Clinical trial NCT03249792
Conditions: Solid Tumor Lymphoma
Sponsor: Merck Sharp & Dohme LLC
Start date: 2017-09-20; Completion date: 2023-02-22
Enrollment: 140 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
The purposes of this study are to: 1) assess the safety and tolerability and 2) establish a preliminary recommended Phase 2 dose (RP2D) and/or a maximum tolerated dose (MTD) or a maximum administered dose (MAD) of MK-2118 when administered via intratumoral (IT) injection as monotherapy and in combination with pembrolizumab (MK-3475) intravenous (IV) infusion, or via subcutaneous (SC) injection in combination with pembrolizumab IV infusion in the treatment of adult participants with advanced/metastatic solid tumors or lymphomas.

Participants will receive either MK-2118 monotherapy or MK-2118 in combination with pembrolizumab for up to 35 cycles for Arms 1-3 or up to 36 cycles for Arm 4 (up to approximately 2 years).

All participants will undergo at least a 24-hour observation period following the first three administrations of MK-2118 (Arms 1-3: Cycle 1 Days 1, 8, and 15. Arm 4: Cycle 1 Days 1 and 8; and Cycle 2 Day 1).

Qualified participants who experience radiographic or clinical progression in Arm 1 (MK-2118 Intra-tumoral \[IT\] monotherapy) may switch over to Arm 2 (MK-2118 IT + Pembrolizumab IV Combination Therapy) at an eligible dose.

Pharmacokinetic (PK) outcome measures will not be analyzed separately for the switch-over treatment arms, per protocol.

Detailed description:
Arm 3 did not enroll any participants.

Data for the pembrolizumab Cmin outcome measure were not collected.

Arms: arm 1: Participants receive MK-2118 100 µg via IT injection once weekly (Q1W) on Days 1, 8 and 15 of Cycles 1-3 followed by once every 3 weeks (Q3W) on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 2: Participants receive MK-2118 300 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 3: Participants receive MK-2118 900 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 4: Participants receive MK-2118 2700 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 5: Participants receive MK-2118 5400 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 6: Participants receive MK-2118 7700 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 7: Participants receive MK-2118 10000 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 8: Participants receive MK-2118 15000 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 9: Participants receive MK-2118 20000 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 10: Participants receive MK-2118 2700 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of each cycle for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 11: Participants receive MK-2118 5400 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of each cycle for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 12: Participants receive MK-2118 7700 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of each cycle for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 13: Participants receive MK-2118 10000 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of each cycle for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 14: Participants receive MK-2118 15000 µg via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-3 followed by Q3W on Day 1 of Cycle 4 and beyond, for a total of up to \~35 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of each cycle for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 15: Participants receive MK-2118 via IT injection Q1W on Days 1, 8 and 15 of Cycles 1-2 followed by Q3W on Day 1 of Cycle 3 and beyond, for a total of up to \~35 cycles (up to \~2 years) and pembrolizumab 200 mg via IV infusion on Day 1 of each cycle for a total of up to \~35 cycles (up to \~2 years). Each cycle is 3 weeks long. arm 16: Participants receive MK-2118 5000 µg via SC injection Q1W on Days 1 and 8 of Cycle 1 followed by Q1W on Days 1, 8 and 15 of Cycles 2-4, followed Q3W Day 1 of Cycle 5 and beyond, for a total of up to 36 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of Cycle 2 and beyond for a total of up to 36 cycles (up to \~2 years). Cycle 1 is 2 weeks long and Cycles 2 to 36 are 3 weeks long. arm 17: Participants receive MK-2118 10000 µg via SC injection Q1W on Days 1 and 8 of Cycle 1 followed by Q1W on Days 1, 8 and 15 of Cycles 2-4, followed Q3W Day 1 of Cycle 5 and beyond, for a total of up to 36 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of Cycle 2 and beyond for a total of up to 36 cycles (up to \~2 years). Cycle 1 is 2 weeks long and Cycles 2 to 36 are 3 weeks long. arm 18: Participants receive MK-2118 15000 µg via SC injection Q1W on Days 1 and 8 of Cycle 1 followed by Q1W on Days 1, 8 and 15 of Cycles 2-4, followed Q3W Day 1 of Cycle 5 and beyond, for a total of up to 36 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of Cycle 2 and beyond for a total of up to 36 cycles (up to \~2 years). Cycle 1 is 2 weeks long and Cycles 2 to 36 are 3 weeks long. arm 19: Participants receive MK-2118 20000 µg via SC injection Q1W on Days 1 and 8 of Cycle 1 followed by Q1W on Days 1, 8 and 15 of Cycles 2-4, followed Q3W Day 1 of Cycle 5 and beyond, for a total of up to 36 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of Cycle 2 and beyond for a total of up to 36 cycles (up to \~2 years). Cycle 1 is 2 weeks long and Cycles 2 to 36 are 3 weeks long. arm 20: Participants receive MK-2118 30000 µg via SC injection Q1W on Days 1 and 8 of Cycle 1 followed by Q1W on Days 1, 8 and 15 of Cycles 2-4, followed Q3W Day 1 of Cycle 5 and beyond, for a total of up to 36 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of Cycle 2 and beyond for a total of up to 36 cycles (up to \~2 years). Cycle 1 is 2 weeks long and Cycles 2 to 36 are 3 weeks long. arm 21: Participants receive MK-2118 45000 µg via SC injection Q1W on Days 1 and 8 of Cycle 1 followed by Q1W on Days 1, 8 and 15 of Cycles 2-4, followed Q3W Day 1 of Cycle 5 and beyond, for a total of up to 36 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of Cycle 2 and beyond for a total of up to 36 cycles (up to \~2 years). Cycle 1 is 2 weeks long and Cycles 2 to 36 are 3 weeks long. arm 22: Participants receive MK-2118 60000 µg via SC injection Q1W on Days 1 and 8 of Cycle 1 followed by Q1W on Days 1, 8 and 15 of Cycles 2-4, followed Q3W Day 1 of Cycle 5 and beyond, for a total of up to 36 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of Cycle 2 and beyond for a total of up to 36 cycles (up to \~2 years). Cycle 1 is 2 weeks long and Cycles 2 to 36 are 3 weeks long. arm 23: Participants receive MK-2118 90000 µg via SC injection Q1W on Days 1 and 8 of Cycle 1 followed by Q1W on Days 1, 8 and 15 of Cycles 2-4, followed Q3W Day 1 of Cycle 5 and beyond, for a total of up to 36 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of Cycle 2 and beyond for a total of up to 36 cycles (up to \~2 years). Cycle 1 is 2 weeks long and Cycles 2 to 36 are 3 weeks long. arm 24: Participants receive MK-2118 120000 µg via SC injection Q1W on Days 1 and 8 of Cycle 1 followed by Q1W on Days 1, 8 and 15 of Cycles 2-4, followed Q3W Day 1 of Cycle 5 and beyond, for a total of up to 36 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of Cycle 2 and beyond for a total of up to 36 cycles (up to \~2 years). Cycle 1 is 2 weeks long and Cycles 2 to 36 are 3 weeks long. arm 25: Participants receive MK-2118 150000 µg via SC injection Q1W on Days 1 and 8 of Cycle 1 followed by Q1W on Days 1, 8 and 15 of Cycles 2-4, followed Q3W Day 1 of Cycle 5 and beyond, for a total of up to 36 cycles (up to \~2 years) and receive pembrolizumab 200 mg via IV infusion on Day 1 of Cycle 2 and beyond for a total of up to 36 cycles (up to \~2 years). Cycle 1 is 2 weeks long and Cycles 2 to 36 are 3 weeks long.
Interventions: intervention 1: MK-2118 (IT) intervention 2: MK-2118 (SC) intervention 3: Pembrolizumab
Intervention descriptions: intervention 1: IT injection intervention 2: SC injection intervention 3: IV infusion

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
A Phase 1 Open-label, Multicenter Study of 
MK-2118 Administered by Intratumoral Injection as 
Monotherapy and in Combination with 
Pembrolizumab or by Subcutaneous Injection in 
Combination with Pembrolizumab for Patients with 
Advanced/Metastatic Solid Tumors or Lymphomas
NCT03249792
22-September-2022


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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 1 Open-label, Multicenter Study of MK-2118 Administered by 
Intratumoral Injection as Monotherapy and in Combination with Pembrolizumab or by 
Subcutaneous Injection in Combination with Pembrolizumab for Patients with 
Advanced/Metastatic Solid Tumors or Lymphomas
Protocol Number: 001-08
Compound Number: MK-2118
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme LLC 
(hereafter called the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
IND NUMBER:   133985
NCT NUMBER: NCT03249792
EudraCT NUMBER: Not applicable
Approval Date:  27 September 2022
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor Contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
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.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 08
27-SEP-2022
Merck Sharp & Dohme Corp. underwent an entity name and address 
change to Merck Sharp & Dohme LLC, Rahway, NJ, USA. This 
conversion resulted only in an entity name change and update to the 
address.
Amendment 07
27-MAY-2021
To update the dose modification and toxicity management guidelines for 
irAEs.
Amendment 06
21-DEC-2020
To increase the potential maximum dose to
 of MK-2118 
administered subcutaneously in Arm 4 and to adjust the number of 
participants estimated for enrollment accordingly.
Amendment 05
04-AUG-2020
To update the timepoints for biomarker sample collection, the addition of 
the itRECIST response assessment guidelines, and to update the 
requirements for contraception to adopt the most stringent option.. 
Amendment 04
21-MAR-2019
Added inpatient observation periods following the second and third 
administrations of MK-2118 in order to provide additional safety 
monitoring and added intermediate dose levels for subcutaneous (SC) 
MK-2118 administration with corresponding volumes of administration.
Amendment 03
03-AUG-2018
To expand the top dose of MK-2118 beyond 
; 
additionally, Arm 3 was modified to begin with an accelerated titration 
design (ATD) at a starting dose of 
MK-2118
CCI
CCI
CCI
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Document
Date of Issue
Overall Rationale
Amendment 02
27-MAR-2018
To provide a response assessment for participants with cutaneous T-cell 
lymphoma, and for the addition of Arm 3 to evaluate intratumoral (IT) 
injection into liver metastasis/ lesions and Arm 4 to evaluate 
subcutaneous administration of MK-2118.
Amendment 01
19-JUN-2017
To implement clarifications requested by the United States (US) Food 
and Drug Administration (FDA) regarding the following:  

timing of STING dosing relative to pembrolizumab 
administration, 

communication of dosing and escalation decisions to sites, 

wording of inclusion criterion #1 to ensure that participants with 
SOC options are not enrolled

wording of inclusion criterion #3 to clarify lymphoma lesion size
Original Protocol
21-APR-2017
Not appliable.
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 08
Overall Rationale for the Amendments:
Sponsor underwent an entity name change and update to the address
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
Title Page
Section 12.3 Appendix 3: 
Study Governance 
Considerations
Throughout
Sponsor entity name and address change.
Merck Sharp & Dohme Corp. underwent an entity name 
and address change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
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Table of Contents
DOCUMENT HISTORY ....................................................................................................... 3
PROTOCOL AMENDMENT SUMMARY OF CHANGES.............................................. 5
1
Synopsis...................................................................................................................... 18
2
Schedule of Activities (SoA)..................................................................................... 23
2.1
Schedule of Activities for Initial Screening for Arms 1 to 4 and for 
Crossover into Arm 2 ........................................................................................... 23
2.2
Schedule of Activities for the Treatment Period, IT Administration for 
Arm 1 (Monotherapy) and Arm 2 (Combination Therapy – Including 
Crossover to Arm 2) ............................................................................................. 26
2.3
Schedule of Activities for the Treatment Period of Arm 3 (Visceral IT 
Administration)..................................................................................................... 32
2.4
Schedule of Activities for the Treatment Period of Arm 4 (Subcutaneous 
Administration)..................................................................................................... 37
2.5
Discontinuation / End of Treatment and Post-treatment Follow-up for 
Arms 1 to 4............................................................................................................. 45
3
Introduction............................................................................................................... 47
3.1
Study Rationale..................................................................................................... 47
3.2
Background ........................................................................................................... 48
3.2.1
Pharmaceutical and Therapeutic Background .................................................... 48
3.2.2
Mechanism of Action.......................................................................................... 48
3.2.3
Preclinical Trials of MK-2118............................................................................ 49
3.2.4
Pembrolizumab Background............................................................................... 49
3.3
Benefit/Risk Assessment....................................................................................... 50
4
Objectives/Hypotheses and Endpoints.................................................................... 50
5
Study Design.............................................................................................................. 52
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5.1
Overall Design....................................................................................................... 52
5.1.1
Study Diagram .................................................................................................... 57
5.2
Number of Participants........................................................................................ 57
5.3
Beginning and End of Study Definition.............................................................. 58
5.3.1
Clinical Criteria for Early Trial Termination...................................................... 58
5.4
Scientific Rationale for Study Design.................................................................. 58
5.4.1
Efficacy Endpoints.............................................................................................. 58
5.4.1.1
Immune-related RECIST (irRECIST) ......................................................... 59
5.4.1.2
IT Immunotherapy RECIST (itRECIST)..................................................... 60
5.4.1.3
IWG Revised Response Criteria for Malignant Lymphomas...................... 60
5.4.1.4
Response Assessment for Cutaneous T-cell Lymphoma............................. 61
5.4.1.5
Overall Survival........................................................................................... 61
5.4.2
Safety Endpoints ................................................................................................. 61
5.4.3
Pharmacokinetic Endpoints ................................................................................ 61
5.4.4
Systemic Cytokines............................................................................................. 62
5.4.5
Pharmacodynamic Endpoints.............................................................................. 62
5.4.6
Planned Exploratory Biomarker Research.......................................................... 62
5.4.6.1
Planned Genetic Analysis ............................................................................ 62
5.4.6.2
Rationale for Planned Biomarker Research................................................. 63
5.4.6.3
Future Biomedical Research (FBR)............................................................. 64
5.5
Justification for Dose............................................................................................ 65
5.5.1
Starting Dose for This Trial ................................................................................ 65
5.5.1.1
Starting Dose for Arm 1 and Arm 2............................................................. 65
5.5.1.2
Starting Dose for Arm 3............................................................................... 68
5.5.1.3
Starting Dose for Arm 4............................................................................... 69
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5.5.2
Maximum Dose/Exposure for This Trial............................................................ 70
5.5.2.1
Maximum Dose Exposure for IT Dosing..................................................... 70
5.5.2.2
Maximum Dose/Exposure for Subcutaneous Dosing.................................. 70
5.5.3
Rationale for Dose Interval and Trial Design..................................................... 71
5.5.3.1
Rationale for Design of Arm 3 (Visceral IT Injection)................................ 71
5.5.3.2
Rationale for Design of Arm 4 (Subcutaneous/Systemic 
Administration)............................................................................................ 72
6
Study Population....................................................................................................... 72
6.1
Inclusion Criteria.................................................................................................. 72
6.1.1
Inclusion Criteria for Arm 1 and Arm 2 ............................................................. 72
6.1.2
Inclusion Criteria for Crossover into Arm 2....................................................... 76
6.1.3
Inclusion Criteria for Arm 3
Visceral IT Injection .......................................... 79
6.1.4
Inclusion Criteria for Arm 4 Subcutaneous Injection...................................... 82
6.2
Exclusion Criteria................................................................................................. 85
6.2.1
Exclusion Criteria for Initial Treatment.............................................................. 85
6.2.2
Exclusion Criteria for Crossover into Arm 2...................................................... 87
6.3
Lifestyle Restrictions ............................................................................................ 89
6.3.1
Meals and Dietary Restrictions........................................................................... 89
6.3.2
Caffeine, Alcohol, and Tobacco ......................................................................... 89
6.3.3
Activity ............................................................................................................... 90
6.3.4
Contraception...................................................................................................... 90
6.3.5
Pregnancy............................................................................................................ 90
6.3.6
Use in Nursing Women....................................................................................... 90
6.4
Screen Failures...................................................................................................... 91
6.5
Participant Replacement Strategy ...................................................................... 91
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7
Treatments................................................................................................................. 91
7.1
Treatments Administered .................................................................................... 91
7.1.1
IT Injection (Arm 1, Arm 2, and Arm 3) ............................................................ 92
7.1.2
Subcutaneous Injection (Arm 4) ......................................................................... 94
7.2
Dose Modification (Escalation/Titration/Other)................................................ 94
7.2.1
Accelerated Titration Design .............................................................................. 94
7.2.2
Dose Finding During Modified Toxicity Probability Interval Design................ 95
7.2.3
Definition of Dose-limiting Toxicity.................................................................. 97
7.2.4
Dose Modification/Interruption Due to Adverse Events .................................... 99
7.2.4.1
Dose Modification for MK-2118............................................................... 100
7.2.4.2
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)............................................................................................... 106
7.2.4.3
Management of Infusion Reaction............................................................. 110
7.2.4.4
Management of Cytokine Release Syndrome............................................ 111
7.2.4.5
Other Allowed Dose Interruption for MK-2118 or Pembrolizumab ......... 113
7.2.5
Intraparticipant Dose Escalation....................................................................... 113
7.3
Method of Treatment Assignment..................................................................... 113
7.3.1
Stratification...................................................................................................... 114
7.4
Blinding................................................................................................................ 114
7.5
Preparation/Handling/Storage/Accountability ................................................ 114
7.5.1
Dose Preparation............................................................................................... 114
7.5.2
Handling, Storage and Accountability.............................................................. 114
7.6
Treatment Compliance....................................................................................... 115
7.7
Concomitant Therapy......................................................................................... 115
7.7.1
Rescue Medications & Supportive Care........................................................... 116
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7.8
Treatment After the End of the Study.............................................................. 117
7.9
Lost to Follow-up ................................................................................................ 117
7.10
Clinical Supplies Disclosure............................................................................... 117
8
Discontinuation/Withdrawal Criteria................................................................... 117
8.1
Discontinuation of Study Treatment................................................................. 117
8.2
Withdrawal from the Study............................................................................... 119
9
Study Assessments and Procedures....................................................................... 119
9.1
Administrative and General Procedures .......................................................... 119
9.1.1
Informed Consent.............................................................................................. 119
9.1.1.1
General Informed Consent......................................................................... 120
9.1.1.2
Consent and Collection of Specimens for Future Biomedical Research... 120
9.1.2
Inclusion/Exclusion Criteria ............................................................................. 120
9.1.3
Participant Identification Card.......................................................................... 120
9.1.4
Medical History ................................................................................................ 121
9.1.5
Disease Details.................................................................................................. 121
9.1.6
Prior Oncology Treatment History ................................................................... 121
9.1.7
Eastern Cooperative Oncology Group Performance Status.............................. 121
9.1.8
Prior and Concomitant Medications Review .................................................... 121
9.1.8.1
Prior Medications....................................................................................... 121
9.1.8.2
Concomitant Medications.......................................................................... 121
9.1.9
Assignment of Screening Number.................................................................... 122
9.1.10 Assignment of Treatment/Randomization Number.......................................... 122
9.1.11 Treatment Administration................................................................................. 122
9.1.11.1 Timing of Dose Administration................................................................. 123
9.1.12 Discontinuation and Withdrawal ...................................................................... 123
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9.1.12.1 Withdrawal From Future Biomedical Research ........................................ 124
9.1.13 Participant Blinding/Unblinding....................................................................... 124
9.1.14 Domiciling ........................................................................................................ 124
9.1.15 Calibration of Equipment.................................................................................. 124
9.2
Efficacy Assessments .......................................................................................... 125
9.2.1
Tumor Imaging and Medical Photography....................................................... 125
9.2.2
Response Assessments...................................................................................... 125
9.2.2.1
Immune-related RECIST ........................................................................... 125
9.2.2.2
IT Immunotherapy RECIST (itRECIST)................................................... 127
9.2.2.3
IWG Revised Response Criteria for Malignant Lymphomas.................... 128
9.2.2.4
Response Assessment for Cutaneous T-cell Lymphoma........................... 130
9.2.3
Tumor Marker Assessments ............................................................................. 135
9.3
Adverse Events, Serious Adverse Events and Other Reportable Safety 
Events................................................................................................................... 135
9.3.1
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information.................................................................................. 136
9.3.2
Method of Detecting AE, SAE and Other Reportable Safety Events............... 137
9.3.3
Follow-up of AE, SAE and Other Reportable Safety Event Information......... 138
9.3.4
Regulatory Reporting Requirements for SAE .................................................. 138
9.3.5
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying 
as AEs or SAEs................................................................................................. 138
9.3.6
Pregnancy and Exposure During Breastfeeding ............................................... 138
9.3.7
Events of Clinical Interest (ECI)....................................................................... 139
9.4
Treatment of Overdose....................................................................................... 139
9.5
Safety.................................................................................................................... 140
9.5.1
Physical Examinations...................................................................................... 140
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9.5.2
Vital Signs......................................................................................................... 140
9.5.3
Electrocardiograms ........................................................................................... 140
9.5.4
Clinical Safety Laboratory Assessments........................................................... 140
9.6
Pharmacokinetics................................................................................................ 141
9.6.1
Blood Collection for PK ................................................................................... 141
9.6.2
Blood Collection for Anti-pembrolizumab Antibodies .................................... 141
9.6.3
Urine Collection for Urinary MK-2118............................................................ 142
9.7
Pharmacodynamics............................................................................................. 142
9.7.1
Blood for Pharmacodynamic Markers.............................................................. 142
9.7.2
Tumor Biopsy ................................................................................................... 142
9.8
Future Biomedical Research Sample Collection.............................................. 144
9.9
Biomarkers .......................................................................................................... 144
9.9.1
Planned Genetic Analysis Sample Collection................................................... 144
9.9.2
Blood for Genotyping ....................................................................................... 144
9.9.3
Immunogenicity Assessments........................................................................... 144
9.9.4
Blood for Serum Cytokine Analysis................................................................. 144
9.9.5
Blood for RNA Analysis................................................................................... 145
9.10
Visit Requirements ............................................................................................. 145
9.10.1 Screening........................................................................................................... 145
9.10.2 Treatment Period............................................................................................... 145
9.10.2.1 Treatment Period beyond Disease Progression.......................................... 146
9.10.3 Post-treatment Follow-up.................................................................................. 146
9.10.3.1 30-Day Safety Follow-up Visit.................................................................. 146
9.10.3.2 Survival Follow-up .................................................................................... 146
10
Statistical Analysis Plan ......................................................................................... 147
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10.1
Statistical Analysis Plan Summary ................................................................... 147
10.2
Responsibility for Analyses/In-House Blinding ............................................... 148
10.3
Hypotheses/Estimation....................................................................................... 149
10.4
Analysis Endpoints ............................................................................................. 149
10.4.1 Efficacy/Pharmacokinetic Endpoints................................................................ 149
10.4.2 Safety Endpoints ............................................................................................... 149
10.5
Analysis Populations........................................................................................... 149
10.5.1 Safety Analysis Population............................................................................... 149
10.5.2 Pharmacokinetic Analysis and Target Engagement Populations...................... 150
10.5.3 Efficacy Analysis Populations .......................................................................... 150
10.6
Statistical Methods.............................................................................................. 150
10.6.1 Statistical Methods for Efficacy Analyses........................................................ 150
10.6.2 Statistical Methods for Safety Analyses ........................................................... 150
10.6.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses.. 151
10.6.3.1 Demographic and Baseline Characteristics ............................................... 151
10.6.3.2 Pharmacokinetics and Pharmacodynamics Modeling Analysis ................ 151
10.7
Interim Analyses ................................................................................................. 151
10.8
Multiplicity .......................................................................................................... 151
10.9
Sample Size and Power Calculations ................................................................ 151
10.10 Subgroup Analyses ............................................................................................. 152
10.11 Compliance (Medication Adherence)................................................................ 152
10.12 Extent of Exposure.............................................................................................. 152
11
References................................................................................................................ 153
12
Appendices............................................................................................................... 156
12.1
Appendix 1: Abbreviations and Trademarks .................................................. 156
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12.2
Appendix 2: Clinical Laboratory Tests ............................................................ 161
12.3
Appendix 3: Study Governance Considerations.............................................. 163
Code of Conduct for Clinical Trials.............................................................................. 163
Financial Disclosure...................................................................................................... 165
Data Protection.............................................................................................................. 166
Confidentiality of Data ................................................................................................. 166
Confidentiality of Participant Records.......................................................................... 166
Confidentiality of IRB/IEC Information....................................................................... 166
Publication Policy..................................................................................................... 167
Compliance with Trial Registration and Results Posting Requirements...................... 167
Compliance with Law, Audit and Debarment .............................................................. 167
Data Quality Assurance ................................................................................................ 168
Source Documents ........................................................................................................ 169
Study and Site Closure.................................................................................................. 169
12.4
Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................. 170
Definition of AE ........................................................................................................... 170
Definition of SAE ......................................................................................................... 171
Recording AE and SAE ................................................................................................ 173
Reporting of AE, SAE, and Other Reportable Safety Events to the Sponsor............... 176
12.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing ...................... 178
Contraception Requirements......................................................................................... 179
Pregnancy Testing......................................................................................................... 180
12.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research........................................................................................... 181
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12.7
Appendix 7: Prioritization of IT Lesion Injection........................................... 186
12.8
Appendix 8: itRECIST Supplementary Figures.............................................. 188
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LIST OF TABLES
Table 1
Summary of Study Treatment Arms 1, 2, 3, and 4 ............................................... 20
Table 2
Trial Treatment for IT MK-2118 Monotherapy (Arm 1)...................................... 66
Table 3
Trial Treatment for IT MK-2118 Combination Therapy with Pembrolizumab 
(Arm 2).................................................................................................................. 67
Table 4
Trial Treatment for Visceral IT MK-2118 Combination Therapy with 
Pembrolizumab (Arm 3) ....................................................................................... 68
Table 5
Trial Treatment for MK-2118 Subcutaneous Administration in Combination 
with Pembrolizumab (Arm 4)............................................................................... 69
Table 6
Adequate Organ Function Laboratory Values...................................................... 74
Table 7
Study Treatment(s)................................................................................................ 92
Table 8
Determination of MK-2118 Injection Volume for Cutaneous and 
Subcutaneous Injections Based on Lesion Size (Arms 1 and 2)........................... 93
Table 9
Determination of MK-2118 Injection Volume for IT Injections Based on 
Visceral Lesion Size (Arm 3) ............................................................................... 94
Table 10
Dose-finding Rules per mTPI Design................................................................... 97
Table 11
MK-2118 Dose Modification Guidelines for Drug-related Adverse Events in 
Monotherapy IT (Arm 1), Combination Therapy IT (Arm 2), Combination 
Therapy Visceral IT (Arm 3), and Combination Therapy Subcutaneous 
Administration (Arm 4) ...................................................................................... 100
Table 12
Dose Modification and Toxicity Management Guidelines for Immune-related 
Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .................................................................. 107
Table 13
Infusion Reaction Treatment Guidelines ............................................................ 110
Table 14
Cytokine Release Syndrome Treatment Guidelines ........................................... 112
Table 15
Response Criteria for Malignant Lymphoma ..................................................... 129
Table 16
Modified Severity Weighted Assessment Tool .................................................. 130
Table 17
Response in Skin (Cutaneous T-cell Lymphoma) .............................................. 131
Table 18
Response in Lymph Nodes (Cutaneous T-cell Lymphoma)............................... 132
Table 19
Response in Viscera (Cutaneous T-cell Lymphoma) ......................................... 133
Table 20
Response in Blood (Cutaneous T-cell Lymphoma)............................................ 134
Table 21
Global Response Score for Cutaneous T-cell Lymphoma.................................. 135
Table 22
Reporting Time Periods and Timeframes for Adverse Events and Other 
Reportable Safety Events.................................................................................... 137
Table 23
Protocol-required Safety Laboratory Assessments............................................. 162
Table 24
Highly Effective Contraception Methods........................................................... 180
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LIST OF FIGURES
Figure 1
Schematic Diagram Showing Mechanism of the Enhancement of T-cell 
Driven Antitumor Immunity Through the Action of STING Agonists................ 49
Figure 2
Trial Design Diagram ........................................................................................... 57
Figure 3
Algorithm for Classification of Lesions at Baseline........................................... 188
Figure 4
Reclassification of Noninjected Lesions............................................................. 189
Figure 5
Overall Response Assessment Until Disease Progression.................................. 190
Figure 6
Example of Iterative Assessment of Injected Lesion Response During 
Treatment ............................................................................................................ 191
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1
SYNOPSIS
Protocol Title:  
A Phase 1 Open-label, Multicenter Study of MK-2118 Administered by 
Intratumoral Injection as Monotherapy and in Combination with Pembrolizumab 
or by Subcutaneous Injection in Combination with Pembrolizumab for Patients 
with Advanced/Metastatic Solid Tumors or Lymphomas
Short Title: 
Phase 1b Open-label Study of MK-2118 by IT and SC Injection
Objectives/Hypotheses and Endpoints:
Male/female participants of at least 18 years of age with advanced/metastatic solid tumors or 
lymphomas will be enrolled in this trial.
Objective/Hypothesis
Endpoint
Primary

