may participate and be 
eligible for treatment provided they are stable and asymptomatic (without evidence of 
progression by MRI scan of the brain separated by at least 4 weeks after treatment), have 
no evidence of new or enlarging brain metastases, are evaluated within 4 weeks prior to 
first study intervention administration, and are off immunosuppressive doses of systemic 
steroids at least 2 weeks prior to enrollment.
Note: Participants with asymptomatic, previously untreated brain metastases may 
participate provided there are ≤3 total lesions in the brain and the longest diameter of 
each lesion is <1 cm. Stability of these lesions does not need to be confirmed by repeat 
imaging. Participants may not receive steroids to treat these lesions.
4. Has had a severe hypersensitivity reaction to treatment with the monoclonal 
antibody/components of the study intervention or has a history of any contraindication or 
has a severe hypersensitivity to any components of pembrolizumab (≥Grade 3).
5. Has an active infection requiring therapy.
6. Has a history of (noninfectious) pneumonitis that required steroids or current 
pneumonitis. 
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7. Has an active autoimmune disease that has required systemic treatment in the past 2 years 
(ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs) 
except vitiligo or resolved childhood asthma/atopy. Replacement therapy, such as 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or 
pituitary insufficiency, is not considered a form of systemic treatment and is allowed. 
8. Is on chronic systemic steroid therapy in excess of replacement doses (prednisone 
≤10 mg/day is acceptable), or on any other form of immunosuppressive medication. Use 
of nonsystemic steroids is permitted.
9. Participants with known Hepatitis B or C infections or known to be positive for 
hepatitis B antigen/hepatitis B virus DNA or hepatitis C antibody or RNA. Active 
hepatitis C is defined by a known positive Hepatitis C antibody result and known 
quantitative hepatitis C virus RNA results greater than the lower limits of detection of the 
assay.
10. HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric 
Castleman’s Disease.
11. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
12. 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.
13. Has not fully recovered from any effects of major surgery without significant detectable 
infection. Surgical procedures that required general anesthesia must be completed at least 
2 weeks before first study intervention administration. Surgery requiring 
regional/epidural anesthesia must be completed at least 72 hours before first study 
intervention administration and participants should be recovered.
Prior/Concomitant Therapy
14. Has received a live-virus vaccine within 30 days of planned treatment start. Seasonal flu 
vaccines that do not contain live virus are permitted.
15. Has received prior treatment with either NDV or hIL-12.
Prior/Concurrent Clinical Study Experience
16. Is currently participating and receiving study intervention in a study of an investigational 
agent or has participated and received study intervention in a study of an investigational 
agent or has used an investigational device within 28 days of administration of V938.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks since the last dose of the previous 
investigational agent.
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Note: Prior exposure to immunotherapeutics is allowed, including PD-1 and PD-L1 
inhibitors, provided participant did not experience a ≥Grade 3 drug-related toxicity on 
monotherapy with a PD-1 or PD-L1 inhibitor.
Diagnostic Assessments
Other Exclusions
17. Has an active egg allergy.
18. Has a history of re-irradiation for HNSCC at the projected injection site. 
19. Has a tumor(s) in direct contact or encases a major blood vessel and has ulceration and/or 
fungation onto the skin surface at the projected injection site.
20. Works on a farm or other profession if bird exposure is prominent.
21. For Expansion Cohorts ONLY: Has uveal or ocular melanoma.
22. For Expansion Cohorts ONLY: Has mucosal melanoma.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage AEs 
such as diarrhea, nausea, or vomiting.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
None.
5.3.3
Activity Restrictions
None.
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 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the data entry guidelines.
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5.5
Participant Replacement Strategy in Dose Escalation
In order to adequately evaluate the safety of the doses administered in this study, all 
participants enrolled must meet the criteria for evaluability for Cycle 1 and Cycle 2 for 
Cohorts 1-4 of dose escalation and must meet the criteria for evaluability for Cycle 1 for 
Cohorts 2a-4a. Participants are considered nonevaluable and will be replaced if:
They are allocated but not treated.
They discontinue from the study prior to completing all the safety evaluations for reasons 
other than treatment-related AEs.
They receive less than 75% of the total V938 PFU injection or pembrolizumab infusion in 
the DLT evaluation period (eg, if the infusion had to be discontinued due to an infusion 
reaction) and did not experience a DLT.
Participants who are not evaluable will be replaced unless accrual to the cohort has stopped. 
Nonevaluable participants will not be counted toward the total number of participants in the 
cohort for DLT evaluation.
If a participant experiences a DLT in the DLT evaluation period, study intervention may be 
discontinued following discussion between the Sponsor and investigator. However, if the 
participant is deriving clinical benefit from the study intervention, the participant may be 
allowed to continue after discussion between the Sponsor and the investigator.
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 intervention(s) provided by the Sponsor) will be packaged to support 
enrollment and replacement participants as required. When a replacement participant is 
required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
supplies. 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 3.
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Table 3
Study Interventions
Arm Name
Arm 
Type
Inter-
vention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Dose Escalation 
(All Cohorts)
Experi-
mental
V938
Biological/
Vaccine
Solution for 
Injection
Fixed dose; 
varies with 
injection 
volume
1x107 PFU, 
1x108 PFU, 
3x108 PFU
5x108 PFU
Intratumoral
Cycle 1: Days 1, 3, 
5, and 8
Cycle 2-7: Q3W
beginning at Cycle 
2, Day 1
Experi-
mental
IMP
Provided 
centrally by 
Sponsor
Expansion
Cohorts 
(Arms A-B)
Experi-
mental
V938
Biological/
Vaccine
Solution for 
Injection
Fixed dose; 
varies with 
injection 
volume
RP2D
Intratumoral
Cycle 1: Days 1, 3, 
5, and 8
Cycle 2-7: Q3W
beginning at Cycle 
2, Day 1
Experi-
mental
IMP
Provided 
centrally by 
Sponsor
Dose Escalation 
(Cohorts 1-4)
Experi-
mental
Pembro-
lizumab
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
200 mg
IV Infusion
Q3W, beginning at 
Cycle 2, Day 1
Experi-
mental
IMP
Provided 
centrally by 
Sponsor
Dose Escalation 
(Cohorts 2a-4a)
Experi-
mental
Pembro-
lizumab
Biological/
Vaccine
Solution for 
Infusion
25 mg/mL
200 mg
IV Infusion
Q3W, beginning at 
Cycle 1, Day 1
Experi-
mental
IMP
Provided 
centrally by 
Sponsor
Tumor Immune 
Imaging and 
Tissue Collection 
Study (US only)
Other
89Zr-Df-
IAB22M2C 
tracer
Diagnostic 
Test
Solution for 
Infusion
0.8-1.2 mCi
0.5 mg-1.5 
mg
IV Infusion
Once per CD8 PET 
imaging scan
Diag-
nostic
NIMP
Provided 
centrally by 
the Sponsor
Note: V938 will be administered up to 8 hours prior to pembrolizumab infusion (as appropriate).
Note: Anti-CD8 89Zr-Df-IAB22MC tracer (US ONLY)
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European Commission. Regional 
and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 3 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number.
Refer to Section 8.1.11 for details regarding administration of the study intervention.
6.1.1
Intratumoral Injection
V938 will be administered by IT injection into cutaneous, subcutaneous, and/or nodal lesions 
that are visible, palpable, or detectable by ultrasound guidance. At each dose level, a fixed 
V938 dose is administered to all participants enrolled to that dose level cohort (eg, Dose 
Level 3 = 3x108 PFU) and at each visit for V938 dosing. 
At each treatment, the required dose of V938 will be prepared in 0.5 to 4 mL of total volume 
of injectate based on the total lesion size and the nature of lesions, eg, cutaneous versus. 
subcutaneous or nodal lesions, or lesions with large narcotic areas, hence smaller injectable 
tissues (see Table 4 for estimation on total injected volume for each participant at each visit).
Prioritization of lesions to be injected should include consideration of the following order: if 
multiple lesions exist, a new or progressing lesion should be considered for injection first, 
followed by injection of the largest lesion, then injection of any additional lesions, up to a 
total volume of injectate of 4 mL and a maximum number of 5 lesions.
Selection of participants during screening should consider adequate lesion size for repeat 
lesion injection. Distant lesion(s) assessed for the “abscopal” response should not be injected,
unless approved by the Sponsor.
Table 4
Estimation of Total Injected V938 Volume Based on Estimated Combined Lesion 
Size for Lesions to be Injected at Each V938 Treatment Visit
Estimation of Combined Lesion Size
Estimation of Total Injected Volumea
>5 cm
≤4 mL
>2.5 to 5 cm
≤3 mL
>1.5 to 2.5 cm
≤2 mL
≥1.0 to 1.5 cm
0.5 - 1 mL
a Volumes are estimates; minimum and maximum total volume injected per visit for all tumor lesions
combined is 0.5 mL and 4 mL, respectively.
Details on dose calculation, preparation, and administration of V938 are provided in the 
Laboratory Procedures/Pharmacy Manual.
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Injected tumor area should consist of vital tumor tissue (avoid injection into areas with 
significant necrosis, if feasible).
If at any time after treatment initiation a dose cannot be fully injected into the single 
injectable lesion identified at the start of treatment (eg, due to tissue induration or tumor 
shrinkage), the dose may be split and the remaining amount of V938 may be injected into 
another accessible lesion(s). Documentation of dose volume administered per injected lesion 
should be obtained. If no other lesion is accessible for injection or lesions are no longer 
visible, the remaining amount may alternatively be injected subcutaneously into the tissue 
immediately surrounding the previous injected lesion(s), if assessed feasible by the treating 
physician. Site and volume for each injection must be documented in the eCRF.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of V938 and pembrolizumab are provided in the 
appropriate Pharmacy/Laboratory Procedures Manual.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
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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 
allocated to the following intervention arms: Cohorts 1-4 and 2a-4a in dose escalation, or 
Arms A and B in expansion cohorts.
Each new dose-escalation cohort will open for enrollment without delay once the 
DLT observation period of the previous dose cohort is completed and a dose-escalation 
decision is made.
Treatment allocation will be accomplished by nonrandom assignment by IVRS/IWRS.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this 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
Interruptions from the protocol-specified treatment plan for >3 weeks between V938 or 
pembrolizumab doses for nondrug related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. If there is a clinical indication for any medication specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor. The final decision on any supportive therapy rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study 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 
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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 CRF.
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.
6.5.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phases of this study:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than those specified in this protocol

