Clinical trial NCT04220866
Conditions: Head and Neck Squamous Cell Carcinoma (HNSCC)
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1) intratumoral (IT) metastatic unresectable recurrent ulevostinag pembrolizumab
Sponsor: Merck Sharp & Dohme LLC
Start date: 2020-03-04; Completion date: 2022-09-30
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to assess the efficacy and safety of intratumoral (IT) ulevostinag PLUS pembrolizumab (MK-3475) compared to pembrolizumab alone as a first line treatment of adults with metastatic or unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

The primary study hypotheses are that IT ulevostinag in combination with pembrolizumab results in a superior Objective Response Rate (ORR), per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1), compared to pembrolizumab alone:

1. In participants with a tumor that has a programmed cell death-ligand 1 (PD-L1) Combined Positive Scoring (CPS) ≥ 1, and
2. In participants with a tumor that has a PD-L1 CPS ≥ 20.

Detailed description:

Arms: arm 1: Participants receive ulevostinag 540 ug via intratumoral (IT) injection on Day 1 of every week for two 3-week cycles (Cycles 1-2), then on Day 1 of each 3-week cycle for up 33 cycles (Cycles 3-35), for a total of 35 cycles PLUS pembrolizumab 200 mg via intravenous (IV) infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment is up to approximately 2 years. arm 2: Participants receive pembrolizumab 200 mg via IV infusion on Day 1 of each 3-week cycle for up to 35 cycles. The total duration of treatment is up to approximately 2 years.
Interventions: intervention 1: Ulevostinag intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: IT injection intervention 2: IV infusion

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 2 Study in First Line Metastatic or 
Unresectable, Recurrent Head and Neck 
Squamous Cell Carcinoma to Evaluate Intratumoral 
MK-1454 in Combination with IV Pembrolizumab vs 
IV Pembrolizumab Monotherapy
NCT04220866
20 OCT 2022


