A Phase 1/1b, Open-label Clinical Study of Intratumoral/Intralesional Administration of MK-4621/JetPEI as Monotherapy or in Combination With Pembrolizumab (MK-3475) in Participants With Advanced/Metastatic or Recurrent Solid Tumors
Phase: PHASE1
Conditions: Advanced Solid Tumors
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
A Phase 1/1b, Open-label Clinical Study of Intratumoral/
Intralesional Administration of MK-4621/JetPEI as Monotherapy or 
in Combination with Pembrolizumab (MK-3475) in Participants 
with Advanced/Metastatic or Recurrent Solid
Tumors
27-OCT-2020
NCT03739138

PRODUCT: MK-4621 
1
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A. 
(MSD).
Protocol Title: A Phase 1/1b, Open-label Clinical Study of Intratumoral/Intralesional 
Administration of MK-4621/JetPEI as Monotherapy or in Combination with 
Pembrolizumab (MK-3475) in Participants with Advanced/Metastatic or Recurrent Solid 
Tumors
Protocol Number: 002-04
Compound Number: MK-4621
Sponsor Name:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
EudraCT
2018-000845-37
Approval Date: 27 October 2020
 
 
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PRODUCT: MK-4621 
2
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
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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PRODUCT: MK-4621 
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PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-4621-002-04
27-Oct-2020
The overall rationale for the amendment is 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.
MK-4621-002-03-V2
22-Mar-2019
This amendment (-03) was updated to correct an error in the document footer.
MK-4621-002-03
21-Mar-2019
The main purpose for the amendment is to remove testing for GLDH from Arms 1 
and 2.
MK-4621-002-02
19-Sep-2018
To clarify the order of recruitment to the different arms of the study and the 
maximum duration of treatment with MK-4621/JetPEI.
MK-4621-002-01
26-Jul-2018
To provide for more frequent pregnancy testing; to clarify risk associated with 
MK-4621 with regard to contraception, pregnancy, and breastfeeding; and to extend 
the prohibition of live vaccines from 3 months after the end of the study treatment.
MK-4621-002-00
29-May-2018
Original protocol.
 
 
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PRODUCT: MK-4621 
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PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 04
Overall Rationale for the Amendments:
The overall rationale for the amendment is 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.
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
1  Synopsis
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.
This change will allow this study to be closed.
 
 
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PRODUCT: MK-4621 
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PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities (SoA)................................................................................20
1.3.1
Schedule of Activities for the Initial Screening (Arms 1, 2, and 3) and 
Crossover Screening (Arm 1 to Arm 2).......................................................20
1.3.2
Schedule of Activities for the Treatment Period..........................................22
1.3.2.1
Schedule of Activities for the Treatment Period for Arm 1...............22
1.3.2.2
Schedule of Activities for the Treatment Period for Arm 2...............25
1.3.2.3
Schedule of Activities for the Treatment Period for Arm 3...............29
1.3.3
Schedule of Activities for the End of Treatment and Post-Treatment 
Follow-Up Periods.......................................................................................33
2
INTRODUCTION..........................................................................................................35
2.1
Study Rationale....................................................................................................35
2.2
Background ..........................................................................................................36
2.2.1
Pharmaceutical and Therapeutic Background .............................................36
2.2.1.1
MK-4621/JetPEI Pharmaceutical and Therapeutic Background.......36
2.2.1.2
Mechanism of Action.........................................................................37
2.2.1.3
Preclinical Studies of MK-4621/JetPEI.............................................38
2.2.1.4
Pembrolizumab Pharmaceutical and Therapeutic Background .........38
2.2.2
Ongoing Clinical Studies.............................................................................39
2.2.2.1
MK-4621/JetPEI Clinical Studies......................................................39
2.2.2.2
Pembrolizumab Clinical Studies........................................................39
2.3
Benefit/Risk Assessment......................................................................................39
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS .................................................40
4
STUDY DESIGN............................................................................................................41
4.1
Overall Design......................................................................................................41
4.2
Scientific Rationale for Study Design.................................................................44
4.2.1
Rationale for Endpoints ...............................................................................44
4.2.1.1
Efficacy Endpoints.............................................................................44
4.2.1.1.1
Response Rate Assessed by RECIST 1.1 ................................44
4.2.1.1.2
Response Rate Assessed by Modified Response Evaluation 
Criteria in Solid Tumors 1.1 for Immune-based 
Therapeutics (iRECIST) ..........................................................45
 
 
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4.2.1.2
Safety Endpoints................................................................................45
4.2.1.3
Pharmacokinetic Endpoints ...............................................................46
4.2.1.4
Target Engagement and Pharmacodynamic Endpoints .....................46
4.2.1.5
Planned Exploratory Biomarker Research.........................................46
4.2.1.6
Future Biomedical Research..............................................................48
4.3
Justification for Dose...........................................................................................48
4.3.1
Starting Dose for This Study........................................................................48
4.3.1.1
Rationale for Starting and Maximum Dose of MK-4621..................48
4.3.1.2
Rationale for Fixed Dose of Pembrolizumab.....................................49
4.3.1.3
Rationale for Dose Interval and Escalation Increments.....................50
4.3.1.4
Dose Finding Using a Modified Toxicity Probability Interval 
Design ................................................................................................51
4.4
Beginning and End of Study Definition .............................................................53
4.4.1
Clinical Criteria for Early Study Termination .............................................53
5
STUDY POPULATION ................................................................................................53
5.1
Inclusion Criteria.................................................................................................53
5.2
Exclusion Criteria................................................................................................56
5.3
Lifestyle Considerations......................................................................................58
5.3.1
Meals and Dietary Restrictions....................................................................58
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................59
5.3.3
Activity ........................................................................................................59
5.3.4
Contraception...............................................................................................59
5.3.5
Pregnancy.....................................................................................................59
5.3.6
Use in Nursing Women................................................................................59
5.4
Screen Failures.....................................................................................................60
5.5
Participant Replacement Strategy......................................................................60
6
STUDY INTERVENTION............................................................................................60
6.1
Study Intervention(s) Administered...................................................................60
6.1.1
Intratumoral Injection ..................................................................................61
6.1.2
Medical Devices...........................................................................................65
6.2
Preparation/Handling/Storage/Accountability .................................................65
6.2.1
Dose Preparation..........................................................................................65
6.2.2
Handling, Storage, and Accountability........................................................65
6.3
Measures to Minimize Bias: Randomization and Blinding..............................66
6.3.1
Intervention Assignment..............................................................................66
6.3.2
Stratification.................................................................................................66
6.3.3
Blinding........................................................................................................66
6.4
Study Intervention Compliance..........................................................................67
 
 
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6.5
Concomitant Therapy..........................................................................................67
6.5.1
Acceptable Concomitant Medications .........................................................67
6.5.2
Prohibited Concomitant Medications ..........................................................67
6.5.3
Rescue Medications and Supportive Care ...................................................68
6.5.3.1
MK-4621/JetPEI Supportive Care.....................................................68
6.5.3.2
Pembrolizumab Supportive Care.......................................................69
6.6
Dose Modification (Escalation/Titration/Other)...............................................69
6.6.1
Dose Administration/Escalation ..................................................................69
6.6.1.1
Dose Administration (Preparation)....................................................69
6.6.2
Definition of Dose-limiting Toxicity...........................................................70
6.6.3
Crossover Treatment Phase (Optional)........................................................71
6.6.4
Timing of Dose Administration...................................................................72
6.6.5
Guidelines for Dose Modification for MK-4621/JetPEI and/or 
Pembrolizumab due to Adverse Events .......................................................73
6.6.5.1
Dose Modification for MK-4621/JetPEI ...........................................73
6.6.5.2
Dose Modification for Pembrolizumab .............................................75
6.7
Intervention After the End of the Study............................................................80
6.8
Clinical Supplies Disclosure................................................................................80
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................81
7.1
Discontinuation of Study Intervention...............................................................81
7.2
Participant Withdrawal From the Study...........................................................82
7.3
Lost to Follow-up .................................................................................................82
8
STUDY ASSESSMENTS AND PROCEDURES........................................................83
8.1
Administrative and General Procedures ...........................................................83
8.1.1
Informed Consent.........................................................................................83
8.1.1.1
General Informed Consent.................................................................84
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................84
8.1.2
Inclusion/Exclusion Criteria ........................................................................84
8.1.3
Participant Identification Card.....................................................................84
8.1.4
Medical History ...........................................................................................85
8.1.5
Prior and Concomitant Medications Review...............................................85
8.1.5.1
Prior Medications...............................................................................85
8.1.5.2
Concomitant Medications..................................................................85
8.1.6
Assignment of Screening Number...............................................................85
8.1.7
Assignment of Treatment/Randomization Number.....................................86
8.1.8
Study Intervention Administration ..............................................................86
 
 
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PRODUCT: MK-4621 
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27-OCT-2020
8.1.8.1
Timing of Dose Administration.........................................................86
8.1.9
Discontinuation and Withdrawal .................................................................87
8.1.9.1
Withdrawal From Future Biomedical Research ................................87
8.1.10
Participant Blinding/Unblinding..................................................................88
8.1.11
Domiciling ...................................................................................................88
8.1.12
Calibration of Equipment.............................................................................88
8.2
Efficacy/Immunogenicity Assessments ..............................................................88
8.2.1
Tumor Imaging and Assessment of Disease................................................88
8.2.2
Initial Tumor Imaging..................................................................................89
8.2.3
Tumor Imaging During the Study................................................................89
8.2.4
End of Treatment and Follow-up Tumor Imaging.......................................90
8.2.5
iRECIST Assessment of Disease.................................................................90
8.2.6
Eastern Cooperative Oncology Group (ECOG) Performance Scale ...........96
8.3
Safety Assessments...............................................................................................96
8.3.1
Physical Examinations.................................................................................96
8.3.1.1
Full Physical Exam ............................................................................96
8.3.1.2
Directed Physical Exam.....................................................................96
8.3.2
Vital Signs....................................................................................................96
8.3.3
Electrocardiograms ......................................................................................96
8.3.4
Clinical Safety Laboratory Assessments .....................................................97
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)..........................................................................................97
8.3.4.2
Pregnancy Test...................................................................................98
8.4
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events ....................................................................................98
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................98
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....101
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.101
8.4.4
Regulatory Reporting Requirements for SAE ...........................................101
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................101
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................102
8.4.7
Events of Clinical Interest (ECIs)..............................................................102
8.5
Treatment of Overdose......................................................................................102
8.6
Pharmacokinetics...............................................................................................103
8.6.1
Blood Collection for Plasma MK-4621/JetPEI..........................................103
8.6.2
Blood Collection for Anti-pembrolizumab Antibodies .............................103
 
 
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PRODUCT: MK-4621 
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PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
8.7
Pharmacodynamics............................................................................................103
8.7.1
Blood for Pharmacodynamic Markers.......................................................103
8.7.2
Tumor Biopsy ............................................................................................103
8.7.2.1
Pretreatment Tumor Biopsy.............................................................103
8.7.2.2
Posttreatment Tumor Biopsy ...........................................................104
8.8
Future Biomedical Research Sample Collection.............................................104
8.9
Planned Genetic Analysis Sample Collection..................................................104
8.10
Biomarkers .........................................................................................................105
8.10.1
Planned Genetic Analysis Sample Collection............................................105
8.10.2
Blood Collection for Antidrug Antibodies ................................................105
8.11
Visit Requirements.............................................................................................105
8.11.1
Screening....................................................................................................105
8.12
Treatment Period...............................................................................................106
8.12.1
Discontinued Participants Continuing to be Monitored in the Study ........106
8.12.2
Poststudy....................................................................................................106
8.12.2.1
Safety Follow-up Visit.....................................................................106
8.12.2.2
Imaging Follow-up Visit(s) .............................................................107
8.12.2.3
Survival Follow-up Visits................................................................107
8.12.3
Survival Status ...........................................................................................107
9
STATISTICAL ANALYSIS PLAN ...........................................................................107
9.1
Statistical Analysis Plan Summary...................................................................107
9.2
Responsibility for Analyses/In-house Blinding ...............................................109
9.3
Hypotheses/Estimation ......................................................................................109
9.4
Analysis Endpoints.............................................................................................109
9.4.1
Efficacy/Pharmacokinetics Endpoints .......................................................109
9.4.2
Safety Endpoints........................................................................................110
9.5
Analysis Populations..........................................................................................110
9.5.1
Safety Analysis Populations ......................................................................110
9.5.2
Pharmacokinetic Analysis Populations......................................................110
9.5.3
Efficacy Analysis Populations...................................................................110
9.6
Statistical Methods.............................................................................................111
9.6.1
Statistical Methods for Efficacy Analysis..................................................111
9.6.2
Statistical Methods for Safety Analysis.....................................................111
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................111
9.6.3.1
Demographic and Baseline Characteristics .....................................111
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis..........111
9.7
Interim Analyses ................................................................................................111
 
 
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PRODUCT: MK-4621 
10
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
9.8
Multiplicity .........................................................................................................112
9.9
Sample Size and Power Calculations ...............................................................112
9.10
Subgroup Analyses.............................................................................................112
9.11
Compliance (Medication Adherence)...............................................................112
9.12
Extent of Exposure.............................................................................................112
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................113
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......113
10.1.1
Code of Conduct for Clinical Trials...........................................................113
10.1.2
Financial Disclosure...................................................................................115
10.1.3
Data Protection...........................................................................................115
10.1.3.1
Confidentiality of Data ....................................................................116
10.1.3.2
Confidentiality of Participant Records.............................................116
10.1.3.3
Confidentiality of IRB/IEC Information..........................................116
10.1.4
Committees Structure.................................................................................116
10.1.5
Publication Policy......................................................................................116
10.1.6
Compliance with Study Registration and Results Posting Requirements .117
10.1.7
Compliance with Law, Audit, and Debarment ..........................................117
10.1.8
Data Quality Assurance .............................................................................118
10.1.9
Source Documents .....................................................................................118
10.1.10
Study and Site Closure...............................................................................119
10.2
Appendix 2: Clinical Laboratory Tests............................................................120
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................121
10.3.1
Definition of AE ........................................................................................121
10.3.2
Definition of SAE ......................................................................................122
10.3.3
Additional Events Reported in the Same Manner as SAE.........................123
10.3.4
Recording AE and SAE .............................................................................123
10.3.5
Reporting of AE, SAE, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................127
10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting.........................................129
10.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing......................130
10.5.1
Definitions..................................................................................................130
10.5.2
Contraception Requirements......................................................................130
10.5.3
Pregnancy Testing......................................................................................132
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................133
 
 
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10.7
Appendix 7: Country-specific Requirements..................................................138
10.8
Appendix 8: Abbreviations ...............................................................................141
11
REFERENCES.............................................................................................................144
 
 
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LIST OF TABLES
Table 1
Dose-finding Rules per mTPI Design........................................................52
Table 2
Adequate Organ Function Laboratory Values ...........................................55
Table 3
Determination of Minimum Target Lesion Diameter at Treatment 
Initiation by Dose Level.............................................................................61
Table 4
Determination of MK-4621/JetPEI Injection Volume for Injections 
Administered in More Than one Target Lesion Upon Change in Lesion 
Diameter After Initial Treatment ...............................................................62
Table 5
Study Intervention(s) .................................................................................64
Table 6
MK-4621/JetPEI Dose Modification and Treatment Discontinuation 
Guidelines for Drug-related Adverse Events.............................................74
Table 7
Dose Modification and Toxicity Management Guidelines for 
Immune-related AEs Associated with Pembrolizumab.............................76
Table 8
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................79
Table 9
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease.......................................................................................................95
Table 10
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events...............................................................100
Table 11
Protocol-required Safety Laboratory Assessments..................................120
Table 12
Highly Effective Contraceptive Methods That Have Low User 
Dependency..............................................................................................132
 
 
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27-OCT-2020
LIST OF FIGURES
Figure 1
Overall Study Design.................................................................................19
Figure 2
Schematic Representation of MK-4621/JetPEI Mechanism of Action .....38
 
 
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PRODUCT: MK-4621 
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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 MK-4621/JetPEI as Monotherapy or in Combination with Pembrolizumab 
(MK-3475) in Participants with Advanced/Metastatic or Recurrent Solid Tumors
Short Title: Phase 1/1b Open-label Study of MK-4621/JetPEI by IT Injection
Acronym: Not applicable.
Hypotheses, Objectives, and Endpoints:
Primary Objectives
Primary Endpoints
- Objective: To evaluate the safety and 
tolerability and to establish a preliminary 
recommended Phase 2 dose (RP2D) of 
MK-4621/JetPEI administered as 
monotherapy and in combination with 
pembrolizumab
- Dose-limiting toxicity (DLT)
- Adverse events (AEs)
- Study intervention discontinuations due to 
AEs
Secondary Objectives
Secondary Endpoints
- Objective: To evaluate the 
pharmacokinetics (PK) of MK-4621/JetPEI 
administered as monotherapy and in 
combination with pembrolizumab
- PK parameters of MK-4621/JetPEI, 
including area under the curve (AUC), 
minimum concentration (Cmin), maximum 
concentration (Cmax)
- Objective: To evaluate the objective 
response rate (ORR) as assessed by the 
investigator based on Response Evaluation 
Criteria in Solid Tumors Version 1.1 
(RECIST 1.1) and modified RECIST 1.1 for 
immune-based therapeutics (iRECIST) of 
MK-4621/JetPEI administered as 
monotherapy and in combination with 
pembrolizumab
- Objective response is a confirmed 
complete response (CR) or partial response 
(PR)
 
 
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Overall Design:
Study Phase
Phase 1/1b
Primary Purpose
Treatment
Indication
The treatment of participants with advanced/metastatic or 
recurrent solid tumors.
Population
Participants with any histologically- or 
cytologically-confirmed advanced/metastatic solid tumor 
by pathology report who have received or been intolerant 
to all treatment known to confer clinical benefit
Study Type
Interventional
Intervention Model
This is a mono- and combination-therapy, dose-finding 
and dose-confirmation, 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 2.5 years from the time the first participant 
signs the informed consent until the last participant’s last 
study-related telephone call or visit.
Number of Participants:
Approximately 72 participants will be enrolled in the dose-escalation/dose-confirmation part 
of the study. The final number of participants enrolled in the study will depend on the 
empirical safety data (DLT observations, in particular, at which dose the modified Toxicity 
Probability Interval (mTPI) design is triggered, and at which dose the preliminary RP2D is 
identified). The approximate number of participants in Arm 1 is 8, in Arm 2 is 32, and in 
Arm 3 is 32.
 
 
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Intervention Groups and Duration:
Inter-
vention 
Groups
Inter-
vention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Admin.
Regimen/ 
Treatment 
Period/
Use
Arm 1
MK-4621/JetPEI
0.8 mg
q1w
Intratumoral
via visual 
inspection for 
cutaneous 
lesions, and via 
ultrasound 
guidance for 
subcutaneous 
lesions, as 
needed
Days 1, 8, 
and 15 of 
each 21-day 
cycle
Experi-
mental
Arm 2
Pembrolizumab
200 mg
q3w
IV infusion
Day 1 of 
each 21-day 
cycle
Experi-
mental
MK-4621/ 
JetPEI a
Range: 
0.4 mg 
to 
0.8 mg b
q1w
Intratumoral
via visual 
inspection for 
cutaneous 
lesions, and via 
ultrasound 
guidance for 
subcutaneous 
lesions, as 
needed
Days 1, 8 
and 15 of 
each 21-day 
cycle
Experi-
mental
Arm 3
Pembrolizumab
200 mg
q3w
IV infusion
Day 1 of 
each 21-day 
cycle
beginning 
with Cycle 
2
Experi-
mental
MK-4621/ 
JetPEI a
Range: 
0.2 mg 
to
0.8 mg b
q3w
Intratumoral 
(Visceral)
via ultrasound 
or cross-
sectional 
imaging 
(CT/MRI) 
guidance for 
liver lesions, as 
needed.
Day 1 of 
each 21-day 
cycle
Experi-
mental
a  MK-4621/JetPEI will be administered within 0.5 to 4 hours following completion of pembrolizumab 
IV infusion, as applicable.
b Dose levels will be determined based on emerging safety data.
 