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 in order for the 
participant to be considered evaluable for DLT.
Live vaccines within 30 days prior to the first dose of study intervention and while 
participating in the study. Examples of live vaccines include, but are not limited to the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette–
Guérin, and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are 
live-attenuated vaccines and are not allowed.
Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE of 
suspected immunologic etiology. The use of physiologic doses of corticosteroids may be 
approved after consultation with the Sponsor. Note: A maximum dose of 10 mg prednisone 
(or equivalent) per day is also allowed after consultation with Sponsor.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued from study
treatment. Participants may receive other medications that the investigator deems to be 
medically necessary.
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6.5.3
Supportive Care
6.5.3.1
V938 Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Refer to Table 5, Table 6, and Table 7 for guidelines regarding dose 
modification and supportive care.
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 
Table 8. 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 8 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)
6.6.1
Dose Administration/Escalation
Details on preparation and administration of V938 and pembrolizumab are provided in the 
appropriate Pharmacy/Laboratory Procedures Manual.
6.6.2
Definition of Dose-limiting Toxicity
All toxicities will be graded using CTCAE Version 4.0, with exception of CRS, based on the 
investigator assessment. The CRS grading system used in this protocol is adapted from the 
ASTCT Consensus Grading for CRS [Lee, D. W., et al 2019].
The DLT observation period for Cohorts 1-4 will be 42 days during Cycles 1 and 2 (ie, the 
first monotherapy run-in cycle [Cycle 1] and the first combination therapy cycle [Cycle 2]).
The DLT observation period for Cohorts 2a-4a will be 21 days during Cycle 1 only.
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The occurrence of any of the following toxicities during the DLT observation period 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 thrombocytopenia:
a.
Grade 4 thrombocytopenia of any duration
b. Grade 3 thrombocytopenia associated with clinically significant bleeding
3. Grade 3 nonhematologic AE with the following exceptions: 
a.
Grade 3 fatigue lasting ≤72 hours
b. Grade 3 diarrhea, nausea, or vomiting lasting ≤72 hours without use of antiemetics or 
antidiarrheals per standard of care
c.
Grade 3 rash without use of corticosteroids or anti-inflammatory agents per standard 
of care.
4. Any Grade 3 or Grade 4 nonhematologic laboratory value if:
a.
Clinically significant medical intervention is required to treat the participant, or
b. The abnormality leads to hospitalization, or
c.
The abnormality persists for >1 week
d. The abnormality results in a DILI (see Sections 8.4.1 and 8.4.7 for criteria)
Exceptions: Clinically nonsignificant, treatable, or reversible laboratory abnormalities 
including liver function tests, uric acid, etc.
5. Febrile neutropenia Grade 3 or Grade 4:
a.
Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3°C (101°F) 
or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour.
b. Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3°C (101°F) 
or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour, with 
life-threatening consequences and urgent intervention indicated.
6. Prolonged delay (>2 weeks) in initiating Cycle 3 (for Cohorts 1-4) or Cycle 2 (for 
Cohorts 2a-4a) due to study intervention-related toxicity.
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7. Any study intervention-related toxicity that causes the participant to discontinue 
intervention during the DLT evaluation period.
8. Missing >1 injection of V938 as a result of drug-related AE(s) during the first 2 cycles
(for Cohorts 1-4) or during the first cycle (for Cohort 2a-4a).
9. Grade 5 toxicity.
6.6.3
Timing of Dose Administration
Refer to Table 3 for dosing schedule of V938 and pembrolizumab for cohorts and arms in 
Dose-escalation and Cohort Expansion and allowed treatment windows in Section 1.3.
The reason for any variability in administration of V938 or pembrolizumab outside the 
protocol-specified window should be documented in the participant’s chart and recorded on 
the eCRFs.
The Pharmacy/Laboratory Procedures Manual contains specific instructions (eg, dose 
calculation, reconstitution, preparation) for V938 and pembrolizumab administration.
6.6.4
Guidelines for Dose Modification due to Adverse Events
Adverse events (both nonserious and serious) associated with V938 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 4.0 must be used to grade the severity of AEs with exception of CRS. CRS is 
graded using the grading system adapted from the ASTCT Consensus Grading for CRS. The 
investigator may attribute each toxicity event to V938 alone, to pembrolizumab alone, or to 
the combination, and modify the dose according to Table 5 and/or Table 8.
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 V938 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.
6.6.4.1
Dose Modification and Management for V938
The dose of V938 may be interrupted or dose reduced by 1 dose level from Dose Level 3 
(3x108 PFU) or Dose Level 4 (5x108 PFU) as described in Table 5. If dose cannot be resumed 
following dose interruption with the original or reduced or dose, then V938 treatment should 
be discontinued. If a participant experiences several toxicities, then the treating physician 
should adhere to the most conservative dose adjustment recommended (ie, adjustment based 
on the severest AE reported). Exceptional circumstances to following the dose modification 
tables below may be considered after consultation with the Sponsor.
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Table 5
V938 Dose Modification and Treatment Discontinuation Guidelines for Drug-related Adverse Events
Toxicity
Hold Treatment
Criteria for Restarting 
Treatment
V938 Dose for Restarting 
Treatment
Criteria for Treatment 
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.
Same dose level
If AE persists for 12 weeks 
without resolution
Any Grade 3 hematological
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.
May decrease dose by 1 dose 
level.
If AE persists for 12 weeks 
without resolution 
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.
Same dose level
If AE persists for 12 weeks 
without resolution 
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Toxicity
Hold Treatment
Criteria for Restarting 
Treatment
V938 Dose for Restarting 
Treatment
Criteria for Treatment 
Discontinuation After 
Consultation with 
Sponsor
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.
May decrease dose by 1 dose 
level.
If AE persists for 12 weeks 
without resolution 
Permanent discontinuation 
should be considered for 
any severe or 
life-threatening event
Note: For treatment-related CRS, refer to Table 6 for AE grading and Table 7 for V938 dose modification and AE management.
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6.6.4.1.1
Management of Cytokine Release Syndrome
CRS has been observed in participants who received V938 treatment. CRS toxicity will be 
graded per ASTCT CRS Consensus Grading system as shown in Table 6; the CRS 
management guideline is provided in Table 7.
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Table 6
CRS Grading, Adapted From ASTCT CRS Consensus Grading
CRS Parameter
Grade 1
Grade 2
Grade 3
Grade 4
Fever a
Temperature ≥38°C
Temperature ≥38°C
Temperature ≥38°C
Temperature ≥38°C
With
Hypotension
None
Not requiring 
vasopressors
Requiring a vasopressor 
with or without 
vasopressin
Requiring multiple 
vasopressors (excluding 
vasopressin)
And/or b
Hypoxia
None
Requiring low-flow 
nasal canula c or 
blow-by
Requiring high-flow 
nasal canula c, facemask,
nonrebreather mask, or 
Venturi mask
Requiring positive 
pressure (eg, CPAP, 
BiPAP, intubation, and 
mechanical ventilation)
Abbreviations: ASTCT=American Society for Transplantation and Cellular Therapy; BiPAP= bilevel positive air pressure; CPAP=continuous positive air pressure ; 
CRS=cytokine release syndrome.
Note: Organ toxicities associated with CRS may be graded according to CTCAE v4.0, but they do not influence CRS grading.
Note: Grade 5 is death caused by CRS or its complications after excluding other causes.
a Fever is defined as temperature ≥38°C not attributable to any other cause. In participants who have CRS and then receive antipyretic or anticytokine therapy such as 
tocilizumab or steroids, fever is no longer required to grade subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.
b CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For example, a participant with temperature of 39.5°C, 
hypotension requiring 1 vasopressor, and hypoxia requiring low-flow nasal canula is classified as Grade 3 CRS.
c Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen delivery, sometimes used in pediatrics. High-flow nasal 
cannula is defined as oxygen delivered at >6 L/minute.
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Table 7
Dose Modification and Management Guideline for Treatment-related CRS
CRS Grade per 
ASTCTa
V938 Dose Modification
CRS Management
Premedication for
Subsequent Doses
Grade 1
None 
Increase monitoring of vital signs and oxygen 
saturation, as medically indicated, until the 
participant is deemed medically stable, in the 
opinion of the investigator.
Recommended.
Participant may be
premedicated with 
antipyretic, eg, 
acetaminophen 500 to 
1000 mg po 1.5 h (±30 min), 
or with an antihistamine,
prior to study intervention
administration, or at the 
discretion of the investigator.
Grade 2
Delay next dose until AE is 
resolved, retreatment at the 
same dose level.
For recurrent Grade 2, 
retreatment may be 
allowed at the same dose 
level or 1 dose level down 
upon discussion with the 
Sponsor
Increase monitoring of vital signs and oxygen 
saturation, as medically indicated, until the 
participant is deemed medically stable, in the 
opinion of the investigator. 
Additional appropriate medical therapy may 
include, but is not limited to:

IV fluids

NSAIDs

Acetaminophen

Narcotics

Oxygen
Perform fever workup to exclude infectious
etiologies; treat neutropenia if present.
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CRS Grade per 
ASTCTa
V938 Dose Modification
CRS Management
Premedication for
Subsequent Doses
Grade 3 or Grade 4
Permanently discontinue 
V938
Additional appropriate medical therapy
may include, but is not limited to:

IV fluids

NSAIDS

Acetaminophen

Narcotics

Oxygen

Vasopressors

Corticosteroids

Anti-IL6 (eg, tocilizumab)

Empiric antibiotics
Participants with ≥ Grade 3 CRS need to
be monitored very closely, likely in an 
intensive care setting.
NA
Abbreviations: ASTCT= American Society for Transplantation and Cellular Therapy ; CRS=cytokine release syndrome; 
IL=interleukin; IV=intravenous; NSAIDS=nonsteroidal anti-inflammatory drugs; PO=by mouth.
a CRS Grading adapted from ASTCT Consensus Grading (see Table 6).
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If toxicity does not resolve to Grade 0 or 1 within 6 weeks after last intervention, V938 
should be discontinued. With investigator and Sponsor agreement, participants with a 
laboratory AE still at Grade 2 after 6 weeks may continue intervention in the study only if 
asymptomatic and controlled.
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 or 1 or baseline prior 
to restarting.)
6.6.4.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
AEs associated with pembrolizumab monotherapy, coformulation, or IO combination 
exposure may represent an immune-related response. These irAEs may occur shortly after 
the first dose or several months after the last dose of pembrolizumab monotherapy, 
coformulation, or IO combination treatment and may affect more than one body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications. Based on existing clinical study data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab monotherapy, coformulation, or IO 
combination administration of corticosteroids and/or other supportive care. For suspected 
irAEs, ensure adequate evaluation to confirm etiology or exclude other causes. Additional 
procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be included as part of 
the evaluation.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 8.
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Table 8
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.    Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.    Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.    The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.    If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
pneumonitis
   Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
   Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 
2 or Grade 3 or 4 
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Diarrhea / Colitis 
Grade 2 or 3
Withhold
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
   Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
   Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If 
sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2a
Withhold
   Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
   Monitor with liver function tests (consider weekly 
or more frequently until liver enzyme value 
returned to baseline or is stable)
Grade 3 b or 4c
Permanently 
discontinue
   Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure
Withholdd
   Initiate insulin replacement 
therapy for participants with 
T1DM
   Administer anti-
hyperglycemic in participants 
with hyperglycemia
   Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypophysitis
Grade 2
Withhold
   Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
   Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinued
Hyperthyroidism 
Grade 2
Continue
   Treat with non-selective 
beta-blockers (eg, 
propranolol) or thionamides 
as appropriate
   Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinued
Hypothyroidism
Grade 2-4
Continue
   Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
   Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
renal dysfunction
Grade 2
Withhold
   Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper
   Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
   Based on severity of AE 
administer corticosteroids
   Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
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 
discontinuee
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: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically 
important irAEs (eg, vasculitis and sclerosing cholangitis).
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6.6.4.2.1
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 9.
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Table 9
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 hrs
Stop Infusion
Additional appropriate medical therapy may 
include, but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, from 100 
mL/hr to 50 mL/hr). Otherwise dosing will be held 
until symptoms resolve and the participant should 
be premedicated for the next scheduled dose.
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug intervention.
Participant may be 
premedicated 1.5 h 
(±30 minutes) prior to 
infusion of study 
intervention with:
Diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine).
Acetaminophen 
500-1000 mg po (or 
equivalent dose of 
analgesic).
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy may 
include, but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Participant is permanently discontinued from 
further study drug intervention.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) 
at http://ctep.cancer.gov
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6.6.4.2.2
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.
6.7
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 8.1.12.
A participant must be discontinued from study intervention but continue to be monitored in 
the study for any of the following reasons:

The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.

The participant interrupts study intervention administration for more than 12 consecutive 
weeks.
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
The participant has a medical condition or personal circumstance that, 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 (exception if the 
Sponsor approves treatment continuation).

Unacceptable adverse experiences as described in Section 6.6 and Section 8.4.3.

Use of prohibited concomitant medications as described in Section 6.5.2.

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.

Recurrent Grade 2 pneumonitis.

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).
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 8.1.12. 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.
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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.

The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).

All study-related medical decisions must be made by an investigator who is a qualified 
physician.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.

Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, Hepatitis C), and thus local regulations 
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may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
The approximate amount of blood collected from each participant over the duration of the 
study for each participant for laboratory evaluations is provided in the Laboratory Procedures 
Manual.
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 consent is in place.
8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the trial protocol number, trial 
protocol title, dated signature, and /agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any information provided to the participant 
must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the participant’s or the 
participant’s legally acceptable representative’s dated signature.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
Specifics about the study and the study population are to be included in the study informed 
consent form template at the protocol level. 
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
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8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, or the participant’s legally acceptable representative, answer all of 
his/her questions, and obtain documented informed consent before performing any procedure 
related to future biomedical research. A copy of the informed consent will be given to the 
participant before performing any procedure related to future biomedical research.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria (Sections 5.1 and 5.2) will be reviewed by the 
investigator who is a qualified physician to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
allocation/randomization, site personnel will add the treatment/randomization number to the 
participant identification card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a healthcare provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
is 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. Smoking history will be obtained.
8.1.5
Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
8.1.6
Prior Oncology Treatment History
The investigator or qualified designee will record all prior cancer treatments including 
systemic treatments, radiation, and surgical procedures.
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8.1.7
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess the ECOG performance status at the time 
points specified in the SoA (Section 1.3). Additional ECOG testing may be performed as 
clinically indicated.
8.1.8
Prior and Concomitant Medications Review
8.1.8.1
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 medication/vaccination. Treatment for the disease 
for which the participant has been enrolled in this study will be recorded separately and 
should not be listed in prior medications.
8.1.8.2
Concomitant Medications
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care, with the exceptions of those specifically excluded (see Section 6.5.2). All 
concomitant medication will be recorded on the eCRFs, including all prescription, 
OTC products, herbal supplements, and IV medications, and fluids. If changes occur during 
the study period, documentation of drug dosage, frequency, route, and date should also be 
included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study treatment 
and up to 30 days after the last dose of study treatment should be recorded. Concomitant 
medications administered 30 days after the last dose of study treatment should be recorded 
for SAEs and ECIs as defined in Section 8.4.7.
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 8.4.7.
All new anticancer therapy initiated after the study start must be recorded in the eCRF. If a 
participant initiates another anticancer therapy other than the assigned study intervention(s), 
the study intervention(s) should be discontinued, and the participant will move into the 
survival follow-up phase; if a participant initiates a new anticancer therapy within 30 days 
after the last dose of the study intervention, the 30-day Safety Follow-up Visit should occur 
before the first dose of the new therapy.
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8.1.9
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.
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.
8.1.10
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/randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.11
Study Intervention Administration
Administration of study medication will be witnessed by the investigator and/or study staff. 
The total volume of study intervention administered will be compared to the total volume 
prepared to determine compliance with each dose administered.
Study treatment will begin on C1D1, once all predose assessments have been completed.
8.1.11.1
Timing of Dose Administration
See Sections 1.1, 1.3.2, 4.1.1, and 6.1 for timing of dose administration. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
that are not related to study therapy (eg, elective surgery, unrelated medical events, 
participant vacation, and/or holidays). Participants should be placed back on study therapy 
within 3 weeks of the scheduled interruption, unless otherwise discussed with the Sponsor 
Medical Monitor or designee. The reason for interruption should be documented in the 
participant’s study record.
8.1.12
Discontinuation and Withdrawal
Participants who discontinue study intervention prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
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When a participant withdraws from participation in the study, all applicable activities 
scheduled for the End-of-Treatment Visit should be performed (at the time of withdrawal). 
Any AEs that are present at the time of withdrawal should be followed in accordance with 
the safety requirements outlined in Section 8.4 and Section 8.11.3.
8.1.12.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
8.1.13
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.14
Domiciling
On C1D1 and C1D3, the first 2 participants at each dose level will remain under observation
for a minimum of a 24-hour period (may be longer based on guidance from the individual 
institution) following V938 administration. Observation for the remaining V938 doses for 
these participants and for any additional participants will be at the discretion of the 
investigator, per local IRB, Ethics Review Committee, and/or Health Authority mandate.
8.1.15
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Medical Photography
RECIST 1.1 and iRECIST assessment will be performed for both injected and noninjected 
lesions. Injecting a lesion after treatment has begun will not render it “nonevaluable” for 
response assessment purposes. 
The initial PET/CT scan or MRI for solid tumor imaging as well as medical photography for 
cutaneous lesions must be performed within 28 days prior to enrollment, and the site study 
team must confirm that the participant has measurable disease as defined by RECIST 1.1.
Sites will be required to send in anatomical images/medical photography of the injected 
lesions to a central imaging vendor, as indicated in the SIM.
Tumor imaging and medical photography should be repeated every 9 weeks from the first 
dose of treatment.
Solid tumor imaging should be acquired by CT (strongly preferred). Magnetic resonance 
imaging should be used when CT is contraindicated or for imaging in the brain. For 
subcutaneous lesions, imaging by either MRI or CT is to be obtained at screening and at the 
imaging timepoints outlined in Section 1.3 for assessment of response. Medical photography 
will be performed more frequently, if warranted.
The same imaging technique regarding modality and use of contrast should be used in a 
participant throughout the study to optimize the visualization of existing and new tumor 
burden. Tumor imaging schedule is based on calendar days from the first administration of 
study intervention and will not be postponed due to delays in treatment cycles. Additional 
tumor imaging and medical photography may be performed as clinically indicated.
Sites will be required to submit required anatomical images and medical photography to a 
central imaging vendor who will clean, collect, and hold the images. Images taken of lesions 
being injected (by medical photography and/or ultrasound) should also be submitted in the 
same manner.  Images will be collected for possible analysis by blinded, independent central 
review. Required anatomical images as well as the process for image collection and 
transmission to the central imaging vendor can be found in the SIM.
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. 
8.2.2
Initial Tumor Imaging
Initial tumor imaging at Screening must be performed within 28 days prior to the date of 
allocation.
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Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if they are of diagnostic quality and performed within 42 days prior 
to the date of allocation.
8.2.3
Brain Imaging
Participants with previously treated brain metastases may participate provided they have 
stable brain metastases, ie, without evidence of progression by imaging (confirmed by MRI if 
MRI was used at prior imaging or confirmed by CT imaging if CT used at prior imaging) for 
at least 4 weeks prior to the first dose of study treatment. Any neurologic symptoms must 
have returned to baseline and participants must have no evidence of new or enlarging brain 
metastases and have not used steroids for brain metastases for at least 14 days prior to study
initiation as per local site assessment. This exception does not include carcinomatous 
meningitis, as participants with carcinomatous meningitis are excluded regardless of clinical 
stability.
For participants with stable brain metastases enrolled in the study, the baseline brain image 
must be submitted to the CIV to be held for possible future analysis. For any participant with 
known stable brain metastases at baseline and who achieves a CR during study treatment, 
follow-up brain imaging is required for confirmatory assessment of CR. This image may be 
submitted for independent central radiologic review.
Participants with small cell lung, thyroid cancer, and melanoma 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. For those participants with these tumor types 
subsequently enrolled in the study, this baseline brain scan should be submitted to the CIV, 
but independent central radiologic confirmation of a lack of brain metastases is not required.
Participants with small (<1 cm) asymptomatic brain metastases must be followed with 
regularly scheduled brain MRI scans throughout the study.
If a participant develops a new brain metastasis during treatment, the following steps will be 
taken: 