Objective: To determine the safety and 
tolerability and to establish a preliminary 
RP2D and/or an MTD or an MAD of 
MK-2118 administered via IT) injection 
as monotherapy and in combination with 
pembrolizumab IV infusion or by SC 
injection in combination with 
pembrolizumab IV infusion.

DLT

AE

Discontinuing study treatment 
due to an AE
Secondary

Objective:  To evaluate the PK of 
MK-2118 administered via IT injection 
as monotherapy and in combination with 
pembrolizumab IV infusion, or 
administered via SC injection in 
combination with pembrolizumab IV 
infusion

Pharmacokinetic parameters of 
MK-2118, including Cmin, Cmax, and 
AUC

Objective:  To evaluate the PK of 
pembrolizumab IV infusion in 
combination with MK-2118
administered via IT or SC injection

Pharmacokinetic exposure of 
pembrolizumab
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Overall Design:
Trial Phase
Phase 1b
Clinical Indication
Treatment of advanced/metastatic solid tumors or lymphomas
Population
Participants with any histologically or cytologically confirmed 
advanced/metastatic solid tumor or lymphoma by pathology 
report who have received, or have been intolerant to, all
treatment known to confer clinical benefit.
Trial Type
Interventional
Type of Design
This is a first-in-human, dose escalation and confirmation, 
nonrandomized, 4-arm, multicenter, open-label trial of MK-2118
monotherapy and MK-2118 in combination with pembrolizumab. 
Type of Control
No treatment control
Trial Blinding
Unblinded Open-label
Estimated Duration 
of Trial
The Sponsor estimates that the trial will require approximately 
62 months from the time the first participant signs the informed 
consent until the last participant’s last study-related phone call or 
visit.
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cohorts up to a dose level that meets at least 1 of the following 
criteria:  1) a dose level of at least
is cleared by DLT 
evaluation, OR 2) a ≥Grade 2 toxicity as assessed by the Investigator
to be related, probably related, or possibly related to the drug(s) at any 
dose level. Arm 3 will then proceed to mTPI (Arm 3 Part F) to 
determine the MTD and/or MAD of IT MK-2118 in visceral lesions
in combination with pembrolizumab.
Arm 4 will initiate once the
IT MK-2118 dose level in Arm 1 
has completed DLT evaluation per mTPI design. The starting dose for 
Arm 4 will be up to, but not exceeding,
SC MK-2118. 
There will be a 2-week SC MK-2118 monotherapy treatment period 
in Cycle 1. Subsequent cycles will constitute treatment of SC 
MK-2118 with the addition of pembrolizumab (see Table 1). Arm 4 
will utilize the mTPI design to determine a preliminary RP2D for SC 
MK-2118 in combination with pembrolizumab.
A participant who has radiographic or clinical progression in Arm 1 
(IT MK-2118 monotherapy) may cross over to Arm 2 (IT MK-2118
in combination with pembrolizumab) once they have completed the 
DLT evaluation period of 21 days in his/her assigned monotherapy 
dose level cohort. The crossover participant will initiate Arm 2 at 
screening.
Duration of 
Participation
Each participant will be enrolled in the trial for up to approximately 2 
years from the time that the participant signs the ICF through the final 
contact. Following a screening period of up to 28 days, each 
participant may receive up to 35 cycles of treatment in Arm 1, Arm 2, 
or Arm 3. In Arm 4, treatment begins with a 2-week cycle of SC 
MK-2118 monotherapy (Cycle 1) followed by up to 35 cycles of 
treatment in combination with pembrolizumab.
An Arm 1 crossover participant may receive up to 35 cycles of 
treatment in Arm 2 (IT MK-2118 with pembrolizumab combination 
therapy) regardless of the duration of treatment he/she received in 
Arm 1 (IT MK-2118 monotherapy).
After the end of treatment, each participant will be followed up for 
safety at 30 days. Participants will be monitored for survival every 
12 weeks thereafter. Participants with SAEs, events of clinical 
interest, or who become pregnant will be followed up for 120 days.
Abbreviations are not spelled out at first use. A list of abbreviations used in this document 
can be found in Appendix 1. Study governance considerations are outlined in Appendix 3.
CCI
CCI
CCI
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a.) All participants in Arms 1, 2 and 3 will be required to provide a sample biopsy of the tumor to be injected with MK-2118 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-2118, as well as on the distant, discrete lesion 
that is not intended for IT administration with MK-2118. For the tumor lesion intended for treatment with IT administration of MK-2118, the sample will be 
obtained by either punch biopsy for cutaneous lesions, or ultrasound-guided biopsy for subcutaneous/visceral lesions, or cross-sectional image-guided biopsy for 
visceral lesions. For distant, discrete tumor lesions that are not intended for IT administration with MK-2118, the sample biopsy will be obtained by punch biopsy 
for cutaneous lesions, ultrasound guided biopsy for subcutaneous/visceral lesions, or cross-sectional image-guided biopsy, such as CT/MRI-guided biopsy, for 
additional lesions. 
Participants in Arm 1 (monotherapy) who cross over to Arm 2 (combination therapy) are required to provide a fresh tumor biopsy at screening of both injected 
and noninjected sites, similar to participants who are newly enrolled into the study and assigned to Arm 2, unless one of the following 2 situations occur:
(1) The most recent Arm 1 biopsy occurred within 28 days of C1D1 of Arm 2, OR (2) The investigator deems the biopsy to be medically unsafe.
Participants in Arm 4 will be required to provide a sample biopsy of a discrete, noninjected tumor lesion prior to treatment (Screening), unless deemed medically 
unsafe by the Investigator. The sample biopsy will be obtained by punch biopsy for cutaneous lesions, ultrasound guided biopsy for subcutaneous/visceral
lesions, or cross-sectional image-guided biopsy, such as CT/MRI-guided biopsy, for additional lesions. Method of biopsy will be per guidance of the Investigator
as well as discussion with the Sponsor. 
Biopsies obtained during this study will be submitted as formalin-fixed, paraffin-embedded samples. Leftover main study tissue will be stored for FBR if the 
participant 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. 
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a)
The inpatient observation periods may be extended up to 48 hours at the discretion of the Investigator, per local Institutional Review Board, Ethics Review 
Committee, 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 participant has undergone intraparticipant dose escalation of MK-2118, these samples for biomarker analysis will be collected on Day 1 of the 
first cycle of the escalated new dose. Note: Blood for RNA testing will also be collected on Day 1 of the second cycle of the escalated new dose.
d)
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 signs the FBR consent. 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.
e)
All participants will be required to provide a sample biopsy of the tumor to be injected with MK-2118 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-2118, 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-2118, the sample biopsy will be obtained by punch biopsy for 
cutaneous lesions, ultrasound guided biopsy for subcutaneous lesions, or image-guided biopsy, such as CT-guided biopsy, for additional lesions. Method of 
biopsy will be per guidance of the Investigator as well as discussion with the Sponsor. Biopsies obtained during this study will be submitted as formalin-
fixed, paraffin-embedded samples. Leftover main study tissue will be stored for FBR if the participant consents to FBR. Instructions for tissue collection, 
processing, and shipment are provided in the Procedures Manual.
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a)
The inpatient observation periods may be extended up to 48 hours at the discretion of the Investigator, per local Institutional Review Board, Ethics Review 
Committee, 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 signs the FBR consent. 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 participants will be required to provide a sample biopsy of the tumor to be injected with MK-2118 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-2118, 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-2118, the sample biopsy will be obtained by punch biopsy for 
cutaneous lesions, ultrasound guided biopsy for subcutaneous lesions, or image-guided biopsy, such as CT-guided biopsy, for additional lesions. Method of 
biopsy will be per guidance of the Investigator as well as discussion with the Sponsor. Biopsies obtained during this study will be submitted as formalin-
fixed, paraffin-embedded samples. Leftover main study tissue will be stored for FBR if the participant consents to FBR. Instructions for tissue collection, 
processing, and shipment are provided in the Procedures Manual. 
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a)
The inpatient observation periods may be extended up to 48 hours at the discretion of the Investigator, per local Institutional Review Board, Ethics Review 
Committee, 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 signs the FBR consent. 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 participants in Arm 4 will be required to provide a sample biopsy from a discrete tumor lesion, unless deemed medically unsafe by the Investigator. For 
Arm 4, three serial biopsies (screening, C1D8 and C3D8) from a single discrete tumor lesion will be required. The sample biopsy will be obtained by punch 
biopsy for cutaneous lesions, ultrasound guided biopsy for subcutaneous or visceral lesions, or image-guided biopsy, such as CT/MRI-guided biopsy, for 
additional lesions. Method of biopsy will be per guidance of the Investigator as well as discussion with the Sponsor. Biopsies obtained during this study will 
be submitted as formalin-fixed, paraffin-embedded samples. Leftover main study tissue will be stored for FBR if the participant consents to FBR. 
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3
INTRODUCTION
MK-2118 is a novel small molecule that is an agonist of the intracellular innate immune 
adaptor, STING. MK-2118 is under study for the treatment of solid tumors and lymphomas
as monotherapy and as combination therapy with pembrolizumab. This is a FIH dose
escalation, and dose finding trial to assess the safety and tolerability of IT injection of 
MK-2118, both as monotherapy and as combination therapy with pembrolizumab. 
3.1
Study Rationale
Internal preclinical data demonstrate STING expression in multiple tumor types, supporting 
the study of a broad group of tumor types, including 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 activation in the tumor microenvironment leads to a potent antitumor 
response. IT injection of STING agonist in mice induces regression of established tumors and 
generates systemic immune responses, mediating rejection of distant metastases and 
providing immunologic (T cell) memory [Woo S. R., et al 2014] [Corrales, L., et al 2015]. 
The STING agonist MK-2118, therefore, has potential as a cancer therapeutic and will be 
evaluated in this FIH dose-finding trial. 
The scientific rationale for combining MK-2118 with PD-1 blockade is based on the ability 
of STING agonists to induce type I IFNs and induce strong T-cell activation by promoting 
cross-presentation of tumor antigens. As strong T cell activation is accompanied by up-
regulation of PD-1, which mediates T cell inhibition by tumors, combination therapy with 
anti-PD-1 will prevent the inhibition of T-cell activation. 
The empirical rationale for combining MK-2118 with PD-1 blockade is based on the efficacy 
observed in anti-PD-1 nonresponsive syngeneic mouse tumor models in which sub-
efficacious MK-2118 doses in combination with anti-PD-1 induced improved antitumor
responses and complete tumor regression compared with either monotherapy treatment alone.
The rationale for the addition of a visceral IT arm of MK-2118 is to expand the tumor 
location for IT therapy to deeper and visceral organs such as the liver. In addition, the 
visceral IT arm will evaluate the safety, tolerability, PK, pharmacodynamics, and early 
efficacy of MK-2118 injected into visceral and deeper lesions.
Subcutaneous administration of MK-2118 is under investigation with the objective to expand 
treatment of tumor types beyond what is achievable with IT administration and to 
demonstrate that clinical efficacy can be achieved with systemic exposure of MK-2118. The 
rationale for studying systemic delivery of MK-2118 via SC administration is based on the 
observed therapeutic index in preclinical models. In mouse tumor models, SC dosing of 
MK-2118 as monotherapy and in combination with anti-PD-1 induces complete 
tumor regression. Subcutaneous administration in preclinical species produced toxic effects 
attributed to exaggerated pharmacology, which were observed in a dose-dependent manner. 
The rat and dog Highest Not Severely Toxic Dose Levels achieved exposures that were 
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greater than
 respectively, of the projected efficacious 
exposure with SC MK-2118 administration in cancer patients. Continued clinical 
development of systemically administered SC MK-2118 is supported by evaluation of similar 
non cyclic dinucleotide STING agonist MSA-2 in syngeneic mouse tumor models[Pan, B. S., 
et al 2020]. In syngeneic mouse tumor models, subcutaneous and oral non cyclic dinucleotide 
MSA-2 regimens were well tolerated and stimulated interferon-β secretion in tumors, 
induced tumor regression with durable antitumor immunity, and synergized with anti PD-1 
therapy. IT cytokine levels were demonstrated with this systemically administered regimen.
3.2
Background
Detailed background information on preclinical pharmacology, pharmacokinetics, 
pharmacodynamics, and metabolism of MK-2118 is available in the MK-2118 IB. This is an 
FIH trial.
3.2.1
Pharmaceutical and Therapeutic Background
MK-2118 is a small molecule that binds to STING and stimulates type I IFNs and 
proinflammatory cytokine production. STING agonism enhances the capacity of the innate 
immune system to present tumor-associated antigens to CD8+ T cells through antigen 
cross-presentation and is critical for immune-mediated tumor destruction. MK-2118 is being 
developed as monotherapy and in combination with pembrolizumab for the treatment of 
multiple human cancers. 
MK-2118 demonstrates cross-species activity, exhibits antitumor efficacy in preclinical 
mouse syngeneic tumor models in vivo, and induces significant responses in multiple 
primary human tumor types in situ. MK-2118 is a STING agonist that could induce 
antitumor responses in both injected and noninjected lesions with a reduced risk of inducing 
a harmful systemic elevation of cytokines.
Efficacy data obtained in syngeneic mouse tumor models that are partially responsive or 
non-responsive to anti-PD-1 monotherapy demonstrate that the combination of anti-PD-1 
therapy with STING agonism can lead to improved induction of antitumor responses and 
tumor clearance.
3.2.2
Mechanism of Action
DNA in the cytoplasm of mammalian cells represents a cellular danger signal, and the
cGAS/STING pathway is activated to respond to that potential threat (Figure 1). Free 
cytosolic DNA is recognized by cGAS, catalyzing the generation of the cyclic-dinucleotide 
2’-3’ cyclic GMP-AMP (cGAMP). 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 tumor necrosis factor receptor-associated 
factors -associated nuclear factor NF-κB activator, TBK1, and inducing downstream 
phosphorylation and activation of transcription factors IRF-3 and NF-κB. 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.
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Figure 1
Schematic Diagram Showing Mechanism of the Enhancement of T-cell Driven 
Antitumor Immunity Through the Action of STING Agonists
STING is expressed in numerous cell types, but functional responses (cytokine production in
response to double-stranded DNA) 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. Although the most prevalent non- WT 
STING variants are present at allelic frequencies of up to 20% in the human population, the 
prevalence of homozygous non-WT STING carriers for any of the identified STING variants 
is estimated to be less than 5% [Yi, G., et al 2013]. 
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.
3.2.3
Preclinical Trials of MK-2118
Please refer to the MK-2118 IB for a description of preclinical evaluations of MK-2118.
3.2.4
Pembrolizumab Background
Please refer to the current pembrolizumab IB for a description of preclinical and clinical 
evaluations of pembrolizumab.
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3.3
Benefit/Risk Assessment
Participants in clinical trials generally cannot expect to receive direct 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 participants enrolled in this 
clinical trial may be found in the accompanying IB and Informed Consent documents.
4
OBJECTIVES/HYPOTHESES AND ENDPOINTS
Male/female participants of at least 18 years of age with advanced/metastatic solid tumors or 
lymphomas will be enrolled in this trial.
Objective/Hypothesis
Endpoint
Primary

Objective: To determine the safety and 
tolerability and to establish a preliminary 
RP2D and/or an MTD or an MAD of 
MK-2118 administered via IT) injection 
as monotherapy and in combination with 
pembrolizumab IV infusion or by SC 
injection in combination with 
pembrolizumab IV infusion.