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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2 Study in First Line Metastatic or Unresectable, Recurrent Head 
and Neck Squamous Cell Carcinoma to Evaluate Intratumoral MK-1454 in Combination 
with IV Pembrolizumab vs IV Pembrolizumab Monotherapy
Protocol Number: 002-03
Compound Number: MK-1454
Sponsor Name:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND
144743
EudraCT
2019-003060-42
NCT
NCT04220866
Approval Date: 20 October 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-1454-002-03
20-OCT-2022
Merck Sharp & Dohme Corp. underwent an entity name and 
address change to Merck Sharp & Dohme LLC, Rahway, NJ, 
USA. This conversion resulted only in an entity name change and 
update to the address.
MK-1454-002-02
22-JUL-2021
To update the dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab.
MK-1454-002-01
05-AUG-2020
To address Health Authority requests, including to provide
rationale for minimum creatinine clearance in the eligibility 
criteria, to add clarification for PD-L1 testing to the protocol, to 
clarify ongoing safety monitoring during the conduct of the clinical 
trial, and to provide additional clarifications.
Original Protocol
31-OCT-2019
Not applicable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 03
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address. 
Summary of Changes Table:
Section # and Name
Description of Change 
Brief Rationale 
Title Page
Section 10.1.1 Code of 
Conduct for Clinical Trials
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity name 
and address change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................13
1.1
Synopsis.................................................................................................................13
1.2
Schema ..................................................................................................................17
1.3
Schedule of Activities...........................................................................................18
1.3.1
Schedule of Activities for Screening for All Participants............................18
1.3.2
Schedule of Activities for the Treatment Period for Arm 1 
(Combination Therapy: IT MK-1454 + IV Pembrolizumab) ......................20
1.3.3
Schedule of Activities for the Treatment Period for Arm 2 IV 
Pembrolizumab Monotherapy......................................................................24
1.3.4
Schedule of Activities for the End of Treatment and Posttreatment 
Follow-Up Periods.......................................................................................27
2
INTRODUCTION..........................................................................................................29
2.1
Study Rationale....................................................................................................29
2.2
Background ..........................................................................................................29
2.2.1
Pharmaceutical and Therapeutic Background .............................................30
2.2.1.1
MK-1454 Pharmaceutical and Therapeutic Background...................30
2.2.1.2
Pembrolizumab (MK-3475) Pharmaceutical and Therapeutic 
Background........................................................................................31
2.2.2
Preclinical and Clinical Studies ...................................................................32
2.2.3
Ongoing Clinical Studies.............................................................................32
2.2.3.1
MK-1454 Clinical Studies .................................................................32
2.2.3.2
Pembrolizumab (MK-3475) Clinical Studies ....................................33
2.3
Benefit/Risk Assessment......................................................................................35
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................35
4
STUDY DESIGN............................................................................................................37
4.1
Overall Design......................................................................................................37
4.2
Scientific Rationale for Study Design.................................................................39
4.2.1
Rationale for the Study and Selected Participant Population ......................39
4.2.2
Rationale for Entry Criteria .........................................................................40
4.2.2.1
Use of Combined Positive Scoring for PD-L1 Status........................40
4.2.2.2
Rationale for Minimum Creatinine Clearance...................................40
4.2.3
Rationale for Endpoints ...............................................................................41
4.2.3.1
Efficacy Endpoints.............................................................................41
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4.2.3.1.1
Response Rate Assessed by RECIST Version 1.1...................41
4.2.3.2
Safety Endpoints................................................................................41
4.2.3.3
Pharmacokinetic Endpoints ...............................................................42
4.2.3.4
Pharmacodynamic Endpoints.............................................................42
4.2.3.5
Planned Exploratory Biomarker Research.........................................42
4.2.3.6
Future Biomedical Research..............................................................44
4.2.4
Rationale for the Use of Comparator...........................................................44
4.3
Justification for Dose...........................................................................................44
4.3.1
Rationale for Dose of MK-1454 ..................................................................44
4.4
Beginning and End of Study Definition .............................................................45
4.4.1
Clinical Criteria for Early Study Termination .............................................45
5
STUDY POPULATION ................................................................................................45
5.1
Inclusion Criteria.................................................................................................45
5.2
Exclusion Criteria................................................................................................49
5.3
Lifestyle Considerations......................................................................................52
5.3.1
Meals and Dietary Restrictions....................................................................52
5.4
Screen Failures.....................................................................................................52
5.5
Participant Replacement Strategy......................................................................52
6
STUDY INTERVENTION............................................................................................53
6.1
Study Intervention(s) Administered...................................................................53
6.2
Preparation/Handling/Storage/Accountability .................................................55
6.2.1
Dose Preparation..........................................................................................55
6.2.2
Timing of Study Interventions.....................................................................56
6.2.2.1
Timing for Administration for MK-1454 ..........................................56
6.2.2.2
Timing for Administration of Pembrolizumab ..................................57
6.2.3
Handling, Storage, and Accountability........................................................57
6.3
Measures to Minimize Bias: Randomization and Blinding..............................57
6.3.1
Intervention Assignment..............................................................................57
6.3.2
Stratification.................................................................................................58
6.3.3
Blinding........................................................................................................58
6.4
Study Intervention Compliance..........................................................................58
6.5
Concomitant Therapy..........................................................................................58
6.5.1
Acceptable Concomitant Medications .........................................................58
6.5.2
Prohibited Concomitant Medications ..........................................................59
6.5.3
Supportive Care ...........................................................................................59
6.6
Dose Modification (Escalation/Titration/Other)...............................................60
6.6.1
Dose Modification due to Adverse Events ..................................................60
6.6.1.1
Dose Modification for MK-1454.......................................................61
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6.6.1.1.1
Guidelines for Management of Intratumoral Injection Site 
Reactions..................................................................................61
6.6.1.1.2
Treatment for Cytokine Release Syndrome.............................62
6.6.1.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).......................................................................................65
6.6.1.2.1
Other Allowed Dose Interruption(s) for Pembrolizumab ........71
6.7
Intervention After the End of the Study............................................................71
6.8
Clinical Supplies Disclosure................................................................................71
6.9
Standard Policies..................................................................................................71
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................71
7.1
Discontinuation of Study Intervention...............................................................71
7.2
Participant Withdrawal From the Study...........................................................73
7.3
Lost to Follow-up .................................................................................................73
8
STUDY ASSESSMENTS AND PROCEDURES........................................................73
8.1
Administrative and General Procedures ...........................................................74
8.1.1
Informed Consent.........................................................................................74
8.1.1.1
General Informed Consent.................................................................74
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................75
8.1.2
Inclusion/Exclusion Criteria ........................................................................75
8.1.3
Participant Identification Card.....................................................................75
8.1.4
Medical History ...........................................................................................75
8.1.5
Prior and Concomitant Medications Review...............................................76
8.1.5.1
Prior Medications...............................................................................76
8.1.5.2
Concomitant Medications..................................................................76
8.1.6
Assignment of Screening Number...............................................................76
8.1.7
Assignment of Treatment/Randomization Number.....................................76
8.1.8
Study Intervention Administration ..............................................................76
8.1.8.1
Timing of Dose Administration.........................................................77
8.1.9
Discontinuation and Withdrawal .................................................................77
8.1.9.1
Withdrawal From Future Biomedical Research ................................77
8.1.10
Participant Blinding/Unblinding..................................................................77
8.1.11
Calibration of Equipment.............................................................................78
8.2
Efficacy/Immunogenicity Assessments ..............................................................78
8.2.1
Tumor Imaging and Assessment of Disease................................................78
8.2.2
Initial Tumor Imaging..................................................................................78
8.2.3
Tumor Imaging During the Study................................................................79
8.2.4
End of Treatment and Follow-up Tumor Imaging.......................................79
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8.2.5
iRECIST 1.1 Assessment of Disease...........................................................80
8.2.6
itRECIST......................................................................................................85
8.2.7
Eastern Cooperative Oncology Group Performance Scale..........................86
8.3
Safety Assessments...............................................................................................86
8.3.1
Physical Examinations.................................................................................86
8.3.1.1
Full Physical Examination.................................................................86
8.3.1.2
Directed Physical Examination..........................................................86
8.3.2
Vital Signs....................................................................................................86
8.3.3
Electrocardiograms ......................................................................................87
8.3.4
Clinical Safety Laboratory Assessments .....................................................87
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)..........................................................................................87
8.3.4.2
Pregnancy Test...................................................................................88
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................88
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................88
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......90
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...90
8.4.4
Regulatory Reporting Requirements for SAE .............................................90
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................91
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................91
8.4.7
Events of Clinical Interest............................................................................91
8.5
Treatment of Overdose........................................................................................92
8.6
Pharmacokinetics.................................................................................................92
8.6.1
Blood Collection for Serum Pembrolizumab and Plasma MK-1454...........92
8.6.2
Blood Collection for Antidrug Antibodies ..................................................93
8.7
Pharmacodynamics..............................................................................................93
8.8
Biomarkers ...........................................................................................................93
8.8.1
Planned Genetic Analysis Sample Collection..............................................93
8.9
Future Biomedical Research Sample Collection...............................................93
8.10
Visit Requirements...............................................................................................94
8.10.1
Screening......................................................................................................94
8.10.2
Treatment Period Visit.................................................................................95
8.10.3
Discontinued Participants Continuing to be Monitored in the Study ..........95
8.10.3.1
Safety Follow-up Visit.......................................................................95
8.10.3.2
Imaging Follow-up Visits ..................................................................95
8.10.3.3
Survival Follow-up Visits..................................................................95
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9
STATISTICAL ANALYSIS PLAN .............................................................................96
9.1
Statistical Analysis Plan Summary.....................................................................96
9.2
Responsibility for Analyses/In-house Blinding .................................................98
9.3
Hypotheses/Estimation ........................................................................................98
9.4
Analysis Endpoints...............................................................................................99
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..............................99
9.4.2
Safety Endpoints..........................................................................................99
9.5
Analysis Populations............................................................................................99
9.5.1
Efficacy Analysis Populations.....................................................................99
9.5.2
Safety Analysis Populations ......................................................................100
9.5.3
Pharmacokinetic Analysis Populations......................................................100
9.6
Statistical Methods.............................................................................................100
9.6.1
Statistical Methods for Efficacy Analysis..................................................100
9.6.1.1
Objective Response..........................................................................100
9.6.1.2
Progression-free Survival.................................................................101
9.6.1.3
Overall Survival...............................................................................102
9.6.1.4
Duration of Response.......................................................................102
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints................................103
9.6.2
Statistical Methods for Safety Analysis.....................................................104
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.....................................................................................................106
9.6.3.1
Demographic and Baseline Characteristics .....................................106
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis..........106
9.7
Interim Analyses ................................................................................................106
9.8
Multiplicity .........................................................................................................107
9.9
Sample Size and Power Calculations ...............................................................108
9.10
Subgroup Analyses.............................................................................................110
9.11
Compliance (Medication Adherence)...............................................................111
9.12
Extent of Exposure.............................................................................................111
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................112
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......112
10.1.1
Code of Conduct for Clinical Trials...........................................................112
10.1.2
Financial Disclosure...................................................................................114
10.1.3
Data Protection...........................................................................................114
10.1.3.1
Confidentiality of Data ....................................................................115
10.1.3.2
Confidentiality of Participant Records.............................................115
10.1.3.3
Confidentiality of IRB/IEC Information..........................................115
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10.1.4
Committees Structure.................................................................................116
10.1.4.1
Stage Gate Review Committee........................................................116
10.1.5
Publication Policy......................................................................................116
10.1.6
Compliance with Study Registration and Results Posting Requirements .116
10.1.7
Compliance with Law, Audit, and Debarment ..........................................116
10.1.8
Data Quality Assurance .............................................................................117
10.1.9
Source Documents .....................................................................................118
10.1.10
Study and Site Closure...............................................................................118
10.2
Appendix 2: Clinical Laboratory Tests............................................................119
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 AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................127
10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation..................................129
10.5
Appendix 5: Contraceptive Guidance..............................................................130
10.5.1
Definitions..................................................................................................130
10.5.2
Contraception Requirements......................................................................131
10.5.2.1
Contraception Requirements: Female Participants..........................131
10.5.2.2
Contraception Requirements: Male Participants .............................132
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................133
10.7
Appendix 7: Country-specific Requirements..................................................138
10.8
Appendix 8:  Guidelines for Prioritization of Intratumoral Lesion 
Injection ..............................................................................................................142
10.9
Appendix 9: Eastern Cooperative Oncology Group Performance Status....144
10.10 Appendix 10: itRECIST Supplementary Figures...........................................145
10.11 Appendix 11: Abbreviations .............................................................................150
11
REFERENCES.............................................................................................................154
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LIST OF TABLES
Table 1
Adequate Organ Function..........................................................................46
Table 2
Study Interventions....................................................................................54
Table 3
Determination of Intratumoral MK-1454 Injection Volume Per Lesion 
Based on Lesion Size.................................................................................56
Table 4
Determination of Intratumoral MK-1454 Total Injectate Volume 
Based on Number of Lesions Injected Per Treatment Visit ......................56
Table 5
Intratumoral Injection Site Reaction Management Guidelines..................62
Table 6
Cytokine Release Syndrome Treatment Guidelines ..................................63
Table 7
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .........................................................66
Table 8
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................70
Table 9
Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease.......................................................................................................84
Table 10
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................89
Table 11
Censoring Rules for Primary and Sensitivity Analyses of PFS...............102
Table 12
Censoring Rules for Duration of Response .............................................103
Table 13
Analysis Strategy for Key Efficacy Variables.........................................104
Table 14
Analysis Strategy for Safety Parameters..................................................106
Table 15
Probability of Continuing Enrollment in the Study.................................107
Table 16
Power of ORR After Continuing Enrollment in the Study (200 
participants in total) .................................................................................109
Table 17
Power of ORR without Continuing Enrollment in the Study (130 
participants in total) .................................................................................110
Table 18
Protocol-required Safety Laboratory Assessments..................................119
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LIST OF FIGURES
Figure 1
Study Schema.............................................................................................17
Figure 2
Schematic Diagram Showing Mechanism of the Enhancement of T-
cell Driven Antitumor Immunity Through the Action of STING 
Agonists .....................................................................................................31
Figure 3
Imaging and Treatment for Clinically Stable Participants after First 
Radiologic Evidence of PD Assessed by the Investigator.........................85
Figure 4
Multiplicity Diagram ...............................................................................108
Figure 5
Algorithm for Classification of Lesions at Baseline................................145
Figure 6
Reclassification of Noninjected Lesions..................................................146
Figure 7
Overall Response Assessment Until Disease Progression.......................147
Figure 8
Example of Iterative Assessment of Injected Lesion Response During 
Treatment .................................................................................................148
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2 Study in First Line Metastatic or Unresectable, Recurrent Head 
and Neck Squamous Cell Carcinoma to Evaluate Intratumoral MK-1454 in Combination 
with IV Pembrolizumab vs IV Pembrolizumab Monotherapy
Short Title: Phase 2 Study in 1L HNSCC of IT MK-1454 / MK-3475 IV vs MK-3475 IV
Acronym:
Hypotheses, Objectives, and Endpoints:
In males and females who are at least 18 years of age with metastatic or with unresectable, 
recurrent HNSCC with a tumor PD-L1 IHC CPS ≥1:
Objectives
Endpoints
Primary
•
Objective: To evaluate participants treated 
with IT MK-1454 in combination with 
pembrolizumab or pembrolizumab alone with 
