Conditions: Solid Tumors Lymphoma
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1) Intratumoral (IT)
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 156
Healthy volunteers: no

Brief summary:
The purpose of this study is to identify a maximum tolerated dose (MTD) or maximum administered dose (MAD) of ulevostinag alone and of ulevostinag in combination with pembrolizumab in participants with advanced/metastatic solid tumors or lymphomas in Part 1, and to evaluate the safety and efficacy of ulevostinag via intratumoral (IT) injection in combination with pembrolizumab in selected solid tumors in Part 2.

Ulevostinag will be administered IT; pembrolizumab (pembro) will be administered via intravenous (IV) infusion. In Part 1, participants will be allocated to one of three treatment arms: ulevostinag monotherapy (cutaneous/subcutaneous \[cut/subcut\] lesions), ulevostinag +pembro (cut/subcut lesions), or ulevostinag +pembro (visceral lesions).

In Part 2, participants with head and neck squamous cell carcinoma (HNSCC) who are anti-programmed cell death-protein 1 or anti-programmed cell death-ligand 1 (anti-PD-1/PD-L1) refractory or with anti-PD-1/PD-L1 treatment (TrT)-naïve triple-negative breast cancer (TNBC) or with anti-PD-1/PD-L1 TrT-naïve solid tumors with liver metastases/lesions will receive ulevostinag via IT injection at the preliminary Recommended Phase 2 Dose (RP2D) determined in Part 1 PLUS pembrolizumab via IV infusion for up 35 cycles (up approximately 2 years).

Detailed description:
Participants will receive either ulevostinag monotherapy or ulevostinag in combination with pembrolizumab for up to 35 cycles (approximately 2 years). Participants will undergo at least a 24-hour inpatient observation period following the first dose administration of ulevostinag on Cycle 1 Day 1 in Part 1. For Part 2, the length of the observation period following administration of the first dose of ulevostinag on Cycle 1 Day 1 is at least 8 hours.

Arms:
arm 1: Participants with cutaneous (cut) or subcutaneous (subcut) lesions will receive escalating doses of ulevostinag monotherapy via IT injection on Days 1, 8, and 15 of each 21-day cycle for Cycles 1, 2, and 3 and then on Day 1 of each 21-day cycle for Cycles 4 and beyond for up to 35 cycles (up to approximately 2 years). arm 2: Participants with cut or subcut lesions will receive escalating doses of ulevostinag via IT injection on Days 1, 8, and 15 of each 21-day cycle for Cycles 1, 2, and 3 and then on Day 1 of each 21-day cycle for Cycles 4 and beyond PLUS pembrolizumab (pembro) via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years). arm 3: Participants with visceral lesions will receive escalating dose frequencies of ulevostinag via IT injection at escalating dose frequencies (Day 1 of each 21-day cycle for up to 35 cycles, then Days 1 and 8 of each 21-day cycle for two cycles, then Day 1 of each 21 day cycle up to 35 cycles, then Days 1, 8, and 15 of each 21-day cycle for two cycles followed by Day 1 of each 21-day cycle up to 35 cycles, PLUS pembrolizumab IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (approximately 2 years). arm 4: Participants with HNSCC who are anti-programmed cell death-1 or anti-programmed cell death-ligand 1 refractory will receive ulevostinag at the preliminary Recommended Phase 2 Dose (RP2D) determined by dose escalation in Part 1 Arm 1 and 2 via IT injection on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of each 21-day cycle from Cycle 3 onward (up to a total of 35 cycles) PLUS pembrolizumab via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years). arm 5: Participants with TNBC who are anti-PD-1/PD-L1 treatment-naïve or who have refractory unresectable locally advanced or metastatic TNBC will receive ulevostinag at the preliminary RP2D determined by dose escalation in Part 1 via IT injection on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of each 21-day cycle from Cycle 3 onward (up to a total of 35 cycles) PLUS pembrolizumab via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years). arm 6: Participants with solid tumors with liver metastases/lesions who are anti-PD-1/PD-L1 treatment-naïve will receive ulevostinag at the preliminary RP2D based on Part 1: ulevostinag + pembro (visceral lesions) treatment arm via IT injection in a to-be-determined dose and frequency, based on data from Arm 3, PLUS pembrolizumab via IV infusion on Day 1 of each 21-day cycle for up to 35 cycles (up to approximately 2 years).

Interventions: intervention 1: Ulevostinag intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: IT injection intervention 2: IV infusion

Protocol document:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
Phase 1 Open-label, Multicenter Study of MK-
1454 Administered by Intratumoral Injection
as Monotherapy and in Combination with
Pembrolizumab for Patients with
Advanced/Metastatic Solid Tumors or
Lymphomas


Product:  MK-1454 
1
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
Phase 1 Open-label, Multicenter Study of MK-1454 Administered by Intratumoral Injection 
as 
Monotherapy 
and 
in 
Combination 
with 
Pembrolizumab 
for 
Patients 
with 
Advanced/Metastatic Solid Tumors or Lymphomas
IND NUMBER:  129450
EudraCT NUMBER:  2016-003160-40
NCT:  NCT03010176
087V73


Product:  MK-1454 
2
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 12
SUMMARY OF CHANGES................................................................................................ 14
1.0
TRIAL SUMMARY.................................................................................................. 18
2.0
TRIAL DESIGN........................................................................................................ 20
Trial Design ........................................................................................................... 20
Part I – Dose Escalation and Confirmation Phase .............................................. 20
Part II –Expansion Phase .................................................................................... 23
Trial Diagram........................................................................................................ 24
Trial Diagram for Part I - Dose Escalation and Confirmation............................ 24
Trial Diagram for Part II – Expansion Cohorts .................................................. 26
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 26
Primary Objective(s) & Hypothesis(es).............................................................. 26
Secondary Objective(s) & Hypothesis(es)........................................................... 27
Exploratory Objectives......................................................................................... 27
4.0
BACKGROUND & RATIONALE.......................................................................... 28
Background ........................................................................................................... 28
Pharmaceutical and Therapeutic Background .................................................... 30
MK-1454 Background ................................................................................. 30
Pembrolizumab Background........................................................................ 30
Rationale................................................................................................................ 31
Rationale for the Trial and Selected Subject Population .................................... 31
Rationale for Part I - Dose Escalation and Confirmation ............................ 31
Rationale for Part II - Expansion Cohorts.................................................... 32
4.2.1.2.1
Microsatellite Instability Testing.......................................................... 33
Rationale for Dose Selection/Regimen............................................................... 34
Starting Dose for This Trial......................................................................... 34
Maximum Dose/Exposure for This Trial..................................................... 35
Rationale for Dose Interval and Trial Design.............................................. 35
Rationale for Visceral Intratumoral Injection.............................................. 36
087V73


Product:  MK-1454 
3
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Rationale for Dose of MK-1454 Expansion Cohorts A and B (Part II)....... 36
Rationale for Dose Schedule Expansion Cohorts A and B (Part II)............ 37
Rationale for Endpoints ...................................................................................... 37
Efficacy Endpoints....................................................................................... 37
4.2.3.1.1
Immune-related RECIST (irRECIST) .................................................. 38
4.2.3.1.2
IWG Revised Response Criteria for Malignant Lymphomas............... 38
4.2.3.1.3
Response Assessment for CTCL .......................................................... 39
Safety Endpoints.......................................................................................... 39
Pharmacokinetic Endpoints ......................................................................... 39
Pharmacodynamic Endpoints....................................................................... 39
Planned Exploratory Biomarker Research................................................... 40
4.2.3.5.1
Planned Genetic Analysis ..................................................................... 40
Future Biomedical Research........................................................................ 41
Benefit/Risk ........................................................................................................... 42
5.0
METHODOLOGY ................................................................................................... 42
Entry Criteria........................................................................................................ 42
Diagnosis/Condition for Entry into the Trial...................................................... 42
Subject Inclusion Criteria for Part I - Dose Escalation and Confirmation.......... 42
Subject Inclusion Criteria for Arms 1 and 2 ................................................ 42
Subject Inclusion Criteria for Crossover Into Arm 2................................... 45
Subject Inclusion Criteria for Arm 3 ........................................................... 48
Subject Inclusion Criteria for Part II - Expansion Cohorts................................. 50
Subject Exclusion Criteria for Part I - Dose Escalation and Confirmation ........ 54
Exclusion Criteria for Arms 1, 2, and 3....................................................... 54
Exclusion Criteria for Crossover Into Arm 2............................................... 56
Exclusion Criteria for Part II - Expansion Cohorts............................................. 57
Trial Treatment(s) ................................................................................................ 60
Dose Selection/Modification .............................................................................. 63
Dose Selection (Preparation) ....................................................................... 63
5.2.1.1.1
Dose Selection in Part I - Dose Escalation and Confirmation 
(Arm 1, Arm 2, and Arm 3).................................................................. 63
5.2.1.1.2
Dose Selection in Part II - Expansion Cohorts (Cohorts A and B)....... 64
087V73


Product:  MK-1454 
4
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Accelerated Titration Design in Arms 1, 2, and 3 ....................................... 65
Dose Escalation and Confirmation During Modified Toxicity 
Probability Interval Design.......................................................................... 66
Definition of Dose-Limiting Toxicity................................................................. 68
Dose Modification Due to Adverse Events......................................................... 69
Dose Modification for MK-1454 Drug-related AEs in Part I - Arm 1, 
Arm 2, and Arm 3........................................................................................ 70
Dose Modification for MK-1454 in Part II - Expansion Cohorts................ 77
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)................................................................................................. 78
Treatment for Cytokine Release Syndrome................................................. 84
Intrasubject Dose Escalation............................................................................... 85
Timing of Dose Administration.......................................................................... 86
Timing of MK-1454 Dose Administration in Part I - Dose Escalation 
and Confirmation......................................................................................... 86
Timing of MK-1454 Dose Administration in Part II - Expansion 
Cohorts......................................................................................................... 86
Timing of Pembrolizumab Administration.................................................. 86
Trial Blinding...................................................................................................... 87
Replacement of Subjects During the DLT Evaluation Period............................ 87
Randomization or Treatment Allocation............................................................ 87
Stratification.......................................................................................................... 87
Concomitant Medications/Vaccinations (Allowed and Prohibited)................. 87
Rescue Medications & Supportive Care............................................................. 89
Supportive Care Guidelines ................................................................................ 89
Diet/Activity/Other Considerations..................................................................... 89
Diet...................................................................................................................... 89
Contraception...................................................................................................... 89
Definitions.................................................................................................... 89
Acceptable Contraception Methods............................................................. 90
Use in Pregnancy ................................................................................................ 92
Use in Nursing Women....................................................................................... 92
Subject Withdrawal/Discontinuation Criteria................................................... 92
Discontinuation of Treatment ............................................................................. 92
087V73


Product:  MK-1454 
5
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Withdrawal From the Trial ................................................................................. 93
Participants Who Withdraw Consent During the Study .............................. 93
Subject Replacement Strategy............................................................................. 94
Beginning and End of the Trial ........................................................................... 94
Clinical Criteria for Early Trial Termination ................................................... 94
6.0
SCHEDULE OF ACTIVITIES ............................................................................... 95
Schedule of Activities for Part I - Dose Escalation and Confirmation 
(Arms 1, 2, and 3).................................................................................................. 95
Schedule of Activities for Initial Screening for Arms 1 Through 3 and for 
Crossover Into Arm 2.......................................................................................... 95
Schedule 
of 
Activities 
for 
the 
Treatment 
Period, 
Intratumoral 
Administration for Arm 1 (Monotherapy) and Arm 2 (Combination Therapy 
– Including Crossover to Arm 2) ........................................................................ 98
Schedule of Activities for the Treatment Period of Arm 3 (Visceral IT 
Administration)................................................................................................. 103
Discontinuation / End of Treatment and Posttreatment Follow-up for Arms 1 
to 3 .................................................................................................................... 107
Schedule of Activities for Part II- Expansion Cohorts.................................... 109
Schedule of Activities for Part II - Expansion Cohorts Screening and 
Treatment 
Period, 
MK-1454 
Intratumoral 
Administration 
With 
Pembrolizumab Combination Therapy............................................................. 109
Discontinuation / End of Treatment and Posttreatment Follow-up for Part II 
– Expansion Cohorts......................................................................................... 115
7.0
TRIAL PROCEDURES ......................................................................................... 117
Trial Procedures ................................................................................................. 117
Administrative Procedures................................................................................ 117
Informed Consent....................................................................................... 117
7.1.1.1.1
General Informed Consent.................................................................. 117
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................. 118
Inclusion/Exclusion Criteria ...................................................................... 118
Subject Identification Card ........................................................................ 118
Medical History ......................................................................................... 118
Disease Details........................................................................................... 118
Prior Oncology Treatment History ............................................................ 118
087V73


Product:  MK-1454 
6
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Prior and Concomitant Medications Review............................................. 119
7.1.1.7.1
Prior Medications................................................................................ 119
7.1.1.7.2
Concomitant Medications................................................................... 119
Assignment of Screening Number............................................................. 119
Assignment of Treatment/Randomization Number................................... 119
Trial Compliance (Medication/Diet/Activity/Other)................................. 120
Trial Communication Plan Summary ........................................................ 120
Clinical Procedures/Assessments...................................................................... 120
Adverse Event Monitoring......................................................................... 120
Full Physical Examination......................................................................... 121
Vital Signs and Weight.............................................................................. 121
Electrocardiogram...................................................................................... 121
Eastern Cooperative Oncology Group Performance Status....................... 121
Tumor Imaging and Medical Photography................................................ 122
Response Assessment ................................................................................ 122
7.1.2.7.1
Immune-related RECIST .................................................................... 122
7.1.2.7.2
Intratumoral Immunotherapy RECIST (itRECIST) ........................... 124
7.1.2.7.3
IWG Revised Response Criteria for Malignant Lymphomas............. 124
7.1.2.7.4
Response Assessment Criteria for CTCL ........................................... 126
Laboratory Procedures/Assessments ................................................................ 132
Laboratory 
Safety 
Evaluations 
(Hematology, 
Chemistry, 
and 
Urinalysis).................................................................................................. 132
Pharmacokinetic/Pharmacodynamic Evaluations...................................... 133
7.1.3.2.1
Blood Collection for MK-1454 and Pembrolizumab PK ................... 133
7.1.3.2.2
Blood Collection for Anti-Pembrolizumab Antibodies (ADA).......... 133
7.1.3.2.3
Blood for Pharmacodynamic Markers................................................ 133
7.1.3.2.4
Tumor Biopsy ..................................................................................... 133
Planned Genetic Analysis Sample Collection............................................ 135
Future Biomedical Research Samples ....................................................... 135
Other Procedures............................................................................................... 135
Withdrawal/Discontinuation...................................................................... 135
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................. 136
7.1.4.1.2
Lost to Follow-up................................................................................ 136
087V73


Product:  MK-1454 
7
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Subject Blinding/Unblinding ..................................................................... 136
Domiciling ................................................................................................. 137
Calibration of Equipment........................................................................... 137
Visit Requirements............................................................................................ 137
Screening.................................................................................................... 137
Treatment Period........................................................................................ 137
Treatment Period Beyond Disease Progression......................................... 138
Discontinued Subjects Continuing to be Monitored in the Trial............... 138
30-Day Safety Follow-up Visit.................................................................. 138
Survival Status Monitoring........................................................................ 138
Assessing and Recording Adverse Events ........................................................ 139
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor........................................................................................................ 140
Reporting of Pregnancy and Lactation to the Sponsor ..................................... 140
Immediate Reporting of Adverse Events to the Sponsor.................................. 141
Serious Adverse Events ............................................................................. 141
Events of Clinical Interest.......................................................................... 142
Protocol-Specific Exceptions to Serious Adverse Event Reporting.......... 142
Evaluating Adverse Events............................................................................... 143
Sponsor Responsibility for Reporting Adverse EventsSAEs ........................... 146
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 146
Statistical Analysis Plan Summary ................................................................... 146
Responsibility for Analyses/In-house Blinding ................................................ 148
Hypotheses/Estimation....................................................................................... 148
Analysis Endpoints ............................................................................................. 148
Efficacy/Pharmacokinetic Endpoints................................................................ 148
Safety Endpoints ............................................................................................... 148
Analysis Populations........................................................................................... 148
Safety Analysis Population............................................................................... 148
Pharmacokinetic Analysis and Target Engagement Populations...................... 149
Efficacy Analysis Populations .......................................................................... 149
Statistical Methods.............................................................................................. 149
087V73


Product:  MK-1454 
8
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Statistical Methods for Efficacy Analyses........................................................ 149
Statistical Methods for Safety Analyses ........................................................... 149
Summaries of Baseline Characteristics, Demographics, and Other Analyses.. 150
Demographic and Baseline Characteristics ............................................... 150
Pharmacokinetics and Pharmacodynamics Modeling Analysis ................ 150
Interim Analyses ................................................................................................. 150
Multiplicity .......................................................................................................... 150
Sample Size and Power Calculations ................................................................ 151
Part I Sample Size............................................................................................. 151
Part II Sample Size............................................................................................ 151
Subgroup Analyses and Effect of Baseline Factors ......................................... 152
Compliance (Medication Adherence)................................................................ 152
Extent of Exposure.............................................................................................. 152
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 153
Investigational Product ...................................................................................... 153
Packaging and Labeling Information ............................................................... 153
Clinical Supplies Disclosure............................................................................... 154
Storage and Handling Requirements................................................................ 154
Discard/Destruction/Returns and Reconciliation ............................................ 154
Standard Policies................................................................................................. 154
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 154
Confidentiality..................................................................................................... 154
Confidentiality of Data ..................................................................................... 154
Confidentiality of Subject Records................................................................... 155
Confidentiality of Investigator Information...................................................... 155
Confidentiality of IRB/IEC Information........................................................... 155
Compliance With Financial Disclosure Requirements.................................... 155
Compliance With Law, Audit and Debarment ................................................ 156
Compliance With Trial Registration and Results Posting Requirements..... 158
Quality Management System............................................................................. 158
Data Management............................................................................................... 158
087V73


Product:  MK-1454 
9
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Publications ......................................................................................................... 158
11.0
LIST OF REFERENCES....................................................................................... 160
12.0
APPENDICES......................................................................................................... 164
Merck Code of Conduct for Clinical Trials...................................................... 164
Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 166
Prioritization of Intratumoral Lesion Injection............................................... 170
itRECIST Supplementary Figures.................................................................... 172
Country-specific Requirements......................................................................... 177
List of Abbreviations and Definitions............................................................... 180
13.0
SIGNATURES......................................................................................................... 185
Sponsor's Representative ................................................................................... 185
Investigator.......................................................................................................... 185
087V73


Product:  MK-1454 
10
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values........................................................ 43
Table 2
Anti-PD-1/PD-L1 Antibody Refractory Definition................................................ 52
Table 3
Trial Treatment for MK-1454 IT Monotherapy (Arm 1) ....................................... 60
Table 4
Trial Treatment for MK-1454 IT in Combination with Pembrolizumab 
(Arm 2)................................................................................................................... 61
Table 5
Trial Treatment for MK-1454 Visceral IT in Combination with 
Pembrolizumab (Arm 3)......................................................................................... 62
Table 6
Determination of MK-1454 Injection Volume for Intratumoral Injection of 
Cutaneous Lesions Based on Lesion Size (Part I - Arm 1 and Arm 2).................. 64
Table 7
Determination of MK-1454 Injection Volume for Intratumoral Injection 
into Subcutaneous Lesions Based on Lesion Size (Part I Arm 1 and Arm 2)........ 64
Table 8
Trial Treatment for MK-1454 IT in Combination with Pembrolizumab Part 
II (Expansion Cohorts A, B, and C)....................................................................... 65
Table 9
Injectate Volume for Arm 3 Visceral IT (Part I) and Expansion Cohorts 
(Part II) ................................................................................................................... 65
Table 10 Dose-finding Rules per mTPI Design..................................................................... 68
Table 11 MK-1454 Dose Modification Guidelines for Drug-related AEs in 
Monotherapy (Arm 1), Combination Therapy (Arm 2), and Combination 
Therapy Visceral IT (Arm 3).................................................................................. 71
Table 12 Guidelines for Management of MK-1454 Intratumoral Injection Site 
Reactions ................................................................................................................ 77
Table 13 Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations...................................................................... 79
Table 14 Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines............................................................................................................... 82
Table 15 Cytokine Release Syndrome Treatment Guidelines............................................... 84
Table 16 Response Criteria for Malignant Lymphoma ....................................................... 125
Table 17 Modified Severity Weighted Assessment Tool .................................................... 127
Table 18 Response in Skin (CTCL)..................................................................................... 128
Table 19 Response in Lymph Nodes (CTCL) ..................................................................... 129
Table 20 Response in Viscera (CTCL)................................................................................ 130
Table 21 Response in Blood (CTCL) .................................................................................. 131
Table 22 Global Response Score for CTCL ........................................................................ 131
Table 23 Laboratory Tests ................................................................................................... 132
Table 24 Evaluating Adverse Events................................................................................... 144
Table 25 Estimate and 95% CI of ORR (N=30).................................................................. 152
Table 26 Estimate and 95% CI of ORR (N=60).................................................................. 152
Table 27 Product Descriptions............................................................................................. 153
087V73


Product:  MK-1454 
11
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
LIST OF FIGURES
Figure 1 Part I - Dose Escalation and Confirmation Phase................................................... 24
Figure 2 Arm 3 Dose and Frequency Escalation................................................................... 25
Figure 3 Part II - Expansion Cohorts .................................................................................... 26
Figure 4 Schematic Diagram Showing Mechanism of the Enhancement of T Cell 
Driven Antitumor Immunity through the Action of Cyclic-Dinucleotide 
STING Agonists..................................................................................................... 29
Figure 5 Algorithm for Classification of Lesions at Baseline............................................. 172
Figure 6 Reclassification of Noninjected Lesions............................................................... 173
Figure 7 Overall Response Assessment Until Disease Progression.................................... 174
Figure 8 Example of Iterative Assessment of Injected Lesion Response During 
Treatment.............................................................................................................. 175
087V73


Product:  MK-1454 
12
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-1454-001-08
27-JUL-2021
Updated the dose modification and toxicity management guidelines for irAEs.
MK-1454-001-07
11-AUG-2020
Updated the inclusion criteria for Triple-negative Breast Cancer Expansion Cohort to 
include anti-PD-1/PD-L1 refractory subjects and to add an upper limit for LDH for this 
cohort, removed the requirement for having a second lesion for biopsy in the Expansion 
Cohorts, added itRECIST as an exploratory objective, and updated the contraception 
requirements.
MK-1454-001-06
23-AUG-2019
Documented the Recommended Phase 2 Dose (RP2D) to be used in Expansion Cohorts A 
and B. 
MK-1454-001-05
03-JAN-2019
Updated inclusion criteria for Cohort A at the request of the United States (US) Food and 
Drug Administration (FDA), to allow the inclusion of subjects with head and neck 
squamous cell carcinoma (HNSCC) Stage III, IVa, IVb, and IVc disease per TNM Staging 
AJCC Eighth Edition.
MK-1454-001-04
04-OCT-2018
Designated Dose Escalation and Confirmation phase (Arms 1, 2, and 3) as Part I and 
updated sections accordingly. Added Expansion phase with 3 Expansion Cohorts (Cohorts 
A to C) as Part II of the study and added new subsections to describe design, entry criteria, 
dosing schedule, flow chart, and statistical analysis for the Expansion Cohorts in order to 
evaluate the safety and tolerability of MK-1454 intratumoral (IT) in combination with 
pembrolizumab in specific cancer tumor types. Updated sample size, secondary/exploratory 
objectives, treatments, and schedule of activities to reflect addition of the Expansion 
Cohorts.
Revised the dose escalation and confirmation rules for Arm 3 to include an accelerated 
titration design (ATD) phase starting at
of MK-1454. Visceral IT dosing will 
increase in frequency and escalate dose b
subject tolerance per modified toxicity 
probability interval (mTPI) design. This change was based on an FDA request to start 
visceral IT dosing in combination with pembrolizumab at the No observed adverse effect 
level (NOAEL) dose of 
 
CCI
CCI
087V73


Product:  MK-1454 
13
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Document
Date of Issue
Overall Rationale
MK-1454-001-03
09-MAR-2018
Updated protocol sections to add rationale, background, entry criteria, schedule of activities, 
and 
procedures 
for 
Arm 3 
for 
intratumoral 
(IT) 
injection 
of 
MK-1454 into visceral lesions in combination with pembrolizumab treatment in order to 
allow inclusion of subjects with visceral lesions to be treated by IT injection.
Updated the objectives, inclusion criteria, schedule of activities, and response assessment 
criteria for subjects with cutaneous T-cell lymphoma (CTCL).
MK-1454-001-02
03-JAN-2017
Added detailed guidelines for the management of cytokine release syndrome in response to 
UK Medicines and Healthcare products Regulatory Agency request to add detailed 
supportive care guidelines for potential cytokine release syndrome (CRS).
MK-1454-001-01
07-DEC-2016
Entry criterion #3 text was revised from “for which there is no standard available therapy...” 
to “and who have received, or been intolerant to, all treatment known to confer clinical 
benefit.”  
Definition of a DLT was revised so that causality assessment by the investigator was 
whether the AE was “related, probably related, or possibly related to the drug, excluding 
toxicities clearly not related to the drug, such as disease progression, environmental factors, 
unrelated trauma, etc.,” rather than “unrelated to the underlying disease.” Additionally, Item 
#3 in the definition of a DLT was revised to clarify that exceptions to Grade 3 
nonhematologic toxicity (not laboratory) lasting >3 days as include: Grade 3 fatigue lasting 
≤3 days; Grade 3 diarrhea, nausea, or vomiting without use of antiemetics or antidiarrheals 
per standard of care; Grade 3 rash without use of corticosteroids or anti-inflammatory 
agents per standard of care; Grade 3 fever and Grade 3 flu-like symptoms lasting ≤24 hours 
with negative infectious disease workup (including negative blood and urine cultures).
MK-1454-001-00
17-OCT-2016
Original Protocol
087V73


Product:  MK-1454 
14
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.3.3
Immune-Related Events and 
Dose Modification (Withhold, 
Treat, Discontinue)
The dose modification and 
toxicity management guidelines 
for irAEs and table were 
updated.
Requested by the US FDA in an effort 
to harmonize the presentation of safety 
information across all FDA-approved 
PD-1/L1 antibody prescribing 
information.
6.1.2
6.1.3
6.2.1
7.1.3.2.4
Schedule of Activities for the 
Treatment Period, Intratumoral 
Administration for Arm 1 
(Monotherapy) and Arm 2 
(Combination Therapy –
Including Crossover to Arm 2)
Schedule of Activities for the 
Treatment Period of Arm 3 
(Visceral IT Administration)
Schedule of Activities for Part 
II - Expansion Cohorts 
Screening and Treatment 
Period, MK-1454 Intratumoral 
Administration With 
Pembrolizumab Combination 
Therapy
Urine Collection for MK-1454 
Metabolites
Removed the requirement for a 
urine sample to be obtained for 
metabolite and renal clearance 
analysis.
Analysis of MK-1454 plasma 
metabolites showed low risk, so MK-
1454 urine metabolite analysis is not 
needed. Analysis of renal excretion not 
needed at this time, based on current 
phase of clinical development. 
Section 7.1.3.2.4 Urine Collection for 
MK-1454 Metabolites removed; this 
section number is now used for Tumor 
Biopsy.
087V73


Product:  MK-1454 
15
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
9.1
Investigational Product
Added MK-1454
 
formulation and removed the 
 
formulations.
 MK-1454 formulation is 
available. The 
 
formulations are no longer 
supplied.
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
16
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
5.7.2.2
Acceptable Contraception 
Methods
Deleted instructional text regarding 
hormonal contraception that was 
inadvertently left from the template.
Correction.
2.2.2
Trial Diagram for Part II –
Expansion Cohorts
Updated the trial schema to add “locally 
advanced metastatic” to the Cohort B 
indication description
Corrected an error of omission
2.2.2
Trial Diagram for Part II –
Expansion Cohorts
Corrected figure legend from
 
to 
Correction of typographical 
error.
5.1.2.1
Subject Inclusion Criteria for 
Arms 1 and 2
Corrected the renal function criterion 
for serum creatinine or creatinine 
clearance from “≥1.5 × upper limit of 
normal (ULN)” to “≤1.5 × ULN.”
Added “GFR in place of CrCl.”
Corrected the hepatic function criterion 
for total bilirubin from “≥1.5 × ULN” 
to “≤1.5 × ULN.”
Correction of typographical 
errors and omission of GFR.
6.1.3
Schedule of Activities for the 
Treatment Period of Arm 3 
(Visceral IT Administration)
Deleted the “X” for “Plasma MK-1454 
PK” in Cycle 3
Correction – no samples are to 
be collected in Cycle 3.
CCI
CCI
087V73


Product:  MK-1454 
17
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
6.2.1
Schedule of Activities for Part 
II - Expansion Cohorts 
Screening and Treatment 
Period, MK-1454 Intratumoral 
Administration With 
Pembrolizumab Combination 
Therapy
Removed extraneous language 
regarding ECOG performance status
“Obtain within 72 h prior to MK 1454 
IT administration. Does not need to be 
repeated on C1D1 if screening ECG 
was done within 72 hours of C1D1.”
Sentence was included in error.
7.1.3.1
Laboratory Safety Evaluations 
(Hematology, Chemistry, and 
Urinalysis)
Updated footnote c in Table 23 to allow 
for GFR in place of creatinine 
clearance.
Correction of omission.
12.4
itRECIST Supplementary 
Figures – Figure 8
Corrected word in figure legend 
describing responses in noninjected
lesions from “blue” to “purple”
Correction of typographical 
error
Throughout
NA
Updated the document style to remove 
spelled out abbreviations from the text, 
and corrected format and grammar.
To adhere to current Merck 
template style for future 
content reuse.
087V73


Product:  MK-1454 
18
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
1.0 TRIAL SUMMARY
Abbreviated Title
Phase 1 Study of MK-1454 Administered by Intratumoral Injection 
Sponsor Product Identifiers
MK-1454
Pembrolizumab (MK-3475)
Trial Phase
Phase 1/1b
Clinical Indication
The treatment of subjects with advanced/metastatic solid tumors or 
lymphomas.
Trial Type
Interventional
Type of control
None
Route of administration
Intratumoral (MK-1454)
Intravenous Infusion (pembrolizumab)
Trial Blinding
Unblinded Open-label
Treatment Groups
Subjects will be allocated by IWRS assignment to one of the following 
treatment arms:
Part I:  Dose Escalation and Confirmation
Arm 1:
MK-1454 IT as monotherapy 
 in 
cutaneous or subcutaneous lesions
Arm 2:
MK-1454 IT
in combination with 
pembrolizumab 
in cutaneous or subcutaneous lesions
Arm 3:
MK-1454 IT (at escalating frequencies starting with
 
in combination with pembrolizumab (Q3W) in visceral 
lesions
Part II:  Expansion Cohorts
Eligible subjects with advanced/metastatic solid tumors will be allocated 
by IWRS for treatment with a combination of MK-1454 IT and 
pembrolizumab IV:
Cohort A: HNSCC, anti-PD-1/PD-L1 refractory;
Cohort B: Anti-PD-1/PD-L1 treatment-naïve or refractory unresectable 
locally advanced or metastatic TNBC
Cohort C: Anti-PD-1/PD-L1 treatment-naïve solid tumors with liver 
metastases/lesions
Number of trial subjects
Approximately 235 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the study will require approximately 4.5 to 5 
years from the time the first participant (or their legally acceptable 
representative) provides documented informed consent until the last 
participant’s last study-related contact.
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
19
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Duration of Participation
Each subject will participate in the trial from the time the participant 
provides documented consent through the final contact. After a screening 
phase of up to 28 days, eligible subjects will be allocated by IWRS 
assignment into an open treatment arm. 
During Part I (Dose Escalation and Confirmation), subjects will receive
treatment with MK-1454 as monotherapy (Arm 1) or as combination 
therapy with pembrolizumab (Arm 2 or Arm 3). Study treatment will 
begin on Day 1 of each 21-day cycle. Subjects enrolled in Arm 1
(treatment with MK-1454 as monotherapy) and in Arm 2 or Arm 3
(treatment with MK-1454 and pembrolizumab combination therapy) may
continue treatment for up to 35 cycles (approximately 2 years) from the 
start of treatment. 
Subjects who progress by either clinical or radiographic evaluation on 
monotherapy with MK-1454 (Arm 1), may cross over into the 
combination therapy arm of MK-1454 and pembrolizumab (Arm 2), 
provided they meet eligibility criteria. A crossover subject may receive 
up to 35 cycles of treatment in Arm 2 (MK-1454 with pembrolizumab 
combination therapy) regardless of the duration of treatment received in 
Arm 1 (MK 1454 monotherapy).
Subjects treated with monotherapy MK-1454 (Arm 1) may participate in 
intrasubject dose escalation after the completion of Cycle 3. A subject 
may undergo dose escalation once during monotherapy with MK-1454. 
Subjects in Arm 2 may not participate in intrasubject dose escalation. 
Subjects in Arm 3, an ATD phase, may undergo intrasubject dose 
escalation one time after receiving 3 cycles of treatment without a ≥ 
Grade 2 drug-related toxicity. 
Subjects may continue treatment until one of the following occurs:
disease progression, unacceptable AE(s), intercurrent illness that 
prevents further administration of treatment, investigator’s decision to 
withdraw the subject, subject withdraws consent, pregnancy of the 
subject, noncompliance with trials treatment or procedure requirements, 
or administrative reasons requiring cessation of treatment. After the 
EOT, each subject will be followed up for 30 days for monitoring all 
AEs. SAEs and ECI will be collected for 130 days after the EOT or for 
30 days after the EOT if the subject initiates new anticancer therapy, 
whichever is earlier. 
The Expansion phase (Part II) will open to enroll subjects in Cohorts A 
to C to evaluate the safety and efficacy of MK-1454 IT in combination 
with pembrolizumab 200 mg IV. Cohort A will evaluate MK-1454 in 
30 subjects with anti-PD-1/PD-L1 refractory HNSCC: Cohort B will 
include 30 subjects with anti-PD-1/PD-L1 treatment-naïve or refractory 
TNBC, and Cohort C will include 60 subjects with anti-PD-1/PD-L1 
treatment-naïve solid tumors with liver metastases, with a cap at 
15 subjects each with colorectal cancer (CRC) or pancreatic cancer. The 
starting dose for expansion Cohorts A and B will be the preliminary 
RP2D established in Arm 2. The starting dose and frequency for Cohort 
C will be the RP2D established for visceral IT administration in Arm 3.
All subjects, except for those who withdraw consent or are lost to follow-
up, will be followed up for survival. Subjects who experience confirmed 
disease progression or start a new anticancer therapy, will move into the 
Survival Follow-Up Phase and should be contacted every 12 weeks to 
assess for survival status until death, withdrawal of consent, or the end of 
the study, whichever occurs first.
087V73