DLT

AE

Discontinuing study treatment due to 
an AE
Secondary

Objective:  To evaluate the PK of 
MK-2118 administered via IT injection 
as monotherapy and in combination with 
pembrolizumab IV infusion, or 
administered via SC injection in 
combination with pembrolizumab IV 
infusion

PK parameters of MK-2118, including 
Cmin, Cmax, and AUC

Objective: To evaluate the PK of 
pembrolizumab IV infusion in 
combination with MK-2118 administered 
via IT or SC injection.

PK exposure of pembrolizumab
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Objective/Hypothesis
Endpoint
Tertiary/Exploratory

Objective: To evaluate the ORR and PFS
of participants treated with MK-2118 as 
assessed by Investigator when used as 
monotherapy and in combination with 
pembrolizumab. 

Objective response is a confirmed CR 
or PR. PFS is time from the first dose 
of study medication to the first 
documented disease progression or 
death due to any cause, whichever 
occurs first. In solid tumors, 
assessment will be based on RECIST 
1.1 and irRECIST. In lymphoma, 
assessment will be based on the IWG 
revised response criteria [Cheson, B. 
D., et al 2007].

Objective: To evaluate OS of participants 
treated with MK-2118 both as 
monotherapy and in combination with 
pembrolizumab.

OS is time from the first dose of study
medication to death due to any cause.

Objective: To evaluate the effect of 
MK-2118 on lesions not treated with IT
injections, as assessed by the Investigator 
per itRECIST.

Objective response of CR or PR for 
noninjected lesions as assessed by the 
investigator per itRECIST.

Maximal reduction in the sum of 
diameters of noninjected target lesions 
per itRECIST.
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Objective/Hypothesis
Endpoint

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-2118 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 tumor 
biopsies taken prior to treatment with 
MK-2118 and following treatment
with MK-2118.
c. To investigate the relationship between 
CYP2C9 genetic variants and PK and 
pharmacodynamics of MK-2118 as 
monotherapy and in combination with 
pembrolizumab.
d. To investigate the relationship between 
genetic variations in ADME genes and 
PK and pharmacodynamics of 
MK-2118 as monotherapy and in 
combination with pembrolizumab.

Molecular (genomic, metabolic and/or 
proteomic) determinants of response or 
resistance to treatments, using blood 
and/or tumor tissue; pembrolizumab 
ADA.
5
STUDY DESIGN
5.1
Overall Design
This is a FIH, dose escalation, nonrandomized, 4-arm, multicenter, open-label trial of 
MK-2118 monotherapy and MK-2118 in combination with pembrolizumab in participants 
with advanced/metastatic solid tumors or lymphomas. MK-2118 will be administered IT in 
Arms 1, 2 and 3, and SC in Arm 4. 
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For Arm 1 and Arm 2, the study will enroll participants with cutaneous and subcutaneous 
lesions that are amenable to IT injection by visual inspection, palpation, or ultrasound 
guidance, including at least 1 measurable lesion that is amenable to IT injection and biopsy, 
as well as at least 1 measurable distant, discrete lesion that is amenable to biopsy. The 
distant, discrete lesion will not be injected with MK-2118. Both the injected lesion and the 
distant, discrete noninjected lesion will undergo biopsy prior to MK-2118 IT administration 
during Screening, as well as on Cycle 2 Day 8 following IT administration of MK-2118, 
unless deemed medically unsafe by the Investigator. Participants in Arms 1 and 2 with 
amenable lesions at both injected and noninjected sites may undergo an additional optional 
tumor biopsy on Cycle 3 Day 8 of both the injected lesion and the noninjected lesion (see 
Section 9.7.2).
For Arm 3, the study will enroll participants with liver metastasis/lesions that are amenable 
to IT injection via ultrasound or cross-sectional imaging (CT/MRI) guidance including at 
least 1 measurable lesion that is amenable to IT injection and biopsy, as well as at least 
1 measurable distant, discrete lesion that is amenable to biopsy. The distant, discrete lesion 
will not be injected with MK-2118. Both the injected liver metastasis/lesion and the distant, 
discrete noninjected lesion will undergo biopsy during Screening, as well as on Cycle 2
Day 8, unless deemed medically unsafe by the Investigator. Participants in Arm 3 with 
amenable lesions at both injected and noninjected sites may undergo an additional optional 
tumor biopsy on Cycle 3 Day 1 of both the injected lesion and the noninjected lesion (see 
Section 9.7.2).
For Arm 4, the study will enroll participants with advanced solid tumors or lymphomas with 
at least 1 measurable, discrete lesion that is amenable to biopsy. MK-2118 will be 
administered by subcutaneous injection in Arm 4. There is no IT injection of MK-2118 in 
Arm 4. This discrete lesion will undergo biopsy prior to MK-2118 SC administration during 
Screening, as well as on Cycle 1 Day 8, and on Cycle 3 Day 8, unless deemed medically 
unsafe by the Investigator. Arm 4 will initiate once dose escalation in Arm 1 has proceeded 
beyond the
MK-2118 dose level. Once initiated, Arm 4 will dose escalate 
independently of Arms 1, 2 and 3. 
In Arms 1 and 2, the interval for IT MK-2118 dosing
. For Arm 2, pembrolizumab will be administered Q3W in Cycle 
1 and beyond. Each cycle is 21 days. 
In Arm 3, the interval for IT MK-2118 dosing
. Pembrolizumab will be administered Q3W in Cycle 1 and beyond. Each 
cycle is 21 days. 
In the Arm 4, the interval for SC MK-2118 is
as 
combination therapy with pembrolizumab. Subcutaneously administered MK-2118 in
in combination with pembrolizumab. Pembrolizumab will 
be administered Q3W in Cycle 2 and beyond. For Cycle 2 and beyond, each cycle is 21 days. 
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In Arms 1, 2, and 3, all participants will undergo at least a 24-hour inpatient observation 
period following dose administration on C1D1, C1D8, and C1D15. In Arm 4, a 24-hour 
inpatient observation period will follow MK-2118 administration on C1D1, C1D8, and 
C2D1. These inpatient observation periods may be extended to 48 hours at the discretion of 
the Investigator, per local Institutional Review Board, Ethics Review Committee, and/or 
Health Authority mandate. After discharge from the clinic, participants are to be counseled
with post-discharge instructions.
In all 4 Arms, dose escalation of MK-2118 will proceed based on emerging safety and 
tolerability data. Each participant will be monitored for DLTs over the DLT evaluation 
period (21 days from initiation of study drug in Cycle 1 for Arm 1, Arm 2, and Arm 3; 
35 days from initiation of study drug in Cycle 1 for Arm 4). For each dose level, an 
assessment will be made of the safety and tolerability data prior to escalating to the next dose 
level. The trial will proceed in an ATD up to a dose that meets at least 1 of the following 
criteria:  1) a dose level of at least
is cleared by DLT evaluation OR 2) a ≥ Grade 2 
toxicity as assessed by the Investigator to be related, probably related, or possibly related to 
the drug(s) at any dose level. 
The combination therapy arm (Arm 2 Part C) will initiate once 2 MK-2118 dose levels 
within Arm 1 have been cleared by DLT evaluation. Arm 2 combination therapy will initiate 
in ATD at an IT MK-2118 dose that is at least 2 dose levels behind the IT MK-2118
monotherapy dose. A fixed dose of IV pembrolizumab 200 mg will be administered Q3W in 
Arm 2. IT MK-2118 will be administered within
following completion of 
pembrolizumab IV infusion. If the initiation of IT MK-2118 combination therapy arm with 
pembrolizumab (Arm 2 Part C) was triggered by a ≥ Grade 2 AE observed in the ATD phase 
of monotherapy (Arm 1 Part A), then dose escalation of IT MK-2118 in the combination 
therapy arm (Arm 2) will proceed from the ATD phase to the mTPI phase up to that dose 
level of IT MK-2118 that triggered the ≥ Grade 2 AE in monotherapy (Arm 1).
As illustrated in Figure 2, Arm 1 (Part A), Arm 2 (Part C) and Arm 3 (Part E) treatment arms 
will start with an ATD, which will enroll single-participant- cohorts in order to limit 
participant exposure to subtherapeutic doses. During ATD, up to 3 participants may be 
enrolled per ATD cohort in the event of simultaneous enrollment, provided that there is at 
least a 7-day interval between the first dose of MK-2118 for each of the first 3 participants at 
each dose level evaluated. For Arm 1 (Part B), Arm 2 (Part D), and Arm 3 (Part F), the ATD 
phase will be followed by the mTPI method [Nie, L., et al 2016] [Yang, S., et al 2015], in 
which a minimum of 3 participants and up to 14 participants will be enrolled per cohort. 
There will be an observation period of at least 7 days between the first doses of MK-2118 for 
the first 3 participants treated at each dose level evaluated in the mTPI phase. Dose escalation 
in Arm 4 (Part G) will follow an mTPI design similar to that for Parts B, D and F in Arms 1,
2 and 3.
The number enrolled per cohort during dose escalation will be based on the occurrence of 
DLTs. Once a dose level cohort in the mTPI phase has been cleared for DLT evaluation, and 
a decision made to escalate to the next dose level, the cohort may be expanded to a total of 
14 participants to obtain additional pharmacokinetic and pharmacodynamics data. Dose-
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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.
Intraparticipant dose escalation will be allowed once for qualified participants in Arm 1 
monotherapy after a participant has completed at least 3 cycles of treatment with IT 
MK-2118 monotherapy without a ≥Grade 2 drug-related toxicity, and provided that dose 
escalation has proceeded beyond the next dose level in Arm 1. Intraparticipant dose 
escalation is permitted once during Arm 1 for a qualifying participant. The participant may 
escalate to the highest dose level that has been cleared by DLT evaluation in Arm 1, as 
defined by the minimum number of DLT-evaluable participants within that cohort (for the 
ATD phase, 1 participant per cohort; for the mTPI phase, 3 participants per cohort). 
Intraparticipant dose escalation is not permitted in Arm 2 (Parts C and D), in Arm 3 (Parts E 
and F), nor in Arm 4.
In Arm 3, IT MK-2118 will be administered into liver metastasis/lesions in combination with 
pembrolizumab 200 mg IV. Arm 3 (Part E) will initiate at a dose of 
of IT MK-2118
in ATD. The trial will proceed in an ATD up to a dose that meets at least 1 of the following 
criteria:  1) a dose level of at least
is cleared by DLT evaluation OR 2) a ≥Grade 2 
toxicity as assessed by the Investigator to be related, probably related, or possibly related to 
the drug(s) at any dose level. 
Upon reaching at least 1 of the above triggering criteria, the visceral IT arm (Arm 3) of the 
study will proceed to a dose-finding phase (Part F), using an mTPI design. 
Arm 4 (SC administration of MK-2118) will initiate with a dose up to, but not exceeding
of MK-2118, and dose escalate using the mTPI design. If the safety of IT MK-2118
as monotherapy in Arm 1 cannot be demonstrated at a dose of 
 then Arm 4 will 
initiate at the lower starting dose of
MK-2118. 
The primary objectives are to identify the MTD/MAD of MK-2118 alone (Arm 1), and the 
MTD/MAD of MK-2118 in combination with pembrolizumab (Arms 2, 3, and 4), and to 
identify a preliminary RP2D of IT MK-2118 and SC MK-2118. 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.
Dose escalation of MK-2118 to determine the MTD/MAD will be guided by the mTPI 
design, targeting a DLT rate of 30%, with a tolerance interval of 3%. Doses of MK-2118 for 
IT administration used in combination with pembrolizumab will not exceed the MTD for 
monotherapy. If an MTD for the monotherapy arm is established, then the dose of IT 
MK-2118 in combination may continue escalation up to that established dose. For example, 
if the MTD for monotherapy (Arm 1 Part A) is
MK-2118, then the starting dose for 
combination therapy (Arm 2 Part C), if no DLTs occurred in monotherapy, would be 
MK-2118, with a maximum dose escalation to
MK-2118. If the MTD for 
monotherapy (Arm 1, Part A) is
MK-2118, then the starting dose for combination 
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therapy will be
MK-2118. If in monotherapy (Arm 1, Part A), the dose level of 
MK-2118 is completed and no DLTs occurred in monotherapy, then the starting 
dose in combination therapy (Arm 2 Part C) could be
MK-2118 (assuming sequential 
monotherapy dose cohorts of 
MK-2118). 
Dose escalation of SC MK-2118 in Arm 4 will be guided by clinical safety and tolerability. 
The dose of SC MK-2118 may be higher than the MAD achieved in IT MK-2118
administration in Arms 1, 2 and/or 3. 
Participants may continue on their assigned treatment for up to 35 cycles for Arm 1, 2, and 3, 
and up to 36 cycles for Arm 4 (approximately 2 years) from the start of treatment. Treatment 
may continue until 1 of the following occurs: disease progression, unacceptable AEs, 
intercurrent illness that prevents further administration of treatment, Investigator decision to 
withdraw the participant, participant withdraws consent, pregnancy of the participant, 
noncompliance with trials treatment or procedure requirements, or administrative reasons 
requiring cessation of treatment. 
Participants who progress by either clinical or radiographic evaluation on monotherapy with 
IT MK-2118 (Arm 1), may cross over into the combination therapy arm of IT MK-2118 and 
pembrolizumab (Arm 2), provided that they meet crossover eligibility criteria in Section 
6.1.2 and Section 6.2.2. A participant may not cross over from Arm 1 (monotherapy) into 
Arm 2 (combination therapy with pembrolizumab) until that participant has completed the 
DLT evaluation period (21 days) in Arm 1. Participants who cross over from Arm 1 to Arm 2 
will enter Arm 2 at Screening and will be allocated to a combination dose level cohort in 
Arm 2 through an IWRS. Participants who cross over from Arm 1 to Arm 2 are eligible for 
up to 35 cycles of treatment with MK-2118 in combination therapy with pembrolizumab, 
regardless of the duration of MK-2118 treatment they received in Arm 1. Crossover into 
Arm 3 (visceral IT administration) or Arm 4 (SC administration) is not allowed.
Treatment allocation will be accomplished by nonrandom assignment through an 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. See Section 
7.3 for details on allocation to treatment arms.
The final number of participants enrolled in the study will depend on the empirical safety 
data (DLT observations, in particular, at which dose the mTPI design is triggered, and at 
which dose the preliminary RP2D is identified). 
The total sample size across Parts A-G (Arms 1, 2, 3 and 4) will be approximately 
160 participants. An interim 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-
finding decisions. The trial will be conducted in conformance with GCPs.
Adverse Experiences will be evaluated according to criteria outlined in the NCI CTCAE 
Version 4.0.
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Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial SoA - Section 2. Details of each procedure 
are provided in Section 9 Study Assessments and Procedures.
5.1.1
Study Diagram
The trial design is depicted in Figure 2.
Figure 2
Trial Design Diagram
IT = intratumoral; mTPI = Modified Toxicity Probability Interval; RP2D = Recommended Phase 2 Dose; 
SC = subcutaneous
* Triggering criteria for the start of the mTPI design in Arm 1, Arm 2 and Arm 3: (1) a dose level of at least 
is cleared by DLT evaluation OR (2) a ≥Grade 2 toxicity as assessed by the Investigator to be related, 
y related, or possibly related to the drug(s) at any dose level.
Note: Arm 4 may initiate prior to the initiation of Arm 3.
5.2
Number of Participants
Approximately 200 participants will be allocated in screening through IWRS, such that 
approximately 160 evaluable participants complete the study as described in Section 10.9.
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5.3
Beginning and End of Study Definition
The overall trial begins when the first participant signs the ICF.  The overall trial ends when 
the last participant completes the last study-related phone-call or visit, withdraws consent, or 
is lost to follow up (ie, the participant is unable to be contacted by the investigator).
5.3.1
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.
Ample notification will be provided in the event of Sponsor decision to no longer supply 
MK-2118 or pembrolizumab.
5.4
Scientific Rationale for Study Design
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 
activation in the tumor microenvironment leads to a potent antitumor response. IT injection 
of 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 [Woo S. R., et al 2014], [Corrales, L., et al 2015]. MK-2118, therefore, has 
potential as a cancer therapeutic.
Preclinical efficacy data obtained in syngeneic mouse tumor models that are either partially 
responsive or nonresponsive to anti-PD-1 monotherapy, demonstrated that the combination 
of anti-PD-1 therapy with STING agonism can lead to improved induction of antitumor
responses and tumor clearance. Robust antitumor efficacy in mouse tumor models was also 
seen with SC administration of MK-2118 in combination with anti-PD-1 therapy.
5.4.1
Efficacy Endpoints
An exploratory objective for this trial is to evaluate the antitumor activity of MK-2118 alone 
and MK-2118 in combination with pembrolizumab in participants with advanced or 
metastatic solid tumors and lymphomas. Tumor response in participants with solid tumors 
will be assessed using RECIST 1.1 and irRECIST (see Section 9.2.2.1). Tumor response in 
participants with lymphoma will be assessed using the IWG revised response criteria 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.
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Immunotherapeutic agents such as MK-2118 with 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-2118 with pembrolizumab. Therefore, the participant should not be discontinued from 
treatment unless the initial assessment of PD is confirmed at least 4 weeks later, provided the 
participant’s clinical condition is stable, and irRECIST will thus be used to assess efficacy.
Sites are encouraged to have a multidisciplinary treatment and assessment plan to determine 
in advance which lesions will be treated, biopsied, and/or targeted for tumor assessment. 
Biopsied tumors should not be used for assessment by RECIST 1.1, irRECIST, or revised 
IWG criteria, except in cases with only target lesions available, after consultation with the 
Sponsor. See Section 7.1.1 on prioritization of lesion injection.
5.4.1.1
Immune-related RECIST (irRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen 
with treatment 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 participants experienced delayed or early tumor 
pseudoprogression. Of note, participants who had progressive disease by RECIST 1.1, but
not by irRECIST, had longer OS than participants with progressive disease 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 is RECIST 1.1 adapted to account for the unique tumor response 
seen with immunotherapeutic as described by Nishino, et al. [Nishino, M., et al 2013]. The 
assessment of unidimensional target lesions and response categories per irRECIST are 
identical to RECIST 1.1. However, the Sponsor 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, so that investigators have 
the option to continue therapy after radiographic progression until a repeat scan confirms that 
progression has occurred.
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5.4.1.2
IT Immunotherapy RECIST (itRECIST)
itRECIST, a response assessment tailored to IT immunotherapy, is aligned with RECIST 1.1 
overall response assessment [Goldmacher, G. V., et al 2020], and is further described in 
Section 12.8. 
itRECIST:

provides a guidance on baseline categorization of target and nontarget lesions (Figure 
3).

provides guidance on recategorization of lesions during therapy (Figure 4).

allows for separate response assessment in injected and noninjected lesions (Figure 
5).