 
05MGMC
07W5VB

PRODUCT: MK-4621 
17
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
Total 
Number
3 Arms
Duration 
of 
Participa-
tion
Each participant will participate in the study for approximately 2.5 years from 
the time the participant signs the Informed Consent Form (ICF) through the 
final contact.
After a screening phase of up to 28 days, each participant will be assigned to 
receive study treatment 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 administrations of pembrolizumab 
(approximately 2 years). Participants who progress by either clinical or 
radiographic evaluation on monotherapy with MK-4621/JetPEI(Arm 1) may 
cross over into the combination therapy arm (Arm 2), provided that they meet 
crossover eligibility criteria.
After the end of treatment, each participant will be followed for the 
occurrence of AEs and spontaneously reported pregnancy as described in
Section 8.4.
Participants who discontinue for reasons other than radiographic disease 
progression will have post-treatment follow-up imaging for disease status until 
disease progression is documented radiographically per RECIST 1.1, 
confirmed by the site per iRECIST (for participants treated with 
pembrolizumab), initiating a nonstudy cancer treatment, withdrawing consent, 
or becoming lost to follow-up. All participants will be followed by telephone 
for overall survival until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
Once participants have achieved the study objectives, they will be 
discontinued from this study and may be enrolled into an extension study to 
continue protocol-defined assessments and treatment with pembrolizumab 
monotherapy, as appropriate.
 
 
05MGMC
07W5VB

PRODUCT: MK-4621 
18
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
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.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 8.
 
 
05MGMC
07W5VB

PRODUCT: MK-4621 
19
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
1.2
Schema
NOTE: Participants who progress by either clinical or radiographic evaluation on monotherapy with 
MK-4621/JetPEI (Arm 1) may cross over into the combination therapy arm (Arm 2), provided that they meet 
crossover eligibility criteria.
NOTE: Once participants have achieved the study objectives, they will be discontinued from this study and may 
be enrolled into an extension study to continue protocol-defined assessments and treatment with pembrolizumab 
monotherapy, as appropriate.
Figure 1
Overall Study Design
 
 
05MGMC
07W5VB

PRODUCT: MK-4621
20
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
1.3
Schedule of Activities (SoA)
1.3.1
Schedule of Activities for the Initial Screening (Arms 1, 2, and 3) and Crossover Screening (Arm 1 to Arm 2)
Study Period
Initial and 
Crossover 
Screening
Notes
Visit Days
-28 to -1
Administrative Procedures
Informed Consent
X
Written informed consent must be obtained prior to performing any protocol-specific procedures. Tests performed prior to consent as 
part of routine clinical management are acceptable if performed within the specified timeframe.
Informed Consent for 
Future Biomedical Research (FBR) 
(Optional)
X
Consent for FBR is not required to participate in the study. Any leftover biomarker samples will be stored for FBR if the participant
signs the FBR consent. Detailed instructions for the collection and management of FBR specimens are provided in the Procedure 
Manual.
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
Demographics and Medical History
X
For crossover, update only.
Oncology Disease Status and Prior 
Oncology Treatment History
X
Prior Medication
X
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1, and 
iRECIST Response Assessment
X
Baseline tumor imaging (CT or MRI) as indicated for tumor type and/or medical photography of cutaneous lesions should be 
performed within 28 days of enrollment. Please refer to Imaging Manual for detailed information.
Medical Photography 
(Cutaneous Lesions)
X
Physical Examination
X
A full physical examination should be done at screening. 
Height
X
Weight
X
Vital Signs
X
Includes temperature, pulse, respiratory rate, blood pressure, and oxygen (O2) saturation.
ECOG Performance Status
X
To be performed within 7 days prior to the first dose of study intervention.
12-Lead Electrocardiogram
X
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.
 
 
05MGMC
07W5VB

PRODUCT: MK-4621
21
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
Study Period
Initial and 
Crossover 
Screening
Notes
Visit Days
-28 to -1
Laboratory Procedures/Assessments
CBC with Differential
X
Perform all screening clinical laboratory tests within 72 hours of treatment initiation. Exceptions are hepatitis, HIV and thyroid 
serologies, which may be performed within 28 days prior to first dose.
Participants on anticoagulant therapy should be monitored throughout the study.
GLDH is to be collected for Arm 3 only.
Thyroid function: Total T4 and T3 are preferred over FT4 and FT3.
Chemistry Panel
X
PT/INR and PTT or aPTT
X
LDH, GGT, GLDH
X
Lipase and Amylase
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
Urinalysis
X
Pregnancy test for WOCBP only (urine 
or serum β-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 if 
clinically indicated. Refer to Appendix 7 for country-specific requirements.
HIV/Hepatitis B and C Screen
X
Include HCV antibody or HCV RNA (qualitative) and HBsAg. HIV, and Hepatitis B and C by history are acceptable for exclusion, 
unless testing is required by local regulations. Refer to Appendix 7 for country-specific requirements.
Laboratory Procedures/Assessments – CENTRAL
Blood for RNA Analyses
X
Collect blood for RNA samples (Arm 1, Arm 2, and Arm 3) at initial and crossover screening.
Serum for Cytokine/Chemokine 
Analyses and C-Reactive Protein (CRP)3
X
Collect blood for serum for cytokine/chemokine analyses and C-Reactive Protein (CRP) samples at initial and crossover screening.
Pretreatment Tumor Biopsies
X
Initial Screening (Arm 1 and Arm 2) and Crossover Screening (Arm 1 to Arm 2): Required at initial screening as the predose 
samples (including the tumor lesion that is intended for treatment with IT administration of MK-4621/JetPEI, as well as on the 
distant, discrete lesion that is not intended for IT administration of MK-4621/JetPEI), up to 72 hours prior to treatment. 
Initial Screening (Arm 3): Biopsy and MK-4621/JetPEI injection should be done at the same procedure in 1 tumor on C1D1 (details 
see SoA for Arm 3)
NOTE: Participants who progress by either clinical or radiographic evaluation on monotherapy with MK-4621/JetPEI (Arm 1) may cross over into the combination therapy arm 
(Arm 2), provided that they meet crossover eligibility criteria.
aPTT=activated partial thromboplastin time; β-hCG= β-human chorionic gonadotropin; CT=computed tomography; ECOG=Eastern Cooperative Oncology Group; 
GGT=gamma glutamyl transferase; GLDH=glutamate dehydrogenase; HCV= hepatitis C virus; INR=International Normalized Ratio; IT=intratumoral; LDH=lactate 
dehydrogenase; MRI=magnetic resonance imaging; PET=positron emission tomography; PT=prothrombin time; PTT=partial thromboplastin time; TSH=thyroid stimulating 
hormone; WOCBP=women of childbearing potential.
 
 
05MGMC
07W5VB

PRODUCT: MK-4621
22
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
1.3.2
Schedule of Activities for the Treatment Period
1.3.2.1
Schedule of Activities for the Treatment Period for Arm 1
Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2
Cycles ≥3
For all cycles: Up to 6 cycles of treatment with 
MK-4621/JetPEI
Visit Day (Days)
1
8
15
1
8
15
1
8
15
Visit Window
+3
±1
±1
+3
±3
±3
±3
±3
±3
Arm 1: MK-4621/JetPEI Monotherapy
MK-4621/JetPEI Administration
X
X
X
X
X
X
X
X
X
Study treatment may be administered up to 3 days after 
the scheduled Day 1 of each treatment cycle.
24-Hour Inpatient Observation Period 
(Discretionary)
X
A 24-hour inpatient observation period following 
MK-4621/JetPEI administration on Day 1 of Cycles 1-6
will be at the discretion of the investigator for Arm 1.
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1, and 
iRECIST Response Assessment
Tumor imaging (CT or MRI) as indicated for tumor type 
and/or medical photography of cutaneous lesions should 
be performed every 9 weeks (± 7 days) after the first dose, 
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)
Physical Examination
X
X
X
X
X
X
X
X
X
Directed physical examinations may be performed unless 
a full examination is deemed necessary.
Weight
X
X
Every other cycle (ie, Cycles 1, 3, and 5).
tal Signs
(temperature, pulse, respiratory rate, blood 
pressure, and oxygen (O2) saturation)
X
X
X
X
X
X
X
X
X
To be measured within 1 h (± 30 min) prior to dosing, and 
2, 4, and 6 hours after MK-4621/JetPEI administration in 
Cycle 1. For Cycle 2 to Cycle 6, to be measured within 
1 h (± 30 min) prior to dosing, and 2 and 4 hours after 
MK-4621/JetPEI administration. 
ECOG Performance Status
X
X
X
Performed within 72 hours prior to MK-4621/JetPEI
dosing on Day 1 of each cycle.
12-Lead Electrocardiogram
X
X
X
Performed within 72 hours prior to MK-4621/JetPEI
dosing on Day 1 of each cycle. Postdose ECG will be 
obtained within 30 minutes after following 
MK-4621/JetPEI administration on Day 1 of each cycle 
up to Cycle 4.
Concomitant Medication
X
X
X
X
X
X
X
X
X
Adverse Events
Continuous AE reporting from the time of treatment 
allocation.
 
 
05MGMC
07W5VB

PRODUCT: MK-4621
23
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2
Cycles ≥3
For all cycles: Up to 6 cycles of treatment with 
MK-4621/JetPEI
Visit Day (Days)
1
8
15
1
8
15
1
8
15
Visit Window
+3
±1
±1
+3
±3
±3
±3
±3
±3
Survival Status
Upon Sponsor request, participants may be contacted for 
survival status at any time during the course of the study.
Laboratory Procedures/Assessments
CBC with Differential
X
X
X
X
X
X
X
X
X
Perform all scheduled clinical laboratory tests within 
72 hours prior to the start of each cycle. Screening 
procedures/sample collections done within this timeframe 
do not need to be repeated for the Cycle 1, Day 1 time 
point.
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
X
X
X
X
PT/INR and PTT or aPTT
X
X
X
LDH, GGT
X
X
X
Lipase and Amylase
X
X
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
X
X
Urinalysis
X
X
X
Pregnancy test for WOCBP only (urine or 
serum β-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. Refer to Appendix 7 for country-specific 
requirements.
Laboratory Procedures/Assessments – CENTRAL
Pharmacokinetics for MK-4621
X
X
Collect predose samples 1-8 h before MK-4621/JetPEI
administration on C1D1 and C2D1.
Collect postdose samples on C1D1 and C2D1: end of IT 
injection (up to +5 min), 0.5 h (±5 min), 1.0 h (±10 min), 
2 h (±15 min), 4 h (±15 min), and 6 h (±15 min) after 
MK-4621/JetPEI IT administration. 
Additional postdose samples will be collected at 
24 h (± 4 h) after MK-4621/JetPEI IT administration on 
C1D1 only.
Blood for T Cell Repertoire (TCR)
X
X
X
Collect blood for TCR samples at -4 to 0 h predose of 
MK-4621/JetPEI on Day 1 of Cycle 1 (C1D1), Cycle 2 
(C2D1), Cycle 3 (C3D1), and Cycle 5 (C5D1).
 
 
05MGMC
07W5VB

PRODUCT: MK-4621
24
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycle 2
Cycles ≥3
For all cycles: Up to 6 cycles of treatment with 
MK-4621/JetPEI
Visit Day (Days)
1
8
15
1
8
15
1
8
15
Visit Window
+3
±1
±1
+3
±3
±3
±3
±3
±3
Blood for RNA Analyses
X
X
Collect blood for RNA samples -4 to 0 h predose, and 6 h 
(±15 min) postdose of MK-4621/JetPEI on Day 1 of 
Cycle 1 (C1D1) and Cycle 2 (C2D1).
Serum for Cytokine/Chemokine Analyses and C-
Reactive Protein (CRP)
X
X
X
Collect blood for serum cytokine/chemokine analyses and 
C-Reactive Protein (CRP) samples at -4 to 0 h predose of 
MK-4621/JetPEI on Day 1 of every cycle.
Collect blood for serum cytokine/chemokine analyses and 
C-Reactive Protein (CRP) samples at 2 h (±15 min), 6 h 
(±15 min), and 24 h (±4 h) postdose of MK-4621/JetPEI
on Day 1 of Cycle 1 (C1D1) and Cycle 2 (C2D1).
Collect samples at the same time as for MK-4621/JetPEI
PK when feasible.
Blood for Genetic Analyses
X
Collect prior to treatment.
On-treatment Tumor Biopsy
X
Required post administration of MK-4621/JetPEI
including 2 biopsy samples of both the injected and 
noninjected tumors where predose biopsy samples are 
collected on C3D1 (Week 7).  Biopsy samples will be 
collected 5 h (±2 h) prior to MK-4621/JetPEI injection.
All participants will have the option to provide 2 
additional biopsy samples of both the injected and 
uninjected tumors on C5D1 (Week 13).
aPTT=activated partial thromboplastin time; β-hCG= β-human chorionic gonadotropin; CT=computed tomography; ECOG=Eastern Cooperative Oncology Group; GGT=gamma 
glutamyl transferase; INR=International Normalized Ratio; IT=intratumoral; LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; PET=positron emission 
tomography; PT=prothrombin time; WOCBP=women of childbearing potential.
 
 
05MGMC
07W5VB

PRODUCT: MK-4621
25
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
1.3.2.2
Schedule of Activities for the Treatment Period for Arm 2
Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycles 2-6
Cycles ≥7
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 6 cycles of treatment with 
MK-4621/JetPEI.
Visit Day (Days)
1
8
15
1
8
15
1
8
15
Visit Window
+3
±1
±1
±3
±3
±3
±3
±3
±3
Arm 2: MK-4621/JetPEI and Pembrolizumab Combination Therapy
Pembrolizumab Administration
X
X
X
In Cycle 2, study treatment may be administered up to 
3 days after the scheduled Day 1. Beginning in Cycle 3, 
study treatment may be administered up to 3 days before or 
after the scheduled Day 1. MK-4621/JetPEI will be 
administered within 0.5 to 4 h after completion of the 
pembrolizumab infusion. See Pharmacy Manual.
Participants who crossover to Arm 2 will receive 
combination therapy at the highest dose of 
MK-4621/JetPEI with pembrolizumab that has been 
cleared for DLT in Arm 2 at the time of crossover.
Participants who cross over from Arm 1 to Arm 2 are 
eligible for up to 35 cycles of treatment with 
pembrolizumab therapy and up to a cumulative total of 
6 cycles of treatment with MK-4621/JetPEI inclusive of 
the MK-4621/JetPEI cycles received in Arm 1 and Arm 2.
MK-4621/JetPEI Administration
X
X
X
X
X
X
24-Hour Inpatient Observation Period
X
Xa
There will be a 24-hour inpatient observation period 
following MK-4621/JetPEI administration on C1D1, which 
may be extended to 48 hours at the discretion of the 
investigator, per local Institutional Review Board, Ethics 
Review Committee, and/or Health Authority mandate.
For Cycles 2-6, a 24-hour inpatient observation period 
following MK-4621/JetPEI administration will be at the 
discretion of the investigator.
 
 
05MGMC
07W5VB

PRODUCT: MK-4621
26
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycles 2-6
Cycles ≥7
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 6 cycles of treatment with 
MK-4621/JetPEI.
Visit Day (Days)
1
8
15
1
8
15
1
8
15
Visit Window
+3
±1
±1
±3
±3
±3
±3
±3
±3
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1, and 
iRECIST Response Assessment
Tumor imaging (CT or MRI) as indicated for tumor type 
and/or medical photography of cutaneous lesions should be 
performed every 9 weeks (± 7 days) after the first dose, 
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
om medical photography.
Medical Photography (Cutaneous Lesions)
Physical Examination
X
X
X
X
X
X
X
Directed physical examinations may be performed unless a 
full examination is deemed necessary.
Weight
X
X
X
Every other cycle (ie, Cycles 1, 3, 5, 7, etc.).
Vital Signs
(temperature, pulse, respiratory rate, blood 
pressure, and oxygen (O2) saturation)
X
X
X
X
X
X
X
To be measured within 1 h (± 30 min) prior to dosing, and 
2, 4, and 6 hours after MK-4621/JetPEI administration in 
Cycle 1. For Cycle 2 to Cycle 6, to be measured within 
1 h (± 30 min) prior to dosing, and 2 and 4 hours after 
MK-4621/JetPEI administration. For Cycle 7 and beyond, 
to be measured within 1 h (± 30 min) prior to dosing with 
pembrolizumab on Day 1 only of every cycle. 
ECOG Performance Status
X
X
X
Performed within 72 hours prior to MK-4621/JetPEI
dosing on Day 1 of each cycle. 
12-Lead Electrocardiogram
X
X
Performed within 72 hours prior to MK-4621/JetPEI
dosing on Day 1 of each cycle. Postdose ECG will be 
obtained within 30 minutes after following 
MK-4621/JetPEI administration on Day 1 of each cycle up 
to Cycle 4.
Concomitant Medication
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.
 
 
05MGMC
07W5VB

PRODUCT: MK-4621
27
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycles 2-6
Cycles ≥7
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 6 cycles of treatment with 
MK-4621/JetPEI.
Visit Day (Days)
1
8
15
1
8
15
1
8
15
Visit Window
+3
±1
±1
±3
±3
±3
±3
±3
±3
Laboratory Procedures/Assessments
CBC with Differential
X
X
X
X
X
X
X
Perform all scheduled clinical laboratory tests within 
72 hours prior to the start of each cycle. Screening 
procedures/sample collections done within this timeframe 
do not need to be repeated for the Cycle 1, Day 1 time 
point.
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
X
X
PT/INR and PTT or aPTT
X
X
X
LDH, GGT
X
X
X
Lipase and Amylase
X
X
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
X
X
Urinalysis
X
X
X
Pregnancy test for WOCBP only (urine or 
serum β-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. Refer 
to Appendix 7 for country-specific requirements.
Laboratory Procedures/Assessments – CENTRAL
Anti-pembrolizumab Antibody
X
X
X
Collect samples predose 0 to 4 h before pembrolizumab 
IV infusion on C1D1, C2D1, C4D1, and on Day 1 of every 
4 cycles thereafter (ie, C8, C12, etc.).
Collect with plasma samples for MK-4621/JetPEI PK 
when feasible.
Pharmacokinetics for MK-4621
X
X
Collect predose samples 1-8 h before MK-4621/JetPEI
administration on C1D1 and C2D1 (ie, before any drug 
administration of pembrolizumab and MK-4621/JetPEI)
Collect postdose samples on C1D1 and C2D1 at the 
following time points: end of IT injection (up to +5 min), 
0.5 h (±5 min), 1.0 h (±10 min), 2 h (±15 min), 
4 h (±15 min), and 6 h (±15 min) after MK-462/JetPEI 1 IT 
administration. 
Additional postdose samples will be collected at 
24 h (± 4 h) after MK-4621/JetPEI IT administration on 
C1D1 only.
 