Product:  MK-1454 
20
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Randomization Ratio
Subjects will be allocated without randomization. Allocation will be 
guided 
by 
lesion 
histology 
and 
arm 
completion. 
In the expansion phase, subjects will be allocated to a cohort 
corresponding to the histology and pathology of their lesions and will 
receive MK-1454 in combination with a fixed dose of pembrolizumab.
Abbreviations are not spelled out at first use. A list of abbreviations used in this document 
can be found in Appendix 12.6. Note: Both “subject” or “participant” may be used to refer to 
individuals enrolled in clinical trials. 
2.0 TRIAL DESIGN
Trial Design
This is a nonrandomized, multisite, open-label trial of MK-1454 monotherapy and MK-1454 
combination therapy with a fixed dose of pembrolizumab 200 mg IV in subjects with 
advanced/metastatic solid tumors or lymphomas. MK-1454 will be administered IT. Each 
cycle within the trial is a 21-day cycle. The trial will begin with the Dose Escalation and 
Confirmation phase (Part I) comprising Arms 1, 2, and 3. Subsequently, an expansion phase 
will initiate to further examine safety and efficacy of MK-1454 IT in combination with 
pembrolizumab.
Part I – Dose Escalation and Confirmation Phase
Unless deemed medically unsafe by the investigator, all subjects will be required to undergo
a biopsy of the lesion to be injected with MK-1454, and a biopsy of a noninjected distant,
discrete lesion, during the screening period (prior to MK-1454 administration). Also, in 
Arm 1 and Arm 2 on Cycle 3 Day 15, biopsy of an injected lesion treated with MK-1454, and 
biopsy of a distant, discrete noninjected lesion are to be obtained. In Arm 3, this biopsy will 
occur on Cycle 3 Day 1. On Cycle 6 Day 1, subjects with amenable lesions at both an 
injected and a noninjected site may undergo additional optional tumor biopsies. The optional 
biopsies on Cycle 6 Day 1 will be performed on both an injected lesion treated with MK-
1454, and a noninjected distant, discrete lesion. 
All subjects will undergo at least a 24-hour observation period following the first dose 
administration of MK-1454 on C1D1. The inpatient observation period on C1D1 may be 
extended up to 48 hours at the discretion of the investigator, and/or per local IRB/IEC, and/or 
Health Authority mandate. 
In the Part I, MK-1454 dosing in the first 3 cycles of Arm 1 and Arm 2 is
and dosing in 
Cycles 4 and beyond is
 MK-1454 dosing frequency in Arm 3 to visceral lesions will 
begin at
 and is intended to escalate to a maximum frequency of 
 
thereafter. 
Dose escalation will proceed based on emerging safety and tolerability data of MK-1454 as 
monotherapy and as combination therapy with pembrolizumab. For each dose level, an 
assessment will be made of the safety and tolerability data in order to define the next dose 
level to be tested (see Section 5.2 and Table 3 and Table 4). Arm 1, Arm 2, and Arm 3 will 
start with an ATD phase followed by an mTPI phase to identify an MTD and/or MAD of 
MK-1454 monotherapy (Arm 1) or MK-1454 combination therapy with pembrolizumab 
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
21
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
(Arm 2 and Arm 3). The Dose Escalation and Confirmation phase in Arms 1 and 2 of this 
study will aim to identify a preliminary RP2D of intratumorally administered MK-1454 in 
monotherapy and in combination with pembrolizumab IV infusion. In Arm 3, the aim will be 
to identify the RP2D of MK-1454 IT administered to visceral lesions in combination with 
pembrolizumab IV infusion. The RP2D may be the same as the MTD/MAD, or the RP2D 
may be modified from the MTD/MAD based on overall exposure, emerging safety data, 
pharmacodynamic data, and clinical benefit data from this study. 
Starting with a dose of 
 of MK-1454 in single-subject cohorts (Arm 1, Part A), the trial 
will proceed in an ATD up to a dose that meets at least 1 of the following 3 triggering 
criteria:  1) The
cohort is completed, 2) ≥Grade 2 toxicity as assessed by the 
investigator to be related, probably related, or possibly related to the drug at any dose level, 
or 3) Elevation of systemic TNF-α in blood above baseline levels by ≥3-fold for a given 
subject at any time during the first cycle of MK-1454. 
Upon completion of the ATD phase by reaching at least 1 of the above triggering criteria, the 
monotherapy arm (Arm 1) of the study will proceed to dose escalation and confirmation 
using an mTPI design (Part B). In addition, Arm 2 (Part C), the combination therapy arm, 
will initiate once 2 dose levels have been cleared by DLT evaluation in Arm 1.
Arm 2 (Part C), MK-1454 combination therapy with pembrolizumab, will begin in single-
subject cohorts starting with a dose that is at least 2 dose levels behind MK-1454 
monotherapy dose, and will proceed in an ATD up to a dose level, which meets at least 1 of 
the 3 triggering criteria. Arm 2 will then proceed to mTPI phase (Arm 2, Part D) to determine 
the MTD/MAD of the combination of MK-1454 with pembrolizumab.
Intrasubject dose escalation of MK-1454 to a higher dose level is permitted in Arm 1, 
including Parts A and B. Intrasubject dose escalation will be at the discretion of the 
investigator, provided that the subject remains on study drug after receiving 3 cycles of 
treatment without ≥Grade 2 drug-related toxicity, and provided that the dose escalation has 
proceeded beyond the next dose level. The subject’s dose may be escalated to the highest 
dose level that has been cleared by DLT evaluation. Intrasubject dose escalation is not 
permitted in Arm 2 (Parts C and D).
Arm 3 will assess the safety and tolerability of MK-1454 administered intratumorally to 
visceral lesions in combination with pembrolizumab infusion. Dose escalation in Arm 3 will
begin in an ATD at 
 and proceed to an mTPI when at least 1 of the following 
2 criteria is met: 1) The 
 cohort in combination is completed, 2) ≥ Grade 2 toxicity as 
assessed by the investigator to be related, probably related, or possibly related to the drug at 
any dose level in combination. Arm 3 will use the same dose escalation and confirmation 
rules as in the mTPI method with a minimum of 3 subjects per dose level in order to establish 
an MTD/MAD in visceral lesions for the combination of MK-1454 IT and pembrolizumab 
IV. In mTPI phase, visceral IT dosing of MK-1454 will increase in frequency up to
 
thereafter. Once safety and tolerability of dosing frequency of MK-1454 
visceral IT is established, dose escalation will continue per mTPI. See Section 5.2.1.3 for the 
Arm 3 dosing schedule. Intrasubject dose escalation may be permitted in Arm 3 subjects 
allotted to doses evaluated in the ATD (Part E) part once they have completed 3 cycles of 
treatment without a ≥Grade 2 drug-related toxicity. Intrasubject dose escalation may proceed 
to the highest dose that has cleared DLT evaluation. 
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
22
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
The ATD phase in Arm 1, Arm 2, and Arm 3 will have single-subject cohorts, but may allow 
up to 3 subjects per cohort to account for simultaneous enrollment. During MK-1454 dose 
escalation in Arm 1 (Parts A and B), Arm 2 (Parts C and D), and Arm 3 (Parts E and F), there 
will be at least 7 days of observation between each of the first 2 subjects at each dose level. 
Dose escalation of MK-1454 to determine the MTD/MAD for all 3 treatment arms will be 
guided by the mTPI design, targeting a DLT rate of 30%. Doses of MK-1454 used in 
combination with pembrolizumab will be at least 2 dose levels behind the monotherapy 
MK-1454 dose and will not exceed the MTD for monotherapy. If an MTD for the 
monotherapy arm is established, then the dose of MK-1454 in combination may continue 
escalation up to that dose. For example, if the MTD for monotherapy (Arm 1, Part A) is 
, then the starting dose for combination therapy (Arm 2, Part C), if no DLTs occurred 
in monotherapy, may be
 with a maximum dose escalation to
. If the MTD for 
monotherapy (Arm 1, Part A) is 
 then the starting dose for combination therapy will 
be
 In monotherapy (Arm 1, Part A), if the
dose level is completed, then the 
starting dose in combination therapy (Arm 2, Part C) will be
 
Once a dose level in the mTPI phase has been cleared for DLT, and a decision made to 
escalate to the next dose level, the cohort may be expanded to a total of 14 subjects to obtain 
additional pharmacokinetic and pharmacodynamics data. Dose-limiting toxicity information 
from these “back-filling” cohorts will not be formally included in the mTPI analysis for 
MTD determination but will be taken into consideration for preliminary RP2D determination. 
For each new dose level in the mTPI phase, there may be a minimum of 3 subjects and up to 
6 subjects per cohort. Based on the occurrence of DLTs, up to 14 subjects may enroll per 
dose level. Therefore, during mTPI, up to 14 subjects may be enrolled per dose level, 
depending on the occurrence of a DLT. Subjects may continue their assigned treatment for 
up to 35 cycles (approximately 2 years) from the start of treatment. 
Treatment may continue until one of the following occurs: disease progression, unacceptable 
AEs, intercurrent illness that prevents further administration of treatment, investigator 
decision to withdraw the subject, subject withdraws consent, pregnancy of the subject, 
noncompliance with trials treatment or procedure requirements, or administrative reasons 
requiring cessation of treatment. 
Subjects who progress by either clinical or radiographic evaluation on monotherapy with 
MK-1454 (Arm 1), may cross over into the combination therapy arm of MK-1454 and 
pembrolizumab (Arm 2), provided they meet crossover eligibility criteria in Section 5.1.4 
and Section 5.1.5. Subjects who cross over from Arm 1 to Arm 2 are eligible for up to 
35 cycles of treatment within Arm 2, regardless of the number of cycles of MK-1454
treatment received in Arm 1. Subjects who cross over will enter Arm 2 at the start of Arm 2, 
which will be at screening. 
Treatment allocation will be accomplished by nonrandom assignment through an IWRS. 
When both Arm 1 and Arm 2 are open for enrollment, IWRS will alternate subject
assignment between arms, starting with Arm 1. Establishment of the MTD/MAD in 
combination therapy of MK-1454 and pembrolizumab (Arm 2) requires that at least half of 
the 14 subjects in Arm 2 have no prior exposure to MK-1454 (ie, non-crossover subjects). 
When Arm 3 is opened, eligible subjects will be allocated in a nonrandomized fashion by 
IWRS.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
23
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
The final number of subjects enrolled in the Dose Escalation and Confirmation parts of the 
study will depend on the empirical safety data (DLT observations, the dose that triggers the
mTPI phase, and the preliminary recommended Phase 2 dose). For example, in a scenario 
where MK-1454 monotherapy starts at 
 and continues to the highest dose, the sample 
size across Parts A and B may be approximately 40 subjects. For combination therapy of 
MK-1454 with pembrolizumab, in a scenario where Arm 2 starts at 
of MK-1454 with
200 mg of pembrolizumab, and continues to the highest dose, the sample size across Parts C 
and D may be approximately 40 subjects. For combination therapy of MK-1454 IT in 
visceral lesions with pembrolizumab 200 mg IV (Arm 3), if dosing starts at
 of 
MK-1454 and continues to the highest dose, the sample size across Parts E and F may be 
approximately 35 subjects. In this scenario, the total sample size across Parts A-F will be
approximately 115 subjects. An administrative analysis may be conducted to enable future 
trial planning at the Sponsor’s discretion. The data will be examined on a continuous basis to 
allow for dose escalation and confirmation decisions.
Part II –Expansion Phase
Initiation of Expansion Cohorts will be staggered based on emerging safety and tolerability 
data from Part I. Unless deemed medically unsafe by the investigator, all subjects will be 
required to undergo a biopsy of the lesion to be injected with MK-1454 during the screening 
period (prior to MK-1454 administration). Subjects with an amenable lesion at the injected 
site will also undergo tumor biopsies on Cycle 2 Day 1 and optionally on Cycle 3 Day 1, 
unless deemed medically unsafe by the investigator. The expansion phase of the trial 
(Figure 3) will evaluate MK-1454 in combination with pembrolizumab 200 mg IV in the 
following populations:

Cohort A:  Subjects with HNSCC who are anti-PD-1/PD-L1 refractory 

Cohort B:  Subjects with either anti-PD-1/PD-L1 treatment-naïve or refractory
unresectable locally advanced or metastatic TNBC

Cohort C:  Subjects with other anti-PD-1/PD-L1 treatment-naïve solid tumors with
liver metastases 
Cohorts A and B will begin at the preliminary RP2D from Arm 2. MK-1454 IT will be 
administered 
 from Cycle 3 and beyond, 
in combination with pembrolizumab 200 mg IV Q3W beginning on C1D1). The RP2D dose 
and the dose for expansion is confirmed to be
 MK-1454, administered intratumorally 
to a minimum of 1 lesion per subject per treatment day and a maximum of 3 lesions per 
subject per treatment day, in combination with pembrolizumab IV.
Cohorts A and B will initiate prior to initiation of Cohort C. 
Cohort C will begin at the preliminary RP2D and frequency established from Arm 3. 
Treatment duration in each cohort in Part II will be up 35 cycles (approximately 2 years).
Cohorts A and B will each enroll a maximum of 30 subjects, while Cohort C will enroll up to 
60 subjects, for a total of up to 120 subjects in the expansion phase. The 60 Cohort C subjects 
will be enrolled with approximately 15 non-MSI-H CRC subjects, 15 pancreatic ductal 
adenocarcinoma subjects, and 30 subjects without these specific diagnoses.
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
24
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
The trial will be conducted in conformance with GCP.
AEs will be evaluated according to criteria outlined in the NCI CTCAE v4.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Schedule of Activities - Section 6.0. Details of 
each procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
Trial Diagram for Part I - Dose Escalation and Confirmation
The trial design for the dose escalation and confirmation phase is depicted in Figure 1.
Figure 1
Part I - Dose Escalation and Confirmation Phase
ATD = accelerated titration design; IT = intratumoral; MTD = maximum tolerated dose; mTPI = Modified Toxicity Probability 
Interval; Q3W = once every 3 weeks; RP2D = Recommended Phase 2 Dose.
* Triggering criteria for the start of the mTPI design for Arms 1 and 2: 1) The
 cohort is completed, 2) ≥Grade 2 toxicity as 
assessed by the investigator to be related, probably related, or possibly related to the drug at any dose level, or 3) Elevation of 
systemic TNF-α in blood above baseline by ≥3-fold at any time during the first cycle. For example, baseline TNF-α value of 20 
pg/mL increases to 60 pg/mL during the first cycle. 
** Triggering criterion for the start of the mTPI design for Arm 3:  1) The 
cohort is completed, 2) ≥Grade 2 toxicity as 
assessed by the investigator to be related, probably related, or possibly related to the drug at any dose level.
Treatment in Arm 1, Part A, MK-1454 dose escalation will begin with a
dose and will proceed based on safety events to a 
maximum dose of 
. The doses of MK-1454 used in combination with pembrolizumab will not exceed the MTD for 
monotherapy. Once an MTD for monotherapy is established, the dose of MK-1454 administered in Arm 2 combination with 
pembrolizumab may continue escalation up to that defined dose. At least 7 days of observation will occur between the first and 
second subject treated at each dose level. Arm 3 (visceral IT) will begin at 
 Arm 3, Part F mTPI design will initiate at
a dosing frequency of
followed by increasing frequency and dose escalation by mTPI design. 
CCI
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
25
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Figure 2
Arm 3 Dose and Frequency Escalation 
CCI
087V73


Product:  MK-1454 
26
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Diagram for Part II – Expansion Cohorts
Figure 3
Part II - Expansion Cohorts
IT – intratumoral; IV = intravenous; PD-1 = Programmed death-1 PD-L1 = programmed death ligand 1; 
 
 Q3W = every 3 weeks; RP2D = recommended Phase 2 dose.
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Male/Female subjects of at least 18 years of age with advanced/metastatic solid tumors or 
lymphomas will be enrolled in this trial.
Primary Objective(s) & Hypothesis(es)
(1) Objective:  For Parts I and II, to determine the safety and tolerability and to establish 
a preliminary recommended Phase 2 dose of MK-1454 administered via IT injection 
as monotherapy and in combination with pembrolizumab IV infusion.
CCI
CCI
087V73


Product:  MK-1454 
27
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Secondary Objective(s) & Hypothesis(es)
(1) Objective:  For Parts I and II, to evaluate the pharmacokinetics of MK-1454 
administered via IT injection as monotherapy and to evaluate the pharmacokinetics of
MK-1454 administered via IT injection as combination therapy with pembrolizumab
IV infusion. 
(2) Objective:  For Parts I and II, to evaluate the pharmacokinetics of pembrolizumab IV 
infusion in combination with MK-1454 administered via IT injection.
(3) Objective:  Separately for each tumor type in Part II*, to evaluate the ORR of 
MK-1454 at the preliminary RP2D in combination with pembrolizumab as assessed 
by the investigator by Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST 1.1) modified to follow a maximum of 10 total target lesions with a 
maximum of 5 target lesion per organ.
Exploratory Objectives 
(1) Objective:  For Part I, to evaluate the ORR and PFS of MK-1454 as assessed by
investigator
when used as monotherapy and as
combination therapy with 
pembrolizumab. In solid tumors, assessment will be based on RECIST 1.1 and
irRECIST. ORR and PFS as assessed according to RECIST v1.1 modified to follow a 
maximum of 10 total target lesions with a maximum of 5 target lesions per organ. In 
lymphomas, assessment will be based on the IWG revised response criteria [1]. For 
subjects with CTCL, response assessment will be based on the Global Response 
Score (see Table 22) [2].
(2) Objective:  Separately for each tumor type in Part II*, evaluate PFS of MK-1454 at 
the preliminary RP2D in combination with pembrolizumab as assessed by the 
investigator by RECIST 1.1 modified to follow a maximum of 10 total target lesions 
and a maximum of 5 target lesions per organ.
(3) Objective: In Parts I and II, to evaluate the effect of the study intervention on lesions 
not treated with IT injections, as assessed by investigator. The measurements of effect 
will include the ORR for noninjected lesions and the maximal reduction in the sum of 
diameters of noninjected target lesions, as described in itRECIST [3].
(4) Objective:  In Part I, to evaluate overall survival (OS) of subjects treated with 
MK-1454 both as monotherapy and as combination therapy with pembrolizumab.
Note: Efficacy analyses for each Part II expansion cohort will pool Part I subjects who meet the inclusion 
criteria for the respective Part II tumor type and received the same dose level of MK-1454 in combination with 
pembrolizumab.
087V73


Product:  MK-1454 
28
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
(5) Objective:  Separately for each tumor type in Part II*, to evaluate OS of MK-1454 at 
the 
preliminary 
RP2D 
in 
combination 
with 
pembrolizumab. 
*Note: Efficacy analyses for each Part II expansion cohort will pool Part I subjects 
who meet the inclusion criteria for the respective Part II tumor type and received the 
same dose level of MK-1454 in combination with pembrolizumab.
(6) Objective:  To identify molecular (genomic, metabolic and/or proteomic) biomarkers 
that may be indicative of clinical response/resistance, safety, pharmacodynamic 
activity, and/or the mechanism of action of MK-1454 as monotherapy and in 
combination with pembrolizumab and other treatments.
a. To investigate TNF-α and other cytokines that may correlate with tumor response.
b. To investigate other biomarkers in circulating blood cells or in tumor tissue that 
may correlate with tumor responses, and to evaluate differences in tumor tissue 
characteristics in biopsies taken prior to treatment and following treatment with 
MK-1454.
c. To investigate the relationship between the SNP of the STING gene, and to 
investigate the toxicity/efficacy of MK-1454 as monotherapy and as combination 
therapy with pembrolizumab.
4.0 BACKGROUND & RATIONALE
Background
Detailed background information on preclinical pharmacology, pharmacokinetics, 
pharmacodynamics, 
and 
metabolism 
of 
MK-1454 
is 
available 
in 
the 
MK-1454 IB.
The Sponsor is developing MK-1454, a CDN STING agonist with activity across species. 
DNA in the cytoplasm of mammalian cells represents a cellular danger signal, and the cGAS-
AMP/STING pathway is activated to respond to that potential threat (Figure 4). Free 
cytosolic DNA is recognized by cGAS, catalyzing the generation of the cyclic-dinucleotide 
2’-3’ cGAMP. Cyclic-dinucleotide 2’-3’ cGAMP strongly binds to the endoplasmic 
reticulum-transmembrane adapter protein STING. This leads to a conformational change of 
the STING dimer, enabling the binding and activation of TBK1 and inducing downstream 
phosphorylation and activation of transcription factors IRF-3 and NF-kB. This ultimately 
leads to a strong induction of type I IFNs and proinflammatory cytokines such as IL-6 and
TNF-α, which potentiate T cell activation through multiple mechanisms.
087V73


Product:  MK-1454 
29
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Figure 4
Schematic Diagram Showing Mechanism of the Enhancement of T Cell Driven 
Antitumor Immunity through the Action of Cyclic-Dinucleotide STING Agonists
Abbreviations: APC = antigen-presenting cells; cGAMP = cyclic guanosine monophosphate-adenosine 
monophosphate; cGAS = cyclic (guanosine monophosphate-adenosine monophosphate) synthase; CXCL9/10 = 
chemokine C-X-C motif ligand 9/10; DC = dendritic cell; dsDNA = double-stranded deoxyribonucleic acid; ER 
= endoplasmic reticulum; IFN = interferon; IRF7 = interferon regulatory factor 7; STING = stimulator of 
interferon genes;  TBK1 = tank-binding kinase 1.
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. Single nucleotide polymorphism 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%. 
Recent studies showed that all tested STING variants demonstrated comparable response to 
synthetic CDN-derivative STING agonist. 
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. 
087V73


Product:  MK-1454 
30
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Pharmaceutical and Therapeutic Background
MK-1454 Background
Published and internal data demonstrate that IT delivery of STING agonists leads to 
complete tumor regression or significant tumor growth inhibition in both anti-programmed 
cell death-1 (PD-1)-responsive and nonresponsive mouse syngeneic tumor models, and can 
also induce immune-mediated clearance of noninjected tumors [4] [5] [6].
Importantly, tumor-bearing mice whose tumors completely regress through the action of a 
CDN STING agonist become protected against subsequent challenges with the same tumor, 
indicating that induction of tumor-specific T cell memory has occurred [4]. Recently 
presented external [7] and in-house data demonstrated a discrepancy between the CDN doses 
associated with full eradication of the injected tumor and with maximal protection against 
tumor re-growth in rechallenge studies. These findings suggest that a “bell-shaped”
relationship may exist between CDN STING agonist doses and the potential for abscopal 
action of intratumorally-dosed CDN STING agonist. It is hypothesized that these preclinical 
findings are driven, at higher CDN doses, by innate immune cell activation, cytokine 
production and function in such a robust manner that it hampers the ability of the adaptive 
immune system to develop antitumor adaptive immune memory.
With the success of checkpoint inhibitors in the clinic, combination therapies focused on 
boosting the ability of the host’s innate immune system to activate adaptive immune 
antitumor responses are increasingly being advanced in preclinical studies and clinical trials 
[8]. 
With this in mind, the Sponsor is developing a CDN STING agonist that demonstrates 
antitumor efficacy in multiple syngeneic mouse models, with an acceptable safety profile. 
Attributes of MK-1454 include induction of T cell memory, as evidenced by protection in 
tumor rechallenge models, and enhanced antitumor efficacy in combination with anti-PD-1
mAb.
The mechanism of action (Figure 4) suggests that a CDN STING agonist could provide 
efficacy either as a stand-alone agent or in combination with the anti-PD-1 mAb
pembrolizumab. Based on preclinical data, combination therapy with MK-1454 and 
pembrolizumab may demonstrate efficacy in patients who either did not respond to 
pembrolizumab or who progressed on pembrolizumab therapy, as well as those patients who 
are predicted to be poor responders based on PD-L1 expression in the tumor. MK-1454 will 
be presented in the clinic as a sterile liquid in a single use vial for IT injection. The active 
formulation will be available in low and high concentrations, along with diluent to enable 
customization of the dosing concentration per tumor size/ administered volume. 
Pembrolizumab Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [9]. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
087V73


Product:  MK-1454 
31
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
malignancies. In particular, the presence of CD8+ T cells and the ratio of CD8+ effector 
T cells/FoxP3+ regulatory T cells correlates with improved prognosis and long-term survival 
in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating lymphocytes 
can be expanded ex vivo and reinfused, inducing durable objective tumor responses in 
cancers such as melanoma [10] [11]. 
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 
programmed cell death-1 ligand 2 [PD-L2]) [12] [13]. 
The structure of murine PD-1 has been resolved [14]. PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable–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, protein kinase C-θ, and ZAP70, 
which are involved in the CD3 T cell signaling cascade [15] [16], [17]. 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 [18] [19]. As a 
consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic intervention in 
solid tumors and lymphomas (see the IB).
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) of 
the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1, and PD-L2. Pembrolizumab has shown clinical activity in multiple tumor 
types [20]. Please refer to the current label. 
Pembrolizumab will be presented in the clinic as a sterile lyophilized powder for 
reconstitution in a single use vial for dilution to be administered as an IV infusion.
Rationale
Rationale for the Trial and Selected Subject Population
Rationale for Part I - Dose Escalation and Confirmation 
Internal data demonstrate STING expression in multiple tumor types, supporting the broad 
inclusion of such tumor types as advanced/metastatic solid tumors and lymphomas. 
Endogenous STING pathway activation within the tumor induces spontaneous T cell priming 
that is necessary for the generation of adaptive immunity. In mouse tumor models, STING 
087V73


Product:  MK-1454 
32
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
activation in the tumor microenvironment leads to a potent antitumor response. Intratumoral 
injection of CDN STING agonist induces regression of established tumors and generates 
systemic immune responses, mediating rejection of distant metastases and providing 
immunologic (T cell) memory in mice [21] [4]. Therefore, a synthetic CDN, such as MK-
1454, has potential as a cancer therapeutic. 
Tumor treatment site selection initially will be based on accessibility of the tumor site to IT
injection. The FIH Phase I study of MK-1454 will enroll subjects with refractory solid 
tumors and lymphomas with cutaneous, subcutaneous, and/or nodal lesions that are visible, 
palpable, or detectable by ultrasound guidance for IT injection, as well as subjects with 
metastatic liver lesions amenable to injection via ultrasound or cross-sectional imaging 
(CT/MRI) guidance. Subjects must have at least one lesion that is amenable to IT injection. 
For solid tumor subjects, this lesion must be ≥1 cm for solid tumors or ≥1.5 cm for nodal 
lesions, and ≤10 cm in longest diameter for both solid tumors and nodal lesions in solid 
tumor subjects. For lymphoma subjects, a nodal lesion ≥1.5 cm in short axis, or an extranodal 
lesion ≥1 cm in 2 dimensions. Nodal lesions ≥1.0 cm and <1.5 cm in the short axis may be 
injected, if involvement by lymphoma has been documented by pathology report. The longest 
diameter for an injectable lesion must be ≤10 cm for both solid tumor subjects and 
lymphoma subjects. 
The injectable lesion must be accessible for biopsy at screening and after IT injection with 
MK-1454. See Section 5.1.2 for Inclusion Criteria. In addition, a distant, discrete noninjected
lesion, which is separate from the injected lesion, will undergo biopsy at screening and after 
the subject has received treatment with MK-1454. This distant, discrete lesion is not injected 
with MK-1454. 
Rationale for Part II - Expansion Cohorts
STING has been reported to be expressed in many human tissues and broadly across multiple 
human tumor subsets, including pancreatic adenocarcinoma, head and neck cancer, 
melanoma, colorectal cancer, TNBC, and other solid tumors. In addition, tumor type 
selection was based on projected accessibility for IT injection into cutaneous lesions, 
subcutaneous solid tumors, subcutaneous lymph nodes, and liver lesions. The selected 
subject populations for Expansion Cohorts represent an unmet medical need. 
In preclinical studies intratumoral 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. In addition, 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 [4] [5] [6].
Existing and emerging, external and internal data suggest that the observed antitumor
efficacy of STING agonism is primarily obtained through enhancing the capacity of the 
innate immune system to present tumor-associated antigens to CD8+ T cells as well as 
through a direct anti-proliferative effect on tumor cells.
087V73


Product:  MK-1454 
33
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Based on preclinical data and mechanism of action of STING agonism, combination therapy 
of MK-1454 with the anti-PD-1 mAb pembrolizumab may demonstrate efficacy in patients 
who did not respond to pembrolizumab or are predicted to be poor responders based on gene 
expression profiling [22], PD-L1 expression and/or low tumor mutational burden. In these 
patients, a two-step process is hypothesized to occur, STING agonism-driven priming and 
initial expansion of antitumor CD8+ T cells and pembrolizumab-driven expansion of relevant 
tumor-specific T cells with prevention of T cell exhaustion.
Therefore, MK-1454 in combination with pembrolizumab may be beneficial for subjects with 
tumor types selected in the Expansion Cohorts, who have received or been intolerant to 
standard of care regimen(s).
4.2.1.2.1 Microsatellite Instability Testing
Pembrolizumab is approved for the treatment of patients with MSI-H or dMMR cancer, 
agnostic of tumor type. This accelerated approval was based on an ORR of 39.6% in a 
population of 149 subjects with 15 different cancer types. This high response rate 
necessitates accounting for MSI-H/dMMR status in any study evaluating the efficacy of 
pembrolizumab therapy, either alone or in combination with additional agents. Additionally, 
in patients with tumors that are not MSI-H/dMMR, where a higher unmet medical need 
exists, agents in combination might enhance responses to pembrolizumab treatment. As such, 
in any expansion cohort in this trial, only subjects with tumors that are not MSI-H/dMMR by 
local testing will be eligible for enrollment.
Prior to this tumor type-agnostic approval of pembrolizumab in MSI-H/dMMR cancer, tumor 
MSI/dMMR local testing was already in clinical use and recommended for management of 
patients with a number of different malignancies. Subsequent to this approval, testing for 
MSI-H/dMMR is now recommended for the management of multiple additional 
malignancies. As such, local testing of tumors for MSI/dMMR is now regularly performed 
and therefore widely available.
For this trial, MSI/dMMR testing must have been performed on any patient being considered 
for expansion cohort enrollment, using either an archival or a newly obtained tumor sample. 
MSI/dMMR status must be determined by examining either (1) 5 tumor microsatellite loci 
using PCR-based assay, or (2) protein expression by IHC of 4 MMR enzymes 
(MLH1/MSH2/MSH6/PMS2), respectively. MSI testing methods based on DNA sequencing 
are also being developed and may be utilized for eligibility testing for this study, provided 
details of such a test are provided to and approved by the Sponsor.
Tumors are classified as MSI-H when at least 2 allelic shifts among the 5 analyzed 
microsatellite markers are detected by PCR and are classified as dMMR when expression of 
at least 1 of 4 MMR proteins is not detected by IHC. In situations where multiple tests have 
been performed, a subject will be considered to have an MSI-H/dMMR tumor if any of these 
tests yields an MSI-H/dMMR result. 
087V73


Product:  MK-1454 
34
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Rationale for Dose Selection/Regimen
Starting Dose for This Trial
The FIH starting dose of MK-1454 is targeted to be a minimally efficacious dose, 
corroborated by an insignificant change in systemic TNF-α concentration, and to have an 
acceptable safety profile in the advanced cancer patient population, in accordance with ICH 
S9 oncology guidance. Based on projected doses evaluated in rat and dog toxicity studies, an
FIH starting dose that is selected based on a fraction of the highest non-severely toxic dose or
the severely toxic dose to 10% of animals would be above the dose predicted to demonstrate 
efficacy in patients with tumors of certain volumes. Given the potential of MK-1454 to 
activate the immune system and the limitations of standard toxicology studies to model these 
effects in the preclinical setting, an FIH starting dose selection was also informed by
modeling a minimally efficacious dose. 
A summary of the approach used to select the FIH starting dose is presented here (see the IB 
for a detailed description and relevant data).
The readout of biological activity that has been used for translation from tumor-bearing mice 
to patients is antitumor efficacy. The dose-efficacy response relationship following at least 
one IT dose for multiple CDN STING agonists including MK-1454 was characterized in 
tumor-bearing mice implanted with MC38 cells. To leverage all the data that has been 
generated with multiple CDN STING agonists, the IT dose for each CDN STING agonist 
was normalized in mice on in vitro potency using mouse immune cells and on the tumor 
volume at the time of the first IT dose to mice. By taking this approach, the normalized dose 
at any level of efficacy could be scaled to patients after adjusting for differences in potency 
between mouse and human cells and initial tumor volume between tumor-bearing mice and 
patients.
Antitumor efficacy was expressed as a percent GRI and was modeled using an assumption 
that tumor growth dynamics are exponential [23]. A dose-efficacy response relationship that 
relates the percent GRI versus the normalized dose was described by a maximum effect 
model (Emax model) and the variability of the model by a 95% confidence band. 
The rationale for FIH dose selection is to choose a safe dose that is not associated with a 
significant change in systemic measures of pharmacology as measured by TNF-α. This dose 
corresponds to 135% GRI in mice suggesting signs of efficacy at this starting dose. In mice, 
135% GRI corresponds to a level of inhibition that will result in tumor volume reduction 
from 80 mm3 to a tumor volume below the limit of quantification within 5 days. A value of 
135% GRI in mice was assumed to be a percent GRI that will result in clinical response in 
patients. The selected FIH starting dose is 
for a total injectable tumor ≥0.5 cm3 (1 cm 
in the longest dimension for a single lesion). The injectate volume will be determined based 
on tumor size (see Table 6 and Table 7).
Cytokine TNF-α was measured to corroborate the efficacy response expected at FIH starting 
dose with a pharmacological readout suggesting no remarkable pharmacological response at 
that dose. In tumor-bearing mice, the plasma concentration of cytokine TNF-α was measured 
CCI
087V73


Product:  MK-1454 
35
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
at 4 hours after IT dose using 6 different CDN STING agonists including MK-1454. No 
remarkable change in cytokine TNF-α concentration was observed at the normalized dose to 
mice (3.3 μg for 80 mm3 tumor) that equates to the FIH starting dose of 
 for any total 
injectable tumor volume ≥0.5 cm3. The rationale for the upper dose limit of 
 is based 
on the maximum dose studied in dogs (3 mg). The therapeutic dose is expected to be less 
than 
 The 
 dose level is near the predicted efficacious dose of MK-1454 for a 
lesion volume of 33.5 cm3 (approximately 4 cm in diameter). Therefore,
 was selected 
as a triggering dose for progression from the ATD phase to the mTPI phase.
This conservative approach is being taken to ensure an acceptable safety profile, while 
continued patient safety will be ensured through appropriate dose escalation design and 
monitoring in the clinic. 
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab across all indications and regardless of tumor type. Please refer to the IB 
for details on the clinical development of pembrolizumab.
Maximum Dose/Exposure for This Trial
The determination of a preliminary RP2D for MK-1454 is an objective of Part I of this trial, 
which may evaluate dose levels up to 
Rationale for Dose Interval and Trial Design
The human starting dose of MK-1454 is based on an integration of nonclinical toxicological, 
pharmacological, and efficacy data. Initial dose escalation in Part I will proceed following an 
ATD in order to minimize the number of subjects treated at potentially subtherapeutic doses 
of MK-1454. The ATD will utilize 1-3 subjects per cohort with up to a 300% dose increment 
increase from the prior dose of MK-1454, followed by a model-based dose escalation mTPI 
approach with 3-14 subjects per cohort using dose increment increases of 30% to 100% of 
the prior dose. Transition from ATD to mTPI will be triggered by the occurrence of at least 1 
of the following 3 events:  1) The
 cohort is completed, 2) ≥ Grade 2 toxicity as 
assessed by the investigator to be related, probably related, or possibly related to the drug at 
any dose level, or 3) Elevation of systemic TNF-α in blood above baseline levels by ≥3-fold
for a given subject at any time during the first cycle of MK-1454. 
Dose escalation decisions will be made upon ongoing review of safety and available
PK/pharmacodynamic data at the current dose level. Weekly safety teleconferences will be 
held with the investigators from all sites. At these weekly safety teleconferences, safety data 
and PK/pharmacodynamic data will be reviewed for the current dose level, and dose 
escalation decisions will be made upon a consensus assessment. Subsequent dose levels will 
be communicated to all sites at the weekly safety teleconferences, and through written 
correspondence subsequent to the safety teleconference. Dose level escalations are Sponsor-
controlled through IWRS, which include the opening and closing of dose level cohorts upon 
dose escalation.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
36
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
To ensure safety, doses of MK-1454 used in combination with pembrolizumab in Arm 2 will 
be at least 2 dose levels behind the monotherapy dose, even if combination therapy was
triggered to start earlier, and will not exceed the MTD/MAD for monotherapy. If an 
MTD/MAD for monotherapy is established, the dose of MK-1454 in combination with 
pembrolizumab may continue escalation up to that dose. Intrasubject dose escalation of 
MK-1454 to the next dose level is permitted in Arm 1 (Parts A and B) at the discretion of the 
investigator provided that the subject remains on study after receiving 3 cycles of treatment 
without a ≥Grade 2 drug-related toxicity, and provided that dose escalation has proceeded 
beyond the next dose level. Intrasubject dose escalation is permitted once during Arm 1 for a 
qualifying subject. Intrasubject dose escalation is not permitted in Arm 2 (Parts C and D) or 
in Arm 3 (Parts E and F).
The starting dose for Arm 3 will be
 in combination with pembrolizumab 200 mg IV. 
MK-1454 will initially be administered to visceral lesions 
. Pembrolizumab will be 
administered Q3W. Arm 3 will proceed in an ATD, then transition to mTPI when at least one 
of the following 2 triggers are met: 1) The 
cohort in combination is completed, 2) ≥ 
Grade 2 toxicity as assessed by the investigator to be related, probably related, or possibly 
related to the drug at any dose level in combination. Dose escalation and increasing dosing
frequency of MK-1454 visceral IT injection (see Table 5 and Figure 2) will be based on 
subject tolerance per mTPI rules. The starting dose of 
MK-1454 in Arm 3 is based on 
the preclinical NOAEL dose level, and the rationale is to reduce redundancy of evaluating 
dose levels in Arm 3 for which safety evaluation of MK-1454 in combination with 
pembrolizumab had already occurred in Arm 2.
Rationale for Visceral Intratumoral Injection
The rationale for the addition of a visceral intratumoral arm of MK-1454 is to expand the 
tumor location for IT therapy to deeper tumor lesions and to visceral organs, such as the 
liver. In addition, the visceral IT arm will evaluate the safety, tolerability, PK/PD, and early 
efficacy of MK-1454 injected into visceral organs and deeper tumor lesions. To mitigate the 
potential safety risk of repeated visceral and deeper lesion IT injections, the IT dosing will 
begin at Q3W. Increased frequency and/or dosage of visceral IT administration as shown in
Figure 2 will be based on subject tolerance and clinical assessment of safety.
Rationale for Dose of MK-1454 Expansion Cohorts A and B (Part II)
The recommended Phase 2 dose for MK-1454 was based on analysis of the safety, 
pharmacodynamic, and early efficacy data from Part I of this Phase 1 study. In Part I dose 
escalation, responses were observed at doses of
 