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 
6).

provides guidelines on prioritization of lesion injection during the course of IT 
immunotherapy (see Appendix 12.7).
itRECIST supports standardized collection of data from IT immunotherapy clinical trials to 
facilitate exploratory response analysis. 
5.4.1.3
IWG Revised Response Criteria for Malignant Lymphomas
The antitumor activity of MK-2118 with pembrolizumab will be evaluated as part of the 
exploratory analyses using the IWG Revised Response Criteria for Malignant Lymphoma 
[Cheson, B. D., et al 2007] as detailed in Section 9.2.2.3.
The IWG response criteria include several components: 1) assessment of nodal and 
extranodal lesions by CT (for size) and FDG-PET (for viability) 2) physical examination
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 participant status (eg, discontinuation of study 
therapy).
Because of the possibility of immunotherapy-related flare, participants 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. 
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5.4.1.4
Response Assessment for Cutaneous T-cell Lymphoma
For participants with CTCL, determination of eligibility will be made in accordance with the 
modified ISCL/Cutaneous Lymphoma Task Force of the EORTC Revision of the TNMB 
Classification of mycosis fungoides/Sézary syndrome [Olsen, E., et al 2007]. The antitumor 
activity of MK-2118 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 [Olsen, E. A., et al 2011].
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 9.2.2.4. 
5.4.1.5
Overall Survival
Participants will be followed up by telephone contact every 12 weeks after the 30-day safety 
follow-up visit to assess OS.
5.4.2
Safety Endpoints
The primary objective of this trial is to characterize the safety and tolerability of MK-2118 as 
monotherapy and as combination therapy with pembrolizumab in participants with advanced/ 
metastatic solid tumors and lymphomas. The primary safety analysis will be based on 
participants who experience toxicities as defined by CTCAE criteria. Safety will be assessed 
by quantifying the toxicities and grades of toxicities experienced by participants who have 
received MK-2118 as monotherapy and in combination with pembrolizumab, including 
SAEs and AEs of special interest.
Safety will be assessed by reported adverse experiences using CTCAE, v 4.0. The attribution 
to drug, time of onset, duration of the event, its resolution, and any concomitant medications 
administered will be recorded. AEs that will be analyzed include, but are not limited to, all 
AEs, SAEs, fatal AEs, and laboratory changes.
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, and outcome of AEs/SAEs; changes in vital signs and laboratory 
values. Adverse events will be assessed as defined by CTCAE, v 4.0.
5.4.3
Pharmacokinetic Endpoints
Secondary objectives of this trial are to characterize the PK profile of MK-2118 following 
administration as a single agent, and to characterize the pharmacokinetic profile of MK-2118
with pembrolizumab following administration as combination therapy. The serum 
concentrations of these agents will serve as the primary readout for the PK, and these data 
will be used to derive PK parameters of the agents alone and in combination. Furthermore, 
the results of these analyses will be used in conjunction with the pharmacodynamics, and the 
safety and exploratory endpoints in assessment of dosing strategies for MK-2118.
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5.4.4
Systemic Cytokines
Because of the immune stimulation by a STING agonist and subsequent potential for 
cytokine release, systemic cytokines, including TNF-α, IL-6, IFNα, MIP-1α, MCP-2, IP-10, 
CXCL11, and CRP, will be monitored to provide supplementary information to assist in the 
evaluation of any safety events.
5.4.5
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 
of study drug at both mRNA and protein level is being 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 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 safety events. The cytokines 
that will be assessed include, but are not limited to, TNF-α, IFNα, IL-6, MIP-1α, MCP-2, 
IP-10), and CXCL11.
5.4.6
Planned Exploratory Biomarker Research
5.4.6.1
Planned Genetic Analysis
Genetic variation may impact a participant’s response to therapy, susceptibility to, and 
severity and progression of disease. Variable response to therapy may be due to genetic 
determinants that impact drug absorption, distribution, metabolism, and excretion; 
mechanism of action of the drug; disease etiology; and/or molecular subtype of the disease 
being treated. Therefore, where local regulations and IRB/IEC allow, a sample will be 
collected for DNA analysis from consenting participants.
DNA samples will be used for research related to the study treatment(s), the disease under 
study and related diseases. They may also be used to develop tests/assays including 
diagnostic tests related to the disease under study, related diseases and study drug(s). Genetic 
research may consist of the analysis of one or more candidate genes or the analysis of genetic 
markers throughout the genome [or analysis of the entire genome] (as appropriate).
DNA samples will be analyzed for variation across the entire genome. Analyses may be 
conducted if it is hypothesized that this may help further understand the clinical data. 
The samples may be analyzed as part of a multi-study assessment of genetic factors involved 
in the response to understand study disease or related conditions.
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5.4.6.2
Rationale for Planned Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these new immunotherapies, as well as the optimal
leverage and combination of these immunotherapies in treating patients, is still under 
investigation. To further illuminate the benefits of immunotherapy and to aid clinical 
decisions, it is important to investigate the determinants of response or resistance to cancer 
immunotherapy, as well as the 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 therapy and combination therapy with immuno-oncology 
drugs. To identify novel biomarkers, we will collect biospecimens (blood components, tumor 
tissue specimen, etc.) to support analyses of cellular components (eg, protein, DNA, RNA, 
metabolites) and other circulating molecules. Investigations may include, but are not limited 
to: 
Germline (blood) Genetic Analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing): This research 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. In addition to 
studying variation across the human genome, CYP2C9 will be investigated. 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 (i.e., 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 (colorectal cancer).
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-2118 with 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 
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identified. Individual genes related to the immune system may also be evaluated (eg, IL-6). 
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 IVD device has been developed 
for use with pembrolizumab in NSCLC. Preliminary data indicates that this association may 
also be true in additional cancer types (ie, triple-negative breast cancer, head and neck 
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 or liquid chromatography/mass spectrometry. This approach could identify 
novel protein biomarkers that could aid in participant selection for MK-2118 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 therapy, as 
well as levels of protein in the tumor. DNA can be analyzed using next generation 
sequencing or polymerase chain reaction-based technologies. An advantage to this method is
that blood is a less invasive compartment from which tumor-derived protein or nucleic acid 
biomarkers may be measured.
5.4.6.3
Future Biomedical Research (FBR)
The Sponsor will conduct FBR on specimens consented for FBR 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 FBR.
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 
participants. The objective of collecting/retaining specimens for FBR is to explore and 
identify biomarkers that inform the scientific understanding of diseases and/or their 
therapeutic treatments. The overarching goal is to use such information to develop safer, 
more effective drugs/vaccines, and/or to ensure that participants receive the correct dose of 
the correct drug/vaccine at the correct time. The details of the FBR are presented in 
Appendix 6
Collection and Management of Specimens for Future Biomedical Research.
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5.5
Justification for Dose
5.5.1
Starting Dose for This Trial
5.5.1.1
Starting Dose for Arm 1 and Arm 2
The human starting dose of MK-2118 for IT injection is based on an integration of 
nonclinical toxicological, pharmacological, and efficacy data (see the IB for detail). The FIH
starting dose of 
 for MK-2118, based on tumor-bearing mouse models, is the dose that 
is associated with an insignificant change in systemic TNF-α concentration, while still being 
potentially efficacious, and have an acceptable safety profile in the advanced cancer patient 
population, in accordance with ICH S9 oncology guidance.
. Given the potential of MK-2118 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 
1 IT dose for multiple STING agonists was characterized in tumor-bearing mice implanted 
with MC38 cells. To leverage all the data that has been generated with multiple STING 
agonists, the IT dose for each 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 [Yamazaki, S., et al 2008]. A dose-efficacy 
response relationship that relates the percent GRI versus the normalized dose was described 
by a maximum effect 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. The value of 
135% GRI refers to an efficacy readout at which injection of a STING agonist resulted in 
complete regression of MC38 tumor in mice. Assuming that mouse data may be translated to 
humans, the starting dose selected is expected to cause complete regression of a relatively 
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Table 3
Trial Treatment for IT MK-2118 Combination Therapy with Pembrolizumab 
(Arm 2)
Drug
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-2118b
Range: 
c
for 
subsequent 
21 day cycles 
IT via visual 
inspection for 
cutaneous lesions, 
and via ultrasound 
guidance for 
subcutaneous 
lesions, as needed
Experimental
Abbreviations: ATD = accelerated titration design; DLT = dose-limiting toxicity; IT = intratumoral; mTPI = 
modified toxicity probability interval ;
a Arm 2 will initiate at least 2 dose levels behind Arm 1, and proceed in ATD (Part C) up to a dose that 
meets at least 1 of the following triggering criteria for a participant at any time during the first treatment 
cycle of MK-2118: (1) a dose level of at least
MK-2118 is cleared by DLT evaluation OR (2) a ≥ 
Grade 2 toxicity as assessed by the Investigator to be related, probably related, or possibly related to the 
drug(s) at any dose level. Dose escalation will then proceed to mTPI (Arm 2 Part D).
b MK-2118 will be administered within
following completion of pembrolizumab IV infusion, 
as applicable.
c Dose levels will be determined based on emerging safety data.
This conservative approach is being taken to ensure an acceptable safety profile, while 
continued participant safety will be ensured through appropriate dose escalation design and 
monitoring in the clinic. 
. Dose escalation decisions will be made 
upon ongoing review of safety and PK/PD 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/PD 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 weekly safety teleconferences. Dose level escalations are 
sponsor-controlled through IWRS, which include the opening and closing of dose level 
cohorts upon dose escalation.
The injectate volume for Arm 1 and Arm 2 will be determined based on tumor size and 
number of lesions injected (see Section 7.1.1).
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The planned dose of pembrolizumab for this study is 200 mg infusion Q3W. This dose is
approved by the Food and Drug Administration (FDA) for treatment of melanoma. 
5.5.1.2
Starting Dose for Arm 3
The starting dose for MK-2118 in Arm 3 (IT administration into visceral lesions) will be 
(Table 4) based on the most conservative subcutaneous NOAEL observed in the 
GLP toxicology study conducted in dogs. Pembrolizumab 200 mg IV will be administered 
Q3W. As of Amendment 03, participants have been treated in Arm 2 (IT administration into 
cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by 
ultrasound guidance) with doses of up to 
with no DLTs and have tolerated treatment 
well. This is to allow for safety/tolerability assessment of IT MK-2118 in visceral lesions, 
while reducing redundancy of testing subtherapeutic doses of IT MK-2118 that have been 
evaluated in Arm 1 and in Arm 2. 
Table 4
Trial Treatment for Visceral IT MK-2118 Combination Therapy 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-2118b
Range: 
c
IT (Visceral) via 
ultrasound or 
cross-sectional 
imaging 
(CT/MRI) 
guidance for 
liver lesions, as 
needed
Experimental
Abbreviations: ATD = accelerated titration design; CT = computed tomography; DLT = dose-limiting 
toxicity; IT = intratumoral; mTPI = modified toxicity probability interval; MRI = magnetic resonance 
imaging;
a Arm 3 dose escalation will initiate in ATD (Part E) up to a dose that meets at least 1 of the following 
triggering criteria for a participant at any time during the first treatment cycle of MK-2118:  (1) a dose level 
of at least
MK-2118 is cleared by DLT evaluation OR (2) a ≥ Grade 2 toxicity as assessed by the 
Investigator to be related, probably related, or possibly related to the drug(s) at any dose level. Dose 
escalation will then proceed to mTPI (Arm 3 Part F).
b MK-2118 will be administered within
following completion of pembrolizumab infusion.
c. Dose levels will be determined based on emerging safety data.
The injectate volume for Arm 3 will be determined based on tumor size and number of 
lesions injected (see Section 7.1.1).
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Dose escalation of SC MK-2118 beyond the projected upper dose limit may be allowed if the 
systemic exposure achieved by SC dosing is significantly lower than expected and SC dosing 
of MK-2118 at the upper dose limit demonstrates sufficient safety and tolerability in patients.
5.5.3
Rationale for Dose Interval and Trial Design
The initial dose escalation will proceed following an ATD in order to minimize the number 
of participants treated at potentially subtherapeutic doses of MK-2118 before starting the 
mTPI design. In the ATD phase of dose escalation, dose escalation will occur in increments 
of 100% to 300%. For example, with a starting dose of 
 and in the absence of DLTs 
within this cohort, and the absence of 1 of the 2 triggering events, the next dose level will be 
 The exact dose of each cohort during dose escalation is not predetermined, which 
will allow for flexibility in dose escalation based on emerging safety data in the clinical trial.
A dose efficacy relationship in MC38 tumor-bearing mice was characterized for multiple 
STING agonists, including MK-2118. The projected efficacious human dose range for IT 
MK-2118 was
 depending on the size of the injected tumor. The goal of the 
ATD with single-participant cohorts and dose escalation up to 300% is to minimize exposure 
to subtherapeutic dose levels in cancer patients. 
The predicted efficacious dose is based on lesion volume. The
starting dose was 
selected based on the predicted efficacy of MK-2118 for a lesion volume of 0.5 cm3, based 
on preclinical studies. The
 dose level is near the predicted efficacious dose of 
MK-2118 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 in dose escalation. 
Further dose finding (Parts B and D) will follow an mTPI design at a target DLT rate of 30%, 
with a tolerance interval of 3% [Nie, L., et al 2016] [Yang, S., et al 2015]. The model-based 
dose escalation mTPI approach will enroll 3 to 14 participants per cohort using dose 
increment increases of 30% to 100% of the prior dose.
5.5.3.1
Rationale for Design of Arm 3 (Visceral IT Injection)
The rationale for the addition of a visceral IT arm of MK-2118 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, pharmacodynamics, 
and early efficacy of MK-2118 injected into visceral organs and deeper tumor lesions. 
. The trial will 
proceed in an ATD up to a dose that meets at least 1 of the 2 triggering criteria (Section 
7.2.1). Upon reaching at least 1 of the triggering criteria, the visceral IT arm (Arm 3) of the 
study will proceed to a dose-finding phase (Part F), using an mTPI design. The MK-2118
starting dose in Arm 3 is based on the most conservative subcutaneous NOAEL observed in 
the GLP toxicology study conducted in dogs. To mitigate the potential safety risk of repeated 
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visceral and deeper lesion IT injections, the duration of weekly IT dosing in Arm 3 has been 
reduced from 9 weeks to 6 weeks.
5.5.3.2
Rationale for Design of Arm 4 (Subcutaneous/Systemic Administration)
The intent of the 2 week MK-2118 monotherapy lead-in period is to allow sufficient 
assessment of safety of MK-2118 SC as monotherapy prior to initiation of combination 
therapy of MK-2118 SC with pembrolizumab. As such, the DLT observation period will be 
extended in the SC administration Arm 4 to 5 weeks to encompass both the 2-week 
monotherapy lead-in and the first 3week cycle of combination therapy with pembrolizumab.
MK-2118 will proceed based on emerging safety and tolerability data using mTPI design 
with a target DLT rate of 30%, and a tolerance interval of 3%. Dose for each cohort will 
increase by 30% to 100% of prior dose.
6
STUDY POPULATION
Male/female participants of at least 18 years of age with advanced/metastatic solid tumors or 
lymphomas will be enrolled in this trial.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
6.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
6.1.1
Inclusion Criteria for Arm 1 and Arm 2
Type of Participant and Disease Characteristics
1. Have any histologically or cytologically confirmed advanced/metastatic solid tumor 
by pathology report and 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. For CTCL, histopathological diagnosis should be confirmed in a skin 
biopsy representative of disease [Olsen, E., et al 2007].
2. Have Stage III or Stage IV disease that is not surgically resectable. Stage IIB 
(T3N0M0B0 1) CTCL participants are eligible [Olsen, E., et al 2007].
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3. Have at least 1 injectable lesion that is amenable to injection and biopsy. Biopsy may 
be performed via visual inspection or ultrasound guidance. IT injection for cutaneous 
lesions may be performed via visual inspection. IT injection for subcutaneous lesions
may be performed via ultrasound guidance or via palpation. This injectable lesion 
must be measurable and meet one of the following criteria:

A cutaneous or subcutaneous lesion ≥1 cm in longest diameter for solid tumors, or 
≥1.5 cm in short axis for a nodal lesion in participants with solid tumor. The 
longest diameter for an injectable lesion must be ≤10 cm for both solid tumors 
and nodal lesions in participants with solid tumor.

Multiple coalescing, superficial lesions that in aggregate have a longest diameter 
of ≥1 cm and ≤10 cm. 

For lymphoma, 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. 
4. Have at least 1 discrete and/or distant noninjected lesion that is amenable to biopsy 
via visual inspection or amenable to biopsy via image guidance. This lesion must be 
measurable as defined by the response criteria used to assess the participant (RECIST 
1.1 for solid tumors or revised IWG criteria for lymphomas).

For RECIST 1.1, ≥1 cm in longest diameter for nonnodal lesions, or ≥1.5 cm in 
the 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.
5. Have an ECOG Performance Status of 0 or 1.
6. Demonstrate adequate organ function as defined by the following table (Table 6).
All screening labs should be performed within 7 days prior to treatment initiation, 
unless otherwise specified.
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Table 6
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
≥1500/mcL (>1,000/mcL for lymphoma 
participants)
Platelets
≥100000/mcL (≥75,000/mcL for lymphoma 
participants)
Hemoglobin
≥9 g/dL or ≥5.6 mmol/La (≥8 g/dL or 
≥5.0 mmol/L for lymphoma participants)
Renal
Serum creatinine or
CrCl (measured or calculated)b or
GFR in place of CrCl
≤1.5 × ULN or
≥30 mL/min for participants with creatinine 
levels >1.5 × institutional ULN
Hepatic
Total bilirubin (serum) 
≤1.5 × ULN or
Direct bilirubin ≤ULN for participants with total 
bilirubin levels >1.5 × ULN
AST and ALT
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
Coagulation
INR or PT
PTT or aPTT
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of 
anticoagulants
Abbreviations: ALT = alanine aminotransferase; aPTT = activated partial thromboplastin time; AST = 
aspartate aminotransferase; CrCl = creatinine clearance; GFR = glomerular filtration rate; PT = 
prothrombin time; PTT = partial thromboplastin time; ULN = upper limit of normal.
a Criteria must be met without packed red blood cell transfusion within the prior 2 weeks. Participants can be 
on stable dose of erythropoietin (≥ approximately 3 months).
b Creatinine clearance should be calculated per institutional standard
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of specific 
chemotherapies.
Demographics
7. Be ≥18 years of age on day of signing informed consent.
Male participants:
8. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 120 days after the last dose of study intervention:

Refrain from donating sperm
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PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent
OR

Must agree to use contraception unless confirmed to be azoospermic 
(vasectomized or secondary to medical cause [Appendix 5]) as detailed below:

Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male
condom during each episode of penile-vaginal penetration.

Contraceptive use by men should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
Female participants:
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 Appendix [5] during the intervention 
period and for at least 120 days after the last dose of study intervention and agrees 
not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the 
purpose of reproduction during this period. The investigator should evaluate the 
potential for contraceptive method failure (ie, noncompliance, recently initiated) 
in relationship to the first dose of study intervention. 

A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] 
as required by local regulations) 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.
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
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.

Contraceptive use by women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
Informed Consent
10. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial. The participant may also provide consent for FBR. 
However, the participant may consent to the main trial without participating in FBR.
Additional Criteria
11. HIV-infected participants must meet these additional criteria: 
a) 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.
b) Have well-controlled HIV on antiretroviral therapy (ART), defined as: 
1) must have a CD4+ T-cell count >350 cells/mm3 at time of screening; 
2) must have achieved and maintained virologic suppression defined as 
confirmed HIV RNA level below 50 or the LLOQ (below the limit of 
detection) using the locally available assay at the time of screening and for at 
least 12 weeks prior to screening; 
3) must have been on a stable regimen, without changes in drugs or dose 
modification, for at least 4 weeks prior to study entry (Day 1).
If temporary ART treatment interruptions are required, sponsor consultation is 
warranted to determine whether the patient can remain on the study or requires 
discontinuation. These interruptions should not result in poor disease control (eg, 
significant CD4 count decrease, uncontrolled viremia).
6.1.2
Inclusion Criteria for Crossover into Arm 2
Type of Participant and Disease Characteristics
In order to be eligible for crossover into Arm 2 of this trial, the participant must:
1. Have either clinical or radiographic disease progression, or progression by global 
response score for CTCL on Arm 1 MK-2118 monotherapy. 
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2. Have completed the DLT evaluation period (21 days of treatment within Cycle 1) in 
Arm 1 MK-2118 monotherapy.
3. Have at least 1 injectable lesion that is amenable to injection and biopsy via visual 
inspection for a cutaneous lesion, or via ultrasound guidance for a subcutaneous 
lesion. This injectable lesion must be measurable and meet one of the following 
criteria:

A cutaneous or subcutaneous lesion ≥1 cm in longest diameter for solid tumors, or 
≥1.5 cm in short axis for a nodal lesion in solid tumor participants. The longest 
diameter for an injectable lesion must be ≤10 cm for both solid tumors and nodal 
lesions in solid tumor participants.

Multiple coalescing, superficial lesions that in aggregate have a longest diameter 
of ≥1 cm and ≤10 cm. 

For lymphoma, 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.
4. Have at least 1 discrete, distant noninjected lesion that is amenable to biopsy via 
visual inspection or amenable to biopsy via image guidance. This lesion must be 
measurable as defined by the response criteria used to assess the participant (RECIST 
1.1 for solid tumors or IWG revised criteria for lymphomas).

For RECIST 1.1, ≥1 cm in longest diameter for nonnodal lesions, or ≥1.5 cm in 
the 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.
5. Have an ECOG Performance Status of 0 or 1.
6. Demonstrate adequate organ function as defined by Table 6. All screening labs 
should be performed within 7 days of treatment initiation.
Demographics
Male Participants:
7. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 120 days after the last dose of study intervention:

Refrain from donating sperm
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PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent.
OR

Must agree to use contraception unless confirmed to be azoospermic 
(vasectomized or secondary to medical cause [Appendix 5]) as detailed below:

Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male 
condom during each episode of penile-vaginal penetration.

Contraceptive use by men should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
Female Participants:
8. A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and at least one of the following conditions applies: 

Is not a WOCBP
OR

Is a WOCBP and using a contraceptive method that is highly effective (with a 
failure rate of <1% per year), with low user dependency, or be abstinent from 
heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-
term and persistent basis), as described in Appendix [5] during the intervention 
period and for at least 120 days after the last dose of study intervention and agrees 
not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the 
purpose of reproduction during this period. The investigator should evaluate the 
potential for contraceptive method failure (ie, noncompliance, recently initiated) 
in relationship to the first dose of study intervention. 

A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] 
as required by local regulations) 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.
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
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.

Contraceptive use by women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
6.1.3
Inclusion Criteria for Arm 3—Visceral IT Injection
Type of Participant and Disease Characteristics
1. Have any histologically or cytologically confirmed advanced/metastatic solid tumor 
by pathology report and have received, have been intolerant to all treatment known to 
confer clinical benefit. Solid tumors and lymphomas of any type are eligible for 
enrollment.   
2. Have Stage III or Stage IV disease that is not surgically resectable.
3. Has metastatic liver and/or liver lesion involvement that does not exceed one third of 
the total liver volume in participants to be treated by liver IT injection. Hepatocellular 
carcinoma participants are excluded from eligibility for IT liver injection. In addition, 
has at least one injectable liver lesion with the following: 

The injectable liver lesion is amenable to image-guided IT injection and biopsy 
via ultrasound guidance or cross-sectional imaging (CT/MRI) guidance. 

Injectable lesion(s) must be ≥1 cm in longest diameter and ≤10 cm in longest 
diameter.
4. Have at least 1 discrete and/or distant noninjected lesion that is amenable to biopsy 
via image guidance. This lesion must be measurable as defined by the response 
criteria used to assess the participant (RECIST 1.1 for solid tumors or revised IWG 
criteria for lymphomas).