 
05MGMC
07W5VB

PRODUCT: MK-4621
28
PROTOCOL/AMENDMENT NO.: 002-04
MK-4621-002-04 FINAL PROTOCOL
27-OCT-2020
Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycles 2-6
Cycles ≥7
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 6 cycles of treatment with 
MK-4621/JetPEI.
Visit Day (Days)
1
8
15
1
8
15
1
8
15
Visit Window
+3
±1
±1
±3
±3
±3
±3
±3
±3
Pharmacokinetics for Pembrolizumab PK
X
X
X
Collect samples predose 0 to 4 h before pembrolizumab 
IV infusion on C1D1, C2D1, C4D1, and on Day 1 of every 
4 cycles thereafter (ie, C8, C12, etc.).
Collect postdose samples at 0.5 h (±5 min) after 
MK-4621/JetPEI administration on C1D1, C2D1, and 
C4D1 in Arm 2.
Collect with plasma samples for MK-4621/JetPEI PK 
when feasible.
Blood for T Cell Repertoire (TCR)
X
X
Collect blood for TCR samples at -4 to 0 h predose of 
MK-4621/JetPEI on Day 1 of Cycle 1 (C1D1), 
Cycle 3 (C3D1), and Cycle 5 (C5D1).
Blood for RNA Analyses
X
X
Collect blood for RNA samples -4 to 0 h predose, and 6 h 
(±15 min) postdose of MK-4621/JetPEI on Day 1 of 
Cycle 1 (C1D1) and Cycle 2 (C2D1).
Serum for Cytokine/Chemokine Analyses and C-
Reactive Protein (CRP)
X
X
Collect blood for serum cytokine/chemokine analyses and 
C-Reactive Protein (CRP)samples at -4 to 0 h predose of 
MK-4621/JetPEI on Day 1 of every cycle.
Collect blood for serum for Cytokine/Chemokine Analyses 
and C-Reactive Protein (CRP) samples at 2 h (±15 min), 
6 h (±15 min), and 24 h (±4 h) postdose of 
MK-4621/JetPEI on Day 1 of Cycle 1 (C1D1) and Cycle 2 
(C2D1).
Collect samples at the same time as for MK-4621/JetPEI
PK when feasible.
Blood for Genetic Analyses
X
Collect prior to treatment
On-treatment Tumor Biopsy
X
Required post administration of MK-4621/JetPEI
(including 2 biopsy samples of both the injected and 
noninjected tumors where predose biopsy samples are 
collected on C3D1 (Week 7). Biopsy samples will be 
collected 5 h (±2 h) prior to MK-4621/JetPEI injection.
All participants will have the option to provide 2 additional 
biopsy samples of both the injected and uninjected tumors 
on C5D1 (Week 13).
aPTT=activated partial thromboplastin time; β-hCG= β-human chorionic gonadotropin; CT=computed tomography; ECOG=Eastern Cooperative Oncology Group; GGT=gamma 
glutamyl transferase; INR=International Normalized Ratio; IT=intratumoral; LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; PET=positron emission 
tomography; PT=prothrombin time; WOCBP=women of childbearing potential.
 
 
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1.3.2.3
Schedule of Activities for the Treatment Period for Arm 3
Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycles 2-6
Cycles ≥7
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 6 cycles of treatment with 
MK-4621/JetPEI.
Visit Day (Days)
1
8
15
1
8
15
1
8
15
+3
±3
±3
±3
±3
±3
±3
±3
±3
Arm 3: MK-4621/JetPEI and Pembrolizumab Combination Therapy (Intrahepatic)
Pembrolizumab Administration
X
X
Beginning in Cycle 2, study treatment may be administered 
up to 3 days before or after the scheduled Day 1. 
MK-4621/JetPEI will be administered within 0.5 to 4 h 
after completion of the pembrolizumab infusion. See 
Pharmacy Manual.
MK-4621/JetPEI Administration
X
X
24-Hour Inpatient Observation Period
X
X
There will be a 24-hour inpatient observation period 
following MK-4621/JetPEI administration on C1D1 and 
following MK-4621/JetPEI and pembrolizumab 
administration on C2D1, which may be extended to 
48 hours at the discretion of the investigator, per local 
Institutional Review Board, Ethics Review Committee, 
and/or Health Authority mandate.
For Cycles 3-6, a 24-hour inpatient observation period 
following MK-4621/JetPEI administration will be at the 
discretion of the investigator.
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1, and iRECIST 
Response Assessment
Tumor imaging (CT or MRI) as indicated for tumor type 
(and medical photography in the case of the presence of 
cutaneous lesions) should be performed every 9 weeks 
(± 7 days) after the first dose, 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)
Physical Examination
X
X
X
X
X
X
X
Directed physical examinations may be performed unless a 
full examination is deemed necessary.
Weight
X
X
X
Every other cycle (ie, Cycles 1, 3, 5, 7, etc.).
 
 
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Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycles 2-6
Cycles ≥7
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 6 cycles of treatment with 
MK-4621/JetPEI.
Visit Day (Days)
1
8
15
1
8
15
1
8
15
+3
±3
±3
±3
±3
±3
±3
±3
±3
Vital Signs
(temperature, pulse, respiratory rate, blood 
pressure, and oxygen (O2) saturation)
X
X
X
X
X
X
X
To be measured within 1 h (± 30 min) prior to dosing, and 
2, 4, and 6 hours after MK-4621/JetPEI administration in 
Cycle 1 and Cycle 2. For Cycle 3 to Cycle 6, to be 
measured within 1 h (± 30 min) prior to dosing, and 2 and 
4 hours after MK-4621/JetPEI administration. For Cycle 7 
and beyond, to be measured within 1 h (± 30 min) prior to 
dosing with pembrolizumab on Day 1 only of every cycle.
ECOG Performance Status
X
X
X
Performed within 72 hours prior to MK-4621/JetPEI
dosing on Day 1 of each cycle. 
12-Lead Electrocardiogram
X
X
Performed within 72 hours prior to MK-4621/JetPEI
dosing on Day 1 of each cycle. Postdose ECG will be 
obtained within 30 minutes after following 
MK-4621/JetPEI administration on Day 1 of each cycle up 
to Cycle 4.
Concomitant Medication
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.
Laboratory Procedures/Assessments
CBC with Differential
X
X
X
X
X
X
X
Perform all scheduled clinical laboratory tests within 
72 hours prior to the start of each cycle. Screening 
procedures/sample collections done within this timeframe 
do not need to be repeated for the Cycle 1, Day 1 time 
point.
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
X
X
PT/INR and PTT or aPTT
X
X
X
X
X
X
X
LDH, GGT, GLDH
X
X
X
Lipase and Amylase
X
X
X
Thyroid Function Testing
(T4 or FT4, T3 or FT3, TSH)
X
X
X
Urinalysis
X
X
X
Pregnancy test for WOCBP only (urine or 
serum β-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. Monthly testing should be conducted per local 
regulations. Refer to Appendix 7 for country-specific 
requirements
 
 
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Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycles 2-6
Cycles ≥7
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 6 cycles of treatment with 
MK-4621/JetPEI.
Visit Day (Days)
1
8
15
1
8
15
1
8
15
+3
±3
±3
±3
±3
±3
±3
±3
±3
Laboratory Procedures/Assessments – CENTRAL
Anti-Pembrolizumab Antibody
X
X
Collect samples predose 0 to 4 h before pembrolizumab 
IV infusion on C2D1, C3D1, C5D1, and on Day 1 of every 
4 cycles thereafter (ie, C9, C13, etc.).
Collect with plasma samples for MK-4621/JetPEI PK 
when feasible.
Pharmacokinetics for MK-4621
X
X
Collect predose samples 1-8 h before MK-4621/JetPEI
administration on C1D1, C2D1 and C3D1 (ie, before any 
drug administration of pembrolizumab and 
MK-4621/JetPEI)
Collect postdose samples on C1D1, C2D1, and C3D1 at 
the following time points: end of IT injection (up to 
+5 min), 0.5 h (±5 min), 1.0 h (±10 min), 2 h (±15 min), 
4 h (±15 min), and 6 h (±15 min) after MK-4621/JetPEI
IT administration. 
Additional postdose samples will be collected at 
24 h (± 4 h) after MK-4621/JetPEI IT administration on 
C1D1 only.
Pharmacokinetics for Pembrolizumab PK
X
X
Collect samples predose 0 to 4 h before pembrolizumab 
IV infusion on C2D1, C3D1, C5D1, and on Day 1 of every 
4 cycles thereafter (ie, C9, C13, etc.).
Collect postdose samples at 0.5 h (±5 min) after 
MK-4621/JetPEI administration on C2D1, C3D1, and 
C5D1.
Collect with plasma samples for MK-4621/JetPEI PK 
when feasible
 
 
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Study Period
Treatment Period
Cycle = 21 days
Notes
Visit Timing
Cycle 1
Cycles 2-6
Cycles ≥7
For all cycles: Up to 35 cycles of treatment with 
pembrolizumab and up to 6 cycles of treatment with 
MK-4621/JetPEI.
Visit Day (Days)
1
8
15
1
8
15
1
8
15
+3
±3
±3
±3
±3
±3
±3
±3
±3
Blood for T Cell Repertoire (TCR)
X
X
Collect blood for TCR samples at -4 to 0 h predose of 
MK-4621/JetPEI on Day 1 of Cycle 1 (C1D1), Cycle 3 
(C3D1), Cycle 4 (C4D1), and Cycle 6 (C6D1).
Blood for RNA Analyses
X
X
Collect blood for RNA samples -4 to 0 h predose, and 
6 h (±15 min) postdose of MK-4621/JetPEI on Day 1 of 
Cycle 1 (C1D1), Cycle 2 (C2D1), and Cycle 3 (C3D1).
Serum for Cytokine/Chemokine Analyses 
and C-Reactive Protein (CRP)
X
X
Collect blood for serum cytokine/chemokine analyses and 
C-Reactive Protein (CRP) samples at -4 to 0 h predose of 
MK-4621/JetPEI on Day 1 of every cycle.
Collect blood for serum cytokine/chemokine analyses and 
C-Reactive Protein (CRP) at 2 h (±15 min), 6 h (±15 min), 
and 24 h (±4 h) postdose of MK-4621/JetPEI on Day 1 of 
Cycle 1 (C1D1), Cycle 2 (C2D1), and Cycle 3 (C3D1).
Collect samples at the same time as for MK-4621/JetPEI
PK when feasible.
Blood for Genetic Analyses
X
Collect prior to treatment.
On-treatment Tumor Biopsy
X
X
X
Two required biopsy samples will be collected on C1D1 
and C4D1 from the same injected tumor. Biopsy collection 
procedure will be done at the same time as 
MK-4621/JetPEI injection at these 2 time points.
All participants will have the option to provide 1 additional 
biopsy sample of the injected tumor on C6D1 (Week 16).  
Biopsy collection procedure will be done at the same time 
as MK-4621/JetPEI injection.
aPTT=activated partial thromboplastin time; β-hCG= β-human chorionic gonadotropin; CT=computed tomography; ECOG=Eastern Cooperative Oncology Group; GGT=gamma 
glutamyl transferase; INR=International Normalized Ratio; IT=intratumoral; LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; PET=positron emission 
tomography; PT=prothrombin time; WOCBP=women of childbearing potential.
 
 
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1.3.3
Schedule of Activities for the End of Treatment and Post-Treatment Follow-Up Periods
Study Period
End of Treatment
(EOT)/ Discontinuation
Post-Treatment Follow-Up
Notes
Safety
Disease 
Status
Survival
Visit Timing
Treatment 
Discontinuation
30 days 
after the 
last dose
Every 9 
weeks
Approximately 
every 12 weeks
Visit Window (Days)
+ 7
±7
±14
Administrative / Clinical Procedures / Assessments
Concomitant Medication
X
X
Physical Examination
X
X
A directed physical examination may be done unless a full examination is deemed 
necessary. 
Weight
X
X
12-Lead ECG
X
Vital Signs
X
X
Measurements include temperature, pulse, respiratory rate, blood pressure, and O2
saturation.
ECOG Performance Status
X
X
Evaluation before study drug administration
Adverse Event Monitoring
X
X
After treatment discontinuation, participants will be monitored for AEs for 30 days and 
SAEs for 90 days (30 days if the participant initiates new anticancer therapy). Participants 
with an ongoing AE at the time of treatment discontinuation will be followed until 
resolution, stabilization, the event is otherwise explained, or the participant is lost to 
follow-up.
Tumor Imaging, RECIST 1.1 and 
iRECIST Response Assessment
X
X
Posttreatment tumor imaging every 9 weeks starting from the first dose of study treatment 
until new anticancer treatment
Medical Photography (Cutaneous
Lesions)
X
New Anticancer Therapy Status
X
X
Survival Status
X
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.
Laboratory Procedures/Assessments – LOCAL
CBC with Differential
X
X
Chemistry Panel
X
X
Thyroid Function Testing
(T4, FT4, T3, FT3, TSH)
X
Lipase and Amylase
X
X
 
 
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Study Period
End of Treatment
(EOT)/ Discontinuation
Post-Treatment Follow-Up
Notes
Safety
Disease 
Status
Survival
Visit Timing
Treatment 
Discontinuation
30 days 
after the 
last dose
Every 9 
weeks
Approximately 
every 12 weeks
Visit Window (Days)
+ 7
±7
±14
Pregnancy test for WOCBP only 
(urine or serum β-hCG)
X
Laboratory Procedures/Assessments
Anti-Pembrolizumab Antibody
X
Only for pembrolizumab-treated participants.
Pharmacokinetics for 
Pembrolizumab PK (Arm 2, 
Arm 3)
X
CT=computed tomography; ECOG=Eastern Cooperative Oncology Group; GGT=gamma glutamyl transferase; IT=intratumoral; LDH=lactate dehydrogenase; MRI=magnetic 
resonance imaging; PET=positron emission tomography; WOCBP=women of childbearing potential.
 
 
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2
INTRODUCTION
In the past few years significant progress has been made in the field of immunotherapy. In 
particular antibodies targeting immune checkpoints have yielded impressive improvements in 
clinical outcomes for a range of tumor types. Despite this the majority of advanced cancer 
patients do not respond to immunotherapy, due to local immune tolerance at the tumor, 
absence of effector cells, or the development of resistance through a variety of adaptive 
mechanisms. MK-4621 (RGT-100) is a double-stranded 5’-triphosphate RNA that binds to 
Retinoic acid Inducible Gene I (RIG-I), a cytosolic receptor of the innate immune system, for 
intratumoral/intralesional injection. In preclinical experiments, MK-4621/JetPEI injection 
activates RIG-I, which induces a potent innate as well as adaptive immune response. The 
immune activation is accompanied by the induction of apoptosis in tumor cells. In 
nonmalignant cells, stimulation of RIG-I leads to a secretion of type I interferons, but not to 
apoptosis. Tumor antigens released during apoptosis can enhance antitumor immune 
response. In combination, these mechanisms lead to antitumor effects in injected tumor and 
untreated metastases (abscopal effect). Strong immune activation and release of neoantigens
allows for a vaccination-like effect. 
Treatment of relapsed/refractory malignancies represents a substantial challenge for clinical 
oncologists and there is a large area of unmet medical need for more effective therapy. As 
shown in preclinical studies, MK-4621/JetPEI has a potential to improve efficacy when used 
as a monotherapy or in combination with an anti-PD-1 inhibitor and other 
immunomodulatory agents.
2.1
Study Rationale
Limited efficacy of immune checkpoint inhibitors (ICI) has been recently elucidated in 
numerous clinical studies. Therefore, there is a great unmet need for agents that are able to 
enhance the effect of ICIs. Based on the results of preclinical experiments, multifaceted 
antitumor mechanisms of MK-4621/JetPEI can be exploited to overcome tumor resistance to 
ICI via direct stimulation of innate and adaptive immunity, in situ vaccination effects, and 
reprogramming tumor microenvironment. MK-4621/JetPEI is positioned to be the 
first--in-class RIG-I agonist in oncology.
MK-4621/JetPEI (originally RGT100-PEI, developed by Rigontec) represents a 
double-stranded triphosphate RNA that binds to and activates RIG-I, a cytosolic receptor 
molecule that results in the induction of a potent innate as well as adaptive antitumoral 
immune responses. Preclinical experiments have demonstrated broad antitumoral activity in 
multiple in vivo models. 
The empirical rationale for combining MK-4621/JetPEI with PD-1 ICI is based on the data 
from experiments in anti-PD-1-resistant syngeneic mouse tumor models in which the 
combination of these agents enhanced antitumor responses compared with monotherapy 
treatment. It was also shown that MK-4621/JetPEI upregulated PD-1 expression and resulted 
in increased activity when combined with a PD-1 inhibitor. For further details please refer to 
the MK-4621 Investigator’s Brochure (IB).
 
 
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PD-1 blockade by pembrolizumab can exhibit a protective effect on a newly generated 
immune cell effectors in hostile tumor microenvironment and prevent inhibition of immune 
response. Therefore, a combination of the 2 treatment strategies can potentially enhance an 
antitumor response.
The rationale for an intrahepatic intratumoral arm of MK-4621/JetPEI is to expand the tumor 
location for IT therapy to deeper and visceral organs such as the liver.
This Phase 1/1b multicenter, open label, dose escalation and confirmation study will evaluate 
the safety, tolerability, and preliminary antitumor activity of intratumoral/intralesional 
injections of MK-4621/JetPEI in participants with advanced or recurrent tumors.
Results from this study will support further clinical development of MK-4621/JetPEI. The
study will be performed in compliance with the protocol, International Council for 
Harmonisation (ICH), Good Clinical Practice (GCP), and local regulatory requirements. 
Aspects of the study concerned with manufacture and labelling of MK-4621/JetPEI will meet 
the requirements of Good Manufacturing Practice.
2.2
Background
Refer to the IBs for detailed background information on MK-4621/JetPEI and 
pembrolizumab.
MK-4621/JetPEI (originally RGT100-PEI, developed by Rigontec) is a double-stranded 
triphosphate RNA that binds to and activates RIG-I, a cytosolic receptor molecule that results 
in the induction of a potent innate as well as adaptive antitumoral immune responses. 
Preclinical experiments have demonstrated broad antitumoral activity in multiple in vivo 
models. 
Pembrolizumab is a potent humanized immunoglobulin (Ig) G4 monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2). Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1. Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies. Keytruda™ (pembrolizumab) is indicated for the treatment of 
patients across a number of indications. For more details on specific indications refer to the 
IB for pembrolizumab.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
MK-4621/JetPEI Pharmaceutical and Therapeutic Background
Retinoic acid–inducible gene I is a cytosolic receptor molecule that was initially discovered 
as a sensor for viral RNAs. 
 
 
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Because RIG-I is a cytosolic receptor, various agents have been investigated to efficiently 
deliver MK-4621 into the cytosol. In vivo-jetPEI™ (Polyplus Transfection) has been 
identified as the most efficient delivery agent. A stable formulation procedure to generate 
stable and defined particles for storage has been developed as ready-to-use dispersion. In 
vivo-jetPEI™ has been tested in several clinical studies for the delivery of DNA in gene 
therapy studies. This linear polyethylenimine agent is regarded as an excipient and has a 
Drug Master File placed at the United States Food and Drug Administration (FDA) for the 
use in clinical studies.
2.2.1.2
Mechanism of Action
Although the expression of many receptors of the innate immune system is restricted to a 
certain subset of cells (eg, only in dendritic cells), RIG-I is ubiquitously expressed. This 
observation is in line with its pivotal role in antiviral defense against RNA viruses, a system 
that must be functional in virtually all somatic cells. RIG-I activation in tumor cell lines 
triggers cells death, whereas nonmalignant cells showed only marginal reduction in cell 
viability. Subsequent studies reveal that RIG-I stimulation initiates the mitochondrial 
apoptosis pathway, which is preferentially due to the induction of the pro-apoptotic 
BH3-only proteins Puma and Noxa in RIG-I–stimulated cells. The same pro-apoptotic signal 
was also observed in nonmalignant cells but these cells were comparatively less sensitive to 
apoptosis induction than melanoma cells, as the upregulation of endogenous Bcl-xL rescued 
primary cells from RIG-I–mediated pro-apoptotic signal. Because Bcl-xL is dysregulated in 
most tumor cells it can no longer serve as a rescue mechanism.
Apart from the direct immune-activating effect of RIG-I agonists in immune cells, RIG-I 
activation in tumor cells leads to formation of immune-activating exosomes. These exosomes 
contain the RIG-I agonist and express the natural killer (NK) cell receptor ligand BAG6 on 
the surface. Thereby they trigger a NK cell-mediated cytotoxicity as well.
Several studies revealed that breaking the local dominance of myeloid-derived suppressor 
cell within the tumor microenvironment was a key step to effective antitumor immunity. 
Interferon α (IFNα), one of the lead cytokines produced after RIG-I activation, can potently 
induce myeloid-derived suppressor cell differentiation. Thereby they exhibit a significantly 
reduced T-cell suppressive phenotype. The immunosuppressive tumor microenvironment is 
converted into a T-cell–promoting environment and this conversion facilitates the generation 
of a T-cell–dependent antitumor immune response. 
Taken together, the RIG-I–dependent antitumor activity can be exploited as immunotherapy 
due to its multifaceted mechanism of action: direct activation if immune effector cells, 
induction of immunogenic cell death in tumor cells, release of immune-activating exosomes 
to promote tumor-specific natural killer cell cytotoxicity, reprogramming of tumor 
microenvironment to facilitate the antitumor immune response (see Figure 2). Local effects 
are most efficiently induced by high concentration of MK-4621/JetPEI in tumor that can be 
achieved by intratumoral administration.
 