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
 
MK-1454 doses of 
, suggesting improved efficacy at 
the lower MK-1454 doses evaluated in Part I (dose escalation) of this Phase 1 study. 
Pharmacodynamic analysis demonstrated nanostring gene signature and IP-10 dose-
dependent increases, which peaked at 
 followed by plateau. Overall safety profile of 
MK-1454 was tolerable. Based on composite evaluation of safety, pharmacodynamic, and 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
37
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
efficacy data, 
 was selected as the recommended Phase 2 dose and dose for Expansion 
Cohorts A and B. To assure that the dose per lesion remained in the efficacious dose range 
when more than one lesion was injected per treatment visit, the total MK-1454 
 dose 
may be administered in a minimum of 1 lesion and a maximum of 3 lesions per visit, with a 
minimum volume of 1 mL to be injected in a single lesion, and a maximum volume of 3 mL 
to be injected per subject per treatment visit. 
Rationale for Dose Schedule Expansion Cohorts A and B (Part II)
The starting dose for expansion Cohorts A and B will be the preliminary RP2D established in 
Arm 2, based on emerging safety, tolerability, and PK/pharmacodynamic data. The rationale 
for weekly dosing for the first 6 weeks (Cycle 1 and Cycle 2), followed by dosing every 3 
weeks thereafter, is to allow for congruence of the dosing schedule of visceral intratumoral 
administration (Part I:  Dose Escalation and Confirmation Arm 3) to the dosing schedule for 
cutaneous and subcutaneous intratumoral administration.
The starting dose and frequency for Cohort C will be the preliminary RP2D established in 
Arm 3.
Rationale for Endpoints
Efficacy Endpoints
An exploratory objective for this trial is to evaluate the antitumor activity of MK-1454 
monotherapy and MK-1454 combination therapy with pembrolizumab in subjects with 
advanced or metastatic solid tumors and lymphomas. Tumor response in subjects with solid 
tumors will be assessed using RECIST 1.1 and irRECIST. International Working Group 
revised response criteria will be applied to lymphoma subjects as assessed by investigator
review. A central imaging vendor will be used to collect, clean, and hold tumor imaging and 
medical photography. Images will be collected for possible analysis by blinded, independent 
central review.
Immunotherapeutic agents such as MK-1454 and pembrolizumab may produce antitumor 
effects by potentiating endogenous cancer-specific immune responses. The response patterns 
seen with such an approach may extend beyond the typical time course of responses seen 
with typical cytotoxic agents and can manifest a clinical response after an initial increase in 
tumor burden or even the appearance of new lesions. Standard response assessment criteria 
may not provide a comprehensive response assessment of immunotherapeutic agents such as 
MK-1454 and pembrolizumab. Therefore, the subject should not be discontinued from 
treatment unless the initial assessment of PD is confirmed at least 4 weeks later, provided the 
subject’s clinical condition is stable. Immune-related RECIST will be used to assess efficacy.
Sites are encouraged to have a multidisciplinary treatment and assessment plan to determine 
in advance that lesions will be treated, biopsied, and/or targeted for tumor assessment. A 
lesion that is designated as target for assessment by RECIST 1.1, irRECIST, or revised IWG 
criteria should ideally not undergo core or punch biopsy. 
CCI
CCI
087V73


Product:  MK-1454 
38
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
4.2.3.1.1 Immune-related RECIST (irRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment with immunotherapeutic agents. Immunotherapeutic agents may produce 
antitumor effects by potentiating endogenous cancer-specific immune responses. The 
response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents and can manifest a clinical response after an initial 
increase in tumor burden or even the appearance of new lesions. Standard RECIST 1.1 may 
thus not provide an accurate response assessment of immunotherapeutic agents. With other 
immunotherapeutic agents, up to 7% of evaluable patients experienced delayed or early 
tumor pseudoprogression. Of note, patients who had PD by RECIST 1.1 but not by 
irRECIST had longer OS than patients with PD by both criteria. These findings support the 
need to apply a modification to RECIST 1.1 that takes into account the unique patterns of 
response in immunotherapy and enables treatment beyond initial radiographic progression. 
Immune-related RECIST (irRECIST) is RECIST 1.1 adapted to account for the unique tumor 
response seen with immunotherapeutics as described by Nishino, et al. [24]. The assessment 
of unidimensional target lesions and response categories per irRECIST are identical to 
RECIST 1.1. However, Merck has implemented an adaptation related to new lesions, 
nontarget and tumor burden assessment in order to confirm radiographic progression. 
Immune-related RECIST will be used by local site investigators to assess tumor response and 
progression, and to make treatment decisions for solid tumors. For lymphomas, a similar 
modification of the revised IWG criteria will be applied.
4.2.3.1.2 IWG Revised Response Criteria for Malignant Lymphomas
For subjects with malignant lymphoma, the antitumor
activity of MK-1454 and 
pembrolizumab will be evaluated as part of the primary and secondary analyses using the 
IWG Revised Response Criteria for Malignant Lymphomas [25] as detailed in Section 
7.1.2.7.2.
The revised response criteria include several components: 1) assessment of nodal and 
extranodal lesions by CT (for size) and FDG-PET (for viability), 2) physical exam 
assessment of liver, spleen, and other possible findings not included in imaging, 3) evaluation 
of B-symptoms and 4) determination by biopsy of bone marrow involvement.
The response criteria will be applied by the site for assessment of disease response and as the
basis for all protocol guidelines related to subject status (eg, discontinuation of study 
therapy).
Because of the possibility of immunotherapy-related flare, subjects who show initial 
radiographic progression, if they are clinically stable, may be continued on therapy at the 
discretion of the investigator. A follow-up scan should be obtained at least 4 weeks later to 
confirm progression. 
087V73


Product:  MK-1454 
39
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
4.2.3.1.3 Response Assessment for CTCL
For subjects with CTCL, determination of eligibility will be made in accordance with the 
modified ISCL/Cutaneous Lymphoma Task Force of the EORTC revision of the 
classification of mycosis fungoides/Sézary syndrome [26]. The antitumor activity of MK-
1454 and pembrolizumab will be evaluated using response criteria described by the ISCL, the 
United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force 
of the EORTC [2].
The CTCL response criteria include a scoring system for assessing tumor burden in skin, 
lymph nodes, blood, and viscera, and a composite global response score, which are detailed 
in Section 7.1.2.7.3. 
Safety Endpoints
The primary objective of this trial is to characterize the safety and tolerability of MK-1454 as 
monotherapy and as combination therapy with pembrolizumab in subjects with advanced/ 
metastatic solid tumors and lymphomas. The primary safety analysis will be based on 
subjects who experience toxicities as defined by CTCAE criteria. Safety will be assessed by 
quantifying the toxicities and grades of toxicities experienced by subjects who have received 
MK-1454 as monotherapy and in combination with pembrolizumab, including SAEs and 
AEs of special interest.
Safety will be assessed by reported adverse experiences using CTCAE, Version 4.0. The 
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.
Safety parameters commonly used for evaluating investigational systemic anticancer 
treatments are included as safety endpoints for the study including, but not limited to, the 
incidence of, causality to, and outcome of AEs/SAEs; changes in vital signs and laboratory 
values. AEs will be assessed as defined by CTCAE, Version 4.0.
Pharmacokinetic Endpoints
Secondary objectives of this trial are to characterize the PK profile of MK-1454 following 
administration as a single agent, and to characterize the PK profile of MK-1454 and 
pembrolizumab following administration as combination therapy. The concentrations of 
these agents will serve as the primary readout for the PK, and these data will be used to 
derive PK parameters of the agents alone and in combination. Furthermore, the results of 
these analyses will be used in conjunction with the pharmacodynamics, safety and 
exploratory endpoints to help assess future dosing strategies for MK-1454.
Pharmacodynamic Endpoints
As a required first step in pharmacologic activity, receptor engagement is fundamental to 
dosing strategies. To evaluate target engagement, a systemic cytokine/chemokine activation 
assay that compares a panel of cytokine/chemokine activation pre- and post–administration 
087V73


Product:  MK-1454 
40
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
of study drug at both mRNA and protein level has been developed. Additional exploratory 
analyses will be performed to assess the effect of study drug on immune cells in tumor 
tissues and in the circulation.
The immediate mediators of CDN STING agonist activity are type I IFNs, proinflammatory 
cytokines, and chemotactic factors. Thus, systemic cytokines will be monitored to provide 
information to assist in the evaluation of target engagement and potential safety events
associated with immune stimulation and cytokine release. The cytokines that will be assessed 
include but are not be limited to TNF-α, IFNβ, IL-6, MIP-1α, MCP-2, IP-10, and CXCL11.
Planned Exploratory Biomarker Research
Introduction:  Cancer immunotherapies represent an important and novel class of antitumor
agents. However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy, as well as determinants of AEs in the 
course of our clinical trials. These efforts will identify novel predictive/pharmacodynamic 
biomarkers and generate information that will better guide single-agent and combination 
therapy with immuno-oncology drugs. To identify novel biomarkers, biospecimens (ie, blood 
components, tumor material) will be collected to support analyses of cellular components 
(eg, protein, DNA, RNA, metabolites) and other circulating molecules. Investigations may 
include but are not limited to planned genetic analysis, as outlined in Section 4.2.3.5.1.
4.2.3.5.1 Planned Genetic Analysis
Germline (blood) Genetic Analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing):  This research will evaluate whether genetic variation within a clinical 
trial population correlates with response to the treatment(s) under evaluation. If genetic 
variation is found to predict efficacy or AEs, the data might inform optimal use of therapies 
in the patient population. Furthermore, it is important to evaluate germline DNA variation 
across the genome in order to interpret tumor-specific DNA mutations. Finally, microsatellite 
instability (MSI) may be evaluated as this is an important biomarker for some cancers (ie, 
colorectal cancer). 
Genetic (DNA) analyses from tumor: The application of new technologies, such as next 
generation sequencing, has provided scientists the opportunity to identify tumor-specific 
DNA changes (ie, mutations, methylation status, MSI). Key molecular changes of interest to 
immune-oncology drug development include (for example) the mutational burden of tumors 
and the clonality of T cells in the tumor microenvironment. Increased mutational burden 
(sometimes referred to as a “hyper-mutated” state) may generate neo-antigen presentation in 
the tumor microenvironment. To conduct this type of research, it is important to identify 
tumor-specific mutations that occur across all genes in the tumor genome. Thus, genome-
wide approaches may be used for this effort. Note that in order to understand tumor-specific 
mutations; it is necessary to compare the tumor genome with the germline genome. 
Microsatellite instability may also be evaluated as this is an important biomarker for some 
cancers (ie, colorectal cancer).
087V73


Product:  MK-1454 
41
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
This research contributes to understanding genetic determinants of efficacy and safety 
associated with the treatments in this study.
Tumor and blood RNA analyses:  Both genome-wide and targeted mRNA expression 
profiling and sequencing in tumor tissue and in blood may be performed to define gene 
signatures that correlate clinical response to treatment with MK-1454 and pembrolizumab. 
Pembrolizumab induces a response in tumors that likely reflects an inflamed/ immune 
phenotype. Specific immune-related gene set may be evaluated, and new signatures may be 
identified. Individual genes related to the immune system may also be evaluated (eg, IL-10). 
MicroRNA profiling may also be pursued.
Proteomics and immunohistochemistry (IHC) using blood or tumor:  Tumor and blood 
samples from this study may undergo proteomic analyses (eg, PD-L1, CD8, CD4 IHC). PD-
L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to pembrolizumab in patients with NSCLC, and an in vitro diagnostic device has 
been developed for use with pembrolizumab in NSCLC. Preliminary data indicates that this 
association may also be true in additional cancer types (ie, TNBC, head and neck cancer, and 
gastric cancer). Additional tumor or blood-derived proteins may also correlate with response 
to pembrolizumab. Therefore, tumor tissue may be subjected to proteomic analyses using a 
variety of platforms that could include but are not limited to immunoassays, liquid 
chromatography/mass spectrometry. This approach could identify novel protein biomarkers 
that could aid in patient selection for MK-1454 therapy.
Other Blood-derived Biomarkers:  In addition to expression within the tumor tissue, tumor-
derived proteins (eg, PD-L1) or tumor-derived DNA can be shed from tumor and released 
into the blood. In the case of proteins, enzyme-linked immunosorbent assay can measure 
such proteins in serum and plasma and correlate this expression with response to 
pembrolizumab therapy, as well as levels of protein in the tumor. Deoxynucleic acid can be 
analyzed using next generation sequencing or polymerase chain reaction-based technologies. 
Advantages to this method are that blood is a less invasive compartment from which tumor-
derived protein or nucleic acid biomarkers may be measured.
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens consented for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes, depending on which specimens are consented for future 
biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol and will only be conducted on specimens from appropriately consented 
subjects. The objective of collecting/retaining specimens for Future Biomedical Research is 
to explore and identify biomarkers that inform the scientific understanding of diseases and/or 
their therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that subjects receive the correct dose of the 
correct drug/vaccine at the correct time.  The details of this Future Biomedical Research are 
087V73


Product:  MK-1454 
42
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
presented in Section 12.2 – Collection and Management of Specimens for Future Biomedical 
Research.
Benefit/Risk
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment 
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects of at least 18 years of age with advanced/metastatic solid tumors or 
lymphomas will be enrolled in this trial.
Subject Inclusion Criteria for Part I - Dose Escalation and Confirmation
Subject Inclusion Criteria for Arms 1 and 2
In order to be eligible for participation in Arm 1 or Arm 2 of this trial, the subject must:
1. Be ≥18 years of age on day of signing informed consent.
2. Voluntarily agreed to participate by providing documented informed consent. The subject
may also provide consent for Future Biomedical Research. However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
3. Have a histologically or cytologically confirmed advanced/metastatic solid tumor or 
lymphoma by pathology report and who have received, or have been intolerant to, all 
treatment known to confer clinical benefit. Solid tumors and lymphomas of any type are 
eligible for enrollment. Tumor types of greatest interest include, but are not limited to, 
malignant melanoma, HNSCC, breast adenocarcinoma, and lymphomas. 
4. Have Stage III or Stage IV disease that is not surgically resectable. Stage IIB
(T3N0M0B0-1) CTCL subjects are eligible [26]. 
5. Have at least 1 injectable lesion which is amenable to injection and biopsy. Biopsy may 
be performed via visual inspection, ultrasound guidance, or cross-sectional imaging.
Intratumoral injection for cutaneous lesions may be performed via visual inspection. 
Intratumoral 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 subjects. The longest 
087V73


Product:  MK-1454 
43
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
diameter for an injectable lesion must be ≤10 cm for both solid tumors and nodal 
lesions in solid tumor subjects.

Multiple coalescing, superficial lesions which in aggregate have a longest 
diameter of ≥1 cm and ≤10 cm. 

For lymphoma subjects, a nodal lesion ≥1.5 cm in short axis, or an extranodal 
lesion ≥1 cm in 2 dimensions. Nodal lesions ≥1.0 cm and <1.5 cm in the short 
axis may be injected, if involvement by lymphoma has been documented by 
pathology report. The longest diameter for an injectable lesion must be ≤10 cm. 
6. Have at least 1 distant and/or discrete noninjected lesion that is amenable to biopsy via 
visual inspection or amenable to biopsy via image guidance, such as ultrasound or 
CT/MRI. This lesion must be measurable as defined by the response criteria used to 
assess the subject (RECIST 1.1 for solid tumors or revised IWG criteria for lymphomas).

For RECIST 1.1, ≥1 cm in longest diameter for non-nodal lesions, or ≥1.5 cm in 
short axis for nodal lesions.

For revised IWG, a nodal lesion >1.5 cm in longest diameter or >1.0 cm in short 
axis, or an extranodal lesion ≥1 cm in 2 dimensions.
7. Have an ECOG Performance Status of 0 or 1.
8. Demonstrate adequate organ function as defined by Table 1. 
All screening labs should be performed within 7 days prior to treatment initiation. 
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
≥1,500/mcL(>1,000/mcL 
for 
lymphoma 
subjects)  
Platelets
≥100,000/mcL (≥75,000/mcL for lymphoma 
subjects)
Hemoglobin
≥9 g/dL or ≥5.6 mmol/La (≥8 g/dL or 
≥5.0 mmol/L for lymphoma subjects)
Renal
Serum Creatinine or
CrCl (measured or calculatedb) or
GFR in place of CrCl
≤1.5 × ULN or
≥60 mL/min for subject with creatinine 
levels >1.5 X ULN
Hepatic
Total bilirubin (serum) 
≤1.5 × ULN or
Direct bilirubin ≤ULN for subjects with 
total bilirubin levels >1.5 X ULN
AST and ALT
≤2.5 × ULN 
≤5 × ULN for subjects with liver metastases
087V73


Product:  MK-1454 
44
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
System
Laboratory Value
Coagulation
INR or PT
PTT or aPTT
≤1.5 × ULN 
≤1.5 × ULN
Abbreviations: ALT = Alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = 
aspartate aminotransferase 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. Subjects can be on 
stable dose of erythropoietin (≥ approximately 3 months).
b CrCl should be calculated per institutional standard.
9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 

Is not a 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 Section 5.7.2 during the intervention 
period and for at least 130 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 Section 5.7.2.

The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.

Contraceptive use by women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
087V73


Product:  MK-1454 
45
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
10. Male subjects are eligible to participate if they agree to the following during the 
intervention period and for at least 130 days after the last dose of study intervention:

Refrain from donating sperm
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
OR

Must agree to use contraception unless confirmed to be azoospermic 
(vasectomized or secondary to medical cause [Section 5.7.2]) 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.
11. HIV-infected subjects must meet these additional criteria: 

Have HIV-1 infection documented by any licensed rapid HIV test or HIV E/CIA 
test kit at any time prior to study entry (Day 1) and confirmed by 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.

Have well-controlled HIV on ART, defined as: 
-
must have a CD4+ T cell count >350 cells/mm3 at time of screening;
-
must have achieved and maintained virologic suppression defined as 
confirmed HIV RNA level below 50 or the LLOQ (below the limit of 
quantification) using the locally available assay at the time of screening and 
for at least 12 weeks prior to screening; 
-
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).
Subject Inclusion Criteria for Crossover Into Arm 2
In order to be eligible for crossover into Arm 2 of this trial, the subject must:
1. Have either clinical or radiographic disease progression, or progression by global 
response score for CTCL on Arm 1 MK-1454 monotherapy. 
2. Have at least one injectable lesion which is amenable to injection and biopsy. Biopsy 
may be performed via visual inspection, ultrasound guidance, or cross-sectional imaging
guidance. Intratumoral injection for a cutaneous lesion may be performed via visual 
inspection. Intratumoral injection for subcutaneous lesions may be performed via
087V73


Product:  MK-1454 
46
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
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 subjects. The longest 
diameter for an injectable lesion must be ≤10 cm for both solid tumors and nodal 
lesions in solid tumor subjects.

Multiple coalescing, superficial lesions which in aggregate have a longest 
diameter of ≥1 cm and ≤10 cm. 

For lymphoma subjects, a nodal lesion ≥1.5 cm in short axis, or an extranodal 
lesion ≥1 cm in 2 dimensions. Nodal lesions ≥1.0 cm and <1.5 cm in the short 
axis may be injected, if involvement by lymphoma has been documented by 
pathology report. The longest diameter for an injectable lesion must be ≤10 cm.
3. Have at least one distant and/or discrete noninjected lesion that is amenable to biopsy via 
visual inspection or amenable to biopsy via image guidance. Biopsy may be performed 
via visual inspection, ultrasound guidance, or cross-sectional imaging guidance. This 
lesion must be measurable as defined by the response criteria used to assess the subject 
(RECIST 1.1 for solid tumors or IWG revised criteria for lymphomas).

For RECIST 1.1, ≥1 cm in longest diameter for non-nodal lesions, or ≥1.5 cm in 
short axis for nodal lesions.

For revised IWG, a nodal lesion >1.5 cm in longest diameter or >1.0 cm in short 
axis, or an extranodal lesion ≥1 cm in 2 dimensions.
4. Have an ECOG Performance Status of 0 or 1.
5. Demonstrate adequate organ function as defined by Table 1 within 7 days prior to 
treatment initiation. All screening labs should be performed within 7 days prior to 
treatment initiation.
6. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 

Is not a 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 Section 5.7.2 during the intervention 
period and for at least 130 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.
087V73


Product:  MK-1454 
47
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
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 Section 5.7.2.

The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.

Contraceptive use by women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
7. Male subjects are eligible to participate if they agree to the following during the 
intervention period and for at least 130 days) after the last dose of study intervention:

Refrain from donating sperm
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
OR

Must agree to use contraception unless confirmed to be azoospermic 
(vasectomized or secondary to medical cause [Section 5.7.2]) 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.
8. HIV-infected subjects must meet these additional criteria: 

Have HIV-1 infection documented by any licensed rapid HIV test or HIV enzyme 
or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study 
entry (Day 1) and confirmed by 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.

Have well-controlled HIV on ART, defined as: 
-
must have a CD4+ T cell count >350 cells/mm3 at time of screening;
-
must have achieved and maintained virologic suppression defined as 
confirmed HIV RNA level below 50 or the LLOQ (below the limit of 
quantification) using the locally available assay at the time of screening and 
for at least 12 weeks prior to screening; 
087V73


Product:  MK-1454 
48
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
-
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).
Subject Inclusion Criteria for Arm 3
In order to be eligible for participation in Arm 3 of this trial, the subject must meet the 
following inclusion criteria:
1. Be ≥18 years of age on day of signing informed consent.
2. Voluntarily agreed to participate by providing documented informed consent. The subject 
may also provide consent for Future Biomedical Research. However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
3. Have a histologically- or cytologically confirmed advanced/metastatic solid tumor or 
lymphoma by pathology report and who have received or have been intolerant to all 
treatment known to confer clinical benefit. Solid tumors and lymphomas of any type are 
eligible for enrollment. Tumor types of greatest interest include, but are not limited to, 
malignant melanoma, HNSCC, breast adenocarcinoma, and lymphomas. 
4. Have Stage III or Stage IV disease that is not surgically resectable. 
5. Has metastatic liver involvement that does not exceed one-third of the total liver volume 
in subjects to be treated by liver IT injection. Hepatocellular carcinoma subjects are 
excluded from eligibility of intratumoral liver injection. In addition, has at least one 
injectable liver lesion with the following: 

The injectable liver lesion is amenable to image-guided intratumoral injection and 
biopsy via ultrasound guidance or cross-sectional imaging (CT/MRI). 

Injectable lesion(s) must be ≥1 cm in longest diameter and ≤10 cm in longest 
diameter.
6.
Have at least 1 distant and/or discrete noninjected lesion that is amenable to biopsy via 
visual inspection or amenable to biopsy via image guidance, such as ultrasound or 
CT/MRI. This lesion must be measurable as defined by the response criteria used to 
assess the subject (RECIST 1.1 for solid tumors or revised IWG criteria for 
lymphomas).

For RECIST 1.1, ≥1 cm in longest diameter for non-nodal lesions, or ≥1.5 cm in 
short axis for nodal lesions.

For revised IWG, a nodal lesion >1.5 cm in longest diameter or >1.0 cm in short 
axis, or an extranodal lesion ≥1 cm in 2 dimensions.
7.
Have an ECOG Performance Status of 0 or 1.
8.
Demonstrate adequate organ function as defined by Table 1.
All screening labs should be performed within 7 days prior to treatment initiation. 
087V73


Product:  MK-1454 
49
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
9.
A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 

Is not a 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 Section 5.7.2 during the intervention 
period and for at least 130 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 Section 5.7.2.

The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.

Contraceptive use by women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
10.
Male subjects are eligible to participate if they agree to the following during the 
intervention period and for at least 130 days after the last dose of study intervention:

Refrain from donating sperm
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
OR

Must agree to use contraception unless confirmed to be azoospermic 
(vasectomized or secondary to medical cause [Section 5.7.2]) 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.
087V73


Product:  MK-1454 
50
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Contraceptive use by men should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
11.
HIV-infected subjects must meet these additional criteria: 

Have HIV-1 infection documented by any licensed rapid HIV test or HIV E/CIA 
test kit at any time prior to study entry (Day 1) and confirmed by 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.

Have well-controlled HIV on ART, defined as: 
-
must have a CD4+ T cell count >350 cells/mm3 at time of screening;
-
must have achieved and maintained virologic suppression defined as 
confirmed HIV RNA level below 50 or the LLOQ (below the limit of 
quantification) using the locally available assay at the time of screening and 
for at least 12 weeks prior to screening; 
-
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).
Subject Inclusion Criteria for Part II - Expansion Cohorts
1. Be ≥18 years of age on day of signing informed consent.
2. Voluntarily agreed to participate by providing documented informed consent. The subject 
may also provide consent for Future Biomedical Research. However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
3. Have at least one measurable lesion which is amenable to injection. Tumor lesions 
situated in a previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions. Intratumoral injection for cutaneous lesions may be 
performed via visual inspection. Intratumoral injection for subcutaneous lesions may be 
performed via ultrasound guidance or via palpation. This injectable lesion must 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 subjects. The longest 
diameter for an injectable lesion must be ≤10 cm for both solid tumors and nodal 
lesions in solid tumor subjects.
OR

Multiple coalescing, superficial lesions which in aggregate have a longest 
diameter of ≥1 cm and ≤10 cm. 
087V73


Product:  MK-1454 
51
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
4. In subjects to be treated by liver IT injection, has metastatic liver involvement that does 
not exceed one-third of the total liver volume. Hepatocellular carcinoma subjects are 
excluded from eligibility for intratumoral liver injection. In addition, has at least one 
injectable liver lesion that meets both the following conditions: 

The injectable liver lesion is amenable to image-guided intratumoral injection and 
biopsy via ultrasound guidance or cross-sectional imaging (CT/MRI). 
AND

Injectable lesion(s) must be ≥1 cm in longest diameter and ≤10 cm in longest 
diameter.
5. Subjects with any one of the following solid malignancies who meet all listed conditions 
of eligibility for an expansion cohort:

Cohort A:  HNSCC of the oral cavity, oropharynx, hypopharynx, or larynx; 
anti-PD-1/PD-L1 refractory (see Table 2) metastatic or recurrent. Subjects may 
not have a primary tumor site of the nasopharynx (any histology). 
o
Have histologically confirmed Stage III, IVa, or IVb disease per TNM 
staging, AJCC Eighth edition, with recurrent or persistent disease after 
definitive chemoradiation, deemed unresectable and considered refractory to 
both platinum-based combination chemotherapy and anti-PD-1/PD-L1
antibody therapy.
OR
o
Have histologically confirmed Stage IVc disease per TNM staging, AJCC 
Eighth edition,
considered refractory to platinum-based combination 
chemotherapy and anti-PD-1/PD-L1 antibody therapy.

Cohort B: Either anti-PD-1/PD-L1 treatment-naïve or refractory (see Table 2) 
TNBC
o
Have confirmed unresectable locally advanced or metastatic TNBC as locally 
determined according to the ASCO-CAP guidelines [27] on a newly obtained 
core or excisional biopsy from a not previously irradiated, tumor lesion. 
o
Have received at least one prior systemic treatment for breast cancer and have 
documented disease progression on or after their most recent therapy. 
o
Have been previously treated with an anthracycline and/or taxane in the 
(neo)adjuvant 
or 
metastatic 
setting
unless 
there 
was 
a 
medical 
contraindication to this treatment regimen.
o
Have LDH <2.5 × ULN [28] [29] [30].

Cohort C:  Other anti-PD-1/PD-L1 treatment-naïve solid tumors with liver 
metastases (including pancreatic cancer, non-MSI-H CRC, and other solid tumors. 
MSI-H status is to be determined by local testing).
o
Have histologically or cytologically confirmed Stage IV solid tumor that is 
not surgically resectable. 
087V73


Product:  MK-1454 
52
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 2
Anti-PD-1/PD-L1 Antibody Refractory Definition
Patients must have progressed on treatment with an anti-PD-1/PD-L1 monoclonal antibody 
(mAb) administered either as monotherapy, or in combination with other checkpoint 
inhibitors or other therapies. anti-PD-1/PD-L1 treatment progression is defined by meeting 
all of the following criteria:
a) Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb. 
b) Has demonstrated disease progression after anti-PD-1/PD-L1 as defined by 
RECIST v1.1. The initial evidence of disease progression (PD) is to be 
confirmed by a second assessment no less than 4 weeks from the date of the 
first documented PD, in the absence of rapid clinical progression.1,2.
c) Progressive disease has been documented within 12 weeks from the last 
dose of anti-PD-1/PD-L1 mAb. 
1.
Seymour et al; iRECIST: Guidelines for response criteria for use in trials testing 
immunotherapeutics. Lancet Oncol 18: e143-52
2.
This determination is made by the investigator. Once PD is confirmed, the initial 
date of PD documentation will be considered the date of disease progression.
6. Complete resolution of toxic effect(s) of the most recent prior chemotherapy to Grade 1 
or baseline (except alopecia). If the subject received major surgery or radiation therapy of 
>30 Gy, they must have recovered from the toxicity and/or complications from the 
intervention.
7. Have an ECOG Performance Status of 0 or 1.
8. Demonstrate adequate organ function as defined by Table 1. All screening labs should be 
performed within 7 days prior to treatment initiation. 
9. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 

Is not a 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 Section 5.7.2 during the intervention 
period and for at least 130 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.
087V73


Product:  MK-1454 
53
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential

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 Section 5.7.2.

The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.

Contraceptive use by women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
10. Male subjects are eligible to participate if they agree to the following during the 
intervention period and for at least 130 days after the last dose of study intervention:

Refrain from donating sperm
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent
OR

Must agree to use contraception unless confirmed to be azoospermic 
(vasectomized or secondary to medical cause [Section 5.7.2]) 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.
11. HIV-infected subjects must meet these additional criteria: 

Have HIV-1 infection documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
(Day 1) and confirmed by 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.