regard to the objective response rate (ORR) 
per Response Evaluation Criteria in Solid 
Tumors Version 1.1 (RECIST 1.1) by 
blinded independent central review (BICR).
•
Hypothesis (H1): IT MK-1454 in 
combination with pembrolizumab results in a 
superior ORR, per RECIST 1.1 based on 
BICR, compared to pembrolizumab alone in 
participants with tumor combined positive 
scoring (CPS) ≥1.
•
Hypothesis (H2): IT MK-1454 in 
combination with pembrolizumab results in a 
superior ORR, per RECIST 1.1 based on 
BICR, compared to pembrolizumab alone in 
participants with tumor CPS ≥20.
The study is considered to have met its primary 
objective if IT MK-1454, in combination with 
pembrolizumab, results in a superior ORR, per 
RECIST 1.1 based on BICR, compared to 
pembrolizumab alone either in participants with 
tumor CPS ≥1 or in participants with tumor CPS 
≥20.
•
Objective response is a confirmed 
complete response (CR) or partial 
response (PR)
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Objectives
Endpoints
Secondary
•
Objective: To evaluate participants treated 
with IT MK-1454 in combination with 
pembrolizumab or pembrolizumab alone with 
regard to progression-free survival (PFS) per 
RECIST 1.1 by BICR.
•
PFS, defined as the time from 
randomization to the first 
documented progressive disease (PD) 
or death from any cause, whichever 
occurs first
•
Objective: To evaluate participants treated 
with IT MK-1454 in combination with 
pembrolizumab or pembrolizumab alone with 
regard to Duration of Response (DOR) per 
RECIST 1.1 by BICR.
•
DOR, defined as the time from the 
first documented evidence of CR or 
PR until PD or death due to any 
cause, whichever occurs first, in 
participants demonstrating CR or PR
•
Objective: To evaluate participants treated 
with IT MK-1454 in combination with 
pembrolizumab or pembrolizumab alone with 
regard to overall survival (OS).
•
OS, defined as the time from 
randomization to the date of death 
from any cause
•
Objective: To assess participants treated with 
IT MK-1454 in combination with 
pembrolizumab or pembrolizumab alone with 
regard to the safety and tolerability of study 
intervention. 
•
Adverse events (AEs)
•
Discontinuing study intervention due 
to an AE
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Metastatic or unresectable, recurrent HNSCC
Population
Participants with a histologically or cytologically confirmed diagnosis of 
metastatic or unresectable, recurrent HNSCC with tumor CPS ≥1
Study Type
Interventional
Intervention 
Model
Parallel
This is a multi-site study.
Type of Control
Active control without placebo
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Study Blinding
Unblinded Open-label
Blinding Roles
No Blinding
Estimated 
Duration of 
Study
The Sponsor estimates that the study will require approximately 
60 months 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 200 participants will be randomized in the study, as described in Section 9.9.
Intervention Groups and Duration:
Intervention 
Groups
Intervention 
Group 
Name
Drug
Dose 
Strength
Dose 
Frequency
Route of 
Administration
Treatment 
Period
Use
Arm 1
MK
1454
Q1W × 6, 
then Q3W
Intratumoral
Up to 35 
cycles
Experimental
MK
3475
200 mg
Q3W
Intravenous
Experimental
Arm 2
MK
3475
200 mg
Q3W
Intravenous
Up to 35 
cycles
Comparator
Q1W  once each week; Q3W  once every 3 weeks
Other current or former name(s) or alias(es) for study intervention(s) are as 
follows: MK-3475  pembrolizumab  KEYTRUDA®.
Total 
Number
2 arms
Duration of 
Participation
Each participant will participate in the study for up to approximately 2 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 
may receive assigned intervention for up to approximately 35 cycles. After
the end of treatment, each participant will be followed up for 30 days for the 
occurrence of AEs and spontaneously reported pregnancy. All participants 
will be followed by telephone for OS until death, withdrawal of consent, or 
end of the study.
CCI
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Study Governance Committees:
Steering Committee
No
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Stage Gate Review Committee 
Yes
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Volunteers: No
A list of abbreviations used in this document can be found in Appendix 10.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Schema
CPS = combined positive score; ECOG = Eastern Cooperative Oncology Group; HNSCC = head and neck 
squamous cell carcinoma; HPV = human papilloma virus; IT = intratumoral; IV = intravenous; PD-L1 = 
programmed cell death ligand 1; Q1W = once each week; Q3W = once every 3 weeks.
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1.3
Schedule of Activities
1.3.1
Schedule of Activities for Screening for All Participants
Study Period
Screening
Notes
Visit Days
-28 to -1
Administrative Procedures
Informed Consent
X
Informed consent must be documented 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 FBR (Optional)
X
Consent for FBR is not required to participate in the study. 
Inclusion/Exclusion Criteria
X
Participant Identification Card
X
Participant identification card to be updated with treatment number at the time of treatment randomization.
Demographics and Medical History
X
Current Disease Details
X
Prior Treatment for Head and Neck Cancer
X
Mutational Status / Tumor Genetic
Alteration(s)
X
Tumor genetic alteration(s) per standard of care, by history if available, as determined by local testing results 
(eg, MSI, dMMR).
Prior Medication
X
Clinical Procedures/Assessments
Tumor Imaging, RECIST 1.1, and 
iRECIST Response Assessment
X
Baseline tumor imaging (CT or MRI) and/or medical photography of cutaneous lesions should be performed within 
28 days prior to the date of enrollment and submitted to the iCRO for confirmation of measurable disease (allow 
14 days). Please refer to Imaging Manual for detailed information. 
Medical Photography (Cutaneous Lesions)
X
Full Physical Examination
X
Vital Signs
X
Vital signs include heart rate, respiratory rate, 02 saturation, blood pressure, and temperature. 
Weight and Height
X
Height will only be measured at screening.
ECOG performance status
X
To be performed within 7 days prior to the first dose of study intervention.
12 Lead Electrocardiogram (Local)
X
AE Monitoring
X
All AEs that occur after the consent form is signed but before treatment allocation must be reported by the investigator 
if the event causes the participant to be excluded from the study or is the result of a protocol specified intervention. 
There is to be continuous AE reporting from the time of treatment allocation.
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Study Period
Screening
Notes
Visit Days
-28 to -1
Laboratory Procedures/Assessments - LOCAL
CBC with Differential
X
Perform these screening clinical laboratory tests, with exception of hepatitis and thyroid testing, within 7 days prior to 
the first dose of study intervention. 
Participants on anticoagulant therapy should be monitored throughout the study with PT or INR and PTT or aPTT as 
clinically indicated.
Chemistry Panel
X
PT or INR and PTT or aPTT
X
LDH, GGT
X
Urinalysis
X
Thyroid Function (TSH, T3, FT3, T4, FT4)
X
Thyroid function: Total T3 and Total T4 are preferred over FT3 and FT4.
Pregnancy test for WOCBP only (urine or 
serum β hCG)
X
Perform within 7 days prior to C1D1. Urine pregnancy test to be performed as indicated; if test is positive or cannot be 
confirmed as negative, a serum pregnancy test is required. Additional pregnancy testing can be conducted if required 
by local regulations or if clinically indicated.
HIV, Hepatitis B and C Screen
X
Acceptable to be based on history unless testing is required by local regulation. Include HCV antibody or HCV RNA 
(qualitative) and HBsAg.
Pharmacokinetics/Pharmacodynamics/Future Biomedical Research/Biomarkers 
Tumor Tissue for HPV Status
X
Archival or newly obtained tissue will be collected from participants with oropharyngeal cancer to be tested for HPV 
status for stratification, if HPV status was not previously determined by IHC P16 testing according to the Procedures 
Manual. If test method is not available locally, sample is to be sent to the central laboratory at least 14 days prior to 
randomization. A single sample may be obtained for testing for HPV and assessing PD L1 status.
Tumor Tissue for PD L1 Status 
X
Archival or newly obtained tissue will be collected from all participants for testing by central laboratory. Sample is to 
be sent to the central laboratory at least 14 days prior to randomization. This tissue sample will be analyzed using the 
IUO version of the US FDA approved PD L1 IHC 22C3 kit to confirm the PD L1 CPS ≥1 status for eligibility and for 
stratification by CPS (≥1 to <20 vs. ≥20).
Abbreviations:  AE
adverse event; aPTT
activated partial thromboplastin time; β hCG
β human chorionic gonadotropin; C1D1
Cycle 1 Day 1; CBC
complete blood 
count; CPS
combined positive score; CT
computed tomography; ctDNA  circulating tumor deoxyribonucleic acid; dMMR
deficient mismatch repair; ECOG
Eastern 
Cooperative Oncology Group; FBR
future biomedical research; FDA
Food and Drug Administration; FT3
free triiodothyronine; FT4
free thyroxine; GGT
gamma
glutamyl transpeptidase; HBsAg
Hepatitis B surface antigen; HCV
hepatitis C virus; HIV
human immunodeficiency virus; HPV
human papilloma virus;; iCRO
imaging 
contract research organization; IHC
immunohistochemistry; INR
International Normalized Ratio; iRECIST
modified RECIST 1.1 for immune based therapeutics; 
IUO Investigational Use Only; LDH
lactate dehydrogenase; MRI
magnetic resonance imaging; MSI
microsatellite instability; PD L1
programmed cell death ligand 1; 
PT
prothrombin time; PTT
partial thromboplastin time; RECIST 1.1
Response Evaluation Criteria in Solid Tumors; version 1.1; RNA
ribonucleic acid; 
T3
triiodothyronine; T4
thyroxine; TSH
thyroid stimulating hormone; US
United States; vs.  versus; WOCBP
women of childbearing potential.
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1.3.2
Schedule of Activities for the Treatment Period for Arm 1 (Combination Therapy: IT MK-1454 + IV 
Pembrolizumab)
Study Period:
Combination Treatment Phase (3-Week Cycles)
Notes
Treatment 
Cycle/Title:
Cycle 1
Cycle 2
Cycle 3 
Cycle 4 
and 
Beyond
Treatment Days:
1
8
15
1
8
15
1
1
Scheduled Day and 
Window:
+3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent
X
Additional consent is required for treatment beyond disease 
progression.
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
Participant 
Identification Card
X
Participant identification card to be updated with 
treatment/randomization number at the time of intervention 
randomization.
Treatment 
Randomization
X
Treatment must occur within 72 h of intervention randomization.
MK-1454
Administration/ 
Dispensing
X
X
X
X
X
X
X
X
On days when both MK-1454 and pembrolizumab are to be 
administered, MK-1454 will be administered within 0.5 to 4 h after 
completion of pembrolizumab IV infusion.
Pembrolizumab 
Administration/ 
Dispensing 
X
X
X
X
See Pembrolizumab Pharmacy Manual.
Efficacy Procedures
Tumor Imaging,
RECIST 1.1, 
iRECIST, and/or 
itRECIST Response 
Assessment
X
X
Tumor imaging (CT or MRI) and medical photography (for cutaneous 
lesions) to be performed 6 weeks (42-49 days) after the first dose, and 
then every 6 weeks (42 days  ± 7 days) for the first year, then every 
9 weeks (63 days ± 7 days) thereafter. Imaging schedule should follow 
calendar days and should not be adjusted for delays in cycle starts. 
Continue imaging schedule until confirmed disease progression, 
discontinuation from study, or start of new anticancer treatment. 
Medical photography can be performed more often as medically 
warranted.
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Study Period:
Combination Treatment Phase (3-Week Cycles)
Notes
Treatment 
Cycle/Title:
Cycle 1
Cycle 2
Cycle 3 
Cycle 4 
and 
Beyond
Treatment Days:
1
8
15
1
8
15
1
1
Scheduled Day and 
Window:
+3
±3
±3
±3
±3
±3
±3
±3
Medical Photography 
(Cutaneous Lesions)
X
X
Safety Procedures
Directed Physical 
Examination
X
X
X
X
Weight
X
X
X
X
Vital Signs 
X
X
X
X
X
X
X
X
Measure prior to study intervention. Vital signs include heart rate, 
respiratory rate, blood pressure, 02 saturation, and temperature.
ECOG performance 
status
X
X
X
X
Performed within 72 h prior to study intervention dosing on Day 1 of 
each cycle. Additional ECOG can be performed as clinically indicated.
12-Lead 
Electrocardiogram 
(Local)
X
Pregnancy test – Urine 
or Serum β-hCG for 
WOCBP 
X
Required within 24 h prior to first dose of study medication. Does not 
need to be repeated if screening pregnancy test was done within 24 h 
of the first dose of study medication on C1D1. If a urine pregnancy 
test cannot be confirmed as negative, a serum pregnancy test is 
required. Pregnancy testing must be done as required by local 
regulation. Refer to Appendix 7 for country-specific requirements.
Urinalysis
X
X
X
X
Required within 72 h of C1D1. Does not need to be repeated if 
screening labs were done within 72 h of C1D1. May be performed up 
to 72 h prior to dosing for subsequent cycles when scheduled.
PTT may be performed if the local lab is unable to perform aPTT. Any 
participant receiving anticoagulant therapy should have coagulation 
factors monitored closely throughout the study.
CBC with Differential
X
X
X
X
X
X
X
X
PT or INR and PTT or 
aPTT
X
X
X
X
Chemistry Panel
X
X
X
X
X
X
X
X
LDH, GGT
X
X
X
X
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Study Period:
Combination Treatment Phase (3-Week Cycles)
Notes
Treatment 
Cycle/Title:
Cycle 1
Cycle 2
Cycle 3 
Cycle 4 
and 
Beyond
Treatment Days:
1
8
15
1
8
15
1
1
Scheduled Day and 
Window:
+3
±3
±3
±3
±3
±3
±3
±3
Thyroid Function 
Testing (TSH, T3 [or
FT3], T4 [or FT4])
X
X
X*
Total T3 and Total T4 are preferred over FT3 and FT4. Required 
within 72 h prior to Day 1 of C1, C3, C5*, C7, C9, C11, and at every 
other subsequent treatment cycle. Does not need to be repeated on 
C1D1 if screening labs were done within 72 h of C1D1. *Cycle 4 not 
required.
AE Monitoring
X
CCI
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Study Period:
Combination Treatment Phase (3-Week Cycles)
Notes
Treatment 
Cycle/Title:
Cycle 1
Cycle 2
Cycle 3 
Cycle 4 
and 
Beyond
Treatment Days:
1
8
15
1
8
15
1
1
Scheduled Day and 
Window:
+3
±3
±3
±3
±3
±3
±3
±3
Abbreviations: AE
adverse event; aPTT
activated partial thromboplastin time; β hCG
β human chorionic gonadotropin; C
Cycle; CBC
complete blood count; 
CT
computed tomography; ctDNA
circulating tumor deoxyribonucleic acid; D
Day; ECOG
Eastern Cooperative Oncology Group; FT3
free triiodothyronine; FT4
free 
thyroxine; GGT
gamma glutamyl transferase; INR
international normalized ratio; iRECIST
immune related RECIST; itRECIST
intratumoral immunotherapy RECIST; 
IV
intravenous; LDH
lactate dehydrogenase; MRI
magnetic resonance imaging;  PK
pharmacokinetics; PT
prothrombin time; PTT
partial thromboplastin time;
RECIST v1.1
Response Evaluation Criteria In Solid Tumors, version 1.1; RNA
ribonucleic acid; T3
total triiodothyronine; T4
total thyroxine; TSH
thyroid stimulating 
hormone; WOCBP
women of childbearing potential.
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1.3.3
Schedule of Activities for the Treatment Period for Arm 2 – IV Pembrolizumab Monotherapy
Study Period:
Treatment Phase (3-Week Cycles)
Notes
Treatment 
Cycle/Title:
Cycle 1
Cycle 2
Cycle 3 
Cycle 4 
and 
Beyond
Treatment Days:
1
1
1
1
Scheduled Day 
and Window:
+3
±3
±3
±3
Administrative Procedures
Informed Consent
X
Additional consent is required for treatment beyond disease progression.
Prior/Concomitant 
Medication 
Review
X
X
X
X
Participant 
Identification Card
X
Participant identification card to be updated with treatment number at the time of 
treatment intervention randomization.
Treatment 
Randomization
X
Treatment must occur within 72 h of intervention randomization.
Pembrolizumab 
Administration/ 
Dispensing 
X
X
X
X
See Pembrolizumab Pharmacy Manual.
Efficacy Procedures
Tumor Imaging,
RECIST 1.1, 
iRECIST, and/or 
itRECIST
Response 
Assessment
X
X
Tumor imaging (CT or MRI) and medical photography (for cutaneous lesions) to 
be performed 6 weeks (42-49 days) after the first dose, and then every 6 weeks
(42 days ± 7 days) for the first year, then every 9 weeks (63 days  ± 7 days ) 
thereafter. Imaging schedule should follow calendar days and should not be 
adjusted for delays in cycle starts. Continue imaging schedule until confirmed 
disease progression, discontinuation from study, or start of a new antitumor 
treatment. Medical photography can be performed more often as medically 
warranted.
Medical 
Photography 
(cutaneous lesions)
X
X
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Study Period:
Treatment Phase (3-Week Cycles)
Notes
Treatment 
Cycle/Title:
Cycle 1
Cycle 2
Cycle 3 
Cycle 4 
and 
Beyond
Treatment Days:
1
1
1
1
Scheduled Day 
and Window:
+3
±3
±3
±3
Safety Procedures
Directed Physical 
Examination
X
X
X
X
Weight
X
X
X
X
Vital Signs 
X
X
X
X
Measure prior to study intervention. Vital signs include heart rate, respiratory 
rate, blood pressure, 02 saturation, and temperature.
ECOG 
performance status
X
X
X
X
Performed within 72 h prior to study intervention dosing on Day 1 of each cycle. 
Additional ECOG can be performed as clinically indicated.
12-Lead 
Electrocardiogram 
(Local)
X
Pregnancy test –
Urine or Serum 
β-hCG for 
WOCBP 
X
Required within 24 h prior to first dose of study medication. Does not need to be 
repeated if screening pregnancy test was done within 24 h of C1D1. If a urine 
pregnancy test cannot be confirmed as negative, a serum pregnancy test is 
required. Pregnancy testing must be done as required by local regulation. Refer to 
Appendix 7 for country-specific requirements.
Urinalysis
X
X
X
X
Required within 72 h of C1D1. Does not need to be repeated if screening labs 
were done within 72 h of C1D1. May be performed up to 72 h prior to dosing for 
subsequent cycles when scheduled.
CBC with 
Differential
X
X
X
X
Chemistry Panel
X
X
X
X
LDH, GGT
X
X
X
X
Thyroid Function 
Testing (TSH, T3 
[or FT3], T4 [or 
FT4])
X
X
X*
Total T3 and T4 are preferred over FT3 and FT4. Required within 72 h prior to 
Day 1 of C1, C3, C5*, C7, C9, C11, and at every other subsequent treatment 
cycle. Does not need to be repeated on C1D1 if screening labs were done within 
72 h of C1D1. *Cycle 4 not required.
AE Monitoring
X
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Study Period:
Treatment Phase (3-Week Cycles)
Notes
Treatment 
Cycle/Title:
Cycle 1
Cycle 2
Cycle 3 
Cycle 4 
and 
Beyond
Treatment Days:
1
1
1
1
Scheduled Day 
and Window:
+3
±3
±3
±3
Abbreviations: AE
adverse event; aPTT
activated partial thromboplastin time; β hCG
β human chorionic gonadotropin; C
Cycle; CBC
complete blood count; 
CT
computed tomography; ctDNA
circulating tumor deoxyribonucleic acid; D
Day; ECOG
Eastern Cooperative Oncology Group; FT3
free triiodothyronine; FT4
free 
thyroxine; GGT
gamma glutamyl transferase;  INR
international normalized ratio; iRECIST  immune related RECIST; itRECIST
intratumoral immunotherapy RECIST; 
LDH
lactate dehydrogenase; MRI
magnetic resonance imaging;  PK
pharmacokinetics; PT
prothrombin time; PTT
partial thromboplastin time; RECIST 
v1.1
Response Evaluation Criteria In Solid Tumors, version 1.1; RNA
ribonucleic acid; T3
total triiodothyronine; T4
total thyroxine; TSH
thyroid stimulating hormone.; 
WOCBP
women of childbearing potential.
CCI
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1.3.4
Schedule of Activities for the End of Treatment and Posttreatment Follow-Up Periods
Study Period
EOT/ Discontinuation
Posttreatment Period
Notes
30-Day 
Safety 
Follow-up 
Visit
Imaging 
Follow-up
Survival 
Follow-up
Visit Timing
30 days 
after the 
last dose
Every 
6 weeks for 
1 year, then 
every 
9 weeks
Approxi-
mately 
every 
12 weeks
Visit Window (Days)
±7
+7
±7
±14
Administrative Procedures
Concomitant Medication
X
X
Efficacy Procedures
See Imaging Manual All imaging 
visits have a ± 7-day window
Tumor Imaging, RECIST 1.1, iRECIST, and/or
itRECIST Response Assessment 
X
X
Medical Photography (Cutaneous Lesions) 
X
X
New Anticancer Therapy Status
X
X
X
Survival Status Monitoring
Upon Sponsor request, participants 
may be contacted for survival status 
at any time during the course of the 
study. After confirmed disease 
progression, each participant will be 
contacted for survival status until 
participant withdrawal of consent, 
becoming lost to follow-up, death, or 
the end of the study.
Safety Assessments and Procedures
See Procedures Manual for 
collection and management of 
samples.
AE Monitoring
X
X
X
Full Physical Examination 
X
Directed Physical Examination
X
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Study Period
EOT/ Discontinuation
Posttreatment Period
Notes
30-Day 
Safety 
Follow-up 
Visit
Imaging 
Follow-up
Survival 
Follow-up
Visit Timing
30 days 
after the 
last dose
Every 
6 weeks for 
1 year, then 
every 
9 weeks
Approxi-
mately 
every 
12 weeks
Visit Window (Days)
±7
+7
±7
±14
Weight
X
X
Vital Signs
X
X
Heart rate, respiratory rate, blood 
pressure, 02 saturation, and 
temperature.
ECOG performance status 
X
X
CBC with Differential 
X
X
Chemistry Panel 
X
X
Urinalysis
X
Pregnancy Test for WOCBP – Urine or Serum 
β-hCG
X
For WOCBP, perform as required 
locally. If a urine pregnancy test 
cannot be confirmed as negative, a 
serum pregnancy test is required.
Refer to Appendix 7 for 
country-specific requirements.
Thyroid Function (TSH, T3 [or FT3], T4 [or 
FT4])
X
Total T3 and T4 are preferred over 
FT3 and FT4.
Pharmacokinetics (PK)/Pharmacodynamics/ Future Biomedical Research/Biomarkers
See Procedures Manual for 
collection and management of 
samples.
Blood for ctDNA Analysis
X
Abbreviations: AE  adverse event; β hCG
β human chorionic gonadotropin; CBC
complete blood count; ECOG
Eastern Cooperative Oncology Group; EOT  end of 
treatment; FT3
free triiodothyronine; FT4
free thyroxine; iRECIST
immune related RECIST; itRECIST
intratumoral immunotherapy RECIST; RECIST v1.1
Response 
Evaluation Criteria In Solid Tumors, version 1.1; T3
total triiodothyronine; T4
total thyroxine; TSH
thyroid stimulating hormone; WOCBP
women of childbearing
potential.
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2
INTRODUCTION
MK-1454 is a novel CDN that is a STING agonist under study for the treatment of HNSCC
as monotherapy and as combination therapy with pembrolizumab. This is a Phase 2 study to 
assess the efficacy, safety, and tolerability of IT MK-1454 in combination with 
pembrolizumab versus pembrolizumab monotherapy.
2.1
Study Rationale
Endogenous STING pathway activation within the tumor induces spontaneous T-cell priming 
that is necessary for the generation of adaptive immunity. The scientific rationale for 
combining MK-1454 with PD-1 blockade is based on the ability of STING agonists to induce 
type I IFNs and induce strong T-cell activation by promoting cross-presentation of tumor 
antigens. As strong T-cell activation is accompanied by up-regulation of PD-1, which 
mediates T-cell inhibition by tumors, combination therapy with anti-PD-1 will prevent the 
inhibition of T-cell activation. The initial empirical rationale for combining MK-1454 with 
PD-1 blockade is based on the efficacy observed in anti-PD-1 nonresponsive syngeneic 
mouse tumor models where subefficacious MK-1454 doses in combination with anti-PD-1 
induced improved antitumor responses and complete tumor regression compared to either 
monotherapy treatment alone (see MK-1454 IB for details).
This response was demonstrated in a Phase 1 study, in which IT injection of STING agonist 
in combination with pembrolizumab induced regression of established tumors and generated
systemic immune responses, mediating rejection of distant metastases, and providing 
immunologic (T cell) memory. Preliminary results reported from the ongoing FIH study 
showed a PR to IT MK-1454 in combination with IV pembrolizumab in participants with 
HNSCC, TNBC, and anaplastic thyroid cancer [Harrington, K. J., et al 2018]. Dose-response 
data from this study led to the proposed 
total dose per treatment visit of MK-1454 for 
IT injection into multiple sites. See Section 2.2.3.1 for further details of the FIH study.
Pembrolizumab monotherapy is approved as first-line treatment of patients with metastatic or 
with unresectable, recurrent HNSCC for patients whose tumors express PD-L1 (CPS ≥1) or 
in combination with platinum and fluorouracil regardless of PD-L1 expression. Refer to the 
IB/approved local product label for list of approvals for pembrolizumab. Clinical experience 
with MK-1454 in combination with pembrolizumab thus far, indicates that this combination 
may provide a greater benefit as a cancer therapeutic in the HNSCC patient population.
2.2
Background
Refer to the IB/approved labeling for detailed background information on MK-1454, and the 
MK-3475 IB for detailed background information on pembrolizumab.
CCI
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2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1 MK-1454 Pharmaceutical and Therapeutic Background 
MK-1454 is a CDN STING agonist with activity across species. The presence of DNA in the 
cytoplasm of mammalian cells represents a cellular danger signal, and the cGAS/STING 
pathway is activated to respond to that potentially infectious threat [Barber GN 2015]. Free 
cytosolic DNA is recognized by cGAS, catalyzing the generation of the cyclic GMP-AMP. 
cGAMP strongly binds to the ER-transmembrane adapter protein STING, inducing the 
activation of transcription factor IRF-3 [Sun, L., et al 2013] [Burdette, D. L., et al 2011]. This 
ultimately leads to a strong induction of type 1 IFN and proinflammatory cytokines such as 
IL-6, TNF-α, and IFN-γ, which potentiate T-cell activation through multiple mechanisms.
STING is expressed in numerous cell types, but functional responses (cytokine production)
in response to dsDNA were demonstrated only in a small subset of STING-expressing cells, 
mainly innate immune cells. SNP analysis and sequencing studies have revealed the 
existence of 4 main STING variants in humans, with amino acid changes at positions 71, 
230, 232, and 293. While the most prevalent non-WT STING variants are present at allelic 
frequencies of up to 20% in the human population, the prevalence of homozygous non-WT 
STING carriers for any of the identified STING variants is estimated to be less than 5% [Yi, 