 
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Figure 2
Schematic Representation of MK-4621/JetPEI Mechanism of Action
2.2.1.3
Preclinical Studies of MK-4621/JetPEI
Please refer to the MK-4621 IB for a description of preclinical evaluations.
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 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
of CD8+ effector T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. 
Tumor-infiltrating lymphocytes can be expanded ex vivo and reinfused, inducing durable 
objective tumor responses in cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, 
N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an 
immunoglobulin (Ig) superfamily member related to cluster of differentiation 28 (CD28) and 
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) that has been shown to negatively 
 
 
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regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV-type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 
and SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein 
kinase C-theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T cell responses is similar to, but distinct from, that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005]
[Francisco, L. M., et al 2010]. As a consequence, the PD-1/PD-L1 pathway is an attractive 
target for therapeutic intervention in solid tumors. Please refer to the current pembrolizumab 
IB for a description of preclinical and clinical evaluations of pembrolizumab.
2.2.2
Ongoing Clinical Studies
2.2.2.1
MK-4621/JetPEI Clinical Studies
One first-in-human and first-in-class study is currently being performed with 
MK-4621/JetPEI (Study MK-4621-001). This is a Phase 1/1b, open-label, dose-escalation 
study in participants with advanced solid tumors. A conventional 3+3 design was used and 
the dose has been safely escalated up to 0.8 mg. Fifteen participants have been treated and no 
DLTs have occurred. Related AEs have been mainly fever reactions up to Grade 3.
2.2.2.2
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.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Potential risks associated with the administration of MK-4621/JetPEI based on nonclinical 
data may include the following:
•
Local reactions at the injected tumor site (swelling, induration, and erythema)
 
 
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•
Altered liver function (increases in alanine transaminase [ALT], aspartate transaminase 
[AST], and lactate dehydrogenase [LDH], decreases in erythrocyte counts, hemoglobin 
levels, and hematocrit)
•
Immune-related adverse events (irAEs) (including colitis, hepatitis, impaired thyroid 
function) or fever, chills, muscle aches, fatigue, headache, diarrhea, nausea and vomiting,
and low blood pressure based on the fact that the mode of action of MK-4621/JetPEI is 
based upon activation of the immune system.
For intrahepatic administration of MK-4621/JetPEI in Arm 3, there is an increased risk 
associated with the procedure (eg, bleeding, liver damage).
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying MK-4621 and pembrolizumab IBs and ICF 
documents.
3
HYPOTHESIS, OBJECTIVES, AND ENDPOINTS
Objectives
Endpoints
Primary
•
Objective: To evaluate the safety and 
tolerability and to establish a 
preliminary recommended Phase 2 dose 
(RP2D) of MK-4621/JetPEI
administered as monotherapy and in 
combination with pembrolizumab
•
Dose-limiting toxicity (DLT)
•
Adverse events (AEs)
•
Study intervention discontinuations due 
to AEs
Secondary
•
Objective: To evaluate the 
pharmacokinetics (PK) of 
MK-4621/JetPEI administered as 
monotherapy and in combination with 
pembrolizumab
•
PK parameters of MK-4621/JetPEI, 
including area under the curve (AUC), 
minimum concentration (Cmin), maximum 
concentration (Cmax)
•
Objective: To evaluate the objective 
response rate (ORR) as assessed by the 
investigator based on Response 
Evaluation Criteria in Solid Tumors 
Version 1.1 (RECIST 1.1) and modified 
RECIST 1.1 for immune-based 
therapeutics (iRECIST) of 
MK-4621/JetPEI administered as 
monotherapy and in combination with 
pembrolizumab
•
Objective response is a complete 
response (CR) or partial response (PR)
 
 
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Tertiary/Exploratory
•
Objective: To evaluate progression-free 
survival (PFS) as assessed by the 
investigator based on RECIST 1.1 and 
iRECIST, and overall survival (OS) for
participants administered MK-
4621/JetPEI as monotherapy and in 
combination with pembrolizumab
•
OS is the time from the first dose of 
study intervention to death due to any 
cause.
•
PFS is the time from first dose of study 
intervention to the first documented 
disease progression or death due to any 
cause, whichever occurs first.
•
Objective: To evaluate the 
pharmacokinetics (PK) of 
pembrolizumab administered in 
combination with MK-4621/JetPEI
•
PK parameters of pembrolizumab 
including minimum concentration (Cmin) 
and maximum concentration (Cmax)
•
Objective: To evaluate the development 
of circulating anti-pembrolizumab 
antibodies, as appropriate, following 
administration of MK-4621/JetPEI alone 
and in combination with pembrolizumab
•
Antidrug antibody levels
•
Objective: To identify molecular 
(genomic, metabolic and/or proteomic) 
biomarkers that may be indicative of 
clinical response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of 
MK-4621/JetPEI as monotherapy and in 
combination with pembrolizumab
•
Germline genetic variation, genetic 
(DNA) mutations from tumor, tumor and 
blood RNA variation, proteomics and 
IHC, and other biomarkers.
4
STUDY DESIGN
4.1
Overall Design
This is a Phase 1/1b, dose-escalation, nonrandomized, multicenter, open-label study of 
MK-4621/JetPEI as monotherapy and in combination with pembrolizumab in participants 
with advanced/metastatic solid tumors.
For Arm 1 (MK-4621/JetPEI monotherapy dose confirmation and cohort expansion) and 
Arm 2 (MK-4621/JetPEI + pembrolizumab, dose escalation, dose confirmation, and 
cohort expansion), the study will enroll participants with cutaneous, subcutaneous, and/or 
nodal lesions that are amenable to IT injection by visual inspection or ultrasound guidance. 
Participants need to have 1 measurable lesion that is amenable to IT injection and biopsy,
1 measurable discrete and/or distant lesion (bystander lesion) that is amenable to biopsy to 
 
 
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evaluate any abscopal effect, as well as 1 measurable noninjected, nonbiopsied lesion for 
RECIST assessment. Arm 2 will be opened for enrollment prior to Arm 1.
For Arm 3 (intrahepatic administration of MK-4621/JetPEI, dose escalation, 
dose confirmation, and cohort expansion), the study will enroll participants with liver 
metastases/lesions that are amenable to injection via ultrasound or cross-sectional 
imaging (CT/MRI) guidance. Participants need to have 1 measurable lesion that is amenable 
to IT injection and biopsy and 1 measurable noninjected, nonbiopsied discrete and/or distant 
lesion for RECIST assessment. Enrollment into Arm 3 will only start once the dose 
escalation of Arm 2 has reached the highest dose level (0.8 mg) and this has been cleared for 
DLT.
Each treatment cycle is 21 days. In Arm 1 (dose confirmation), MK-4621/JetPEI dosing is 
q1w for each 21-day cycle. In Arm 2, MK-4621/JetPEI dosing is q1w for each 21-day cycle. 
In Arm 3, MK-4621/JetPEI will be injected q3w in combination with pembrolizumab. 
Pembrolizumab in Arm 2 and Arm 3 (post run-in phase) will be administered at a fixed dose 
200 mg q3w. See Section 8.1.11 for a detailed description of mandatory and discretionary 
observation periods. For each dose level (DL), the first participant will start treatment at least 
7 days before the next participant of the dose level is treated. Further participants should start 
treatment at least 3 days apart. This allows initial assessment of safety by the treating 
investigator and to detect potential major safety risks with a certain dose level prior to 
exposing more participants to this dose.
In Arm 1, the dose of 0.8 mg will be used to start the mTPI part to confirm this highest dose 
tested in the dose escalation study (MK-4621-001). In the event of any DLT, it may be 
decided to down-escalate 1 dose level (to 0.6 mg). The DLT period will last 1 cycle 
(3 weeks). Dose escalation of MK-4621/JetPEI in Arm 2 will start with 0.4 mg, the second 
dose level cleared for DLT in the MK-4621-001, and will proceed to the dose level of 0.6 mg 
and then to the highest dose of 0.8 mg based on emerging safety and tolerability data. The 
DLT evaluation period will be 21 days (1 cycle). Treatment allocation between Arms 1 and 2 
is described in Section 6.3.1. In Arm 3, the initial dose will be 0.2 mg and dose escalation 
will go up to 0.4, 0.6, and 0.8 mg. The DLT evaluation period will be 42 days (2 cycles: 
1 cycle in monotherapy and 1 cycle in combination therapy) (see Section 6.6.2 for more 
details). 
The decision on further dose escalation in Arms 2 and 3 may be made based on the entirety 
of the data from the study. Each participant will be monitored for DLTs over the DLT 
evaluation period. For each dose level, an assessment will be made of the safety and 
tolerability data in order to define the next dose level to be tested. Once a preliminary 
maximum tolerated dose/maximum administered dose (MTD/MAD) has been determined in 
the mTPI phase, expansion cohorts may be implemented to expand to a total of 40 
participants to obtain additional PK/pharmacodynamic data, confirm RP2D, and explore 
antitumor activity in particular tumor types. Tumor indications will be specified based on 
safety and efficacy data as well as feasibility derived from the dose escalation/confirmation 
phase. Several factors will be considered to define particular tumor types for cohort 
expansion. Based on the data accumulated to date (internally as well as in the peer-reviewed 
 
 
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literature), gene expression profile (GEP), and mutational load (ML) can provide a rationale 
for pembrolizumab combination. Both biomarkers have been shown to be strong independent 
predictors of response to PD-1 inhibitors. Tumor types of particular interest are those in 
which pembrolizumab demonstrated only modest clinical success. Tumors known for the 
high rate of response to PD-1/PD-L1 blockade (eg, melanoma) can serve as a reference for 
MK-4621/JetPEI efficacy when it is used in a monotherapy regimen.
The safety data from individual participants will be closely followed by the 
principal/sub-investigator and the Sponsor on an ongoing basis and shared at regular safety 
teleconferences (typically biweekly). The safety and tolerability of all participants, including 
those undergoing DLT evaluation, as well as those who have completed DLT evaluation, will 
be reviewed prior to the start of the next dose level at dose escalation/dose confirmation 
decision meetings. The Sponsor and principal/sub-investigators will jointly assess the 
appropriateness of predetermined protocol dose escalation/dose confirmation rules (refer to 
Section 4.3) based on safety and tolerability data at the completion of each dose level, and 
prior to the opening of enrollment for the next dose level. The joint committee of Sponsor 
and principal/sub-investigators will render the formal decision regarding subsequent dose 
level to be tested in the participants, and a memorandum will be sent to each site to 
communicate the specified next dose level. Participants will be enrolled and allocated via 
Interactive Response Technology (IRT) according to the dose escalation and confirmation 
mTPI guidelines outlined in Section 4.3. The dose at each cohort will be specified via IRT. 
Cohorts will be opened or closed through IRT to ensure correct dosing in each cohort.
Duration of the treatment with MK-4621/JetPEI is limited to 6 cycles. Participants may 
continue on treatment with pembrolizumab for up to 35 cycles (approximately 2 years) from 
the start of treatment. Treatment with either of the agents may continue until discontinuation 
criteria are fulfilled (see Section 7). Treatment allocation will be accomplished by 
nonrandom assignment through an interactive response technology (IRT).
Participants who progress by either clinical or radiographic evaluation on monotherapy with 
MK-4621/JetPEI (Arm 1) may cross over into the combination therapy arm (Arm 2), 
provided that they meet crossover eligibility criteria in Section 1.3.1. Participants who cross 
over from Arm 1 to Arm 2 will enter Arm 2 at Screening and will be allocated to a 
combination dose level cohort in Arm 2 through an IRT. Participants who cross over from 
Arm 1 to Arm 2 are eligible for up to 35 cycles of treatment with pembrolizumab therapy and 
up to a cumulative total of 6 cycles of treatment with MK-4621/JetPEI, inclusive of cycles 
received in Arm 1 and Arm 2. Participants who crossover to Arm 2 will receive combination 
therapy at the highest dose of MK-4621/JetPEI with pembrolizumab that has been cleared for 
DLT in Arm 2 at the time of crossover.
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. 
Adverse events will be evaluated according to criteria outlined in the National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
 
 
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Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the SoA in Section 1.3. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
MK-4621/JetPEI is being developed for the treatment of solid tumors. This is the 
first-in-class RIG-I agonist being evaluated in clinical study designed to assess the safety, 
tolerability, PK, and PD of escalating doses of MK-4621/JetPEI when used as monotherapy 
and in combination with pembrolizumab in participants with advanced/refractory solid 
tumors.
The study exposes a small number of participants to each dose of MK-4621/JetPEI alone or 
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 in a new 
cohort.
The mTPI design is considered a safe design for a dose-escalation study in this population. 
Frequent assessments of safety will be conducted to support the primary objective for 
conducting the study. 
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), PFS and OS (exploratory 
endpoints).
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 will be assessed by investigators using RECIST 1.1 and iRECIST.
4.2.1.1.1 Response Rate Assessed by RECIST 1.1
RECIST 1.1 will be used to determine the treatment 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)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
following treatment with MK-4621/JetPEI ± pembrolizumab (Section 8.2.5). 
Immunotherapeutic agents such as MK-4621/JetPEI ± pembrolizumab may produce 
antitumor effects by potentiating endogenous cancer-specific immune responses. The 
response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents, and patients treated with pembrolizumab may manifest 
a clinical response after an initial increase in tumor burden or even the appearance of new 
lesions. Thus, standard RECIST 1.1 may not provide an accurate response assessment of 
immunotherapeutic agents such as pembrolizumab. Based on an analysis of participants with 
melanoma enrolled in KEYNOTE-001 (KN001), 7% of evaluable participants experienced 
delayed or early tumor pseudo-progression. Of note, participants who had progressive 
disease (PD) by RECIST 1.1 but not by the immune-related response criteria [Wolchok, J. 
D., et al 2009] had longer overall survival than participants with PD by both criteria [Hodi, F. 
S., et al 2014]. Additionally, the data suggest that RECIST 1.1 may underestimate the benefit 
of pembrolizumab in approximately 15% of participants. These findings support the need to 
apply a modification to RECIST 1.1 that takes into account the unique patterns of atypical 
responses in immunotherapy and enables treatment beyond initial radiographic progression, 
if the participant is clinically stable. 
Modified RECIST 1.1 for immune-based therapeutics (iRECIST) assessment has been 
developed and published by the RECIST Working Group, with input from leading experts 
from industry and academia, along with participation from the US Food and Drug 
Administration and the European Medicines Agency [Seymour, L., et al 2017]. The 
unidimensional measurement of target lesions, qualitative assessment of nontarget lesions, 
and response categories are identical to RECIST 1.1, until progression is seen by 
RECIST 1.1. However, if a participant is clinically stable, additional imaging may be 
performed to confirm radiographic progression. iRECIST will be used by investigators to 
assess tumor response and progression and make treatment decisions as well as for secondary 
efficacy analyses where specified.
For further information on iRECIST, see Section 8.2.5.
4.2.1.2
Safety Endpoints
The primary objective of this study is to characterize the safety and tolerability of 
MK-4621/JetPEI as monotherapy and as combination therapy 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. 
Safety will be assessed by quantifying the toxicities and grades of toxicities experienced by 
participants who have received MK-4621/JetPEI as monotherapy and in combination with 
pembrolizumab.
 
 
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For adverse events, attribution to drug, time-of-onset, duration of the event, its resolution, 
and any concomitant medications administered will be recorded. AEs that will be analyzed 
include, but are not limited to, all AEs, SAEs, fatal AEs, and laboratory changes.
4.2.1.3
Pharmacokinetic Endpoints
A secondary objective of this study is to characterize the pharmacokinetic (PK) profile of 
MK-4621/JetPEI following administration as a single agent and in combination with 
pembrolizumab. An exploratory objective is to characterize the pharmacokinetic profile of 
pembrolizumab following administration as combination therapy. The plasma concentrations
of these agents will serve as the primary readout for the PK, and these data will be used to 
derive PK parameters of the agents when administered alone and in combination. 
Furthermore, the results of these analyses will be used in conjunction with the 
pharmacodynamics, safety, and exploratory endpoint data to help assess future dosing 
strategies for MK-4621/JetPEI as monotherapy or in combination with pembrolizumab.
4.2.1.4
Target Engagement and Pharmacodynamic Endpoints
Given the nature of RIG-I as an intracellular receptor and its ubiquitous expression in many 
cell types, 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
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 
 
 
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(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 
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 
 
 
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(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.
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
4.2.1.6
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the 
measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
Future Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this Future Biomedical Research substudy are presented in Appendix 2 –
Collection and Management of Specimens for Future Biomedical Research.
4.3
Justification for Dose
4.3.1
Starting Dose for This Study
4.3.1.1
Rationale for Starting and Maximum Dose of MK-4621
Based on the pharmacodynamic data and the dose/tumor size correlation observed (refer to 
MK-4621 IB, Section 4.2.1.4), 0.2 mg MK-4621/JetPEI can be considered a 
pharmacologically active dose for intratumoral injection when extrapolated from tumors in 
mice to a human lesion with a diameter of 20 mm.
Accordingly, a starting dose (DL1) of 1 mL (0.2 mg) of MK-4621/JetPEI was considered for 
the first-in-human clinical study of intratumoral/intralesional injection (MK-4621-001) into 
cutaneous or hepatic lesions. Local administration is limited by maximum injection volumes 
feasible in target tumor tissue. The concentration of the MK-4621 particles in the injection 
dispersion is fixed to 0.2 mg/mL to achieve stable complexes. Therefore, the maximum dose 
of MK-4621/JetPEI per tumor is planned to be a maximum injectate of 4 mL (0.8 mg). This 
reflects also experience with other compounds that are applied intratumorally.
 