Have well-controlled HIV on ART, defined as: 
o
must have a CD4+ T cell count >350 cells/mm3 at time of screening;
o
must have achieved and maintained virologic suppression defined as 
confirmed HIV RNA level below 50 or the LLOQ (below the limit of 
quantification) using the locally available assay at the time of screening and 
for at least 12 weeks prior to screening; 
087V73


Product:  MK-1454 
54
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
o
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).
Subject Exclusion Criteria for Part I - Dose Escalation and Confirmation
The subject must be excluded from participating in any arm of the trial if the subject:
Exclusion Criteria for Arms 1, 2, and 3
1. Has had chemotherapy, definitive radiation, or biological cancer therapy within 
4 weeks (2 weeks for palliative radiation) prior to the first dose of study therapy, 
or has not recovered to baseline or CTCAE Grade 1 (Grade 2 alopecia is allowed) 
from the AEs due to cancer therapeutics administered more than 4 weeks earlier.
2. Is currently participating and receiving study therapy or has participated in a study 
of an investigational agent and has received study therapy or has used an 
investigational device within 28 days of administration of MK-1454. 
Note:  Prior exposure to immunotherapeutics is allowed, including PD-1 and 
PD-L1 inhibitors, provided patient did not experience a ≥Grade 3 drug-related 
toxicity on monotherapy with a PD-1 or PD-L1 inhibitor.
3. Is expected to require any other form of antineoplastic therapy while on study.
4. Is on chronic systemic steroid therapy in excess of replacement doses (prednisone 
≤10 mg/day is acceptable), or on any other form of immunosuppressive 
medication. For CTCL, continued use of either prednisone ≤10 mg/day or 
continued use of topical steroids is acceptable.
Note:  The use of physiologic replacement doses of corticosteroids may be 
approved after consultation with the Sponsor Medical Monitor or designee.
5. Has a history of a second malignancy, unless potentially curative treatment has 
been completed, with no evidence of malignancy for 2 years.
Note: The time requirement does not apply to subjects who underwent successful 
definitive resection of basal cell carcinoma of the skin, superficial bladder cancer 
or in situ cervical cancer.
6. Has clinically active central nervous system metastases and/or carcinomatous 
meningitis. Subjects 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 drug 
administration, and are off immunosuppressive doses of systemic steroids at least 
2 weeks from enrollment.
7. Has had a severe hypersensitivity reaction to treatment with a monoclonal 
antibody.
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 
087V73


Product:  MK-1454 
55
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
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. 
9. Has a history of vasculitis.
10. Has an active infection requiring therapy.
11. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
12. Has undergone prior allogeneic hematopoietic stem cell transplantation within the 
last 5 years. 
Note:  Subjects who have had a transplant greater than 5 years ago are eligible as 
long as there are no symptoms of GVHD.
13. Has Hepatitis B or C infections, or is known to be positive for Hepatitis B surface 
antigen/Hepatitis B virus (HBsAg/HBV) DNA or Hepatitis C Antibody (Hep C 
Ab) or ribonucleic acid (RNA). Active Hepatitis C virus (HCV) 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.
14. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the study, interfere with the 
subject’s participation for the full duration of the study, would make 
administration of the study drugs hazardous or make it difficult to monitor 
adverse effects such that it is not in the best interest of the subject to participate, 
in the opinion of the treating investigator.
15. Has known psychiatric or substance abuse disorders that would interfere in
cooperation with the requirements of the trial.
16. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study.
17. Has not fully recovered from any effects of major surgery, and is free of 
significant detectable infection. Surgeries that required general anesthesia must be 
completed at least 2 weeks before first study drug administration. Surgery
requiring regional/epidural anesthesia must be completed at least 72 hours before 
first study drug administration and subjects should be recovered. 
18. Has received a live vaccine within 30 days prior to first dose.
19. Has a history of re-irradiation for HNSCC at the projected injection site.
20. Has a tumor(s) in direct contact or encases a major blood vessel, and has
ulceration and/or fungation onto the skin surface at the projected injection site. 
21. HIV-infected subjects with history of Kaposi’s sarcoma and/or multicentric 
Castleman’s disease.
22. HIV-infected subjects who have had an HIV-related opportunistic infection 
within 6 months.
087V73


Product:  MK-1454 
56
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
23. 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 MOA of 
the study drug. Patients 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.
Exclusion Criteria for Crossover Into Arm 2 
The subject must be excluded from crossover into Arm 2 of the trial if the subject:
1. Has had chemotherapy, definitive radiation, or biological cancer therapy within 
4 weeks (2 weeks for palliative radiation) prior to the first dose of study therapy, 
or has not recovered to baseline or CTCAE Grade 1 (Grade 2 alopecia is allowed) 
from the AEs due to cancer therapeutics administered more than 4 weeks earlier.
2. Is currently participating and receiving study therapy or has participated in a study 
of an investigational agent and has received study therapy or has used an 
investigational device within 28 days of administration of MK-1454. 
Note:  Prior exposure to MK-1454 is allowed, provided the patient has a washout 
period of at least 14 days and did not experience Grade 3 or higher drug-related 
toxicity. 
Note:  Prior exposure to immunotherapeutics is allowed, including PD-1 and 
PD-L1 inhibitors, provided patient did not experience a ≥ Grade 3 drug-related 
toxicity on monotherapy with a PD-1 or PD-L1 inhibitor 
3. Is expected to require any other form of antineoplastic therapy while on study.
4. Is on chronic systemic steroid therapy in excess of replacement doses (prednisone 
≤10 mg/day is acceptable), or on any other form of immunosuppressive 
medication.
Note:  The use of physiologic replacement doses of corticosteroids may be 
approved after consultation with the Sponsor Medical Monitor.
5. Has clinically active central nervous system metastases and/or carcinomatous 
meningitis. Subjects 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 drug 
administration, and are off immunosuppressive doses of systemic steroids at least 
2 weeks from enrollment.
6. Has had a severe hypersensitivity reaction to treatment with a monoclonal 
antibody.
7. Has an active infection requiring therapy.
8. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
087V73


Product:  MK-1454 
57
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
9. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the study, interfere with the 
subject’s participation for the full duration of the study, would make 
administration of the study drugs hazardous or make it difficult to monitor 
adverse effects such that it is not in the best interest of the subject to participate, 
in the opinion of the treating investigator.
10. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study.
11. Has not fully recovered from any effects of major surgery, and be free of 
significant detectable infection. Surgeries that required general anesthesia must be 
completed at least 2 weeks before first study drug administration. Surgery 
requiring regional/epidural anesthesia must be completed at least 72 hours before 
first study drug administration and subjects should be recovered. 
12. Has received a live vaccine within 30 days prior to first dose.
13. Has a history of re-irradiation for SCCHN at the projected injection site.
14. Has a tumor(s) in direct contact or encases a major blood vessel and has
ulceration and/or fungation onto the skin surface at the projected injection site.
Exclusion Criteria for Part II - Expansion Cohorts
1. Has had chemotherapy, definitive radiation, or biological cancer therapy within 
4 weeks (2 weeks for palliative radiation) prior to the first dose of study therapy, 
or has not recovered to baseline or CTCAE Grade 1 (Grade 2 alopecia is allowed) 
from the AEs due to cancer therapeutics administered more than 4 weeks earlier
(this includes subjects with previous immunomodulatory therapy with residual 
immune-related AEs). Subjects receiving ongoing replacement hormone therapy 
for endocrine immune-related AEs will not be excluded from participation in this 
study.
2. Is currently participating and receiving study therapy or has participated in a study 
of an investigational agent and has received study therapy or has used an 
investigational device within 28 days of administration of MK-1454. 
Note:  Where prior exposure to immunotherapeutics is allowed, including PD-1 
and PD-L1 inhibitors, patient has experienced a Grade 3 or higher drug-related 
toxicity on monotherapy with a PD-1 or PD-L1 inhibitor requiring steroid 
treatment (>10 mg/day prednisone or equivalent) for >12 weeks or CTCAE Grade 
2 or higher pneumonitis regardless of steroid treatment. 
3. Is expected to require any other form of antineoplastic therapy while on study.
4. Is on chronic systemic steroid therapy in excess of replacement doses (prednisone 
≤10 mg/day is acceptable), or on any other form of immunosuppressive 
medication. 
Note:  The use of physiologic replacement doses of corticosteroids may be 
approved after consultation with the Sponsor Medical Monitor or designee.
087V73


Product:  MK-1454 
58
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
5. Has a history of a second malignancy, unless potentially curative treatment has 
been completed, with no evidence of malignancy for 2 years.
Note:  The time requirement does not apply to subjects who underwent successful 
definitive resection of basal cell carcinoma of the skin, superficial bladder cancer,
in situ cervical cancer, or other in situ cancers.
6. Has clinically active central nervous system metastases and/or carcinomatous 
meningitis. Subjects 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 drug 
administration, and are off immunosuppressive doses of systemic steroids at least 
2 weeks from enrollment.
7. Has had a severe hypersensitivity reaction to treatment with a monoclonal 
antibody.
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. 
9. Has a history of vasculitis.
10. Has a history of interstitial lung disease.
11. Has an active infection requiring therapy.
12. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis.
13. Has a history or current evidence of a gastrointestinal (GI) condition (eg, 
inflammatory bowel disease, Crohn’s disease, ulcerative colitis) or impaired liver 
function or diseases that in the opinion of the investigator may significantly alter 
the absorption or metabolism of oral medications; any condition, therapy, or 
laboratory abnormality that might confound the results of the study, interfere with 
the subject’s participation for the full duration of the study, make administration 
of the study drugs hazardous, or make it difficult to monitor adverse effects such 
that it is not in the best interest of the subject to participate, in the opinion of the 
treating investigator.
14. Has undergone prior allogeneic hematopoietic stem cell transplantation within the 
last 5 years. 
Note:  Subjects who have had a transplant greater than 5 years ago are eligible as 
long as there are no symptoms of GVHD.
15. Has Hepatitis B or C infections, or is known to be positive for HBsAg/HBV DNA 
or Hep C Ab or RNA. Active HCV is defined by a known positive Hep C Ab 
087V73


Product:  MK-1454 
59
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
result and known quantitative HCV RNA results greater than the lower limits of 
detection of the assay.
16. HIV-infected subjects with history of Kaposi’s sarcoma and/or multicentric 
Castleman’s disease.
17. HIV-infected subjects who have had an HIV-related opportunistic infection 
within 6 months.
18. 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 MOA of 
the study drug. Patients 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.
19. Has been treated with a STING agonist (eg, MK-1454, ADU-S100).
20. Has a history or current evidence of any condition, therapy, or laboratory 
abnormality that might confound the results of the study, interfere with the 
subject’s participation for the full duration of the study, would make 
administration of the study drugs hazardous or make it difficult to monitor 
adverse effects such that it is not in the best interest of the subject to participate, 
in the opinion of the treating investigator.
21. Has known psychiatric or substance abuse disorders that would interfere in 
cooperation with the requirements of the trial.
22. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study.
23. Has not fully recovered from any effects of major surgery and be free of 
significant detectable infection. Surgeries that required general anesthesia must be 
completed at least 2 weeks before first study drug administration. Surgery 
requiring regional/epidural anesthesia must be completed at least 72 hours before 
first study drug administration and subjects should be recovered. 
24. Has received a live vaccine within 30 days prior to first dose.
25. Has a history of re-irradiation for SCCHN at the projected injection site in the 
head and neck.
26. Has a tumor(s) in direct contact or encases a major blood vessel and has
ulceration and/or fungation onto the skin surface at the projected injection site in 
the head or neck. 
27. Has experienced weight loss >10% over 2 months prior to first dose of study 
therapy.
28. Has clinically relevant ascites at baseline (defined as requiring paracentesis) or 
with moderate radiographic ascites. A minimal amount of radiographic ascites is 
allowed.
087V73


Product:  MK-1454 
60
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
29. For Cohort C, subjects with MSI-H CRC are excluded.
Trial Treatment(s)
The human starting dose of MK-1454 for IT injection is based on an integration of 
nonclinical toxicological, pharmacological, and efficacy data (see Section 4.2.2). The 
treatments to be used in Arm 1 and Arm 2 of this trial are outlined below in Table 3 and 
Table 4, respectively, and for Arm 3 are provided in Table 5.
Dose escalation will proceed based on emerging safety and tolerability data of MK-1454 as 
monotherapy and in combination with pembrolizumab. For each dose level, an assessment 
will be made of the safety and tolerability data in order to define the next dose level to be 
tested. For the ATD phase, in both Arm 1 and Arm 2, dose escalation may proceed in 
increments of up to 300%. For example, during ATD, in the absence of DLTs and toxicity, 
dose escalation may proceed from
 For the 
mTPI phase, in both Arm 1 and Arm 2, dose escalation may proceed in increments of 30% to 
100%. For example, during mTPI, in the absence of DLTs and toxicity, dose escalation may 
proceed from
Intermediate doses between 
 
ments are within a 300% increase 
from prior dose for the ATD phase and within a 30% to 100% increase from prior dose for 
the mTPI phase. For example, in the ATD phase with toxicity findings, dose escalation may 
proceed from
See Section 5.2.2 for dose delays fulfilling DLT 
criteria during
for directions on how to proceed in the case of an 
AE.
Arm 3 will initiate in an ATD at 
 and escalate as shown in Figure 2 and Table 5.
Table 3
Trial Treatment for MK-1454 IT Monotherapy (Arm 1)
Drug, 
Vaccine, 
Biologic, 
Device, 
etc.
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Period
Use
MK-1454
Range:
Intratumoral
Via visual 
inspection for 
cutaneous 
lesions, and via 
ultrasound 
guidance or 
palpation for 
subcutaneous 
lesions, as 
needed
Experimental
a Dose levels will be determined based on emerging safety data.
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
61
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 4
Trial Treatment for MK-1454 IT in Combination with Pembrolizumab (Arm 2)
Drug, Vaccine, 
Biologic, Device, 
etc.
Dose/
Potency
Dose 
Frequency
Route of 
Administration
Regimen/
Treatment 
Perioda
Use
Pembrolizumab
200 mg
IV infusion
Day 1 of each 
21-day cycle
Experimental
MK-1454b
Range: 
Intratumoral 
Via visual 
inspection for 
cutaneous lesions, 
and via ultrasound 
guidance or 
palpation for 
subcutaneous 
lesions, as needed
Experimental
a Cohorts staggered at least 2 dose levels behind Arm 1, triggered by at least 1 of the following: 1) The
 MK-1454 
cohort is completed, 2) ≥ Grade 2 toxicity as assessed by the investigator to be related, probably related, or possibly 
related to the drug at any dose level, or 3) Elevation of systemic TNF-α in blood above baseline levels by ≥3-fold for a 
given subject at any time during the first cycle of MK-1454 (eg, increase from 20 pg/mL to 60 pg/mL). 
b MK-1454 will be administered within 0.5 to 4 hours following completion of pembrolizumab infusion, as applicable.
c Dose levels will be determined based on emerging safety data.
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
62
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 5
Trial Treatment for MK-1454 Visceral IT in Combination with Pembrolizumab 
(Arm 3)
Drug, 
Vaccine, 
Biologic, 
Device, etc.
Dose/ 
Potency
Dose Frequency
Route of 
Administration
Regimen/ 
Treatment 
Perioda
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 
21-day cycle
Experimental
MK-1454
ATD phase – Q3W
mTPIb:
Dose frequency to 
escalate as follows:
Intratumoral 
(Visceral)
Via ultrasound or 
cross-sectional 
imaging 
(CT/MRI) 
guidance for liver 
lesions, as needed
Experimental
ATD = Accelerated titration design; mTPI = modified toxicity probability interval
a MK-1454 will be administered within 0.5 to 4 hours following completion of pembrolizumab infusion.
b Dose frequency of visceral IT injections may increase with each cohort based on subject tolerance and clinical 
assessment of safety. Once a dose level is administered at the highest frequency and cleared by mTPI design, the next 
dose level may begin.
Trial treatment should begin on the day of treatment allocation/randomization or as close as 
possible to the date on which the subject is allocated/assigned.
All supplies indicated in Table 3 through Table 5 above will be provided centrally by the 
Sponsor or locally by the trial site, subsidiary or designee, depending on local country 
operational or regulatory requirements.
For any commercially available product that is provided by the trial site, subsidiary or 
designee every attempt will be made to source these supplies from a single lot/batch number. 
The trial site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
CCI
CCI
CCI
087V73


Product:  MK-1454 
63
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
Dose Selection (Preparation)
5.2.1.1.1 Dose Selection in Part I - Dose Escalation and Confirmation (Arm 1, Arm 2, 
and Arm 3)
MK-1454 will be administered as a sterile aqueous solution with a total volume of injectate 
of up to 4 mL per treatment visit for all injected lesions combined for Arm 1 and Arm 2. For 
Arm 3, the maximum injectate volume will be 3 mL. MK-1454 will be administered by 
injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or 
detectable by ultrasound guidance or cross-sectional imaging guidance as clinically 
appropriate. As well as into liver lesions that are detectable by ultrasound guidance or cross-
sectional imaging guidance as clinically appropriate. 
During dose escalation in both Arm 1 and Arm 2 (Parts A-D), each subject at a given dose 
level will receive a fixed dose of MK-1454 diluted in a volume of 0.5 mL to 4 mL of 
injectate. For Arm 3, each subject at a given dose level will receive a fixed dose of MK-1454 
diluted in a volume of 1.0 mL to 3 mL of injectate. See Table 3 and Table 4 and Table 5 for 
dose level range within Arm 1, Arm 2, and Arm 3 respectively. The volume of injectate 
delivered to each lesion will be based on the longest dimension of the target lesion as shown 
in Table 6 and Table 7, and on the number of lesions injected. 
Regarding prioritization of lesions to be injected at a treatment visit, any new or progressing 
lesion should be injected first, followed by injection of the largest lesion, with up to a total 
volume of injectate of 4 mL per treatment visit for Arm 1 and Arm 2, and 3 mL per treatment 
visit for Arm 3. As clinically feasible, injection of more than one lesion may be performed. 
Injectate volume per lesion based on lesion size is specified in Table 6 for cutaneous lesions 
and in Table 7 for subcutaneous lesions. See Appendix 12.3 for further guidance on lesion 
injection prioritization.
For cutaneous lesions, up to a maximum of 8 lesions may be injected per treatment visit, with 
a minimum injectate volume of 0.5 mL per lesion. For subcutaneous tumor lesions, a 
maximum of 4 lesions may be injected per treatment visit, with a minimum injectate volume 
of 1.0 mL. For visceral lesions, a maximum of 3 lesions may be injected per treatment visit, 
with a minimum injectate volume of 1.0 mL. The total injectate volume per treatment visit
per subject is of 4 mL for subjects in Arm 1 and Arm 2, and 3 mL for subjects in Arm 3. 
Documentation of dose volume administered per lesion will be obtained. 
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 6 for individual lesions may be permitted upon approval by the Sponsor 
Medical Monitor or designee under selected scenarios.
087V73


Product:  MK-1454 
64
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 6
Determination of MK-1454 Injection Volume for Intratumoral Injection of
Cutaneous Lesions Based on Lesion Size (Part I - Arm 1 and Arm 2) 
Lesion Size (longest dimension)
Injection Volume
>5 cm
≤4 mL
>2.5 cm to 5 cm
≤2 mL
>1.5 cm to 2.5 cm
≤1 mL
≥1.0 cm to 1.5 cm
0.5 mL
Details on dose calculation, preparation, and administration of MK-1454 are provided in the 
Procedures Manual.
Table 7
Determination of MK-1454 Injection Volume for Intratumoral Injection into 
Subcutaneous Lesions Based on Lesion Size (Part I Arm 1 and Arm 2)
Lesion Size (longest dimension)
Injection Volume
>5 cm 
≤4 mL
>2.5 cm to 5 cm
≤2 mL
>1.5 cm to 2.5 cm
≤1.5 mL
≥1.0 cm to 1.5 cm
1.0 mL
5.2.1.1.2 Dose Selection in Part II - Expansion Cohorts (Cohorts A and B)
The starting dose for Cohorts A and B is confirmed to be 
based on the safety, PK, and 
PD data from dose escalation and confirmation of MK-1454 IT in combination with 
pembrolizumab in Arm 2 (Table 8). The minimum number of lesions per subject per 
treatment visit to be injected is 1 lesion, and the maximum number of lesions to be injected 
per subject per treatment visit is 3 lesions. Each subject at this
 dose level will receive 
a fixed dose of intratumoral MK-1454 prepared in a volume of 1 mL to 3 mL of injectate, 
based on lesion size (see Table 9). 
The starting dose for Cohort C will be the preliminary RP2D (both dose level and frequency) 
from the dose escalation and confirmation of MK-1454 visceral IT established in 
combination with pembrolizumab in Arm 3. 
Dose volume for Expansion Cohorts will be determined by lesion size, as detailed in Table 9.
CCI
CCI
087V73


Product:  MK-1454 
65
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 8
Trial Treatment for MK-1454 IT in Combination with Pembrolizumab Part II 
(Expansion Cohorts A, B, and C)
Drug, Vaccine, 
Biologic, Device, 
etc.
Dose/ 
Potency
Dose 
Frequency
Route of 
Administration
Regimen/ 
Treatment 
Period
Use
Pembrolizumab
200 mg
Q3W
IV infusion
Day 1 of each 
21-day cycle
Experimental
MK-1454a
Cohorts A 
and B: 
Cohort C: 
Preliminary 
RP2D 
established in 
Arm 3
Cohorts A and
B:
 
Cohort C:
TBDb
Intratumoral
Via visual 
inspection for 
cutaneous lesions, 
or via ultrasound 
or cross-sectional 
imaging 
(CT/MRI) 
guidance, as 
needed
Cohorts A and
B: 
 
 
 
 
Cohort C:
TBDb
Experimental
CT = computed tomography; MTD/MAD = maximum tolerated dose/maximum administered dose; MRI = magnetic 
resonance imaging; QW = once each week; Q3W = once every 3 weeks; RP2D = Recommended Phase 2 Dose; TBD = 
to be determined.
a MK-1454 will be administered within 0.5 to 4 hours following completion of pembrolizumab infusion.
b Dose frequency will be determined in Arm 3.
Table 9
Injectate Volume for Arm 3 Visceral IT (Part I) and Expansion Cohorts (Part II)
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
Accelerated Titration Design in Arms 1, 2, and 3
The initial dose escalation in Arms 1, 2, and 3 will proceed following an ATD. 
Single subjects will be enrolled into sequential dose levels with up to 300% dose increment 
increases from the previous dose, eg
Dose ranges are outlined in Table 3, 
Table 4, and Table 5. Up to 3 subjects per cohort may be allowed in the event of
simultaneous enrollment. The first 2 subjects who will receive MK-1454 treatment at a new 
dose level must be at least 7 days apart. The subsequent dose level to be tested in the next 
cohort of subjects will be communicated to the investigator or designee following each dose 
escalation decision meeting. 
The dose for ending ATD will be the dose level at which one of the following occurs:

The 
 cohort is completed.

≥ Grade 2 toxicity as assessed by the investigator to be related, probably related, or 
possibly related to the drug according to NCI CTCAE v4.
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
66
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential

Elevation of systemic TNF-α in blood above baseline levels by ≥3-fold in a given 
subject during the first cycle of MK-1454 (Arm 1 and 2 only).
Dose Escalation and Confirmation During Modified Toxicity Probability 
Interval Design
Dose escalation and confirmation of MK-1454 will proceed from ATD phase (Part A, Part C, 
or Part E) to mTPI phase (Part B, Part D, or Part F) once at least 1 of the 3 triggering criteria 
is met (see Section 2.1) [31]. Subjects will be enrolled via IWRS according to the dose 
escalation and confirmation guidelines outlined in Section 5.2. The target DLT rate is 30%, 
with a tolerance interval of 3%. The specific dose levels for the ATD and mTPI phases will 
be determined through emerging safety and toxicity data. For the mTPI phase, dose 
escalation will proceed at dose increments between 30% and 100% of the prior dose level. 
The dose to be tested in the next cohort of subjects will be communicated to the investigator
or designee following each dose escalation decision meeting. Depending on the accrual rate, 
there may be a minimum of 3 and up to 6 subjects enrolled within 21 days of initiation at 
each new dose level. The first 2 subjects in each new dose level will receive 
MK-1454 treatment at least 7 days apart. Based on the occurrence of DLTs, up to 14 subjects 
may enroll per dose level. Enrollment will be monitored through IWRS. 
Dose escalation based on the mTPI design will be conducted according to Table 10, which
provides the rules for determining the next dose [32] [33]. In Table 10, the columns show the
number of patients treated at a dose level, and the rows correspond to the number of subjects 
who experience a DLT. The entries of the table are dose-finding decisions: E, S, D, and DU,
which represent the following parameters: Escalating the dose, Staying at the same dose, 
De-escalating the dose, and excluding the Dose from the trial due to Unacceptable toxicity. 
For example, if 0 out of the first 3 subjects in a given dose level develop a DLT, then the 
dose can escalate to the next level without further expansion. If 2 subjects out of the first 
3 subjects develop a DLT, then the dose will be de-escalated to the next lower dose level. If 3 
out of the first 3 subjects develop a DLT, then this indicates an unacceptable toxicity. If 1 out 
of the first 3 subjects of a given dose level develops a DLT, then the current dose level cohort 
will be expanded by continuing enrollment according to Table 10. The same principle will be 
applied whether 3, 4, 5 or 6 subjects are initially enrolled in the same dose cohort according 
to Table 10.
The number of subjects who are enrolled at each dose is capped to minimize the exposure to 
a dose that may be unacceptably toxic (denoted as DU in Table 10). To find out how many 
more subjects may be enrolled, count steps in a diagonal direction (down and to the right) 
from the cell (3 subjects, 1 DLT) to the first cell marked DU. For example, if 1/3 of the 
subjects have experienced a DLT at a given dose level, then no more than an additional 
3 subjects should be enrolled at this dose level until additional DLT data are available. This 
is because this dose level would be considered unacceptably toxic if all 3 of the additional 
subjects experience a DLT (ie, 4/6 subjects with DLT in Table 10). 
De-escalation (D) or excluding the dose from the trial due to unacceptable toxicity (DU) at 
the starting dose level of Arm 1 of the study indicates stopping of the trial. Escalation (E) at 
the highest dose level indicates staying at that level. During dose escalation and 
confirmation, it may be acceptable to de-escalate to an intermediate, not predefined and not 
087V73


Product:  MK-1454 
67
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
previously-studied dose if evaluation of toxicity at such a dose is desired. If this approach is 
taken, 3-6 new subjects may be enrolled at the new intermediate dose, and the 
aforementioned rules should be used to determine further enrollment at this dose level. After
14 subjects have been enrolled at any of the tested doses (including intermediate doses), dose 
finding will stop if the mTPI table indicates “S” for staying at current dose. Otherwise, up to 
14 new subjects may be enrolled at a lower dose if “D” or “DU” is indicated, or at a higher 
dose if “E” is indicated. Establishment of the MTD/MAD for the combination of MK-1454 
and pembrolizumab in Arm 2 requires that at least half of the 14 subjects in the MTD/MAD 
cohort have had no prior exposure to MK-1454 (ie, non-crossover subjects). Priority for 
enrollment in the MTD/MAD confirmation cohort of Arm 2 will be given to MK-1454-naïve 
subjects.
While the mTPI design is applied separately to Arm 1 and Arm 2, doses of MK-1454 used in 
combination with pembrolizumab via cutaneous or subcutaneous IT injection will be at least 
2 dose levels behind the MK-1454 monotherapy dose, and will not exceed the MTD for 
monotherapy. If an MTD for monotherapy (Arm 1) is established, then the dose of MK-1454 
in Arm 2 may continue escalation up to that established dose. 
For Arm 3, dose escalation will proceed by incrementing dose frequency then dosage level. 
The initial dose frequency of visceral IT will be 
. Per mTPI design, frequency will 
increase in the next cohort to 
, then to 
thereafter. Further 
increase in visceral IT injection frequency to 
for 2 cycles, followed by 
 thereafter
in a subsequent cohort will be based on mTPI design. After Cycle 3, the frequency of visceral 
IT administration may be modified based on clinical assessment of safety by the investigator 
in consultation with Sponsor. Dose decisions will be made jointly with the investigators. 
Enrollment into Arm 3 will be monitored through IWRS.
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
68
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 10
Dose-finding Rules per mTPI Design
Number of subjects evaluable for DLT at current dose
Number 
of
subjects with at 
least 1 DLT
3
4
5
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
D = De-escalate to the next lower dose
DU = The current dose is unacceptably toxic
E = Escalate to the next higher dose
S = Stay at the current dose
Target toxicity rate = 30%
Flat non-informative prior Beta (1,1) is used as a prior and ε1=ε2=0.03 [31] [34]
Definition of Dose-Limiting Toxicity
Dose-limiting toxicities will be defined from toxicities observed during the first cycle of 
treatment (21 days) for each dose level. See Section 5.9 for rules on replacement of subjects 
in the DLT period.
Subjects who experience a DLT in Cycle 1 will be discontinued from treatment. However, if 
in the opinion of the investigator the subject is deriving clinical benefit from the study 
treatment (for example a marked reduction in tumor burden), the subject may be allowed to 
continue on the study at a reduced dose level of MK-1454 upon resolution of the DLT to a 
≤Grade 1 AEs or to baseline, and upon discussion with the Sponsor Therefore, flexibility of 
rechallenge of MK-1454 at a lower dose per dose modification guidance below subsequent to 
a DLT may be considered.
The occurrence of any of the following toxicities during Cycle 1, if assessed by the 
investigator to be related, probably related, or possibly related to the drug will be considered 
a DLT, excluding toxicities clearly not related to the drug, such as disease progression, 
environmental factors, unrelated trauma, etc.:
1. Grade 4 nonhematologic toxicity (not laboratory)
087V73


Product:  MK-1454 
69
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
2. Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia
a.
Grade 4 thrombocytopenia of any duration
b. Grade 3 thrombocytopenia is a DLT if associated with clinically significant 
bleeding
3. Any nonhematologic AE ≥ Grade 3 in severity should be considered a DLT, with the 
following exceptions: Grade 3 fatigue lasting ≤3 days; Grade 3 nausea, vomiting, or 
diarrhea lasting ≤3 days in the absence of antiemetics or antidiarrheals per standard of 
care; Grade 3 rash without use of corticosteroids or anti-inflammatory agents per 
standard of care; Grade 3 fever and Grade 3 flu-like symptoms lasting ≤24 hours with 
negative infectious disease workup (including negative blood and urine cultures)
4. Any Grade 3 or Grade 4 nonhematologic laboratory abnormality, if

medical intervention is required, or

the abnormality leads to hospitalization, or

the abnormality persists for >1 week
5. Febrile neutropenia Grade 3 or Grade 4
6. Any drug-related toxicity that causes treatment discontinuation or dose delay >7 days 
between consecutive doses during Cycle 1
7. Any drug-related toxicity that causes a greater than 2-week delay in initiation of 
Cycle 2
8. Any elevated AST or ALT lab value that is ≥3× ULN and an elevated total bilirubin 
lab value that is ≥2× ULN and an alkaline phosphatase lab value that is <2× ULN, in 
which no alternative reasons can be found to explain the combination of increased 
AST/ALT and total bilirubin, such as viral Hepatitis A, B or C, preexisting or acute 
liver diseases, or another drug capable of causing the observed injury
9. Any ≥Grade 2 immune-mediated uveitis
10. Grade 5 toxicity
Dose Modification Due to Adverse Events
The Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE 4.0) must be 
used to grade the severity of AEs. The investigator may attribute each toxicity event to 
MK-1454 alone, or to pembrolizumab alone, or to combination therapy. Use dose 
modification according to Table 11, Table 12, , Table 14, or Table 15. 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. Dose modifications are always based on the previous cycle.
Subjects may have a maximum of 2 dose modifications of MK-1454 throughout the course of 
the study for toxicities, as described in Section 5.2.3.1. If further toxicity occurs or the 
criteria for resuming treatment are not met, the subject must be discontinued from the agent. 
If a subject experiences several toxicities and there are conflicting recommendations, follow 
the most conservative dose adjustment recommended (dose reduction appropriate to the most 
severe toxicity).
087V73


Product:  MK-1454 
70
Protocol/Amendment No.:  001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Reduction or holding of one agent and not the other agent is appropriate if, in the opinion of 
the investigator, the toxicity is clearly related to one of the study drugs. For example, in the 
combination arms (Arm 2 and Arm 3), if MK-1454 is held due to an AE attributed to that 
drug, then pembrolizumab may continue to be administered. Appropriate documentation is 
required regarding which drug the investigator is attributing the AE to. If, in the opinion of 
the investigator, the toxicity is related to the combination of 2 agents, then both drugs should 
be held according to recommended dose modifications. 
AEs (both nonserious and serious) associated with MK-1454 and pembrolizumab exposure 
may represent an immunological etiology. These AEs may occur shortly after the first dose 
or several months after the last dose of treatment. 
Exceptional circumstances to following the dose modification tables below may be 
considered after consultation with the Sponsor.
Dose Modification for MK-1454 Drug-related AEs in Part I - Arm 1, Arm 2, 
and Arm 3
Dose modification guidelines for MK-1454 drug-related AEs are presented in Table 11. In 
Arm 2, pembrolizumab treatment will be modified for the AEs as described below in . See 
Table 15 for treatment guidelines for cytokine release syndrome.
087V73


Product:  MK-1454 
71
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 11
MK-1454 Dose Modification Guidelines for Drug-related AEs in Monotherapy (Arm 1), Combination Therapy (Arm 2),
and Combination Therapy Visceral IT (Arm 3)
Toxicity
Hold 
Treatment
Criteria 
for 
Restarting Treatment
Dose/Schedule for Restarting Treatment
Criteria 
for 
Discontinuation 
after 
Consultation 
with 
Sponsor
Hematological toxicities:
Any Grade 1
hematological toxicity
No
N/A
N/A
N/A
Any Grade 2
hematological toxicity
Per medical 
assessment 
of the 
investigator
Per medical assessment 
of the investigator
Per medical assessment of the investigator:  
First, decrease dose by one dose level  
If AE persists, and upon discussion with 
Sponsor, then consider modification of dosing 
schedule per below:
Arm 1 and Arm 2: 
Cycle 1, 2, and 3: Reduce dosing schedule to 
Arm 3:
Cycle 1 and 2: Reduce dosing schedule to 
Arm 1 and Arm 2:  
Cycle 4 and beyond:  
Maintain dosing schedule at 
 unless AE 
persists for 2 additional cycles, then reduce 
dosing schedule to
Arm 3:
Cycle 3 and beyond:  
Maintain dosing schedule at 
unless AE 
persists for 2 additional cycles, then reduce 
dosing schedule to
If AE persists for 12 weeks 
without resolution following the 
last dose of study drug 
administered
CCI
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
72
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Toxicity
Hold 
Treatment
Criteria 
for 
Restarting Treatment
Dose/Schedule for Restarting Treatment
Criteria 
for 
Discontinuation 
after 
Consultation 
with 
Sponsor
Any Grade 3a
hematological toxicity
Yesa
Treatment may be 
restarted when AE 
resolves back to 
baseline or to Grade 1b
First, decrease dose by one dose level  
If AE persists, and upon discussion with 
Sponsor, then consider modification of dosing 
schedule per below:
Arm 1 and Arm 2:
Cycle 1, 2, and 3: Reduce dosing schedule to 
Arm 3:
Cycle 1 and 2: Reduce dosing schedule to 
Arm 1 and Arm 2:
Cycle 4 and beyond:  
Maintain dosing schedule at 
 unless AE 
persists for 2 additional cycles, then reduce 
dosing schedule to 
Arm 3:
Cycle 3 and beyond:
Maintain dosing schedule at 
unless AE 
persists for 2 additional cycles, then reduce 
dosing schedule to 
If AE persists for 12 weeks 
without resolution following the 
last dose of study drug 
administered
Permanent discontinuation 
should be considered for any 
severe or life-threatening event
CCI
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
73
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Toxicity
Hold 
Treatment
Criteria 
for 
Restarting Treatment
Dose/Schedule for Restarting Treatment
Criteria 
for 
Discontinuation 
after 
Consultation 
with 
Sponsor
Any Grade 4
hematological toxicity
Yes
Treatment may be 
restarted when AE 
resolves back to 
baseline or to Grade 1b
First, decrease dose by one dose level 
If AE persists, and upon discussion with 
Sponsor, then consider modification of dosing 
schedule per below:
Arm 1 and Arm 2:
Cycle 1, 2, and 3: Reduce dosing schedule to 
Arm 3:
Cycle 1 and 2: Reduce dosing schedule to 
Arm 1 and Arm 2:
Cycle 4 and beyond:  
Maintain dosing schedule at 
s unless AE 
persists for 2 additional cycles, then reduce 
dosing schedule to 
Arm 3:
Cycle 3 and beyond:  
Maintain dosing schedule at 
 unless AE 
persists for 2 additional cycles, then reduce 
dosing schedule to 
If AE persists for 12 weeks 
without resolution following the 
last dose of study drug 
administered
Permanent discontinuation 
should be considered for any 
severe or life-threatening event
Nonhematological toxicities:
Any Grade 1 
nonhematological toxicity 
Grade 2 alopecia
Grade 2 fatigue
No 
N/A
N/A
N/A
CCI
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
74
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Toxicity
Hold 
Treatment
Criteria 
for 
Restarting Treatment
Dose/Schedule for Restarting Treatment
Criteria 
for 
Discontinuation 
after 
Consultation 
with 
Sponsor
Any Grade 2 
nonhematological toxicity 
except Grade 2 alopecia 
and Grade 2 fatigue
Per medical 
assessment 
of the 
investigator
Per medical assessment 
of the investigator
Per medical assessment of the investigator: 
First, decrease dose by one dose level  
If AE persists, and upon discussion with 
Sponsor, then consider modification of dosing 
schedule per below:
Arm 1 and Arm 2:
Cycle 1, 2, and 3: Reduce dosing schedule to 
Arm 3:
Cycle 1 and 2: Reduce dosing schedule to 
Arm 1 and Arm 2:
Cycle 4 and beyond:  
Maintain dosing schedule at 
 unless AE 
persists for 2 additional cycles, then reduce 
dosing schedule to 
Arm 3:
Cycle 3 and beyond:  
Maintain dosing schedule at 
 unless AE 
persists for 2 additional cycles, then reduce 
dosing schedule to
If AE persists for 12 weeks 
without resolution after the last 
dose of study drug administered
CCI
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
75
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Toxicity
Hold 
Treatment
Criteria 
for 
Restarting Treatment
Dose/Schedule for Restarting Treatment
Criteria 
for 
Discontinuation 
after 
Consultation 
with 
Sponsor
Any Grade 3 
nonhematological toxicity
Yes
Treatment may be 
restarted when AE 
resolves back to 
baseline or to Grade 1b
First, decrease dose by one dose level 
If AE persists, and upon discussion with 
Sponsor, then consider modification of dosing 
schedule per below:
Arm 1 and Arm 2:
Cycle 1, 2, and 3: Reduce dosing schedule to 
Arm 3:
Cycle 1 and 2: Reduce dosing schedule to 
Arm 1 and Arm 2:
Cycle 4 and beyond:  
Maintain dosing schedule at 
 unless AE 
persists for 2 additional cycles, then reduce 
dosing schedule to
Arm 3:
Cycle 3 and beyond:  
Maintain dosing schedule at 
 unless
AE persists for 2 additional cycles, then reduce 
dosing schedule to 
If AE persists for 12 weeks 
without resolution following the 
last dose of study drug 
administered
Permanent discontinuation 
should be considered for any 
severe or life-threatening event
CCI
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
76
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Toxicity
Hold 
Treatment
Criteria 
for 
Restarting Treatment
Dose/Schedule for Restarting Treatment
Criteria 
for 
Discontinuation 
after 
Consultation 
with 
Sponsor
Any Grade 4 
nonhematological toxicity
Yes
Treatment may be 
restarted when AE 
resolves back to 
baseline or to Grade 1c
First, decrease dose by one dose level
If AE persists, and upon discussion with 
Sponsor, then consider modification of dosing 
schedule per below:
Arm 1 and Arm 2:
Cycle 1, 2, and 3: Reduce dosing schedule to 
Arm 3:
Cycle 1 and 2:  Reduce dosing schedule to 
Arm 1 and Arm 2:
Cycle 4 and beyond:  
Maintain dosing schedule at 
unless AE 
persists for 2 additional cycles, then reduce 
dosing schedule to 
Arm 3:
Cycle 3 and beyond:  
Maintain dosing schedule at 
unless AE 
persists for 2 additional cycles, then reduce 
dosing schedule to 
If AE persists for 12 weeks 
without resolution following the 
last dose of study drug 
administered
Permanent discontinuation 
should be considered for any 
severe or life-threatening event
AE = adverse event; Q3W = every 3 weeks;
a For Lymphoma subjects, the dose modification for Grade 3 hematological toxicities is to be determined per investigator medical assessment. Consideration 
should be given to underlying disease, disease progression, or prior cytotoxic therapy. Grade 1, Grade 2, and Grade 4 hematological toxicities, as well as all 
grades of nonhematological toxicities have the same dose modification guidelines for both solid tumor and lymphoma subjects.
b In case toxicity does not resolve back to baseline or to Grade 1 within 12 weeks following dose modification, MK-1454 should be considered for 
discontinuation after consultation with the Sponsor. 
c After any Grade 4 drug-related AE, subjects should not restart study treatment without consultation with the Sponsor. (Toxicity must have resolved to baseline 
or to Grade 1 prior to restarting study treatment) 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
77
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Dose Modification for MK-1454 in Part II - Expansion Cohorts
Guidelines for dose modification and/or treatment discontinuation for treatment-related 
injection site reactions and for CRS AEs are provided in Table 12. 
Table 12
Guidelines for Management of MK-1454 Intratumoral Injection Site Reactions
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 450 µg and limit 
injections to a maximum 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 450 µg 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.
NCI CTCAE ver. 5
087V73