For RECIST 1.1, ≥1 cm in longest diameter for nonnodal lesions, or ≥1.5 cm in 
the 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.
5. Have an ECOG Performance Status of 0 or 1.
6. Demonstrate adequate organ function as defined by Table 6.
All screening labs should be performed within 7 days of treatment initiation, unless 
otherwise specified.
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Demographics
7. Be ≥18 years of age on day of signing informed consent.
Male participants:
8. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 120 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 [Appendix 5]) as detailed below:

Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male 
condom during each episode of penile-vaginal penetration.

Contraceptive use by men should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
Female participants:
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 Appendix [5] during the intervention 
period and for at least 120 days after the last dose of study intervention and agrees 
not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the 
purpose of reproduction during this period. The investigator should evaluate the 
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potential for contraceptive method failure (ie, noncompliance, recently initiated) 
in relationship to the first dose of study intervention. 

A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] 
as required by local regulations) within 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.

The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.

Contraceptive use by women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
Informed Consent
10. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial. The participant may also provide consent for FBR. 
However, the participant may consent to the main trial without participating in FBR.
Additional Criteria
11. HIV-infected participants must meet these additional criteria: 
a) 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.
b) Have well-controlled HIV on antiretroviral therapy (ART), defined as: 
1) must have a CD4+ T-cell count >350 cells/mm3 at time of screening; 
2) must have achieved and maintained virologic suppression defined as 
confirmed HIV RNA level below 50 or the LLOQ (below the limit of 
detection) using the locally available assay at the time of screening and for at 
least 12 weeks prior to screening; 
3) must have been on a stable regimen, without changes in drugs or dose 
modification, for at least 4 weeks prior to study entry (Day 1).
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If temporary ART treatment interruptions are required, sponsor consultation is 
warranted to determine whether the patient can remain on the study or requires 
discontinuation. These interruptions should not result in poor disease control (eg, 
significant CD4 count decrease, uncontrolled viremia).
6.1.4
Inclusion Criteria for Arm 4 – Subcutaneous Injection
In order to be eligible for Arm 4 of this trial, the participant must:
1. Have any histologically or cytologically confirmed advanced/metastatic solid tumor 
by pathology report and 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. For CTCL, histopathological diagnosis should be confirmed in a skin 
biopsy representative of disease [Olsen, E., et al 2007]. 
2. Have Stage III or Stage IV disease that is not surgically resectable. Stage IIB 
(T3N0M0B0 1) CTCL participants are eligible [Olsen, E., et al 2007].
3. Have measurable disease by RECIST 1.1 criteria for solid tumors or revised IWG 
revised criteria for lymphomas as assessed by the local site investigator/radiology. 
Lesions situated in a previously irradiated area are considered measurable if 
progression has been demonstrated in such lesions.
4. Have one or more discrete malignant lesions that are amenable to a minimum of three
separate biopsies guided by one of the following modalities: visual inspection, 
ultrasound guidance, or cross-sectional image guidance (computed 
tomography/magnetic resonance imaging [CT/MRI]). 
Note: Participants should only be enrolled if during the screening assessment the 
investigator deems the biopsy of such lesions to be medically safe.
5. Have an ECOG Performance Status of 0 or 1.
6. Demonstrate adequate organ function as defined by Table 6. 
All screening labs should be performed within 7 days of treatment initiation, unless 
otherwise specified.
Demographics
7. Be ≥18 years of age on day of signing informed consent. 
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Male Participants:
8. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 120 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 [Appendix 5]) as detailed below:

Agree to use a male condom plus partner use of an additional contraceptive 
method when having penile-vaginal intercourse with a WOCBP who is not 
currently pregnant. Note: Men with a pregnant or breastfeeding partner must 
agree to remain abstinent from penile-vaginal intercourse or use a male 
condom during each episode of penile-vaginal penetration.

Contraceptive use by men should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.
Female Participants:
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 Appendix [5] during the intervention 
period and for at least 120 days after the last dose of study intervention and agrees 
not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the 
purpose of reproduction during this period. The investigator should evaluate the 
potential for contraceptive method failure (ie, noncompliance, recently initiated) 
in relationship to the first dose of study intervention. 
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
A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] 
as required by local regulations) 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.

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.
Additional Criteria
10. HIV-infected participants must meet these additional criteria: 
a) 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.
b) Have well-controlled HIV on antiretroviral therapy (ART), defined as: 
1) must have a CD4+ T-cell count >350 cells/mm3 at time of screening; 
2) must have achieved and maintained virologic suppression defined as 
confirmed HIV RNA level below 50 or the LLOQ (below the limit of 
detection) using the locally available assay at the time of screening and for at 
least 12 weeks prior to screening; 
3) must have been on a stable regimen, without changes in drugs or dose 
modification, for at least 4 weeks prior to study entry (Day 1).
If temporary ART treatment interruptions are required, sponsor consultation is 
warranted to determine whether the patient can remain on the study or requires 
discontinuation. These interruptions should not result in poor disease control (eg, 
significant CD4 count decrease, uncontrolled viremia).
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6.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
6.2.1
Exclusion Criteria for Initial Treatment
Medical Conditions 
1. Has a history of a second malignancy, unless potentially curative treatment has been 
completed, with no evidence of malignancy for 2 years.
Note: The time requirement does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, superficial bladder cancer, or 
in situ cervical cancer.
2. Has clinically active central nervous system metastases and/or carcinomatous
meningitis. Participants with previously treated brain or meningeal metastases may 
participate and be eligible for treatment provided they are stable and asymptomatic 
(without evidence of progression by MRI scan of the brain separated by at least 
4 weeks after treatment), have no evidence of new or enlarging brain metastases, are 
evaluated within 4 weeks prior to first study drug administration, and are off
immunosuppressive doses of systemic steroids at least 2 weeks from enrollment.
3. Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody.
4. 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. 
5. Has a history of vasculitis.
6. Has an active infection requiring therapy.
7. Has a history of (noninfectious) pneumonitis that required steroids or current 
pneumonitis.
8. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 
5 years. 
Note:  Participants who have had a stem cell transplant greater than 5 years ago are 
eligible as long as there are no symptoms of GVHD.
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9. Participants with known Hepatitis B or C infections or 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 result and known quantitative HCV RNA results greater than the 
lower limits of detection of the assay.
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s
compliance 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 participant to be enrolled, in the opinion of the treating 
investigator.
11. Has known psychiatric or substance abuse disorders that would interfere in 
cooperation with the requirements of the trial.
12. Is pregnant or breastfeeding or expecting to conceive or father children within the
projected duration of the study.
13. 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 participants should be recovered. 
14. HIV-infected participants with history of Kaposi’s sarcoma and/or multicentric 
Castleman’s disease
15. HIV-infected participants who have had an HIV-related opportunistic infection within 
6 months
16. 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 MOA of 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.
Prior/Concomitant Therapy
17. 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.
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18. Has been treated within 2 weeks of Cycle 1 Day1 with any of the following:

strong/moderate CYP2C9 inhibitors, such as:  amiodarone, felbamate, 
fluconazole, miconazole, piperine, oxandrolone, fluorouracil and its derivatives 
(TS-1, UFT, tegafur, carmofur, doxifluridine, capecitabine), sulfaphenazole, 
cyclosporine, bucurol, and tienilic acid.

UGT1A3 inhibitors, which include ritonavir, quinidine, probenecid, and valproic 
acid.

strong CBR inhibitors, which include quercetin, menadione, glycyrrhetinic acid, 
and flufenamic acid.
19. 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-2118. 
Note:  Prior exposure to immunotherapeutics is allowed, including PD-1 and PD-L1 
inhibitors, provided participant did not experience ≥Grade 3 drug-related toxicity on 
monotherapy with a PD-1 or PD-L1 inhibitor. 
20. Is expected to require any other form of antineoplastic therapy while on study.
21. 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.
22. Has received a live vaccine within 28 days prior to first dose.
23. Has been treated with a STING agonist (eg, MK-1454, ADU-S100).
24. Has a history of re-irradiation for HNSCC at the projected injection site.
6.2.2
Exclusion Criteria for Crossover into Arm 2
The participant must be excluded from crossover into Arm 2 of the trial if the participant:
Medical Conditions 
1. Has clinically active central nervous system metastases and/or carcinomatous 
meningitis. Participants with previously treated brain or meningeal metastases may 
participate and be eligible for treatment provided they are stable and asymptomatic 
(without evidence of progression by MRI scan of the brain separated by at least 
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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.
2. Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody.
3. Has an active infection requiring therapy.
4. Has a history of (noninfectious) pneumonitis that required steroids or current 
pneumonitis.
5. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s
compliance 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 participant to be enrolled, in the opinion of the treating 
investigator.
6. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study.
7. 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 participants should be recovered. 
8. 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.
Prior/Concomitant Therapy
9. 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.
10. 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-2118. 
Note:  Prior exposure to MK-2118 is allowed, provided the participant has a washout 
period of at least 14 days and did not experience ≥Grade 3 drug-related toxicity. 
Note:  Prior exposure to immunotherapeutics is allowed, including PD-1 and PD-L1 
inhibitors, provided participant did not experience a ≥Grade 3 drug-related toxicity 
on monotherapy with a PD-1 or PD-L1 inhibitor
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11. Is expected to require any other form of antineoplastic therapy while on study.
12. 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.
13. Has been treated within 2 weeks of Cycle 1 Day1 with any of the following:

strong/moderate CYP2C9 inhibitors, such as:  amiodarone, felbamate, 
fluconazole, miconazole, piperine, oxandrolone, fluorouracil and its derivatives 
(TS-1, UFT, tegafur, carmofur, doxifluridine, capecitabine), sulfaphenazole, 
cyclosporine, bucurol, tienilic acid.

UGT1A3 inhibitors, which include ritonavir, quinidine, probenecid, and valproic 
acid

strong CBR inhibitors, which include quercetin, menadione, glycyrrhetinic acid, 
and flufenamic acid.
14. Has received a live vaccine within 28 days prior to first dose.
15. Has been treated with a STING agonist other than MK-2118 in Arm 1 (eg, MK-1454, 
ADU-S100).
16. Has a history of re-irradiation for HNSCC at the projected injection site.
6.3
Lifestyle Restrictions
6.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage AEs 
such as diarrhea, nausea, or vomiting.
6.3.2
Caffeine, Alcohol, and Tobacco
There are no restrictions on caffeine.
During each dosing session, participants will abstain from alcohol for 24 hours before the 
start of dosing until after collection of the final PK and/or pharmacodynamic sample. 
Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical unit.
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6.3.3
Activity
Sunscreen should be applied daily to exposed skin areas regardless of season. Participants 
should be encouraged to stay out of the sun. Protective clothing for sun protection and 
wearing a hat is recommended.
6.3.4
Contraception
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm. 
MK-2118 should not be used by pregnant women.
Participants should be informed that taking the trial medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the trial. In order to participate 
in the trial, women of childbearing potential must adhere to the contraception requirement
from the day of trial medication initiation (or 14 days prior to the initiation of trial 
medication for oral contraception) throughout the trial period up to 120 days after the last 
dose of trial medication. If there is any question that a woman of childbearing potential will 
not reliably comply with the requirements for contraception, that participant should not be 
entered into the trial. 
Definitions of WOCBP and standards for adequate contraception are outlined in Appendix 5.
6.3.5
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab or 
MK-2118, the participant will be immediately discontinued from trial treatment. The site will 
contact the participant at least monthly and document the participant’s status until the 
pregnancy has been completed or terminated. The outcome of the pregnancy will be reported 
to the Sponsor without delay and within 24 hours if the outcome is an SAE (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn). The trial investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor. If a male participant impregnates his female partner, the trial personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 9.3.6.
6.3.6
Use in Nursing Women
It is unknown whether pembrolizumab or MK-2118 is excreted in human milk. Because 
many drugs are excreted in human milk, and because of the potential for serious adverse 
reactions in the nursing infant, participants who are breastfeeding are not eligible for 
enrollment.
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6.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any AEs or SAEs meeting reporting 
requirements as outlined in the entry guidelines.
6.5
Participant Replacement Strategy
Participants in Arms 1, 2, and 3 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. 
Participants in Arm 4 discontinuing within 35 days of the first dose due to reasons unrelated 
to study treatment will also not be considered evaluable for DLTs and may be replaced. 
Participants with a DLT within the DLT period should not be replaced. See Section 10.5.1
for description of safety analysis population.
7
TREATMENTS
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment and replacement participants as required.  When a replacement participant is 
required, the Sponsor or designee needs to be contacted prior to dosing the replacement 
supplies.  Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
7.1
Treatments Administered
The study treatments to be used in this trial are outlined below in Table 7.
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Table 7
Study Treatment(s)
Study Treatment Name:
MK-2118a
Pembrolizumab, 
(MK-3475) Arms 2, 
3, and 4
MK-2118 Diluent
Dosage Formulation:
Solution for injection
Solution for infusion
Solution for dosage preparation
Unit Dose Strength(s):
100 mg/4 mL
Dosage Level(s):
200 mg
Route of Administration:
IT injection or
SC injection
IV infusion
IT injection or SC injection
Sourcing:
Provided centrally by 
the Sponsor
Provided centrally by 
the Sponsor
Provided centrally by the 
Sponsor or locally by the study 
site, subsidiary, or designee
Abbreviations: IT = intratumoral; IV = intravenous; SC = subcutaneous.
a In Arm 2, 3, and 4, MK-2118 will be administered within
following completion of 
pembrolizumab IV infusion.
b Dose levels will be determined based on emerging safety data.
All supplies indicated in Table 7 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements.  Every attempt should be made to source these 
supplies from a single lot/batch number. The 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.
Refer to section 9.1.8 for details regarding administration of the study treatment.
7.1.1
IT Injection (Arm 1, Arm 2, and Arm 3)
In Arms 1 and 2, MK-2118 will be administered by IT injection into cutaneous,
subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound
guidance. 
In Arm 3, MK-2118 will be administered by injection into liver metastasis/lesions by 
ultrasound or cross-sectional imaging guidance (CT/MRI).
During dose escalation in both Arm 1 and Arm 2, each participant at a given dose level will 
receive a fixed dose of MK-2118 diluted in a volume of
of diluent. See Table 
2 and Table 3 for dose level ranges within Arm 1 and Arm 2, respectively. The volume of 
injectate delivered to each lesion will be based on the longest dimension of the target lesion 
as shown in Table 8, and on the number of lesions injected [Rehman, H., et al 2016].
Documentation of dose volume administered per lesion will be obtained. 
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During dose escalation in Arm 3, each participant at a given dose level will receive a fixed 
dose of MK-2118 diluted in a volume of
of diluent. See Table 4 for dose
level ranges within Arm 3. The volume of injectate delivered to each lesion will be based on 
the longest dimension of the target lesion as shown in Table 9, 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. Injection of more than one lesion, if feasible, 
is suggested. See Appendix 7 for further guidance. 
For Arms 1 and 2, if there are multiple lesions, then up to a maximum of 8 lesions may be 
injected per treatment visit, with a minimum injectate volume of 0.5 mL per lesion, and a 
total injectate volume of 4 mL per treatment visit. 
For Arm 3, if there are multiple lesions, then up to a maximum of 4 lesions may be injected 
per treatment visit, with a minimum injectate volume of 1 mL per lesion, and a total injectate 
volume of 4 mL per treatment visit. 
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 8 and in Table 9 for individual lesions may be permitted upon approval by 
the Sponsor Medical Monitor or designee under selected scenarios; eg, allocating the total 
injectate volume among multiple lesions rather than delivering the entire volume to the 
largest lesion.
Details on dose calculation, preparation, and administration of MK-2118 are provided in the 
Procedures Manual.
Table 8
Determination of MK-2118 Injection Volume for Cutaneous and Subcutaneous 
Injections Based on Lesion Size (Arms 1 and 2)
Lesion Size (longest dimension)
Injection Volume
>5.0 cm
≤4 mL
>2.5 cm to 5.0 cm
≤2 mL
>1.5 cm to 2.5 cm
≤1 mL
≥1.0 cm to 1.5 cm a
0.5 mL
a Doses
require a minimum of 1 mL of total injectate volume.
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Table 9
Determination of MK-2118 Injection Volume for IT Injections Based on Visceral 
Lesion Size (Arm 3)
Lesion Size (longest dimension)
Injection Volume
>5.0 cm
≤4 mL
>2.5 cm to 5.0 cm
≤2 mL
>1.5 cm to 2.5 cm
≤1.5 mL
≥1.0 cm to 1.5 cm a
1.0 mL
a Doses
require a minimum of 1 mL of total injectate volume.
7.1.2
Subcutaneous Injection (Arm 4)
Sites will be supplied with 
for dosing SC MK-2118. Sites will determine the appropriate 
volume of subcutaneous injection based on the dose to be administered at each dose cohort. 
The Procedures Manual provides a guide to injection volume calculation for subcutaneous 
administration by dose. Note that lesion size does not impact the volume administered of 
MK-2118 in Arm 4. Administration will be via injection into the subcutaneous anterolateral 
abdominal tissue or into the subcutaneous anterolateral thigh tissue. Subcutaneous 
administration of MK-2118 is by the Investigator or qualified designee.
Dose escalation of subcutaneous MK-2118 beyond the projected upper dose limit may be 
allowed if the systemic exposure achieved by SC dosing is significantly lower than expected,
or if the subcutaneous dosing of MK-2118 at the upper dose limit demonstrates sufficient 
safety and tolerability in humans.
7.2
Dose Modification (Escalation/Titration/Other)
7.2.1
Accelerated Titration Design
The initial dose escalation in Arms 1, 2, and 3 will proceed following an ATD.
Single participants will be enrolled into sequential dose levels with up to a 300% dose 
increment increases from the prior dose of MK-2118. Up to 3 participants per cohort may be 
allowed in the event of simultaneous enrollment. The first 2 participants in each cohort in the 
trial who receive MK-2118 treatment at a new dose level must be treated at least 7 days 
apart. The subsequent dose level to be tested in the next cohort of participants will be 
communicated to the investigators or designees following each dose escalation decision. 
Dose ranges for the ATD are outlined in Table 2, Table 3, and Table 4. Transition from ATD 
to mTPI will be triggered by the occurrence of at least 1 of the following events:  