 
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Results from the 4-week toxicity studies in mice and cynomolgus monkeys suggest the 
following no-observed-adverse-effect levels (NOAELs) and human equivalent doses (HEDs) 
after IV administration of MK-4621/JetPEI:

NOAEL/MTD in mice=1.6 mg/kg IV HED=0.13 mg/kg

NOAEL in cynomolgus monkeys=0.16 mg/kg HED=0.05 mg/kg 

MTD in cynomolgus monkeys=1.5 mg/kg HED=0.5 mg/kg
Leakage of MK-4621/JetPEI from the lesion after intratumoral injection is expected to be 
marginal because, after intratumoral injection in mice, 100% of the compound remained local 
(refer to MK-4621 IB, Section 4.2.1.4). However, for the calculation of safety margins, 
complete leakage (eg, accidental administration into a blood vessel) was used as a worst case 
assumption. A theoretical complete leakage from a cutaneous lesion was mimicked in the 
subcutaneous toxicity studies. Local toxicity after direct injection into the liver was not 
examined, but results from a preliminary biodistribution study showed that most 
MK-4621/JetPEI is found in the liver after IV injection. Therefore, the IV toxicity data can 
be used to extrapolate the safety of leakage into healthy liver tissue.
Thus, assuming a theoretical complete systemic ad hoc exposure after intratumoral 
administration, a starting dose of 1 mL (0.2 mg MK-4621/JetPEI) in a 60-kg human 
(0.0033 mg/kg) would lead to the following safety factors (calculated with unrounded raw 
data): 

Safety factor for mouse NOAEL/MTD: 0.13/0.0033=40

Safety factor for cynomolgus monkey NOAEL: 0.05/0.0033=15

Safety factor for cynomolgus monkey MTD: 0.5/0.0033=150
Of note, the safety factor of 40 for the mouse has been calculated based on the NOAEL/MTD 
of 1.6 mg/kg (HED=0.13 mg/kg) observed in the pivotal 4-week toxicity study. Nevertheless, 
in single-dose IV studies in mice (LPT studies 32867 and 33090) at a dose of 2 mg/kg 
(HED=0.16 mg/kg) or 3 mg/kg MK-4621/JetPEI, acute clinical signs and mortality were 
observed within 2 hours after administration of MK-4621/JetPEI. Therefore, the safety factor 
for the minimum lethal dose is 48. Because this safety factor is based on the worst case 
assumption of complete leakage, it is considered acceptable for the intended patient 
population with advanced cancer.
4.3.1.2
Rationale for Fixed Dose of Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (q3w).  Based on 
the totality of data generated in the Keytruda development program, 200 mg q3w is the 
appropriate dose of pembrolizumab for adults across all indications and regardless of tumor 
type. As outlined below, this dose is justified by:
 
 
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
Clinical data from 8 randomized studies demonstrating flat dose- and 
exposure-efficacy relationships from 2 mg/kg q3w to 10 mg/kg every 2 weeks (q2w),

Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg q3w across multiple indications, and

Pharmacology data showing full target saturation in both systemic circulation 
(inferred from PK data) and tumor (inferred from physiologically-based PK [PBPK] 
analysis) at 200 mg q3w.
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled 
with melanoma and non-small cell lung cancer (NSCLC), covering different disease settings 
(treatment naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment 
settings (monotherapy and in combination with chemotherapy). Five studies compared 
2 mg/kg q3w versus 10 mg/kg q3w (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, 
and KN021), and 3 studies compared 10 mg/kg q3w versus 10 mg/kg q2w (KN001 
Cohort B3, KN001 Cohort F2 and KN006). All of these studies demonstrated flat dose- and 
exposure-response relationships across the doses studied representing an approximate 5- to 
7.5-fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) q3w provided similar 
responses to the highest doses studied. Subsequently, flat dose-exposure-response 
relationships were also observed in other tumor types including head and neck cancer, 
bladder cancer, gastric cancer, and classical Hodgkin Lymphoma, confirming 200 mg q3w as 
the appropriate dose independent of the tumor type. These findings are consistent with the 
mechanism of action of pembrolizumab, which acts by interaction with immune cells, and 
not via direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg q3w. First, PK data 
in KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg q3w. Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression. This evaluation concluded that pembrolizumab at 200 mg 
q3w achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other participant covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg q3w fixed dose and 2 mg/kg q3w dose. 
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg q3w fixed-dose was 
selected for evaluation across all pembrolizumab protocols.
4.3.1.3
Rationale for Dose Interval and Escalation Increments
The human starting dose and dosing interval of MK-4621/JetPEI are based on an integration 
of nonclinical toxicological, pharmacological, and efficacy data. Dose finding will proceed 
with a model-based mTPI approach with 3-14 participants treated per dose level using dose 
 
 
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increment increases of 30% to 100% of the prior dose. Planned dose levels (DL) are
DL1=0.2 mg (1 mL), DL2=0.4 mg (2 mL), DL3=0.6 mg (3 mL), and DL4=0.8 mg (4 mL). 
Arm 1 will start at DL4 (0.8 mg), as DLs 1-3 have already been found to be tolerable in 
Study MK-4621-001, as reflected in Section 4.1 - Study Design. After careful evaluation of 
all safety data it may be decided to further escalate to a higher dose as well as to use an 
intermediate dose level. 
4.3.1.4
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. 
A minimum of 3 participants are required at each dose. However, depending on the accrual 
rate, 3, 4, 5, or 6 participants may be enrolled within the first cycle of the opening of a dose 
cohort. 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 out of 3 participants at a given dose 
level develop a DLT, then the dose can escalate to the next level. 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 develops a DLT, then additional participants should be 
enrolled at that dose level following the rules below.
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). Secondly, 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.
 
 
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After 14 participants have been enrolled at any of the tested doses (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.
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 the dose-expansion phase of the study, and the escalation 
schedule may be adjusted based on PD, PK, and safety data emerging throughout the study. 
The preliminary RP2D of MK-4621/JetPEI in the combination arm (Arm 2) will not exceed, 
but may be equal to, the preliminary RP2D in the MK-4621/JetPEI monotherapy arm 
(Arm 1).
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%).
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
E = Escalate to the next higher dose; S = Stay at the current dose; D = De-escalate to the next lower dose; DU 
= The current dose is unacceptably toxic.
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]
 
 
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4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone-call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
Once participants have achieved the study objectives, they will be discontinued from this 
study and may be enrolled into an extension study to continue protocol-defined assessments 
and treatment with pembrolizumab monotherapy, as appropriate.
4.4.1
Clinical Criteria for Early Study Termination
Early study termination will be the result of the criteria specified below:
1. Incidence or severity of adverse drug reactions in this or other studies suggest a 
potential health hazard to participants
2. Plans to modify or discontinue the development of the study drug
3. Poor adherence to protocol and regulatory requirements
4. 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 
MK-4621/JetPEI or pembrolizumab.
5
STUDY POPULATION
Male/female participants at least 18 years of age with advanced solid tumors 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
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Have a histologically- or cytologically-confirmed advanced/metastatic solid tumor by 
pathology report and have received, or been intolerant to, all treatment known to 
confer clinical benefit.
2. For Arms 1 and 2: have 3 lesions as defined below: 

at least 1 cutaneous or subcutaneous lesion that is amenable to injection and 
biopsy (lesion 1). This injectable lesion must be measurable as defined by the 
 
 
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response criteria (RECIST 1.1): ≥1 cm in longest diameter for nonnodal 
lesion, or ≥1.5 cm in short axis for a nodal lesion. The longest diameter for an 
injectable lesion must be ≤10 cm. In case of multiple coalescing, superficial 
lesions the longest diameter in aggregate should be ≥1 cm and ≤10 cm.

at least 1 discrete noninjected, nonbiopsied lesion that is measurable as 
defined by the response criteria (RECIST 1.1): ≥1 cm in longest diameter for 
non-nodal lesions, or ≥1.5 cm in the short axis for nodal lesions (lesion 2).

at least 1 discrete and/or distant noninjected lesion amenable for biopsy 
(lesion 3).
3. For Arm 3 only: Have metastatic liver and/or liver lesion involvement that does not 
exceed one third of the total liver volume in participants to be treated by liver 
IT injection. Hepatocellular carcinoma participants are excluded from eligibility of 
intratumoral liver injection. For Arm 3, at least 2 lesions have to be identified as 
described below:

at least 1 liver lesion amenable to image-guided intratumoral injection and 
biopsy via ultrasound guidance or cross-sectional imaging (CT/MRI) guidance 
and must be measurable as defined by the response criteria (RECIST 1.1)
≥1 cm in longest diameter. The longest diameter for an injectable lesion must 
be ≥1 cm and ≤ 10 cm (lesion 1).

at least 1 other discrete noninjected, nonbiopsied lesion that is measurable as 
defined by the response criteria (RECIST 1.1): ≥1 cm in longest diameter
(lesion 2).
4. Submit an evaluable baseline tumor sample for analysis before start of treatment 
from: the lesion to be injected (lesion 1 in Arm 1, 2, and 3); and from a discrete 
noninjected lesion (lesion 3 in Arms 1 and 2) for assessing potential abscopal effects.
Details pertaining to tumor tissue submission can be found in the Procedures Manual.
5. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology 
Group (ECOG) Performance Scale.
6. Demonstrate adequate organ function as defined in Table 2. Specimens must be 
collected within 72 hours prior to the start of study treatment.
 
 
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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 
creatinine clearance (CrCl) 
(measured or calculated)b or
Glomerular Filtration Rate (GFR) in 
place of CrCl
≤1.5 X ULN or 
≥30 mL/min for participant with creatinine 
levels >1.5 X 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 ≤3 × ULN for participants 
with liver metastases
Coagulation
International Normalized Ratio 
(INR) or Prothrombin Time (PT)
Activated Partial Thromboplastin 
Time (aPTT)
<1.5 × ULN (unless participant is receiving 
anticoagulant therapy, in which case PT/INR
or aPTT should be within the therapeutic 
range of intended use of anticoagulants)
a Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants 
can be on stable dose of erythropoietin (≥ approximately 3 months).
b Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies.
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal.
Demographics
Male Participants
7. A male participant must agree to use a form of contraception as detailed in 
Appendix 5 of this protocol during the treatment period and for at least 120 days after 
the last dose of study intervention and refrain from donating sperm during this period.
 
 
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Female Participants
8. A female participant is eligible to participate if she is not pregnant (Appendix 5), not 
breastfeeding, and at least 1 of the following conditions applies:
a) Not a woman of childbearing potential (WOCBP) as defined in Appendix 5.
OR
b) A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during 
the treatment period and for at least 120 days after the last dose of study 
intervention.
Informed Consent
9. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the study. The participant may also provide consent for Future 
Biomedical research (FBR). However, the participant may consent to the main study
without participating in FBR.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
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 therapy, or 
has not recovered to CTCAE Grade 1 or better from any adverse events that were due 
to cancer therapeutics administered more than 4 weeks earlier (this includes 
participants with previous immunomodulatory therapy with residual immune-related 
adverse events). Participants receiving ongoing replacement hormone therapy for 
endocrine immune-related adverse events 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 hepatocellular carcinoma (for Arm 3 only).
4. Has clinically active central nervous system (CNS) 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 
 
 
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(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 treatment administration, and are off 
immunosuppressive doses of systemic steroids at least 2 weeks prior to enrollment.
5. Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody/
components of the study treatment.
6. Has an active infection requiring therapy.
7. Has a history of interstitial lung disease.
8. Has a history of (noninfectious) pneumonitis that required steroids or current 
pneumonitis.
9. 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. Use of nonsystemic steroids is permitted.
10. Participants with known human immunodeficiency virus (HIV) and/or Hepatitis B or 
C infections, or known to be positive for Hepatitis B surface
antigen (HBsAg)/Hepatitis B virus (HBV) DNA or Hepatitis C Antibody or RNA. 
Active Hepatitis C is defined by a known positive Hep C Ab result and known 
quantitative HCV RNA results greater than the lower limits of detection of the assay.
11. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s 
participation for the full duration of the study, make administration of the study drugs 
hazardous, or make it difficult to monitor adverse effects such that it is not in the best 
interest of the participant to participate, in the opinion of the treating investigator.
12. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
13. 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 treatment. 
14. Has not fully recovered from any effects of major surgery without significant 
detectable infection. Surgeries that required general anesthesia must be completed at 
least 2 weeks before first study treatment administration. Surgery requiring 
regional/epidural anesthesia must be completed at least 72 hours before first study 
treatment administration and participants should be recovered.
 
 
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15. A WOCBP who has a positive urine pregnancy test within 72 hours before the first 
dose of study treatment. If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.
Prior/Concomitant Therapy
16. Has received a live-virus vaccine within 30 days of planned treatment start. Seasonal 
flu vaccines that do not contain live virus are permitted.
Prior/Concurrent Clinical Study Experience
17. Is currently participating and receiving study therapy in a study of an investigational 
agent or has participated and received study therapy in a study of an investigational 
agent or has used an investigational device within 28 days of administration of 
MK-4621/JetPEI.
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.
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 
18. Has a history of re-irradiation for squamous cell carcinoma of head and neck
(SCCHN) 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. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 
5 years. 
Note:  Participants who have had a stem cell transplant greater than 5 years ago are 
eligible as long as there are no symptoms of graft-versus-host disease (GVHD).
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.
 
 
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5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
There are no restrictions on consumption of caffeine or tobacco. Reasonable alcohol 
consumption is allowed but patients with alcohol abuse should not be enrolled into the study. 
5.3.3
Activity
There are no restrictions on activity.
5.3.4
Contraception
Pembrolizumab or MK-4621/Jet/PEI may have adverse effects on a fetus in utero. Refer to 
Appendix 5 for approved methods of contraception.
Participants should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to participate 
in the study, participants of childbearing potential must adhere to the contraception 
requirement (Appendix 5) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 
120 days after the last dose of study medication. If there is any question that a participant of 
childbearing potential will not reliably comply with the requirements for contraception, that 
participant should not be entered into the study. 
5.3.5
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab or 
MK-4621/JetPEI, the participant will be immediately discontinued from study intervention. 
The site will contact the participant at least monthly and document the participant’s status 
until the pregnancy has been completed or terminated. The outcome of the pregnancy will be 
reported to the Sponsor without delay and within 24 hours if the outcome is a serious adverse 
event (SAE) (eg, death, abortion, congenital anomaly, or other disabling or life-threatening 
complication to the mother or newborn). The study investigator will make every effort to 
obtain permission to follow the outcome of the pregnancy and report the condition of the 
fetus or newborn to the Sponsor. If a male participant impregnates his female partner, the 
study personnel at the site must be informed immediately and the pregnancy must be reported 
to the Sponsor and followed as described in Section 8.4.5.
5.3.6
Use in Nursing Women
It is unknown whether pembrolizumab or MK-4621/JetPEI is excreted in human milk.  
Because many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions in the nursing infant, participants who are breastfeeding are not eligible for 
enrollment.
 
 
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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.
5.5
Participant Replacement Strategy
In order to adequately evaluate the safety of the doses administered in this study, all 
participants enrolled must meet the criteria for evaluability for the DLT evaluation period. 
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 adverse events

They receive less than 75% of the total MK-4621/JetPEI injection or pembrolizumab 
infusion in Cycle 1 (Cycles 1 and 2 for Arm 3) (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 during DLT evaluation period, study treatment may be 
discontinued following discussion between the sponsor and investigator. However, if the 
participant is deriving clinical benefit from the study treatment, 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 will be packaged to support enrollment. Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study treatments to be used in this study are outlined in Table 5.
 
 
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The formulation for MK-4621/JetPEI is the same as that used in the first-in-human study 
MK-4621-001.
All products indicated in Table 5 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study treatment.
6.1.1
Intratumoral Injection
In Arms 1 and 2, MK-4621/JetPEI will be administered by intratumoral injection into 
cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by 
ultrasound guidance.  In Arm 3, MK-4621/JetPEI will be administered by injection into liver 
metastasis/lesions by ultrasound or cross-sectional imaging guidance (CT/MRI). This 
injectable lesion must be a measurable target lesion as defined by the response criteria 
(RECIST 1.1):, ≥ 1 cm in longest diameter for non-nodal lesion, or ≥ 1.5 cm in short axis for 
a nodal lesion.
The injectable target lesion at the initiation of the treatment must be sufficiently sized to 
allow for injection of a total volume of the respective dose level as per the judgment of the 
treating physician in accordance with the minimum lesion diameters provided in Table 3. 
Table 3
Determination of Minimum Target Lesion Diameter at Treatment Initiation by 
Dose Level 
Dose Level
Maximum Injection 
Volume per Treatment 
Visit
Minimum Target Lesion 
Diameter at Treatment 
Initiation
1
0.2 mg
1 mL
≥1 cm
2
0.4 mg
2 mL
≥2 cm
3
0.6 mg
3 mL
≥3 cm
4
0.8 mg
4 mL
≥4 cm
 
 
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Maximum MK-4621/JetPEI injection volume should be administered to a single sufficiently 
sized target lesion at treatment initiation. Injected tumor area should consist of vital tumor 
tissue (avoid injection into areas with significant necrosis). Injected, single, sufficiently-sized 
target lesion at treatment initiation should be the same lesion that underwent pretreatment 
biopsy. If dose cannot be fully injected into the single biopsied target lesion planned for 
treatment initiation according to treating physician’s assessment, discuss with Sponsor before 
treatment initiation.
If at a certain point after treatment initiation a dose cannot be fully injected into the single 
target lesion identified at the start of treatment (eg, due to tissue induration, tumor shrinkage 
or similar), it is permissible to split the dose and inject the remaining amount of 
MK-4621/JetPEI into another accessible target lesion(s). The volume of injectate delivered to 
each target lesion will be based on the longest dimension of the target lesion, as shown in 
Table 4, and on the number of target lesions injected. If there are multiple target lesions of 
similar size, then up to a maximum of 4 target lesions may be injected per treatment visit, 
with a minimum injectate volume of 1 mL per lesion, and a total injectate volume less than or 
equal to the maximum volume set for the dose level. Documentation of dose volume 
administered per target lesion will be obtained.
Table 4
Determination of MK-4621/JetPEI Injection Volume for Injections Administered 
in More Than one Target Lesion Upon Change in Lesion Diameter After Initial Treatment
Target Lesion Size (longest dimension)
Injection Volume
≥4 cm 
4 mL
≥ 3 cm to < 4 cm
3 mL
≥2 cm to < 3 cm
2 mL
≥1 cm to < 2 cm
1 mL
Regarding prioritization of target lesions to be injected at a treatment visit, any new or 
progressing lesion should be injected first, followed by injection of another accessible 
lesion(s) in order of size, as permitted by total volume determined for dose level per 
treatment visit. In Arms 1 and 2, if no other target lesion is accessible for injection, the 
remaining amount may alternatively be injected subcutaneously into the tissue immediately 
surrounding the target lesion, if assessed feasible by the treating physician. In Arm 3, 
injection into different liver target lesions is permitted only, but not into peritumoral liver 
tissue.
It is desirable to administer the full dose of MK-4621/JetPEI at each treatment date 
throughout a treatment cycle, when feasible. If a remaining amount cannot be injected
 
 
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according to treating physician’s assessment, this amount needs to be documented for each 
injection as described in the Pharmacy Manual. 
For lesions that are no longer visible following treatment, discuss with Sponsor for continued 
injection. Distant bystander lesion(s) assessed for “abscopal” response should not be injected
unless approved by the Sponsor Medical Monitor or designee. Deviation from the injectate 
volumes specified in Table 3 and in Table 4 for individual target lesions may be permitted
upon approval by the Sponsor Medical Monitor or designee under selected scenarios; 
eg, allocating the total injectate volume among multiple target lesions rather than delivering 
the entire volume to the largest target lesion.
Details on dose calculation, preparation, and administration of MK-4621/JetPEI are provided
in the Pharmacy Manual.
 
 
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Table 5
Study Intervention(s)
Arm 
Name
Arm 
Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administra-
tion
Regimen/Treat-
ment Period
Use
IMP/
NIMP
Sourcing
Arm 1
Experi-
mental
MK-4621/
JetPEI
Drug
Dispersion 
for injection
0.2 mg/mL
0.8 mg 
= 4 mL
Intratumoral
q1w for each 
21-day cycle
Experi-
mental
IMP
Provided 
centrally 
by 
Sponsor
Arm 2
Experi-
mental
MK-4621/
JetPEI
Drug
Dispersion 
for injection
0.2 mg/mL
0.4 to 
0.8 mg 
= 2-4 
mLa, b
Intratumoral
q1w for each
21-day cycle
Experi-
mental
IMP
Provided 
centrally 
by 
Sponsor
Arm 2
Experi-
mental
Pembro-
lizumab
Drug
Solution for 
infusion
25 mg/mL
200 mg 
= 8 mL
Intravenous
q3w
Experi-
mental
IMP
Provided 
centrally 
by 
Sponsor
Arm 3
Experi-
mental
MK-4621/
JetPEI
Drug
Dispersion 
for injection
0.2 mg/mL
0.4 to 
0.8 mg 
= 
2-4 
mLa, b
Intratumoral
q3w for each 
21-day cycle
Experi-
mental
IMP
Provided 
centrally 
by 
Sponsor
Arm 3
Experi-
mental
Pembro-
lizumab
Drug
Solution for 
infusion
25 mg/mL
200 mg 
= 8 mL
Intravenous
q3w beginning 
Cycle 2
Experi-
mental
IMP
Provided 
centrally 
by 
Sponsor
a In Arms 2 and 3, MK-4621/JetPEI will be administered within 0.5-4 hours following completion of pembrolizumab IV infusion.
b Dose levels will be determined based on emerging safety data.
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 5 will be provided per the "Sourcing" row depending upon 
local country operational requirements. Every attempt should be made to source these 
supplies from a single lot/batch number. The study site is responsible for recording the lot 
number, manufacturer, and expiry date for any locally purchased product per local guidelines 
unless otherwise instructed by the Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.2
Medical Devices
Not applicable.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
The investigational medical product in this study is MK-4621, which is a double-stranded 
3-phosphate-RNA that binds to RIG-I; in vivo jetPEI™ is the delivery vehicle. 
MK-4621/JetPEI will be applied intratumorally/intralesionally. MK-4621/JetPEI will be 
provided as ready-to-use formulation in 10-mL vials with an extractable volume of at least 
5 mL. Details on preparation and administration of MK-4621/JetPEI (and pembrolizumab) 
are provided in the appropriate Pharmacy 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.
 