Product:  MK-1454 
78
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
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. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 13.
087V73


Product:  MK-1454 
79
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 13
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated with 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations, or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations, or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
pneumonitis
Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid 
treatment
Add prophylactic antibiotics for opportunistic 
infections
Recurrent Grade 2 
or Grade 3 or 4 
Permanently 
discontinue
Diarrhea / Colitis 
Grade 2 or 3
Withhold
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
Participants with ≥Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis
Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion.
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
087V73


Product:  MK-1454 
80
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations, or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
AST 
/ 
ALT 
Elevation 
or 
Increased 
Bilirubin
Grade 2
Withhold
Administer corticosteroids 
(initial dose of 0.5-1 mg/kg 
prednisone or equivalent) 
followed by taper
Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable)
Grade 3 or 4 
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
T1DM 
or 
Hyperglycemia
New onset T1DM 
or 
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence of β-cell 
failure
Withhold a
Initiate 
insulin 
replacement therapy for 
participants with T1DM
Administer 
anti-
hyperglycemic 
in 
participants 
with 
hyperglycemia
Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes
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 a
Hyperthyroidism 
Grade 2
Continue
Treat with non-selective 
beta-blockers 
(eg, 
propranolol) 
or 
thionamides as appropriate
· Monitor for signs and symptoms of thyroid disorders
Grade 3 or 4
Withhold or 
Permanently 
discontinue a
087V73


Product:  MK-1454 
81
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
irAEs
Toxicity Grade 
(CTCAEv4.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations, or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Hypothyroidism
Grade 2-4
Continue
Initiate 
thyroid 
replacement hormones (eg, 
levothyroxine 
or 
liothyronine) per standard 
of care
Monitor for signs and symptoms of thyroid disorders
Nephritis 
and 
renal dysfunction
Grade 2
Withhold
Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper
Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3, or 4
Permanently 
discontinue
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 b
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; 
DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; 
SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
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.
b
Events that require discontinuation include, but are not limited to: Guillain-Barre Syndrome, encephalitis, myelitis, DRESS, SJS, TEN and other clinically 
important irAEs (eg, vasculitis and sclerosing cholangitis).
087V73


Product:  MK-1454 
82
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
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 14. 
Table 14
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 subject is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDs, 
narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs.
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the subject 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 (e.g. from 100 
mL/hr to 50 mL/hr). Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Subject may be 
premedicated 1.5h (± 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).
087V73


Product:  MK-1454 
83
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
NCI CTCAE Grade
Treatment
Premedication 
at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated 
for other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support 
indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should 
be used immediately.
Subject is permanently discontinued from 
further study drug treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other allowed dose interruption for pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study therapy. 
However, study therapy is to be restarted within 3 weeks of the originally scheduled dose, 
unless otherwise discussed with the Sponsor. The reason for interruption is to be documented 
in the subject’s study record.
087V73


Product:  MK-1454 
84
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Treatment for Cytokine Release Syndrome
Table 15
Cytokine Release Syndrome Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication 
at
subsequent dosing
Grade 1
Mild reaction: Therapy interruption 
not indicated. Intervention not 
indicated.
Increase monitoring of vital signs 
and oxygen saturation, as 
medically indicated, until the 
subject 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
Increase monitoring of vital signs 
and oxygen saturation, as 
medically indicated, until the 
subject 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
Subject may be premedicated 
1.5 hours (± 30 minutes) prior to 
MK-1454 administration with 
acetaminophen 500 to 1000 mg 
po (or equivalent dose of 
antipyretic)
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)
Additional appropriate medical 
therapy may include, but is not 
limited to:
IV fluids
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Anti-IL6 (eg tocilizumab)
Empiric antibiotics 
Subjects 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 MK-
1454 treatment. Upon approval 
by Sponsor, MK-1454 may be 
restarted at a reduced dose when 
AE resolves back to baseline or 
to Grade 1 (see Table 11).
Subject may be premedicated 
1.5 hours
(± 30 minutes) prior to MK-
1454 administration with 
acetaminophen 500 to 1000 mg 
po (or equivalent dose of 
antipyretic)
087V73


Product:  MK-1454 
85
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
NCI CTCAE Grade
Treatment
Premedication 
at
subsequent dosing
Grade 4
Life-threatening consequences; 
pressor or ventilatory support 
indicated
Additional appropriate medical 
therapy may include, but is not 
limited to:
IV fluids
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Anti-IL6 (eg tocilizumab)
Empiric antibiotics 
Subjects with ≥Grade 3 CRS need 
to be monitored very closely, likely 
in an intensive care setting
Permanently discontinue MK-
1454 in subjects who develop 
Grade 4 CRS  
Treatment by local surgery and/or radiation therapy of isolated or symptomatic progressing 
lesions in the setting of improving baseline disease may be permitted for palliative or 
potentially curative management following completion of Cycle 2. Subsequently, all 
interventions, including continuation of study drug, should be discussed with the Sponsor 
Medical Monitor or designee.
Intrasubject Dose Escalation
Intrasubject dose escalation will be allowed for subjects in Arm 1 (Parts A and B) 
monotherapy at the discretion of the investigator provided that the subject remains on study 
after receiving 3 cycles of treatment with MK-1454 monotherapy without a ≥Grade 2 drug-
related toxicity, and provided that dose escalation has proceeded beyond the next dose level. 
The subject may undergo intrasubject dose escalation one time while enrolled in this 
treatment arm. 
Subjects enrolled in the ATD phase of Arm 3 may undergo dose escalation one time after 
receiving 3 cycles of treatment without a ≥Grade 2 drug-related toxicity.
Intrasubject dose escalation is not permitted during the DLT evaluation period.
The subject may escalate to the highest dose level (and frequency for Arm 3) that has been 
cleared by DLT evaluation. This dose will be communicated to the site via written consent 
from the Sponsor and administered by IWRS. De-escalation from this dose will be based on 
occurrence of DLTs per dose escalation guidelines for either the ATD or the mTPI phase (see 
Section 5.2.1), as appropriate. Dose modification will be based on CTCAEs per Dose 
Modification Guidelines (see Section 5.2.3).
087V73


Product:  MK-1454 
86
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Timing of Dose Administration
Each subject may undergo up to 35 cycles (approximately 2 years) of MK-1454 treatment in 
both the monotherapy arm (Arm 1) and the combination therapy arms (Arm 2 and Arm 3), as 
well as the Expansion Cohorts (Cohort A to C).
After C1D1, trial treatment may be administered up to 3 days before, or up to 3 days after the 
scheduled treatment day within each cycle. Dosing interruptions are permitted in the case of 
medical/surgical events or logistical reasons that are not related to study therapy (eg, elective 
surgery, unrelated medical events, patient vacation, and/or holidays). Subjects should be 
placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor Medical Monitor or designee. The reason for interruption should 
be documented in the subject’s study record.
Timing of MK-1454 Dose Administration in Part I - Dose Escalation and 
Confirmation 
MK-1454 will be administered on Day 1, Day 8, and Day 15 in each 21-day cycle for Cycles 
1, 2, and 3 for Arms 1 and 2. Beginning with Cycle 4, MK-1454 will be administered on 
Day 1 of each 21-day cycle. 
For Arm 3, MK-1454 will be administered IT to visceral lesions at escalating frequencies. In 
the ATD phase, MK-1454 will be administered 
 In the 
mTPI phase, frequency of administration will begin with 
 Escalation of frequency may 
proceed first to a 
 on 
Day 1 of Cycle 3 and beyond. Escalation of frequency may then proceed to 
 
 After Cycle 3, 
frequency of visceral IT administration may be modified by the investigator based on clinical 
assessment of the investigator and discussion with the Sponsor.
In Arm 2 and Arm 3 of the trial, MK-1454 will be administered within 0.5 to 4 hours 
following completion of pembrolizumab infusion. 
Timing of MK-1454 Dose Administration in Part II - Expansion Cohorts
In Cohorts A and B, MK-1454 IT will be administered on Day 1, Day 8, and Day 15 in each 
21-day cycle for Cycles 1 and 2. Beginning with Cycle 3, MK-1454 will be administered on 
Day 1 of each 21-day cycle. 
Cohort C will initiate MK-1454 visceral IT treatment at the dose and frequency established 
as the RP2D from Arm 3.
Timing of Pembrolizumab Administration
Pembrolizumab 200 mg will be administered as an IV infusion on Day 1 of each 21-day 
cycle, in all combination treatment arms in Part I and Part II.
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
87
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Blinding 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Replacement of Subjects During the DLT Evaluation Period
Subjects discontinuing within 21 days of the first dose due to reasons unrelated to study 
treatment will not be considered evaluable for DLTs and may be replaced. Subjects with a 
DLT within 21 days of the first dose should not be replaced. See Section 8.5.1 for description 
of safety analysis population.
Randomization or Treatment Allocation
Treatment allocation in the dose escalation and confirmation phase (Arms 1, 2, and 3) will be 
accomplished by nonrandom
assignment. Enrollment into Arm 2 (MK-1454 with
pembrolizumab combination therapy) will begin once:
1. At least 1 of the 3 triggering criteria are met in Arm 1 (MK-1454 monotherapy)
2. A dose escalation decision has been made
3. 2 dose levels within Arm 1 have been cleared by DLT evaluation
When Arm 1 and Arm 2 are open for enrollment, alternating subject assignment between 
Arm 1 and Arm 2, starting with Arm 1, will be via IWRS. For example, once the 
dose 
cohort of Arm 1 (MK-1454 monotherapy) and the 
dose cohort of Arm 2 (MK-1454 
combination therapy with pembrolizumab) are open for enrollment, then the first subject will 
be allocated to Arm 1, the second subject will be allocated to Arm 2, the third subject will be 
allocated to Arm 1, etc. Subjects will be allocated to Arm 3 by nonrandom assignment via 
IWRS.
In the expansion phase, eligible subjects will be allocated to an appropriate open treatment 
arm by IWRS. For Cohorts A and B, 30 subjects will be allocated to each cohort. For 
Cohort C, 60 subjects will be allocated to treatment in total. There will be a cap at 15 subjects 
each for non MSI-H CRC and pancreatic cancer.
Stratification
No stratification based on age, sex, or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed and Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
CCI
CCI
087V73


Product:  MK-1454 
88
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator and in keeping with the community 
standards of medical care. All concomitant medication will be recorded on the CRF including 
all prescription, OTC, herbal supplements, and IV medications and IV fluids. If changes 
occur during the trial period, then documentation of drug dosage, frequency, route, and date 
will also be included in the CRF.
All concomitant medications received within 30 days before the first dose of trial treatment 
through the 30-day Safety Follow-up Visit should be recorded. If subjects experience an SAE 
or ECI, all concomitant medications administered 30 days after the last dose of study 
intervention are to be recorded, as defined in Section 7.2.
Subjects are prohibited from receiving the following therapies during the Screening, and 
Treatment Phases of this trial:

Immunotherapy not specified in this protocol.

Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol.

Investigational agents not specified in this protocol.

Radiation therapy; radiotherapy for symptom management is allowed beyond Cycle 2
upon approval by the Sponsor Medical Monitor or designee.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chickenpox, yellow fever, rabies, Bacillus
Chalmette Guerin, 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.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study. 
Subjects may receive other medications that the investigator deems to be medically 
necessary.
The Exclusion Criteria describe other medications which are prohibited in this trial.
There are no prohibited therapies during the Follow-up visits.
087V73


Product:  MK-1454 
89
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Rescue Medications & Supportive Care
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.3.2 ( and Table 14). Where appropriate, these guidelines include the use of oral or 
IV treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms 
do not improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 11 for 
treatment guidelines for AEs that are related to MK-1454 treatment and to Table 15 for 
guidelines regarding dose modification and supportive care for CRS. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage AEs 
such as diarrhea, nausea, or vomiting.
Contraception
MK-1454 and pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is 
not known if either drug has transient adverse effects on the composition of sperm. 
Consequently, subjects should be informed that taking either MK-1454 or pembrolizumab 
may involve unknown risks to the fetus if pregnancy were to occur during the study, and 
should be advised not to conceive or father children during treatment and for up to 130 days
after the last dose. If there is any question that a subject of childbearing potential will not 
reliably comply with the requirements for contraception, that subject should not be entered 
into the study.
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
087V73


Product:  MK-1454 
90
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
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 subject’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.
Male subjects receiving MK-1454 or pembrolizumab should be advised to have sperm 
samples frozen and stored before treatment.
Acceptable Contraception Methods
Acceptable methods of contraception are as followsa:
Single method (one of the following is acceptable):

Progestogen-only subdermal contraceptive implant b,c
087V73


Product:  MK-1454 
91
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential

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 subject’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 
subject.
a Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for subjects of clinical studies. Where local regulations require monthly pregnancy 
testing, see Appendix 12.5.
b  If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those that 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, postovulation 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).
‡If a contraceptive method listed above is restricted by local regulations/guidelines, then 
it does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region.
Please see Appendix 12.5 for country-specific pregnancy testing.
087V73


Product:  MK-1454 
92
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with MK-1454 or 
pembrolizumab, the subject will immediately be removed from treatment. The site will 
contact the subject at least monthly and document the subject’s status until the pregnancy has 
been completed or terminated. The outcome of the pregnancy will be reported to the Sponsor
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The study investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male subject impregnates his female partner the study personnel at the site must 
be informed immediately and the pregnancy reported to the Sponsor and followed as 
described above and in Section 7.2.2.
Use in Nursing Women
It is unknown whether MK-1454 or pembrolizumab is excreted in human milk. Since many 
drugs are excreted in human milk, and due to the potential for serious adverse reactions in the 
nursing infant, subjects who are breastfeeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation may be important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment 
prior to completion of the treatment will still continue to participate in the trial as specified in 
Section 6.0 - Schedule of Activities and Section 7.1.5.4 – Discontinued Subjects Continuing 
to be Monitored in the Trial.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment 
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:
○
The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
Confirmed radiographic disease progression outlined in Section 7.1.2.7 (exception if the 
Sponsor approves treatment continuation).
087V73


Product:  MK-1454 
93
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
o
The subject interrupts trial medication administration for more than 12 consecutive 
weeks.
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment.
o
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
o
Recurrent Grade 2 pneumonitis.
o
The subject is noncompliant with the protocol.
o
The subject has a medical condition or personal circumstance which, in the opinion of the 
investigator and/or Sponsor, placed the subject at unnecessary risk from continued 
administration of study drug.
o
The subject has a confirmed positive serum pregnancy test.
o
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 subjects who are discontinued from treatment but continue to be monitored in the trial, 
see Section 6.0 – Schedule of Activities and Section 7.1.5.4 – Discontinued Subjects
Continuing to be Monitored in the Trial for those procedures to be completed at each 
specified visit.
For subjects who progress on monotherapy MK-1454 in Arm 1, crossover into Arm 2 will be 
allowed if the subject meets the crossover eligibility criteria stated in Section 5.1.4 and 
Section 5.1.5. Subjects who cross over from Arm 1 into Arm 2 will enter Arm 2 at the start of 
Arm 2 (at screening).
Withdrawal From the Trial
If a subject fails to return for scheduled visits and/or if the study site is unable to contact the 
subject after multiple attempts (ie, is lost to follow-up), the procedures to be performed are 
outlined in Section 7.1.4.1.
If a subject decides not to continue receiving study medication, the subject is to be 
encouraged to continue visits in the study for follow-up, imaging, and vital status assessment.
Participants Who Withdraw Consent During the Study
If the participant or participant’s legally acceptable representative withdraws consent, the 
participant must be withdrawn from the study.
Section 7.4.1 delineates the specific procedures performed at the time of withdrawal and 
withdrawal from future biomedical research.
087V73


Product:  MK-1454 
94
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Any AEs that are present at the time of withdrawal should be followed in accordance with 
the safety requirements outlined in Section 7.1.5.4 and Section 7.2.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced except as described in 
Section 5.2.7 Replacement of Subjects During the DLT Evaluation Period. 
Beginning and End of the Trial
The overall study begins when the first subject (or their legally acceptable representative) 
provides written documented informed consent. The overall study ends when the last subject 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
subject is unable to be contacted by the investigator).
Clinical Criteria for Early Trial Termination
The clinical trial 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 trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
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.
087V73


Product:  MK-1454 
95
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
6.0 SCHEDULE OF ACTIVITIES
Schedule of Activities for Part I - Dose Escalation and Confirmation (Arms 1, 2, and 3)
Schedule of Activities for Initial Screening for Arms 1 Through 3 and for Crossover Into Arm 2
Scheduled Day
Initial 
Screening
Crossover 
Screening
Notes
Screening and Day 1 cannot be on the same day.
-28 to -1
-28 to -1
Administrative Procedures
Informed Consent 
X
Documented informed consent must be obtained prior to performing any 
protocol-specific procedures. An ICF signed >28 days prior to C1D1 does not 
need to be replaced.
Informed Consent for FBR (Optional)
X
Subject Identification Card
X
Inclusion/Exclusion Criteria
X
X
Demographics and Medical History 
X
X
For Crossover into Arm 2, update only. Assessments obtained during Arm 1 
may be eligible as a screening test for Arm 2 if they were obtained within 28 
days of treatment initiation into Arm 2.
Prior Medication and Concomitant 
Medication Review
X
X
Disease Details and Prior Oncology 
Treatment History 
X
X
HPV status
X
HPV testing results by history in HNSCC and other squamous cell carcinoma 
tumors (eg, p16 IHC; multiplex NASBA or other PCR-based assays) should be 
recorded if available, as determined per institutional standard.
Tumor genetic alteration(s)
X
Tumor genetic alteration(s), if available, as determined by local testing results
(eg, BRCA1, MSI-H).
Efficacy Procedures
See also: Imaging Manual
Tumor Imaging, RECIST v.1.1,
irRECIST, and/or itRECIST Response 
Assessment 
X
X
Baseline tumor imaging (CT, PET/CT, or MRI, as indicated for tumor type) 
and/or medical photography of cutaneous lesions should be performed within 28 
days of enrollment. Medical photography may be performed more often as 
medically warranted.
Medical Photography (Cutaneous Lesions) 
X
X
IWG Revised Response Criteria for 
Lymphoma 
X
X
CTCL Response Assessment
X
X
The pretreatment evaluation and scoring of response parameters should be done 
at baseline (screening).
087V73


Product:  MK-1454 
96
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Scheduled Day
Initial 
Screening
Crossover 
Screening
Notes
Screening and Day 1 cannot be on the same day.
-28 to -1
-28 to -1
Bone Marrow Biopsy/ Aspirate 
(Lymphoma Subjects Only [excluding 
CTCL subjects]) 
X
X
Must be performed if not previously done within 8 weeks prior to Screening 
with negative results. For a crossover subject, a repeat bone marrow biopsy at 
screening is required when the subject crosses over into Arm 2 if bone marrow 
biopsy results were negative at Screening in Arm 1. 
Safety Assessments and Procedures
See Procedures Manual for collection and management of tissue samples
Full Physical Examination 
X
X
Height
X
Weight
X
X
12-lead Electrocardiogram (ECG)
X
X
ECG will be obtained within 7 days prior to MK-1454 IT administration on 
C1D1.
Vital Signs
X
X
Temperature, pulse, respiratory rate, blood pressure, and oxygen (O2) saturation
ECOG Performance Status 
X
X
Additional ECOG assessments may be performed as clinically indicated.
Tumor Markers 
X
X
Perform all screening clinical laboratory tests within 7 days prior to treatment 
initiation. Tests performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test, if the test is 
performed within the specified time frame. Specific tumor markers (eg, CEA, 
CA-125, CA-19-9, and alpha fetoprotein) are to be obtained as clinically 
indicated.
CBC with Differential 
X
X
PT/INR and PTT or aPTT
X
X
Chemistry Panel 
X
X
LDH, GGT
X
X
Lipase and Amylase
X
X
Urinalysis
X
X
Thyroid Function (TSH, T3, FT3, T4, FT4)
X
X
Pregnancy Test for WOCBP– Urine or 
Serum hCG
X
X
Perform within 7 days prior to treatment initiation. If a urine pregnancy test 
cannot be confirmed as negative, a serum pregnancy test is required. Perform 
pregnancy testing per local regulations.
Hepatitis B and C
X
Include HCV antibody or HCV RNA (qualitative) and HBsAg. HIV by history 
is acceptable for exclusion, unless testing is required by local regulations.
Laboratory Procedures/Assessments: Analysis performed by
CENTRAL laboratory
See Procedures Manual for collection and management of tissue samples.
Serum for Cytokine Panel and C-Reactive 
Protein (CRP) for MK-1454
Pharmacodynamics 
X
X
Blood samples for serum cytokine panels and CRP taken at Screening should be 
obtained either both in the morning (8 AM to 12 PM) or both in the afternoon 
(1 PM to 5 PM). Collect with the samples for MK-1454 PK, when feasible.
Blood for Plasma Biomarker Analysis 
X
X
Blood for Serum Biomarker Analysis 
X
X
Tumor Tissue Biopsy a
Xa
Xa
087V73


Product:  MK-1454 
97
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Scheduled Day
Initial 
Screening
Crossover 
Screening
Notes
Screening and Day 1 cannot be on the same day.
-28 to -1
-28 to -1
aPTT = activated partial thromboplastin time; CBC = complete blood count; hCG = Beta-human chorionic gonadotropin; CRP = C-reactive protein; CT = computed 
tomography; CTCL = cutaneous T-cell lymphoma; ECOG = Eastern Cooperative Oncology Group; FBR = future biomedical research; GGT = gamma glutamyl transferase; 
HIV = human immunodeficiency virus; HNSCC = Head and Neck Squamous Cell Carcinoma; HPV = human papillomavirus; INR = international normalized ratio; IT = 
intratumoral; IWG = International Working Group; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; NASBA = nucleic acid sequence-based amplification; 
PET = positron emission tomography; PT = prothrombin time; PTT = partial thromboplastin time; RNA = ribonucleic acid; RECIST v1.1 = Response Evaluation Criteria In 
Solid Tumors, version 1.1; irRECIST = immune-related RECIST; (F)T3 = (free) triiodothyronine; (F)T4 = (free) thyroxine; TSH = thyroid-stimulating hormone; WOCBP = 
women of childbearing potential.
a.)
All subjects will be required to provide a sample biopsy of the tumor to be injected with MK-1454 and a sample biopsy from a distant, discrete noninjected site (at least 
2 biopsies at each site) at Screening, unless deemed medically unsafe by the investigator. This predose tumor biopsy at Screening will be performed on both the tumor lesion 
that is intended for treatment with IT administration of MK-1454, as well as on the distant lesion that is not intended for IT administration with MK-1454. For the tumor lesion 
intended for treatment with IT administration of MK-1454, the sample will be obtained by either punch biopsy for cutaneous lesions, or ultrasound guided biopsy for 
subcutaneous lesions, or cross-sectional image-guided biopsy for visceral and deeper tumor lesions. For distant, discrete tumor lesions that are not intended for IT 
administration with MK-1454, the sample biopsy will be obtained by punch biopsy for cutaneous lesions, ultrasound guided biopsy for subcutaneous lesions/visceral lesions, or 
cross-sectional image-guided biopsy, such as CT-guided biopsy, for visceral and deeper tumor lesions. Method of biopsy will be per guidance of the investigator as well as 
discussion with the Sponsor. 
Instructions for tissue collection, processing, and shipment are provided in the Procedures Manual. Leftover main study tissue will be stored for FBR if the subject consents to 
FBR. Samples of archival tumor tissue collected at Screening should be freshly cut, and the slides from this freshly cut archival tumor tissue should be submitted to the testing 
laboratory within 14 days of slide preparation. Instructions for tissue collection, processing, and shipment are provided in the Procedures Manual. 
087V73


Product:  MK-1454 
98
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Schedule of Activities for the Treatment Period, Intratumoral Administration for Arm 1 (Monotherapy) and Arm 2 
(Combination Therapy – Including Crossover to Arm 2)
Trial Period
Treatment Phase
MK-1454 Monotherapy Cycle = 21 Days
MK-1454 and Pembrolizumab Combination Therapy Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent
X
Additional consent is required for treatment beyond disease 
progression.
Prior Medication and 
Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
MK-1454 Administration
(Arm 1 and Arm 2) (Table 3)
There will be an at least a 24-hour inpatient observation 
period following MK-1454 administration on C1D1. In 
Arm 2, MK-1454 will be administered within 0.5 to 4 h
after completion of pembrolizumab IV infusion. See 
Procedures Manual for dose preparation.
Pembrolizumab Administration 
(Arm 2) (Table 4)
X
X
X
X
This is only for combination therapy in Arm 2. See 
Pembrolizumab Pharmacy Manual.
Efficacy Procedures
See Imaging Manual – All imaging visits have a ± 7 day 
window
Tumor Imaging, RECIST, 
irRECIST, and/or itRECIST
Response Assessment 
X
X
For solid tumors, perform at 9 weeks (± 7 days) after first 
dose, and then Q9W. For lymphoma, assess at 12 weeks
(± 7 days), and then Q12W. Tumor imaging (CT, PET/CT,
or MRI, as indicated for tumor type), and medical 
photography should be performed on the same schedule, 
following calendar days, and should not be adjusted for 
delays in cycle starts. Continue imaging schedule until 
disease progression, discontinuation, or EOT. Medical 
photography can be performed more often as medically 
warranted.
Medical Photography 
(Cutaneous Lesions) 
X
X
IWG Revised Response Criteria 
for Lymphoma (excluding 
CTCL)
X
CCI
087V73


Product:  MK-1454 
99
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
Treatment Phase
MK-1454 Monotherapy Cycle = 21 Days
MK-1454 and Pembrolizumab Combination Therapy Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
CTCL Clinical Response 
Assessment (ISCL/Modified 
Severity Weighted Assessment 
Tool – [mSWAT])
X
X
X
X
For CTCL, assess response and perform medical 
photography on Day 1 of every treatment cycle. All 
responses should be documented to be at least 4 weeks in 
duration. In cases where the definition of progressive 
disease or relapse is met, but the clinical impression is 
questionable, documentation for a period of at least 4 weeks 
is recommended.
Bone Marrow Biopsy/ Aspirate 
(Lymphoma Subjects Only)
===================================================
For subjects with a negative bone marrow biopsy at 
screening, follow-up bone marrow biopsy need not be 
performed. Follow-up bone marrow biopsy may be 
performed to confirm a CR if the subject was initially 
positive or if it is clinically indicated. 
Safety Assessments and Procedures
See Procedures Manual for Collection And 
Management of Samples.
AE Monitoring
=========================================
Full Physical Examination 
X
X
X
X
Directed Physical Examination
X
X
X
X
Weight
X
X
X
X
12-lead ECG 
X
X
X
Obtain within 72 h prior to MK-1454 IT administration on 
C1D1, C2D1, and C3D1. Does not need to be repeated on 
C1D1 if screening ECG was done within 72 hours prior to 
C1D1. A postdose ECG will be obtained on C1D1 within 
30 min and at 3 to 4 h following MK-1454 IT 
administration.
Vital Signs
(temperature, pulse, respiratory 
rate, blood pressure, and 
oxygen (O2) saturation)
X
X
X
X
X
X
X
X
X
X
Collect VS predose within 1 h (± 30 min) of MK-1454
administration at each treatment visit. Collect VS postdose
on C1D1 at 2, 4, 6, 8, and 12 h (± 30 min for each time 
point) after MK-1454 administration. At each subsequent 
treatment visit, collect VS at 1 h (±15 min) after MK-1454
administration. Additional VS monitoring may be obtained 
as clinically indicated.
ECOG Performance Status 
X
X
X
X
Additional ECOG can be performed as clinically indicated.
Tumor Markers 
X
X
X
X
Specific tumor markers (eg, CEA, CA-125, CA-19-9, or 
alpha fetoprotein) to be obtained as clinically indicated.
087V73


Product:  MK-1454 
100
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
Treatment Phase
MK-1454 Monotherapy Cycle = 21 Days
MK-1454 and Pembrolizumab Combination Therapy Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
CBC with Differential 
X
X
X
X
X
X
X
X
X
X
Required within 72 h of C1D1. Does not need to be 
repeated if screening labs were done within 72 hours of 
C1D1. May be performed up to 72 h prior to dosing for 
subsequent cycles when scheduled.
PT/INR and PTT or aPTT
X
X
X
X
Chemistry Panel 
X
X
X
X
X
X
X
X
X
X
LDH, GGT
X
X
X
X
Urinalysis
X
X
X
X
Lipase and Amylase
X
X
X
X
Pregnancy Test for WOCBP –
Urine or Serum hCG
X
Required within 24 h prior to first dose of study 
medication. Does not need to be repeated if screening test 
was done within 24 hours 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. Where local regulations require 
monthly pregnancy testing per CTFG guidelines, see 
Appendix 12.5.
Thyroid Function (TSH, T3, 
FT3, T4, FT4)
X
X
X
Required within 72 hours prior to Day 1 of C1, C3, C5, C7, 
C9, C11, and at every other subsequent treatment cycle.
Does not need to be repeated if screening labs were done 
within 72 hours of C1D1.
Pharmacokinetics (PK)/ Pharmacodynamics/ Future Biomedical Research/Biomarkers
See Procedures Manual for Collection and Management 
of Samples.
Serum for Cytokine Panel and 
CRP for MK-1454
Pharmacodynamics b
X
X
Xc
Cytokine and CRP samples should be obtained predose on 
C1D1, C2D1 and C5D1, either both in the morning (8 AM 
to 12 PM) or both in the afternoon (1 PM to 5 PM). 
Postdose serum samples for cytokine panels and CRP will 
be collected on C1D1, C2D1, and C5D1, and if applicable, 
on Day 1 of the first cycle that the subject has undergone 
intrasubject dose escalation of MK-1454. Postdose samples 
will be collected at 4 h (±15 min) and 6 h (±15 min) after 
MK-1454 administration. On C1D1, an additional serum 
sample will be collected at 12 h (± 2 h) and 24 h (± 4 h) 
following MK-1454 administration. 
Collect samples at the same time as for MK-1454 PK when 
feasible.
087V73


Product:  MK-1454 
101
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
Treatment Phase
MK-1454 Monotherapy Cycle = 21 Days
MK-1454 and Pembrolizumab Combination Therapy Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Plasma MK-1454 PK b,c
X
X
Xc
Collect predose samples 1-8 h before MK-1454
administration on C1D1 and C2D1.
Collect postdose samples on C1D1 and C2D1 at the
following time points: end of IT injection (up to +15 min), 
0.5 h (±15 min), 1 h (±15 min), 1.5 h (±15 min), 4 h (±15 
min), and 6 h (±15 min). Additional postdose samples will 
be collected at 12 h (±2 h) and 24 h (±4 h) following MK-
1454 IT administration on C1D1 only. If applicable, collect 
on Day 1 of the first cycle that the subject has undergone 
intrasubject dose escalation of MK-1454. Collect samples 
at the same time as for cytokines and CRP, and for 
pembrolizumab PK, when feasible. 
Serum for Pembrolizumab PK 
X
X
X
Pembrolizumab PK and ADA are for pembrolizumab-
treated subjects only. Collect samples predose 0 to 4 h 
before pembrolizumab IV infusion on C1D1, C2D1, C4D1, 
and on Day 1 of every 4 cycles thereafter (ie, C8, C12, 
etc.). Collect pembrolizumab and MK-1454 PK samples
together, when feasible.
Serum for ADA
X
X
X
Blood for Plasma Biomarker 
Analysis
X
X
Collect prior to MK-1454 administration (Arm 1) and prior 
to pembrolizumab administration (Arm 2) on C2D1 and 
C5D1.
Blood for Serum Biomarker 
Analysis 
X
X
Blood for RNA Analysis 
X
c
Collect predose 0-4 h before MK-1454 administration on 
C1D1.
Collect postdose 6 h (±15 min) after MK-1454
administration on C1D1.
Blood for Genetic Analysis d
X
Collect prior to treatment.
087V73