Participants with symptomatic brain metastases will be removed from study treatment.

Participants with asymptomatic brain metastases (no need for steroids, no symptoms and 
signs indicating clinically significant progression of disease, no decline in ECOG 
performance status) can continue on study treatment under the following conditions:

If no immediate WBRT, both systemic lesions and brain lesions, can be followed by 
iRECIST.

If immediate WBRT is chosen, the brain lesions will be nonevaluable for iRECIST. 

Brain MRI will be required at each subsequent image assessment.
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8.2.4
Imaging for Bone Metastases
For any participant with clinical symptoms suggesting bone metastases, bone imaging 
(eg, bone scan or PET scan) should be performed to identify possible bone metastases. If 
bone metastases are identified that have not been imaged on the CT/MRI performed for 
Initial Tumor Imaging (Section 8.2.2), then additional baseline and all subsequent tumor 
imaging studies should include such lesions in the imaging field.
8.2.5
Tumor Imaging During the Study
Sites will be required to send in anatomical images/medical photography of the injected 
lesions to a central imaging vendor, as indicated in the SIM.
On-study imaging assessment for solid tumors should be performed at 9 weeks (±7 days) 
from the date of allocation. Subsequent tumor imaging should be performed every 
9 weeks (±7 days) or more frequently if clinically indicated. After 54 weeks, participants 
who remain on treatment will have imaging performed every 12 weeks (±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, or death, 
whichever occurs first.
Partial response 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, whichever is clinically indicated. 
Participants will then return to regular scheduled imaging every 9 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. 
Note that response does not typically need to be verified in real time by the central imaging 
vendor.
Per iRECIST (Section 8.2.7.1), 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 8.2.7.1. 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 8.2.7.
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8.2.6
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. 
8.2.7
Response Assessment
8.2.7.1
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 
intervention until repeat imaging is obtained (using iRECIST for participant management 
(see Table 10). 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. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
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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. 
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
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-
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.
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 
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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 Section 1.3 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
-
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.
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Additional details about iRECIST are provided in the iRECIST publication.
Table 10
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.
iCPD = immune confirmed progressive disease; iUPD = immune unconfirmed progressive disease; iCR = 
immune complete response; iRECIST = immune-related response evaluation criteria in solid tumors; PD = 
progressive disease; PFS = progression-free survival; iPR = immune partial response; iSD = immune stable 
disease
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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8.2.7.2
itRECIST
itRECIST is a response assessment that is tailored to intratumoral immunotherapy, is aligned 
with RECIST 1.1 overall response assessment [Goldmacher, G. V., et al 2020], and is further 
described in Section 10.8.
itRECIST:

Provides a guidance on baseline categorization of target and non-target lesions (Figure 2)

Provides guidance on recategorization of lesions during therapy (Figure 3)

Allows for separate response assessment in injected and noninjected lesions (Figure 4)

For injected lesions, provides an iterative response assessment process that adapts to 
changes in lesion selection for intratumoral immunotherapy (an example is provided in 
Figure 5)

Provides guidelines on prioritization of lesion injection during the course of intratumoral 
immunotherapy (see Appendix 8)
itRECIST supports standardized collection of data from intratumoral immunotherapy clinical 
studies to facilitate exploratory response analysis.
8.2.8
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 over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Laboratory 
Procedures Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings should be recorded 
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as AEs. Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs. Investigators should pay special attention to clinical 
signs related to previous serious illnesses.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of study intervention and during the follow-up period as 
specified in the SoA. Vital signs include temperature, pulse, respiratory rate, weight and 
blood pressure. Height will be measured at Visit 1 only. Weight will be measured once a 
cycle.
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
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.

The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the case report form 
(CRF). The laboratory reports must be filed with the source documents. Clinically 
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 Procedures Manual and the SoA.