 
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The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Treatment allocation will be accomplished by nonrandom assignment by IRT.  Arm 1 and 
Arm 2 may not be opened for enrollment at the same time. When Arms 1 and 2 are open for 
enrollment simultaneously, IRT will alternate participant assignment between Arm 1 and 
Arm 2, with consideration of eligible lesion size for dose level. During the dose-confirmation 
phase, in the event that both Arms 1 and 2 are open for enrollment of participants, IRT will 
distribute successive participants across the treatment arms/dose-levels. Each new dose-level
will open for enrollment without delay once the DLT evaluation period of the previous dose 
cohort is completed and a dose escalation decision has been made. For example, once the 
0.8 mg dose cohort of Arm 1 (MK-4621/JetPEI monotherapy) and the 0.4 mg dose cohort of 
Arm 2 (MK-4621/JetPEI + pembrolizumab) are open for enrollment, the first participant will 
be allocated to Arm 1, the second participant will be allocated to Arm 2, the third participant
will be allocated to Arm 1, etc.
The enrollment to Arm 3 is independent of Arms 1 and 2 due to different location of 
injectable tumor, and will be opened after the DLT evaluation period is cleared at the highest 
dose for the first 3 participants in Arm 2. If all 3 arms are open for enrollment, participants 
with tumors located predominantly in the liver, accessible for intrahepatic injection and not 
suitable for Arms 1 and 2 will be enrolled into Arm 3. Otherwise, priority will be given to 
Arms 1 and 2.
For Arms 2 and 3, an observation period of at least 24 hours will occur after treatment 
initiation in participants enrolled within each dose level. Each new dose cohort will open for 
enrollment without delay once DLT evaluation period of the previous dose cohort is 
completed and a dose-escalation decision is made.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This study is an open-label study; therefore, the Sponsor, investigator and participant will 
know the treatment administered.
 
 
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6.4
Study Intervention Compliance
Interruptions from the protocol specified treatment plan for >12 weeks between 
MK-4621/JetPEI 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 treatment may be required. The investigator should discuss any 
questions regarding this with the Sponsor. The final decision on any supportive therapy rests 
with the investigator and/or the participant's primary physician. However, the decision to 
continue the participant on study treatment requires the mutual agreement of the investigator, 
the Sponsor, and the participant.
6.5.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care except for those that are prohibited as described in Section 6.5.2. All 
concomitant medication will be recorded on the case report form (CRF) including all 
prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids. If 
changes occur during the study period, documentation of drug dosage, frequency, route, and 
date may also be included on the CRF.
Anticoagulants or antiplatelet agents are allowed however may be discontinued temporarily 
for the biopsy and injection procedures; benefit/risk of the interruption needs to be weighed 
by the investigator. The timing and duration of the interruption and further management will 
be done according to the sites routine procedures. Coagulation parameter should be carefully 
monitored and the potential bleeding risk of the intrahepatic administration of the drug needs 
to be taken into consideration. 
All concomitant medications received within 28 days before the first dose of study treatment 
and 30 days after the last dose of study treatment should be recorded. Concomitant 
medications administered after 30 days after the last dose of study treatment 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 (including retreatment for post-complete response relapse) of this study:

Antineoplastic systemic chemotherapy or biological therapy 

Immunotherapy not specified in this protocol
 
 
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
Chemotherapy not specified in this protocol

Investigational agents other than MK-4621/JetPEI and pembrolizumab

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 evaluation period.

Live vaccines within 30 days prior to the first dose of study treatment 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 (BCG), and typhoid vaccine. Seasonal influenza vaccines 
for injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
adverse event of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from treatment. 
Participants may receive other medications that the investigator deems to be medically 
necessary.
6.5.3
Rescue Medications and Supportive Care
6.5.3.1
MK-4621/JetPEI Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including, but not limited to, the items outlined below:

Pyrexia: Fever reactions are expected during treatment with MK-4621/JetPEI. 
Investigators may treat the fever with their standard antipyretics (eg, paracetamol) at 
their discretion. Pretreatment with antipyretics is also allowed in a case in which a 
participant showed a fever reaction after an earlier injection. This pretreatment is also 
at the discretion of the investigator.
Hypersensitivity is seen as a potential safety risk in general with novel compounds. In 
addition (based upon published preclinical experiences) the excipient PEI and its variants are 
seen as a potential source for hypersensitivity reactions. Therefore, it is recommended to 
monitor all participants carefully for any such potential reaction and to take appropriate 
measures where seen as needed (eg, premedication) as per treating physician’s assessment. In 
case any such hypersensitivity reaction (infusion-related reaction [IRR]; anaphylaxis/ 
anaphylactoid reactions or other cytokine release-related events and similar) may occur 
within the first 48 hours of injection that presents as AE ≥Grade 2, the participant should 
 
 
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receive medication according to the institutions local policies. A premedication with 
methylprednisolone, an antihistamine and an H2-blocker may appear recommendable with 
subsequent injections to avoid any such IRR if seen as recommendable by the investigator. 
Treatment shall be permanently discontinued in any case of Grade 4 hypersensitivity 
reaction.
In the first 15 participants, local reactions at the injection site have been seen, as well as fever 
reactions and fatigue, mainly Grade 1. A Grade 3 fever reaction occurred once and resolved 
in less than 24 hours. Grade 3 fatigue was also reported.
Treatment by local surgery and/or radiation therapy of isolated or symptomatic progressing 
lesions in the setting of improving baseline disease, may be permitted for palliative or 
potentially curative management following completion of Cycle 2. Subsequently, all 
interventions, including continuation of study treatment, should be discussed with the 
Sponsor Clinical Director or designee.
6.5.3.2
Pembrolizumab Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6.5.2, Table 7. 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 7 in 
Section 6.6.5.2 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
6.6.1.1
Dose Administration (Preparation)
Details on preparation and administration of MK-4621/JetPEI and pembrolizumab are 
provided in the appropriate Pharmacy Manual.
 
 
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6.6.2
Definition of Dose-limiting Toxicity
All toxicities will be graded using NCI-CTCAE Version 4.0 based on the investigator 
assessment.
The DLT window of observation will be during Cycle 1 for Arms 1 and 2. For Arm 3, the
DLT evaluation period will be the first 2 cycles (ie, the first monotherapy run-in 
cycle [Cycle 1]) and the first combination therapy cycle [Cycle 2]).
The occurrence of any of the following toxicities during DLT evaluation period will be 
considered a DLT, if assessed by the investigator to be possibly, probably, or definitely 
related to study treatment administration.
1. Grade 4 nonhematologic toxicity (not laboratory).
2. Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia:

Grade 4 thrombocytopenia of any duration

Grade 3 thrombocytopenia associated with clinically significant bleeding 
3. Any nonhematologic AE ≥Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤3 days; Grade 3 diarrhea, nausea, or 
vomiting without use of antiemetics or antidiarrheals per standard of care; Grade 3 
rash without use of corticosteroids or anti-inflammatory agents per standard of care; 
Grade 3, drug-related fever that resolves within 24 hours.
4. Any Grade 3 or Grade 4 nonhematologic laboratory value if:

Clinically significant medical intervention is required to treat the participant, or

The abnormality leads to hospitalization, or

The abnormality persists for >1 week; or

The abnormality results in a Drug-induced Liver Injury (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:

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.
 
 
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
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 2 due to treatment-related toxicity.
7. Any treatment-related toxicity that causes the participant to discontinue treatment 
during Cycle 1, or Cycles 1 and 2 for Arm 3.
8. Missing >2 injections of MK-4621/JetPEI doses in Arms 1 and 2 and >1 injection in 
Arm 3 as a result of drug-related AE(s) during the first cycle of Arms 1 or 2 or the 
first 2 cycles of Arm 3, respectively.
9. Grade 5 toxicity.
The following toxicities will not be considered as DLTs:
1. Grade 3 AE of tumor flare (defined as local pain, irritation, or rash localized at sites 
of known or suspected tumor) or injection procedure related local pain that is 
clinically manageable as per investigator’s assessment.
2. Grade 3 injection/hypersensitivity reactions that resolve to Grade ≤1 within 24 hours.
6.6.3
Crossover Treatment Phase (Optional)
Participants with disease progression following treatment with MK-4621/JetPEI in the 
monotherapy arm (Arm 1) may be eligible to participate in the crossover treatment phase of 
this study and cross over to Arm 2. Participants who permanently discontinue 
MK-4621/JetPEI monotherapy due to an AE, withdrawal of consent, or for any reason other 
than disease progression are not eligible for crossover. Crossover is optional, is at the 
discretion of the investigator, and requires the Sponsor’s approval.
Eligibility criteria for crossover include:

Participants must have disease progression following treatment with MK-4621/JetPEI
in the monotherapy arm (Arm 1)
Note: Disease progression must be assessed by imaging study using RECIST 1.1 and 
be confirmed by iRECIST, as assessed by the site. Participants with overt progression 
before confirmed PD may initiate crossover upon Sponsor consultation on a case-by-
case basis. The imaging that confirms the progression will be used to establish a new 
baseline for the crossover phase.

Participants must have adequate organ function as indicated by the laboratory values 
in Table 2;

Participants must have no evidence of new or enlarging brain metastases; and

Participants must have an ECOG performance status of 0 or 1.
 
 
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If crossover is being considered, the participant must be re-consented and the risks and 
benefits of continuing study treatment after disease progression should be reviewed prior to 
performing any crossover-related procedures.
Although intraparticipant dose escalation is not allowed, at crossover, the participant may be
eligible to receive the highest dose of MK-4621/JetPEI that has passed the DLT evaluation 
period in the combination treatment arm at the time of crossover. The participant will receive 
the highest dose of MK-4621/JetPEI that has passed an initial DLT evaluation period in the 
combination treatment arm. Participants who cross over to the combination treatment arm 
will not be counted toward the total number of participants in the cohort for DLT evaluation.
The first dose of study treatment in the combination treatment arm should be administered no
earlier than 21 days (3 weeks) and no later than 42 days (6 weeks) from the last dose of
MK-4621/JetPEI in the monotherapy arm unless otherwise discussed with the Sponsor.
The study procedures are to be completed in the crossover treatment phase and safety and 
efficacy data from participants who crossover into the combination arm will be presented 
separately and will include all events starting from the date of the first dose of combination 
study treatment.
6.6.4
Timing of Dose Administration
Arm 1: MK-4621/JetPEI will be administered once weekly in each cycle, for a maximum 
duration of 6 cycles. A cycle is defined as 3 weeks. 
Arm 2: Pembrolizumab will be administered once every 3 weeks starting with D1C1. 
MK-4621/JetPEI will be injected intratumorally once weekly for each cycle. The injection 
will be done 0.5-4 hours after the infusion of pembrolizumab.
Arm 3: Run-in Phase (Cycle 1): MK-4621/JetPEI as monotherapy will be administered on 
Day 1 of Cycle 1.
Combination Phase (Cycles 2-6): Pembrolizumab and MK-4621/JetPEI will be administered 
once every 3 weeks. On Day 1 of each cycle, MK-4621/JetPEI will be injected 0.5-4 hours
after pembrolizumab.
If neither pembrolizumab treatment nor MK-4621/JetPEI treatment can be performed on the 
Treatment Cycle Day 1, the Treatment Cycle will not be initiated. If either pembrolizumab 
treatment or MK-4621/JetPEI treatment can be performed on the Treatment Cycle Day 1, the 
Treatment Cycle will be initiated. If treatment cannot be performed within the given time 
window during a Treatment Cycle, the dose is missed and will not be replaced; the 
participant will continue with the next visit according to the Treatment Cycle schedule.
The reason for any variability in administration of MK-4621/JetPEI and pembrolizumab 
outside of the protocol-specified window should be documented in the participant’s chart and 
recorded on the electronic Case Report Forms (eCRFs). All study treatments will begin on 
Day 1 of each cycle after all predose study procedures and assessments have been completed 
 
 
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as detailed in Section 1.3, Schedule of Activities. The Pharmacy Manual contains specific 
instructions for dose calculation, reconstitution, and preparation of MK-4621/JetPEI, and 
administration.
6.6.5
Guidelines for Dose Modification for MK-4621/JetPEI and/or Pembrolizumab 
due to Adverse Events
Adverse events (both nonserious and serious) associated with MK-4621/JetPEI and 
pembrolizumab exposure may represent an immunologic etiology. These adverse events may 
occur shortly after the first dose or several months after the last dose of treatment. 
The CTCAE must be used to grade the severity of adverse events. The investigator may 
attribute each toxicity event to MK-4621/JetPEI alone, to pembrolizumab alone, or to the 
combination, and modify the dose according to Table 6 and Table 7. If a dose modification 
for toxicity occurs with MK-4621/JetPEI, the dose may not be re-escalated to the dose that 
preceded the dose modification. Dose modifications are always based on the previous cycle.
Reduction or holding of 1 agent and not the other agent is appropriate if, in the opinion of the 
investigator, the toxicity is clearly related to 1 of the study treatments. For example, in the 
combination arm (Arm 2), if MK-4621/JetPEI is held due to an AE attributed to that drug, 
then pembrolizumab may continue to be administered. Appropriate documentation is 
required regarding to which drug the investigator is attributing the 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. 
6.6.5.1
Dose Modification for MK-4621/JetPEI
Participants may have up to 2 dose modifications of MK-4621/JetPEI throughout the course 
of the study, as described in Table 6. If further toxicity occurs or the criteria for resuming 
treatment are not met, the participant must be discontinued from the study treatment. If a 
participant experiences several toxicities and there are conflicting recommendations, follow 
the most conservative dose adjustment recommended (dose reduction appropriate to the most 
severe toxicity).
Exceptional circumstances to following the dose modification tables below may be 
considered after consultation with the Sponsor.
 
 
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Table 6
MK-4621/JetPEI Dose Modification and Treatment Discontinuation Guidelines 
for Drug-related Adverse Events 
Toxicity
Hold 
Treatment
Criteria for 
Restarting 
Treatment
Dose/Schedule for 
Restarting Treatment
Criteria for 
Discontinuation 
After Consultation 
with Sponsor
Hematological toxicities:
Any Grade 1 
hematological 
toxicity
No
N/A
N/A
N/A
Any Grade 2 
hematological 
toxicity, or Grade 3 
toxicity that persists 
for ≤5 days
Per medical 
assessment 
of the 
investigator
If treatment held, 
may be restarted 
when AE resolves 
back to baseline 
or to Grade 1
Per medical assessment of the 
investigator: may decrease 
dose by 1 dose level
If AE persists for 
12 weeks without 
resolution following 
reduction in dose
Any Grade 3 
hematologic toxicity 
that persists for 
>5 days, or Grade 4 
hematological 
toxicity
Febrile neutropenia
Grade 3 
thrombocytopenia of 
any duration if 
associated with 
bleeding
Yes
Treatment may be 
restarted when 
AE resolves back 
to baseline or to 
Grade 1.
Decrease dose by 1 dose level.
If AE persists for 
12 weeks without 
resolution following 
reduction in dosing 
schedule.
Permanent 
discontinuation should 
be considered for any 
severe or 
life-threatening event
Nonhematological toxicities:
Any Grade 1 
nonhematological 
toxicity 
Grade 2 alopecia
Grade 2 fatigue
Grade 2 pyrexia
No 
N/A
N/A
N/A
Any Grade 2 
nonhematological 
toxicity except 
Grade 2 alopecia, 
Grade 2 fatigue, and 
Grade 2 pyrexia
Per medical 
assessment 
of the 
investigator
If treatment held, 
may be restarted 
when AE resolves 
back to baseline 
or to Grade 1.
Per medical assessment of the 
investigator: may decrease 
dose by 1 dose level.
If AE persists for 
12 weeks without 
resolution following 
reduction in dose.
Any Grade 3 or 4 
nonhematological 
toxicity (not 
including laboratory, 
unless clinically 
significant medical 
intervention is 
required to treat the 
participant, or the 
abnormality leads to 
hospitalization, or 
the abnormality 
persists for >1 week)
Yes
Treatment may be 
restarted when 
AE resolves back 
to baseline or to 
Grade 1.
Decrease dose by 1 dose level. 
If AE persists for 
12 weeks without 
resolution following 
reduction in dose.
Permanent 
discontinuation should 
be considered for any 
severe or 
life-threatening event
 
 
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In case toxicity does not resolve to Grade 0-1 within 12 weeks after last treatment, 
MK-4621/JetPEI should be discontinued after consultation with the Sponsor. 
With investigator and Sponsor agreement, participants with a laboratory adverse event still at 
Grade 2 after 12 weeks may continue treatment in the study only if asymptomatic and 
controlled.
After any Grade 4, drug-related adverse event, participants should not restart study treatment 
without consultation with the Sponsor; toxicity must have resolved to Grade 0-1 or baseline 
prior to restarting. 
6.6.5.2
Dose Modification for Pembrolizumab
Dose modification and toxicity management for immune-related AEs associated with 
pembrolizumab
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology. These immune-related AEs (irAEs) may occur shortly after the first dose or several 
months after the last dose of pembrolizumab treatment and may affect more than one body 
system simultaneously. Therefore, early recognition and initiation of treatment is critical to
reduce complications. Based on existing clinical study data, most irAEs were reversible and 
could be managed with interruptions of pembrolizumab, administration of corticosteroids, 
and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of 
irAEs, withhold or permanently discontinue pembrolizumab and administer corticosteroids. 
Dose modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided in Table 7. 
 
 
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Table 7
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should 
be initiated if irAEs cannot be controlled by corticosteroids.
Immune-
related AEs
Toxicity Grade or 
Conditions 
(CTCAEv4.0)
Action Taken with 
Pembrolizumab
irAE Management with 
Corticosteroid and/or Other 
Therapies 
Monitor 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
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / 
Colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus).

Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-
related AEs
Toxicity Grade or 
Conditions 
(CTCAEv4.0)
Action Taken with 
Pembrolizumab
irAE Management with 
Corticosteroid and/or Other 
Therapies 
Monitor and Follow-up 
AST / ALT 
Elevation or 
Increased 
Bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 Diabetes 
Mellitus 
(T1DM) or 
Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement therapy 
for participants with T1DM

Administer antihyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with nonselective 
beta-blockers (eg, propranolol) or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
permanently 
discontinue1
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
 
 
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Immune-
related AEs
Toxicity Grade or 
Conditions 
(CTCAEv4.0)
Action Taken with 
Pembrolizumab
irAE Management with 
Corticosteroid and/or Other 
Therapies 
Monitor and Follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE administer 
corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All Other 
Immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or 
discontinue based 
on the type of event. 
Events that require 
discontinuation 
include and not 
limited to:Guillain-
Barre Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1 Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy for which withholding of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).
 
 
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 8.
Table 8
Pembrolizumab Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE 
Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; 
infusion interruption 
not indicated; 
intervention not 
indicated
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of the 
investigator.
None
Grade 2
Requires therapy or 
infusion interruption 
but responds 
promptly to 
symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, 
IV fluids); 
prophylactic 
medications 
indicated for ≤24 h
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, from 
100 mL/h to 50 mL/h). Otherwise dosing will 
be held until symptoms resolve and the 
participant should be premedicated for the 
next scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment.
Participant may be 
premedicated 1.5h (± 30 
minutes) prior to infusion 
of pembrolizumab with:
diphenhydramine 50 mg 
po (or equivalent dose of 
antihistamine and/or H2 
blocker).
Paracetamol 
(acetaminophen) 500-
1000 mg po (or equivalent 
dose of analgesic).
 
 
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NCI CTCAE 
Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms 
following initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary 
infiltrates)
Grade 4:
Life-threatening; 
pressor or 
ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of the 
investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should 
be used immediately.
Participant is permanently discontinued 
from further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily 
available during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 
(CTCAE) at http://ctep.cancer.gov
Other allowed dose interruption for pembrolizumab or MK-4621/JetPEI
Pembrolizumab or MK-4621/JetPEI may be interrupted for situations other than 
treatment-related AEs such as medical / surgical events or logistical reasons not related to 
study therapy. Participants should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient'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 treatment (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
 
 
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention discontinuation may be 
important to the study, they must be collected through the participant’s last scheduled follow-
up, even if the participant has discontinued study intervention. Therefore, all participants 
who discontinue study intervention 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 8.12.
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 8.1.9.
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 has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.

The participant has a confirmed positive serum pregnancy test.

Confirmed radiographic disease progression outlined in Section 8.2 (exception if the 
Sponsor approves treatment continuation, or if a participant progresses on Arm 1 and 
crosses over to Arm 2).

Unacceptable adverse experiences as described in Section 8.3.