A dose level of at least
is cleared by DLT evaluation OR
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
A ≥Grade 2 toxicity as assessed by the investigator to be related, probably related, or 
possibly related to the drug(s) at any dose level. 
If a DLT occurs in the ATD phase, then the cohort in which the DLT occurred will be 
expanded at this dose, per mTPI guidelines. This dose expansion will include a minimum of 
3 participants, and up to 14 participants per cohort (see Table 10 Dose Finding Rules). 
Therefore, dose escalation will have proceeded to the mTPI phase. If no DLT occurs in the 
ATD phase, then the ATD phase will proceed to the mTPI phase once 1 of the above triggers 
is met. In such a case, the starting dose for the mTPI phase will increase by a 
increment from the last ATD dose.
To ensure safety, MK-2118 in Arm 2 (combination therapy with pembrolizumab) will initiate 
at least 2 dose levels behind the current Arm 1 monotherapy dose and will not exceed the 
MTD for monotherapy. If an MTD for the monotherapy arm is established, the dose of IT 
MK-2118 in combination with pembrolizumab may continue escalation up to that dose. 
Intraparticipant dose escalation of IT MK-2118 is permitted once in Arm 1 (Parts A and B) 
for a qualifying participant at the discretion of the investigator, provided that the participant
has completed at least 3 cycles of treatment with IT MK-2118 monotherapy without a 
≥Grade 2 drug-related toxicity, and that dose escalation has proceeded beyond the next dose 
level in Arm 1. Intraparticipant dose escalation is not permitted in Arm 2 (Parts C and D), in 
Arm 3 (Parts E and F), nor in Arm 4.
7.2.2
Dose Finding During Modified Toxicity Probability Interval Design
Dose escalation and de-escalation decisions based on the mTPI design depend on the number 
of participants enrolled and the number of DLTs observed at the current dose level. The 
dosing decisions for this study are outlined in Table 10 [Nie, L., et al 2016] [Yang, S., et al 
2015].
A minimum of 3 participants are required at each dose. However, depending on the accrual 
rate, 3, 4, 5, or 6 participants may be enrolled at each new dose level. In Table 10, the 
columns indicate the number of participants treated at the current dose level, and the rows
indicate the number of participants experiencing DLT. The entries of the table are the dose-
finding decisions: E  escalate to the next higher dose; S  stay at the current dose; D  de-
escalate to the next lower dose; and DU  the current dose is unacceptably toxic. For 
example, if 0 out of 3 participants at a given dose level develop a DLT, then the dose can 
escalate to the next level. If 2 participants out of 3 develop a DLT, the dose will be de-
escalated to the next lower dose level. If 3 out of 3 participants develop a DLT, this indicates 
an unacceptable toxicity at this dose. The dose should be de-escalated, and the current dose 
will not be explored further. If 1 out of 3 participants at a given dose level develops a DLT, 
then additional participants should be enrolled at that dose level following the rules below. 
When adding participants to a dose level in response to a “stay” decision in Table 10, the 
same principles will be applied whether 3, 4, 5 or 6 participants are initially enrolled at that 
dose level. First, the number of additional participants to be enrolled is capped to minimize 
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the exposure to a dose that may be unacceptably toxic (denoted as “DU” in Table 10). 
Secondly, to determine how many more participants can be enrolled at the dose level, count 
steps in diagonal direction (down and to the right) from the current cell to the first cell
marked “DU.” For example, if 1 of 3 participants have experienced a DLT at a given dose 
level, no more than an additional 3 participants should be enrolled at this dose level until 
additional DLT data are available. This is because this dose level would be considered 
unacceptably toxic if all 3 of the additional participants experience a DLT (ie, 4/6 
participants with DLT in Table 10).
A “D” or “DU” decision at the starting dose level of Arm 1 of the study will stop the trial. An 
E decision at the highest dose level will result in staying at that level. During dose finding, it 
may be acceptable to de-escalate to an intermediate dose that was not predefined and not 
previously studied if evaluation of toxicity at such a dose is desired. If this approach is taken, 
3 to 6 new participants may be enrolled at the new intermediate dose, and the aforementioned 
rules should be used to determine further enrollment at this dose level. 
After 14 participants have been enrolled at any of the tested doses (including intermediate 
doses), dose finding will stop if the mTPI table indicates “S” for staying at current dose. 
Otherwise, up to 14 new participants may be enrolled at a lower dose if “D” or “DU” is 
indicated, or at a higher dose if “E” is indicated. 
The pool-adjacent-violators-algorithm [Ji, Y., et al 2007] will be used to estimate the DLT 
rates across doses. The dose with an estimated DLT rate closest to 30% will be treated as a 
preliminary MTD. However, the totality of the data will be considered before deciding on the 
dose(s) to carry forward to Phase 2, and the escalation schedule may be adjusted based on 
pharmacodynamic, PK, and safety data emerging throughout the trial. The preliminary RP2D 
of MK-2118 in the combination arm (Arm 2) will not exceed, but may equal, the preliminary 
RP2D in the MK-2118 monotherapy arm (Arm 1).
Note that although 30% was the target toxicity rate used to generate the guidelines in
Table 10, the observed rates of participants with DLTs at the MTD may be slightly above or 
below 30%. The target DLT rate will be 30% with a tolerance interval of 3%.
Establishment of the MTD/MAD for the combination of IT MK-2118 with pembrolizumab 
(Arm 2) requires that at least half of the participants in that cohort have no prior exposure to 
MK-2118 (ie, noncrossover participants). Priority for enrollment in Arm 2 will be given to 
MK-2118-naïve participants. Enrollment into Arm 2 will be monitored through IWRS.
Once the triggering criterion is met in the ATD phase, Arm 3 will use the same dose 
escalation and confirmation rules as in the mTPI method with a minimum of 3 participants
per dose level. Enrollment to Arm 3 will be monitored through IWRS.
The starting dose for Arm 4 will be up to, but not exceeding,
 Arm 4 will use the 
same dose escalation and confirmation rules as in the mTPI method with a minimum of 
3 participants per dose level. Enrollment to Arm 4 will be monitored through IWRS.
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Table 10
Dose-finding Rules per mTPI Design
Number of participants evaluable at current dose
Number of 
participants with 
at least 1 DLT
3
4
5
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
D = de-escalate to the next lower dose; DLT = dose-limiting toxicity; DU = current dose is unacceptably 
toxic; E = escalate to the next higher dose; mTPI = modified toxicity probability interval; S = stay at the 
current dose.
Target toxicity rate = 30%
Flat noninformative prior Beta (1,1) is used as a prior and ε1=ε2=0.0 [Ji, Y., et al 2007] [Ji, Y. and Wang, S.-
J. 2013]
7.2.3
Definition of Dose-limiting Toxicity
Dose-limiting toxicities will be defined from toxicities observed during the DLT period, 
defined as the first cycle of treatment (21 days) for each dose level in Arms 1, 2, and 3; and 
during the monotherapy run-in and the first cycle of pembrolizumab (35 days) in Arm 4. See 
Section 6.5 for rules on replacement of participants in the DLT period.
Participants who experience a DLT in the DLT period will be discontinued from treatment. 
However, if in the opinion of the Investigator the participant is deriving clinical benefit from 
the study treatment (for example a marked reduction in tumor burden), then the participant
may be allowed to continue on the study at a reduced dose level of MK-2118 upon resolution 
of the DLT to a ≤Grade 1 adverse event or to baseline, and upon discussion with the 
Sponsor. Therefore, flexibility of rechallenge of MK-2118 at a lower dose per dose 
modification guidance below subsequent to a DLT may be considered. Exceptional 
circumstances to following the dose modification tables below may be considered after 
consultation with the Sponsor.
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The occurrence of any of the following toxicities during the DLT period of each treatment 
arm, if assessed by the investigator to be related, probably related, or possibly related to the 
drug(s) will be considered a DLT, excluding toxicities clearly not related to the drug(s), such 
as disease progression, environmental factors, unrelated trauma, etc.:
1. Grade 4 nonhematologic toxicity (not laboratory)
2. Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia
a.
Grade 4 thrombocytopenia of any duration
b. Grade 3 thrombocytopenia 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

Clinically significant medical intervention is required to treat the participant, or

the abnormality leads to hospitalization, or

the abnormality persists for >1 week.
5. Febrile neutropenia Grade 3 or Grade 4:

Grade 3 is defined as ANC <1000/mm3 with a single temperature of >38.3°C 
(101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour.

Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3°C 
(101°F) or a sustained temperature of ≥38°C (100.4°F) for more than 1 hour, with 
life-threatening consequences and urgent intervention indicated
6. Any toxicity that causes treatment discontinuation or causes the participant to miss at 
least 1 dose during the DLT period
7. Prolonged delay (>2 weeks) in initiating Cycle 2 due to intervention-related toxicity
8. Any elevated aspartate aminotransferase (AST) or alanine aminotransferase (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 
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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
7.2.4
Dose Modification/Interruption Due to Adverse Events
The CTCAE v 4.0 must be used to grade the severity of AEs. The investigator may attribute 
each toxicity event to MK-2118 alone, or to pembrolizumab alone, or to combination 
therapy. Use dose modification according to Table 11 or Table 12. If a dose modification for 
toxicity occurs with MK-2118, the dose may not be re-escalated to the dose that preceded the 
dose modification. Dose modifications are always based on the previous cycle.
Participants may have up to 2 dose modifications of MK-2118 throughout the course of the 
study, as described in Section 7.2. If further toxicity occurs or the criteria for resuming 
treatment are not met, the participant must be discontinued from the study drug. If a 
participant experiences several toxicities and there are conflicting recommendations, follow 
the most conservative dose adjustment recommended (dose reduction appropriate to the most 
severe toxicity).
Reduction or holding of 1 agent and not the other agent is appropriate if, in the opinion of the 
investigator, the toxicity is clearly related to 1 of the study drugs. For example, in a 
combination therapy arm (Arm 2, Arm 3, or Arm 4) if MK-2118 is held due to an AE 
attributed to that drug, then pembrolizumab may continue to be administered. Appropriate 
documentation of which drug the investigator is attributing the AE to is required. If, in the 
opinion of the investigator, the toxicity is related to the combination of 2 study drugs, then 
both drugs should be held according to recommended dose modifications. 
Adverse events (both nonserious and serious) associated with MK-2118 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. 
Participants who experience a DLT in the DLT evaluation period will be discontinued from 
treatment. However, if in the opinion of the Investigator the participant is deriving clinical 
benefit from the study treatment (for example a marked reduction in tumor burden), the 
participant may be allowed to continue on the study at a reduced dose level of MK-2118
upon resolution of the DLT to a ≤Grade 1 adverse event or to baseline, and upon discussion 
with the Sponsor. Therefore, flexibility for rechallenge with MK-2118 at a lower dose per 
dose modification guidance below subsequent to a DLT may be considered.
Exceptional circumstances to the dose modification tables below may be considered after 
consultation with the Sponsor.
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7.2.4.1
Dose Modification for MK-2118
Dose modification guidelines for drug-related AEs are presented in Table 11. See Table 14 for treatment guidelines for cytokine 
release syndrome.
Table 11
MK-2118 Dose Modification Guidelines for Drug-related Adverse Events in Monotherapy IT (Arm 1), Combination 
Therapy IT (Arm 2), Combination Therapy Visceral IT (Arm 3), and Combination Therapy Subcutaneous Administration (Arm 4)
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 1 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 4:
Cycle 1, 2, 3, and 4: 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
If AE persists for 12 weeks without 
resolution following the last dose of 
study drug administered
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Toxicity
Hold 
Treatment
Criteria for 
Restarting Treatment
Dose/Schedule for Restarting Treatment
Criteria for Discontinuation After 
Consultation with Sponsor
Arm 3:
Cycle 3 and beyond:  
Maintain dosing schedule at
unless
AE persists for 2 additional cycles, then 
reduce dosing schedule to
Arm 4: 
Cycle 5 and beyond:
Maintain dosing schedule at
unless 
AE persists for 2 additional cycles, then 
reduce dosing schedule to
Any Grade 3a
hematological toxicity
Yesa
Treatment may be 
restarted when AE 
resolves back to 
baseline or to Grade 1
First, decrease dose by 1 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 4:
Cycle 1, 2, 3, and 4:  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
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Toxicity
Hold 
Treatment
Criteria for 
Restarting Treatment
Dose/Schedule for Restarting Treatment
Criteria for Discontinuation After 
Consultation with Sponsor
Arm 4:
Cycle 5 and beyond:  Maintain dosing 
schedule at
unless AE persists for 2 
additional cycles, then reduce dosing 
schedule to
Any Grade 4 hematological 
toxicity
Yes
Treatment may be 
restarted when AE 
resolves back to 
baseline or to Grade 1
First, decrease dose by 1 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 4:
Cycle 1, 2, 3, and 4:  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 
Arm 4: 
Cycle 5 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
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Toxicity
Hold 
Treatment
Criteria for 
Restarting Treatment
Dose/Schedule for Restarting Treatment
Criteria for Discontinuation After 
Consultation with Sponsor
Nonhematological toxicities:
Any Grade 1 
nonhematological toxicity
Grade 2 alopecia
Grade 2 fatigue
No 
N/A
N/A
N/A
Any Grade 2 
nonhematological toxicity 
except Grade 2 alopecia 
and Grade 2 fatigue
Per medical 
assessment 
of the 
investigator
Per medical 
assessment of the 
investigator
Per medical assessment of the investigator: 
First, decrease dose by 1 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 4:
Cycle 1, 2, 3, and 4: 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
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Toxicity
Hold 
Treatment
Criteria for 
Restarting Treatment
Dose/Schedule for Restarting Treatment
Criteria for Discontinuation After 
Consultation with Sponsor
Arm 4:
Cycle 5 and beyond: 
Maintain dosing schedule at
unless
AE persists for 2 additional c
, then 
reduce dosing schedule to
Any Grade 3 
nonhematological toxicity
Yes
Treatment may be 
restarted when AE 
resolves back to 
baseline or to Grade 1
First, decrease dose by 1 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 4:
Cycle 1, 2, 3, and 4:  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
Arm 4:
Cycle 5 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
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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 1 
First, decrease dose by 1 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 4:
Cycle 1, 2, 3, and 4:  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
Arm 4:
Cycle 5 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
a For Lymphoma participants, 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 participants with solid tumors or lymphomas.
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In case toxicity does not resolve back to baseline or to Grade 1 within 12 weeks following 
dose modification, MK-2118 should be considered for discontinuation after consultation with 
the Sponsor. 
After any Grade 4 drug-related AE, participants 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).
In Arm 2, Arm 3, and Arm 4, pembrolizumab treatment will be modified for the AEs as 
described in Table 12.
7.2.4.2
Immune-Related Events and Dose Modification (Withhold, Treat, Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications.
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. 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 12.
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7.2.4.3
Management of Infusion Reaction
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 within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on pembrolizumab-associated infusion 
reaction are provided in Table 13.
Table 13
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
None
Grade 2
Requires infusion 
interruption, but responds 
promptly to symptomatic 
treatment (eg, 
antihistamines, 
nonsteroidal anti-
inflammatories 
(NSAIDS), narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hours
Stop infusion and monitor symptoms.
Additional appropriate medical therapy may include, 
but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of the 
original infusion rate (eg, from 100 mL/h to 50 mL/h). 
Otherwise dosing will be held until symptoms resolve 
and the participant should be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment
Participant may be 
Premedicated 1.5 h 
(± 30 min) prior to 
infusion of 
pembrolizumab and/or 
MK-2118 if it can be 
determined which drug 
caused reaction (if 
suspect drug cannot be 
identified on Arm 2, 
premedicate prior to 
pembrolizumab) with:
Diphenhydramine 
50 mg po (or 
equivalent dose of 
antihistamine).
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical sequelae 
(eg, renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop infusion.
Additional appropriate medical therapy may include, 
but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Epinephrine
Increase monitoring of vital signs as medically 
indicated until the participant is deemed medically 
stable in the opinion of the investigator.
Hospitalization may be indicated.
Participant is permanently discontinued from 
further trial treatment administration.
No subsequent dosing
Appropriate resuscitation equipment should be available in the room and a physician readily available during 
the period of drug administration. For further information, please refer to the CTCAE v 4.0 at 
http://ctep.cancer.gov
7.2.4.4
Management of Cytokine Release Syndrome
CRS is defined in CTCAE v 4.0 as a disorder characterized by nausea, headache, 
tachycardia, hypotension, rash, and shortness of breath. CRS occurs when lymphocytes (B 
cells, T cells, and/or natural killer cells) and/or myeloid cells (macrophages, dendritic cells, 
and monocytes) become activated and release inflammatory cytokines [Lee, D. W., et al 
2014]. In addition to the symptomatology defined under CTCAE, CRS may present with 
fever, chills, myalgias, and malaise. Table 14 shows treatment guidelines for participants 
who experience CRS.
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Table 14
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 participant is 
deemed medically stable in the opinion 
of the investigator
None
Grade 2
Therapy interruption 
indicated, but responds 
promptly to symptomatic 
treatment (eg, NSAIDS, 
narcotics, IV fluids). 
Prophylactic medications 
indicated for ≤24 hours
Increase monitoring of vital signs and 
oxygen saturation, as medically 
indicated, until the participant is 
deemed medically stable in the opinion 
of the investigator
Additional appropriate medical therapy 
may include, but is not limited to:
IV fluids
NSAIDS
Acetaminophen
Narcotics
Oxygen
Perform fever work-up to exclude 
infectious etiologies; treat neutropenia 
if present
Participant may be premedicated 
1.5 hours (± 30 minutes) prior to 
MK-2118 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 
Participants with ≥Grade 3 CRS need 
to be monitored very closely, likely in 
an intensive care setting
For Grade 3 CRS, discuss with 
Sponsor prior to restart of 
MK-2118 treatment. Upon 
approval by Sponsor, MK-2118
may be restarted at a reduced dose 
when AE resolves back to baseline 
or to Grade 1 (see Table 11 – Dose 
Modification Guidelines).
Participant may be premedicated 
1.5 hours (± 30 minutes) prior to 
MK-2118 administration with 
acetaminophen 500 to 1000 mg po 
(or equivalent dose of antipyretic)
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 
Participants with ≥Grade 3 CRS need 
to be monitored very closely, likely in 
an intensive care setting
Permanently discontinue MK-2118
in participants who develop 
Grade 4 CRS  
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7.2.4.5
Other Allowed Dose Interruption for MK-2118 or Pembrolizumab
Pembrolizumab or MK-2118 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 and within 42 days of the previously administered dose, unless otherwise discussed with 
the Sponsor. The reason for interruption should be documented in the participant's study 
record.
7.2.5
Intraparticipant Dose Escalation
Intraparticipant dose escalation will be allowed once for qualified participants in Arm 1 
monotherapy, after they have completed at least 3 cycles of treatment with MK-2118
monotherapy without a ≥ Grade 2 drug-related toxicity, and provided that dose escalation has 
proceeded beyond the next dose level in Arm 1. The participant may escalate to the highest 
dose level that has been cleared by DLT evaluation in Arm 1, as defined by the minimum 
number of DLT-evaluable participants within that cohort (for the ATD phase, 1 participant 
per cohort; for the mTPI phase, 3 participants per cohort). This dose will be communicated to 
the site via written communication 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 7.2.1), as appropriate. Dose modification 
will be based on CTCAEs per Dose Modification Guidelines (see Section 7.2.4). 
Intraparticipant dose escalation is not permitted in Arm 2 (Parts C and D), in Arm 3 (Parts E 
and F), nor in Arm 4 (Part G).
7.3
Method of Treatment Assignment
Treatment allocation will be accomplished by nonrandom assignment by IWRS. 
When Arms 1 and 2 are open for enrollment, IWRS will alternate participant assignment 
between Arm 1 and Arm 2, starting with Arm 1. For example, if the
dose cohort of 
Arm 1 (MK-2118 monotherapy) and the
dose cohort of Arm 2 (MK-2118
combination therapy with pembrolizumab) are open for enrollment, then the first participant
will be allocated to Arm 1, the second participant will be allocated to Arm 2, the third 
participant will be allocated to Arm 1, etc.
At least half of the participants in Arm 2 must have no prior exposure to IT MK-2118 (ie, 
noncrossover/ IT MK-2118-naïve participants) in order to establish the MTD/MAD dose 
level in the combination therapy arm of IT MK-2118 with pembrolizumab (Arm 2). 
Investigator assessment of eligibility and lesion location will guide participant allocation to 
Arms 1/2, Arm 3, or Arm 4. The enrollment into Arm 3 and into Arm 4 is independent of 
enrollment into Arm 1 and into Arm 2, due to different inclusion/exclusion criteria. In the 
event that a participant qualifies for multiple arms, preference will be given to enrollment 
into the IT arms over the SC arm, based on presumed difficulty of identifying participants 
amenable to IT therapy. 
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7.3.1
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
7.4
Blinding
This is an open-label trial; therefore, the Sponsor, investigator and participant will know the 
treatment administered.
7.5
Preparation/Handling/Storage/Accountability
7.5.1
Dose Preparation
MK-2118 will be administered as a sterile aqueous solution with a total volume of injectate 
for IT injection of 
per treatment visit for all injected lesions combined as well as 
a sterile aqueous solution for SC injection. Details on the dose calculation, preparation, and 
administration of MK-2118 for IT injection and SC injection are provided in the Procedures 
Manual. 
7.5.2
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie,
receipt, reconciliation, and final disposition records).
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.
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.
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The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
7.6
Treatment Compliance
All doses of MK-2118 with pembrolizumab will be administered under the supervision of a 
qualified physician and/or designee experienced in the use of anticancer agents.
7.7
Concomitant Therapy
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 participant's primary physician.  However, the decision to continue 
the participant on study treatment requires the mutual agreement of the investigator, the 
Sponsor and the participant.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the CRF including all 
prescription, OTC, herbal supplements, and IV medications and fluids. If changes occur
during the trial period, documentation of drug dosage, frequency, route, and date will also be
included on the CRF.
All concomitant medications received within 28 days before the first dose of trial treatment
through the Safety Follow-up Visit should be recorded. If participants 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 in Section 9.3.1.
Participants are prohibited from receiving the following therapies during the Screening, and
Treatment Phases of this trial:
1. Immunotherapy not specified in this protocol.
2. Antineoplastic systemic chemotherapy or biological therapy not specified in this 
protocol.
3. Investigational agents not specified in this protocol.
4. Radiation therapy; radiotherapy for symptom management is allowed beyond Cycle 2
upon approval by the Sponsor Medical Monitor or designee.
5. Live vaccines within 28 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 
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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.
6. Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
adverse event of suspected immunologic etiology. The use of physiologic doses of 
corticosteroids may be approved after consultation with the Sponsor.
7. Strong/moderate CYP2C9 inhibitors from 2 weeks of Cycle 1 Day 1 through the 30 day 
Safety Follow-up Visit. This includes, but is not limited to:
Strong/moderate CYP2C9 inhibitors, such as amiodarone, felbamate, fluconazole, 
miconazole, piperine, oxandrolone, fluorouracil and its derivatives (TS-1, UFT, 
tegafur, carmofur, doxifluridine, capecitabine), sulfaphenazole, cyclosporine, bucurol, 
and tienilic acid.
8. Co-administered UGT1A3 inhibitors that include ritonavir, quinidine, probenecid, and 
valproic acid.
9. Strong CBR inhibitors that include quercetin, menadione, glycyrrhetinic acid, and 
flufenamic acid.
If the investigator determines that a participant requires any of the aforementioned treatments 
for any reason, study intervention (MK-2118 and pembrolizumab) must be discontinued.
Participants 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.
7.7.1
Rescue Medications & Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 7.2.4. 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. 
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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 and Table 
12 in Section 7.2.4.1 and Section 7.2.4.2, respectively, for guidelines regarding dose 
modification and supportive care. Refer to Table 11 for treatment guidelines for AEs that are 
related to MK-2118 treatment and to Table 14 for guidelines regarding dose modification and 
supportive care for cytokine release syndrome.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
7.8
Treatment After the End of the Study
There is no study-specified treatment following the end of the study.
7.9
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
o
The site must attempt to contact the participant and reschedule the missed visit.  If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
o
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, phone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
o
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant.  The amount of missing data for the participant will be 
managed via the pre-specified data handling and analysis guidelines.
7.10
Clinical Supplies Disclosure
This trial is open-label; therefore, the participant, the trial site personnel, the Sponsor and/or 
designee are not blinded. Study treatment (name, strength or potency) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
8
DISCONTINUATION/WITHDRAWAL CRITERIA
8.1
Discontinuation of Study Treatment
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment.  Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
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will still continue to participate in the study as specified in Section 2 - SoA and Section 
9.10.3 Discontinued Participants Continuing to be Monitored in the Study.
Participants may discontinue study treatment at any time for any reason or be dropped from 
the study treatment at the discretion of the investigator should any untoward effect occur.  In 
addition, a participant may be discontinued from study treatment by the investigator or the 
Sponsor if study treatment is inappropriate, the trial plan is violated, or for administrative 
and/or other safety reasons.  Specific details regarding procedures to be performed at study 
treatment discontinuation are provided in Section 9.1.12
Discontinuation and Withdrawal.
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
o
Confirmed radiographic disease progression outlined in Section 9.2.2 (exception if the 
Sponsor approves treatment continuation).
o
The participant 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 participant is noncompliant with the protocol.
o
The participant has a medical condition or personal circumstance, which, in the opinion 
of the investigator and/or Sponsor, placed the participant at unnecessary risk from 
continued administration of study drug.
o
The participant has a confirmed positive serum pregnancy test.
o
Side effects of and/or concomitant medications required for treatment of HIV and/or its 
complications that are incompatible with continued study treatment.
For participants who are discontinued from treatment, but continue to be monitored in the 
trial, see the SoA in Section 2.5 Discontinuation / End of Treatment and Post-treatment 
Follow-up, and Section 9.10.3 Post-treatment Follow-up for those procedures to be 
completed at each specified visit.
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For participants who progress by clinical or radiographic progression on monotherapy IT 
MK-2118 in Arm 1, crossover into Arm 2 will be allowed if the participant meets the 
crossover eligibility criteria stated in Section 6.1.2 and Section 6.2.2. Participants who cross 
over from Arm 1 into Arm 2 will enter Arm 2 at the start of Arm 2 (at screening).
8.2
Withdrawal from the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study including the procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant, as well as 
specific details regarding withdrawal from Future Biomedical Research are outlined in 
Section 9.1.12
Discontinuation and Withdrawal.
9
STUDY ASSESSMENTS AND PROCEDURES
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
The approximate amount of blood collected from each participant for laboratory evaluations 
is provided in the Procedures Manual.
9.1
Administrative and General Procedures
9.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical trial or Future Biomedical Research. If there are changes to the participant’s status 
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during the trial (eg, health or age of majority requirements), the investigator or qualified 
designee must ensure the appropriate consent is in place. 
9.1.1.1
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the participant before 
participation in the trial.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant must receive the IRB/IEC’s approval/favorable opinion in advance of use.  
The participant or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the participant’s 
willingness to continue participation in the 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 participant’s dated signature or by the participant’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/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
9.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
9.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria (Section 6.1 and 6.2) will be reviewed by the investigator
or qualified designee to ensure that the participant qualifies for the trial.
9.1.3
Participant Identification Card
All participants will be given a Participant 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 participant with a Participant Identification Card 
immediately after the participant provides written informed consent. At the time of treatment 
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allocation/randomization, site personnel will add the treatment/randomization number to the 
Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
9.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered clinically significant by the investigator. Details regarding the disease for 
which the participant has been enrolled in the trial will be recorded separately and should not 
be listed in the medical history. Smoking history will be obtained.
9.1.5
Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status. 
9.1.6
Prior Oncology Treatment History
The investigator or qualified designee will record all prior cancer treatments including 
systemic treatments, radiation, and surgeries.
9.1.7
Eastern Cooperative Oncology Group Performance Status
The investigator or qualified designee will assess the ECOG performance status as the time
points specified in the SoA (Section 2). Additional ECOG testing may be performed as 
clinically indicated.
9.1.8
Prior and Concomitant Medications Review
9.1.8.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant
within 28 days before first dose of trial medication. Treatment for the disease for which the 
participant has been enrolled in this trial will be recorded separately and should not be listed 
in prior medications.
9.1.8.2
Concomitant Medications
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care, with the exception of those specifically excluded (see Section 6.2). All 
concomitant medication will be recorded on the eCRFs, including all prescription, OTC 
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products, herbal supplements, and IV medications, and fluids. If changes occur during the 
trial period, documentation of drug dosage, frequency, route, and date should also be 
included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of trial treatment 
and up to 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered 30 days after the last dose of trial treatment should be recorded for 
SAEs and events of clinical interest (ECIs) as defined in Section 9.3.7. The investigator or 
qualified designee will record medication, if any, taken by the participant during the trial.
9.1.9
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to treatment allocation.  Each 
participant will be assigned only one screening number.  Screening numbers must not be re-
used for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Participants who crossed over from Arm 1 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 9.10.1.
9.1.10 Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.
Once a treatment/randomization number is assigned to a participant, it can never be re-
assigned to another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
9.1.11 Treatment Administration
Administration of trial medication will be witnessed by the investigator and/or trial staff.
Study treatment will begin on Cycle 1 Day 1, once all predose assessments have been 
completed. 
See Section 7 for a description of treatment modifications. Instructions for preparing and 
administering study drugs will be provided in the Procedures Manual.
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9.1.12.1 Withdrawal From Future Biomedical Research
Participants may withdraw their consent for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the principal investigator for the main trial.  If 
medical records for the main trial are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@MSD.com).  Subsequently, 
the participant's consent for Future Biomedical Research will be withdrawn.  A letter will be 
sent from the Sponsor to the investigator confirming the withdrawal. It is the responsibility of 
the investigator to inform the participant of completion of withdrawal.  Any analyses in 
progress at the time of request for withdrawal or already performed prior to the request being 
received by the Sponsor will continue to be used as part of the overall research 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 (eg, 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 
participant’s personal information and their specimens.  In this situation, the request for 
specimen withdrawal cannot be processed.
9.1.13 Participant Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
9.1.14 Domiciling
Participants enrolled in Arms 1, 2, and 3 will report to the clinical research unit on C1D1. 
Participants will remain in the unit for an observation period of at least 24 hours, post study 
drug administration on C1D1, C1D8, and C1D15. For Arm 4, participants will remain in the 
unit for an observation period of at least 24 hours post study drug administration on C1D1, 
C1D8, and C2D1. At the discretion of the investigator, the inpatient observation periods may 
be extended beyond 24 hours and up to 48 hours post study drug administration. This 
requirement may be waived at the discretion of the Sponsor and will be communicated to 
sites via a memorandum.
After discharge from the clinic, participants are to be counseled with post-discharge 
instructions.
9.1.15 Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical trial that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and 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.
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9.2
Efficacy Assessments
9.2.1
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 participant has measurable disease as defined by RECIST version 
1.1, IWG revised criteria, or ISCL criteria to confirm eligibility. In participants with CTCL, 
it is recommended that CT scans be performed at screening.
Solid tumor imaging should be acquired by CT. An MRI should be used when CT is 
contraindicated or for imaging of the brain. 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. 
For participants with CTCL, include medical photography with tumor imaging every 
12 weeks. Medical photography may be done more frequently, if warranted.
For participants with solid tumors assessed by RECIST 1.1, PR and CR should be confirmed 
by a repeat imaging assessment. The imaging for confirmation of response may be performed 
at least 4 weeks after the first indication of response. Participants who receive additional 
imaging for confirmation may resume imaging at subsequent scheduled tumor imaging 
timepoint. If the additional confirmation imaging was within 4 weeks of subsequent 
scheduled tumor imaging timepoint, then tumor imaging does not need to be repeated. 
The same imaging technique and the same imaging modality with/without the use of contrast 
for assessment of response should be performed in a participant throughout the trial to 
optimize visualization of existing and new tumor burden. Tumor imaging schedule for all 
indications being studied 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 used to collect, clean, and hold tumor imaging and medical 
photography. Images will be collected for possible analysis by blinded, independent central 
review.
9.2.2
Response Assessments
9.2.2.1
Immune-related RECIST
Tumor imaging and/or medical photography for solid tumors should be repeated every 
9 weeks (± 7 days) from the first dose of treatment. 
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RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen in 
treatment with pembrolizumab and MK-2118. 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-2118. Immune-related RECIST (irRECIST) is 
RECIST 1.1 adapted as described below to account for the unique tumor response seen with 
immuno-therapeutics. 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 participants 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 
tumors should not be used for assessment by RECIST 1.1 or irRECIST, except in cases with 
only target lesions available, after consultation with the Sponsor.
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
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In participants who have initial evidence of radiological PD, it is at the discretion of the 
investigator whether to continue a participant on study treatment until repeat imaging is 
obtained. This clinical judgment decision should be based on the participant’s overall clinical 
condition, including performance status, clinical symptoms, and laboratory data. Participants 
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, participants should not be discontinued until progression is confirmed. This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some participants can have a transient tumor flare in the first few months 
after the start of immunotherapy, and still have a subsequent disease response. Participants 
who are deemed clinically unstable are not required to have repeat imaging for confirmation 
of PD. In participants who discontinue trial treatment, tumor imaging should be performed at 
the time of treatment discontinuation (±4-week window). If a previous scan was obtained 
within 4 weeks prior to the date of discontinuation, then a scan at treatment discontinuation is 
not mandatory. In participants who discontinue trial treatment due to documented disease 
progression, this is the final required tumor imaging.
Confirmation of PR and CR is required at least 4 weeks after the initial response assessment 
of PR and CR.
9.2.2.2
IT Immunotherapy RECIST (itRECIST)
itRECIST, a response assessment tailored to IT immunotherapy, is aligned with RECIST 1.1 
overall response assessment [Goldmacher, G. V., et al 2020] and is further described in 
Appendix 8, Section 12.8. 
itRECIST:

provides a guidance on baseline categorization of target and nontarget lesions (Figure 3).

provides guidance on recategorization of lesions during therapy (Figure 4).

allows for separate response assessment in injected and noninjected lesions (Figure 5).
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
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 6).

provides guidelines on prioritization of lesion injection during the course of IT 
immunotherapy (see Appendix 12.7).
itRECIST supports standardized collection of data from IT immunotherapy clinical trials to 
facilitate exploratory response analysis. 
9.2.2.3
IWG Revised Response Criteria for Malignant Lymphomas
Response to treatment for lymphomas will be assessed every 12 weeks (± 7 days) from the 
first dose of treatment. 
Response to therapy will be assessed by CT, with or without PET, and bone marrow biopsy,
and clinical information including physical examination and symptoms (fever, night sweats, 
weight loss), using the IWG revised response criteria for malignant lymphomas [Cheson, B. 
D., et al 2007]. Information collected for this assessment 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, at 
follow-up visits if there is nodal involvement in the neck at screening. FDG-PET 
scans may be obtained to supplement the anatomic 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 participant 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 15 as 
appropriate. Suspected relapse or disease progression must be confirmed by physical 
examination, laboratory assessments, repeat bone marrow biopsy [Cheson, B. D., et al 2007], 
and CT scan. Participants with suspected relapse or disease progression should continue to 
follow study procedures until they need another therapy. If a participant 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 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 malignant lymphoma
[Cheson, B. D., et al 2007]. For purposes of this protocol, biopsied tumors should not be used 
for assessment by revised IWG criteria, except in cases with only target lesions available,
after consultation with the Sponsor.
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Table 15
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
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: CR = complete response; CT = computed tomography; FDG = fluorodeoxyglucose; PD = 
progressive disease; PET = positron emission tomography; PR = partial response; SPD = Sum of the products of 
the greatest diameters. 
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9.2.2.4
Response Assessment for Cutaneous T-cell Lymphoma
The mSWAT (Table 16) will be used to evaluate the extent of disease in the CTCL 
participants prior to treatment at each cycle per the SoA. Imaging (CT scans and medical 
photography) will be performed at screening/baseline for all CTCL participants. 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 [Olsen, E. A., et al 2011].
Each scheduled response assessment will include evaluations of skin (Table 17), lymph 
nodes (Table 18), viscera (Table 19), and blood (Table 20); and will determine a global 
response score (Table 21) for CTCL participants. Medical photography will also be 
performed at the time of each response assessment (see SoA), or more often as warranted.
Table 16
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.
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Table 17
Response in Skin (Cutaneous T-cell Lymphoma)
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.
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Table 18
Response in Lymph Nodes (Cutaneous T-cell Lymphoma)
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.
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Table 19
Response in Viscera (Cutaneous T-cell Lymphoma)
Response
Definition
CR
Liver or spleen or any organ considered involved at baseline should not be 
enlarged on physical examination and should be considered normal by 
imaging; no nodules should be present on imaging of liver or spleen; any post 
treatment 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.
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Table 20
Response in Blood (Cutaneous T-cell Lymphoma)
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[Cheson, 
B. D., et al 1996]
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.
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Table 21
Global Response Score for Cutaneous T-cell Lymphoma
Global 
Score
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
Abbreviations: CR, complete response; NI, noninvolved; PR, partial response; PD, progressive disease; SD, 
stable disease.
*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.
9.2.3
Tumor Marker Assessments
Tumor markers alone cannot be used to assess response. However, some disease specific and 
validated tumor markers (eg, CEA, CA-125, CA-19-9, or alpha fetoprotein,) can be 
integrated as nontarget disease markers. If markers are initially above the upper-normal limit,
they must normalize for a participant to be considered in complete clinical response when all 
lesions have disappeared. 
Blood samples for tumor markers will be obtained at time points indicated in Section 2 -
SoA, as clinically appropriate for the participant. Additional assessments may be done if 
clinically indicated, eg, progression.
9.3
Adverse Events, Serious Adverse Events and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE and other reportable safety event reports can be found in Appendix 4.
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Progression of the cancer under study is not considered an adverse event as described in 
Section 9.3.5 Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as 
AEs or SAEs, and Appendix 4.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant's legally authorized 
representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs and other reportable safety events for outcome according to Section 9.3.3.
9.3.1
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information
Progression of the cancer under study is not considered an AE unless it results in 
hospitalization or death.
All AEs, SAEs and other reportable safety events that occur after the consent form is signed, 
but before treatment allocation/randomization, must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event cause the 
participant to be excluded from the trial, or is the result of a protocol-specified intervention, 
including, but not limited to, washout or discontinuation of usual therapy, diet, or a 
procedure. 
●
All AEs from the time of treatment allocation/randomization through 30 days following 
cessation of study treatment must be reported by the investigator. 
●
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 120 days following cessation of study treatment, or 30 days following 
cessation of study treatment if the participant initiates new anticancer therapy, 
whichever is earlier must be reported by the investigator. 
●
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 
30 days following cessation of study treatment if the participant initiates new anticancer 
therapy must be reported by the investigator. 
●
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the 
event is considered to be drug-related.
Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
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9.3.3
Follow-up of AE, SAE and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE and other reportable safety events 
including pregnancy and exposure during breastfeeding, ECI, Cancer and Overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 8.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in randomized participants for 
outcome. Further information on follow-up procedures is given in Appendix 4.
9.3.4
Regulatory Reporting Requirements for SAE

Prompt notification (within 24 hours) by the investigator to the sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. All AEs will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R1) Guidelines for Good Clinical Practice.

Investigator safety reports must be prepared for SUSAR according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAE) from the sponsor will file 
it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate 
according to local requirements.
9.3.5
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Progression of the cancer under study is not considered a reportable event. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the trial. Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
9.3.6
Pregnancy and Exposure During Breastfeeding
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 participant
(spontaneously reported to them), including the pregnancy of a male participant's female 
partner that occurs during the trial. Pregnancies and lactations of participants and female 
partners of male participants from the time the consent form is signed, but before treatment 
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allocation/randomization, must be reported by the investigator if they cause the participant 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 of participants and female partners of male participants 
that occur from the time of treatment allocation/randomization through 120 days following 
cessation of Sponsor’s product, or 30 days following cessation of trial treatment if the 
participant initiates new anticancer therapy, whichever is earlier, must be reported. 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 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).
9.3.7
Events of Clinical Interest (ECI)
Selected non-serious and SAEs are also known as ECIs and must be reported to the Sponsor.
Events of clinical interest for this trial include: 
1. an overdose of Sponsor's product, as defined in Section 9.4 Treatment of Overdose, 
that is not associated with clinical symptoms or abnormal laboratory results.
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2X 
the upper limit of normal and, at the same time, an alkaline phosphatase lab value that 
is less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
9.4
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any
 or 
greater. No specific information is available on the treatment of overdose of pembrolizumab. 
In the event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
For MK-2118, an overdose will be defined as any dose exceeding the prescribed dose by 
≥20%. No specific information is available on the treatment of an overdose of MK-2118.  In 
CCI
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the event of an overdose of MK-2118, the participant should be observed closely for signs of 
toxicity and provided appropriate supportive treatment, as clinically indicated.
9.5
Safety 
Details regarding specific safety 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 pretrial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant, can be found in the Procedures 
Manual.
Planned time points for all safety assessments are provided in the SoA.
9.5.1
Physical Examinations
The investigator or qualified designee will perform a complete physical examination during 
the Screening Period and at additional time points as defined in the SoA (Section 2). Height 
should be recorded only at Screening. Clinically significant findings from the screening 
examination should be recorded as medical history. 
A directed physical examination should be repeated at the visits indicated in the SoA
(Section 2). After the first dose of study treatment, new clinically significant abnormal 
findings should be recorded as AEs.
Weight should be recorded at Screening and at the visits indicated in the SoA (Section 2).
9.5.2
Vital Signs
Vital signs (VS) will include temperature, systolic and diastolic blood pressure, pulse, and O2
saturation (pulse oximetry). Additional VS monitoring may be obtained as clinically 
indicated.
9.5.3
Electrocardiograms
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 SoA (Section 2). Clinically significant 
abnormal findings seen on any ECGs performed after Screening should be recorded as AEs.
9.5.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
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CRF. The laboratory reports must be filed with the source documents. Clinically 
significant abnormal laboratory findings are those that are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected 
for the participant's condition.
●
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
●
If laboratory values from nonprotocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF.
●
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 
treatment, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator. 
Laboratory samples, which cannot be processed locally, may be sent to the central laboratory.
9.6
Pharmacokinetics
To evaluate the immunogenicity (ADA) and exposure of pembrolizumab and exposure of 
MK-2118 in this indication, sample collections for analysis of ADA and PK are currently 
planned as shown in the Trial Flowchart. Blood samples for PK and ADA collected may be 
stored only at this time. Further analysis may be performed if required. If ongoing PK and/or 
ADA sampling is deemed to be unnecessary by the Sponsor, it may be reduced or 
discontinued.
9.6.1
Blood Collection for PK
Blood sample collection, processing, storage, and shipment instructions are provided in the 
Procedures Manual. PK samples should be drawn according to the PK collection schedule for 
all participants (Section 2). 
Time points may be changed or eliminated based on emerging PK data. The MK-2118 PK 
plasma samples may also be used for MK-2118 metabolite measurements.
9.6.2
Blood Collection for Anti-pembrolizumab Antibodies
Sample collection, storage, and shipment instructions for serum samples are provided in the 
procedure manual. Anti-pembrolizumab antibody samples should be drawn according to the 
ADA collection schedule for all participants (Section 2). Simultaneous PK sampling is 
required for interpretation of ADA analysis. Time points may be changed or eliminated based 
on emerging ADA data.
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9.6.3
Urine Collection for Urinary MK-2118
Urine samples for the evaluation of MK-2118 metabolites will be collected at the time points 
identified in Section 2 SoA. Sample collection, storage and shipment instructions for urine 
samples are provided in the Procedures Manual. The urine samples may also be used for 
MK-2118 metabolite measurements.
9.7
Pharmacodynamics
9.7.1
Blood for Pharmacodynamic Markers
Blood sample collection, storage, and shipment instructions for pharmacodynamic analysis 
are provided in the Procedures Manual.
The time points for pharmacodynamics sampling are described in Section 2 - SoA.
9.7.2
Tumor Biopsy
All participants in Arms 1, 2 and 3 will be required to provide a sample biopsy of the tumor 
to be injected with MK-2118 and a sample biopsy from a distant, discrete, noninjected site 
(at least 2 biopsies at each site) prior to or after IT administration of MK-2118, unless 
deemed medically unsafe by the investigator. Participants in Arm 4 will be required to 
provide a sample biopsy from a discrete lesion, irrespective of injection site. Tumor samples 
will be collected at the time points described in Section 2
SoA.
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-2118 FIH study 
assured selection of sites that have investigative staff who are highly experienced in tumor 
biopsies. 
For participants with lymphoma in Arms 1 or 2, only those participants that have superficial 
lesions amenable to IT injection will be eligible (cutaneous lesions injected via visual 
inspection, and subcutaneous lymph nodes injected via ultrasound guidance or palpation). No 
participants with lymphoma with exclusively deep lymph nodes will be included in this 
study. Participants with lymphoma 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. In Arm 4, lymphoma patients are eligible regardless of the lesion location.
In Arms 1, 2, and 3, a predose tumor biopsy will be performed at Screening on both the 
tumor lesion which is intended for treatment with IT injection of MK-2118, as well as on the 
distant lesion which is not intended for IT injection of MK-2118. Participants in Arm 1 
(monotherapy) who cross over to Arm 2 (combination therapy) are required to provide a 
fresh tumor biopsy at screening of both injected and noninjected sites, similar to participants 
who are newly enrolled into the study and assigned to Arm 2, unless one of the following 2 
situations occur: 1) The most recent Arm 1 biopsy occurred within 28 days of C1D1 of Arm 
2, OR 2) The investigator deems the biopsy to be medically unsafe. In Arm 4, a predose 
tumor biopsy will be performed at Screening on a single discrete, noninjected lesion.
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For Arm 1 and 2, the tumor lesion intended for treatment with IT injection of MK-2118, the 
sample will be obtained by either punch biopsy for cutaneous lesions, or by ultrasound 
guided biopsy for subcutaneous lesions. For the tumor lesion that is treated with IT injection 
of MK-2118, the postdose tumor biopsy will be collected on the same day as treatment, at 
5 hours (± 2 hours) following IT administration of MK-2118 on C2D8, and optionally on 
C3D8, at 5 hours (± 2 hours) following IT administration of MK-2118. On-treatment biopsy 
site location may vary from baseline biopsy site location based on lesion accessibility and 
participant tolerance. 
For Arm 3, the liver metastasis/lesion intended for treatment with IT injection of MK-2118, 
the biopsy sample will be obtained by either ultrasound guidance or cross-sectional imaging 
guidance (CT/MRI). For the liver lesion that is treated with IT injection of MK-2118, the 
predose tumor biopsy will be collected prior to IT administration of MK-2118 on C2D8, and 
optionally on C3D1. Lesions which undergo biopsy during treatment may vary from lesions 
which undergo biopsy during screening, based on lesion accessibility and participant 
tolerance.
For Arm 1, 2, and 3 distant discrete tumor lesions that are not intended for IT injection with 
MK-2118, the sample biopsy will be obtained by 1 of the following:  punch biopsy for 
cutaneous lesions, ultrasound-guided biopsy for subcutaneous lesions, or image-guided 
biopsy, such as CT-guided biopsy for additional lesions. Method of biopsy will be per 
guidance of the investigator, as well as discussion with the Sponsor. The tumor biopsy of the 
noninjected distant, discrete lesion should, if feasible, be performed on the same day as the 
day of MK-2118 treatment, however may be performed up to 3 days after treatment. 
For Arm 4, biopsies from a single discrete tumor lesion will be required. 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/MRI-guided biopsy, for 
additional lesions. The postdose tumor biopsies will be collected on the same day as 
treatment, at 5 hours (± 2 hours) following SC administration of MK-2118 on C1D8 and 
C3D8. Method of biopsy will be per guidance of the Investigator as well as discussion with 
the Sponsor. 
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. Biopsies obtained during this study will be submitted as 
formalin-fixed, paraffin-embedded samples. 
Leftover main study tissue will be stored for FBR if the participant signs the FBR consent. 
Detailed instructions for tissue collection, processing, and shipment are provided in the 
Procedures Manual.
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9.8
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