G., et al 2013]. Recent studies showed that all tested STING variants demonstrated 
comparable response to synthetic CDN-derivative STING agonists.
Enhancing the capacity of the innate immune system to present tumor-associated antigens to 
CD8+ T cells through antigen cross-presentation is critical for immune-mediated tumor 
destruction, and STING agonism enhances this response [Deng, L., et al 2014] [Woo S. R., et 
al 2014] as illustrated in Figure 2.
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Figure 2
Schematic Diagram Showing Mechanism of the Enhancement of T-cell Driven 
Antitumor Immunity Through the Action of STING Agonists
cGAMP Cyclic guanosine monophosphate adenosine monophosphate, cGAS  Cyclic guanosine monophosphate adenosine 
monophosphate synthase; IFN interferon; IRF3  interferon regulatory factor 3, NF κB  nuclear factor kappa light chain 
enhancer of activated B cells; STING stimulator of interferon genes, TBK1 TANK binding kinase 1.
Working model of pharmacological STING activation leading to antitumor immune responses in vivo. 
Therapeutically, the STING pathway can be stimulated by STING agonists when the compounds are injected into the tumor 
site, leading to the activation of intratumoral dendritic cells (DC). This results in the phosphorylation of TBK1 and 
activation of the transcription factors that induce expression of the type 1 IFN genes, proinflammatory cytokines, 
chemokines, etc. Type 1 IFN signaling in CD8α+ CD103+ cross presenting DC leads to antigen specific T cell priming and 
generation of spontaneous antitumor T cell responses in vivo. Recruitment of effector T cells into the tumor 
microenvironment is facilitated by the release of CXCL9/CXCL10 chemokines from DCs and other cells at the tumor site. 
Successfully recruited activated T cells additionally induce direct tumor cell killing, leading to measurable tumor shrinkage.
Source:  Figure adapted from [Woo, S. R., et al 2015] [Corrales, L. 2016].
Published and internal data show that IT delivery of STING agonists leads to complete tumor 
regression or significant tumor growth inhibition in both anti-PD-1 -responsive and 
nonresponsive mouse syngeneic tumor models and can also induce immune-mediated 
clearance of noninjected tumors [Corrales, L., et al 2015] [Fu, J., et al 2015] [Baird, J. R., et 
al 2016]. Finally, tumor-bearing mice whose tumors completely regress through the action of 
a STING agonist become protected against subsequent challenges with the same tumor, 
indicating that induction of a durable tumor-specific T-cell memory has occurred [Fu, J., et al 
2015].
2.2.1.2
Pembrolizumab (MK-3475) Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable 
prognosis in various malignancies. In particular, the presence of CD8+ T-cells and the ratio 
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of CD8+ effector T-cells/FoxP3+ T-regs correlates with improved prognosis and long-term 
survival in solid malignancies such as ovarian, colorectal, pancreatic cancer, hepatocellular 
carcinoma, malignant melanoma, and renal cell carcinoma. Tumor-infiltrating lymphocytes 
can be expanded ex vivo and reinfused, inducing durable objective tumor responses in 
cancers such as melanoma [Dudley, M. E., et al 2005] [Hunder, N. N., et al 2008].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T-
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) 
[Greenwald, R. J., et al 2005] [Okazaki, T., et al 2001].
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an IgV-type domain responsible 
for ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules. 
The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based switch motif. 
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to 
the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, which are 
involved in the CD3 T-cell signaling cascade [Okazaki, T., et al 2001] [Chemnitz, J. M., et al 
2004] [Sheppard, K-A, et al 2004] [Riley, J. L. 2009]. The mechanism by which PD-1 down-
modulates T-cell responses is similar to but distinct from that of CTLA-4, because both 
molecules regulate an overlapping set of signaling proteins [Parry, R. V., et al 2005] 
[Francisco, L. M., et al 2010].
Pembrolizumab is currently approved for treatment of a variety of neoplasms, including 
metastatic or unresectable, recurrent HNSCC with disease progression on or after platinum-
containing chemotherapy [U.S. Prescribing Information 2019].
2.2.2
Preclinical and Clinical Studies
For a review of preclinical studies of MK-1454, please see the IB.
2.2.3
Ongoing Clinical Studies
2.2.3.1
MK-1454 Clinical Studies
The ongoing FIH study, as of 06-JUN-2019, MK-1454-001, has evaluated IT MK-1454
doses of up to
as monotherapy, and IT MK-1454 doses of up to
in 
combination with pembrolizumab 200 mg IV Q3W. Dose-dependent increases in exposure to 
MK-1454 were observed, with a half-life of approximately 1.5 hours. Serum cytokines 
increased in a dose-dependent manner up to
followed by a plateau seen at
in 
monotherapy (n 27) and
in combination therapy (n 33). The expression of STING-
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Among the 882 patients, the study population characteristics were: median age of 61 years 
(range, 20 to 94), 36% age 65 or older; 83% male; 73% white, 20% Asian, and 2.4% black; 
61% had ECOG performance status of 1; and 79% were former or current smokers. Twenty-
two percent of patients’ tumors were HPV-positive; 23% had PD-L1 TPS ≥50%; and 95% 
had stage IV disease (19% were stage IVA, 6% were stage IVB, and 70% were stage IVC). 
Eighty-five percent of patients’ tumors had PD-L1 expression of CPS ≥1, and 43% had CPS 
≥20. The median duration of exposure to pembrolizumab 200 mg Q3W was 3.5 months 
(range, 1 day to 24.2 months) in the monotherapy arm and was 5.8 months (range, 3 days to 
24.2 months) in the combination arm.
The main efficacy outcome measures were OS and PFS as assessed by BICR according to 
RECIST v1.1 (modified to follow a maximum of 10 target lesions and a maximum of 5 target 
lesions per organ) sequentially analyzed in the subgroup of patients with CPS ≥20, the 
subgroup of patients with CPS ≥1 and the overall population.
Pembrolizumab demonstrated a significant improvement in OS compared with the 
EXTREME regimen (cetuximab with carboplatin or cisplatin plus fluorouracil), as 
monotherapy in patients whose tumors expressed PD-L1 (CPS ≥1) with a median OS of 
13.6 months versus 10.4 months, respectively; (HR 0.65 [95% CI, 0.53-0.80]; p 0.00002) 
and in combination with chemotherapy in the total study population (HR 0.77 [95% CI, 
0.63-0.93]; p 0.0067).
Among participants whose tumors were CPS ≥20, OS was also significantly improved in 
those treated with pembrolizumab plus chemotherapy versus the EXTREME regimen: HR  
0.60 (95% CI, 0.45, 0.82); p
0.00044. Assessment by HPV status (participants with 
oropharyngeal cancer) indicated that among those who were HPV-positive, pembrolizumab 
plus chemotherapy showed clear improvement; median OS was 23.9 months (95% CI: 16.2, 
34.5) compared with 15.9 months for standard treatment HR  0.56 (95%CI: 0.36, 0.87). 
Assessment of OS by the ECOG subgroups were consistent with the CIs of the primary 
findings overlapping the primary HR outcome CI.
Pembrolizumab was discontinued for adverse reactions in 12% of patients in the 
monotherapy arm. The most common adverse reactions resulting in permanent 
discontinuation of pembrolizumab were sepsis (1.7%) and pneumonia (1.3%). Adverse 
reactions leading to the interruption of pembrolizumab occurred in 31% of patients; the most 
common adverse reactions leading to the interruption of pembrolizumab (≥2%) were 
pneumonia (2.3%), pneumonitis (2.3%) and hyponatremia (2%). The most common adverse 
reactions (≥20%) with pembrolizumab as monotherapy were fatigue (33%), constipation 
(20%), and rash (20%).
Pembrolizumab is approved for use in the treatment of multiple tumor types [U.S. 
Prescribing Information 2019], and 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.
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2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
For MK-1454-001, drug-related AEs reported most frequently by investigators (>10% of 
participants) were
 The most frequently reported SAEs in treated 
participants were
Efficacy data from participants dosed with MK-1454 are available from 30 participants dosed 
in monotherapy (Arm 1) and 60 participants dosed in combination therapy (Arm 2) 
(including crossover participants). There have been no objective responses in monotherapy. 
In combination therapy, including crossover, there has been 1 CR in a participant with 
TNBC, and an additional 9 participants with a PR.
Based on composite evaluation of safety, pharmacodynamic, and efficacy data,
was 
selected as the recommended Phase 2 dose. Safety and efficacy data to date support the 
conclusion that MK-1454 has an acceptable benefit/risk profile for continued investigation.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the MK-1454 IB and pembrolizumab label/IB and informed 
consent documents.
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
Throughout this protocol, the term RECIST refers to a modification of RECIST to include a 
maximum of 10 target lesions and a maximum of 5 target lesions per organ.
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In males and females who are at least 18 years of age with metastatic or with unresectable, 
recurrent HNSCC with a tumor PD-L1 IHC CPS ≥1:
Objectives
Endpoints
Primary
•
Objective: To evaluate participants 
treated with IT MK-1454 in combination 
with pembrolizumab or pembrolizumab 
alone with regard to the ORR per 
RECIST 1.1 by BICR.
•
Hypothesis (H1): IT MK-1454 in 
combination with pembrolizumab results 
in a superior ORR, per RECIST 1.1 based 
on BICR, compared to pembrolizumab 
alone, in participants with tumor CPS ≥1.
•
Hypothesis (H2): IT MK-1454 in 
combination with pembrolizumab results 
in a superior ORR, per RECIST 1.1 based 
on BICR, compared to pembrolizumab 
alone, in participants with tumor 
CPS ≥20.
The study is considered to have met its 
primary objective if IT MK-1454, in 
combination with pembrolizumab, results in a 
superior ORR, per RECIST 1.1 based on 
BICR, compared to pembrolizumab alone
either in participants with tumor CPS ≥1 or in 
participants with tumor CPS ≥20.
•
Objective response is a confirmed CR or 
PR
Secondary
•
Objective: To evaluate participants 
treated with IT MK-1454 in combination 
with pembrolizumab or pembrolizumab 
alone with regard to progression-free 
survival (PFS) per RECIST 1.1 by BICR.
•
PFS, defined as the time from 
randomization to the first documented 
PD or death from any cause, whichever 
occurs first.
•
Objective: To evaluate participants 
treated with IT MK-1454 in combination 
with pembrolizumab or pembrolizumab 
alone with regard to DOR per 
RECIST 1.1 by BICR.
•
DOR, defined as the time from the first 
documented evidence of CR or PR until 
PD or death due to any cause, whichever 
occurs first, in participants 
demonstrating CR or PR.
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Objectives
Endpoints
•
Objective: To evaluate participants 
treated with IT MK-1454 in combination 
with pembrolizumab or pembrolizumab 
alone with regard to OS.
•
OS, defined as the time from 
randomization to the date of death from 
any cause.
•
Objective: To assess participants treated 
with IT MK-1454 in combination with 
pembrolizumab or pembrolizumab alone 
with regard to the safety and tolerability 
of study intervention. 
•
AEs
•
Discontinuing study intervention due to 
an AE.
Tertiary/Exploratory
4
STUDY DESIGN
4.1
Overall Design
This is a randomized, active-controlled, parallel group, multicenter, open-label, Phase 2 study 
of IT MK-1454 in combination with pembrolizumab versus pembrolizumab monotherapy in 
participants with a histologically or cytologically confirmed diagnosis of metastatic or 
unresectable, recurrent HNSCC with a tumor CPS ≥1 [Kulangara, K., et al 2018] as first-line 
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treatment. Participants need to have at least 1 measurable lesion that is amenable to IT 
injection for RECIST assessment.
This study will evaluate the efficacy, safety, and tolerability of IT MK-1454 in combination 
with pembrolizumab IV versus pembrolizumab IV alone. Figure 1 depicts a summary of the 
study design. Approximately 200 participants will be randomized 1:1 using IRT to receive IT 
MK-1454 at a dose of 
in combination with pembrolizumab (Arm 1) or 
pembrolizumab monotherapy (Arm 2). Randomization will be stratified by PD-L1 expression 
level defined by CPS (≥1 to <20 vs ≥20), ECOG performance status (0 vs. 1) and tumor HPV 
status (positive, negative). In Arm 1, study intervention will be IT MK-1454
administered Q1W for 6 weeks, then Q3W, in combination with pembrolizumab 200 mg IV 
Q3W. In Arm 2, study intervention will be pembrolizumab 200 mg IV Q3W.
After a screening period of up to 28 days, participants will be randomized 1:1 to Arm 1 or 
Arm 2. Participants may be treated for up to 35 cycles (approximately 24 months) after 
initiation of treatment with pembrolizumab alone or in combination with MK-1454. 
Discontinuation Follow-Up will be 30 days after the last dose.
Participants will be treated until PD, unacceptable toxicity, or other protocol-specified 
criterion for cessation of treatment, at which point they will be discontinued from the study 
intervention. Participants who discontinue study intervention will have posttreatment follow-
up for disease status (including imaging) until PD, initiating a new anticancer therapy, 
withdrawing consent for study participation, or becoming lost to follow-up. This protocol 
does not allow participants to cross over to the other arm if they experience progression.
After confirmed PD, each participant will be followed up for safety at 30 days after the EOT, 
then will be contacted by telephone every 12 weeks (84±7 days) for survival until death, end 
of the study, withdrawal of consent to participate in the study, or becoming lost to follow-up, 
whichever occurs first.
The primary efficacy objective will be ORR based on the RECIST 1.1 as assessed by BICR. 
PFS and DOR based on RECIST 1.1 per BICR, and OS will be evaluated as secondary
objectives. ORR, PFS, and DOR will also be assessed by iRECIST. Participants may 
continue to receive study intervention until tumor assessment is repeated 4 to 8 weeks later,
in order to confirm PD by iRECIST per site assessment.
AEs will be evaluated by the investigator, according to criteria outlined in the NCI CTCAE, 
Version 5.0, to establish the safety and tolerability of MK-1454 when administered in 
monotherapy or in combination with pembrolizumab. Sponsor assessment of safety will be
ongoing from the start of the study. Assessment of safety will be monitored continuously 
throughout this Phase 2 study, including ongoing frequent medical monitoring of AEs as they 
occur. SAEs will be followed until resolution, stabilization, until the event is otherwise 
explained, or the participant is lost to follow-up.
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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
The current study is randomized but is not blinded due to the unfavorable risk/benefit of 
injecting placebo saline into lesions of participants randomized to Arm 2, monotherapy 
pembrolizumab. Such risks include bleeding, infection, and injection site pain. BICR will be 
used for primary endpoints to minimize bias in ORR and PFS determinations. An IA will be 
performed after 70 participants (~35 in each arm) are enrolled and participants have at least 2 
postbaseline scans.
4.2.1
Rationale for the Study and Selected Participant Population
Head and neck cancers are an anatomically heterogeneous group of cancers that arise most 
often from the oral cavity, oropharynx, hypopharynx, and larynx [Salazar, C. R., et al 2014]. 
Approximately 90% of all new cases are squamous cell carcinoma of the head and neck and 
HNSCC is the ninth leading cancer by incidence worldwide [Gupta, B., et al 2016]. Although 
the head and neck region contains a wide diversity of structures and cell types, the vast 
majority of head and neck cancers arise from the mucosa of the upper aerodigestive tract and 
are predominantly squamous cell in origin.
A large number of patients with head and neck cancer initially present with locally advanced,
Stage III/IV disease that is initially treated with combinations of chemotherapy, radiation 
and/or surgery. This initial treatment is generally designated as “definitive” therapy, which 
typically combines chemoradiation and surgery and can result in disease control rates ranging 
between 33% to 86% of patients. Patients who progress after initial definitive therapy require 
subsequent treatment for recurrent disease. Patients who initially present with metastatic 
disease generally receive the same therapy as those with recurrent disease after definitive 
treatment. Together, patients with recurrent or metastatic disease receive the first-line 
chemotherapies.
In this study, participants with oropharynx cancer will be stratified by HPV status (positive 
or negative). HNSCC is based on HPV status, as HPV-positive and HPV-negative tumors are 
2 different diseases, each with a distinct biology, clinical presentation, and prognosis [Price, 
K. A. 2012] [Dorsey, K. 2013]. Preliminary data of single-agent pembrolizumab in head and 
neck cancer patients in KEYNOTE-012 demonstrate efficacy in both HPV-positive and 
HPV-negative patients. Investigator site assessment of HPV using IHC staining for the p16 
protein will be used for the participants with oropharyngeal cancer prior to randomization.
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4.2.2
Rationale for Entry Criteria
4.2.2.1
Use of Combined Positive Scoring for PD-L1 Status
The CPS levels selected, CPS ≥1 for inclusion, and CPS ≥1 to <20 versus CPS ≥20 level for 
stratification, were selected based on prior experience in pembrolizumab studies. Biomarker 
results from KEYNOTE-012 and KEYNOTE-055 showed that inclusion of both tumor cells 
and inflammatory cells in IHC scoring CPS improves the ability to predict response based on 
PD-L1 status compared to tumor cells alone (TPS) in patients with recurrent/metastatic
HNSCC.
Based on the results from the KEYNOTE-048 study in first-line recurrent/metastatic 
HNSCC, 85% of participants’ tumors had PD-L1 expression levels of CPS ≥1 and 43% had 
CPS ≥20. Pembrolizumab significantly improved OS over the EXTREME regimen 
(cetuximab 400 mg/m2 loading/250 mg/m2 QW + cisplatin) in the PD-L1 CPS ≥20 and ≥1 
populations and was noninferior in the total population with favorable safety. These results 
showed that CPS correlates with responsiveness to PD-1 inhibition and is a useful guide for 
the selection of treatment. This study will evaluate PD-L1 expression using a CPS ≥1 and 
≥20, which balance all factors including positive predictive value, prevalence, and the 
biomarker specificity/sensitivity. This tissue sample will be analyzed using the IUO version 
of the US FDA-approved PD-L1 IHC 22C3 kit to confirm the PD-L1 CPS ≥1 status for 
eligibility and for stratification by CPS (≥1 to <20 vs ≥20). Randomization will be stratified 
according to CPS ≥1 and <20 versus CPS ≥20, and PD-L1 expression will be correlated with 
clinical outcome according to both IHC criteria.
4.2.2.2
Rationale for Minimum Creatinine Clearance
In preclinical studies with tritiated MK-1454, 20% and 28% of MK-1454-derived 
radioactivity (<5% as MK-1454) was renally excreted in dogs and rats, respectively, 
suggesting renal excretion is not a major component of MK-1454 clearance preclinically. 
Clinically, MK-1454 has been tested in combination with pembrolizumab at doses up to 
MK-1454, without reaching MTD. This is a 3.7-fold margin compared to the 
proposed dose of
in the Phase 2 study. Therefore, including participants with 
creatinine clearance of ≥30 mL/min poses minimal safety risk based on available data [Kim, 
E. S., et al 2017]. Furthermore, MSD is collecting urine to measure renal clearance of 
MK-1454 in the clinic in the Phase 1 study to assess the impact on renal function. 
Historically, pembrolizumab clinical studies have included participants with creatine 
clearance of ≥30 mL/min, with no adverse outcomes. Pembrolizumab is an IgG4 monoclonal 
antibody. Therefore, it is not expected that pembrolizumab has significant renal clearance 
based on the large molecular weight. This rationale is confirmed by PK analysis in subjects 
with normal and impaired renal function which has evaluated the safety of pembrolizumab in 
participants with impaired renal function. Based on the population PK analysis, both 
clearance and exposure of pembrolizumab are similar regardless of renal impairment status 
based on eGFR. Evaluation of safety data indicates that the risk of AEs and AEOSIs in 
participants receiving pembrolizumab is not impacted by their renal function.
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4.2.3
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
The efficacy objective of this study is to evaluate the antitumor activity of the MK-1454 and 
pembrolizumab combination. The primary efficacy endpoint will be ORR, as assessed by 
BICR, according to tumor response criteria. ORR is an acceptable measure of clinical benefit 
to demonstrate a new antineoplastic combination therapy. The use of BICR and RECIST 1.1 
criteria to evaluate ORR is considered acceptable by regulatory authorities for this stage of 
development.
The secondary objectives include assessment of PFS, DOR, and OS.
Progression-free survival is an acceptable measure of clinical benefit for a study that 
demonstrates superiority of a new antineoplastic therapy, especially if the magnitude of the 
effect is large and the therapy has an acceptable risk/benefit profile. The use of BICR and 
RECIST 1.1 to assess PFS is typically considered acceptable by regulatory authorities. 
Images will be submitted to an iCRO and read by an independent central review blinded to 
treatment assignment to minimize bias in the response assessments. In addition, the final 
determination of radiologic progression will be based on the central assessment of 
progression, rather than a local site investigator/radiology assessment.
DOR per RECIST 1.1, assessed by BICR, will serve as an additional measure of efficacy and 
is a commonly accepted endpoint by both regulatory authorities and the oncology 
community.
The endpoint of OS is a standard for demonstrating superiority of antineoplastic therapy in 
clinical studies. Additionally, as seen in multiple studies with pembrolizumab, there is a 
proportion of patients who experience long-term benefit and are represented in the tail-end of 
the survival curve.
4.2.3.1.1
Response Rate Assessed by RECIST Version 1.1
RECIST 1.1 will be used to determine the objective response. Although RECIST 1.1 
references a maximum of 5 target lesions in total and 2 per organ, MSD allows a maximum 
of 10 target lesions in total and 5 per organ, if clinically relevant, to enable a broader 
sampling of tumor burden.
4.2.3.2
Safety Endpoints
The safety analysis will be based on participants who experience toxicities, as defined by 
CTCAE Version 5.0 criteria. Safety will be assessed by quantifying the toxicities and grades 
of toxicities experienced by participants who have received MK-1454 in combination with 
pembrolizumab versus pembrolizumab monotherapy.
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For AEs, attribution to drug, time of onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. Adverse events that will be analyzed 
include, but are not limited to, all AEs, SAEs, fatal AEs, and laboratory changes.
4.2.3.3
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4.2.3.6
4.2.4
Rationale for the Use of Comparator
The comparator, pembrolizumab 200 mg IV Q3W monotherapy, is currently approved for 
first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC as 
monotherapy for patients whose tumors express PD-L1 (CPS ≥1) or in combination with 
platinum and fluorouracil regardless of PD-L1 expression.
4.3
Justification for Dose
4.3.1
Rationale for Dose of MK-1454
The recommended Phase 2 dose for MK-1454 was based on analysis of the safety, 
pharmacodynamic, and early efficacy data from Part I of the Phase 1 study (Section 2.2.3.1). 
In the Part 1 dose escalation, responses were observed at doses of 
and
Preclinical data in mice suggested a bell-shaped dose response for 
immunologic memory induced by STING agonism. In combination therapy with 
pembrolizumab, greater reduction in injected and noninjected target lesions was seen at 
MK-1454 doses of 
to
compared to MK-1454 doses of
to
suggesting improved efficacy at the lower MK-1454 doses evaluated in the Phase 1 study. 
Pharmacodynamic analysis demonstrated nanostring gene signature and IP-10 
dose-dependent increases, which peaked at
 and plateaued thereafter. The overall 
safety profile of MK-1454 was tolerable. Based on composite evaluation of safety, 
pharmacodynamic, and efficacy data,
was selected as the recommended Phase 2 dose. 
To assure that the dose per lesion remains in the efficacious dose range when more than 
1 lesion is injected per treatment visit, the total MK-1454
 dose may be administered 
to a maximum of 3 lesions per treatment visit, with a minimum injectate volume of 1 mL to 
be injected in a single lesion, and a maximum injectate volume of 3 mL to be injected per 
participant per treatment visit.
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4.4
Beginning and End of Study Definition
The overall study begins when the first participant signs the ICF. The overall study ends 
when the last participant completes the last study-related telephone call or visit, withdraws 
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the 
investigator).
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
is unacceptable. In addition, further recruitment in the study or at a particular study site(s) 
may be stopped due to insufficient compliance with the protocol, GCP and/or other 
applicable regulatory requirements, procedure-related problems or the number of 
discontinuations for administrative reasons is too high.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has histologically or cytologically confirmed diagnosis of metastatic or unresectable, 
recurrent HNSCC that is considered incurable by local therapies.