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.
 
 
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
Investigator’s decision to discontinue treatment.

Recurrent Grade 2 pneumonitis.

Completion of 6 cycles of treatment with MK-4621/JetPEI in Arm 1 or 35 treatments 
with pembrolizumab in Arms 2 and 3. Participants who cross over from Arm 1 to Arm 2 
are eligible for up to 35 cycles of treatment with pembrolizumab therapy and up to a 
cumulative total of 6 cycles of treatment with MK-4621/JetPEI, inclusive of the 
MK-4621/JetPEI cycles received in Arm 1 and Arm 2.
Participants may discontinue from one of the study medications (Arm 2 and 3) but continue 
with the other study medication if considered reasonable by the investigator.
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
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 treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study,as well as specific details regarding withdrawal from future biomedical research, are 
outlined in Section 8.1.9. The procedures to be performed should a participant repeatedly fail 
to return for scheduled visits and/or if the study site is unable to contact the participant are 
outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:

The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.

The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.

Note: A participant is not considered lost to follow-up until the last scheduled visit for 
the individual participant. The missing data for the participant will be managed via 
the prespecified statistical data handling and analysis guidelines.
 
 
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8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).

All study-related medical (or dental) decisions must be made by an investigator who 
is a qualified physician (or dentist when appropriate).

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.

Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C), and 
thus local regulations may require that additional informed consent be obtained from 
the participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
The maximum amount of blood collected from each participant, including any extra 
assessments that may be required over the duration of the study, will not exceed 500 mL
(refer to 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 
 
 
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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
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion.
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF, and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s 
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level.
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, 
and Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the future biomedical research 
consent to the participant, answer all of his/her questions, and obtain written informed 
consent before performing any procedure related to the future biomedical research substudy. 
A copy of the informed consent will be given to the participant.
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 or qualified designee 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 
 
 
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the participant provides written informed consent. At the time of intervention allocation/
randomization, site personnel will add the intervention/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 
are considered to be clinically significant by the investigator. Details regarding the disease 
for which the participant has enrolled in the study will be recorded separately and not listed 
as medical history.
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before first dose of study medication. 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.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
All medications related to reportable SAEs and events of clinical interest (ECIs) should be 
recorded as defined in Section 8.4.
All new anticancer therapy initiated after the study start must be recorded in the eCRF. If a 
participant initiates another anticancer therapy other than the assigned study treatment(s), the 
study treatment(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 treatment, the 30-day Safety Follow-up visit should occur before the 
first dose of the new therapy.
8.1.6
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to intervention allocation. Each 
participant will be assigned only 1 screening number. Screening numbers must not be re-used 
for different participants.
 
 
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8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/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.
8.1.8
Study Intervention Administration
Administration of study medication will be witnessed by the investigator and/or study staff. 
The total volume of study treatment injected and/or infused will be compared to the total 
volume prepared to determine compliance with each dose administered.
Study treatment will begin on Cycle 1 Day 1, once all predose assessments have been 
completed.
See Section 6 for a description of treatment modifications. Instructions for preparing and 
administering study intervention will be provided in the Pharmacy Manual.
8.1.8.1
Timing of Dose Administration
In Arm 1 (monotherapy), MK-4621/JetPEI will be administered on Days 1, 8, and 15 of the 
of each cycle. Each participant may undergo up to 6 cycles of MK-4621/JetPEI treatment in 
Arm 1.
In Arm 2, MK-4621/JetPEI will be administered on Days 1, 8, and 15 of each 21-day cycle. 
MK-4621/JetPEI will be administered within 0.5 to 4 hours following completion of 
pembrolizumab IV infusion. Each participant may undergo up to 6 cycles of 
MK-4621/JetPEI treatment in Arm 2.
For Arm 3, MK-4621/JetPEI will be administered on Day 1 of each 21-day cycle. 
MK-4621/JetPEI will be administered within 0.5 to 4 hours following completion of 
pembrolizumab IV infusion. Each participant may undergo up to 6 cycles of 
MK-4621/JetPEI treatment in Arm 3.
In Arms 2 and 3, pembrolizumab 200 mg will be administered as an IV infusion on Day 1 of 
each 21-day cycle (except for Cycle 1 of Arm 3). Participants may continue treatment with 
pembrolizumab for up to a total of 35 cycles (approximately 2 years).
In Cycle 2, study intervention may be administered up to 3 days after the scheduled Day 1. 
Beginning in Cycle 3, study treatment may be administered up to 3 days before or after the 
scheduled Day 1. Dosing interruptions are permitted in the case of medical/surgical events or 
logistical reasons that are not related to study therapy (eg, elective surgery, unrelated medical 
events, participant vacation, and/or holidays). Participants should be placed back on study 
 
 
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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.
8.1.9
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.
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 8.12.2.1. The investigator or 
study coordinator must notify the Sponsor when a participant has been 
discontinued/withdrawn from the study and/or treatment. If a participant discontinues for any 
reason at any time during the course of the study and/or treatment, the participant may be 
asked to return to the clinic (or be contacted) for a poststudy visit as per the number of days 
described in Section 8.4 and Section 8.12.2.1 to have the applicable procedures conducted. 
However, the investigator may decide to perform the poststudy procedures at the time of 
discontinuation or as soon as possible after discontinuation. If the poststudy visit occurs prior 
to the safety follow-up timeframe as specified in Section 8.4.1, the investigator should 
perform a follow-up telephone call at the end of the follow-up period (Section 8.4.1.) to 
determine if any AEs have occurred since the poststudy clinic visit. Any AEs that are present 
at the time of discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.9.1
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@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed. 
 
 
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8.1.10 Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11 Domiciling
Participants will report to the clinical research unit (CRU) on Cycle 1 Day 1. For Arm 1, on 
Day 1 of Cycles 1-6, a 24-hour inpatient observation period following MK-4621/JetPEI 
administration will be at the discretion of the investigator. All participants in Arm 2 will 
undergo at least a 24-hour observation period following first dose administration on C1D1, 
which may be extended to 48 hours at the discretion of the investigator. For Arm 2, on Day 1 
of Cycles 2-6, a 24-hour inpatient observation period following MK-4621/JetPEI 
administration will be at the discretion of the investigator. All participants in Arm 3 will 
undergo at least a 24-hour observation period following dose administration on C1D1 and 
C2D1, which may be extended to 48 hours at the discretion of the investigator. For Arm 3, on 
Day 1 of Cycles 3-6, a 24-hour inpatient observation period following MK-4621/JetPEI 
administration will be at the discretion of the investigator. For all the required inpatient 
observation periods, observation time may be extended to 48 hours at the discretion of the 
investigator, per local Institutional Review Board, Ethics Review Committee, and/or Health 
Authority mandate. This requirement may be waived at the discretion of the Sponsor and will 
be communicated to sites via a memorandum.
8.1.12 Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Assessment of Disease
RECIST 1.1 and iRECIST assessment will be done on the basis of 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.
Tumor imaging should be acquired by computed tomography (CT, strongly preferred). MRI
should be used when CT is contraindicated or for imaging in the brain. The same imaging 
technique regarding modality and use of contrast media should be used in a participant 
throughout the study to optimize the visualization of existing and new tumor burden. 
 
 
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Required anatomical images as well as the process for image collection and transmission to 
the central imaging vendor can be found in the Site Imaging Manual (SIM).
A central imaging vendor will be made available for possible future independent review.
Although RECIST 1.1 references to a maximum of 5 target lesions in total and 2 per organ, 
Merck 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.
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. 
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 28 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.
8.2.3
Tumor Imaging During the Study
The first on-study imaging assessment 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. Imaging timing should follow calendar days and 
should not be adjusted for delays in cycle starts. Imaging should continue to be performed 
until disease progression is identified by the investigator, the start of new anticancer 
treatment, withdrawal of consent, death, or the end of the study, whichever occurs first. 
Per iRECIST (Section 8.2.5), disease progression should be confirmed by the site 
4 to 8 weeks after site-assessed first radiologic evidence of PD in clinically stable 
participants. Participants who have unconfirmed disease progression may continue on 
treatment at the discretion of the investigator until progression is confirmed provided they 
have met the conditions detailed in Section 8.2.5. Participants who receive confirmatory 
imaging do not need to undergo the next scheduled tumor imaging if it is less than 4 weeks 
later; tumor imaging may resume at the subsequent scheduled imaging time point if clinically 
stable. Participants who have confirmed disease progression by iRECIST, as assessed by the 
site, will discontinue the treatment. Exception is detailed in Section 8.2.5.
 
 
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8.2.4
End of Treatment and Follow-up Tumor Imaging
In participants who discontinue study intervention, tumor imaging should be performed at the 
time of treatment discontinuation (± 4 week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory. For participants who discontinue study treatment due to documented 
disease progression, this is the final required tumor imaging the investigator elects to not to 
implement iRECIST.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used while on treatment (every 9 weeks) to monitor disease 
status until the start of a new anticancer treatment, disease progression, pregnancy, death, 
withdrawal of consent, or the end of the study, whichever occurs first.
8.2.5
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by 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 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 9). 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 treatment at 
site-assessed first radiologic evidence of PD, and is not required to have repeat imaging for 
confirmation of PD by iRECIST.
 
 
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If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective blinded independent central review.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.

Unequivocal progression of nontarget lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including iUPD (unconfirmed progressive 
disease) and iCPD (confirmed progressive disease). For purposes of iRECIST assessment, 
the first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression. 
At this visit, target and nontarget lesions identified at baseline by RECIST 1.1 will be 
assessed as usual. 
New lesions will be classified as measurable or nonmeasurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target. 
The sum of diameters of these lesions will be calculated, and kept distinct from the sum of 
diameters for target lesions at baseline. All other new lesions will be followed qualitatively 
as New Lesions – Nontarget.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the initial iUPD show worsening:
o
For target lesions, worsening is a further increase in the sum of diameters of 
≥5mm, compared to any prior iUPD timepoint.
 
 
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o
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD timepoint; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5mm from a prior 
iUPD timepoint 

Visible growth of new nontarget lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1.
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
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.
 
 
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Management following the confirmatory imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the Investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue 
treatment may be considered following consultation with the Sponsor. In this case, if study 
treatment is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3, Schedule of Activities, 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
o
Sum of diameters reaches the PD threshold (20% & 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.

Nontarget lesions
o
If nontarget lesions have never shown unequivocal progression, their doing so 
for the first time results in iUPD.
o
If nontarget lesions had shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth 
of nontarget lesions, taken as a whole.

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the 
new lesion sum of diameters, from the nadir value of that sum
o
Previously identified nontarget lesions show any significant growth
 
 
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If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication.
 
 
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Table 9
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD 
by RECIST 1.1 
Repeat imaging 
at 4 to 8 weeks 
to confirm PD
May continue study 
treatment at the 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
N/A
Repeat tumor 
imaging shows 
iUPD by 
iRECIST, per 
local assessment
Repeat imaging 
at 4-8 weeks to 
confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit.
Continue study 
treatment at the local 
site investigator’s 
discretion
Repeat imaging at 4-
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 
treatment at the local 
site investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments
May restart study 
treatment if condition 
has improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumor imaging
should occur 
according to the 
regular imaging 
schedule 
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.
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.
 
 
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8.2.6
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of study treatment on Day 1 of every cycle, 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 Section 8.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
8.3.1.1
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period, including height and weight. Height will be measured at Visit 1 only.
Clinically significant abnormal findings should be recorded as medical history. The time 
points for full physical exam are described in the SoA. After the first dose of study treatment, 
new clinically significant abnormal findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Exam
For cycles that do not required a full physical exam per the Schedule of Activities, the 
investigator or qualified designee will perform a directed physical exam as clinically 
indicated prior to study treatment administration. New clinically significant abnormal 
findings should be recorded as AEs.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior and after the 
administration of study treatment and during the follow-up period as specified in the SoA. 
Vital signs include temperature, pulse, respiratory rate, blood pressure, and oxygen 
saturation. 
8.3.3
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the Schedule of Activities in Section 1.3. Clinically significant 
abnormal findings should be recorded as medical history before study treatment and as an AE 
 
 
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if occurring under study treatment. 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 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).

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 3 days prior to the first dose of 
study treatment. An exception is hepatitis, HIV 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 treatment. Unresolved 
abnormal laboratory values that are drug-related AEs should be followed until resolution. 
Laboratory tests do not need to be repeated after the end of treatment if laboratory results are 
within normal range.
 
 
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8.3.4.2
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 treatment. 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.
8.4
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 4.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6 
and Appendix 4.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators remain responsible for following up AE, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
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 consent form is signed 
but before treatment 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 treatment 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 treatment 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.
 
 
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
All pregnancies and exposure during breastfeeding, from the time of treatment 
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 drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study 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 10.
 
 
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Table 10
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
Timeframe to 
Report Event 
and Follow-up 
Information to 
SPONSOR:
Non-Serious 
Adverse Event 
(NSAE) 
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes 
exclusion
- participant is 
receiving placebo 
run-in or other 
run-in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/Lactation 
Exposure
Report if:
- 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 DILI
- Require 
regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (Do not 
require regulatory 
reporting)
Report if:
- due to 
intervention
- causes 
exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 
5 calendar days 
of learning of 
event
 
 
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE s and/or SAE s and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECI), 
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. All 
AEs will be reported to regulatory authorities, IRB/IECs, and investigators in accordance 
with all applicable global laws and regulations (ie, per ICH Topic E6 (R2) Guidelines for 
Good Clinical Practice [GCP]).
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 is 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 
 
 
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serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs 
or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint which upon review 
is not progression of the cancer under study will be forwarded to Global Pharmacovigilance 
as an SAE within 24 hours of determination that the event is not progression 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: 

An overdose of Sponsor's product, as defined in Section 8.5, that is not associated 
with clinical symptoms or abnormal laboratory results.

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 must trigger 
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 MK-4621/JetPEI by ≥20% 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 MK-4621/JetPEI or pembrolizumab. In the event of overdose, 
MK-4621/JetPEI or pembrolizumab should be discontinued and the participant should be 
 
 
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observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated.
8.6
Pharmacokinetics
To evaluate the immunogenicity (ADA) and exposure of pembrolizumab and exposure of 
MK-4621/JetPEI in this indication, sample collections for analysis of anti-drug antibodies 
(ADA) and PK are currently planned as shown in the SoA. Blood samples for PK and ADA 
collected may be stored only at this time. Further analysis may be performed if required. If 
ongoing PK and/or ADA sampling is deemed to be unnecessary by the Sponsor, it may be 
reduced or discontinued.
8.6.1
Blood Collection for Plasma MK-4621/JetPEI
Blood sample collection, processing, storage, and shipment instructions are provided in the 
Procedures Manual. Pharmacokinetic samples should be drawn according to the 
PK collection schedule for all participants (Section 1.3 - Schedule of Activities).
Time points may be changed or eliminated based on emerging PK data. 
8.6.2
Blood Collection for Anti-pembrolizumab Antibodies
Sample collection, storage, and shipment instructions for serum samples are provided in the 
procedure manual. Anti-pembrolizumab antibody samples should be drawn according to the 
ADA collection schedule for all participants (Section 1.3 Schedule of Activities). 
Simultaneous PK sampling is required for interpretation of ADA analysis. Time points may 
be changed or eliminated based on emerging ADA data.
8.7
Pharmacodynamics
Blood, serum, and tumor biopsy sample collection, storage, and shipment instructions for 
pharmacodynamics analysis are provided in the Procedure Manual.
8.7.1
Blood for Pharmacodynamic Markers
The time points for pharmacodynamic sampling are described in Section 1.3 – Schedule of 
Activities.
8.7.2
Tumor Biopsy
8.7.2.1
Pretreatment Tumor Biopsy
All participants will be required to provide a sample biopsy of the tumor to be injected with 
MK-4621/JetPEI and a sample biopsy from a distant, discrete noninjected site at initial 
screening as the predose samples. This predose tumor biopsy at screening will be performed 
on both the tumor lesion that is intended for treatment with IT administration of 
MK-4621/JetPEI, as well as on the distant, discrete lesion that is not intended for 
 
 
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IT administration of MK-4621/JetPEI. Predose tumor biopsies (injected and noninjected 
tumors) should be collected on the same day as treatment, but if this is not possible, must be 
collected within 72 hours prior to treatment.
The samples will be obtained by either punch biopsy (according to sites routine procedure) 
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 with discussion with the Sponsor. Biopsies obtained 
during this study will be submitted as formalin-fixed, paraffin-embedded samples. 
Instructions for tissue collection, processing, and shipment are provided in the Procedures 
Manual.
8.7.2.2
Posttreatment Tumor Biopsy
Post administration of MK-4621/JetPEI, all participants will be required to provide 2 biopsy 
samples of both the injected and noninjected tumors where predose biopsy samples are 
collected (see above in pretreatment tumor biopsy collection) on C3D1 (Week 7) in Arm 1 
and Arm 2 and on C4D1 (Week 8) in Arm 3. 
All participants will have the option to provide 2 additional biopsy samples of both the 
injected and uninjected tumors on C5D1 (Week 13) in Arm 1 and Arm 2, and on C6D1 
(Week 16) in Arm 3, unless deemed medically unsafe by the investigator.
Sample collection and processing are the same as for pretreatment tumor biopsy 
(Section 8.7.2.1). Instructions for tissue collection, processing, and shipment are provided in 
the Procedures Manual.
8.8
Future Biomedical Research Sample Collection
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:
Leftover samples listed in 8.10 – Biomarkers.
8.9
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for future biomedical research if the participant signs 
the future biomedical research consent. If the planned genetic analysis is not approved, but 
future biomedical research is approved and consent is given, this sample will be collected for 
the purpose of future biomedical research.
 
 
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8.10
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants in this study as specified in the SoA:

Blood for Genetic Analysis

Serum for Cytokine/Chemokine Analyses and C-Reactive Protein (CRP)Blood for T 
cell repertoire (TCR)

Blood for RNA analysis

Pre-treatment Tumor Biopsy

Post-treatment Biopsy
8.10.1 Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for planned genetic analysis samples 
will be provided in the Procedures Manual. The timing of collection of samples is provided 
in Section 1.3 – Schedule of Activities.
8.10.2 Blood Collection for Antidrug Antibodies 
Sample collection, storage and shipment instructions for serum samples will be provided in 
the procedure manual. Anti-pembrolizumab antibody samples should be drawn according to 
the ADA collection schedule for all participants (Section 1.3.1). Every effort should be taken 
to collect samples at 30 days after end of study treatment for ADA. Simultaneous PK 
sampling is required for interpretation of ADA 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
Approximately 28 days prior to treatment allocation/randomization, potential participants 
will be evaluated to determine that they fulfill the entry requirements as set forth in 
Section 5. Screening procedures may be repeated after consultation with the Sponsor.

Written consent must be obtained prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant signing consent as part 
of routine management are acceptable in lieu of a screening test if performed within 
the specified time frame. Screening procedures are to be completed within 28 days 
prior to the first dose of study intervention except for the following:
 
 
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
Laboratory tests are to be performed within 72 hours prior to the first dose of study
treatment. An exception is hepatitis, HIV and thyroid serologies, which may be done 
up to 28 days prior to the first dose of study intervention.

Evaluation of ECOG is to be performed within 7 days prior to the first dose of study
treatment.

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). Additional pregnancy testing 
can be conducted if required by local regulations or if clinically indicated. Refer to 
Appendix 7 for country-specific requirements.
8.12
Treatment Period
Visit requirements are outlined in Section 1.3 – Schedule of Activities. Specific 
procedure-related details are provided above in Section 8 – Study Assessments and 
Procedures.
8.12.1 Discontinued Participants Continuing to be Monitored in the Study
The Discontinuation Visit should occur at the time study treatment is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study treatment, 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 - Schedule of Activities. Additional details regarding participant 
withdrawal and discontinuation are presented in Section 8 – Discontinuation/Withdrawal 
Criteria.
8.12.2 Poststudy
Participants will be required to return to clinic approximately 14 days after the last dose of 
study intervention for the poststudy visit. If the poststudy visit occurs less than 14 days after 
the last dose of study intervention, a subsequent follow-up telephone call should be made at 
14 days post the last dose of study intervention to determine if any AEs have occurred since 
the poststudy clinic visit.
8.12.2.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before 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).
 