If laboratory values from nonprotocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
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
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.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
Laboratory tests for screening should be performed within 72 hours 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.
8.3.4.2
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 72 hours prior to 
Cycle 1 of study intervention. If a urine test is positive or not evaluable, a serum test will be 
required. Participants must be excluded/discontinued from the study in the event of a positive 
or borderline-positive test result.
8.3.5
Viral Shedding
Detailed information is provided in the Laboratory Procedures Manual.
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6 
and Appendix 3.
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).
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The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the participant provides 
documented informed consent but before intervention allocation/randomization must be 
reported by the investigator if the participant is receiving placebo run-in or other run-in 
treatment, if the event cause the participant to be excluded from the study, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, or a procedure.
All AEs from the time of intervention allocation/randomization through 30 days following 
cessation of study intervention must be reported by the investigator.
All AEs meeting serious criteria, from the time of intervention allocation/randomization 
through 90 days following cessation of study intervention or 30 days following cessation of 
study intervention if the participant initiates new anticancer therapy, whichever is earlier, 
must be reported by the investigator.
All pregnancies and exposure during breastfeeding, from the time of intervention
allocation/randomization through 120 days following cessation of study intervention, or 30 
days following cessation of study intervention if the participant initiates new anticancer
therapy must be reported by the investigator.
Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
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 11.
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Table 11
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through 
Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious Adverse 
Event (NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse Event 
(SAE) including 
Cancer and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- potential drug-
induced liver 
injury (DILI)
- require 
regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs 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, events of clinical interest (ECIs), 
cancer, and overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
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.
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Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that upon review is 
not progression of the cancer under study will be forwarded to Global Pharmacovigilance as 
an SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
8.4.7
Events of Clinical Interest (ECIs)
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5, that is not associated with 
clinical symptoms or abnormal laboratory results.
2. An elevated AST or ALT 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).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for V938 by >40% 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 V938 or pembrolizumab. In the event of overdose, V938 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
To further evaluate V938 and pembrolizumab immunogenicity and exposure in this 
indication, and to evaluate exposure of the proposed dosing regimen, sample collections for 
analysis of ADA and PK are currently planned as shown in Section 1.3. Blood samples will 
be obtained to measure PK of serum MK-3475 and NDV RNA. Pharmacokinetic parameters 
for pembrolizumab (eg, Cmax and Ctrough) at planned visits and times will be summarized.
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Pharmacokinetic parameters for NDV RNA (eg, AUC and Cmax) at planned visits and times 
will be summarized.
Blood samples for PK and antidrug antibodies for pembrolizumab and V938 may be decided 
to be stored, reduce further sample collection, or discontinue in this trial.  Should this occur, 
it will be communicated by an administrative memo.
8.6.1
Blood Collection for Pembrolizumab and V938 PK
Pharmacokinetic samples should be drawn according to the PK collection schedule for all 
participants. Every effort should be taken to collect samples at 30 days after end-of-study 
intervention.
8.6.2
Viral Shedding
Sample collection, storage, and shipment instructions for oral cavity/throat, urine, injection 
site, and anal swab samples will be provided in the Laboratory Procedures Manual.
8.7
Pharmacodynamics
Sample collection, storage, and shipment instructions for pharmacodynamic samples will be 
provided in the Laboratory Procedures Manual.
8.7.1
Blood for Pharmacodynamic Markers
The time points for PD sampling are described in Section 1.3.
8.7.2
Tumor Biopsy
All participants in Cohorts 2a-4a and the Expansion Cohorts will be required to provide 
sample biopsies of the tumor to be injected with V938 unless deemed medically unsafe by 
the investigator. For the Expansion Cohorts ONLY, a sample biopsy from a distant, discrete, 
noninjected site after IT administration of V938 is optional. Tumor samples will be collected 
at the time points described in Section 1.3.
Tumor biopsies will only be performed at tumor sites that are deemed medically safe, in 
accordance with local guidelines. Sponsor selection criteria for the V938 FIH study ensured 
selection of sites that have investigative staff who are highly experienced in tumor biopsies.
A mandatory predose tumor biopsy will be performed at screening on the tumor lesion that is 
intended for treatment with IT injection of V938, and mandatory biopsy will also occur 
within 10 days  prior to C3D1. For the tumor lesion intended for treatment with IT injection 
of V938, the sample will be obtained by either punch biopsy for cutaneous lesions, or by 
ultrasound-guided biopsy for subcutaneous lesions. On-treatment biopsy site location may 
vary from baseline biopsy site location based on lesion accessibility and participant 
tolerance.
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For the optional biopsy of distant, discrete tumor lesions that are not intended for IT injection 
with V938 in the Expansion Cohorts, the sample biopsy will be obtained by 1 of the 
following: punch biopsy for cutaneous lesions, ultrasound-guided biopsy for subcutaneous 
lesions, or image-guided biopsy, such as CT guided biopsy for additional lesions. Method of 
biopsy will be per guidance of the investigator, as well as discussion with the Sponsor. The 
tumor biopsy of the noninjected distant, discrete lesion should, if feasible, be performed on 
the same day as the other biopsies are performed.
Leftover main study tissue will be stored for future biomedical research if the participant 
signs the future biomedical research consent.
Detailed instructions for tissue collection, processing, and shipment are provided in the 
Laboratory Procedures Manual.
8.8
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 biomarker specimens listed in Section 8.10
8.9
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for planned genetic analysis samples 
will be provided in the Laboratory Procedures Manual. Samples should be collected for 
planned analysis of associations between genetic variants in germline/tumor DNA and drug 
response. If a documented law or regulation prohibits (or local IRB/IEC does not approve) 
sample collection for these purposes, then such samples should not be collected at the 
corresponding sites. Leftover DNA extracted from planned genetic analysis samples will be 
stored for future biomedical research only if participant provides documented informed 
consent for future biomedical research.
8.10
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analysis of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants as specified in the SoA:

Blood for genetic analysis

Blood for RNA biomarker analyses

Serum for cytokine/chemokine analyses

Tumor tissue for biomarker analysis

Blood for ctDNA analysis (for participants in the Cohort Expansion Phase only)
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Sample collection, storage, and shipment instructions for exploratory biomarker specimens 
will be provided in the Laboratory Manual.
8.10.1
Blood Collection for Anti-drug Antibodies
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Laboratory Procedures Manual. ADA and neutralizing antibodies samples should be 
drawn according to the ADA and neutralizing antibodies collection schedule for all 
participants (Section 1.3). Every effort should be taken to collect samples at 30 days after 
end-of-study intervention for ADA and neutralizing antibodies. Simultaneous PK sampling is 
required for interpretation of ADA and neutralizing antibodies analysis.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Within 28 days prior to treatment allocation, potential participants will be evaluated to 
determine that they fulfill the entry requirements as set forth in Sections 5.1 and 5.2. 
Screening procedures may be repeated after consultation with the Sponsor.
Documented 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. Exceptions are thyroid and hepatitis testing, which may be done up to 
28 days prior to the first dose of study intervention.

Evaluation of ECOG is to be performed within 72 hours prior to the first dose of study 
intervention.

For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 72 hours prior to the first dose of study intervention. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed by 
the local study site laboratory).
8.11.2
Treatment Period/Vaccination Visit
The treatment period in each treatment arm begins with Cycle 1 and may continue for up to 
35 cycles (approximately 2 years) from the start of treatment until disease progression, 
unacceptable AE(s), intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the participant, participant withdraws consent, pregnancy 
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of the participant, noncompliance with study treatment or procedure requirements, or 
administrative reasons requiring cessation of treatment. Each cycle includes study medication
administration and all associated assessments as outlined in the SoA (see Section 1.3). 
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
above in Section 8.
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
Discontinuation of treatment does not represent withdrawal from the study.
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional Safety Follow-up procedures should be performed. Visit requirements are 
outlined in Section 1.3. Additional details regarding participant withdrawal and 
discontinuation are presented in Section 7.
8.11.4
Posttreatment Visits
8.11.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days (+7 days) 
after the last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
All AEs that occur prior to the Safety Follow-up Visit should be recorded (up to 30 days 
following end of treatment).
After the end of treatment, each participant will be followed up for at least 30 days for AE 
monitoring and 120 days for SAEs, ECIs, and spontaneously reported pregnancy. Serious 
adverse events, ECIs, and spontaneously reported pregnancy will be reported for 30 days 
after the end of treatment if the participant initiates new anticancer therapy. Progression of 
the cancer under study is not considered an AE.
8.11.4.2
Imaging Follow-up Visits
Participants who complete the protocol-required cycles of study intervention or who 
discontinue study intervention for reasons other than verified progressive disease should 
continue with imaging assessments per the protocol-defined schedule until: (1) progressive 
disease is verified or further confirmed by the investigator, (2) initiation of a new anticancer 
treatment, (3) death, (4) withdrawal of consent, or (5) study conclusion or early termination, 
whichever occurs first. Participants with an AE of Grade >1 will be followed up until 
resolution of the AE to Grade 0 or 1 or until the beginning of a new antineoplastic therapy, 
whichever occurs first. Participants who completed all imaging assessments and/or will not 
have further imaging assessments must enter the Survival Follow-up Phase.
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8.11.4.3
Survival Follow-up Visits
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The first survival follow-up assessment should be scheduled as described below: 

For participants who discontinue treatment intervention and who will not enter the 
Imaging Follow-up Phase, the first survival follow-up contact will be scheduled 12 weeks 
after the Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).  

For participants who completed assessments in the Imaging Follow-up Phase, the first 
survival follow-up contact will be scheduled 12 weeks after the last efficacy assessment 
Follow-up Visit has been performed.
The Sponsor may request survival status be assessed at additional time points during the 
course of the study. For example, these additional time points may be requested prior to an 
efficacy interim analysis, and/or final analysis. All participants who are not known to have 
died prior to the request for these additional survival status time points will be contacted at 
that time.
8.12
CD8 Tracer PET Imaging (ONLY at Preapproved Sites in the US)
At preapproved sites in the US only for CD8 tracer PET imaging, 7 to 10 participants will 
undergo CD8 tracer PET imaging evaluation during the screening period once the participant 
has been determined to be eligible for the study by all other criteria, and within 10 days prior 
to C3D1. At each time point, participants will be injected with a dose of 0.5 mg-1.5 mg, or 
0.8-1.2 mCi of 89Zr-Df-IAB22M2C tracer as an IV infusion over 5-10 minutes using a 
syringe pump via a peripheral vein and return for PET imaging scans, one at 24 hours 
(±3 hours) and an optional second scan at 6 days (±1 day) after tracer infusion. CD8 tracer  
infusion will occur 1 to 4 days prior to tumor biopsy. Details of CD8 tracer PET imaging and 
tissue collection will be provided in a separate manual (CD8 PET Imaging Manual). Details
will be provided via a memo to the preapproved participating sites in the US regarding the 
storage conditions and timeframe for holding the samples collected on C3D1.
This study will assess and quantify any detectable changes in 89Zr-Df-IAB22M2C uptake 
from baseline to posttreatment and establish the relationship of 89Zr-Df-IAB22M2C 
accumulation in tumors with CD8+ TIL density. This will be achieved by comparing PET 
imaging data (SUVmean) and CD8 immunofluorescence data collected from biopsied lesions 
(% CD8+ cells per mm2). Further exploratory correlative analyses will also be performed 
using PET image data.
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9
STATISTICAL ANALYSIS PLAN
9.1
Statistical Analysis Plan Summary
This section outlines the statistical analysis strategies and procedures for the study. Changes 
to analyses made after the protocol has been finalized, but prior to the conduct of any 
analyses, will be documented in a sSAP as needed and referenced in the CSR for the study. 
Post hoc exploratory analyses will be clearly identified in the CSR.
Key elements of the statistical analysis plan are summarized below: the comprehensive plan 
is provided in Sections 9.2 to 9.12.
Study Design Overview
Phase 1/1b study of V938 in combination with pembrolizumab in 
participants with histologically or cytologically confirmed diagnosis of an 
advanced solid tumor. In the dose-escalation phase, this study applies mTPI 
to identify a RP2D.
Intervention Assignment
Participants will be allocated centrally through IVRS/IWRS to V938 in 
combination with pembrolizumab based on cohort assigned.
Analysis Populations
Safety (Primary): ASaT and DLTe
PK (Secondary): Per-Protocol (PP)
Efficacy (Secondary): FAS
Primary Endpoint(s)