Has not had prior systemic therapy administered in the recurrent or metastatic setting. 
Systemic therapy, which was completed more than 6 months prior to signing consent,
if given as part of multimodal treatment for locally advanced disease, is allowed.

The eligible primary tumor must be located in oropharynx, oral cavity, hypopharynx,
or larynx. Participants may not have a primary tumor site of nasopharynx (any 
histology).
2. Has tumor PD-L1 expression of CPS ≥1.
Note: Tumor tissue must be provided for PD-L1 biomarker analysis. An archival tissue 
sample is acceptable, otherwise a newly obtained biopsy may be obtained (please see the 
Procedures Manual for details).
3. Has measurable disease per RECIST 1.1, as assessed by BICR. Lesions situated in a 
previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions.
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4. Has at least 1 measurable lesion which is amenable to injection. IT injection for 
cutaneous lesions may be performed via visual inspection. IT injection for subcutaneous 
lesions may be performed via ultrasound guidance or via palpation. This injectable lesion 
must be measurable and meet one of the following criteria:

A cutaneous or subcutaneous lesion ≥1 cm in longest diameter for solid tumors, or 
≥1.5 cm in short axis for a nodal lesion in solid tumor participants. The longest
diameter for an injectable lesion must be ≤10 cm for both solid tumors and nodal 
lesions in solid tumor participants.

Multiple coalescing, superficial lesions which in aggregate have a longest diameter of 
≥1 cm and ≤10 cm.
5. Has an ECOG performance status of 0 or 1.
6. Demonstrates adequate organ function, as defined by Table 1.
All screening labs are to be performed within 7 days prior to treatment initiation.
Table 1
Adequate Organ Function
System
Laboratory Value
Hematological
Absolute neutrophil count
≥1,500/µL
Platelets
≥100,000/µL 
Hemoglobin
≥9 g/dL or ≥5.6 mmol/La
Renal
Creatinine OR
CrCl (measured or calculatedb)
(GFR can also be used in place of 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participants with serum 
creatinine >1.5 × ULN [Kim, E. S., et al 2017]
Hepatic
Total bilirubin (serum) 
≤1.5 × ULN or
Direct bilirubin ≤ULN for participants with 
total bilirubin levels >1.5 × ULN
AST and ALT
≤2.5 × ULN or
≤5 × ULN for participants with liver metastases
Coagulation
INR or PT
PTT or aPTT
≤1.5 × ULN
Abbreviations: aPTT = activated partial thromboplastin time; ALT = Alanine aminotransferase; AST = 
aspartate aminotransferase; GFR = glomerular filtration rate; INR = International Normalized Ratio’; PT = 
prothrombin time; PTT = partial thromboplastin time; ULN = upper limit of normal
a Criteria must be met without packed red blood cell transfusion within the prior 2 weeks. Participants can be on 
stable dose of erythropoietin (≥approximately 3 months).
b CrCl should be calculated per institutional standard.
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7. Has results from testing of HPV status for oropharyngeal cancer defined as p16 IHC 
testing using CINtec® p16 Histology assay and a 70% cutoff point (please see the 
Procedures Manual for details). If HPV status was previously tested, then no additional 
testing is required.
Note:  Tumor p16 expression must be evaluated by assessment of IHC analysis with 
CINtec® p16 Histology assay (Ventana Medical Systems Inc., Tucson AZ) using 
“Benchmark Ultra” autostainer (Ventana, Tucson, AZ) and standard protocol. 
Positive p16 expression is defined as strong and diffuse nuclear and cytoplasmic 
staining in 70% or more of the tumor cells.
Note:  HPV stratification in this study in participants with oropharyngeal cancer will 
be performed according to HPV status using the specified method.
Note: If local p16 testing results are not available, or cannot be assessed by the 
specified method, a tumor tissue sample must be submitted for p16 testing at the 
designated central laboratory.
Note: Oral cavity, hypopharynx, and larynx cancer are not required to undergo HPV 
testing by p16 IHC as stratification by HPV status will only be assessed for 
oropharyngeal cancer. Other tumor locations are assumed to be HPV-negative for 
stratification purposes only.
Demographics
8. Is male or female, from 18 years to unlimited years of age inclusive, at the time of 
signing the informed consent.
Male Participants
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
9. Male participants are eligible to participate if they agree to the following during the 
intervention period with MK-1454 and for at least 120 days after the last dose of 
MK-1454:
•
Refrain from donating sperm
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR
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•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
•
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Note: Contraceptive requirements do not apply to participants taking pembrolizumab 
monotherapy.
Female Participants
10. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate 
of <1% per year), with low user dependency, or be abstinent from heterosexual 
intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent 
basis), as described in Appendix [5] during the intervention period and for at least 
120 days after the last dose of study intervention and agrees not to donate eggs (ova, 
oocytes) to others or freeze/store for her own use for the purpose of reproduction during 
this period. The investigator should evaluate the potential for contraceptive method
failure (ie, noncompliance, recently initiated) in relationship to the first dose of study 
intervention. 
•
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) within 
24 hours before the first dose of study intervention.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix [2].
•
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
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11. Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
12. Has voluntarily agreed to participate by providing documented informed consent. The 
participant may also provide consent for FBR. However, the participant may participate 
in the main study without participating in FBR.
Additional Categories
13. HIV-infected participants must meet these additional criteria: 
a) Have HIV-1 infection documented by using any licensed rapid HIV test or HIV 
E/CIA test kit at any time prior to study entry (Day 1). HIV-1 infection is to be 
confirmed by using a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or by HIV-1 p24 antigen, or plasma 
HIV-1 RNA VL.
b) Have well-controlled HIV on anti-retroviral therapy, defined as: 
1) must have a CD4+ T-cell count >350 cells/mm3 at time of screening;
2) must have achieved and maintained virologic suppression, defined as 
confirmed HIV RNA level below 50 copies/mL or below the LLOQ using the 
locally available assay at the time of screening and for at least 12 weeks prior 
to screening; 
3) must have been on a stable regimen, without changes in drugs or dose 
modification, for at least 4 weeks prior to study entry (Day 1).
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has disease that is suitable for local therapy administered with curative intent.
2. Has PD within 6 months of completion of curatively intended systemic treatment for 
locoregionally advanced HNSCC.
3. Has had chemotherapy or biological cancer therapy in the recurrent or metastatic setting 
for the treatment of HNSCC.
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4. Has had radiation therapy (or other nonsystemic therapy) within 2 weeks prior to 
randomization or participant has not fully recovered (ie, ≤Grade 1 or at baseline) from 
AEs due to a previously administered treatment.
Note: Subjects with ≤Grade 2 neuropathy, ≤Grade 2 alopecia, or laboratory values on 
Table 1 are an exception to this criterion and may qualify for the study.
Note: If participant received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.
5. Is expected to require any other form of antineoplastic therapy while on study.
6. Has a history of a second malignancy, unless potentially curative treatment has been 
completed, with no evidence of malignancy for at least 2 years.
Note: The time requirement does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers.
7. Has clinically active central nervous system metastases and/or carcinomatous meningitis. 
Participants with previously-treated brain or meningeal metastases may participate and be 
eligible for treatment provided they are stable and asymptomatic (without evidence of 
progression by MRI scan of the brain separated by at least 4 weeks after treatment), have 
no evidence of new or enlarging brain metastases, are evaluated within 4 weeks prior to 
first study intervention administration, and are off immunosuppressive doses of systemic 
steroids at least 2 weeks prior to enrollment.
8. 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
(prednisone ≤10 mg/day is acceptable). Use of nonsystemic steroids is permitted.
9. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of study
treatment. Corticosteroid use as premedication for allergic reactions (eg, IV contrast) is 
allowed.
10. Has had an allogenic tissue/solid organ transplant.
11. Has a history of vasculitis.
12. Has a history of interstitial lung disease.
13. Has an active infection requiring systemic therapy.
14. Has a known history of active tuberculosis (TB; Bacillus tuberculosis).
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15. Has a history of (noninfectious) pneumonitis that required steroids or current 
pneumonitis.
16. Has had a severe hypersensitivity reaction to treatment a monoclonal 
antibody/components of the study intervention.
17. 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, would make administration of the study interventions 
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.
18. Participants with known hepatitis B or C infections or known to be positive for 
HBsAg/HBV DNA or hepatitis C Antibody or RNA. Active hepatitis C is defined by a 
known positive Hep C Ab result and known quantitative HCV RNA results greater than 
the lower limits of detection of the assay.
19. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or if the 
participant has previously participated in MSD MK-3475 clinical studies.
20. HIV-infected participants who have had an HIV-related opportunistic infection within 
6 months.
21. HIV-infected participants with a history of Kaposi’s sarcoma and/or Multicentric 
Castleman’s Disease.
22. Has known psychiatric or substance abuse disorders that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
23. Is pregnant, breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the Screening Visit through 120 days after 
the last dose of study intervention.
24. Has not fully recovered from any effects of major surgery without significant detectable 
infection. Surgeries that required general anesthesia must be completed at least 2 weeks 
before first study intervention administration. Surgery requiring regional/epidural 
anesthesia must be completed at least 72 hours before first study intervention 
administration and participants should be recovered.
25. Has a tumor(s) in direct contact or encases a major blood vessel with or without
ulceration and/or fungation onto the skin surface at the projected injection site in the head 
or neck.
26. Has a history of reirradiation for HNSCC at the projected injection site in the head and 
neck.
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Prior/Concomitant Therapy
27. Has received a live-virus vaccine within 30 days of planned treatment start. Seasonal flu 
vaccines that do not contain live virus are permitted.
28. Drug-drug interactions have to be taken into consideration, and decisions whether a 
particular drug can be used as a concomitant medication in the study should be based on 
recommendations at the time of the study and depending on the mechanism of action of 
the study intervention. Participants on ART agents with a potentially significant 
overlapping toxicity profile should be excluded if the therapy cannot be switched to the 
regimen without overlapping toxicity.
29. Has been treated with a STING agonist (eg, MK-1454, ADU-S100).
Prior/Concurrent Clinical Study Experience
30. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy, or used an investigational device, any of 
which occurred within 4 weeks of the first dose of treatment. Note: Participation in the 
Follow-up Phase (receiving no study treatment) of a prior study is allowed.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage AEs 
such as diarrhea, nausea or vomiting.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently enrolled in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines. 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria are met. Subjects may be rescreened more than once at the 
discretion of the investigator.
5.5
Participant Replacement Strategy
A participant who withdraws from the study will not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies (study interventions provided by the Sponsor) will be packaged to support 
enrollment as required. Clinical supplies will be affixed with a clinical label in accordance 
with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention(s) to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administra-
tion
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP/
NIMP
Sourcing
Arm 1
Experi-
mental
Pembrolizumab
Drug
Solution for 
Infusion
100 mg /4 
mL
200 mg
IV Infusion
200 mg IV Q3W
Experi-
mental
IMP
Sponsor
Arm 1
Experi-
mental
MK-1454
Drug
Sterile 
Solution
mg/mL 
Intratumoral
IT Q1W × 
6, then Q3W
Experi-
mental
IMP
Sponsor
Arm 2
Active 
Comparator
Pembrolizumab
Drug
Solution for 
Infusion
100 mg /4 
mL
200 mg
IV Infusion
200 mg IV Q3W
Experi-
mental
IMP
Sponsor
IMP  Investigational Medicinal Product; IV  intravenous; NIMP  Noninvestigational Medicinal Product; Q1W  once each week; Q3W
every 3 weeks. 
Definition of IMP and 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.
CCI
CCI
CCI
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number where possible (eg, not applicable in the 
case where multiple lots or batches may be required due to the length of the study, etc.).
1. Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
MK-1454 will be administered as a sterile aqueous solution with a total volume of injectate 
of up to 3 mL per treatment visit for all injected lesions combined. MK-1454 will be 
administered by injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, 
palpable, and/or detectable by ultrasound guidance or cross-sectional imaging guidance as 
clinically appropriate.
Each participant randomized to Arm 1 will receive a
dose of MK-1454 diluted in a 
volume of 1.0 mL to 3 mL of injectate. The volume of injectate delivered to each lesion will 
be based on the longest dimension of the lesion(s) intended for injection as shown in Table 3, 
and on the total number of lesions injected at the treatment visit. Injection of more than 
1 lesion, if feasible, is suggested.
Regarding prioritization of lesions to be injected at a treatment visit, any new or progressing 
lesion should be prioritized first for injection, followed by injection of the largest lesion, with 
up to a total volume of injectate of 3 mL per treatment visit (Appendix 8). 
A maximum of 3 lesions may be injected per treatment visit, with a minimum injectate 
volume of 1.0 mL (Table 4). The maximum total injectate volume per treatment visit per 
participant is 3 mL for all participants. Documentation of dose volume administered per 
lesion will be recorded. For image-guided procedures, document the needle tip within the 
lesion during IT injection. Detailed guidance on injectate volume and lesion injection is 
provided in the Procedures Manual.
For lesions that are no longer visible following treatment, discuss with Sponsor for continued 
injection. Distant 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 Table 4 for individual lesions may be permitted upon approval by 
the Sponsor Medical Monitor or designee.
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Table 3
Determination of Intratumoral MK-1454 Injection Volume Per Lesion Based on 
Lesion Size
Lesion Size (longest dimension)
Injection Volume
>5 cm 
3 mL
>2.5 cm to 5 cm
2 mL
≥1.0 cm to 2.5 cm
1 mL
Table 4
Determination of Intratumoral MK-1454 Total Injectate Volume Based on 
Number of Lesions Injected Per Treatment Visit
Deliverable Volume
1 mL
2 mL
3 mL
Number of Lesions
1
1 × 1 mL
1 × 2 mL
1 × 3 mL
2
NA
2 × 1 mL
1 × 1 mL + 1 × 2 mL
3
NA
NA
3 × 1 mL
NA  not applicable.
Details on dose calculation, preparation, and administration of MK-1454 are provided in the 
Procedures Manual.
6.2.2
Timing of Study Interventions
Treatment cycles for this study are 21 days each cycle. All study interventions will begin 
after all predose study procedures and assessments have been completed, as detailed in 
Section 1.3. Every effort should be made to begin the first dose of study intervention on the 
day of randomization; however, if this is not achieved, study intervention is be initiated no 
later than 3 days from the date of randomization. All subsequent cycles of study intervention 
may be administered up to 3 days before or 3 days after the scheduled day due to 
administrative reasons per the investigator’s judgment. 
The reason for any variability in the administration of the study intervention(s) outside of the 
protocol-specified windows is to be documented in the participant’s chart and recorded in the 
eCRFs.
6.2.2.1
Timing for Administration for MK-1454
MK-1454 will be administered as an IT injection on Day 1, Day 8, and Day 15 of the first 
2 cycles (Q1W for Cycles 1 and 2), then on Day 1 of every 21-day cycle (Q3W) from 
Cycle 3 onward.
On days when both MK-1454 and pembrolizumab are to be administered, MK-1454 will be 
administered within 0.5 to 4 h after completion of the pembrolizumab IV infusion.
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6.2.2.2
Timing for Administration of Pembrolizumab
Pembrolizumab will be administered as an IV infusion on Day 1 of each 21-day cycle after 
all predose study procedures and assessments have been completed, as detailed in 
Section 1.3.
The Pembrolizumab Pharmacy Manual contains specific instructions for dose preparation 
and administration.
6.2.3
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions must be stored 
in a secure, environmentally controlled, and monitored (manual or automated) area in 
accordance with the labeled storage conditions with access limited to the investigator and 
authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Intervention allocation will occur centrally using an IRT. There are 2 intervention arms. 
Participants will be randomized to 1 of 2 intervention arms: MK-1454 in combination with 
pembrolizumab (Arm 1) or pembrolizumab monotherapy (Arm 2).
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6.3.2
Stratification
Intervention randomization will be stratified according to the following factors:
1. PD-L1 status (CPS ≥1 to <20 vs CPS ≥20)
2.
ECOG performance status (0 vs 1)
3.
HPV status (positive vs negative): HPV status for oropharynx cancer is determined by 
p16 IHC (positive vs negative); HPV status for participants without oropharynx cancer 
(eg, cancers of the oral cavity, hypopharynx and larynx) is considered HPV-negative.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
Interruptions from the protocol-specified treatment plan for >12 weeks between MK-1454 or 
pembrolizumab doses for non drug-related or administrative reasons require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management. 
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. If there is a clinical indication for any medication specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor. The final decision on any supportive therapy rests 
with the investigator and/or the participant’s primary physician. However, the decision to 
continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
6.5.1
Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered, at the discretion of the investigator, in keeping with the community standards 
of medical care except for those that are prohibited, as described in Section 6.5.2. All 
concomitant medication will be recorded in the eCRF including all prescription, OTC, herbal 
supplements, and IV medications and fluids. If changes occur during the study period, 
documentation of drug dosage, frequency, route, and date may also be included in the eCRF.
All concomitant medications received within 30 days before the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
Concomitant medications administered after 30 days after the last dose of study intervention 
should be recorded for SAEs and ECIs as defined in Section 8.4.
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6.5.2
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the Screening and 
Treatment Phases (including retreatment for post-CR relapse) of this study:
•
Antineoplastic systemic chemotherapy or biological therapy
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than pembrolizumab or MK-1454
•
Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
considered on an exceptional case-by-case basis after consultation with Sponsor. The 
participant must have clear measurable disease outside the radiated field. Administration 
of palliative radiation therapy will be considered clinical progression for the purposes of 
determining PFS.
•
Live vaccines within 30 days prior to the first dose of study intervention and while 
participating in the study. Examples of live vaccines include, but are not limited to the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed.
•
Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE 
of suspected immunologic etiology. The use of physiologic doses of corticosteroids may 
be approved after consultation with the Sponsor.
Participants who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.
Participants may receive other medications that the investigator deems to be medically 
necessary.
6.5.3
Supportive Care
Treatment guidelines for participants who experience drug-related AEs are provided in 
Section 6.6.
Participants should receive appropriate supportive care measures, as deemed necessary by the 
treating investigator including, but not limited to, the items outlined below:
•
Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic 
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therapy according to standard institutional practice. Participants should be strongly 
encouraged to maintain liberal oral fluid intake.
•
Anemia: Transfusions and/or erythropoietin may be utilized as clinically indicated for the 
treatment of anemia but should be clearly noted as concomitant medications.
•
Neutropenia: Prophylactic use of colony-stimulating factors including G-CSF, pegylated 
G-CSF, or GM-CSF is not allowed in this study. Therapeutic use of G-CSF is allowed in 
participants with Grade 3-4 febrile neutropenia.
•
Thrombocytopenia: Transfusion of platelets may be used if clinically indicated. ITP 
should be ruled out before initiation of platelet transfusion.
•
Anti-infectives: Participants with a documented infectious complication should receive 
oral or IV antibiotics or other anti-infective agents, as considered appropriate by the 
treating investigator for a given infectious condition, according to standard institutional 
practice.
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. Subsequently, all interventions, including continuation of 
study intervention, should be discussed with the Sponsor Clinical Director or designee.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Dose Modification due to Adverse Events
AEs (both nonserious and serious) associated with MK-1454 and/or pembrolizumab 
exposure may represent an immunologic etiology. These AEs may occur shortly after the 
first dose or several months after the last dose of treatment.
The CTCAE Version 5.0 must be used to grade the severity of AEs. The investigator may 
attribute each toxicity event to MK-1454 alone, to pembrolizumab alone, or to the 
combination, and modify the dose according to Table 5, Table 6, and Table 7. If a dose 
modification for toxicity occurs with MK-1454, the dose may not be re-escalated to the dose 
that preceded the dose modification. If 1 (or more) treatment is held for toxicity, the schedule 
for restarting the agents should correspond with the next treatment cycle once the toxicity is 
resolved.
Holding of 1 treatment and not the other treatment is appropriate if, in the opinion of the 
investigator, the toxicity is clearly related to one of the study interventions. For example, in 
the combination arm (Arm 1), if MK-1454 is held due to an AE attributed to it, then 
pembrolizumab may continue to be administered. Appropriate documentation is required 
with regard to which treatment the investigator is attributing the AE. If, in the opinion of the 
investigator, the toxicity is related to the combination of 2 treatments, then both treatments
should be held according to recommended dose modifications.
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Participants may have only 1 dose modification of MK-1454 throughout the course of the 
study. If further toxicity occurs or the criteria for resuming treatment are not met, the 
participant must be discontinued from MK-1454. If a participant experiences several 
toxicities and there are conflicting recommendations, follow the most conservative 
recommendation.
Exceptional circumstances to following the dose modification tables below may be 
considered after consultation with the Sponsor.
6.6.1.1
Dose Modification for MK-1454
Guidelines for dose modification and/or treatment discontinuation for drug-related injection 
site reactions and for CRS AEs are provided in Table 5 and Table 6, respectively.
The investigator should first assess an AE to determine the CTCAE Version 5.0 severity 
grade. For AEs that are ≤Grade 2, the decision to hold treatment is per medical assessment 
by the investigator. Once the AE has resolved to Grade 0 or 1, treatment with MK-1454 can 
be restarted. If the AE persists, discuss with the Sponsor with regard to selecting a different 
injection site or discontinuation. MK-1454 should be discontinued permanently following a 
severe or life-threatening AE.
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last intervention, 
MK-1454 should be discontinued after consultation with the Sponsor.
With investigator and Sponsor agreement, participants with a laboratory AE still at Grade 2 
after 12 weeks may continue intervention in the study only if asymptomatic and controlled.
After any Grade 4 drug-related AE, participants should not restart study intervention without 
consultation with the Sponsor (Toxicity must have resolved to Grade 0-1 or baseline prior to 
restarting).
Pembrolizumab treatment will be modified for the AEs described in Section 6.6.1.4.
6.6.1.1.1
Guidelines for Management of Intratumoral Injection Site Reactions
Guidelines for management of injection site reaction from intratumoral injection of MK-1454 
are detailed in Table 5.
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Table 5
Intratumoral Injection Site Reaction Management Guidelines
NCI CTCAE Grade
MK-1454 Dose Modification
Treatment
Grade 1
Tenderness with or without 
associated symptoms (eg, warmth, 
erythema, itching)
No dose reduction warranted.
Observe. Dose to be held per 
medical assessment of the 
investigator.
Analgesia as needed.
Grade 2
Pain; lipodystrophy; edema; 
phlebitis  
Per medical assessment of the 
investigator:

Consider holding dose until 
resolution to Grade 1 or baseline.

Consider decreasing dose of IT 
MK-1454 to
 and limit 
injections to 
mum of 
2 lesions per study visit. 

If AE persists, discuss 
continuation with Sponsor.
Observe. Local care to injection 
site.
Analgesia as needed.
Consider injection into a different 
lesion, if available.
Grade 3
Ulceration or necrosis; severe 
tissue damage; operative 
intervention indicated

Hold dose until resolution to 
Grade 1 or Baseline. 

Decrease dose of IT MK-1454 to 
and limit injections to a 
maximum of 2 lesions per study 
visit.

If AE persists, discuss 
continuation with Sponsor.
Wound care with consultation 
from institutional wound care 
specialist.
Analgesia as needed.
Consider injection into a different 
lesion, if available.
Grade 4
Life-threatening consequences; 
urgent intervention indicated

Permanently discontinue IT 
MK-1454 treatment.
Aggressive wound care with 
surgical consultation. 
Analgesia as needed.
AE adverse events; CTCAE Common Terminology Criteria for Adverse Events (Version 5.0); IT intratumoral; 
NCI National Cancer Institute.
6.6.1.1.2
Treatment for Cytokine Release Syndrome
CRS is defined in CTCAE Version 5.0 as a disorder characterized by nausea, headache, 
tachycardia, hypotension, rash, and shortness of breath. CRS occurs when lymphocytes 
(B cells, T cells, and/or natural killer cells) and/or myeloid cells (macrophages, dendritic 
cells, and monocytes) become activated and release inflammatory cytokines [Lee, D. W., et 
al 2014]. In addition to the symptomatology defined under CTCAE, CRS may present with 
fever, chills, myalgias, and malaise. Table 6 shows treatment guidelines for participants who 
experience CRS. 
CCI
CCI
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Table 6
Cytokine Release Syndrome Treatment Guidelines
NCI CTCAE Grade
MK-1454 Dose Modification
Treatment
Premedication at
Subsequent Dosing
Grade 1
Mild reaction: Therapy interruption 
not indicated. Intervention not 
indicated.
No dose reduction warranted.
Increase monitoring of vital signs and 
oxygen saturation, as medically 
indicated, until the participant is deemed 
medically stable, in the opinion of the 
investigator.
None.
Grade 2
Therapy interruption indicated but 
responds promptly to symptomatic 
treatment (eg, NSAIDs, narcotics, IV 
fluids). Prophylactic medications 
indicated for ≤24 hours.
Per medical assessment of the 
investigator:
Consider holding dose until 
resolution to Grade 1 or baseline.
Consider decreasing dose of IT MK-
1454 to
and limit injections 
to a maximum of 2 lesions per study 
visit. 
If AE persists, discuss continuation 
with Sponsor.
Increase monitoring of vital signs and 
oxygen saturation, as medically 
indicated, until the participant is deemed 
medically stable, in the opinion of the 
investigator.
Additional appropriate medical therapy 
may include, but is not limited to:
IV fluids
NSAIDs
Acetaminophen
Narcotics
Oxygen
Perform fever workup to exclude 
infectious etiologies; treat neutropenia if 
present.
Participant may be premedicated 
with acetaminophen 1.5 hours 
(± 30 minutes) prior to study 
intervention administration 500 
to 1000 mg po (or equivalent 
dose of antipyretic).
CCI
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NCI CTCAE Grade
MK-1454 Dose Modification
Treatment
Premedication at
Subsequent Dosing
Grade 3
Prolonged (eg, not rapidly responsive 
to symptomatic medication); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for clinical sequelae (eg, 
renal impairment, pulmonary 
infiltrates).
Hold dose until resolution to 
Grade 1 or baseline. 
Decrease dose of IT MK-1454 to 
and limit injections to a 
maximum of 2 lesions per study 
visit.
If AE persists, discuss continuation 
with Sponsor.
Additional appropriate medical therapy 
may include, but is not limited to:
IV fluids
NSAIDS
Acetaminophen
Narcotics
Oxygen
Vasopressors
Corticosteroids
Anti-IL6 (eg, tocilizumab)
Empiric antibiotics 
Participants with ≥Grade 3 CRS need to 
be monitored very closely, likely in an 
intensive care setting.
For Grade 3 CRS, discuss with 
Sponsor prior to restart of study 
intervention. Upon approval by 
Sponsor, MK-1454 may be 
restarted at
after AE 
resolves back to baseline or to 
Grade 1. 
Participant may be premedicated 
1.5 hours(± 30 minutes) prior to 
study intervention administration 
with acetaminophen 500 to 
1000 mg po (or equivalent dose 
of antipyretic).
Grade 4
Life-threatening consequences; 
pressor or ventilatory support 
indicated.
Permanently discontinue IT MK 
1454 treatment.
Additional appropriate medical therapy 
may include, but is not limited to:
IV fluids
NSAIDs
Acetaminophen
Narcotics
Oxygen
Vasopressors
Corticosteroids
Anti-IL6 (eg, tocilizumab)
Empiric antibiotics 
Participants with ≥Grade 3 CRS need to 
be monitored very closely, likely in an 
intensive care setting.
Permanently discontinue study 
intervention in participants who 
develop Grade 4 CRS.
AE adverse events; CRS cytokine release syndrome; CTCAE Common Terminology Criteria for Adverse Events (Version 5.0); IT intratumoral; IV intravenous; NCI National 
Cancer Institute; NSAID nonsteroidal anti inflammatory drug; po orally.
CCI
CCI
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6.6.1.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 7.
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Table 7
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin 
if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Add prophylactic antibiotics for 
opportunistic infections
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate 
corticosteroid treatment
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood 
or mucus in stool with or without fever) and of 
bowel perforation (ie, peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids. 
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST or ALT 
Elevation or 
Increased Bilirubin
Grade 2 a
Withhold
Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
Grade 3 b or 4 c
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM or 
Hyperglycemia
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d
Initiate insulin replacement 
therapy for participants with 
T1DM
Administer antihyperglycemic 
in participants with 
hyperglycemia
Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
Administer corticosteroids and 
initiate hormonal replacements 
as clinically indicated
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
Hyperthyroidism
Grade 2
Continue
Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
· Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue d
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2, 3 or 4
Continue
Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of 
care
Monitor for signs and symptoms of thyroid 
disorders
Nephritis:
grading according 
to increased 
creatinine or acute 
kidney injury
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
or exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
All Other irAEs
Persistent Grade 2
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
or exclude other causes
Grade 3
Withhold or 
discontinue based on 
the event e
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or IO 
Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AE(s) adverse event(s); ALT  alanine aminotransferase; AST aspartate aminotransferase; CTCAE Common Terminology Criteria for Adverse Events; DRESS Drug Rash 
with Eosinophilia and Systemic Symptom; GI gastrointestinal; IO immuno oncology; ir immune related; IV intravenous; SJS Stevens Johnson Syndrome; T1DM type 1 
diabetes mellitus; TEN Toxic Epidermal Necrolysis; ULN upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if 
baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 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 intervention treatment
Participant may be 
premedicated 1.5 h (± 30 
minutes) prior to infusion of 
pembrolizumab with:
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine).
Acetaminophen 500 1000 mg 
po (or equivalent dose of 
analgesic).
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life threatening; pressor or 
ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy may include but 
is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs, as medically indicated,
until the participant is deemed medically stable, in the 
opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be used 
immediately.
Participant is permanently discontinued from further 
study intervention treatment.
No subsequent dosing.
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
CTCAE  Common Terminology Criteria for Adverse Events (Version 5.0); h  hours; IV  intravenous; NCI  National Cancer Institute; 
NSAID  nonsteroidal anti inflammatory drug; po  orally.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug 
administration.
For further information, please refer to the CTCAE Version 5.0 at http://ctep.cancer.gov
6.6.1.2.1
Other Allowed Dose Interruption(s) for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs, such as 
medical/surgical events or logistical reasons not related to study intervention. Participants 
should be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption is to be documented in the 
participant’s study record.
6.7
Intervention After the End of the Study
There is no study-specified intervention 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.
6.9
Standard Policies
Study site personnel will have access to a central electronic treatment 
allocation/randomization system (IRT system) to allocate subjects, to assign treatment to 
subjects and to manage the distribution of clinical supplies. Each person accessing the IRT 
system must be assigned an individual unique PIN. They must use only their assigned PIN to 
access the system, and they must not share their assigned PIN with anyone.
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 8.1.9, or if available, Protocol Clarification Letter.
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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 interrupts study intervention administration for more than 12 consecutive 
weeks. 
•
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).
•
Progression or recurrence of any malignancy, or any occurrence of another malignancy 
that requires active treatment.
•
Any study-intervention-related toxicity specified as a reason for permanent 
discontinuation in the guidelines for dose modification due to AEs in Section 6.6.
•
Intercurrent illness other than another malignancy, as noted above, that prevents further 
administration of treatment.
•
Investigator’s decision to discontinue treatment.
•
Completion of 35 treatments with pembrolizumab.
Note: 35 cycles (approximately 2 years) are calculated from the first dose.
Side effects and/or concomitant medications required for treatment of HIV and/or its 
complications that are incompatible with continued study treatment (Exceptions are 
permissible but should be discussed with the Sponsor.).
For participants who are discontinued from study intervention but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
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7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits. 
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. 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.
8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA. 
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of study 
site personnel responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
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•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be utilized for screening or baseline 
purposes provided the procedure met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented consent from each potential participant or each participant’s legally 
acceptable representative prior to participating in a clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
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 ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s dated signature or by the participant’s legally acceptable 
representative’s dated signature.
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The participant or his/her legally acceptable representative will be asked to sign consent at 
the point of initial radiographic disease progression.
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 FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention
randomization, site personnel will add the treatment/randomization number to the participant 
identification card.
The participant 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 as current 
disease details and not listed as medical history.
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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 administration of the first dose of study medication. Details regarding 
prior treatments for head and neck cancer will be recorded separately.
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 ECIs should be recorded, as defined in 
Section 8.4.
All new anticancer therapy initiated after the study start must be recorded in the eCRF. If a 
participant initiates another anticancer therapy other than the assigned study intervention(s), 
the study intervention(s) should be discontinued, and the participant will move into the 
Survival Follow-up Phase. If a participant initiates a new anticancer therapy within 30 days 
after the last dose of the study intervention, the 30-day Safety Follow-up Visit is to occur 
before administration of 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 randomization. Each participant 
will be assigned only 1 screening number. Screening numbers must not be re-used for 
different participants.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment randomization. Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
For infusion:
Pembrolizumab 200 mg will be administered in 30 minutes, with a window of -5 minutes and 
+10 minutes, as an IV infusion on Day 1 of each 21-day cycle. Do not administer 
pembrolizumab as an IV push nor as a bolus injection. Administration of study medication 
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will be monitored by the investigator and/or study staff. The total volume of study 
intervention infused will be compared to the total volume prepared to determine compliance 
with each dose administered. Please refer to the pembrolizumab (MK-3475) Pharmacy 
Manual. 
For IT injection:
Refer to Section 6 for MK-1454 dose and treatment details, and to the SoA (Section 1.3) for 
timing of IT injections. Guidelines for prioritization of lesions for IT injection are provided 
in Appendix 8.
8.1.8.1
Timing of Dose Administration
See the SoA in Section 1.3.
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 as outlined in 
the SoA and Section 8.10.3.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the End of Treatment/Discontinuation 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 8.4.3.
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 investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor using 
the designated mailbox (clinical.specimen.management@MSD.com). Subsequently, the 
participant's consent for FBR will be withdrawn. A letter will be sent from the Sponsor to the 
investigator confirming the withdrawal. It is the responsibility of the investigator to inform 
the participant of completion of withdrawal. Any analyses in progress at the time of request 
for withdrawal or already performed prior to the request being received by the Sponsor will 
continue to be used as part of the overall research study data and results. No new analyses 
would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
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8.1.11
Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
8.2
Efficacy/Immunogenicity Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Tumor imaging should be acquired by CT (strongly preferred). MRI should be used when CT 
is contraindicated or for imaging of the brain. The same imaging technique, ie, modality and 
use of contrast, should be used for a participant throughout the study to optimize the 
visualization of existing and new tumor burden. Required anatomical images, as well as the 
process for image collection and transmission to the iCRO, can be found in the Site Imaging 
Manual.
8.2.2
Initial Tumor Imaging
The process for image collection and transmission to the central vendor can be found in the 
Site Imaging Manual. Tumor imaging may be performed by CT (preferred) or MRI; 
however, the same imaging technique should be used on a participant throughout the study. 
CT scan is the more commonly used modality and is preferred for the majority of subjects. 
An MRI can be utilized, if clinically appropriate. 
Imaging should include the head and neck, chest, and abdomen at all timepoints specified in 
the Study Flow Chart. Imaging of the pelvis is optional. For an individual participant, 
imaging should be consistent at all timepoints, (ie, follow-up imaging should cover the same 
areas as the baseline area, using the same imaging modality).
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
allocation. The screening imaging must be submitted to the iCRO for confirmation of 
measurable disease per RECIST 1.1 for eligibility prior to randomization. Tumor imaging 
performed as part of routine clinical management is acceptable for use as screening tumor 
imaging if they are of diagnostic quality and performed within 28 days prior to the date of 
randomization.
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 was used for prior 
imaging) for at least 4 weeks prior to the first dose of study intervention. Any neurologic 
symptoms must have returned to baseline, and participants must have no evidence of new or 
enlarging brain metastases and have not used steroids for brain metastases for at least 14 days 
prior to study initiation, as per local site assessment. This exception does not include 
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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 6 weeks (42-49 days) from the 
date of first dose. Subsequent tumor imaging should be performed every 6 weeks (42 days 
±7 days) (or more frequently if clinically indicated). After 1 year, participants who remain on 
treatment will have imaging performed every 9 weeks (63 days ±7 days). Imaging timing 
should follow calendar days and should not be adjusted for delays in cycle starts. Imaging 
should continue to be performed until disease progression is identified by the investigator, 
the start of new anticancer treatment, withdrawal of consent, or death, or notification by the 
Sponsor, whichever occurs first. All supplemental imaging must be submitted to the iCRO.
Objective response should be confirmed by a repeat imaging assessment. Tumor imaging to 
confirm PR or CR should be performed at least 4 weeks after the first indication of response
is observed. Participants will then return to regularly scheduled imaging, starting with the 
next scheduled imaging time point. Participants who receive additional imaging for 
confirmation do not need to undergo the next scheduled tumor imaging if it is less than 
4 weeks later; tumor imaging may resume at the subsequent scheduled imaging time point. 
Note: Response does not typically need to be verified in real time by the BICR.
Per iRECIST (Section 8.2.5), 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. Exceptions are detailed in Section 8.2.5.
8.2.4
End of Treatment and Follow-up Tumor Imaging
In participants who discontinue study intervention, tumor imaging should be performed at the 
time of intervention discontinuation (±4-week window). If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at intervention 
discontinuation is not mandatory. For participants who discontinue study intervention due to 
documented disease progression, this is the final required tumor imaging if the investigator 
elects to not 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 6 weeks in Year 1 or 
9 weeks after Year 1). 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.
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8.2.5
iRECIST 1.1 Assessment of Disease
iRECIST is based on RECIST 1.1, but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by investigator/local radiology 
reviewers to assess tumor response and progression, and to make treatment decisions. When 
clinically stable, participants should not be discontinued until progression is confirmed by the 
investigator, working with local radiology, according to the rules outlined below. This 
allowance to continue treatment despite initial radiologic PD takes into account the 
observation that some participants can have a transient tumor flare in the first few months 
after the start of immunotherapy, and then experience subsequent disease response. These 
data will be collected and captured in the clinical database. 
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study 
intervention until repeat imaging is obtained using iRECIST for participant management (see 
Table 9 and Figure 3). This decision by the investigator should be based on the participant’s 
overall condition.
Clinical stability is defined as the following:
•
Absence of symptoms and signs indicating clinically significant progression of disease
•
No decline in ECOG performance status
•
No requirements for intensified management, including increased analgesia, radiation, or 
other palliative care
Any participant deemed clinically unstable should be discontinued from study intervention at 
site-assessed first radiologic evidence of PD and is not required to have repeat imaging for 
confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study intervention and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:
•
Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and ≥5 
mm from nadir
-
Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original RECIST 
1.1 terminology.
•
Unequivocal progression of nontarget lesion(s) identified at baseline
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•
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:
-
For target lesions, worsening is a further increase in the sum of diameters of ≥5 mm, 
compared to any prior iUPD time point
-
For nontarget lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the “unequivocal” 
standard of RECIST 1.1
-
For new lesions, worsening is any of these:
◦
An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD time 
point
◦
Visible growth of new nontarget lesions
◦
The appearance of additional new lesions
•
Any new factor appears that would have triggered PD by RECIST 1.1
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Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:
•
None of the progression-confirming factors identified above occurs AND
•
The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule. The 
assessment of the subsequent confirmation scan proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR if:
•
None of the progression-confirming factors identified above occurs, AND
•
The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudoprogression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study intervention may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
intervention. 
Note: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue 
treatment may be considered following consultation with the Sponsor. In this case, if study 
intervention is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3 and submitted to the central imaging vendor. 
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Detection of Progression at Visits after Pseudoprogression Resolves
After resolution of pseudoprogression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:
•
Target lesions
-
Sum of diameters reaches the PD threshold (20% and 5 mm increase from nadir) 
either for the first time, or after resolution of previous pseudoprogression. The nadir 
is always the smallest SOD seen during the entire study, either before or after an 
instance of pseudoprogression.
•
Nontarget lesions
-
If nontarget lesions have never shown unequivocal progression, their doing so for the 
first time results in iUPD
-
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
-
New lesions appear for the first time
-
Additional new lesions appear
-
Previously identified new target lesions show an increase of ≥5 mm in the new lesion 
sum of diameters, from the nadir value of that sum
-
Previously identified nontarget lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception: if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD. If any of the factors 
above indicate iUPD, the iUPD evaluation process repeats, just as on the first occurrence of 
iUPD.
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 per 
iRECIST
May continue study 
intervention at the 
local site 
investigator’s 
discretion and after 
obtaining participant’s 
consent 
Repeat imaging at 
4 to 8 weeks to 
confirm PD per 
physician 
discretion only
Discontinue treatment
Repeat tumor 
imaging confirms 
PD (iCPD) by 
iRECIST per 
local assessment
No additional 
imaging required
Discontinue treatment 
(exception is possible 
upon consultation 
with Sponsor)
No additional 
imaging required
Not applicable
Repeat tumor 
imaging shows 
iUPD by 
iRECIST, per 
local assessment
Repeat imaging at 
4 to 8 weeks to 
confirm PD 
Continue study 
intervention at the 
local site 
investigator’s 
discretion
No additional 
imaging required
Discontinue treatment
Repeat tumor 
imaging shows 
iSD, iPR, or iCR 
by iRECIST per 
local assessment
Continue 
regularly 
scheduled 
imaging 
assessments
Continue study 
intervention at the 
local site 
investigator’s 
discretion
No additional 
imaging required
Discontinue treatment
iCPD  immune confirmed progressive disease; iCR  immune complete response; iSD  immune stable disease; iRECIST 
 immune related response evaluation criteria in solid tumors; iUPD  immune unconfirmed progressive disease; PD  
progressive disease; PFS  progression free survival; iPR  immune partial response.
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Figure 3
Imaging and Treatment for Clinically Stable Participants after First Radiologic 
Evidence of PD Assessed by the Investigator
iCRO = imaging contract research organization; iCR = immune complete response; iPR = immune partial 
response; iSD = immune stable disease; iUPD = immune unconfirmed progressive disease; PD = progressive 
disease; iRECIST = Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics; RECIST 
= Response Evaluation Criteria in Solid Tumors
8.2.6
itRECIST
itRECIST is a response assessment that is tailored to intratumoral immunotherapy, is aligned 
with RECIST 1.1 overall response assessment [Goldmacher, G. V., et al 2020], and is further 
described in Section 10.10. 
itRECIST
•
provides a guidance on baseline categorization of target and nontarget lesions (Figure 5)
•
provides guidance on recategorization of lesions during therapy (Figure 6)
•
allows for separate response assessment in injected and noninjected lesions (Figure 7)
•
for injected lesions, provides an iterative response assessment process that adapts to 
changes in lesion selection for intratumoral immunotherapy (an example is provided in 
Figure 8)
•
provides guidelines on prioritization of lesion injection during the course of intratumoral 
immunotherapy (see Section 10.8)
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itRECIST supports standardized collection of data from intratumoral immunotherapy clinical 
studies to facilitate exploratory response analysis.
8.2.7
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG status (Appendix 9), prior to the 
administration of study intervention on Day 1 of each cycle at the timepoints identified in the 
SoA.
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood/tissue to be drawn/collected over the course of the study 
(from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Procedures 
Manual.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
Physical examinations (full or directed) will be conducted by an investigator or medically 
qualified designee (consistent with local requirements) as per institutional standard. The time 
points for full physical examinations are described in Section 1.3. 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the screening period. Height and weight will also be measured and recorded. Clinically 
significant abnormal findings should be recorded as medical history. After the first dose of 
study intervention, new clinically significant abnormal findings should be recorded as AEs.
8.3.1.2
Directed Physical Examination
For cycles that do not required a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to study intervention administration. Weight will also be measured and 
recorded. 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 to the 
administration of each dose of study intervention and during the follow-up period as 
specified in the SoA. Vital signs include heart rate, respiratory rate, 02 saturation, blood 
pressure, and temperature.
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8.3.3
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the SoA. Clinically significant abnormal findings should be recorded as 
medical history. Additional ECGs may be performed as clinically necessary.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the 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 7 days prior to the first dose of 
study intervention. An exception is hepatitis and thyroid serologies, which may be performed 
within 28 days prior to first dose. After Cycle 1, predose laboratory safety tests can be 
conducted up to 72 hours prior to dosing unless otherwise noted on the flow charts.
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of study intervention. Unresolved 
abnormal laboratory values that are drug-related AEs should be followed until resolution. 
Laboratory tests do not need to be repeated after the EOT 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 24 hours of the 
first dose of study medication on C1D1 and 30 days posttreatment. Additional pregnancy 
testing can be conducted if required by local regulations or if clinically indicated. 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. Refer to Appendix 7 for country-specific requirements.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
AEs, 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 AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3.
The investigator, who is a qualified physician, will assess events that meet the definition of 
an AE or SAE as well as other reportable safety events with respect to seriousness, 
intensity/toxicity and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed
but before intervention randomization must be reported by the investigator if the participant
is receiving placebo run-in or other run-in treatment, if the event cause the participant to be
excluded from the study, or is the result of a protocol-specified intervention, including but
not limited to washout or discontinuation of usual therapy, diet, or a procedure.
•
All AEs from the time of intervention randomization through 30 days following cessation
of study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention randomization through 90
days following cessation of study intervention or 30 days following cessation of study
intervention if the participant initiates new anticancer therapy, whichever is earlier, must
be reported by the investigator.
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•
All pregnancies and exposure during breastfeeding, from the time of intervention
randomization through 120 days following cessation of study intervention, or 30 days 
following cessation of study intervention if the participant initiates new anticancer
therapy must be reported by the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside of
the time period specified above must be reported immediately to the Sponsor if the event
is considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the Sponsor.
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.
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
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Nonserious 
Adverse Event 
(NSAE) 
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 
hours of 
learning of 
event
Pregnancy/
Lactation 
Exposure
Report if:
- due to intervention
- causes exclusion
Report all
Previously reported –
Follow to completion/
termination; report 
outcome
Within 24 
hours of 
learning of 
event
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Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the Protocol-
specified Follow-up 
Period
Time Frame 
to Report 
Event and 
Follow-up 
Information 
to Sponsor:
Event of Clinical 
Interest (ECI) 
(require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential drug-
induced liver injury 
(DILI)
- require regulatory 
reporting
Not required
Within 24 
hours of 
learning of 
event
Event of Clinical 
Interest (do not 
require regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 
calendar days 
of learning of 
event
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events,
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 3.
8.4.4
Regulatory Reporting Requirements for SAE
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is essential 
so that legal obligations and ethical responsibilities towards the safety of participants and the 
safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to investigators as necessary.
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An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints, as outlined in this section, will not be reported to the Sponsor, as 
described in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint that upon review is 
not progression of the cancer under study will be forwarded to Global Pharmacovigilance as 
an SAE within 24 hours of determination that the event is not progression of the cancer under 
study.
8.4.7
Events of Clinical Interest
Selected nonserious and SAEs are also known as ECIs and must be reported to the Sponsor. 
Events of clinical interest for this study include: 
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. An elevated AST or ALT lab value that is greater than or equal to 3 × ULN and an 
elevated total bilirubin lab value that is greater than or equal to 2 × ULN and, at the same 
time, an alkaline phosphatase lab value that is less than 2 × ULN, as determined by way 
of protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
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assessment and follow-up of these criteria can be found in the Investigator Study File 
Binder (or equivalent). 
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8.10
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.10.1
Screening
Approximately 28 days prior to treatment randomization, potential participants will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 5. 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria are met.
Documented informed consent must be obtained prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant providing documented 
informed consent as part of routine management are acceptable in lieu of a screening test if 
performed within the specified time frame. Screening procedures are to be completed within 
28 days prior to the first dose of study intervention except for the following:
•
Laboratory tests are to be performed within 7 days prior to the first dose of study 
intervention. An exception is hepatitis and thyroid function testing, which may be done 
up to 28 days prior to the first dose of study intervention.
•
Evaluation of ECOG is to be performed within 7 days prior to the first dose of study 
intervention.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 24 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). Refer to Appendix 7 for country-specific requirements.
•
Tumor tissue testing for PD-L1 status (all participants) and HPV status (oropharyngeal 
cancer participants) are required for stratification prior to randomization. The sample 
should be sent to the central laboratory at least 14 days prior to randomization, unless 
testing locally (see Procedures Manual for details regarding tumor tissue collection). If 
testing locally, or reporting HPV status by history, tumor p16 expression must be 
evaluated by assessment of IHC analysis with CINtec® p16 Histology assay (Ventana 
Medical Systems Inc., Tucson AZ) using the “Benchmark Ultra” autostainer (Ventana, 
Tucson, AZ) and standard protocol. 
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8.10.2
Treatment Period Visit
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.1.
8.10.3
Discontinued Participants Continuing to be Monitored in the Study
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional Safety Follow-up procedures should be performed. Visit requirements are 
outlined in Section 1.3. Additional details regarding participant withdrawal and 
discontinuation are presented in Section 7.
8.10.3.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
All AEs that occur prior to the Safety Follow-up Visit should be recorded up to 30 days 
following EOT.
8.10.3.2
Imaging Follow-up Visits
Participants who discontinue study intervention for reasons other than documented PD 
should continue with imaging assessments per the protocol-defined schedule until: (1) PD is 
assessed by the investigator, (2) initiation of a new anticancer treatment, (3) death, 
(4) withdrawal of consent, or (5) study conclusion or early termination, whichever occurs 
first.
8.10.3.3
Survival Follow-up Visits
Participants who experience confirmed PD or start a new anticancer therapy will move into 
the Survival Follow-up Phase and should be contacted by telephone every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The Sponsor may request survival status be assessed at additional time points during the 
course of the study. For example, these additional time points may be requested prior to but 
not limited to an efficacy IA for internal decision-making and/or final analysis. All 
participants who are not known to have died prior to the request for these additional survival 
status time points will be contacted at that time.
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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 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 CSR for the study.
9.1
Statistical Analysis Plan Summary
Key elements of the SAP are summarized. The comprehensive plan is provided in 
Sections 9.2 through 9.12.
Study Design Overview
This is a randomized, active-controlled, parallel group, multicenter, open-
label, Phase 2 study of IT MK-1454 in combination with pembrolizumab IV 
versus pembrolizumab IV monotherapy in participants with a histologically or 
cytologically confirmed diagnosis of metastatic, or unresectable, recurrent
HNSCC with a tumor CPS ≥1 as first-line therapy.
Intervention Assignment
Approximately 200 participants will be randomized in a 1:1 ratio to Arm 1 (IT 
MK-1454 plus pembrolizumab IV) and Arm 2 (pembrolizumab IV). The 
stratification factors are PD-L1 expression level defined by CPS (≥1 to <20 vs 
≥20), ECOG performance status (0 versus 1) and HPV status (positive, 
negative for participants with oropharyngeal cancer).
Analysis Populations
Efficacy (Primary and Secondary): ITT 
Safety (Secondary): APaT
Primary Endpoint(s)
OR is a confirmed CR or PR) by RECIST 1.1 as assessed by BICR.
Secondary Endpoints

PFS by RECIST 1.1 as assessed by BICR

DOR by RECIST 1.1 as assessed by BICR

OS

AEs

Discontinuing study intervention due to AE
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Statistical Methods for Key 
Efficacy Analyses
The dual primary hypotheses comparing Arm 1 to Arm 2 for participants with 
CPS ≥1 and CPS ≥20 with regard to ORR will be evaluated using the stratified 
Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985]. The 
difference in ORR will be estimated using the stratified Miettinen and 
Nurminen method with strata weighting by sample size.
Statistical Methods for Key 
Safety Analyses
The analysis of safety results will follow a tiered approach for the comparison 
of Arm 1 versus Arm 2. The tiers differ with respect to the analyses that will be 
performed. There is no Tier 1 safety endpoint for this study. Tier 2 parameters 
will be assessed via point estimates with 95% CIs provided for between-arm 
comparisons; only point estimates by treatment arm are provided for Tier 3 
safety parameters. The 95% CIs for the between-treatment differences in 
percentages will be provided using the Miettinen and Nurminen method
[Miettinen, O. and Nurminen, M. 1985].
Interim Analyses
Multiplicity
The overall type I error rate for the primary endpoint (OR)
will be strongly controlled at α =2.5% (one-sided) [Chen, 
C., et al 2018].
α=1% 
(one-sided) will be allocated to ORR in participants with CPS ≥1 and α=1.5% 
(one-sided) will be allocated to ORR in participants with CPS ≥20. The 
graphical approach of Maurer and Bretz [Maurer, W. and Bretz, F. 2013] will be 
applied to reallocate alpha between the dual primary hypotheses if either 
primary hypothesis is rejected. 
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Sample Size and Power
The overall sample size will be approximately
200,
it provides approximate 84.0% power to detect a 21% 
difference in ORR (40% in Arm 1 versus 19% in Arm 2) at the type I error of 
1% (one-sided) for participants with CPS ≥1. Based on MK-3475 KN048 data, 
the prevalence rate of the participants with CPS≥20 among participants with 
CPS ≥1 is assumed to be 50%. With 50 participants per arm, the study has 
approximately 86.3% power to detect a 31% difference in ORR (55% in Arm 1 
versus 24% in Arm 2) at the type I error of 1.5% (one-sided) for participants 
with CPS ≥20. It has approximately 91.5% power to show that Arm 1 is 
superior to Arm 2 in at least 1 population (participants with CPS ≥1 or 
participants with CPS ≥20) at an overall type I error of 2.5% (one-sided). 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The Sponsor will generate the randomized allocation schedule(s) for study treatment 
assignment for this protocol, and the randomization will be implemented in IRT.
Although the study is an open-label study, analyses or summaries generated by randomized 
treatment assignment, and actual treatment received will be limited and documented. Further 
documentation will be provided in the sSAP. In addition, independent radiologist(s) will 
perform the central imaging review without knowledge of treatment assignments.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3.
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9.4
Analysis Endpoints
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Primary Efficacy Endpoint

OR: a confirmed CR or PR per RECIST 1.1 based on BICR. ORR is the proportion of 
participants with objective response.
Secondary Efficacy Endpoints

PFS: time from randomization to the first documented PD per RECIST 1.1 based on 
BICR or death from any cause, whichever occurs first. See Section 9.6.1 for the 
definition of censoring.