Product:  MK-1454 
102
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
Treatment Phase
MK-1454 Monotherapy Cycle = 21 Days
MK-1454 and Pembrolizumab Combination Therapy Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Tumor Tissue Biopsye
X
X
For the tumor lesion that is treated with IT administration 
of MK-1454, collect postdose tumor biopsy on the same 
day as treatment, 5 h (± 2 h) following IT administration of 
MK-1454 on C3D15, and optionally on C6D1 at 5 h (± 2 h) 
following IT administration of MK-1454. Biopsy of a 
distant, discrete, noninjected site is preferred on the same 
day as the IT administration of MK-1454, but may be 
performed up to 3 days after treatment of the injected 
lesion. The C6D1 biopsy time point is encouraged, but 
optional.
ADA = antidrug antibodies; AE = adverse event; aPTT = activated partial thromboplastin time; CBC = complete blood count; CRP = C-reactive protein; CT = computed 
tomography; CTCL = cutaneous T-cell lymphoma; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FBR = future biomedical research; GGT = 
gamma glutamyl transferase; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; HNSCC = Head and Neck Squamous Cell Carcinoma; HPV = 
human papillomavirus; IEC = Institutional Ethics Committee; INR = international normalized ratio; IRB= Institutional Review Board; ISCL = International Society for 
Cutaneous Lymphomas; IT = intratumoral; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; PET = positron emission tomography; PT = prothrombin 
time; PTT = partial thromboplastin time; RNA = ribonucleic acid; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors, version 1.1; irRECIST = immune-related 
RECIST; (F)T3 = (free) triiodothyronine; (F)T4 = (free) thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
a)
The inpatient observation period may be extended up to 48 hours at the discretion of the investigator, per local IRB/IEC, and/or Health Authority mandate. 
b)
Up to 2 additional serum samples may be collected if deemed medically necessary (eg, in the setting of an AE). 
c)
In the event a subject has undergone intrasubject dose escalation of MK-1454, these samples for biomarker analysis will be collected on Day 1 of the first cycle of the 
escalated new dose.
d)
This sample will be drawn for genetic variations in absorption, distribution, metabolism, and excretion (ADME) and planned analysis of the association between genetic 
variants in DNA and drug response. If the IRB/IEC does not approve of the planned analysis of the association between DNA variation and drug response, or if there is a 
local law or regulation prohibiting the same, then data analysis will be limited to investigate ADME genetic variations. If the sample is collected, leftover extracted DNA 
will be stored for FBR if the participant (or their legally acceptable representative) provides documented informed consent for FBR. If the planned genetic analysis is not 
approved, but FBR is approved and consent is given, then this sample will be collected for the purpose of FBR.
All subjects will be required to provide a sample biopsy of the tumor to be injected with MK-1454 and a sample biopsy from a distant, discrete noninjected site (at least 
2 biopsies at each site), unless deemed medically unsafe by the investigator. For the tumor lesion intended for treatment with IT administration of MK-1454, the sample will 
be obtained by either punch biopsy for cutaneous lesions, or ultrasound guided biopsy for subcutaneous lesions. For distant, discrete tumor lesions that are not intended for IT 
administration with MK-1454, the sample biopsy will be obtained by punch biopsy for cutaneous lesions, ultrasound guided biopsy for subcutaneous/visceral lesions, or 
image-guided biopsy, such as CT-guided biopsy, for visceral and deeper tumor lesions. Method of biopsy will be per guidance of the investigator as well as discussion with 
the Sponsor. Instructions for tissue collection, processing, and shipment are provided in the Procedures Manual. Leftover main study tissue will be stored for FBR if the 
subject consents to FBR. Instructions for tissue collection, processing, and shipment are provided in the Procedures Manual.
087V73


Product:  MK-1454 
103
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Schedule of Activities for the Treatment Period of Arm 3 (Visceral IT Administration)
Trial Period
Treatment Phase
MK-1454 Monotherapy Cycle =
 then Q3W
MK-1454 and Pembrolizumab Combination Therapy Cycle = 
21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
1
8
15
1
8
15
1
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
Informed Consent
X
Additional consent is required for treatment beyond disease 
progression.
Prior Medication and 
Concomitant Medication 
Review
X
X
X
X
X
X
X
X
MK-1454 Administration  
(Arm 3) (Table 5)
There will be an at least a 24-hour inpatient observation period 
following MK-1454 administration on C1D1. MK-1454 will be 
administered within 0.5 to 4 h after completion of pembrolizumab IV 
infusion. Frequency of visceral IT administration may be modified by 
Investigator in consultation with Sponsor based on subject tolerance 
and clinical assessment of safety. 
*Administration on Day 8 and Day 15 of Cycles 1 and 2 will be based 
on cohort designation in Arm 3. See Procedures Manual for dose 
preparation.
Pembrolizumab Administration 
(Table 5)
X
X
X
X
See Procedures Manual for dose preparation.
Efficacy Procedures
See Imaging Manual – All imaging visits have a ± 7 day window
Tumor Imaging, RECIST, 
irRECIST, and/or itRECIST
Response Assessment 
X
For solid tumors, to be performed at 9 weeks after the first dose, and 
then every 9 weeks. For lymphoma, assess at 12 weeks, and then every 
12 weeks. Tumor imaging (CT, PET/CT, or MRI, as indicated for 
tumor type), and medical photography should be performed on the 
same schedule, following calendar days, and should not be adjusted 
for delays in cycle starts. Continue imaging schedule until disease 
progression, discontinuation, or EOT. Medical photography can be 
performed more often as medically warranted.
Medical Photography 
(Cutaneous Lesions) 
X
IWG Revised Response 
Criteria for Lymphoma 
X
Bone Marrow Biopsy/ Aspirate 
(Lymphoma Subjects Only)
=========================================
For subjects with a negative bone marrow biopsy at screening, follow-
up bone marrow biopsy need not be performed. Follow-up bone 
marrow biopsy may be performed to confirm a CR if the subject was 
initially positive or if it is clinically indicated. 
CCI
C
CI
087V73


Product:  MK-1454 
104
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
Treatment Phase
MK-1454 Monotherapy Cycle = 
, then Q3W
MK-1454 and Pembrolizumab Combination Therapy Cycle = 
21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
1
8
15
1
8
15
1
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
Safety Assessments and Procedures
See Procedures Manual for Collection And Management of 
Samples.
AE Monitoring
=========================================
Full Physical Examination 
X
X
X
X
Directed Physical Examination
X
X
X
X
Weight
X
X
X
X
12-lead ECG 
X
X
X
Obtain within 72 h prior to MK-1454 IT administration on C1D1, 
C2D1, and C3D1. Does not need to be repeated on C1D1 if screening 
ECG was done within 72 hours of C1D1. A postdose ECG will be 
obtained on C1D1 within 30 min and at 3 to 4 h following MK-1454 
IT administration. 
Vital Signs
(temperature, pulse, respiratory 
rate, blood pressure, and 
oxygen (O2) saturation)
X
X
X
X
X
X
X
X
Collect VS predose within 1 h (± 30 min) MK-1454 administration at 
each treatment visit. Collect VS postdose on C1D1 at 2, 4, 6, 8, and 
12 h (± 30 min for each time point) after MK-1454 administration. At 
each subsequent treatment visit, collect VS at 1 h (±15 min) after 
MK-1454 administration. Additional VS monitoring may be obtained 
as clinically indicated.
ECOG Performance Status 
X
X
X
X
Additional ECOG can be performed as clinically indicated.
Tumor Markers 
X
X
X
X
Specific tumor markers (eg, CEA, CA-125, CA-19-9, or alpha 
fetoprotein) to be obtained as clinically indicated
CBC with Differential 
X
X
X
X
X
X
X
X
Required within 72 h of C1D1. Does not need to be repeated if 
screening labs were done within 72 hours of C1D1. May be performed 
up to 72 h prior to dosing for subsequent cycles when scheduled.
PT/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
Urinalysis
X
X
X
X
Lipase and Amylase
X
X
X
X
Pregnancy Test for WOCBP –
Urine or Serum hCG
X
Required within 24 h prior to first dose of study medication. Does not 
need to be repeated if screening test was done within 24 hours 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. Where local regulations require monthly 
pregnancy testing per CTFG guidelines, see Appendix 12.5.
CCI
087V73


Product:  MK-1454 
105
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
Treatment Phase
MK-1454 Monotherapy Cycle = 
, then Q3W
MK-1454 and Pembrolizumab Combination Therapy Cycle = 
21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
1
8
15
1
8
15
1
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
Thyroid Function (T4, FT4, T3, 
FT3, TSH) 
X
X
X
To be performed within 72 hours prior to Day 1 of C1, C3, C5, C7, 
C9, C11, and at every other subsequent treatment cycle. Does not need 
to be repeated if screening labs were done within 72 hours of C1D1.
Pharmacokinetics (PK)/ Pharmacodynamics/ Future Biomedical Research/Biomarkers
See Procedures Manual for Collection and Management of 
Samples.
Serum for Cytokine Panel and 
CRP for MK-1454 
Pharmacodynamics b
X
X
Xb
Cytokine and CRP samples should be obtained predose on C1D1 and 
C2D1 either both in the morning (8 AM to 12 PM) or both in the 
afternoon (1 PM to 5 PM). Postdose serum samples for cytokine 
panels and CRP will be collected on C1D1, C2D1, and C5D1. 
Postdose samples will be collected at 4 h (±15 min) and 6 h (±15 min) 
after MK-1454 administration. On C1D1, an additional serum sample 
will be collected at 12 h (± 2 h) and 24 h (± 4 h) following MK-1454 
administration. 
Collect samples at the same time as for MK-1454 PK when feasible.
Plasma MK-1454 PK 
X
X
Xb
Collect predose samples 1-8 h before MK-1454 administration on 
C1D1 and C2D1.
Collect postdose samples on C1D1 and C2D1 at the following time 
points:   end of IT injection (up to +15 min), 0.5 h (±15 min), 1.0 h 
(±15 min), 1.5 h (±15 min), 4 h (±15 min), and 6 h (±15 min). 
Additional postdose samples will be collected at 12 h (± 4 h) and 24 h 
(± 4 h) following MK-1454 IT administration on C1D1 only. Collect 
samples at the same time as for cytokines and CRP, and for 
pembrolizumab PK, when feasible. 
Serum for Pembrolizumab PK 
X
X
X
Collect samples predose 0 to 4 h before pembrolizumab IV infusion 
on C1D1, C2D1, C4D1, and on Day 1 of every 4 cycles thereafter (ie, 
C8, C12, etc.). 
Collect with plasma samples for MK-1454 PK when feasible.
Serum for ADA
X
X
X
Blood for Plasma Biomarker 
Analysis
X
X
Collect prior to MK-1454 administration (Arm 1) and prior to 
pembrolizumab administration (Arm 2 and Arm 3) on C2D1 and 
C5D1.
Blood for Serum Biomarker 
Analysis 
X
X
CCI
087V73


Product:  MK-1454 
106
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
Treatment Phase
MK-1454 Monotherapy Cycle = 
 then Q3W
MK-1454 and Pembrolizumab Combination Therapy Cycle = 
21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
1
8
15
1
8
15
1
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
Blood for RNA Analysis 
X
Collect predose 0-4 h before MK-1454 administration on C1D1 
Collect postdose 6 h (±15 min) after MK-1454 administration on 
C1D1.
Blood for Genetic Analysis c
X
Collect prior to treatment.
Tumor Tissue Biopsyd
X
X
For the tumor lesion that is treated with IT administration of 
MK-1454, collect predose tumor biopsy on the same day as treatment 
prior to IT administration of MK-1454 on C3D1, or up to 3 days prior 
to treatment on C3D1, and optionally on C6D1 prior to IT 
administration of MK-1454, or up to 3 days prior to treatment on 
C6D1. If available, biopsy of a distant, discrete, noninjected site is 
preferred on the same day as the IT administration of MK-1454 but
may be performed up to 3 days after treatment of the injected lesion. 
The C6D1 biopsy time point is encouraged, but optional.
ADA = antidrug antibodies; AE = adverse event; aPTT = activated partial thromboplastin time; CBC = complete blood count; CRP = C-reactive protein; CT = computed 
tomography; CTCL = cutaneous T-cell lymphoma; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative Oncology Group; FBR = future 
biomedical research; GGT = gamma glutamyl transferase; hCG = human chorionic gonadotropin; HIV = human immunodeficiency virus; HNSCC = Head and Neck 
Squamous Cell Carcinoma; HPV = human papillomavirus; IEC = Institutional Ethics Committee; INR = international normalized ratio; IRB = Institutional Review Board; 
irRECIST = immune-related RECIST; ISCL = International Society for Cutaneous Lymphomas; IT = intratumoral; LDH = lactate dehydrogenase; MRI = magnetic 
resonance imaging; PET = positron emission tomography; PT = prothrombin time; PTT = partial thromboplastin time; RECIST v1.1 = Response Evaluation Criteria In Solid 
Tumors, version 1.1; RNA = ribonucleic acid; (F)T3 = (free) triiodothyronine; (F)T4 = (free) thyroxine; TSH = thyroid-stimulating hormone; WOCBP = women of 
childbearing potential.
a)
The inpatient observation period may be extended up to 48 hours at the discretion of the investigator, per local IRB/IEC, and/or Health Authority mandate. 
b)
Up to 2 additional serum samples may be collected if deemed medically necessary (eg, in the setting of an AE). 
c)
This sample will be drawn for genetic variations in ADME and planned analysis of the association between genetic variants in DNA and drug response. If the IRB/IEC 
does not approve of the planned analysis of the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, data 
analysis will be limited to investigate ADME genetic variations. If the sample is collected, leftover extracted DNA will be stored for FBR if the participant (or their 
legally acceptable representative) provides documented informed consent for FBR. If the planned genetic analysis is not approved, but FBR is approved and consent is 
given, this sample will be collected for the purpose of FBR.
d)
All subjects will be required to provide a sample biopsy of the tumor to be injected with MK-1454 and a sample biopsy from a distant, discrete noninjected site (at least 2 
biopsies at each site), unless deemed medically unsafe by the investigator. The sample will be obtained by ultrasound guidance or cross-sectional imaging (CT/MRI) 
guidance. Method of biopsy will be per guidance of the investigator as well as discussion with the Sponsor. Instructions for tissue collection, processing, and shipment are 
provided in the Procedures Manual. Leftover main study tissue will be stored for FBR if the subject consents to FBR. Instructions for tissue collection, processing, and 
shipment are provided in the Procedures Manual. 
CCI
087V73


Product:  MK-1454 
107
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Discontinuation / End of Treatment and Posttreatment Follow-up for Arms 1 to 3
Trial Period
EOT/ Discontinuation
Posttreatment Period
Notes
30-Day Safety 
Follow-up Visit
Survival 
Follow-up 
Scheduling Day
30 days post last 
dose
Q12W
Scheduled Window
±7
+7
±14
Administrative Procedures
Prior 
Medication 
and 
Concomitant 
Medication 
Review
X
X
Efficacy Procedures
Tumor 
Imaging, 
RECIST, 
irRECIST, 
and/or 
itRECIST Response Assessment 
X
Medical Photography (Cutaneous Lesions) 
X
IWG Revised Response Criteria for Lymphoma 
(excluding CTCL)
X
CTCL Response Criteria
X
Survival Status Monitoring
Updated 
survival 
status 
may 
be 
requested by the Sponsor at any time 
during the course of the study. Upon 
Sponsor notification, all subjects who 
do not/will not have a scheduled study 
visit or study contact during the 
Sponsor defined time period will be 
contacted for their survival status 
(excluding subjects that have a death 
event previously recorded).
Safety Assessments and Procedures
See Procedures Manual for collection 
and management of samples.
AEs Monitoring
X
X
Full Physical Examination 
X
X
Weight
X
X
12-lead ECG 
X
Vital Signs
X
X
Temperature, pulse, respiratory rate, 
blood pressure, and O2 saturation
ECOG Performance Status 
X
X
CBC with Differential 
X
X
Chemistry Panel 
X
X
Lipase and Amylase
X
X
087V73


Product:  MK-1454 
108
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
EOT/ Discontinuation
Posttreatment Period
Notes
30-Day Safety 
Follow-up Visit
Survival 
Follow-up 
Scheduling Day
30 days post last 
dose
Q12W
Scheduled Window
±7
+7
±14
Pregnancy Test for WOCBP  – Urine or Serum hCG
X
For WOCBP, perform as required 
locally. If a urine pregnancy test cannot 
be confirmed as negative, a serum 
pregnancy test is required. 
Thyroid Function (TSH, T3, FT3, T4, FT4) 
X
PK/Pharmacodynamics/ Future Biomedical Research/Biomarkers
See Procedures Manual for collection 
and management of samples.
Serum for Pembrolizumab PK 
X
Only for pembrolizumab-treated 
subjects.
Serum for ADA
X
Blood for Plasma Biomarker Analysis
X
Blood for Serum Biomarker Analysis
X
ADA = antidrug antibodies; AE = adverse event; CBC = complete blood count; CTCL = cutaneous T-cell lymphoma; DNA = deoxyribonucleic acid; ECG = electrocardiogram; 
ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; (F)T3 = (free) triiodothyronine; (F)T4 = (free) thyroxine; hCG = human chorionic gonadotropin;
irRECIST = immune-related RECIST; PK = pharmacokinetic; RECIST = Response Evaluation Criteria In Solid Tumors; RNA = ribonucleic acid; TSH = thyroid-stimulating 
hormone; WOCBP = women of childbearing potential.
087V73


Product:  MK-1454 
109
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Schedule of Activities for Part II- Expansion Cohorts
Schedule of Activities for Part II - Expansion Cohorts Screening and Treatment Period, MK-1454 Intratumoral 
Administration With Pembrolizumab Combination Therapy
Trial Period
Screening
Treatment Phase
MK-1454 Cycle =
, then Q3W; or Q3W
Pembrolizumab Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
-28 to -1
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Informed Consent 
X
Documented informed consent must be obtained prior 
to performing any protocol-specific procedures. An ICF
signed >28 days prior to C1D1 does not need to be 
replaced. Additional informed consent is required for 
treatment beyond progression.
Informed Consent for 
FBR (Optional)
X
Subject Identification 
Card
X
Inclusion/Exclusion 
Criteria
X
Demographics and 
Medical History 
X
Prior Medication and 
Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
HPV status
X
HPV testing results of HNSCC and other squamous cell 
carcinoma tumors (eg, p16 IHC; multiplex NASBA or other 
PCR-based assays) should be collected if available, as 
determined per institutional standard.
Tumor genetic 
alteration(s)
X
Tumor genetic alteration(s), if available, as determined by the 
local testing results (eg, BCRA1, MSI-H.).
CCI
087V73


Product:  MK-1454 
110
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
Screening
Treatment Phase
MK-1454 Cycle =
 then Q3W; or Q3W
Pembrolizumab Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
-28 to -1
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
MK-1454
Administration
(Table 8)
There will be an at least an 8-hour observation period 
following MK-1454 administration on C1D1. MK-1454 will 
be administered within 0.5 to 4 h after completion of 
pembrolizumab IV infusion. See Procedures Manual for dose 
preparation.
Pembrolizumab 
Administration 
(Table 8)
X
X
X
X
See Pembrolizumab Pharmacy Manual.
Efficacy Procedures
See Imaging Manual – All imaging visits have a ± 7 day 
window
Tumor Imaging, 
RECIST, irRECIST, 
and/or itRECIST 
Response Assessment 
Cohort B
X
X
X
To be performed at 9 weeks (± 7 days) after the first dose, 
and then every 9 weeks thereafter. Tumor imaging (CT, 
PET/CT, or MRI, as indicated for tumor type), and medical 
photography should be performed on the same schedule, 
following calendar days, and should not be adjusted for 
delays in cycle starts. Continue imaging schedule until 
disease progression, discontinuation, or EOT. Medical 
photography can be performed more often as medically 
warranted.
Medical Photography 
(Cutaneous Lesions) 
X
X
X
Safety Assessments and Procedures
See Procedures Manual for Collection And Management 
of Samples.
AE Monitoring
=========================================
Full Physical 
Examination 
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X
Weight
X
X
X
X
X
Height
X
12-lead ECG 
X
CCI
C
CI
087V73


Product:  MK-1454 
111
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
Screening
Treatment Phase
MK-1454 Cycle = 
 then Q3W; or Q3W
Pembrolizumab Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
-28 to -1
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Vital Signs
(temperature, pulse, 
respiratory rate, blood 
pressure, and oxygen 
(O2) saturation)
X
X
X
X
X
X
X
X
X
X
X
Collect VS predose within 1 h (± 30 min) of MK-1454
administration at each treatment visit. Collect VS postdose on 
C1D1 at 2, 4, 6, and 8h (± 30 min for each time point) after 
MK-1454 administration. At each subsequent treatment visit, 
collect VS at 1 h (±15 min) after MK-1454 administration.
Additional VS monitoring may be obtained as clinically 
indicated.
ECOG Performance 
Status 
X
X
X
X
X
Additional ECOG can be performed as clinically indicated.
Tumor Markers 
X
X
X
X
X
Specific tumor markers (eg, CEA, CA-125, CA-19-9, or alpha 
fetoprotein) to be obtained as clinically indicated.
CBC with Differential 
X
X
X
X
X
X
X
X
X
X
X
Perform all screening clinical laboratory tests within 7 days 
prior to C1D1. Tests performed prior to the subject signing 
consent as part of routine clinical management are acceptable 
in lieu of a screening test, if the test is performed within the 
specified time frame. For C1D1 and subsequent cycles 
testing must be performed within 72 h prior to dosing when 
scheduled. Does not need to be repeated on C1D1 if 
screening labs were done within 72 hours of C1D1.
PT/INR and PTT or 
aPTT
X
X
X
X
X
Chemistry Panel 
X
X
X
X
X
X
X
X
X
X
X
LDH, GGT
X
X
X
X
X
Urinalysis
X
X
X
X
X
Lipase and Amylase
X
X
X
X
X
Pregnancy Test for 
WOCBP – Urine or 
Serum hCG
X
X
Required within 24 h prior to first dose of study medication. 
Does not need to be repeated if screening test was done 
within 24 hours 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. Where local regulations require monthly 
pregnancy testing per CTFG guidelines, see Appendix 12.5.
Thyroid Function 
(TSH, T3, FT3, T4, 
FT4)
X
X
X
X
Required within 72 hours 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 hours of C1D1.
HIV, Hepatitis B and 
C screen (per site 
SOP)
X
Include HCV antibody or HCV RNA (qualitative) and 
HBsAg. 
CCI
087V73


Product:  MK-1454 
112
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
Screening
Treatment Phase
MK-1454 Cycle = 
 then Q3W; or Q3W
Pembrolizumab Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
-28 to -1
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Laboratory Procedures/Assessments: Analysis performed by
CENTRAL laboratory
See Procedures Manual for Collection and Management 
of Samples.
Serum for Cytokine 
Panel and CRP for 
MK-1454 
Pharmacodynamics b
X
X
X
X,
Cytokine and CRP samples should be obtained at Screening, 
and predose on C1D1, C2D1 and C5D1, either both in the 
morning (8 AM to 12 PM) or both in the afternoon (1 PM to 5 
PM). Postdose serum samples for cytokine panels and CRP 
will be collected on C1D1, C2D1, and C5D1. Postdose 
samples will be collected at 4 h (±15 min) and 6 h (±15 min) 
after MK-1454 administration. 
Collect samples at the same time as for MK-1454 PK when 
feasible.
Plasma MK-1454 PK b
X
X
X
Collect predose samples 1-8 h before MK-1454
administration on C1D1 and C2D1.
Collect postdose samples on C1D1 and C2D1 at the 
following time points:  end of IT injection (up to +15 min), 
0.5 h (±15 min), 1 h (±15 min), 1.5 h (±15 min), 4 h (±15 
min), and 6 h (±15 min). Collect samples at the same time as 
for cytokines and CRP, and for pembrolizumab PK, when 
feasible.
CCI
087V73


Product:  MK-1454 
113
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
Screening
Treatment Phase
MK-1454 Cycle =
 then Q3W; or Q3W
Pembrolizumab Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
-28 to -1
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Serum for 
Pembrolizumab PK 
X
X
X
Collect samples predose 0 to 4 h before pembrolizumab IV 
infusion on C1D1, C2D1, C4D1, and on Day 1 of every 4 
cycles thereafter (ie, C8, C12, etc.). Collect pembrolizumab 
and MK-1454 PK samples together, when feasible.
Serum for ADA
X
X
X
Blood for Plasma 
Biomarker Analysis
X
X
Collect prior to MK-1454 administration (Arm 1) and prior to 
pembrolizumab administration (Arm 2) on C2D1 and C5D1.
Blood for Serum 
Biomarker Analysis 
X
X
Blood for RNA 
Analysis 
X
Collect predose 0-4 h before MK-1454 administration on 
C1D1
Collect postdose 6 h (±15 min) after MK-1454 administration 
on C1D1.
Blood for Genetic 
Analysis c
X
Collect prior to treatment.
Tumor Tissue Biopsyd
X
X
X
For the tumor lesion that is treated with IT administration of 
MK-1454, collect predose tumor biopsy on the same day as 
treatment prior to IT administration of MK-1454, or up to 5
days prior to treatment on C2D1 and on C3D1 (optional). If 
available, biopsy of a distant, discrete, noninjected site may 
be performed up to 5 days before treatment of the injected 
lesion.
AE = adverse event; aPTT = activated partial thromboplastin time; CBC = complete blood count; CRP = C-reactive protein; CT = computed tomography; CTCL = cutaneous T-
cell lymphoma; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FBR = future biomedical research; (F)T3 = (free) triiodothyronine; (F)T4 = (free) 
thyroxine; GGT = gamma glutamyl transferase; hCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HNSCC = Head and 
Neck Squamous Cell Carcinoma; HPV = human papillomavirus; INR = international normalized ratio; irRECIST = immune-related RECIST; ISCL = International Society for 
Cutaneous Lymphomas; IT = intratumoral; LDH = lactate dehydrogenase; MRI = magnetic resonance imaging; NASBA = nucleic acid sequence-based amplification; PET = 
positron emission tomography; PK = pharmacokinetics; PT = prothrombin time; PTT = partial thromboplastin time; RECIST v1.1 = Response Evaluation Criteria In Solid 
Tumors, version 1.1; RNA = ribonucleic acid; TSH = thyroid-stimulating hormone; WOCBP = women of childbearing potential.
CCI
087V73


Product:  MK-1454 
114
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
Screening
Treatment Phase
MK-1454 Cycle =
 then Q3W; or Q3W
Pembrolizumab Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
-28 to -1
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
a)
The observation period may be extended at the discretion of the investigator, per local IRB/IEC, and/or Health Authority mandate. 
b)
Up to 2 additional serum samples may be collected if deemed medically necessary (eg, in the setting of an AE). 
c)
This sample will be drawn for genetic variations in ADME and planned analysis of the association between genetic variants in DNA and drug response. If the IRB/IEC does 
not approve of the planned analysis of the association between DNA variation and drug response, or if there is a local law or regulation prohibiting the same, then data 
analysis will be limited to investigate ADME genetic variations. If the sample is collected, leftover extracted DNA will be stored for FBR if the participant (or their legally 
acceptable representative) provides documented informed consent for FBR. If the planned genetic analysis is not approved, but FBR is approved and consent is given, then 
this sample will be collected for the purpose of FBR.
d)
All subjects will be required to provide a sample biopsy of the tumor to be injected with MK-1454 and, if available, a sample biopsy from a distant, discrete noninjected site 
(at least 2 biopsies at each site), unless deemed medically unsafe by the investigator. For the tumor lesion intended for treatment with IT administration of MK-1454, the 
sample will be obtained by either punch biopsy for cutaneous lesions, or ultrasound guided biopsy for subcutaneous lesions. If available, for distant, discrete tumor lesions 
that are not intended for IT administration with MK-1454, the sample biopsy will be obtained by punch biopsy for cutaneous lesions, ultrasound guided biopsy for 
subcutaneous/visceral lesions, or image-guided biopsy, such as CT-guided biopsy, for visceral and deeper tumor lesions. Method of biopsy will be per guidance of the 
investigator as well as discussion with the Sponsor. Instructions for tissue collection, processing, and shipment are provided in the Procedures Manual. Leftover main study 
tissue will be stored for FBR if the subject consents to FBR. Instructions for tissue collection, processing, and shipment are provided in the Procedures Manual. 
CCI
087V73


Product:  MK-1454 
115
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Discontinuation / End of Treatment and Posttreatment Follow-up for Part II – Expansion Cohorts
Trial Period
End of Treatment (EOT)/ 
Discontinuation
Posttreatment Period
Notes
30-Day Safety 
Follow-up Visit
Survival 
Follow-up 
Scheduling Day
30 days post last 
dose
Q12W
Scheduled Window
±7
+7
±14
Administrative Procedures
Prior 
Medication 
and 
Concomitant 
Medication 
Review
X
X
Efficacy Procedures
Tumor 
Imaging, 
RECIST, 
irRECIST, 
and/or 
itRECIST Response Assessment 
X
Medical Photography (Cutaneous Lesions) 
X
Survival Status Monitoring
Updated 
survival 
status 
may 
be 
requested by the Sponsor at any time 
during the course of the study. Upon 
Sponsor notification, all subjects who 
do not/will not have a scheduled study 
visit or study contact during the 
Sponsor defined time period will be 
contacted for their survival status 
(excluding subjects that have a death 
event previously recorded).
Safety Assessments and Procedures
See Procedures Manual for collection 
and management of samples.
AE Monitoring
X
X
Full Physical Examination 
X
X
Weight
X
X
12-lead ECG 
X
Vital Signs
X
X
Temperature, pulse, respiratory rate, 
blood pressure, and O2 saturation
ECOG Performance Status 
X
X
CBC with Differential 
X
X
Chemistry Panel 
X
X
Lipase and Amylase
X
X
Pregnancy Test for WOCBP  – Urine or Serum hCG
X
For WOCBP, perform as required 
locally. If a urine pregnancy test cannot 
be confirmed as negative, a serum 
pregnancy test is required. 
087V73


Product:  MK-1454 
116
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Trial Period
End of Treatment (EOT)/ 
Discontinuation
Posttreatment Period
Notes
30-Day Safety 
Follow-up Visit
Survival 
Follow-up 
Scheduling Day
30 days post last 
dose
Q12W
Scheduled Window
±7
+7
±14
Thyroid Function (TSH, T3, FT3, T4, FT4)  
X
Pharmacokinetics (PK)/Pharmacodynamics/ Future Biomedical Research/Biomarkers
See Procedures Manual for collection 
and management of samples.
Serum for Pembrolizumab PK 
X
Only for pembrolizumab-treated 
subjects.
Serum for ADA
X
Blood for Plasma Biomarker Analysis
X
Blood for Serum Biomarker Analysis
X
ADA = antidrug antibodies; AE = adverse event; CT = computed tomography; DNA = deoxyribonucleic acid; ECG = electrocardiogram; ECOG = Eastern Cooperative 
Oncology Group; (F)T3 = (free) triiodothyronine; (F)T4 = (free) thyroxine; hCG = human chorionic gonadotropin; irRECIST = immune-related RECIST; MRI = magnetic 
resonance imaging; PET = positron emission tomography; RECIST v1.1 = Response Evaluation Criteria In Solid Tumors, version 1.1; RNA = ribonucleic acid; TSH = thyroid-
stimulating hormone; WOCBP = women of childbearing potential.
087V73


Product:  MK-1454 
117
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
7.0 TRIAL PROCEDURES
Trial Procedures
The Schedule of Activities - Section 6.0 summarizes the trial procedures to be performed at 
each visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial 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 documented informed consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’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 subject before 
participation in the trial.
The initial informed consent form, any subsequent revised informed consent form and any 
written information provided to the subject must receive the IRB/ERC’s approval/favorable 
opinion in advance of use.  The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to 
the subject’s willingness to continue participation in the trial.  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 subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
087V73


Product:  MK-1454 
118
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the FBR consent to the subject, or the 
subject’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 subject before performing any procedure related to 
FBR.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides documented informed consent. At the time of treatment allocation/randomization, 
site personnel will add the treatment/randomization number to the Subject Identification 
Card.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
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 clinically significant by the investigator. Details regarding the disease for 
which the subject has been enrolled in the trial will be recorded separately and should not be 
listed in the medical history. Smoking history will be obtained.
Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
Prior Oncology Treatment History
The investigator or qualified designee will record all prior cancer treatments including 
systemic treatments, radiation, and surgeries.
087V73


Product:  MK-1454 
119
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Prior and Concomitant Medications Review
7.1.1.7.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before first dose of trial medication. Treatment for the disease for which the 
subject has been enrolled in this trial will be recorded separately and should not be listed in 
prior medications.
7.1.1.7.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial and through the 30-day Safety Follow-up Visit. After the Safety Visit, record 
all medications related to reportable SAEs and ECIs.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2 – Assessing and Recording Adverse Events.
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Subjects who crossed over into Arm 2 will retain the original screening number assigned at 
the initial screening visit. Specific details on the screening visit requirements (screening/
rescreening) are provided in Section 7.1.5.1. 
Assignment of Treatment/Randomization Number
Part I
All eligible subjects will be allocated, by IWRS assignment, and will receive a treatment
number. The treatment number identifies the subject for all procedures occurring after 
treatment allocation. The assigned screening number will become the subjects' treatment 
number. Once a treatment number is assigned to a subject, it can never be reassigned to 
another subject.
A single subject cannot be assigned more than 1 treatment number. 
This treatment number will be used throughout the protocol for operational purposes. The 
treatment number will be assigned by IWRS at the time of enrollment. Treatment allocation 
will be accomplished by nonrandom assignment by IWRS. When more than one treatment 
arm is open for enrollment, investigator assessment of eligibility, tumor accessibility to IT 
therapy, location of lesion, as well as presence of a distant discrete measurable lesion that can 
be biopsied, will determine allocation. 
087V73


Product:  MK-1454 
120
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Part II
Treatment allocation will be accomplished by nonrandom assignment by IWRS. When more
than one cohort is open for enrollment, investigator assessment of tumor histology, 
eligibility, and lesion accessibility to IT therapy will determine allocation. 
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for ≥3 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on subject management.
All doses of MK-1454 and pembrolizumab will be administered under the supervision of a 
qualified physician and/or designee experienced in the use of anticancer agents.
Instructions for preparing and administering study drugs will be provided in the Procedures
Manual.
Trial Communication Plan Summary
Safety data from individual subjects will be closely followed by the Principal Investigator 
and the Sponsor on an ongoing basis and shared at regular safety teleconferences (typically 
once per week). The safety and tolerability of all subjects, including those undergoing DLT 
evaluation as well as those who have completed DLT evaluation, will be reviewed prior to 
the start of the next cohort. The Sponsor and principal investigators will assess the 
appropriateness of dose escalation and assess safety and tolerability at the completion of each 
cohort, and prior to the opening of enrollment for the next cohort. The subsequent dose level 
to be tested in the next cohort of subjects will be communicated to the investigator or 
designee following each dose escalation decision meeting. A memorandum will be sent to 
each site to communicate the specified next dose level. Subjects will be enrolled and 
allocated via IWRS according to the dose escalation and confirmation guidelines outlined in 
Section 5.2. The dose at each cohort will be specified via IWRS. Cohorts will be opened or 
closed through IWRS to assure correct dosing in each cohort. 
Clinical Procedures/Assessments
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Schedule of Activities and more frequently if clinically 
indicated. AEs will be graded according to NCI CTCAE Version 4. Toxicities will be 
characterized in terms of seriousness, causality, toxicity grade, and action taken with regard 
to trial treatment. 
All AEs of unknown etiology associated with MK-1454 and pembrolizumab exposure should 
be evaluated to determine if it is an ECI of a potential immunological etiology (irAE). See 
Section 7.2.3.2 regarding the identification, evaluation, and management of AEs of a 
potential immunological etiology.
087V73


Product:  MK-1454 
121
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
This is a dose escalation trial to establish the MTD of MK-1454 alone and MK-1454 in
combination with pembrolizumab. Therefore, each dose escalation will be based on the 
safety and tolerability experienced by subjects at each dose level. The safety and tolerability 
of each cohort for the DLT evaluation period will be reviewed prior to the start of the next 
cohort. The Sponsor and the principal investigators or subinvestigators will review the safety 
and tolerability of each trial treatment, assess the appropriateness of dose escalation, decide 
the completion of each cohort, and decide the opening of enrollment for the next cohort. 
Frequency of these communications will depend on the enrollment of each cohort, as well as 
any potential new information regarding a safety concern in this trial or other relevant trials.
As a Phase 1 trial, there is no plan for an external safety reviewer. Data from individual 
subjects will be closely followed on an ongoing basis by the Principal Investigator and the 
Sponsor.
Full Physical Examination
The investigator or qualified designee will perform a complete physical exam during the 
screening period and at additional time points as defined in the Schedule of Activities
(Section 6.0). Clinically significant findings from the screening exam should be recorded as 
medical history. 
A directed physical exam should be repeated according to the frequency defined in the 
Schedule of Activities (Section 6.0). After the first dose of study treatment, new clinically 
significant abnormal findings should be recorded as AEs.
Vital Signs and Weight
Vital signs include temperature, pulse, respiratory rate, blood pressure, and oxygen saturation
(pulse oximetry) at the frequency defined in the Schedule of Activities (Section 6.0).
Weight will be obtained at Screening, at C1D1 of each treatment cycle, at EOT, and at the 
30-day Safety Follow-up Visit. Height will be obtained at Screening only.
Electrocardiogram
A standard 12-lead ECG will be performed using local standard procedure at Screening, with 
any clinically significant abnormal findings recorded as medical history. 
Additional time points for ECGs are according to the Schedule of Activities (Section 6.0).
Clinically significant abnormal findings seen on all ECGs performed after Screening should 
be recorded as AEs.
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess the ECOG performance status as the time
points specified in the Schedule of Activities (Section 6.0). Additional ECOG testing may be 
performed as clinically indicated.
087V73