 
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8.12.2.2
Imaging Follow-up Visit(s)
Participants who discontinue treatment for reasons other than confirmed PD should continue 
with imaging assessments per the protocol defined schedule until: (1) PD is verified or 
further confirmed by the investigator, (2) initiation of a new anti-cancer treatment, (3) death, 
(4) withdrawal of consent, or (5) study conclusion or early termination, whichever occurs 
first.
8.12.2.3
Survival Follow-up Visits
Participants, who experience confirmed disease progression or start a new anticancer therapy 
will move into the Survival Follow-Up Phase and should be contacted by telephone 
approximately every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
8.12.3 Survival Status 
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. 
Upon Sponsor notification, all participants who do not/will not have a scheduled study visit 
or study contact during the Sponsor-defined time period will be contacted for their survival 
status (excluding participants who have a previously recorded death event in the collection 
tool).
9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study. Exploratory and other nonconfirmatory analyses will be 
outlined in a separate supplemental Statistical Analysis Plan (sSAP).
If, after the study has begun, changes are made to primary and/or secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other nonconfirmatory analyses made 
after the protocol has been finalized, but prior to the conduct of any analyses, will be 
documented in the sSAP as needed and referenced in the Clinical Study Report (CSR) for the 
study. Post hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this study. Full details are 
in the Statistical Analysis Plan (SAP), Section 9.2 through Section 9.9.
 
 
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Study Design 
Overview
Phase 1/1b study of MK-4621/JetPEI monotherapy (Arm 1), 
MK-4621/JetPEI in combination with pembrolizumab 
(Arm 2), and MK-4621/JetPEI in combination with 
pembrolizumab via visceral IT injection (Arm 3) in 
participants with advanced/metastatic solid tumors. The 
study applies a modified TPI design for dose finding.
Treatment
Assignment
After initial enrollment (screening), participants will be 
allocated centrally through IRT by nonrandom assignment to 
single agent MK-4621/JetPEI (Arm 1), MK-4621/JetPEI via 
cutaneous IT injection coadministered with pembrolizumab
(Arm 2), and MK-4621/JetPEI via visceral IT injection 
coadministered with pembrolizumab Arm 3 based on 
eligibility for open dose levels.
Analysis Populations
Safety (Primary): All-Participants-as-Treated (APaT) and 
DLT-evaluable (DLTe)
PK (Secondary): Per-Protocol (PP)
Efficacy (Secondary): Full Analysis Set (FAS) 
Primary Endpoint(s)

Dose-limiting toxicity (DLT)

Adverse event (AE)

Discontinuing study treatment due to an AE
Secondary Endpoints
PK parameters of MK-4621/JetPEI monotherapy and 
MK-4621/JetPEI in combination with pembrolizumab; 
PK parameters of pembrolizumab in combination with 
MK-4621/JetPEI; ORR based on RECIST 1.1 and iRECIST.
Statistical Methods for 
Efficacy/ 
Pharmacokinetic 
Analyses
ORR will be estimated using an exact method based on the 
binomial distribution (Clopper-Pearson interval). Exploratory 
efficacy analyses (eg, PFS and 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 MTD/MAD of MK-4621/JetPEI and 
the 80% Bayesian credible intervals for the estimate will be 
provided for each treatment arm.
 
 
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Interim Analyses
Interim analyses 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.
Multiplicity
No multiplicity adjustment is planned in this Phase 1/1b
study.
Sample Size and 
Power 
The overall sample size for this study depends on the 
observed DLT profiles of MK-4621/JetPEI monotherapy
(Arm 1) and MK-4621/JetPEI in combination with 
pembrolizumab (Arms 2 and 3). A target sample size of 
72 participants will be used for study planning purposes. 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The study is open-label, ie, participants, investigators, and Sponsor personnel will be aware 
of participant treatment assignment after each participant is enrolled and treatment is 
assigned. Participants will be allocated by nonrandom assignment.
9.3
Hypotheses/Estimation
Objectives of the study are outlined in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy/Pharmacokinetics Endpoints
Preliminary efficacy will be evaluated using ORR and PFS, assessed by the investigator 
based on the RECIST 1.1 or iRECIST, and OS. ORR is a secondary endpoint in this study. 
PFS and OS are exploratory endpoints. Details of the analysis plan will be documented in the 
sSAP. A description of efficacy measures is provided in Section 8.2.
ORR is defined as the proportion of participants who have achieved confirmed CR or PR. 
PFS is defined as the time from the first dose of study treatment to the first documented 
disease progression or death due to any cause, whichever occurs first. 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.
Pharmacokinetic endpoints include PK exposure of MK-4621/JetPEI and pembrolizumab, as 
well as derived PK parameters.
The exploratory evaluation of biomarkers to be measured in this study is described in 
Section 8.10.
 
 
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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, and 
vital signs.
A description of safety measures is provided in Section 8.3 and Section 8.4.
9.5
Analysis Populations
9.5.1
Safety Analysis Populations
The All-Participants-as-Treated (APaT) population will be used for the analysis of safety 
data in this study. The APaT population consists of all participants who received at least 1 
dose of study treatment. In case of treatment administration errors, participants will be 
analyzed according to the treatment they actually received.
The DLT-evaluable (DLTe) population includes APaT participants who meet the criteria for 
DLT evaluability (eg, finished the DLT evaluation period without a DLT or experienced a 
DLT in the DLT evaluation period). See Section 6.6.2 for details. Safety data from crossover 
participants will also be presented separately.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.5.2
Pharmacokinetic Analysis Populations
The Per-Protocol (PP) population will be used for the analysis of PK 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 medicine.
Efficacy data from crossover participants will be presented separately.
 
 
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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.
9.6.1
Statistical Methods for Efficacy Analysis
ORR will be estimated using an exact method based on the binomial distribution (Clopper-
Pearson interval). The statistical methods for analyses of PFS and OS will be documented in 
the sSAP. All efficacy analysis will be done by treatment arm and dose level of 
MK-4621/JetPEI for the dose-escalation/dose-confirmation part and by tumor type for the 
expansion cohorts.
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 
treatment arm. Laboratory tests, vital signs, and other safety endpoints will be summarized as 
appropriate.
Dose-limiting toxicities will be listed and summarized by dose level of MK-4621/JetPEI and 
treatment arm. 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 MTD/MAD and the 80% Bayesian credible interval based on a prior 
distribution of Beta (1,1) for the estimate will be provided for each treatment arm.
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.
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis
Concentrations of study medicines will be summarized by planned visit and time for each 
dose separately 
9.7
Interim Analyses
Interim analyses 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.
 
 
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9.8
Multiplicity
There will be no multiplicity control in this study.
9.9
Sample Size and Power Calculations
The actual sample size for Arm 1, Arm 2, and Arm3 of study is dependent on the number of 
dose levels tested and emerging safety data following mTPI design (refer to Section 4.3.1.4). 
The mTPI phase will have up to 3 to 6 participants in the first cohort at each dose level, and
based on the occurrence of DLTs, up to 14 participants may be enrolled per dose level.
Assuming all dose levels are tolerable and 4 dose levels are to be tested in Arm 2 and Arm 3, 
the overall sample size for the dose-escalation/dose-confirmation part of this Phase 1/1b
study is expected to be up to approximately 72 participants (approximately 8 participants in
Arm 1, 32 participants on Arm 2, and 32 participants in Arm 3, assuming 6 participants at 
each dose level and 8 more participants at the MTD/MAD). Enrollment of additional 
participants in the expansion cohorts will be specified in a future protocol amendment.
9.10
Subgroup Analyses
Subgroup analyses of efficacy endpoints will be documented in the sSAP. 
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
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 and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (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.
 
 
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MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (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 report form data. By signing the consent form, the participant agrees 
to this process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4 Committees Structure
Not applicable.
10.1.5 Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
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.  
 
 
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Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6 Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries. 
10.1.7 Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use GCP: Consolidated Guideline and other generally 
accepted standards of good clinical practice); 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 
 
 
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will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8 Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICF, 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. Source documents are filed at the investigator’s site.
 
 
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Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
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 11 will be performed by the local laboratory. Laboratory 
samples that cannot be processed locally may be sent to the central laboratory.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 11
Protocol-required Safety Laboratory Assessments
Hematology
Comprehensive Chemistry 
Panel
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or urine)a
Hemoglobin
Alkaline phosphatase
Glucose
PT/INR
Platelet count
Alanine aminotransferase
Protein
aPTT or PTT
WBC (total and 
differential)d
Aspartate aminotransferase
Specific gravity 
Total T3 (or Free T3 [FT3]), Total T4 
(or Free T4[FT4]), and TSHb,c
RBC
Bicarbonated
Microscopic exam, if 
abnormal results are 
noted
Anti-HCV
Absolute lymphocyte 
counte
Calcium
HCV viral loadc
Chloride
HCV genotypec
Absolute neutrophil 
counte
Creatinine
anti-HBsc
Glucose
Phosphorus
HBsAg 
Potassium
Anti-HBc (total and IgM)c
Sodium
HBeAgc
Total bilirubin  
anti-HBec
Direct bilirubin
HBV viral loadc
Total protein
Anti-HDV c
Amylase
HIV
Lipase
GLDHc
GGTc
Blood urea nitrogen (BUN)/
Ureaf
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.
Total T3 and T4 are preferred; if not available, free T3 and T4 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 Procedure Manual.
d. 
If bicarbonate/CO2 is not done as part of standard of care in your region, then these tests do not need to be 
performed.
e. 
Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
f. 
Blood urea nitrogen is preferred; if not available urea may be tested
BUN=blood urea nitrogen; GGT=gamma glutamyl transferase; GLDH=glutamate dehydrogenase; HIV=human 
immunodeficiency virus; 
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
 
 
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1 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, 
device, diagnostic agent, or protocol specified procedure whether investigational 
(including placebo or active comparator product) or marketed, manufactured by, 
licensed by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, 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 a reportable event. 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 8.4.7 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.
d. Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
 
 
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•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3 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 timeframe as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.

Is a new cancer (that is not a condition of the study)

Is associated with an overdose
10.3.4 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.
 
 
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
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

An event is defined as “serious” when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, not when it is rated as severe.
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology for Adverse Events 
(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 activities of daily living (ADL).
Grade 3:  Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL.
Grade 4: Life threatening consequences; urgent intervention indicated.
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the 
AE form ensures that a medically qualified assessment of causality was done. This 
initialed document must be retained for the required regulatory time frame. The criteria 
below are intended as reference guidelines to assist the investigator in assessing the 
 
 
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likelihood of a relationship between the test product and the AE based upon the available 
information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely the Sponsor’s product 
caused the AE:
Exposure:  Is there evidence that the participant was actually exposed to the Sponsor’s 
product such as: reliable history, acceptable compliance assessment (pill count, diary, 
etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily 
specimen?
Time Course:  Did the AE follow in a reasonable temporal sequence from administration 
of the Sponsor’s product? Is the time of onset of the AE compatible with a drug-induced 
effect (applies to studies with investigational medicinal product)?
Likely Cause:  Is the AE not reasonably explained by another etiology such as underlying 
disease, other drug(s)/vaccine(s), or other host or environmental factors.
Dechallenge:  Was the Sponsor’s product discontinued or dose/exposure/frequency 
reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge.
If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent 
disability; (2) the AE resolved/improved despite continuation of the Sponsor ’ s product; 
(3) the study is a single-dose drug study; or (4) Sponsor ’ s product(s) is/are only used 
1 time.)
Rechallenge:  Was the participant re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
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.)
 
 
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NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile:  Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug 
class pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to 
be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable possibility of Sponsor’s product relationship:
There is evidence of exposure to the Sponsor’s product. The temporal 
sequence of the AE onset relative to the administration of the Sponsor’s 
product is reasonable. The AE is more likely explained by the Sponsor’s 
product than by another cause.
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor’s product OR temporal sequence of 
the AE onset relative to administration of the Sponsor’s product is not 
reasonable OR the AE is more likely explained by another cause than the 
Sponsor’s product. (Also entered for a participant with overdose without an 
associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
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.
 
 
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•
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 AE, SAE, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the electronic data collection 
(EDC) tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
 
 
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•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
 
 
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10.4
Appendix 4: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
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.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
•
A high follicle stimulating hormone (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 2 FSH measurements in the postmenopausal range is 
required.
-
Females on HRT and whose menopausal status is in doubt will be required to use 1 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.
10.5.2 Contraception Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to 1 of the following during the protocol defined time frame in Section 5.1:
 
 
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•
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
•
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.
The following are not acceptable methods of contraception:
•
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method (LAM).
•
Male condom with cap, diaphragm, or sponge with spermicide.
•
Male and female condom cannot be used together.
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 
penetration.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to 
consistent and correct use of a highly effective method of contraception as described in 
Table 12 during the protocol-defined time frame in Section 5.1.
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception that has a low user dependency consistently and 
correctly as described in Table 12 during the protocol-defined time frame in Section 5.1. 
 
 
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Table 12
Highly Effective Contraceptive Methods That Have Low User Dependency
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●Progestogen-only contraceptive implant a, b
●Intrauterine hormone-releasing system (IUS) b
●Intrauterine device (IUD)
●Bilateral tubal occlusion
●Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
●Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant. 
Notes:
Use should be consistent with local regulations regarding the use of contraceptive methods 
for participants of clinical studies.
a) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) 
guidelines, acceptable contraceptive implants are limited to those which inhibit ovulation.
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least [120 days, corresponding to time needed to eliminate study 
treatment plus 30 days for study treatments with genotoxic potential] after the last dose of 
study intervention.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable hormonal contraceptives are limited to those which inhibit ovulation.
10.5.3 Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.
Following initiation of treatment additional pregnancy testing will be performed monthly
during the treatment period, if required locally, and at 90 days after the last dose of study 
intervention, as required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research

Definitions
1.
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. 
2.
Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
3.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
4.
DNA: Deoxyribonucleic acid.
5.
RNA: Ribonucleic acid.

Scope of Future Biomedical Research
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.

Summary of Procedures for Future Biomedical Research.
1.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy
 
 
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2.
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.
3.
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.
4.
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.

Confidential Participant Information for Future Biomedical Research
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and treatment outcomes are 
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
 
 
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
Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in this substudy. Future biomedical research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.

Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed.

Retention of Specimens
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
 
 
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specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.

Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.

Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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.

Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.

Risks Versus Benefits of Future Biomedical Research
For future biomedical research, risks to the participant have been minimized and are 
described in the Future Biomedical Research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.

Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@merck.com.
 
 
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
References

National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618

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 

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/ 

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 Initial Screening (Arms 1, 2, and 3) and 
Crossover Screening (Arm 1 to Arm 2)
Assessment
Note
HIV/Hepatitis B and C 
Screen
Include HCV antibody or HCV RNA (qualitative) and 
HBsAg. HIV, and Hepatitis B and C by history are 
acceptable for exclusion; testing for HIV, Hepatitis B or 
Hepatitis C is required at screening.
Pregnancy test for WOCBP 
only (urine or serum 
β-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 1.3.2   Schedule of Activities for the Treatment Period
Assessment
Note
Pregnancy test for WOCBP 
only (urine or serum 
β-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 5.2 Exclusion Criteria
10. Participants with known human immunodeficiency virus (HIV) and/or Hepatitis B or C 
infections, or known to be positive for Hepatitis B surface antigen (HBsAg)/Hepatitis B virus 
(HBV) DNA or Hepatitis C Antibody or RNA. Active Hepatitis C is defined by a known 
positive Hep C Ab result and known quantitative HCV RNA results greater than the lower 
limits of detection of the assay. Testing for HIV, Hepatitis B or Hepatitis C is required at 
screening.
Section 8.7.2.1 Pretreatment Biopsy
Only ultrasound-guided biopsies will be taken.
 
 
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Section 8.7.2.2 Posttreatment Biopsy
Only ultrasound-guided biopsies will be taken.
Section 8.11.1 Screening
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). Monthly pregnancy testing should be conducted as per local 
regulations, or as clinically indicated.
Appendix 2 Clinical Laboratory Tests
Other Screening Tests: Serology (HIV RNA, hepatitis B surface antigen [HBsAg], and 
hepatitis C virus antibody).
Appendix 5 Contraceptive Guidance and Pregnancy Testing
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. Monthly pregnancy testing should be conducted as per local regulations.
United Kingdom
Sections 1.3.2.1, 1.3.2.2, and 1.3.2.3 - Schedule of Activities for the Treatment Period
Assessment
Note
Pregnancy test for WOCBP 
only (urine or serum 
β-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. Thereafter, pregnancy testing should be performed 
approximately monthly.
Section 6.5.2 – Prohibited Concomitant Medications

Live vaccines within 30 days prior to the first dose of study treatment while 
participating in the study and for 3 months after the end of study treatment. Examples 
of live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are 
live attenuated vaccines and are not allowed.
 
 
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Section 8.3.4.2 – Pregnancy Testing
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 treatment. 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. During study treatment, pregnancy testing should be 
repeated approximately monthly and then again 30 days after the last study dose of study 
treatment.
Section 8.11.1 Screening
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).
Appendix 2 Clinical Laboratory Tests
Footnote to Table 11 reads: 
a.
Perform on women of childbearing potential only 72 hours prior to Day 1 of Cycle 1. 
Pregnancy tests must be repeated approximately monthly.
Appendix 5 Contraceptive Guidance and Pregnancy Testing
Pregnancy Testing
Following initiation of treatment additional pregnancy testing will be performed 
approximately monthly during study treatment period, and at 30 days after the last dose of 
study intervention, as required locally.
 
 
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
aPTT
activated partial thromboplastin time
ADA
anti-drug antibodies
ALT
alanine transaminase
ANC
absolute neutrophil count
APaT
All-Participants-as-Treated
AST
aspartate transaminase
AUC
area under the curve
BCG
Bacillus Calmette–Guérin
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
Cmax
maximum concentration
Cmin
minimum concentration
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRF
case report form 
CRP
C-reactive protein
CRU
clinical research unit
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DL
dose level
DL1
starting dose
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 
ELISA
enzyme-linked immunoassay
EMA
European Medicines Agency
FAS
full analysis set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
GEP
gene expression profile
GFR
glomerular filtration rate
GGT
gamma glutamyl transferase
GLDH
glutamate dehydrogenase
HBsAG
hepatitis B surface antigen
HBV
hepatitis B virus
 
 
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Abbreviation
Expanded Term
HED
human equivalent dose
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
informed consent form 
ICH
International Conference on Harmonization
ICI
immune checkpoint inhibitors
iCR
immune complete response
IEC
Independent Ethics Committee
IFNα
interferon α  
Ig
immunoglobulin
IHC
immunohistochemistry
INR
international normalized ratio
iPR
immune partial response
irAE
immune‑related adverse event
iRECIST
immune-related RECIST
IRR
infusion-related reaction 
IRB
Institutional Review Board 
IRT
interactive response technology
iSD
immune stable disease
IT
intratumoral
IUD
intrauterine device
iUPD
immune unconfirmed progressive disease
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic (device)
LDH
lactate dehydrogenase
mAb
monoclonal antibody
MAD
maximum administered dose
ML
mutational load
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
mTPI
modified Toxicity Probability Interval
MTD
maximum tolerated dose 
NCI
National Cancer Institute
NK
natural killer
NOAEL
no observed adverse effect level 
NSCLC
non-small cell lung cancer
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PBPK
physiologically-based Pharmacokinetics
PD
progressive disease
PD 1
programmed cell death 1
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression free survival
PK
pharmacokinetic
PKCθ
protein kinase C-theta
 
 
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Abbreviation
Expanded Term
PP
per-protocol
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
q1w
every week
q2w
every 2 weeks
q3w
every 3 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RIG-I
Retinoic acid Inducible Gene I
RNA
ribonucleic acid
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SCCHN
squamous cell carcinoma of head and neck
SIM
Site Imaging Manual
SoA
Schedule of Activities
SOD
sum of the diameters
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TCR
T cell repertoire
T1DM
Type 1 diabetes mellitis
TMDD
Target-mediated drug disposition
TSH
thyroid-stimulating hormone
ULN
upper limit of normal
WOCBP
woman/women of childbearing potential 
ZAP70
zeta-chain-associated protein kinase
 
 
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11
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