DOR: time from the first documented evidence of CR or PR until PD per RECIST 1.1 
as assessed by BICR or death due to any cause, whichever occurs first, in participants 
demonstrating CR or PR.

OS: time from randomization to the date of death due to any cause.
9.4.2
Safety Endpoints
Safety endpoint is the number/proportion of participants with AEs, and who discontinue 
study treatment due to AEs. In addition, safety and tolerability will be assessed by clinical 
review of all relevant parameters including AEs, laboratory tests, and vital signs.
A description of safety measures is provided in Section 8.3 Safety Assessments.
9.5
Analysis Populations
9.5.1
Efficacy Analysis Populations
The analyses of efficacy endpoints (ORR, PFS, and OS) are based on the ITT population. All 
randomized participants will be included in this population. Participants will be analyzed in 
the treatment arm to which they are randomized. For the analysis of DOR, only participants 
with a CR or PR in the ITT population will be included.
A supportive approach using a modified ITT population may be performed for the efficacy 
endpoints. The modified ITT population consists of all randomized participants who receive 
scheduled treatments without substantial dose interruption as defined in the sSAP. These
details will be documented in the sSAP.
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9.5.2
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all randomized participants who receive at least 1 dose of study 
treatment. Participants will be analyzed in the treatment arm corresponding to the study 
treatment they actually receive. For most participants, this will be the treatment group to 
which they are randomized. Participants who receive incorrect study treatment for the entire 
treatment period will be included in the treatment arm corresponding to the study treatment 
actually received. Any participant who receives incorrect study medication for 1 cycle, but 
receives the correct treatment for all other cycles, will be analyzed according to the correct 
treatment group, and a narrative will be provided for any events that occur during the cycle 
for which the participant is incorrectly dosed.
At least 1 laboratory or vital sign measurement obtained 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.
9.6
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
Efficacy results that will be deemed to be statistically significant after consideration of the 
Type I error control strategy are described in Section 9.8. Nominal p-values will be computed 
for other efficacy analyses but should be interpreted with caution due to potential issues of 
multiplicity. For the stratified analyses, if the number of participants or events in a cell is 
small, the stratification factor(s) may be removed.
9.6.1.1
Objective Response
The stratified Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] will 
be used for the ORR comparison (Arm 1 vs Arm 2) in participants with CPS ≥1 and in 
participants with CPS ≥20. The difference in ORR, 95% CI and p-values from the stratified 
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Miettinen and Nurminen method [Miettinen, O. and Nurminen, M. 1985] with strata 
weighting by sample size will be reported. The stratification factor used for randomization 
(Section 6.3.2) will be applied to the analysis. In the IA for continuing enrollment 
decision-making, the stratification will be based on PD-L1 CPS (≥1 to <20 vs ≥20). 
Sensitivity analyses will be performed for comparison of ORR based on the investigator’s 
assessment.
9.6.1.2
Progression-free Survival
The nonparametric Kaplan-Meier method [Kaplan, E. L. 1958] will be used to estimate the 
PFS curve for each treatment group in participants with CPS ≥1 and in participants with CPS
≥20. The treatment difference in PFS will be assessed by the stratified log-rank test. A 
stratified Cox proportional hazard model [Cox, D. R. 1972] with Efron’s method [Efron, B. 
1977] of tie handling will be used to assess the magnitude of the treatment difference (ie, the 
HR) between the treatment arms. The HR and its 95% CI from the stratified Cox model with 
Efron’s method of tie handling and with a single treatment covariate will be reported. The 
stratification factor used for randomization (Section 6.3.2) will be applied to both the 
stratified log-rank test and the stratified Cox model. 
Because disease progression is assessed periodically, PD can occur any time in the interval 
between the last assessment when PD is not documented and the assessment when PD is 
documented. For the primary analysis, for participants with PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is 
objectively documented per RECIST 1.1, based on BICR. Death is always considered as a 
confirmed PD event. Participants who do not experience a PFS event will be censored at the 
last disease assessment. Sensitivity analyses will be performed for comparison of PFS based 
on the investigator’s assessment.
In order to evaluate the robustness of the PFS endpoint per RECIST 1.1 by BICR, 1 primary 
and 2 sensitivity analyses with a different set of censoring rules will be performed. For the 
primary analysis, if the events (PD or death) are immediately after more than 1 missed 
disease assessment, the data are censored at the last disease assessment prior to the missed 
visits. Also, data after new anticancer therapy are censored at the last disease assessment 
prior to the initiation of new anticancer therapy. The first sensitivity analysis follows the ITT
principle. That is, PDs/deaths are counted as events regardless of missed study visits or 
initiation of new anticancer therapy. The second sensitivity analysis considers initiation of 
new anticancer treatment or discontinuation of treatment due to reasons other than CR to be a 
PD event for participants without documented PD or death. If a participant meets multiple 
criteria for censoring, the censoring criterion that occurs earliest will be applied. The 
censoring rules for primary and sensitivity analyses are summarized in Table 11.
In case there is an imbalance between the treatment groups on disease assessment schedules 
or censoring patterns, we may also perform a sensitivity analysis for PFS using interval 
censored data [Finkelstein, D. M. 1986], which modifies the Cox proportional hazard model 
for interval censored data. The interval will be constructed so that the left endpoint is the date 
of the last disease assessment without documented PD and the right endpoint is the date of 
documented PD or death, whichever occurs earlier.
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Table 11
Censoring Rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
PD or death documented 
after ≤1 missed disease 
assessment, and before 
new anticancer therapy, 
if any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
PD or death documented 
immediately after ≥2 
consecutive missed 
disease assessments or 
after new anticancer 
therapy, if any
Censored at last disease 
assessment prior to 
the earlier date of ≥2 
consecutive missed 
disease assessments and 
new anticancer therapy, if 
any
Progressed at date of 
documented PD or death
Progressed at date of 
documented PD or death
No PD and no death; 
new anticancer treatment 
is not initiated
Censored at last disease 
assessment 
Censored at last disease 
assessment 
Progressed at treatment 
discontinuation due to 
reasons other than CR; 
otherwise censored at 
last disease assessment if 
participant is still 
receiving study 
treatment or has 
completed study 
treatment
No PD and no death; 
new anticancer treatment 
is initiated
Censored at last disease 
assessment before new 
anticancer treatment 
Censored at last disease 
assessment
Progressed at date of 
new anticancer treatment
PD
progressive disease; PFS  progression free survival.
9.6.1.3
Overall Survival
The nonparametric Kaplan-Meier method [Kaplan, E. L. 1958] will be used to estimate the 
survival curves. The treatment difference in survival will be assessed by the stratified log-
rank test in participants with CPS ≥1 and in participants with CPS ≥20. A Cox proportional 
hazard model with Efron’s method [Efron, B. 1977] of tie handling will be used to assess the 
magnitude of the treatment difference (ie, the HR). The HR and its 95% CI from the Cox 
model with a single treatment covariate will be reported. The stratification factors used for 
randomization (Section 6.3.2) will be applied to both the stratified log-rank test and the 
stratified Cox model. Participants without documented death at the time of analysis will be 
censored at the date of last known contact. 
9.6.1.4
Duration of Response
For participants with a CR or PR, whichever occurs first, censoring rules for DOR are 
summarized in Table 12. DOR will be assessed using RECIST 1.1 by BICR.
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For each DOR analysis, a corresponding summary of the reasons for which responding 
participants are censored will also be provided. Responses in participants who are alive, have 
not progressed, have not initiated new anticancer treatment, and have not been determined to 
be lost to follow-up, and who have had a disease assessment within approximately 5 months 
of the data cutoff date, are considered ongoing at the time of analysis. If a participant meets 
multiple criteria for censoring, the censoring criterion that occurs earliest will be applied.
If the sample size permits, DOR will be summarized descriptively using Kaplan-Meier 
medians and quartiles. Only the subset of participants with a confirmed CR or PR will be 
included in this analysis. 
Table 12
Censoring Rules for Duration of Response
Situation
Date of Progression or Censoring
Outcome
No progression nor death, no new 
anticancer therapy initiated
Last adequate disease assessment
Censor
(non-event)
No progression nor death, new 
anticancer therapy initiated
Last adequate disease assessment before 
new anticancer therapy was initiated
Censor
(non-event)
Death or progression immediately after 
≥2 consecutive missed disease 
assessments or after new anticancer 
therapy, if any
Earlier date of last adequate disease 
assessment prior to ≥2 missed adequate 
disease assessments and new anticancer 
therapy, if any
Censor
(non-event)
Death or progression after ≤1 missed 
disease assessments and before new 
anticancer therapy, if any
PD or death
End of response
(Event)
PD progressive disease.
A missed disease assessment includes any assessment that is not obtained or is considered inadequate for evaluation of 
response.
9.6.1.5
Analysis Strategy for Key Efficacy Endpoints
Table 13 summarizes the analysis strategy for the primary and secondary efficacy endpoints.
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Table 13
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
OR/ORR (RECIST 
1.1by BICR)
Test and estimation:
Stratified Miettinen and 
Nurminen method.
ITT
Participants with missing data are 
considered nonresponders.
Secondary Analyses
PFS (RECIST 1.1 
by BICR)
Summary statistics using Kaplan-
Meier method
Estimation: stratified Cox model 
with Efron’s tie-handling method 
ITT
Censored according to rules in 
Table 11.
DOR (RECIST 1.1 
by BICR)
Summary statistics using Kaplan-
Meier method
All 
responders 
in ITT
Censored according to rules in 
Table 12.
OS 
Summary statistics using Kaplan-
Meier method
Estimation: stratified Cox model 
with Efron’s tie-handling method
ITT
Censored at last known alive date.
BICR
blinded independent central review; DOR
duration of response; ITT
intention to treat; ORR
objective 
response rate; OS
overall survival; PFS
progression free survival; RECIST 1.1
Response Evaluation Criteria in Solid 
Tumors Version 1; iRECIST modified RECIST 1.1 for immune based therapeutics.
Sensitivity analyses will be performed for ORR, PFS, and DOR using RECIST 1.1 and iRECIST based on investigator’s 
assessment.
9.6.2
Statistical Methods for Safety Analysis
There are no safety hypotheses for this study. Safety and tolerability will be assessed by 
clinical review of all relevant parameters, including AEs, laboratory tests, and vital signs. 
The analysis of safety results will follow a tiered approach (Table 14). The tiered approach 
will be used for the comparisons of Arm 1 versus Arm 2. The tiers differ with respect to the 
analyses that will be performed. AEs (specific terms as well as system organ class terms) and 
events in laboratory, vital sign, and ECG parameters are either prespecified as Tier 1 events 
or will be classified as belonging to Tier 2 or Tier 3 based on the percentage of events 
observed.
Tier 1 Events
Safety parameters or AEOSIs that are identified a priori constitute Tier 1 safety events that 
will be subject to inferential testing for statistical significance. 
AEOSIs that are immune-mediated or potentially immune-mediated are well documented and 
will be evaluated separately; however, these events have been characterized consistently 
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throughout the pembrolizumab clinical development program and determination of statistical 
significance is not expected to add value to the safety evaluation. Based on review of historic 
data from ongoing MK-1454 and pembrolizumab clinical studies, there are no known AEs 
associated with participants for which determination of a p-value is expected to impact the 
safety assessment. Therefore, there are no Tier 1 events for this protocol.
Tier 2 Events
Tier 2 events will be assessed via point estimates with 95% CIs provided for differences in 
the proportion of participants with events using the Miettinen and Nurminen method, an 
unconditional, asymptotic method [Miettinen, O. and Nurminen, M. 1985].
Membership in Tier 2 requires that at least 10% of participants in any treatment arm exhibit 
the event. The threshold of at least 10% was chosen because participants enrolled in this 
study are in critical condition and usually experience various AEs of similar types regardless 
of treatment, events reported less frequently than in 10% of participants would obscure the 
assessment of the overall safety profile and add little to the interpretation of potentially 
meaningful treatment differences. In addition, Grades 3 to 5 AEs (≥5% of participants in one 
of the treatment arms) and SAEs (≥5% of participants in one of the treatment arms) will be 
considered Tier 2 events. Because many 95% CIs may be provided without adjustment for 
multiplicity, the CIs should be regarded as a helpful descriptive measure to be used in safety 
review, not a formal method for assessing the statistical significance of the between treatment 
differences.
Tier 3 Events
Safety events that are not Tier 1 or Tier 2 events will be considered Tier 3 events. Only point 
estimates by treatment arm will be provided for Tier 3 safety parameters.
Continuous Safety Measures
For continuous measures such as changes from baseline in laboratory, vital sign, and ECG 
parameters, summary statistics for baseline, on-treatment, and change from baseline values 
will be provided by treatment arm in table format.
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Table 14
Analysis Strategy for Safety Parameters
Safety 
Tier
Safety Endpoint
95% CI for 
Treatment 
Comparison
Descriptive 
Statistics
Tier 2
Any AE (≥10% of participants in one of the treatment arms)
X
X
Any Grades 3 to 5 AE (≥5% of participants in one of the 
treatment arms)
X
X
Any serious AE (≥5% of participants in one of the treatment 
arms)
X
X
Tier 3
Any AE
X
Any change from baseline results (laboratory tests, vital 
signs, ECGs)
X
AE adverse event, CI confidence interval; ECG electrocardiogram
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics
The comparability of the treatment groups for each relevant demographic and baseline 
characteristic will be presented in tables and/or graphs. No statistical hypothesis tests will be 
performed on these characteristics. The number and percentage of participants randomized 
and the primary reason for discontinuation will be displayed. Demographic variables (such as 
age) and baseline characteristics will be summarized by treatment either by descriptive 
statistics or categorical tables.
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Based on MK-3475 KN048 data, the prevalence rate of the participants with CPS ≥20 among 
participants with CPS ≥1 is assumed to be 50%. Table 16 provides the power to claim
superior ORR of Arm 1 in participants with CPS ≥1 or CPS ≥20 if study continues to enroll 
up to approximately 200 participants. A study with 100 participants per arm provides 
approximate 84.0% power to detect a 21% difference in ORR (40% in Arm 1 vs 19% in Arm 
2) at the type I error of 1% (1-sided) for participants with CPS ≥1. With 50 participants per 
arm, the study has approximately 86.3% power to detect a 31% difference in ORR (55% in 
Arm 1 vs 24% in Arm 2) at the type I error of 1.5% (1-sided) for participants with CPS ≥20. 
It has approximately 91.5% power to show that Arm 1 is superior to Arm 2 in at least 1 
population (participants with CPS ≥1 or participants with CPS ≥20) at an overall type I error 
of 2.5% (one-sided). An observed ORR difference of approximately 15% (e.g., 34% vs. 
19%) in CPS ≥1 or 21% (eg, 45% vs 24%) in CPS≥20 is needed to achieve a positive ORR 
outcome. The powers to claim superior ORR of Arm 1 at the type I error of 2.5% (1-sided) 
are also provided in Table 16 when one of null hypotheses is rejected and the α allocated to 
that hypothesis is reallocated to the other hypothesis test.
Table 16
Power of ORR
in the Study (200 participants in 
total)
Hypothesis
Population
Alpha 
Level
(one-
sided)
True difference in ORR
(Arm 1 versus Arm 2)
Power
Power at study level
(at least one 
population win)
H1
CPS ≥1 
0.010
21%
84.0%
91.5%
0.025
21%
91.8%
H2
CPS ≥20
0.015
31%
86.3%
0.025
31%
90.4%
CPS combined positive scoring; H hypothesis; ORR objective response rate.
Assume true ORR of Arm 2 is 19% and 24% in participants with CPS ≥1 and CPS ≥20, respectively.
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9.10
Subgroup Analyses
To determine whether the treatment effect is consistent across various subgroups, the 
estimate of the between-group treatment effect (with a nominal 95% CI) for ORR, PFS and 
OS will be estimated within each category of each subgroup. The following are examples of 
classification variables:

Stratification factors
o
PD-L1 expression level (defined by CPS ≥1 to <20 vs CPS ≥20)
o
ECOG status (0 vs. 1)
o
HPV status as determined by p16 IHC (positive vs. negative) (for participants 
with oropharyngeal cancer only)

Age category (<65 vs ≥65 years)

Sex (female vs male)

Race (white vs non-white)

Region (North America [NAm] vs EU vs Rest of the World [ROW])

Smoking status (never vs former vs current)