Product:  MK-1454 
122
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Tumor Imaging and Medical Photography
The initial PET/CT scan or MRI for solid tumor imaging as well as medical photography for
cutaneous lesions must be performed within 28 days prior to enrollment, and the site study 
team must confirm that the subject has measurable disease as defined by RECIST version 
1.1, IWG revised criteria, or ISCL criteria to confirm eligibility. In subjects with CTCL, it is 
recommended that CT and PET scans be performed at screening. 
Part I – Dose Escalation and Confirmation
For Arms 1, 2, and 3 (Part I), tumor imaging and/or medical photography should be repeated 
every 9 weeks for solid tumors or every 12 weeks for lymphomas from the first dose of 
treatment. For subjects with CTCL, medical photography will be performed at each treatment 
cycle, however, tumor imaging will be repeated only to document and confirm PR, CR, or
PD. 
Part II – Expansion Cohorts
For Cohort A (HNSCC) and Cohort B (TNBC), imaging will begin at 9 weeks and occur 
every 9 weeks thereafter. Imaging for HNSCC should include the head, neck, chest, and 
abdomen at all timepoints. Imaging of the pelvis is optional.
Solid tumor imaging should be acquired by CT (with PET for CTCL, as clinically indicated). 
For subcutaneous lesions, imaging by either MRI or CT is to be obtained at screening and at 
the imaging time points outlined in Section 2 SoA for assessment of response. MRI should be 
used when CT is contraindicated or for imaging of the brain. The same imaging technique 
and the same imaging modality with/without the use of contrast should be performed for 
assessment of response in a subject throughout the trial to optimize visualization of existing 
and new tumor burden. Tumor imaging schedule is based on calendar days from the first 
drug administration, and will not be postponed due to delays in treatment cycles. Additional 
tumor imaging and/or medical photography may be performed as clinically indicated.
Please refer to the Site Imaging Manual for detailed instructions regarding tumor imaging 
and medical photography.
A central imaging vendor will be made available for possible future independent review. 
Response Assessment
7.1.2.7.1 Immune-related RECIST
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen in
treatment with pembrolizumab
and MK-1454. Immunotherapeutic agents such as 
pembrolizumab may produce antitumor effects by potentiating endogenous cancer-specific 
immune responses. The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents and can manifest a clinical 
response after an initial increase in tumor burden or even the appearance of new lesions. 
Standard RECIST may not provide an accurate response assessment of immunotherapeutic 
agents such as pembrolizumab and MK-1454. Immune-related RECIST (irRECIST) is 
RECIST 1.1 adapted as described below to account for the unique tumor response seen with 
087V73


Product:  MK-1454 
123
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
immunotherapeutics. irRECIST will be used by site investigators to assess tumor response 
and progression, and to make treatment decisions. 
Therefore, RECIST 1.1 will be used with the following adaptations:
If radiologic imaging by local radiology shows initial PD, tumor assessment should be 
repeated at least 4 weeks later in order to confirm PD, with the option of continuing 
treatment while awaiting radiologic confirmation of progression, as described below. 
If repeat imaging shows <20% increase in tumor burden compared to nadir, stable, or 
improved previous new lesion (that may have been identified as the cause for initial PD), and 
stable/improved nontarget disease (that may have been identified as the cause for initial PD), 
then PD is not confirmed. Treatment may be continued and will then follow the regular 
imaging schedule. 
If repeat imaging confirms PD due to any of the scenarios listed below, then subjects will be 
discontinued from study therapy. The initial date of Progression will be recorded as the PD 
date.
In determining whether the tumor burden has increased or decreased, the investigator should 
consider all target lesions as well as nontarget lesions. For purposes of this protocol, biopsied 
lesions will not be target lesions for RECIST 1.1 or irRECIST.
Scenarios where PD is confirmed at repeat imaging:

Tumor burden increase remains ≥ 20% and at least 5 mm absolute increase compared to 
nadir

Nontarget disease resulting in initial PD is worse (qualitative)

New lesion resulting in initial PD is worse (qualitative)

Additional new lesion(s) since last evaluation

Additional new nontarget progression since last evaluation
In subjects who have initial evidence of radiological PD, it is at the discretion of the 
investigator whether to continue a subject on study treatment until repeat imaging is 
obtained. This clinical judgment decision should be based on the subject’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data. Subjects 
may receive study treatment while waiting for confirmation of PD, if they are clinically 
stable as defined by the following criteria:

Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values

No decline in ECOG performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention
When feasible, subjects should not be discontinued until progression is confirmed. This 
allowance to continue treatment despite initial radiologic progression takes into account the 
087V73


Product:  MK-1454 
124
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
observation that some subjects can have a transient tumor flare in the first few months after 
the start of immunotherapy, and still have a subsequent disease response. Subjects who are 
deemed clinically unstable are not required to have repeat imaging for confirmation of PD. 
NOTE:  In subjects who discontinue study therapy without documented disease progression, 
every effort should be made to continue monitoring of their disease status by radiologic 
imaging every 9 weeks (± 7 days) until: (1) the start of new anticancer treatment, (2) disease 
progression (3) death, or (4) the end of the study, whichever occurs first.
Confirmation of PR and CR is required at least 4 weeks after the initial response assessment 
of PR and CR.
7.1.2.7.2 Intratumoral Immunotherapy RECIST (itRECIST)
itRECIST is a response assessment that is tailored to IT immunotherapy, is aligned with 
RECIST 1.1 overall response assessment [3] and is further described in Appendix 12.4. 
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 IT immunotherapy (an example is provided in
Figure 8); and

provides guidelines on prioritization of lesion injection during the course of 
intratumoral immunotherapy (see Appendix 12.3)
itRECIST supports standardized collection of data from IT immunotherapy clinical trials to 
facilitate exploratory response analysis.
7.1.2.7.3 IWG Revised Response Criteria for Malignant Lymphomas
Response to treatment for lymphomas will continue to be assessed every 12 weeks that a 
subject remains in the trial. 
Response to therapy will be assessed by CT or CT/PET, bone marrow biopsy, and clinical 
information including physical exam and symptoms, using the IWG Revised Response 
Criteria for Malignant Lymphomas [25]. Information collected includes: 
1. At a minimum, thoracic, abdominal, and pelvic CT scans will be performed even if 
those areas were not initially involved because of the unpredictable pattern of 
recurrence in malignant lymphoma. Neck CT should be performed at Screening, and 
at follow-up visits if there is nodal involvement in the neck at screening. 
Fluorodeoxyglucose-PET scans may be obtained to supplement the anatomic 
087V73


Product:  MK-1454 
125
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
imaging, and should always be collected at Screening, 12 weeks, 24 weeks, and when 
CR is suspected.
2. Unilateral bone marrow biopsy and aspirates will be performed at Screening, if not 
previously performed within 8 weeks prior to Screening with negative results. The 
bone marrow biopsy will be performed to confirm a CR if the subject was initially 
positive or if it is clinically indicated by new abnormalities in the peripheral blood 
counts or blood smear.
Response of lesions will be recorded on the eCRF based on the definitions in Table 16 as 
appropriate. Suspected relapse or disease progression must be confirmed by physical exam, 
laboratory assessments, repeat bone marrow biopsy [25], and CT scan. Subjects with 
suspected relapse or disease progression should continue to follow study procedures until 
they need another therapy. If a subject requires another therapy, date of treatment and type of 
treatment will be recorded, and they will then be removed from the trial. 
Tumor progression is defined as ≥50% increase from nadir in the sum of the products of 
diameters (SPD), of target lesions, or by growth of a single nodal target lesion, or by growth 
of nontarget lesions, or the appearance of new lesions, as defined in the IWG revised 
response criteria for malignancy lymphoma [25]. 
Table 16
Response Criteria for Malignant Lymphoma
Response 
Category
Physical 
Examination
Nodal Masses
Spleen, Liver
Bone Marrow
Complete 
Response
Disappearance of 
all evidence of 
disease
(a) FDG-avid or 
PET positive prior 
to therapy; mass of 
any size permitted 
if PET negative
(b) Variably FDG-
avid or PET 
negative; 
regression to 
normal size on CT
Not palpable, 
nodules 
disappeared
Infiltrate cleared on 
repeat biopsy; if 
indeterminate by 
morphology, 
immunohistochemistry 
should be negative
Partial 
Response
No progression of 
palpable disease 
and no new sites
≥ 50% decrease in 
SPD of up to 6 
largest dominant 
masses; no 
increase in size of 
other nodes
(a) FDG-avid or 
PET positive prior 
to therapy; one or 
more PET positive 
at previously 
involved site
(b) Variably FDG-
avid or PET 
negative; 
regression on CT
≥ 50% decrease in 
SPD of nodules 
(for single nodule 
in greatest 
transverse 
diameter); no 
increase in size of 
liver or spleen
Irrelevant if positive 
prior to therapy; cell 
type should be 
specified
087V73


Product:  MK-1454 
126
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Response 
Category
Physical 
Examination
Nodal Masses
Spleen, Liver
Bone Marrow
Stable Disease
Failure to attain 
CR/PR or PD
(a) FDG-avid or 
PET positive prior 
to therapy; PET 
positive at prior 
sites of disease and 
no new sites on CT 
or PET
(b) Variably FDG-
avid or PET 
negative; no 
change in size of 
previous lesions on 
CT
Relapse/ 
Progression
Any new lesion or 
increase by ≥50% 
of previously 
involved sites from 
nadir
Appearance of a 
new lesion(s) _ 
1.5 cm in any axis, 
≥50% increase in 
SPD of more than 
one node, or 
≥50% increase in 
longest diameter of 
a previously 
identified node 
>1 cm in short axis 
Lesions PET 
positive if FDG-
avid lymphoma or 
PET positive prior 
to therapy
≥50% increase 
from nadir in the 
SPD of any 
previous lesions
New or recurrent 
involvement
Abbreviations: CT = computed tomography; FDG = fluorodeoxyglucose; PET = positron-emission tomography; 
SPD = sum of the product of the longest bidimensional diameters
7.1.2.7.4 Response Assessment Criteria for CTCL
The Modified Severity Weighted Assessment Tool (mSWAT - Table 17) will be used to 
evaluate the extent of disease in the CTCL subjects prior to treatment at each cycle per the 
SoA. Imaging (CT scans and medical photography) will be performed at screening/baseline 
for all CTCL subjects. In those patients with advanced disease at baseline (maximum/current 
stage greater than or equal to Stage IIB [T3N0M0B0]), repeat imaging studies should be 
performed at the time of PR and CR by assessment of the skin, and any time there is a 
question of new or PD in the lymph nodes or the viscera; and at the end of the study [2].
Each scheduled response assessment will include evaluations of skin (Table 18), lymph 
nodes (Table 19), viscera (Table 20), and blood (Table 21); and will determine a global
response score (Table 22) for CTCL subjects. Medical photography will also be performed at 
the time of each response assessment (see SoA), or more often as warranted.
087V73


Product:  MK-1454 
127
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 17
Modified Severity Weighted Assessment Tool
Body Regions
% BSA in 
Body 
Region
Assessment of Involvement in Patient’s Skin
Patcha
Plaqueb
Tumorc
Head
7
Neck
2
Anterior trunk
13
Arms
8
Forearms
6
Hands
5
Posterior trunk
13
Buttocks
5
Thighs
19
Legs
14
Feet
7
Groin
1
Subtotal of lesion 
BSA
Weighting factor
× 1
× 2
× 4
Subtotal lesion BSA
× weighting factor
Abbreviations: BSA = body surface area; mSWAT = modified Severity Weighted Assessment Tool
NOTE:  mSWAT score equals summation of each column line
a. Any size lesion without induration of significant elevation above the surrounding uninvolved skin; 
poikiloderma may be present.
b. Any size lesion that is elevated or indurated, crusting, ulceration, or poikiloderma may be present.
c. Any solid or nodular lesion ≥1 cm in diameter with evidence of deep infiltration in the skin and/or vertical 
growth.
087V73


Product:  MK-1454 
128
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 18
Response in Skin (CTCL)
Response
Definition
CR
100% clearance of skin lesions
PR
50%-99% clearance of skin disease from baseline without new tumors (T3) 
in patients with T1, T2 or T4 only skin disease
SD
<25% increase to <50% clearance in skin disease from baseline without new 
tumors (T3) in patients with T1, T2, or T4 only skin disease
PD
Whichever criterion occurs first:
≥25% increase in skin disease from baseline 
OR 
New tumors (T3) in patients with T1, T2 or T4 only skin disease
OR
Loss of response: in those with complete or partial response, increase of skin 
score of greater than the sum of nadir plus 50% baseline score
Relapse
Any disease recurrence in those with complete response
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable 
disease
NOTE. Based on Modified Severity Weighted Assessment Tool (mSWAT) score. A biopsy of normal 
appearing skin is unnecessary to assign a complete response. However, a skin biopsy should be performed of 
a representative area of the skin if there is any question of residual disease (persistent erythema or 
pigmentary change) where otherwise a complete response would exist. If histologic features are suspicious or 
suggestive of mycosis fungoides/Sézary syndrome, the response should be considered a partial response 
only.
087V73


Product:  MK-1454 
129
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 19
Response in Lymph Nodes (CTCL)
Response
Definition (peripheral and/or central lymph nodes)
CR
All lymph nodes are now ≤1.5 cm in greatest transverse (long axis) diameter 
by method used to assess lymph nodes at baseline or biopsy negative for 
lymphoma; in addition, lymph nodes that were N3 classification and ≤1.5 cm 
in their long axis and >1 cm in their short axis at baseline, must now be ≤1 
cm in their short axis or biopsy negative for lymphoma
PR
Cumulative reduction ≥50% of the SPD of each abnormal lymph node at 
baseline and no new lymph node >1.5 cm in the diameter of the long axis or 
>1.0 cm in the diameter of the short axis if the long axis is 1-1.5 cm 
diameter
SD
Fails to attain the criteria for CR, PR, and PD
PD
Whichever criterion occurs first:
≥50% increase in SPD from baseline of lymph nodes 
OR
Any new node >1.5 cm in the long axis or >1 cm in the short axis if 1-1.5 
cm in the long axis that is proven to be N3 histologically 
OR
Loss of response: >50% increase from nadir in SPD of lymph nodes in those 
with PR
Relapse
Any new lymph node >1.5 cm in the long axis in those with CR proven to be 
N3 histologically
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable 
disease; SPD = sum of the product of the longest bidimensional diameters
087V73


Product:  MK-1454 
130
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 20
Response in Viscera (CTCL)
Response
Definition
CR
Liver or spleen or any organ considered involved at baseline should not be 
enlarged on physical exam and should be considered normal by imaging; no 
nodules should be present on imaging of liver or spleen; any posttreatment 
mass must be determined by biopsy to be negative for lymphoma
PR
≥50% regression in any splenic or liver nodules, or in measurable disease 
(SPD) in any organs abnormal at baseline; no increase in size of liver or 
spleen and no new sites of involvement
SD
Fails to attain the criteria for CR, PR, or PD
PD
Whichever criterion occurs first:
>50% increase in size (SPD) of any organs involved at baseline 
OR
New organ involvement 
OR
Loss of response: >50% increase from nadir in the size (SPD) of any 
previous organ involvement in those with PR
Relapse
New organ involvement in those with CR
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable 
disease; SPD = sum of the product of the longest bidimensional diameters
087V73


Product:  MK-1454 
131
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 21
Response in Blood (CTCL)
Responsea
Definition
CRb
B0
PRc
>50% decrease in quantitative measurements of blood tumor burden from 
baseline in those with high tumor burden at baseline (B2)
SD
Fails to attain criteria for CR, PR, or PD
PD
Whichever criterion occurs first:
B0 to B2
OR
>50% increase from baseline and at least 5,000 neoplastic cells/µL [35]
OR
Loss of response: in those with PR who were originally B2 at baseline, 
>50%increase from nadir and at least 5,000 neoplastic cells/µL
Relapse
Increase of neoplastic blood lymphocytes to ≥ B1 in those with CR
Abbreviations: CR = complete response; PD = progressive disease; PR = partial response; SD = stable 
disease
a As determined by absolute numbers of neoplastic cells/µL.
b If a bone marrow biopsy was performed at baseline and determined to unequivocally be indicative of 
lymphomatous involvement, then to confirm a global CR where blood assessment now meets criteria for B0, 
a repeat bone marrow biopsy must show no residual disease, or the response should be considered a PR only.
c There is no PR in those with B1 disease at baseline as the difference within the range of neoplastic cells that 
define B1 is not considered significant and should not affect determination of global objective response.
Table 22
Global Response Score for CTCL
Global
Scorea
Definition
Skin
Nodes, Blood, Viscera
CR
Complete disappearance of all 
clinical evidence of disease
CR
All categories have CR/NI
PR
Regression of measurable disease
CR
All categories do not have a 
CR/NI and no category has a PD
PR
No category has a PD and if any 
category involved at baseline, at 
least one has a CR or PR
SD
Failure to attain CR, PR, or PD 
representative of all disease
PR
No category has a PD and if any 
category involved at baseline, no 
CR or PR in any
SD
CR/NI, PR, SD in any category 
and no category has a PD
PD
Progressive disease
PD in any category
Relapse
Recurrence disease in prior CR
Relapse in any category
087V73


Product:  MK-1454 
132
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Global
Scorea
Definition
Skin
Nodes, Blood, Viscera
Abbreviations: CR = complete response; NI = noninvolved; PD, progressive disease; PR = partial response; SD
= stable disease.
a It is recommended that not only the proportion of patients who achieve a response or an unfavorable outcome 
be calculated but a life table account for the length of the interval during which each patient is under 
observation also be generated.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures 
Manual.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 23.
Table 23
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
FSHa
Hemoglobin
Alkaline phosphatase
Glucose
Serum hCG
Platelet count
ALT
Protein
Hepatitis
WBC (total and 
differential)b
AST
Specific gravity 
HIV
RBC
Carbon Dioxide or Bicarbonate
Microscopic exam, if 
abnormal results are 
noted
T3 or FT3
PT or INR
Calcium
Urine pregnancy testa
T4 or FT4
PTT or aPTT
Chloride
TSH
Creatinined
HPVe
GGT
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the ULN
Total protein
BUNe
LDH
Uric acid
087V73


Product:  MK-1454 
133
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Hematology
Chemistry
Urinalysis
Other
ALT=alanine aminotransferase;
aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; FT3=free triiodothyronine; FT4=free thyroxine; FSH=follicle stimulating hormone; 
GGT=gamma glutamyl transpeptidase; HCG=human chorionic gonadotropin; HNSCC = head and neck squamous cell 
carcinoma; HPV=human papilloma virus; INR=International Normalized Ratio; LDH=lactic dehydrogenase; 
PT=prothrombin time; PTT=partial thromboplastin time; RBC=red blood count; SCC = squamous cell carcinoma;
T3=total triiodothyronine; T4=total thyroxine; TSH=thyroid stimulating hormone; ULN=upper limit of normal; 
WBC=white blood count; WOCBP = women of childbearing potential..
a Perform on WOCBP only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required.
b Absolute or % acceptable per institutional standard
c For subjects 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.
d HNSCC or other SCC subjects only
e BUN is preferred; if not available urea may be tested
Laboratory safety tests for screening should be performed within 28 days prior to first dose 
of study medication, unless otherwise specified in the SoA. After Cycle 1, predose laboratory 
tests can be performed up to 72 hours prior to dosing. Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to dosing.
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2.1 Blood Collection for MK-1454 and Pembrolizumab PK
Blood sample collection, storage, and shipment instructions will be provided in the 
Procedures Manual. MK-1454 PK samples can be used for metabolite analysis. 
Pembrolizumab PK and ADA samples can be discontinued based on early data.
7.1.3.2.2 Blood Collection for Anti-Pembrolizumab Antibodies (ADA)
Blood sample collection, storage, and shipment instructions for ADA analysis will be 
provided in the Procedures Manual.
7.1.3.2.3 Blood for Pharmacodynamic Markers
Blood sample collection, storage, and shipment instructions for PD analysis will be provided 
in the Procedures Manual.
The time points for PD sampling are described in Section 6.0-Schedule of Activities. 
7.1.3.2.4 Tumor Biopsy
Tumor samples will be collected at the time points described in Section 6.0 – Schedule of 
Activities.
All subjects will be required to provide a sample biopsy of the tumor to be injected with 
MK-1454 and a sample biopsy from a distant, discrete noninjected site (if feasible) (at least 2 
biopsies at each site) after IT administration of MK-1454, unless deemed medically unsafe 
by the investigator. For Part II Expansion Cohort, only the injected tumor biopsy is required, 
087V73


Product:  MK-1454 
134
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
unless deemed medically unsafe by the investigator. The noninjected lesion should be 
measurable as defined by RECIST 1.1. Tumor dimensions must be ≥1 cm in longest diameter 
for non-nodal lesions, or ≥1.5 cm in short axis for nodal lesions.
Tumor biopsies will only be performed at tumor sites that are deemed medically safe, in 
accordance with local guidelines. Sponsor selection criteria for the MK-1454 FIH study 
assured selection of sites that had investigative staff that were highly experienced in tumor 
biopsies.
For subjects with lymphoma, only those subjects that have superficial lesions amendable to 
intratumoral injection will be eligible (cutaneous lesions injected via visual inspection, and 
subcutaneous lymph nodes injected via ultrasound guidance or palpation). No lymphoma 
subjects with exclusively deep lymph nodes will be included in this study. Lymphoma 
subjects who have both superficial and deep lymph nodes will be eligible for enrollment into 
this study, however only the superficial lymph nodes will be injected. 
A predose tumor biopsy will be performed at screening on both the tumor lesion which is 
intended for treatment with IT injection of MK-1454, as well as on the distant lesion which is 
not intended for IT injection with MK-1454. For Part II Expansion Cohort, only the injected 
tumor biopsy is required, unless deemed medically unsafe by the investigator.
For the tumor lesion intended for treatment with IT injection of MK-1454, the sample will be 
obtained by either punch biopsy for cutaneous lesions, by ultrasound guided biopsy for 
subcutaneous/visceral lesions, or by cross-sectional imaging guidance for visceral lesions.   
For distant discrete tumor lesions which are not intended for IT injection with MK-1454, the 
sample biopsy will be obtained by one of the following: punch biopsy for cutaneous lesions, 
ultrasound guided biopsy for subcutaneous/visceral lesions, or image-guided biopsy, such as 
CT-guided biopsy for visceral lesions and deeper tumor lesions. On-treatment biopsy site 
location may vary from baseline biopsy site location based on lesion accessibility and subject
tolerance. Method of biopsy will be per guidance of the investigator, as well as discussion 
with the Sponsor.   
For visceral lesions, the sample biopsy will be obtained via ultrasound guidance or cross-
sectional imaging (CT/MRI) guidance.
Leftover main study tissue will be stored for FBR if the subject consents to FBR.
Samples of archival tumor tissue collected at screening should be freshly cut, and the slides 
from this freshly cut archival tumor tissue should be submitted to the testing laboratory 
within 14 days of slide preparation. Instructions for tissue collection, processing, and 
shipment are provided in the Procedures Manual.   
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
087V73


Product:  MK-1454 
135
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual. This sample should be drawn for planned 
analysis of the association between genetic variants in DNA and drug response. If there is 
either a documented law or regulation prohibiting collection, or if the IRB/IEC does not 
approve the collection of the sample for these purposes, then this sample will not be collected 
at that site. If the sample is collected, leftover extracted DNA will be stored for FBR if the 
subject provides documented informed consent for FBR. If the planned genetic analysis is 
not approved, but FBR is approved and consent is given, this sample will be collected for the 
purpose of FBR.
Future Biomedical Research Samples
The following specimens are to be obtained as part of FBR:

DNA for future research
In addition, any tissue obtained for protocol-specified assessments that is remaining after the 
assessment is completed will be stored for future research, including:

RNA 

Serum 

Plasma 

Tumor tissue

Bone marrow biopsy/aspirate
Instructions for the collection and management of FBR specimens are provided in the 
Procedures Manual and Appendix 12.2.
Other Procedures
Withdrawal/Discontinuation
It has been well documented that a higher rate of withdrawal can render a study 
uninterpretable; therefore, unnecessary withdrawal of subjects should be avoided. As clinical 
event data are important to study endpoints, subjects who discontinue/withdraw from 
treatment prior to completion of the treatment regimen should be encouraged to continue to 
be followed for all remaining study visits for follow-up and vital status assessments as 
outlined in the SoA.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any AEs
which are present at the time of discontinuation/withdrawal should be followed in accordance 
with the safety requirements outlined in Section 7.2 - Assessing and Recording Adverse 
Events.
087V73


Product:  MK-1454 
136
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
The Investigator is to inform the subjects that
- they may discontinue from study medication at any time during the study, and
- they are encouraged to continue visits in the study for follow-up, imaging, and vital status 
assessment.
If participants elect to stop study procedures, they are encouraged to continue to be followed, 
which allows periodic survival follow-up and vital status data to be collected.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for FBR.  Subjects may withdraw consent at any time 
by contacting the principal investigator for the main trial.  If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com).  Subsequently, the subject'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 subject 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 trial data and results.  No new analyses would be generated after the 
request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
7.1.4.1.2 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit. If the 
subject is contacted, the subject 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 
subject at each missed visit (eg, phone calls and/or a certified letter to the 
subject’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the subject’s medical record.

Note:  A subject is not considered lost to follow-up until the last scheduled visit 
for the individual subject. The amount of missing data for the subject will be 
managed via the prespecified data handling and analysis guidelines.
Subject Blinding/Unblinding
This is an open-label trial; there is no blinding for this trial.
087V73


Product:  MK-1454 
137
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Domiciling
Subjects in Part I (Arms 1 2, and 3) will report to the CRU on C1D1 and will remain for 
inpatient observation for at least 24 hours post MK-1454 administration on C1D1. The
inpatient observation period post MK-1454 administration on C1D1 may be extended to 
48 hours, based on the discretion of the investigator, and/or local IRB/IEC, and/or Health 
Authority mandate.
This requirement may be waived at the discretion of the Sponsor and will be communicated 
to sites via a memorandum. 
Subjects in Part II (Expansion Cohorts A, B, and C) will report to the CRU on C1D1 and will 
remain in the clinic for at least 8 hours post MK-1454 administration on C1D1. The 
observation period post MK-1454 administration on C1D1 may be extended based on the 
discretion of the investigator and/or local IRB/IEC, and/or Health Authority mandate.
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 trial that provides information
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible.  
Documentation of equipment calibration must be retained as source documentation at the 
trial site.
Visit Requirements
Visit requirements are outlined in Section 6.0 – Schedule of Activites. Specific procedure-
related details are provided above in Section 7.1 - Trial Procedures.
Screening
Up to 28 days prior to treatment allocation/randomization, potential subjects will be 
evaluated to determine if they fulfill the entry requirements as set forth in Section 5.1. Tests 
performed as part of routine clinical management prior to the subject signing consent are 
acceptable in lieu of a screening test, if these tests are performed within the specified time 
frame of 28 days prior to treatment allocation/randomization. Bone marrow biopsy results for 
lymphoma subjects are permissible up to 8 weeks prior to screening.
Screening procedures may be repeated after consultation with the Sponsor.
Treatment Period
The treatment period in each treatment arm or expansion cohort (Arm 1, Arm 2, and Arm 3; 
Cohorts A, B, and C) begins with Cycle 1 and may continue for up to 35 cycles 
(approximately 2 years) from the start of treatment until disease progression, unacceptable 
AE(s), intercurrent illness that prevents further administration of treatment, investigator’s 
decision to withdraw the subject, subject withdraws consent, pregnancy of the subject, 
noncompliance with trials treatment or procedure requirements, or administrative reasons 
requiring cessation of treatment. Subjects who cross over from Arm 1 to Arm 2 are eligible 
087V73


Product:  MK-1454 
138
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
for up to 35 cycles of treatment within Arm 2, regardless of the number of cycles of
MK-1454 treatment received in Arm 1. Each cycle includes study drug administration and all 
associated assessments as outlined in the Schedule of Activities (see Section 6.0). 
Specific procedure-related details are provided throughout Section 7.0.
Treatment Period Beyond Disease Progression
See Section 7.1.2.7.
Discontinued Subjects Continuing to be Monitored in the Trial
The Discontinuation Visit should occur at the time study treatment is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study treatment, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional Safety Follow-up procedures should be performed. Visit requirements are 
outlined in Section 6 - Schedule of Activities. Additional details regarding subject
withdrawal 
and 
discontinuation 
are 
presented 
in 
Section 
5.8 
–Subject 
Withdrawal/Discontinuation Criteria.
30-Day Safety Follow-up Visit
The mandatory 30-day Safety Follow-up Visit should be conducted approximately 30 days 
(+7 days) after the last dose of trial treatment or before the initiation of a new antineoplastic 
treatment, whichever comes first. All AEs that occur prior to the 30-day Safety Follow-up 
Visit should be recorded. Subjects with an AE of Grade >1 will be followed until the 
resolution of the AE to Grade 0-1 or until the beginning of a new antineoplastic therapy, 
whichever occurs first. 
After the EOT, each subject will be followed for 30 days for AE monitoring and 130 days for 
SAEs, ECI, and spontaneously reported pregnancy. SAEs, ECI, and spontaneously reported 
pregnancy will be reported for 30 days after the EOT if the subject initiates new anticancer 
therapy. Progression of the cancer under study is not considered an AE.
Survival Status Monitoring
All subjects, with the exception of those who withdraw consent or are lost to follow-up, will 
be followed up for survival and will be contacted approximately every 12 weeks (±14 days) 
to monitor survival status. Subjects who experience confirmed disease progression or start a 
new anticancer therapy, will move into the Survival Follow-Up Phase and should be 
contacted by telephone every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to interim and/or final analysis. 
Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or 
study contact during the Sponsor-defined time period will be contacted for their survival 
087V73


Product:  MK-1454 
139
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
status (excluding subjects who have withdrawn consent or have a previously recorded death 
event in the collection tool).
Every effort should be made to collect information regarding disease status until the start of 
new antineoplastic therapy, disease progression, death, or the end of the study.
Assessing and Recording Adverse Events     
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of a medicinal product or protocol-specified 
procedure, whether or not considered related to the medicinal product or protocol-specified 
procedure.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a preexisting condition that is temporally associated with the use of the 
Sponsor’s product, is also an AE.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered AEs.  Examples of this 
may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
AEs may occur during clinical trials, or as prescribed in clinical practice, from overdose 
(whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an AE.
All 
AEs 
that 
occur 
after 
consent 
is 
documented 
but 
before 
treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all AEs must be reported by the investigator. Such events will be 
recorded at each examination on the AE CRFs/worksheets.  The reporting timeframe for AEs 
meeting any serious criteria is described in section 7.2.3.1. The investigator will make every 
attempt to follow all subjects with nonserious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
AEs will not be collected for subjects during the pre-screening period (for determination of 
archival tissue status) as long as that subject has not undergone any protocol-specified 
procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy etc., the 
subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting.
087V73


Product:  MK-1454 
140
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-1454 by 20% of the indicated dose or a pembrolizumab dose of ≥1000 mg 
(≥5 times the indicated dose). No specific information is available on the treatment of 
overdose of MK-1454 or pembrolizumab. In the event of overdose, treatment with MK-1454 
and/or pembrolizumab should be discontinued and the subject should be observed closely for 
signs of toxicity.  Appropriate supportive treatment should be provided if clinically indicated.
If an AE(s) is associated with (“results from”) the overdose of Sponsor's product or vaccine, 
the AE(s) is/are reported as an SAE, even if no other seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious ECI, using the terminology “accidental or intentional overdose 
without adverse effect.”
All reports of overdose with and without an AE must be reported by the investigator within 
24 hours to the Sponsor either by electronic media or paper. Electronic reporting procedures 
can be found in the EDC data entry guidelines. Paper reporting procedures can be found in 
the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered AEs, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment, or a 
procedure. Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 130 days following cessation of Sponsor’s product, or 
30 days following cessation of trial treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator. 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.
Such events must be reported within 24 hours to the Sponsor by either electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
087V73


Product:  MK-1454 
141
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
An SAE is any AE occurring at any dose or during any use of Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is another important medical event.
Note: In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same timeframe as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 24 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any SAE, or follow up to a SAE, including death due to any cause, 
that occurs to any subject must be reported within 24 hours to the Sponsor if it causes the 
subject to be excluded from the trial, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 130 days 
following cessation of trial treatment, or 30 days following cessation of trial treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any SAE, or follow up to an 
SAE, including death due to any cause, whether or not related to the Sponsor's product, must 
be reported within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any SAE, considered by an investigator who is a qualified physician to be 
related to the Sponsor's product that is brought to the attention of the investigator at any time 
following consent through the end of the specified safety follow-up period specified in the 
paragraph above, or at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to the Sponsor.  
All subjects with SAEs must be followed up for outcome.
087V73


Product:  MK-1454 
142
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Events of Clinical Interest
Selected nonserious AEs and SAEs are also known as ECI and must be reported to the 
Sponsor.
For the time period beginning when consent is documented until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 130 days 
following cessation of treatment, or 30 days following cessation of trial treatment if the 
subject initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an 
ECI, whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines.  Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the ULN and an 
elevated total bilirubin lab value that is greater than or equal to 2X the ULN and, at the 
same time, an alkaline phosphatase lab value that is less than 2X the 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 trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3. Any such event will be submitted to the Sponsor within 24 hours either by 
electronic or paper media.
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 efficacy endpoint events and safety data to ensure the safety of the 
subjects in the trial. Any suspected endpoint which upon review is not progression of the 
cancer under study will be forwarded to global safety as an SAE within 24 hours of 
determination that the event is not progression of the cancer under study. 
087V73


Product:  MK-1454 
143
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all AEs according to the NCI 
CTCAE, version 4.0 (Table 24). Any AE which changes CTCAE grade over the course of a 
given episode will have each change of grade recorded on the AE CRF/worksheets.
All AEs regardless of CTCAE grade must also be evaluated for seriousness.
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 (i.e., to all agents in the regimen). However, causality attribution may be assigned to 
a single agent if in the investigator’s opinion, there is sufficient data to support full 
attribution of the AE to the single agent.
087V73


Product:  MK-1454 
144
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 24
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all AEs as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid 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 or hospitalization indicated; disabling; 
limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
An SAE is any AE occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an AE
that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient 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 a Merck product and is documented in the patient’s 
medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any AE associated with an overdose is considered an SAE for collection purposes. An overdose that is not 
associated with an AE is considered a nonserious ECI and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed previously 
(designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the AE cause the Sponsor’s product to be discontinued?
Relationship 
to Sponsor’s 
Product
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 drug and the AE based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the AE:
Exposure
Is there evidence that the subject 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 trials 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
087V73


Product:  MK-1454 
145
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
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; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge

Was the subject 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 trial is a single-dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE 
SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS 
PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
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.
Record one of the following
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
Subject 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 subject with overdose without an 
associated AE.)
087V73


Product:  MK-1454 
146
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Sponsor Responsibility for Reporting Adverse EventsSAEs
All Adverse EventsSAEs will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations, i.e., per ICH 
Topic E6 (R1) Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategies and procedures for the primary and key 
secondary analyses of the study. Exploratory and other non-confirmatory analyses will be 
outlined in a separate sSAP. 
If, after the study has begun, changes are made to the 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 non-confirmatory 
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. Post hoc 
exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full details are
in the Statistical Analysis Plan, Sections 8.2 through 8.12.
Study Design Overview
Phase 1 trial of MK-1454 IT as monotherapy and in combination with 
pembrolizumab in subjects with advanced/metastatic solid tumors or 
lymphomas. Part I, dose escalation and confirmation, includes 
monotherapy (cutaneous or subcutaneous lesions) (Arm 1), MK-1454 IT 
in combination with pembrolizumab (cutaneous or subcutaneous lesions)
(Arm 2), and MK-1454 IT in combination with pembrolizumab (visceral 
lesions) (Arm 3) in subjects with advanced/metastatic solid tumors or 
lymphomas. For Arms 1, 2, and 3, the study applies an ATD followed by 
a modified TPI design for dose escalation and confirmation to establish an
MTD/MAD and to identify a preliminary RP2D in each treatment arm. In 
the expansion phase of this trial, Part II, Cohort A and B will begin 
enrolling after the preliminary RP2D is established from Arm 2 and will 
evaluate MK-1454 in combination with pembrolizumab. Expansion 
Cohort C will begin enrolling after the preliminary RP2D is established 
from Arm 3 and will evaluate MK-1454 in combination with 
pembrolizumab.
Analysis Populations
Safety (Primary): ASa and DLTe
PK (Secondary): PP
Efficacy (Secondary and Exploratory): Full Analysis Set (FAS) 
Primary Endpoint(s)

DLT

AE

Discontinuing study treatment due to an AE
087V73


Product:  MK-1454 
147
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Key Secondary Endpoints

PK parameters of MK-1454 monotherapy, PK parameters for MK-1454 
in combination with pembrolizumab, and PK parameters for 
pembrolizumab in combination with MK-1454.