Dose-limiting toxicity (DLT)

Adverse event (AE)

Discontinuing study treatment due to an AE
Secondary Endpoints

Objective response (confirmed CR or PR)
Statistical Methods for 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Objective response rate will be estimated using an exact method based on 
the binomial distribution (Clopper-Pearson interval) along with its 
95% confidence interval.
Methods for the exploratory efficacy analyses (PFS, OS) are documented in 
the sSAP. 
PK parameters of study medicines will be summarized by planned visit and 
time for each dose separately. 
Statistical Methods for 
Safety Analyses
Summary statistics will be provided for the safety endpoints as appropriate. 
The pool adjacent violators algorithm [Ji Y, Li Y, Bekele BN 2007] will be 
used to estimate the DLT rates across doses. The estimate of the DLT rate 
among participants treated at RP2D of V938 in combination with 
pembrolizumab and the 80% Bayesian credible intervals for the estimate 
will be provided for each treatment arm.
Interim Analyses
An interim analysis may be conducted to enable future study planning at the 
Sponsor’s discretion and data will be examined on a continuous basis to 
allow for dose-finding decisions.
For Arm A and B of the Cohort Expansion Phase, if there are ≤2 responders
among the initial 20 participants enrolled, the arm may be stopped early for 
futility.
Multiplicity
No multiplicity adjustment is planned in this Phase 1 study.
Sample Size and Power
The overall sample size for this study depends on the observed DLT profiles 
of V938 in combination with pembrolizumab. A target sample size of 69 to 
124 participants will be used for study planning purposes.
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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). Allocation to treatment will not be randomized in either phase of the study.
9.3
Hypotheses/Estimation
Objectives of the study are outlined in Section 3. There is no hypothesis testing in this study.
9.4
Analysis Endpoints
Efficacy and safety endpoints are listed below, followed by descriptions of selected 
endpoints.
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Objective response rate is the secondary endpoint in this study. Objective response rate is 
defined as the proportion of participants in the analysis population who experience CR or PR
using RECIST 1.1 or iRECIST criteria as assessed by investigator review. 
Other endpoints (eg, PFS or OS) are exploratory endpoints in this study and details of the 
analysis plan will be documented in the sSAP. Progression-free survival is defined as the 
time from the first dose of study treatment to the first documented disease progression, using 
RECIST 1.1 criteria as assessed by investigator review, or death due to any cause, whichever 
occurs first. 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. A description of efficacy measures is provided in Section 4.2.1.1.
Pharmacokinetic endpoints include serum concentrations of V938 and pembrolizumab, as 
well as derived PK parameters (AUC and Cmax of NDV RNA).
9.4.2
Safety Endpoints
The primary safety endpoint is the incidence of DLTs. In addition, safety and tolerability will 
be assessed by clinical review of all relevant parameters including AEs, laboratory tests, vital 
signs, and viral shedding.
A description of safety measures is provided in Section 8.3 and Section 8.4.
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9.5
Analysis Populations
9.5.1
Safety Analysis Populations
The ASaT population will be used for the analysis of safety data in this study. The ASaT 
population consists of all participants who received at least 1 dose of study intervention.
The DLT-evaluable population includes ASaT participants that meet the criteria for 
DLT evaluability (see Section 6.6.2 for details).
At least 1 laboratory or vital sign measurement obtained after 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.
The primary safety and DLT analysis will include participants in the dose-escalation cohorts. 
For the expansion cohorts, the safety and DLT analysis will pool participants with the same 
dose across arms.
9.5.2
Pharmacokinetic Analysis Populations
The PP population will be used for the analysis of PK and target engagement data in this 
study. The PP population consists of the subset of participants who complied with the 
protocol sufficiently to ensure that their data will be likely to exhibit the effects of treatment, 
according to the underlying scientific model. Compliance includes such considerations as 
exposure to treatment, availability of measurements, and the absence of major protocol 
violations. Any participants or data values excluded from the analyses will be identified, 
along with the reasons for exclusion, in the CSR. At the end of the study, all participants who 
were compliant with the study procedures and have available data from at least 1 treatment 
will be included in the PP analysis dataset.
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.
There will be no formal efficacy analysis during the dose-escalation phase. Participants in the 
dose-escalation phase that meet the inclusion criteria for the respective cohort expansion arm 
and received the same dose level may be pooled as part of the FAS population.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory endpoints will be described in the sSAP.
For the cohort expansion phase, safety and efficacy analyses for each cohort expansion arm 
(Arms A and B) will pool dose-escalation participants who meet the inclusion criteria for the
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respective cohort expansion arm and received the same dose level of V938 in combination
with pembrolizumab.
9.6.1
Statistical Methods for Efficacy Analysis
The statistical methods for efficacy analyses of exploratory nature (PFS, OS) will be 
documented in the sSAP. Additional details on efficacy analyses relating to abscopal 
responses (target injected lesions vs target noninjected lesions) are also included. ORR, along 
with the confidence interval, will be estimated using an exact method based on the binomial 
distribution (Clopper-Pearson Interval). For the cohort expansion phase, ORR will be 
assessed by arm and overall. For the dose-escalation phase, while safety is of primary 
interest, ORR will be assessed by dose level and overall.
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.
Adverse events will be summarized by counts and frequencies for each dose level and cohort. 
Laboratory tests, vital signs, and other safety endpoints will be summarized as appropriate.
Dose-limiting toxicities will be listed and summarized by dose level. The pool adjacent
violators algorithm [Ji Y, Li Y, Bekele BN 2007], which forces the DLT rate estimates to be 
nondecreasing with increasing dose levels and pools adjacent violators for weighted 
estimates by sample size, will be used to estimate the DLT rates across doses in each 
treatment arm. The estimate of the DLT rate among participants treated at the RP2D and the 
80% 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. For the dose-escalation phase, these analyses 
will be performed by dose and overall. For the cohort expansion phase, these analyses will be 
performed by arm and overall. 
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis
Pharmacokinetic parameters of study interventions will be summarized by planned visit and 
time for each dose separately.
Pharmacokinetics and pharmacodynamics modeling analyses will be documented in the 
sSAP.
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9.7
Interim Analyses
An interim analysis may be conducted to enable future study planning at the Sponsor’s 
discretion. Data will be examined on a continuous basis to allow for dose-finding decisions.
For each of the arms in the cohort expansion phase (Arms A and B), a futility check will be 
performed once there are approximately 20 evaluable participants. An evaluable participant 
has at least 2 posttreatment tumor assessment that is evaluable. 
For both Arm A and Arm B, if there are ≤2 responders, the arm may be stopped early for 
futility. If the true ORR is 30%, there is a 96% chance of continuing; if the true ORR is 20%, 
there is a 79% chance of continuing (Table 12). This bar may change depending on the 
number of treatment-naive participants enrolled.
The futility bar is not binding, and the totality of the data will be evaluated before making a 
decision to discontinue enrollment. The data will be analyzed on a continuous basis and 
enrollment will not be paused in the time between when the 20th participant in a particular 
arm is enrolled and when interim analyses are performed.
Table 12
Probability of Continuing Study (Interim at N=20), by True ORR and Futility Bar
Futility Bar (# of 
Confirmed Responses)
ORR = 15%
ORR = 20%
ORR = 25%
ORR = 30%
0
0.96
0.99
~1.00
~1.00
≤1
0.82
0.93
0.98
0.99
≤2
0.59
0.79
0.91
0.96
≤3
0.35
0.59
0.77
0.89
≤4
0.17
0.37
0.59
0.76
Abbreviations: ORR=objective response rate.
9.8
Multiplicity
There will be no multiplicity control in this study.
9.9
Sample Size and Power Calculations
Dose-escalation Cohorts Sample Size:
The overall sample size for the dose-escalation phase is expected to be in a range of 20 to 44 
participants. During mTPI, each dose level will enroll 3 to 6 participants initially. Based on 
the occurrence of DLTs, up to 14 participants may enroll per dose level.
The final sample size of the dose-escalation phase is dependent on the number of dose levels 
tested and emerging safety data. 
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Expansion Cohorts Sample Size:
The overall sample size for the cohort expansion phase is expected to be approximately 
80 participants if both arms pass futility and will each enroll 40 participants.
The key efficacy endpoint will be ORR based on investigator assessment per RECIST 1.1. 
Table 13 and Table 14 show the ORR estimate and 95% CI (Clopper-Pearson) for N=20 
(interim analysis sample size for Arms A and B) and N=40 (fully enrolled Arms A and B).
Table 13
Estimate and 95% CI of ORR (N=20)
Sample Size
Number of 
Responses (PR/CR)
Observed ORR
95% CI of ORR
20
1
5%
(0.1%, 24.9%)
2
10%
(1.2%, 31.7%)
3
15%
(3.2%, 37.9%)
4
20%
(5.7%, 43.7%)
5
25%
(8.7%, 49.1%)
6
30%
(11.9%, 54.3%)
8
40%
(19.1%, 63.9%)
10
50%
(27.2%, 72.8%)
Abbreviations: CI = confidence interval; CR = complete response; ORR = objective response rate; PR = partial response.
Table 14
Estimate and 95% CI of ORR (N=40)
Sample Size
Number of 
Responses (PR/CR)
Observed ORR
95% CI of ORR
40
4
10%
(2.8%, 23.7%)
5
12.5%
(4.2%, 26.8%)
6
15%
(5.7%, 29.8%)
7
17.5%
(7.3%, 32.8%)
8
20%
(9.1%, 35.6%)
9
22.5%
(10.8%, 38.5%)
10
25%
(12.7%, 41.2%)
15
37.5%
(22.7%, 54.2%)
Abbreviations: CI = confidence interval; CR = complete response; ORR = objective response rate; PR = partial response.
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9.10
Subgroup Analyses
Subgroup analyses of efficacy endpoints will be documented in the sSAP. Subgroups of 
interest for this study may include PD-L1 status and lactate dehydrogenase (high versus 
normal).
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 of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (eg, International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (eg, 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 (ie, participant population, duration, statistical power) must be adequate to address the specific
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of 
Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data 
are verified versus source documentation according to standard operating procedures. Per MSD policies and 
procedures, if fraud, scientific/research misconduct, or serious GCP-noncompliance is suspected, the issues 
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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 primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing, in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have 
access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
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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 (eg, to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Internal Medical Monitoring Team
This study does not meet the FDA criteria for requiring an independent Study Safety 
Committee, as it is a Phase 1 open-label exploratory study, rather than a large, 
randomized/blinded study with OS as an endpoint.
Mechanisms have been put in place by the Sponsor to closely monitor participant safety. An 
MMT consisting of a core team of employees of the Sponsor has been formed to oversee the 
medical monitoring of this study. The roles and description of the members of the MMT are 
as follows:
Clinical Scientist: MMT Chair; identifies types of safety reports and topics for review to 
monitor participant safety
Clinical Director: Provides medical oversite as the Medical Monitor
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Statistician: Analyzes trends and monitors participant safety
Statistical Programmer: Programs reports identified by the MMT
Data Manager: monitors participant safety, monitors SAEs and ECIs, and ensures AEs are 
properly encoded
Clinical Safety Scientist: Monitors participant safety
Formal monthly meetings will be scheduled during which the members of the MMT will 
review specific safety reports and any emerging participant safety themes.
During the MMT meetings, reports will be generated to review the following data points as 
well as any other findings relevant to participant safety; the plan includes, but is not limited 
to, review of the following endpoints and deviations: 
Endpoint or Important 
Protocol Deviations
Endpoint Category
Types of Data the MMT Will Monitor
DILI
Event of Clinical Interest 
(Endpoint)
ECI (DILI):  ALT or AST ≥3X ULN and 
TBili ≥2X ULN and AP <2X ULN
Overdose
Event of Clinical Interest 
(Endpoint)
V938: any dose exceeding the prescribed 
dose for V938 by >40%
Pembro:  ≥1000 mg (≥5 times the indicated 
dose)
DLT
Primary (Endpoint)
Refer to Section 6.6.2 of the protocol for 
definition.
AE
Primary (Endpoint)
Refer to Appendix 3 of the protocol.
Discontinuing study 
intervention due to AE
Primary (Endpoint)
Refer to Section 7.1 of the protocol.
IT RECIST
Tertiary/Exploratory 
(Endpoint)
Consistency in identification of 
injected/biopsied lesions and ensuring 
collection of injected lesion images
OS
Tertiary/Exploratory 
(Endpoint)
The time from randomization to death due 
to any cause
PFS
Tertiary/Exploratory 
(Endpoint)
The time from randomization to the first 
documented disease progression or death 
due to any cause, whichever occurs first
Pembro PK
Tertiary/Exploratory 
(Endpoint)
Ensure critical samples are being collected 
per protocol
Exploratory Molecular 
Biomarker
Tertiary/Exploratory 
(Endpoint)
Ensure critical samples are being collected 
per protocol
Pharmacokinetic Endpoints -
V938 (RNA)
Secondary (Endpoint)
Ensure critical samples are being collected 
per protocol
Viral Shedding
Secondary (Endpoint)
Ensure critical samples are being collected 
per protocol
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Endpoint or Important 
Protocol Deviations
Endpoint Category
Types of Data the MMT Will Monitor
ORR
Secondary (Endpoint)
Solid Tumor:   Participants who have a 
confirmed complete response or partial 
response. Assessment will be based on 
RECIST 1.1 and iRECIST.
Antidrug Antibody Levels
Tertiary/Exploratory 
(Endpoint)
Ensure critical samples are being collected 
per protocol
Important Protocol 
Deviations
Informed Consent (LIPD)
Participant had no documented initial 
consent to enter the study.
Important Protocol 
Deviations
Safety Reporting (LIPD)
Participant had a reportable Safety Event 
and/or follow-up Safety Event information 
that was not reported per the timelines 
outlined in the protocol.
Abbreviations: AE=adverse event; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
DILI=drug-induced liver injury; DLT=dose-limiting toxicity; ECI=events of clinical interest; 
iRECIST=immune-related Response Evaluation Criteria in Solid Tumors; IT=intratumoral; LIPD=list of 
important protocol deviations; ORR=overall response rate; OS=overall survival; PFS=progression-free 
survival; PK=pharmacokinetics; RECIST= Response Evaluation Criteria in Solid Tumors; RNA=ribonucleic 
acid; ULN=upper limit of normal.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
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disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Studies.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
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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 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
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10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
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10.2
Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 15 below will be performed by the local laboratory.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations.

Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
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 15
Protocol-required Safety Laboratory Assessments
Hematology
Comprehensive Chemistry 
Panel
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine)a
Hemoglobin
Alkaline phosphatase
Glucose
Total T3 (or Free T3 
[FT3]), Total T4 (or Free 
T4 [FT4]), and TSHb,c
Platelet count
Alanine aminotransferase
Protein
Anti-HCV d
WBC (total and 
differential)e
Aspartate aminotransferase
Specific gravity 
HCV viral loadc,d
RBC
Carbon dioxide or 
bicarbonate
Microscopic examination, 
if abnormal results are 
noted
HIV Viral Load, HIV 1,2 
Antibody f
Absolute 
lymphocyte count e
Calcium
anti-HBsc,d
Chloride
HbsAg d
Absolute neutrophil 
count e
Creatinine
anti-HBc (total and 
IgM)c,d
PT/INR
Glucose
HbeAgc, d
PTT or aPTT
Phosphorus/phosphate
anti-Hbec,d
Basophil
Potassium
HBV viral loadc,d
Eosinophil
Sodium
CD4 T-cell count f
Monocyte
Total bilirubin
Direct bilirubin g
Total protein
Blood urea nitrogen or urea h
Lactate dehydrogenase
Uric acid
Magnesium
Creatine kinase
Abbreviations: aPTT=activated partial thromboplastin time; F=free; HBc=hepatitis B core antigen; HBeAg=hepatitis B e 
antigen; HBsAg=hepatitis B surface antigen; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus; INR=International Normalized Ratio; PT=prothrombin time; PTT=partial thromboplastin time; 
RBC=red blood count; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WBC=white blood count.
a  Perform on women of childbearing potential only 72 hours prior to Day 1 of Cycle 1. Pregnancy tests must be repeated 
prior to every cycle if required or as specified per local regulatory guidance.
b  T3 is preferred; if not available, Free T3 may be tested.
c  If the local laboratory is unable to perform these tests, the site should submit the sample to the central laboratory for 
testing. Details are provided in the Laboratory Procedures Manual.
d   To be performed only if required by local regulatory agencies
e  Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
f    To be performed for HIV positive participants only.
g    Direct bilirubin to be performed if total bilirubin is elevated above the upper limit of normal
h   BUN is preferred. If BUN is not available, urea may be tested.
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
Definition of AE
AE definition

An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.

NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in the 
medical and scientific judgment of the investigator.

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.

For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
Any new cancer (that is not a condition of the study). Progression of the cancer under study 
is not considered a reportable event unless it results in hospitalization or death. Refer to 
Section 8.4.6 for additional details.
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Events NOT meeting the AE definition

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.

Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.

Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening

The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization

Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a 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.
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d. Results in persistent or significant disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.

This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.

Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
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
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10.3.4
Recording AE and SAE
AE and SAE recording

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.

The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.

It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.

There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity

An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.

The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 4. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
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Assessment of causality

Did the Sponsor’s product cause the AE?

The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.

The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the Sponsor’s 
product caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the 
Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
-
Time Course: Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor’s product? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
◦
If yes, did the AE resolve or improve?
◦
If yes, this is a positive dechallenge.
◦
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor’s 
product; (3) the study is a single-dose drug study; or (4) Sponsor’s product(s) is/are 
only used 1 time.)
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-
Rechallenge: Was the participant re-exposed to the Sponsor’s product in this 
study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.

Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?

The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.

Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence 
of the AE onset relative to the administration of the Sponsor’s product is 
reasonable. The AE is more likely explained by the Sponsor’s product than by 
another cause.
-
No, there is not a reasonable possibility of Sponsor's product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable 
OR the AE is more likely explained by another cause than the Sponsor’s 
product. (Also entered for a participant with overdose without an associated 
AE.)
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
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.

The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.

For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

New or updated information will be recorded in the CRF.