Disease status (metastatic vs. unresectable, recurrent)
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9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in number of cycles or 
administrations as appropriate. Summary statistics will be provided on extent of exposure for 
the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH GCP), and also in accordance with the 
ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability 
to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if fraud, 
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scientific/research misconduct or serious GCP non compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval.  
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by 
law, only the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, and/or regulatory 
authorities will have access to confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
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IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time and labor intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information that would make the participant identifiable will not be transferred.
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
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10.1.4
Committees Structure
10.1.4.1
Stage Gate Review Committee
An internal Stage Gate Review Committee will review results of 
accumulative safety data for decision-making. Logistical details and review 
guidance will be provided in the Stage Gate Review Committee Charter.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA Clinical Trial Directive 2001/20/EC, 
the Sponsor of the study is solely responsible for determining whether the study and its 
results are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA Clinical Trial Directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA Clinical Trials Directive, or other locally mandated registries are that of 
the Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
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 
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accepted standards of GCP); and all applicable federal, state and local laws, rules and 
regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding data management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
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The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including 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. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 18 will be performed by the local laboratory. Laboratory 
samples, which cannot be processed locally, may be sent to the central laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Sections 5.1 and 5.2 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
•
Pregnancy testing:
- Pregnancy testing requirements for study inclusion are described in Section 5.1.
- Pregnancy testing (urine or serum as required by local regulations) should be 
conducted 120 days after the last dose of study intervention.
- Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the 
absence of pregnancy at any time during the participant's participation in the study.
Table 18
Protocol-required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine)a
Hemoglobin
Alkaline phosphatase
Glucose
FSH b
Platelet count
Alanine aminotransferase
Protein
T3 or FT3 c
WBC (total and 
differential)d
Aspartate aminotransferase
Specific gravity 
T4 or FT4 c
RBC
Bicarbonate or Carbon 
Dioxide
Microscopic exam, if 
abnormal results are 
noted
TSH
PT or INR
Calcium
Anti-HCV
aPTT or PTT
Chloride
HCV viral load
Serum Creatinine
HCV genotype
Creatinine clearance 
(measured or calculated)e
anti-HBs
GGT
HbsAg
Glucose
Anti-HBc (total and IgM)
Phosphorus
HBeAg
Potassium
anti-HBe
Sodium
Anti-HDV
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Hematology
Chemistry
Urinalysis
Other
Total bilirubin  
HPV viral loadf
Direct bilirubin
Total protein
BUN or Ureag
LDH
aPTT activated partial thromboplastin time; BUN blood urea nitrogen; FT3 free triiodothyronine; FT4 free thyroxine; 
FSH follicle stimulating hormone; GFR  glomerular filtration rate; GGT gamma glutamyl transpeptidase; HBc hepatitis 
B core antigen; HBeAg hepatitis B e antigen; HBsAg hepatitis B surface antigen; HCV hepatitis C virus; HDV hepatitis 
D virus; HPV human papilloma virus; INR International Normalized Ratio; LDH lactic dehydrogenase; PT prothrombin 
time; PTT partial thromboplastin time; RBC red blood count; T3 total triiodothyronine; T4 total thyroxine; TSH thyroid
stimulating hormone; WBC white blood count.
a
Perform on women of childbearing potential only 24 hours prior to C1D1. Pregnancy tests must be repeated prior to 
every cycle if required or as specified per local regulatory guidance. Refer to Appendix 7 for country specific 
requirements.
b
A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using 
hormonal contraception or HRT. However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal range is required.
c
Total T3 and Total T4 are preferred; if not available, Free T3 or Free T4 may be tested.
d
Report % or absolute results per standard of practice. Report the results in the same manner throughout the study. 
e
For participants with a baseline calculated creatinine clearance that is below the normal institutional laboratory range, a 
baseline measured creatinine clearance should be performed. GFR can be used in place of creatinine clearance.
f
For participants diagnosed with oropharyngeal cancer only, HPV p16 IHC must be performed by central lab if not 
previously tested per the Procedures Manual.
g
BUN is preferred; if not available urea may be tested
Investigators must document their review of each laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
NOTE: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, 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.”
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Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.2
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
1.
Results in death
2.
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.
3.
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.
4.
Results in persistent or significant disability/incapacity
•
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
•
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
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and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
5.
Is a congenital anomaly/birth defect
•
In offspring of participant taking the product regardless of time to diagnosis.
6.
Other important medical events
•
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that require reporting in the same manner as SAE
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study)
•
Is associated with an overdose 
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
eCRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE eCRF page.
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•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, Version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade recorded on 
the AE eCRFs/worksheets.
Grade 1:
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
Grade 2:
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL.
Grade 3:
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL.
Grade 4:
Life-threatening consequences; urgent intervention indicated.
Grade 5:
Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
•
The determination of the likelihood that the Sponsor’s product caused the AE will be 
provided by an investigator who is a qualified physician. The investigator’s signed/dated 
initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed 
document must be retained for the required regulatory time frame. The criteria below are 
intended as reference guidelines to assist the investigator in assessing the likelihood of a 
relationship between the test product and the AE based upon the available information.
•
The following components are to be used to assess the relationship between the 
Sponsor’s product and the AE; the greater the correlation with the components and 
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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.)
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 
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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.
•
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 
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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 eCRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
•
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
•
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
•
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
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SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Device Events, Adverse Device Events, and Medical Device 
Incidents: Definitions, Collection, and Documentation
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions 
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception Requirements
10.5.2.1
Contraception Requirements: Female Participants
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
IUSc,d
•
Nonhormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
Sexual Abstinence
•
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle 
of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c
Male condoms must be used in addition to hormonal contraception.
d
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
- Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus 
interruptus), spermicides only, and LAM.
- Male condom with cap, diaphragm, or sponge with spermicide.
- Male and female condom should not be used together (due to risk of failure with friction).
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10.5.2.2
Contraception Requirements: Male Participants
Male participants are eligible to participate if they agree to the following during the 
intervention period with MK-1454 and for at least 120 days after the last dose of MK-1454:
•
Refrain from donating sperm
PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
•
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies
•
Note:  Contraceptive requirements do not apply to participants taking pembrolizumab 
monotherapy.
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1.
Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that 
is a sign of a normal or abnormal process or of a condition or disease. A biomarker 
may be used to see how well the body responds to a treatment for a disease or 
condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA 
characteristics as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the 
influence of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2.
Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.9 will 
be used in various experiments to understand:
◦
The biology of how drugs/vaccines work
◦
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
◦
Other pathways with which drugs/vaccines may interact
◦
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
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3.
Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at 
a study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated 
in the SoA. If delayed, present consent at next possible Participant Visit. Consent 
forms signed by the participant will be kept at the clinical study site under secure 
storage for regulatory reasons.
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be 
captured in the eCRFs. Any specimens for which such an informed consent cannot 
be verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as 
outlined in the SoA. In general, if additional blood specimens are being collected 
for future biomedical research, these will usually be obtained at a time when the 
participant is having blood drawn for other study purposes.
4.
Confidential Participant Information for Future Biomedical 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 intervention outcomes 
are critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number which does not contain any personally 
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identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers 
will appear on the specimen tube.
5.
Biorepository Specimen 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 the future biomedical research 
protocol and consent. Future biomedical research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6.
Withdrawal From Future Biomedical 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 investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@MSD.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if 
the investigator is no longer required by regulatory authorities to retain the main study 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this 
situation, the request for withdrawal of consent and/or destruction cannot be processed.
7.
Retention of 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.
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Specimens from the study site will be shipped to a central laboratory and then shipped 
to the Sponsor-designated biorepository. If a central laboratory is not utilized in a 
particular study, the study site will ship directly to the Sponsor-designated 
biorepository. The specimens will be stored under strict supervision in a limited access 
facility which operates to assure the integrity of the specimens. Specimens will be 
destroyed according to Sponsor policies and procedures and this destruction will be 
documented in the biorepository database.
8.
Data 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.
9.
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.
10.
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.
11.
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.
12.
Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
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13.
References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid 45618
2. International Conference on Harmonization [Internet]: E15: Definitions for 
Genomic Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and 
Sample Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html 
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/ 
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
For countries or sites that follow the CTFG guidance requiring monthly pregnancy 
testing, please use the following:
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Section 1.3.2   Schedule of Activities for the Treatment Period for Arm 1 (Combination Therapy: IT MK-1454 and IV Pembrolizumab)
Study Period:
Combination Treatment Phase (3-Week Cycles)
Notes
Treatment 
Cycle/Title:
Cycle 1
Cycle 2
Cycle 3 
Cycle 4 
and 
Beyond
Treatment Days:
1
8
15
1
8
15
1
1
Scheduled Day and 
Window:
+3
±3
±3
±3
±3
±3
±3
±3
Pregnancy test –
Urine or Serum 
β-hCG for WOCBP 
X
X
X
X
Required within 24 h prior to first dose of study medication. Does not 
need to be repeated if screening pregnancy test was done within 24 h of 
the first dose of study medication on C1D1. If a urine pregnancy test 
cannot be confirmed as negative, a serum pregnancy test is required. 
Thereafter, pregnancy testing should be performed Day 1 of each 
subsequent cycle.
β-hCG = β-human chorionic gonadotropin; EOT = end of treatment; WOCBP = women of childbearing potential.
Section 1.3.3   Schedule of Activities for the Treatment Period for Arm 2 IV Pembrolizumab Monotherapy)
Study Period:
Treatment Phase (3-Week Cycles)
Notes
Treatment 
Cycle/Title:
Cycle 1
Cycle 2
Cycle 3 
Cycle 4 
and 
Beyond
Treatment 
Days:
1
1
1
1
Scheduled Day 
and Window:
+3
±3
±3
±3
Pregnancy test –
Urine or Serum 
β-hCG for 
WOCBP 
X
X
X
X
Required within 24 h prior to first dose of study medication. Does not need to be 
repeated if screening pregnancy test was done within 24 h of C1D1. If a urine 
pregnancy test cannot be confirmed as negative, a serum pregnancy test is 
required. Thereafter, pregnancy testing should be performed Day 1 of each 
subsequent cycle.
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Section 1.3.4   Schedule of Activities for the End of Treatment and Post-treatment Follow-Up Periods)
Study Period
EOT/ Discontinuation
Post-treatment Period
Notes
30-Day 
Safety 
Follow-up 
Visit
Imaging 
Follow-up
Survival 
Follow-up
Visit Timing
30 days 
after the last 
dose
Every 
6 weeks for 
1 year, then 
every 
9 weeks
Approxi-
mately 
every 
12 weeks
Visit Window (Days)
±7
+7
±7
±14
Pregnancy Test for WOCBP – Urine or Serum β-
hCG
X
For WOCBP, perform as required 
locally. If a urine pregnancy test 
cannot be confirmed as negative, a 
serum pregnancy test is required. 
Thereafter, pregnancy testing 
should be performed 
approximately monthly up to 120 
days following the 
discontinuation of study 
intervention.
β-hCG = β-human chorionic gonadotropin; EOT = end of treatment; WOCBP = women of childbearing potential.
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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 24 hours of the 
first dose of study medication on C1D1 and 30 days post-treatment. Additional pregnancy 
testing can be conducted if required by local regulations or if clinically indicated. 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 on Day 1 of each cycle
and then again 30 days after the last study dose of study treatment, and approximately 
monthly up to 120 days after the last study dose of study treatment.
8.10.1 Screening
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 24 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). Thereafter, pregnancy testing should be conducted Day 1 of each 
subsequent cycle.
Appendix 2 Clinical Laboratory Tests
Footnote to Table 18 reads: 
a.
Perform on WOCBP only 24 hours prior to Cycle 1 Day 1 (C1D1). Thereafter, 
pregnancy testing should be conducted Day 1 of each subsequent cycle.
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10.8 Appendix 8: Guidelines for Prioritization of Intratumoral Lesion Injection
The selection and prioritization of lesions for intratumoral injection may be a complex set of 
decisions made by the clinician at each treatment visit. Ultimately, lesion prioritization is 
based on clinical judgment and patient tolerance. A set of guiding principles is provided.
Patient Safety
The first priority is patient safety. Lesions are to be selected that minimize the potential for 
procedural complications and maximize patient comfort. Important safety factors are
vascularity within a lesion, and vascularity adjacent to a lesion. Injection into intratumoral 
vasculature should be avoided to minimize systemic administration. Vessels adjacent to a 
tumor should ideally not be traversed to minimize bleeding risk. Areas of vascular 
encasement should be avoided in high risk locations, such as inferior vena cava encasement 
for liver lesions, or carotid artery encasement for head and neck tumors.
Lesion Accessibility
The next prioritization factor is accessibility. Preference should be given to cutaneous lesions 
which are visible, and superficial subcutaneous lesions and lymph nodes that are easily 
palpable. Deeper lesions, including nonpalpable lymph nodes and nonpalpable extranodal 
lesions in viscera or body cavities, may be more difficult to access. These deeper lesions 
typically require imaging guidance, which increases procedural complexity, and must be 
balanced against the clinical benefit that might result from their treatment, such as 
symptomatic relief.
Lesion Size, Tumor Necrosis, Amount of Viable Tumor Tissue, and Aggressive Tumors
At the initiation of therapy, the next factors that should guide lesion prioritization are the size 
of the lesion, and the amount of viable tumor tissue present in the lesion. Other factors being 
equal, larger lesions are preferred. Larger lesions may have a greater amount of tumor tissue, 
and are generally older in age than smaller lesions, and may therefore have a greater breadth 
of tumor-specific antigens to stimulate a broader repertoire of antigen-specific T-cells. 
Radiographically visible necrosis should be avoided for injection with an intratumoral 
immunotherapeutic. Direct the intratumoral immunotherapeutic into viable portions of a 
lesion, such as at the periphery of a lesion. A larger lesion that is predominantly necrotic may 
be deprioritized compared to a smaller lesion with little or no radiographic necrosis. Another 
feature that should be considered is radiographic evidence of aggressiveness, such as local 
invasiveness. Aggressive lesions should be given higher priority.
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New and/or Enlarging Lesions
During therapy, lesions that are new or enlarging should be given higher priority over lesions 
selected on the basis of size. Safety and accessibility are of course still the primary 
considerations. New and progressing lesions contain actively dividing cells, which may be 
more responsive to injection with an intratumoral immunotherapeutic. Also, new or 
progressing lesions may contain newly mutated tumor cells, allowing for a broader repertoire
of antigen-specific T cells in response to injection with an intratumoral immunotherapeutic, 
and subsequent improved systemic antitumor response. New lesions may contain novel 
tumor antigens compared to previously injected lesions.
Note: Detailed guidance on injectate volume and lesion injection is provided in the 
Procedures Manual.
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10.9
Appendix 9: Eastern Cooperative Oncology Group Performance Status
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group 
Chair.*
GRADE
ECOG PERFORMANCE STATUS
0
Fully active, able to carry on all predisease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light housework, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities; up and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or 
chair
5
Dead
*
Oken M, Creech R, Tormey D, et al. Toxicity and response criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol. 1982;5:649-655
http://ecog-acrin.org/resources/ecog-performance-status
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10.10 Appendix 10: itRECIST Supplementary Figures
Figure 5
Algorithm for Classification of Lesions at Baseline
Source: Adapted from [Goldmacher, G. V., et al 2020].
Lesions are classified first as measurable or nonmeasurable using the standard RECIST 1.1 
rules for measurability. Measurable lesions (those eligible for selection as target lesions) are 
then classified as target (selected to be followed quantitatively) or nontarget (selected to be 
followed qualitatively), and the decisions about which lesions are to be injected are made 
based on the prioritization rules discussed. Lesions selected for injection may be either target 
or nontarget in RECIST 1.1 terms. Between 1 and 5 lesions should be classified as target 
injected, and between 1 and 5 should be classified as target noninjected, for a maximum of 
10 target lesions. All lesions not chosen as target are followed qualitatively as nontarget, and 
some of these may be selected for injection at baseline. T-I lesions and T-NI lesions each 
have their own distinct SOD. A combined SOD also includes all target lesions, injected and 
noninjected. NT-I and NT-NI lesions are followed qualitatively, exactly as in RECIST 1.1, 
classified in aggregate as showing complete response, unequivocal progression, or neither 
(called non-CR/non-PD in RECIST 1.1).
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Figure 6
Reclassification of Noninjected Lesions
Source: Adapted from [Goldmacher, G. V., et al 2020].
Target or nontarget noninjected lesions can be recategorized as injected lesions if the 
decision is made to inject them after baseline assessment. Nontarget noninjected lesions may 
be injected if previously injected nontarget lesions regress completely or become inaccessible 
or if a patient factor such as injection site reaction or patient intolerance precludes further 
injection. Lesions initially selected as target noninjected should remain noninjected for as 
long as possible so the maximal noninjected effect can be evaluated, but they may be injected 
if they are enlarging, or if no other lesions are available for injection, especially if the lesions 
initially designated as target noninjected are not regressing. The barrier between target and 
nontarget categories means that all lesions remain target and nontarget in accordance with the 
initial designation, regardless of whether they are subsequently injected. 
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Figure 7
Overall Response Assessment Until Disease Progression
Source: Adapted from [Goldmacher, G. V., et al 2020].
Overall response until disease progression per RECIST 1.1. The injected response at each 
visit is based on only the changes in the SODs of the lesions designated as target injected. 
The noninjected response at each visit is based on only the changes in the SODs of the target 
noninjected lesions. The overall response is based on the changes in the SODs of all target 
lesions together, the qualitative assessment of all nontarget lesions together, and the 
evaluation for possible new lesions and uses the same response categories and logical 
combination of these that RECIST 1.1 uses. RECIST 1.1, Response Evaluation Criteria in 
Solid Tumors, version 1.1; SOD.
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Figure 8
Example of Iterative Assessment of Injected Lesion Response During Treatment
Abbreviations: iPR = immunotherapeutic partial response; NE = not evaluable; NT-I = nontarget injected; NT-
NI = nontarget noninjected; PD = progressive disease; PR = partial response; iRECIST 1.1 =  
immunotherapeutic Response Evaluation Criteria in Solid Tumors; SD =  stable disease; SOD = sum of 
diameters (longest diameters for extranodal lesions, short axis for lymph nodes); T-I = target injected; T-NI = 
target noninjected.
Source: [Goldmacher, G. V., et al 2020].
This is an illustration of overall, injected, and noninjected response assessment, with a 
particular focus on the iterative assessment of injected lesions. All lesions from a single 
patient are displayed in simple schematic form and are not meant to be anatomically 
adjacent. For purposes of this illustration, the yellow and green lesions were selected at 
baseline as target injected, and the purple and blue lesions were selected as target 
noninjected; there are no nontarget lesions. In this simplified example, a full imaging 
assessment is performed at each treatment visit just before the decision about which lesions 
to inject at that visit. The overall response at each visit was based on the change in SODs for 
all the target lesions together (because there are no nontarget lesions in this example). Once 
progressive disease is observed (in this case, because of a new lesion), the overall response 
assessment thereafter is similar to that of iRECIST. The injected response is based on the 
change in SOD of the injected lesions from the assessment immediately before this one. The 
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noninjected response is based on the changes in SOD from baseline and nadir and is 
considered nonevaluable once any lesion that was initially selected as T-NI is subsequently 
injected, as happens in this case with the purple lesion. If this lesion were to grow later, it 
could contribute to an overall response of PD.
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibodies
ADL
activities of daily living  
AE
adverse event 
AEOSI
adverse event of special interest
APaT
All-Participants-as-Treated
aPTT
activated partial thromboplastin time
AR
adverse reaction
ART
antiretroviral therapy
ATD
accelerated titration design
ATP
adenosine triphosphate
AUC
area under the curve
BCG
Bacillus Calmette–Guérin
BDS
blood drug screen
BICR
blinded independent central review
BID
twice daily
BMI
body mass index
BP
blood pressure
C1D1
Cycle 1 Day 1
CBC
complete blood count
CD28
cluster of differentiation 28
CD3ζ
cluster of differentiation 3 zeta
CDN
cyclic dinucleotide
CF
compact flash
CG
Cockcroft-Gault
cGAS
cyclic GMP-AMP (guanosine monophosphate-adenosine monophosphate) synthase
CI
confidence interval
CI
confidence interval
CL
clearance
Cmax
maximum concentration
CONSORT
Consolidated Standards of Reporting Trials
CPS
combined positive scoring
CR
Complete response
CrCl
creatinine clearance
CRF
Case Report Form 
CRS
cytokine release syndrome
CRU
clinical research unit
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
Circulating tumor deoxyribonucleic acid
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Ctrough
minimum concentration
DC
dendritic cells
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
dMMR
deficient mismatch repair indicated by the loss of expression of one or more of the 
MLH1, MSH2, MSH6, and PMS2 proteins
DNA
deoxyribonucleic acid 
DOR
duration of response
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Abbreviation
Expanded Term
dsDNA
double-stranded DNA
E/CIA
enzyme or chemiluminescence immunoassay
ECG
electrocardiogram 
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
electronic data collection 
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOT
end of treatment
EQ-5D
EuroQoL-5D
ER
endoplasmic-reticulum
FAS
Full Analysis Set
FBR
Future biomedical research
FDAAA
Food and Drug Administration Amendments Act
FFPE
formalin-fixed, paraffin embedded
FIH
first in human
FSH
follicle-stimulating hormone 
FT3
free triiodothyronine
FT4
free thyroxin
GCP
Good Clinical Practice 
G-CSF
Granulocyte Colony-stimulating Factor
GFR
glomerular filtration rate
GGT
gamma-glutamyl transpeptidase
GI
gastrointestinal
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
GMP-AMP
(guanosine monophosphate-adenosine monophosphate) synthase
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HNSCC
head and neck squamous cell carcinoma
HPV
human papilloma virus
HR
hazard ratio
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form 
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
iCPD
immune confirmed progressive disease
iCR
immune complete response
iCRO
imaging CRO
IEC
Independent Ethics Committee
IFN
interferon
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IL
interleukin
IND
Investigational New Drug 
CCI
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Abbreviation
Expanded Term
INR
international normalized ratio
IO
immuno-oncology
iPR
immune partial response
irAEs
immune-related AEs
IRB
Institutional Review Board 
iRECIST
Response Evaluation Criteria in Solid Tumors 1.1 for immune-based therapeutics
IRT
interactive response technology
iSD
immune stable disease
IT
intratumoral
ITP
idiopathic thrombocytopenic purpura
itRECIST
intratumoral immunotherapy RECIST
ITT
intention-to-treat
IUD
intrauterine device
IUO
Investigational use only
iUPD
Immune unconfirmed progressive disease
IUS
intrauterine hormone-releasing system
IV
intravenous
LDH
lactate dehydrogenase
LLOQ
lowest limit of quantitation
mAb
monoclonal antibody
MAD
maximum administered dose
MedDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
NA
not applicable
NAm
North America
NCI
National Cancer Institute
NF-κB
nuclear factor kappa light chain enhancer of activated B cells
NOAEL
no observed adverse effect level 
NSCLC
non–small cell lung cancer
O2
oxygen
OR
objective response
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
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
PIN
personal identification number
PK
pharmacokinetic
PKCθ
protein kinase C-theta
po
orally
PP
per protocol
PR
partial response
PT
prothrombin time
PTT
partial thromboplastin time
Q1W
once each week
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Abbreviation
Expanded Term
Q3W
every 3 weeks
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SoA
schedule of activities
SOD
Sum of diameters
sSAP
supplemental Statistical Analysis Plan
STING
stimulator of interferon genes
SUSAR
suspected unexpected serious adverse reaction
T3
triiodothyronine
T4
thyroxine
TNBC
triple negative breast cancer
TPS
Tumor proportion scoring
T-regs
Regulatory T-cells
TSH
Thyroid-stimulating hormone
V
Volume of distribution
VS
vital sign
WBC
white blood cell
WOCBP
woman/women of childbearing potential 
WT
Wild-type
ZAP70
zeta-chain-associated protein kinase
β-hCG
β-human chorionic gonadotropin
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11
REFERENCES
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