ORR 
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Plasma concentrations of MK-1454 will be summarized by planned visit 
and time for each dose separately; PK parameters will be summarized by 
dose. For pembrolizumab, serum concentrations will be compared to the 
historical monotherapy pembrolizumab data.
ORR will be estimated using an exact method based on the binomial 
distribution (Clopper-Pearson interval) together with its 95% confidence 
interval
Treatment Assignment
In Part I, subjects will be allocated to receive single-agent MK-1454 (Arm 
1), MK 1454 co-administered with pembrolizumab via cutaneous or 
subcutaneous IT injection (Arm 2), or MK 1454 co-administered with 
pembrolizumab via visceral IT injection (Arm 3) centrally through an 
IWRS. Subjects will be allocated by nonrandom assignment. Allocation 
will alternate between Arm 1 and Arm 2 when both arms are open for 
enrollment, and alternating assignment begins with Arm 1. In Part II, 
subjects will be allocated to one of 3 cohorts depending on their tumor 
type and other characteristics through IWRS. The trial is open label.
Statistical Methods for Key 
Safety Analyses
Summary statistics (counts, percentages, means, standard deviations, etc.) 
will be provided for the safety endpoints as appropriate. The pool-
adjacent-violators-algorithm [31] will be used to estimate the DLT rates
across doses. The estimates of the DLT rates among subjects treated at 
MTD (or MAD) of MK-1454 and the 80% Bayesian credible intervals for 
the estimates will be provided.
Interim Analyses
An administrative analysis may be conducted to enable future trial 
planning at the Sponsor’s discretion and data will be examined on a 
continuous basis to allow for dose escalation and confirmation decisions.
For each expansion cohort (Cohorts A-C) in Part II, if there are no 
responders among approximately the first 15 evaluable subjects, the 
cohort may be stopped early.
For Cohort C, an additional futility check may be performed if applicable 
for the first 30 evaluable subjects. If there are 1 or less responders in 
Cohort C, the Cohort may be stopped early for futility. 
Multiplicity
No multiplicity adjustment is planned in this Phase 1 trial.
Sample Size and Power 
The overall sample size for this study depends on the observed DLT 
profiles of MK-1454 monotherapy and MK-1454 in combination with 
pembrolizumab for Part I and the number of Expansion Cohorts to be 
enrolled for Part II. A target sample size of approximately 235 subjects
will be used for study planning purposes.
087V73


Product:  MK-1454 
148
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
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 trial is open label, ie, subjects, investigators, and Sponsor personnel will be aware of 
subject treatment assignment after each subject is enrolled and treatment is assigned. 
Allocation to treatment will not be randomized.
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3.0.
Analysis Endpoints
Efficacy and safety endpoints are listed below, followed by descriptions of selected 
endpoints. 
Efficacy/Pharmacokinetic Endpoints
ORR in subjects treated with MK-1454 in combination with pembrolizumab as assessed by 
investigator using RECIST 1.1 criteria is a secondary endpoint for Part II of the trial. PFS 
and OS are exploratory endpoints in this study. Details of the statistical analysis plan for 
exploratory endpoints will be documented in the sSAP. A description of efficacy measures is 
provided in Section 4.2.3.
ORR is defined as the proportion of subjects who have achieved confirmed CR or PR. 
Progression-free survival is defined as the time from the first dose of study treatment to the
first documented disease progression or death due to any cause, whichever occurs first.
OS is defined as the time from the first dose of study treatment to death due to any cause. 
Subjects who do not die will be censored on the date of the last study assessment or contact.
ORR for noninjected lesions is defined as the proportion of participants who have achieved at 
least 30% reduction in the sum of diameters of noninjected lesions, among participants with 
target noninjected lesions identified at baseline.
PK endpoints include concentrations of MK-1454 and pembrolizumab, as well as any 
derived PK parameters.
Safety Endpoints
The primary safety endpoint is the number/proportion of subjects with DLT(s), AE(s), and 
who discontinue study treatment due to AE(s). A description of safety measures is provided 
in Section 4.2.3.2.
Analysis Populations
Safety Analysis Population
The ASaT population will be used for the analysis of safety data in this study. The ASaT 
population consists of all subjects who received at least one dose of study treatment. In case 
087V73


Product:  MK-1454 
149
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
of treatment administration errors, subjects will be analyzed according to the treatment they 
actually received. The DLTe population includes ASaT subjects that were observed for 
safety for 21 days after the first dose of assigned treatment or experienced a DLT prior to 21 
days after the first dose of assigned treatment. The replacement subjects will also be 
considered evaluable if the above specified criteria are met. 
At least one 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.
Pharmacokinetic Analysis and Target Engagement Populations
The PP population will be used for analysis of PK and target engagement data in this study. 
The PP population consists of the subset of subjects who complied with the protocol 
sufficiently to ensure that the data they generated will be likely to exhibit the effects of 
treatment, according to the underlying scientific model. Compliance covers such 
considerations as exposure to treatment, availability of measurements, and absence of major 
protocol violations. Major protocol violators will be identified, to the extent possible, by 
individuals responsible for data collection/compliance, and its analysis and interpretation. 
Any subjects or data values excluded from analysis will be identified, along with the reasons
for exclusion, in the CSR. At the end of the study, all subjects who were compliant with the 
study procedures and have available data from at least one treatment will be potentially 
included in the PP analysis dataset. 
Efficacy Analysis Populations
The FAS population will be used for analysis of the secondary and exploratory efficacy data 
in this study. It consists of all subjects with a baseline scan that demonstrated measurable 
disease by investigator assessment, and who were administered a dose of study medicine. 
A supportive approach using modified FAS population may be performed for the efficacy 
endpoints. The modified FAS population includes FAS subjects without substantial dose 
interruption as defined in the sSAP. 
Statistical Methods
Statistical Methods for Efficacy Analyses
For the secondary endpoint of ORR, the point estimate and 95% CI will be evaluated in 
Part II subjects treated with MK-1454 in combination with pembrolizumab at the RP2D for 
each tumor cohort separately, using an exact method based on the binomial distribution 
(Clopper-Pearson Interval). Other exploratory endpoints (eg, PFS) may also be examined 
within each expansion cohort. Of note, efficacy analyses for each Part II expansion cohort 
will pool Part I subjects who meet the inclusion criteria for the respective Part II tumor type 
and received the same dose level of MK-1454 in combination with pembrolizumab.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs, SAEs, laboratory tests, vital signs, ECG measurements, and physical examinations.
087V73


Product:  MK-1454 
150
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
AEs will be summarized by counts and frequencies for each dose level, arm, and cohort. 
Laboratory tests, vital signs, and other safety endpoints will be summarized as appropriate.
Dose-limiting toxicities will be listed, and further summarized by dose level and arm. The 
pool adjacent-violators-algorithm [31], which forces the DLT rate estimates to be 
nondecreasing with dose levels and pools adjacent violators for weighted estimates by 
sample size, will be used to estimate the DLT rates across doses in each treatment arm. The 
estimates of the DLT rates among subjects treated at the MTDs (or MADs) and the 80% 
Bayesian credible intervals based on a prior distribution of Beta (1,1) for the estimates will 
be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
Pharmacokinetics and Pharmacodynamics Modeling Analysis
Plasma concentrations of MK-1454 will be summarized by planned visit and time for each 
dose separately; PK parameters will be summarized by dose. For pembrolizumab, serum 
concentrations will be compared to the historical monotherapy pembrolizumab data. Details 
of statistical analysis of pharmacokinetics-pharmacodynamics analyses will be documented 
in the sSAP.
Interim Analyses
An administrative analysis may be conducted to enable future trial planning at the Sponsor’s 
discretion and data will be examined on a continuous basis to allow for dose escalation and 
confirmation decisions.
An interim futility check will be performed for each of the selected solid tumor cohorts in 
Part II (Cohorts A through C). For Cohorts A, B, and C, if there are no responders among 
approximately the first 15 evaluable subjects, the cohort may be stopped early for futility. For 
Cohort C, an additional futility check may be performed if applicable for the first 
30 evaluable subjects. If there is one or less responder among the first 30 evaluable subjects 
in Cohort C, the Cohort may be stopped early for futility. An evaluable subject has at least 
one postbaseline imaging assessment. If the true response rate is 10%, there is an 80% 
chance to observe at least 1 responder among 15 subjects, and an 82% chance to observe at 
least 2 responders among 30 subjects.
The futility bar is not binding, and the totality of the data will be evaluated before making a 
decision to discontinue enrollment. The data will be analyzed on a continuous basis and 
enrollment will not be paused when interim analyses are performed.
Multiplicity
There will be no multiplicity control in this study.
087V73


Product:  MK-1454 
151
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Sample Size and Power Calculations
The overall sample size for this Phase 1 trial is expected to be approximately 235 subjects. 
Part I Sample Size
The overall sample size for Part I is expected to be approximately 115 subjects 
(approximately 40 subjects each in Arm 1 and Arm 2, and 35 in Arm 3). Part A, Part C, and 
Part E (ATD phase) will be followed by Part B, Part D and Part F (mTPI phase) of all 
3 Arms. The ATD phase will have single-subject cohorts that may enroll up to 3 subjects to 
account for simultaneous enrollment. The mTPI phase will have 3 to 6 subjects per cohort, 
based on the occurrence of DLTs; up to 14 subjects may enroll per dose level. 
The sample size for Arm 1, Arm 2, and Arm 3 of this study is dependent on the number of 
dose levels tested and on the emerging safety data. The following scenario provides an
example of the sample size. 
In Arm 1 and Arm 2, in the absence of DLTs, utilizing dose increments of up to 300% for the 
ATD phase, and dose increments of 30% to 100% for the mTPI phase, there would be 
1 subject per dose level treated at
and 3 subjects per dose 
level treated at
and 14 subjects treated at a dose 
level of 
 The total sample size for both Arm 1 and Arm 2 would then be 30. 
In Arm 3, in the absence of DLTs and with 2 possible dose cohorts for the ATD phase and 
dose increments of 30% to 100% for the mTPI phase, there would be 1 subject per dose level 
treated at 
and 14 subjects treated at a dose level of 
 The total sample 
size would then be 34 for Arm 3. 
For dose escalation guidelines and specifications, see Section 5.2 and Table 3, Table 4, and 
Table 5.
Part II Sample Size
The overall sample size for Part II is expected to be approximately 120 subjects. For 
Cohort A (anti-PD-1/PD-L1 refractory HNSCC) and Cohort B (anti-PD-1/PD-L1 treatment-
naïve or refractory unresectable locally advanced or metastatic TNBC), 30 subjects will be 
enrolled in each tumor cohort. For Cohort C (other anti-PD-1/PD-L1 treatment-naïve solid 
tumors with liver metastases), 60 subjects will be enrolled with approximately 15 non-MSI-H
CRC patients, 15 pancreatic ductal adenocarcinoma patients, and 30 patients without these 
specific diagnoses. 
The key efficacy endpoint will be ORR based on investigator assessment per RECIST 1.1.
Table 25 and Table 26 show the ORR estimate and the 95% CI (Clopper-Pearson) for N=30 
(Cohorts A and B, and Cohort C subgroup of Non-CRC/pancreatic tumors) and N=60 
(Cohort C) respectively.
CCI
CCI
CCI
CCI
CCI
087V73


Product:  MK-1454 
152
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Table 25
Estimate and 95% CI of ORR (N=30)
Sample Size
Number of 
Responses (PR/CR)
Observed ORR
95% CI of ORR
Abbreviations: CI = confidence interval; CR = complete response; ORR = objective response rate; PR = 
partial response
Table 26
Estimate and 95% CI of ORR (N=60)
Sample Size
Number of 
Responses (PR/CR)
Observed ORR
95% CI of ORR
Abbreviations: CI = confidence interval; CR = complete response; ORR = objective response rate; PR = 
partial response
Subgroup Analyses and Effect of Baseline Factors
For Cohort C, other solid tumors with liver metastases, subgroup analysis of the efficacy 
endpoint ORR will be conducted between non-MSI-H CRC patients, pancreatic ductal 
adenocarcinoma patients, and the remaining Cohort C patients. 
Other subgroup analyses for the Part II Expansion Cohorts A-C may be conducted as needed, 
for example by age or race.
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the trial. Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
CCI
CCI
087V73


Product:  MK-1454 
153
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 27.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 27
Product Descriptions
Product Name & Potency
Dosage Form
Source/Additional 
Information
MK-1454,
Solution for Injection
Provided centrally by the 
Sponsor.
MK-1454,
Solution for Injection
Provided centrally by the 
Sponsor.
MK-1454, Diluent
Solution for dosage 
preparation
Provided centrally by the 
Sponsor or locally by the 
study site, subsidiary, or 
designee.
Pembrolizumab (MK-3475)
100 mg/4 mL
Solution for Infusion
Provided centrally by the 
Sponsor.
All supplies indicated in Table 27 will be provided per the “Source/Additional Information” 
column depending on local country operational requirements.
Any commercially available product not included in Table 27 will be provided by the trial 
site, subsidiary or designee. Every attempt should be made to source these supplies from a 
single lot/batch number. The trial site is responsible for recording the lot number, 
manufacturer, and expiry date for any locally purchased product as per local guidelines 
unless otherwise instructed by the Sponsor.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
In addition, 10 mL, sterile empty vials will be provided for on-site dosage preparation.
Subjects will receive open-label study drug at each treatment visit. 
CCI
CCI
087V73


Product:  MK-1454 
154
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial 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.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IWRS system) to allocate subjects, to assign treatment to 
subjects and to manage the distribution of clinical supplies. Each person accessing the IWRS
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.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
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 institutional review board, ethics review committee (IRB/ERC) 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 trial 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.
087V73


Product:  MK-1454 
155
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject 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 subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this trial.  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.
Compliance With Financial Disclosure Requirements
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 
087V73


Product:  MK-1454 
156
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
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.
Compliance With Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial 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 as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
087V73


Product:  MK-1454 
157
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the Protocol/CSR 
CI during the anticipated review process, thorough understanding of clinical trial methods, 
appropriate enrollment of subject cohort, timely achievement of trial milestones).  The 
Protocol CI must be a participating trial investigator.
087V73


Product:  MK-1454 
158
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Compliance With Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the trial is solely responsible for determining whether the trial and its results are subject to 
the 
requirements 
for 
submission 
to 
http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries.  Merck, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. 
Merck entries are not limited to FDAAA or the EMA clinical trial directive mandated trials.  
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial 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 trial or its results to those 
registries.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
087V73


Product:  MK-1454 
159
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
087V73


Product:  MK-1454 
160
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
11.0 LIST OF REFERENCES
[1]
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. 
Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25(6):579-
86.
[2]
Olsen EA, Whittaker S, Kim YH, Duvic M, Prince HM, Lessin SR, et al. Clinical 
end points and response criteria in mycosis fungoides and Sezary syndrome: a 
consensus statement of the International Society for Cutaneous Lymphomas, the
United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma 
Task Force of the European Organisation for Research and Treatment of Cancer. 
J Clin Oncol. 2011 Jun 20;29(18):2598-607.
[3]
Goldmacher GV, Khilnani AD, Andtbacka RHI, Luke JJ, Hodi FS, Marabelle A, 
et al. Response criteria for intratumoral immunotherapy in solid tumors: 
itRECIST. J Clin Oncol. In press 2020.
[4]
Corrales L, Glickman LH, McWhirter SM, Kanne DB, et al. Direct Activation of 
STING in the Tumor Microenvironment Leads to Potent and Systemic Tumor 
Regression and Immunity. Cell Rep. 2015 May 19;11(7):1018-30.
[5]
Fu J, Kanne DB, Leong M, Glickman LH, McWhirter SM, et al. STING agonist 
formulated cancer vaccines can cure established tumors resistant to PD-1 
blockade. Sci Transl Med. 2015 Apr 15;7(283):283ra52.
[6]
Baird JR, Friedman D, Cottam B, Dubensky TW Jr, Kanne DB, et al. 
Radiotherapy Combined with Novel STING-Targeting Oligonucleotides Results 
in Regression of Established Tumors. Cancer Res. 2016 Jan 1;76(1):50-61.
[7]
Glickman LH, Kanne DB, Kasibhatla S, Li J, Pferdekamper AC, Gauthier KS, et 
al. Activation in the tumor microenvironment with a synthetic human STING-
activating cyclic dinucleotide leads to potent anti-tumor immunity. Poster session 
presented at: 2016 AACR Annual Meeting; 2016 Apr 16-20; New Orleans, LA.
[8]
Woo SR, Corrales L, Gajewski TF. The STING pathway and the T cell-inflamed 
tumor microenvironment. Trends Immunol. 2015 Apr;36(4):250-6.
[9]
Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531-8.
[10]
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et 
al. 
Adoptive 
cell 
transfer 
therapy 
following 
non-myeloablative 
but 
lymphodepleting chemotherapy for the treatment of patients with refractory 
metastatic melanoma. J Clin Oncol 2005;23(10):2346-57.
[11]
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with autologous CD4+ T cells against NY-
ESO-1. N Engl J Med 2008;358(25):2698-703.
087V73


Product:  MK-1454 
161
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
[12]
Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev 
Immunol 2005;23:515-48.
[13]
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-
containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 
2001;98(24):13866-71.
[14]
Zhang X, Schwartz J-CD, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and 
functional analysis of the costimulatory receptor programmed death-1. Immunity 
2004;20:337-47.
[15]
Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL. SHP-1 and SHP-2 
associate with immunoreceptor tyrosine-based switch motif of programmed death 
1 upon primary human T cell stimulation, but only receptor ligation prevents T 
cell activation. J Immunol 2004;173:945-54.
[16]
Sheppard K-A, Fitz LJ, Lee JM, Benander C, George JA, Wooters J, et al. PD-1 
inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta 
signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004;574:37-41.
[17]
Riley JL. PD-1 signaling in primary T cells. Immunol Rev 2009;229:114-25.
[18]
Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi 
SV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct 
mechanisms. Mol Cell Biol 2005;25(21):9543-53.
[19]
Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and 
autoimmunity. Immunol Rev 2010;236:219-42.
[20]
Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 
Blockade in tumors with mismatch repair deficiency. N Engl J Med. Forthcoming 
2015.
[21]
Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ, Leung MY, et al. 
STING-dependent cytosolic DNA sensing mediates innate immune recognition of 
immunogenic tumors. Immunity. 2014 Nov 20;41(5):830-42.
[22]
Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. 
IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J 
Clin Invest. 2017 Aug;127(8):2930-40.
[23]
Yamazaki S, Skaptason J, Romero D, Lee JH, Zou HY, Christensen JG, et al. 
Pharmacokinetic-pharmacodynamic modeling of biomarker response and tumor 
growth inhibition to an orally available cMet kinase inhibitor in human tumor 
xenograft mouse models. Drug Metab Dispos. 2008 Jul;36(7):1267-74.
087V73


Product:  MK-1454 
162
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
[24]
Nishino M, Giobbie-Hurder A, Gargano M, Suda M, Ramaiya NH, Hodi FS. 
Developing a common language for tumor response to immunotherapy: immune-
related response criteria using unidimensional measurements. Clin Cancer Res. 
2013 Jul 15;19(14):3936-43.
[25]
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ. 
Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25(5):579-
86.
[26]
Olsen E, Vonderheid E, Pimpinelli N, Willemze R, Kim Y, Knobler R, et al. 
Revisions to the staging and classification of mycosis fungoides and Sezary 
syndrome: a proposal of the International Society for Cutaneous Lymphomas 
(ISCL) and the cutaneous lymphoma task force of the European Organization of 
Research and Treatment of Cancer (EORTC). Blood 2007;110(6):1713-22.
[27]
Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. 
American Society of Clinical Oncology/College Of American Pathologists 
guideline recommendations for immunohistochemical testing of estrogen and 
progesterone receptors in breast cancer. J Clin Oncol. 2010 Jun 1;28(16):2784-
95.
[28]
Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, et al. Pembrolizumab 
in patients With Advanced Triple-Negative Breast Cancer: Phase Ib KEYNOTE-
012 study. J Clin Oncol. 2016 Jul 20;34(21):2460-7.
[29]
Adams S, Loi S, Toppmeyer D, Cescon DW, De Laurentiis M, Nanda R, et al. 
Pembrolizumab 
monotherapy 
for 
previously 
untreated, 
PD-L1-positive, 
metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 
study. Ann Oncol. 2019;30(3):405-11.
[30]
Adams S, Schmid P, Rugo HS, Winer EP, Loirat D, Awada A, et al. 
Pembrolizumab monotherapy for previously treated metastatic triple-negative 
breast cancer: cohort A of the phase II KEYNOTE-086 study. Ann Oncol. 
2019;30(3):397-404.
[31]
Ji Y, Li Y, Bekele BN. Dose-finding in phase l clinical trials based on toxicity 
probability intervals. Clin Trials 2007;4:235-44.
[32]
Nie L, Rubin EH, Mehrotra N, Pinheiro J, Fernandes LL, Roy A, et al. Rendering 
the 3 + 3 design to rest: more efficient approaches to oncology dose-finding trials 
in the era of targeted therapy. Clin Cancer Res. 2016 Jun 1;22(11):2623-9.
[33]
Yang S, Wang SJ, Ji Y. An integrated dose-finding tool for phase I trials in 
oncology. Contemp Clin Trials. 2015 Nov;45(Pt B):426-34.
087V73


Product:  MK-1454 
163
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
[34]
Ji Y, Wang S-J. Modified toxicity probability interval design: a safer and more 
reliable method than the 3 + 3 design for practical phase I trials. J Clin Oncol 
2013;31:1-12.
[35]
Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S, et al. 
National Cancer Institute-Sponsored working group guidelines for chronic 
lymphocytic leukemia: Revised guidelines for diagnosis and treatment. Blood 
1996;87(12):4990-7.
087V73


Product:  MK-1454 
164
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, 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 subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck 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 which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
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 Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  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 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. 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.  Merck funding of a trial will be acknowledged in publications. 
087V73


Product:  MK-1454 
165
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects 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.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck 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
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV.Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.  Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck 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 including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
087V73


Product:  MK-1454 
166
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
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 trial as outlined in Section 7.1.3.4 –
Future Biomedical Research Samples will be used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in Future 
Biomedical Research.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on the visit designated in the 
trial flow chart.  If delayed, present consent at next possible Subject Visit.  Consent 
forms signed by the subject will be kept at the clinical trial site under secure storage 
for regulatory reasons.  
087V73


Product:  MK-1454 
167
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
A template of each trial 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 subject consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (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 trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject 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 subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens.  This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between subject identifiers 
and this unique code will be held at the trial 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 (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in future biomedical research 
protocol and consent. Future Biomedical Research specimens remaining with the third 
party after specific analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and ask that their 
biospecimens not be used for Future Biomedical Research.  Subjects may withdraw 
consent at any time by contacting the principal investigator for the main trial. If medical 
records for the main trial are still available, the investigator will contact the Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@merck.com). 
087V73


Product:  MK-1454 
168
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Subsequently, the subject'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 
subject 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 trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’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.
Specimens from the trial 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 
trial, the trial 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 trial 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 Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject 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 subjects.  Subjects will not be identified by 
087V73


Product:  MK-1454 
169
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
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 subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject 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 e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
3. Industry Pharmacogenomics Working Group. 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. Pharmacogenomics Informational 
Brochure for IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
087V73


Product:  MK-1454 
170
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Prioritization of Intratumoral Lesion Injection
The selection and prioritization of lesions for intratumoral injection is a complex set of 
decisions made by the clinician at each treatment visit. Ultimately, lesion prioritization is 
based on clinical judgment and patient tolerance; however, a set of guiding principles can be 
described. 
Patient Safety
The first priority is patient safety. Lesions are to be selected that minimize the potential for 
procedural complications and maximize patient comfort. One important safety factor is 
vascularity within a lesion, and adjacent to a lesion. Injection into intratumoral vessels should 
be avoided to minimize systemic administration. Vessels adjacent to a tumor should not be 
traversed to minimize bleeding risk, and areas of vascular encasement should be avoided in
high risk locations (eg, 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 have a greater breadth of tumor-
specific antigens to stimulate a broader repertoire of antigen-specific T cells. 
Radiographically visible necrosis should be avoided. Direct intratumoral immunotherapy into
viable portions 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.
087V73


Product:  MK-1454 
171
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
New and/or Progressing Lesions
During therapy, lesions that are new or progressing should be given higher priority than 
lesions selected on the basis of size or on the basis of the imaging features described above. 
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 spectrum of antigen-specific T cells in response 
to injection with an intratumoral immunotherapeutic, and a subsequent improved systemic 
antitumor response. New lesions may contain novel tumor antigens compared to previously 
injected lesions. 
087V73


Product:  MK-1454 
172
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
itRECIST Supplementary Figures
Figure 5
Algorithm for Classification of Lesions at Baseline
Lesions are classified first as measurable or nonmeasurable using the standard RECIST 1.1 
rules for measurability. Measurable lesions (those eligible for selection as target lesions) are 
then classified as target (selected to be followed quantitatively) or nontarget (selected to be 
followed qualitatively), and the decisions about which lesions are to be injected are made 
based on the prioritization rules discussed. Lesions selected for injection may be either target 
or nontarget in RECIST 1.1 terms. Between one and 5 lesions should be classified as target 
injected, and between 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).
087V73


Product:  MK-1454 
173
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Figure 6
Reclassification of Noninjected Lesions
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. 
087V73


Product:  MK-1454 
174
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Figure 7
Overall Response Assessment Until Disease Progression
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.
087V73


Product:  MK-1454 
175
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Figure 8
Example of Iterative Assessment of Injected Lesion Response During Treatment
Abbreviations: iPR = immunotherapeutic partial response; iRECIST 1.1 =  immunotherapeutic Response 
Evaluation Criteria in Solid Tumors; NE = not evaluable; NT-I = nontarget injected; NT-NI = nontarget 
noninjected; PD = progressive disease; PR = partial response; 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.
087V73


Product:  MK-1454 
176
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
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 
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.
Source: [3]
087V73


Product:  MK-1454 
177
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Country-specific Requirements
For countries or sites that follow the CTFG guidance requiring monthly pregnancy testing, 
please use the following:
087V73


Product:  MK-1454 
178
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Section 6.1.2
Schedule of Activities for the Treatment Period, Intratumoral Administration for Arm 1 (Monotherapy) and Arm 2 
(Combination Therapy – Including Crossover to Arm 2)
Trial Period
Treatment Phase
MK-1454 Monotherapy Cycle = 21 Days
MK-1454 and Pembrolizumab Combination Therapy Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Pregnancy Test for WOCBP –
Urine or Serum hCG
X
X
X
X
Required within 24 h prior to first dose of study 
medication. Does not need to be repeated if screening test 
was done within 24 hours 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.
6.1.3
Schedule of Activities for the Treatment Period of Arm 3 (Visceral IT Administration)
Trial Period
Treatment Phase
MK-1454 Monotherapy Cycle = 21 Days
MK-1454 and Pembrolizumab Combination Therapy Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
1
8
15
1
8
15
1
8
15
1
Scheduled Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Pregnancy Test for WOCBP –
Urine or Serum hCG
X
X
X
X
Required within 24 h prior to first dose of study 
medication. Does not need to be repeated if screening test 
was done within 24 hours 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.
087V73


Product:  MK-1454 
179
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
6.2.1
Schedule of Activities for Part II - Expansion Cohorts Screening and Treatment Period, MK-1454 Intratumoral Administration 
With Pembrolizumab Combination Therapy
Trial Period
Screening
Treatment Phase
MK-1454 Cycle =
 then Q3W; or Q3W
Pembrolizumab Cycle = 21 Days
Notes
Cycle
Cycle 1
Cycle 2
Cycle 3
Cycle 4 
and 
Beyond
Scheduling Day
-28 to -1
1
8
15
1
8
15
1
8
15
1
Scheduled 
Window
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Administrative Procedures
Pregnancy Test for 
WOCBP – Urine or 
Serum hCG
X
X
X
X
X
Required within 24 h prior to first dose of study medication. 
Does not need to be repeated if screening test was done within 
24 hours 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.
CCI
087V73


Product:  MK-1454 
180
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
List of Abbreviations and Definitions
Abbreviation
Definition
Abscopal
A phenomenon in the treatment of metastatic cancer where localized 
treatment of a tumor causes not only a shrinking of the treated tumor, but 
also a shrinking of tumors outside the scope of the localized treatment
ADA
Anti-drug antibody
ADL
Activities of daily living
ADME
Absorption, distribution, metabolism, and excretion
AE
Adverse event
AJCC
American Joint Committee on Cancer
ALT
Alanine aminotransferase
AMP
Adenosine monophosphate
aPTT
Activated partial thromboplastin time
ART
Antiretroviral therapy
ASaT
All-Subjects-as-Treated
ASCO-CAP
American 
Society 
of 
Clinical 
Oncology/College 
Of 
American 
Pathologists
AST
Aspartate aminotransferase
ATD
Accelerated titration design
C1D1
Cycle 1 Day 1
CBC
Complete blood count
CD
Cluster of differentiation (eg, CD8, CD28)
CDN
Cyclic dinucleotide
cGAMP
Cyclic GMP-AMP
cGAS
Cyclic (guanosine monophosphate-adenosine monophosphate) synthase
CI
Confidence interval
CR
Complete response
CRC
Colorectal cancer
CrCl
Creatinine clearance
CRF
Case report form
CRP
C-reactive protein
CRS
Cytokine release syndrome
CRU
Clinical research unit
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTFG
Clinical Trials Facilitation and Coordination Group
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
087V73


Product:  MK-1454 
181
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Abbreviation
Definition
CXCL11
Chemokine C-X-C motif ligand 11  
DLT
Dose-limiting toxicity
DLTe
DLT-evaluable
dMMR
Deficient mismatch repair
dsDNA
Double-stranded deoxyribonucleic acid
DNA
Deoxynucleic acid
ECI
Event of clinical interest
E/CIA
Enzyme or chemiluminescence immunoassay
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic data capture
EMA
European Medicines Agency
EORTC
European Organisation for Research and Treatment of Cancer 
EOT
End of treatment
FBR
Future biomedical research
FDAAA
Food and Drug Administration Amendments Act
FDG-PET
Fluorodeoxyglucose-positron emission tomography
FIH
First in human
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GFR
Glomerular filtration rate
GGT
Gamma glutamyl transferase
GMP
Guanosine monophosphate 
GRI
Growth rate inhibition
GVHD
Graft-versus-host disease
HBsAg/HBV
Hepatitis B surface antigen/Hepatitis B virus
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
Hep C Ab
Hepatitis C Antibody
HIV
Human immunodeficiency virus
HNSCC
Head and neck squamous cell carcinoma
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
087V73


Product:  MK-1454 
182
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Abbreviation
Definition
IEC
Institutional Ethics Committee
IFN
Interferon
IFNβ
Interferon beta
Ig
Immunoglobulin
IHC
Immunohistochemistry
IL-6
Interleukin-6
INR
International normalized ratio
IO
Immuno-oncology
IP-10
Interferon gamma-induced protein 10 
IRB
Institutional Review Board
irRECIST
Immune-related Response Evaluation Criteria In Solid Tumors
ISCL
International Society for Cutaneous Lymphomas
IT
Intratumoral
itRECIST
Intratumoral immunotherapy Response Evaluation Criteria In Solid 
Tumors
IUD
Intrauterine device
IUS
Intrauterine system
IWG
International Working Group
IWRS
Integrated web response system
LAM
Lymphangioleiomyomatosis
LDH
Lactate dehydrogenase
LLOQ
Lower limit of quantification
mAb
Monoclonal antibody
MAD
Maximum administered dose
MCP-2
Monocyte chemoattractant protein-2
MIP-1α
Macrophage inflammatory protein-1 alpha
MOA
Mechanism of action
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MSI
Microsatellite instability
MSI-H
Microsatellite instability-high
mSWAT
Modified Severity Weighted Assessment Tool
MTD
Maximum tolerated dose
mTPI
Modified toxicity probability interval
NASBA
Nucleic acid sequence-based amplification
NCI
National Cancer Institute 
087V73


Product:  MK-1454 
183
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Abbreviation
Definition
NOAEL
No observed adverse effect level
NT-I
Nontarget injected
NT-NI
Nontarget noninjected
NSCLC
Nonsmall-cell lung cancer
OS
Overall survival
OTC
Over-the-counter
PCR
Polymerase chain reaction
PD
Progressive disease
PD-1
Programmed cell death-1
PD-L1
Programmed cell death-1 ligand 1
PD-L2
Programmed cell death-1 ligand 2
PET
Positron emission tomography
PFS
Progression-free survival
PIN
Patient identification number
PK
Pharmacokinetic
PP
Per-Protocol
PT
Prothrombin time
PTT
Partial thromboplastin time
QD
Once daily
QW
Once a week
Q3W
Every 3 weeks 
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 Dose
SAE
Serious adverse events
SCCHN
Squamous cell carcinoma of the head and neck
SD
Stable disease
SHP-1
Src homology region 2 domain-containing phosphatase-1
SHP-2
Src homology region 2 domain-containing phosphatase-2
SNP
Single nucleotide polymorphism
SoA
Schedule of Activities
SOD
Sum of diameters
sSAP
Supplemental Statistical Analysis Plan
STING
Stimulator of Interferon Genes
CCI
087V73


Product:  MK-1454 
184
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
Abbreviation
Definition
TBK1
TANK-binding kinase 1
T-I
Target injected
T-NI
Target noninjected
TNBC
Triple-negative breast cancer
TNF-α
Tumor necrosis factor-alpha
TNM
Tumor, node, metastases
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
VL
Viral load
VS
Vital sign(s)
WOCBP
Woman of childbearing potential
WT
Wild-type
ZAP70
Zeta-chain-associated protein kinase 70
087V73


Product:  MK-1454 
185
Protocol/Amendment No.: 001-08 
MK-1454-001-08 Final Protocol
27-Jul-2021
Confidential
13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – TRIAL PROCEDURES (Assessing and Recording Adverse 
Events).  I also agree to handle all clinical supplies provided by the Sponsor and collect and 
handle all clinical specimens in accordance with the protocol.  I understand that information 
that identifies me will be used and disclosed as described in the protocol, and that such 
information may be transferred to countries that do not have laws protecting such 
information.  Since the information in this protocol and the referenced Investigator’s 
Brochure is confidential, I understand that its disclosure to any third parties, other than those 
involved in approval, supervision, or conduct of the trial is prohibited.  I will ensure that the 
necessary precautions are taken to protect such information from loss, inadvertent disclosure 
or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
087V73