The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool

The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
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-
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).
SAE reporting to the Sponsor via paper CRF

If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
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 follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.

Progestogen- only contraceptive implantc,d

Intrauterine hormone-releasing system (IUS)c,e

Intrauterine device (IUD)

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner 
of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.

Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable

Progestogen-only hormonal contraceptionc,d
-
Oral
-
Injectable
Sexual Abstinence

Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and 
usual lifestyle of the participant.
Acceptable Contraceptive Methods
Failure rate of >1% per year when used consistently and correctly.

Progesterone-only hormonal contraception where inhibition of ovulation is not the primary mode of 
action

Male or female condom with or without spermicide

Cervical cap, diaphragm, or sponge with spermicide

A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double 
barrier methods)f
a.
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods 
for participants of clinical studies.
b. Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c.
Male condoms must be used in addition to the hormonal contraception.
d. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive implants 
are limited to those which inhibit ovulation.
e.
IUS is a progestin releasing IUD.
f.
A combination of male condom with either cap, diaphragm, or sponge with spermicide are considered acceptable, but not 
highly effective, birth control methods.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM).
-
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 drugs/vaccines may interact with

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 participant’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and intervention outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
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5. Biorepository Specimen Usage3,4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3,4
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@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 Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
Germany
Section 1.3.1   Schedule of Activities for Screening
Assessment
Note
Pregnancy test for WOCBP only (urine or 
serum hCG)
Perform within 72 hours 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. Monthly pregnancy testing 
should be conducted as per local 
regulations, or as clinically indicated.
HIV, Hepatitis B and C Screen
Testing is required at screening.
Section 1.3.2   Schedule of Activities for the Treatment Period
Assessment
Note
Pregnancy test for WOCBP only (urine or 
serum hCG)
Perform within 72 hours 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. Monthly pregnancy testing 
should be conducted as per local 
regulations, or as clinically indicated.
Section 5.1 Inclusion Criteria
Informed Consent
7. The participant has provided 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.
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10.8 Appendix 8: itRECIST Supplementary Figures
Figure 2
Algorithm for Classification of Lesions at Baseline
Source: Adapted from [Goldmacher, G. V., et al 2020]
Lesions are classified first as measurable or nonmeasurable using the standard RECIST 1.1 
rules for measurability. Measurable lesions (those eligible for selection as target lesions) are 
then classified as target (selected to be followed quantitatively) or nontarget (selected to be 
followed qualitatively), and the decisions about which lesions are to be injected are made 
based on the prioritization rules discussed. Lesions selected for injection may be either target 
or nontarget in RECIST 1.1 terms. Between one and 5 lesions should be classified as target 
injected, and between one and 5 should be classified as target noninjected, for a maximum of 
10 target lesions. All lesions not chosen as target are followed qualitatively as nontarget, and 
some of these may be selected for injection at baseline. T-I lesions and T-NI lesions each 
have their own distinct SOD. A combined SOD also includes all target lesions, injected and 
noninjected. NT-I and NT-NI lesions are followed qualitatively, exactly as in RECIST 1.1, 
classified in aggregate as showing complete response, unequivocal progression, or neither 
(called non-CR/non-PD in RECIST 1.1).
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Figure 3
Reclassification of Noninjected Lesions
Source: Adapted from [Goldmacher, G. V., et al 2020].
Target or nontarget noninjected lesions can be recategorized as injected lesions if the 
decision is made to inject them after baseline assessment. Nontarget noninjected lesions may 
be injected if previously injected nontarget lesions regress completely or become inaccessible 
or if a participant factor such as injection site reaction or participant intolerance precludes 
further injection. Lesions initially selected as target noninjected should remain noninjected 
for as long as possible so the maximal noninjected effect can be evaluated, but they may be 
injected if they are enlarging, or if no other lesions are available for injection, especially if 
the lesions initially designated as target noninjected are not regressing. The barrier between 
target and nontarget categories means that all lesions remain target and nontarget in 
accordance with the initial designation, regardless of whether they are subsequently injected. 
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Figure 4
Overall Response Assessment Until Disease Progression
Abbreviations: RECIST 1.1=Response Evaluation Criteria in Solid Tumors, version 1.1.
Source: Adapted from [Goldmacher, G. V., et al 2020].
Overall response until disease progression per RECIST 1.1. The injected response at each 
visit is based on only the changes in the SODs of the lesions designated as target injected. 
The noninjected response at each visit is based on only the changes in the SODs of the target 
noninjected lesions. The overall response is based on the changes in the SODs of all target 
lesions together, the qualitative assessment of all nontarget lesions together, and the 
evaluation for possible new lesions and uses the same response categories and logical 
combination of these that RECIST 1.1 uses. 
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Figure 5
Example of Iterative Assessment of Injected Lesion Response During Treatment
Abbreviations: iPR = immunotherapeutic partial response; NE = not evaluable; NT-I = nontarget injected; NT-NI = 
nontarget noninjected; PD = progressive disease; PR = partial response; iRECIST 1.1 =  immunotherapeutic Response 
Evaluation Criteria in Solid Tumors; SD =  stable disease; SOD = sum of diameters (longest diameters for extranodal 
lesions, short axis for lymph nodes); T-I = target injected; T-NI = target noninjected.
Source: [Goldmacher, G. V., et al 2020]
This is an illustration of overall, injected, and noninjected response assessment, with a 
particular focus on the iterative assessment of injected lesions. All lesions from a single 
participant are displayed in simple schematic form and are not meant to be anatomically 
adjacent. For purposes of this illustration, the yellow and green lesions were selected at 
baseline as target injected, and the purple and blue lesions were selected as target 
noninjected; there are no nontarget lesions. In this simplified example, a full imaging 
assessment is performed at each treatment visit just before the decision about which lesions 
to inject at that visit. The overall response at each visit was based on the change in SODs for 
all the target lesions together (because there are no nontarget lesions in this example). Once 
progressive disease is observed (in this case, because of a new lesion), the overall response 
assessment thereafter is similar to that of iRECIST. The injected response is based on the 
change in SOD of the injected lesions from the assessment immediately before this one. The 
noninjected response is based on the changes in SOD from baseline and nadir and is 
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considered nonevaluable once any lesion that was initially selected as T-NI is subsequently 
injected, as happens in this case with the blue lesion. If this lesion were to grow later, it could 
contribute to an overall response of PD.
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10.9
Appendix 9: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibody
ADL
activities of daily living
AE
adverse event 
ALT
alanine aminotransferase
ANC
absolute neutrophil count
ART
antiretroviral therapy
ASaT
All-Subjects-as-Treated
AST
aspartate aminotransferase
ASTCT
American Society for Transplantation and Cellular Therapy
AUC
area under the curve
BICR
blinded independent central review
BRAF
proto-oncogene B-rapidly accelerated fibrosarcoma
C
cycle
CD
cluster of differentiation
CD3ζ
cluster of differentiation 3 zeta
CIV
central imaging vendor 
Cmax
maximum concentration
Cmin
minimum concentration
Ctrough
lowest concentration of a drug just before the next dose
CR
complete response
CRF
case report form 
CRS
cytokine release syndrome
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor deoxyribonucleic acid
CTLA-4
cytotoxic T lymphocyte associated protein 4
D
day
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DLTe
DLT-evaluable
DNA
deoxyribonucleic acid 
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data collection 
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment of Cancer
EOT
end of treatment
FAS
full analysis set
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FIH
first-in-human
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
GM-CSF
granulocyte-macrophage colony-stimulating factor
GMP
Good Manufacturing Practice
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
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Abbreviation
Expanded Term
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HNSCC
head and neck squamous cell carcinoma
HRT
hormone replacement therapy
HSV
herpes simplex virus
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation
iCPD
immune confirmed progressive disease
iCR
immune complete response
IEC
Independent Ethics Committee
IFN
interferon
Ig
immunoglobulin
IHC
immunohistochemistry
IL
interleukin
iPR
immune partial response
irAE
immune-related adverse event
IRB
Institutional Review Board 
iRECIST
immune-related Response Evaluation Criteria in Solid Tumors
iSD
immune stable disease
IT
intratumoral
iUPD
immune unconfirmed progressive disease
IV
intravenous
IVRS/IWRS
interactive voice response system/integrated web response system
LLOQ
lower limit of quantitation
MMT
Medical Monitoring Team
MRI
magnetic resonance imaging
MSI-H
Microsatellite instability-high
MTD
maximum tolerated dose 
mTPI
modified toxicity probability interval
NDV
Newcastle Disease Virus
NK
natural killer
NOAEL
no observed adverse effect level 
NSCLC
non-small-cell lung carcinoma
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PCR
polymerase chain reaction
PD
progressive disease
PD-1
programmed cell death protein 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression-free survival
PFU
plaque-forming units
PK
pharmacokinetic(s)
PKCθ
protein kinase C theta
po
by mouth
PP
per-protocol
PR
partial response
Q3W
every 3 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
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Abbreviation
Expanded Term
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
SAE
serious adverse event 
SIM
Site Imaging Manual
SoA
Schedule of Activities
SOD
sum of diameters
SPD
sum of the products of diameters
sSAP
supplementary SAP
SUSAR
suspected unexpected serious adverse reaction
SUV
standardized uptake value
TIL
T-cell infiltrating lymphocytes
WBRT
whole brain radiation treatment
WOCBP
woman/women of childbearing potential
ZAP70
zeta chain associated protein kinase
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