DNA for future research

Leftover plasma and serum from biomarker analyses

Leftover RNA

Leftover main trial tumor tissue
9.9
Biomarkers
Collection of samples for other biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants in this 
study as specified in the SoA:

Serum for Cytokine Panel and CRP for MK-2118 Pharmacodynamics Tumor tissue

Blood for Genetic Analysis

Blood for RNA Analysis
9.9.1
Planned Genetic Analysis Sample Collection
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedures Manual. The timing of collection of samples is provided 
in Section 2 SoA.
9.9.2
Blood for Genotyping
Blood sample collection, storage, and shipment instructions for the Screening blood sample 
for genotyping are provided in the Procedures Manual.
9.9.3
Immunogenicity Assessments
Blood sample collection, storage, and shipment instructions for anti-pembrolizumab drug 
antibodies analyses are provided in the Procedures Manual. The timing of collection of 
samples is provided in Section 2 SoA.
9.9.4
Blood for Serum Cytokine Analysis
Sample collection, processing, storage and shipment instructions for biomarker analysis
samples are provided in the Procedures Manual. The timing of collection of samples is 
provided in Section 2 SoA.
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9.9.5
Blood for RNA Analysis
Sample collection, processing, storage and shipment instructions for RNA analysis samples 
are provided in the Procedures Manual. The timing of collection of samples is provided in 
Section 2 SoA.
9.10
Visit Requirements
Visit requirements are outlined in Section 2 Schedule of Activities (SoA).  Specific 
procedure-related details are provided above in Section 9 Study Assessments and 
Procedures.
9.10.1 Screening
Potential participants will be evaluated to determine that they fulfill the entry requirements as 
set forth in Section 6 within 28 days prior to Cycle 1 Day 1. Screening and Cycle 1 Day 1 
cannot be on the same day. 
Perform all screening clinical laboratory tests within 7 days of treatment initiation. Tests 
performed prior to the participant 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. 
Perform pregnancy test for WOCBP within 7 days of treatment initiation. If a urine 
pregnancy test cannot be confirmed as negative, a serum pregnancy test is required.
Genotype testing must be completed prior to Cycle 1 Day 1. Baseline tumor imaging (CT, 
PET/CT, or MRI) and/or medical photography of cutaneous lesions should be performed 
within 28 days of enrollment. For lymphoma participants only, unilateral bone marrow 
biopsy and aspirates will be performed at Screening, if not previously performed within 
8 weeks prior to Screening with negative results.
Participants may be rescreened after consultation with the Sponsor. Rescreening should 
include all screening procedures listed in the protocol SoA, including consent review. Results 
from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criterion is met. A participant who is rescreened will retain their original 
screening number.
9.10.2 Treatment Period
The treatment period in each treatment arm begins with Cycle 1 and may continue for up to 
35 cycles (approximately 2 years) for Arm 1, Arm 2, and Arm 3 and up to 36 cycles for 
Arm 4 (approximately 2 years) from the start of treatment until disease progression, 
unacceptable AE(s), intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the participant, participant withdraws consent, pregnancy 
of the participant, noncompliance with trials treatment or procedure requirements, or 
administrative reasons requiring cessation of treatment. For crossover participants, duration 
of treatment with MK-2118 with pembrolizumab combination therapy is up to 35 cycles in 
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Arm 2, regardless of the duration of treatment he/she received in Arm 1 (MK-2118
monotherapy). Each cycle includes study drug administration and all associated assessments 
as outlined in the SoA (see Section 2). 
Specific procedure-related details are provided throughout Section 9.
9.10.2.1 Treatment Period beyond Disease Progression
See Section 9.2.2.1.
9.10.3 Post-treatment Follow-up
Discontinuation of treatment does not represent withdrawal from the trial. As certain data on 
clinical events beyond treatment discontinuation may be important to the trial, they must be 
collected through the participant’s last scheduled follow-up, even if the participant has 
discontinued treatment.
9.10.3.1 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 anticancer 
treatment, whichever comes first. All AEs that occur prior to the 30-day Safety Follow-up 
Visit should be recorded. Participants with an AE of Grade >1 will be followed up until 
resolution of the AE to Grade 0-1 or until the beginning of a new antineoplastic therapy, 
whichever occurs first. 
After the EOT, each participant will be followed up for at least 30 days for AE monitoring
and 120 days for SAEs, ECIs, and spontaneously reported pregnancy. SAEs, ECI, and
spontaneously reported pregnancy will be reported for 30 days after the EOT if the 
participant initiates new anticancer therapy. Progression of the cancer under study is not 
considered an AE.
Participants who are eligible for crossover to combination therapy with IT MK-2118 and
pembrolizumab may have up to 2 safety follow-up visits, 1 after monotherapy (Arm 1) and 
1 after combination therapy (Arm 2).
9.10.3.2 Survival Follow-up
All participants, with the exception of those who withdraw consent or are lost to follow-up, 
will be followed up for survival and will be contacted every 12 weeks (±14 days) to monitor 
survival status. Participants who experience confirmed disease progression or start a new 
anticancer therapy, will move into the Survival Follow-Up Phase and should be contacted 
approximately 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 
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example, updated survival status may be requested prior to, but not limited to, an eDMC 
safety review, interim and/or final analysis. Upon Sponsor notification, all participants who 
do not/will not have a scheduled study visit or study contact during the Sponsor-defined time 
period will be contacted for their survival status (excluding participants that 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.
10
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 nonconfirmatory analyses will be 
outlined in a separate supplemental Statistical Analysis Plan (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 nonconfirmatory 
analyses made after the protocol has been finalized, but prior to the conduct of any analyses, 
will be documented in the sSAP as needed and referenced in the CSR for the study. Post hoc 
exploratory analyses will be clearly identified in the CSR.
10.1
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, Section 10.6 through Section 10.9.
Study Design Overview
Phase 1 trial in participants with advanced/metastatic solid 
tumors or lymphomas of IT MK-2118 monotherapy (Arm 1),
IT MK-2118 in combination with pembrolizumab (Arm 2), IT 
MK-2118 in combination with pembrolizumab for liver 
metastasis/lesions (Arm 3), and SC administration of MK-2118
in combination with pembrolizumab (Arm 4). For Arm 1, Arm 
2, and Arm 3, the study applies an ATD, followed by mTPI 
design to identify an MTD/MAD and a preliminary RP2D in 
each treatment arm. Arm 4 utilizes the mTPI design to identify 
an MTD/MAD and a preliminary RP2D. 
Analysis Populations
Safety (Primary): All-Participants-as-Treated (APaT) and 
DLTe
PK (Secondary): PP
Efficacy (Exploratory): FAS 
Primary Endpoint(s)

DLT

AE

Discontinuing study treatment due to an AE
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Key Secondary 
Endpoints
PK exposure of MK-2118 monotherapy and MK-2118 in 
combination with pembrolizumab; PK exposure of 
pembrolizumab in combination with MK-2118
Statistical Methods for 
Exploratory Efficacy/ 
Pharmacokinetic 
Analyses
Efficacy analyses are documented in the sSAP. 
Concentrations of MK-2118 will be summarized by planned 
visit and time for each dose separately.
Treatment Assignment
Participants will be allocated to receive single agent MK-2118
via IT injection (Arm 1), MK-2118 via IT injection co-
administered with pembrolizumab (Arm 2), MK-2118 via 
visceral IT injection co-administered with pembrolizumab 
(Arm 3), or SC administration of MK-2118 in combination 
with pembrolizumab (Arm 4) centrally through an IWRS. 
Participants 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. 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 [Ji, Y., et al 
2007] will be used to estimate the DLT rates across doses. The 
estimates of the DLT rates among participants treated at MTD 
(or MAD) of MK-2118 and the 80% Bayesian credible 
intervals for the estimates will be provided.
Interim Analyses
An interim 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-finding decisions.
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-2118 monotherapy (Arm 1) and MK-2118
in combination with pembrolizumab (Arms 2, 3, 4). A target 
sample size of approximately 160 participants will be used for 
study planning purposes. 
Abbreviations: AE = adverse event; APaT = all participants as treated; DLTe = dose-limiting toxicity 
evaluable; FAS = full analysis set; IT = intratumoral; MAD = maximum administered dose; MTD = maximum 
tolerated dose; PP = per protocol; RP2D = recommended Phase 2 dose; SC = subcutaneous
10.2
Responsibility for Analyses/In-House Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
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The trial is open-label, ie, participants, investigators, and Sponsor personnel will be aware of 
participant treatment assignment after each participant is enrolled and treatment is assigned. 
Allocation to treatment will not be randomized.
10.3
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 4.0.
10.4
Analysis Endpoints
Efficacy and safety endpoints are listed below, followed by descriptions of selected 
endpoints. 
10.4.1 Efficacy/Pharmacokinetic Endpoints
Efficacy endpoints are exploratory endpoints in this study. Details of the statistical analysis 
plan will be documented in the sSAP. A description of efficacy measures is provided in 
Section 9.2.
Objective response rate is defined as the proportion of participants 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. Overall survival is defined as the time from the first dose of study 
treatment to death due to any cause. Participants who do not die will be censored on the date 
of the last study assessment or contact. Objective response rate 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.
Pharmacokinetic endpoints include PK exposure of MK-2118 and pembrolizumab.
The exploratory evaluation of biomarkers to be measured in this trial is described in Section 
9.9.
10.4.2 Safety Endpoints
The primary safety endpoint is the number/proportion of participants with DLT(s), AE(s), 
and who discontinue study treatment due to AE(s). A description of safety measures is 
provided in Section 9.3 - Adverse Events, Serious Adverse Events and Other Reportable 
Safety Events, and 9.5 - Safety.
10.5
Analysis Populations
10.5.1 Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT
population consists of all participants who received at least 1 dose of study treatment. In case 
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of treatment administration errors, participants will be analyzed according to the treatment 
they actually received. The DLT-evaluable (DLTe) population for Arms 1, 2, and 3 includes
APaT participants who 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 will 
be used. For Arm 4, the DLTe population includes APaT participants who were observed for 
safety for 35 days after the first dose of treatment or experienced a DLT prior to 35 days after 
the first dose of treatment. The replacement participants will also be considered evaluable if 
the above specified criteria are met. Of note, both crossover participants and MK-2118-naïve 
participants enrolled in Arm 2 will be included for DLT evaluation of Arm 2. Safety data 
from crossover participants will also be presented separately.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
10.5.2 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 participants 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 participants 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 participants who were 
compliant with the study procedures and have available data from at least 1 treatment 
potentially will be included in the PP analysis dataset.
10.5.3 Efficacy Analysis Populations
The FAS population will be used for analysis of exploratory efficacy data in this study. It 
consists of all participants with a baseline scan that demonstrated measurable disease by 
investigator assessment, and who were administered a dose of study medicine. Efficacy data 
from crossover participants will be presented separately.
10.6
Statistical Methods
10.6.1 Statistical Methods for Efficacy Analyses
The statistical methods for efficacy analyses will be documented in the sSAP.
10.6.2 Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including
AEs, SAEs, laboratory tests, VS, ECG measurements, and physical examinations.
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AEs will be summarized by counts and frequencies for each dose level and treatment arm. 
Laboratory tests, VS, and other safety endpoints will be summarized as appropriate.
DLTs will be listed, and further summarized by dose level and treatment arm. The pool
adjacent-violators-algorithm [Ji, Y., et al 2007], which forces the DLT rate estimates to be 
nondecreasing with dose levels and pool 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 participants 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.
10.6.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses
10.6.3.1 Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
10.6.3.2 Pharmacokinetics and Pharmacodynamics Modeling Analysis
Concentrations of study medicines will be summarized by planned visit and time for each 
dose separately.
10.7
Interim Analyses
An interim 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-finding
decisions.
10.8
Multiplicity
There will be no multiplicity control in this study.
10.9
Sample Size and Power Calculations
The overall sample size for this Phase 1 trial is expected to be up to approximately 
160 participants (approximately 35 participants in each Arm 1, Arm 2, and Arm 3; 55 in 
Arm 4). The actual total will depend on the tolerability of the treatment and occurrence of 
DLTs.
Part A, Part C, and Part E (ATD phase) will be followed by Part B, Part D, and Part F (mTPI 
phase) of Arm 1, Arm 2, and Arm 3. The starting dose for Arm 4 will be up to, but not 
exceeding,
Arm 4 will be based on the mTPI design. The ATD phase will have 
single-participant cohorts, but may allow up to 3 participants per cohort in the event of
simultaneous enrollment. The mTPI phase will have up to 3 to 6 participants per cohort, 
however based on the occurrence of DLTs, up to 14 participants may enroll per dose level. 
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11
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Ji Y, Li Y, Bekele BN. Dose-finding in phase l 
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Nishino M, Giobbie-Hurder A, Gargano M, Suda 
M, Ramaiya NH, Hodi FS. Developing a 
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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 
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the United States Cutaneous Lymphoma 
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R, Kim Y, Knobler R, et al. Revisions to the 
staging and classification of mycosis fungoides 
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Schroeder GK, Cumming JN, et al. An orally 
available non-nucleotide STING agonist with 
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12
APPENDICES
12.1
Appendix 1: Abbreviations and Trademarks
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
Antidrug antibody
ADME
Absorption, Distribution, Metabolism, and Excretion
AE
Adverse event
ALT
Alanine aminotransferase
AMP
Adenosine monophosphate
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
APaT
All-Participants-as-Treated
ART
Antiretroviral therapy
AST
Aspartate aminotransferase
ATD
Accelerated titration design
AUC
Area under the time-concentration curve
AUC0 24hr
Area under the time-concentration curve from 0 to 24 hours
β-hCG
Beta-human chorionic gonadotropin
C1D1
Cycle 1 Day 1
CBC
Complete blood count
CBR
Carbonyl reductase
CD
Cluster of differentiation (eg, CD8, CD28)
CDN
Cyclic dinucleotide
cGAMP
Cyclic-dinucleotide 2’-3’ cyclic GMP-AMP
cGAS
Cyclic (guanosine monophosphate-adenosine monophosphate) synthase
CI
Confidence interval
Cmax
Maximum plasma concentration
Cmin
Minimum plasma concentration
CONSORT
Consolidated Standards of Reporting Trials
CR
Complete response
CrCl
Creatinine clearance
CRF/eCRF
Case report form/electronic case report form
CRS
Cytokine release syndrome
CT
Computed tomography
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Abbreviation
Definition
CTCL
Cutaneous T-cell lymphoma
CTCAE
Common Terminology Criteria for Adverse Events
CXCL11
C-X-C motif chemokine 11  
DILI
Drug-induced liver injury
DLT
Dose-limiting toxicity
DNA
Deoxynucleic acid
E/CIA
Enzyme or chemiluminescence immunoassay
ECI
Event of clinical interest
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
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
U.S. Food and Drug Administration
FDAA
Food and Drug Administration Amendments Act
FDG
Fluorodeoxyglucose
FIH
First in human
GCP
Good clinical practice
GGT
Gamma glutamyl transferase 
GI
Gastrointestinal
GLP
Good Laboratory Practice
GMP
Guanosine monophosphate 
GRI
Growth rate inhibition
GVHD
Graft-versus-host disease
HBsAg/HBV
Hepatitis B surface antigen/Hepatitis B virus
HBV
Hepatitis B virus
HCV
Hepatitis C virus
Hep C Ab
Hepatitis C antibody
HIV
Human immunodeficiency virus
HNSCC
Head and neck squamous cell carcinoma
IB
Investigator’s Brochure
ICF
Informed consent form
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Abbreviation
Definition
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IFN
Interferon
IFNα
Interferon alpha
IHC
Immunohistochemistry
IL-6
Interleukin-6
INR
International normalized ratio
IP-10
Interferon gamma-induced protein 10 
irAE
Immune-related adverse event
IRB/IEC
Institutional Review Board/Institutional Ethics Committee
IRF3
Interferon regulatory transcription factor-3
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
IV
Intravenous
IVD
In vitro diagnostic
IVRS/IWRS
Integrated web response system
IWG
International Working Group
LDH
Lactate dehydrogenase
LLOQ
Less than the limit of detection
MAD
Maximum administered dose
MCP-2
Monocyte chemoattractant protein-2
MIP-1α
Macrophage inflammatory protein-1 alpha
MOA
Mechanism of action
mRNA
Messenger ribonucleic acid
MRI
Magnetic resonance imaging
MSI
Microsatellite instability
mSWAT
modified Severity Weighted Assessment Tool
MTD
Maximum tolerated dose
mTPI
Modified toxicity probability interval
N/A
Not applicable
NCI
National Cancer Institute 
NF-κB
Nuclear factor-κB
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Abbreviation
Definition
NOAEL
No observed adverse effect level
NSAIDS
Nonsteroidal anti-inflammatory drugs
NSCLC
Non small cell lung cancer
NT-I
Nontarget injected
NT-NI
Nontarget noninjected
O2
Oxygen
ORR
Objective response rate
OS
Overall survival
OTC
Over-the-counter
PD
Progressive disease
PD-1
Programmed cell death-1
PD-L1
Programmed cell death-1 ligand 1
PD-L2
Programmed cell death-1 ligand 2
PET
Positron emission tomography
PFS
Progression-free survival
PK
Pharmacokinetic
PO
Per os (by mouth)
PP
Per Protocol
PR
Partial response
PT
Prothrombin time
Q1W
Once a week
Q3W
Every three weeks 
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 Dose
SAE
Serious adverse events
SC
Subcutaneous
SNP
Single nucleotide polymorphism
SoA
Schedule of Activities
SOD
Sum of diameters
SPD
Sum of the products of the greatest diameters
sSAP
Supplemental Statistical Analysis Plan
STING
Stimulator of Interferon Genes
SUSAR
Suspected unexpected serious adverse reactions
T1DM
Type 1 diabetes mellitus
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Abbreviation
Definition
TBK1
Tumor necrosis factor receptor-associated factors (TRAF)-associated 
nuclear factor (NF)-κB activator
TNF-α
Tumor necrosis factor-alpha
T-I
Target injected
T-NI
Target noninjected
TS-1
tegafur/gimeracil/oteracil
TSH
Thyroid stimulating hormone
UFT
Ftorafur or tegafur/uracil
ULN
Upper limit of normal
VS
Vital signs
WOCBP
Women of childbearing potential
WT
Wild-type
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12.2
Appendix 2: Clinical Laboratory Tests

The tests detailed in Table 23 will be performed by the local laboratory. Laboratory 
samples, which cannot be processed locally, may be sent to the central laboratory.

Laboratory safety tests for screening should be performed within 7 days prior to first 
dose of study medication. Starting with Cycle 1 Day 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.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 6 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
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Table 23
Protocol-required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Follicle-stimulating 
hormone (FSH)a
Hemoglobin
Alkaline phosphatase
Glucose
Serum β-human chorionic 
gonadotropin (β-hCG)b
Platelet count
Alanine aminotransferase (ALT)
Protein
Hepatitis
WBC (total and 
differential)c
Aspartate aminotransferase 
(AST)
Specific gravity 
Total triiodothyronine (T3) 
or Free T3 (FT3)
RBC
Carbon Dioxide or Bicarbonate
Microscopic 
examination, if abnormal 
results are noted
Total thyroxine (T4) or 
Free T4 (FT4)
PT or INR
Calcium
Urine pregnancy testb
Thyroid Stimulating 
Hormone (TSH)
aPTT or PTT
Chloride
Creatinined
Gamma glutamyl transpeptidase 
(GGT)
Glucose
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood Urea Nitrogene
Lactic dehydrogenase
Uric acid
Lipase
Amylase
a high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal 
state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with two FSH measurements in the postmenopausal range is required.
b Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.
c Absolute or % acceptable per institutional standard  
d For participants with a baseline calculated creatinine clearance that is below the normal institutional laboratory range, a 
baseline measured creatinine clearance should be performed.
e Blood Urea Nitrogen is preferred; if not available urea may be tested
Investigators must document their review of each laboratory safety report.
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12.3
Appendix 3: Study Governance Considerations
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
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clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
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C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time and labor intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request. 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
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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.
Data Protection
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
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/IEC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees. Data generated by this 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.
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data. By signing the consent form, the participant 
agrees to this process. If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the participant will be identified by unique code 
only; full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this trial in accordance with all applicable privacy laws, rules 
and regulations.
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 
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and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Publication Policy
The results of this study may be published or presented at scientific meetings. The sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the sponsor before submission. This allows the sponsor to protect 
proprietary information and to provide comments. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
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. MSD, as Sponsor of this trial, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate 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.
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 (eg, International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 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.
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The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the trial 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
The Investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical 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.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator or 
qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
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 or regulatory authority as a result of an audit or inspection to cure 
deficiencies in the trial documentation and worksheets/case report forms.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
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Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the sponsor. No records may be 
transferred to another location or party without written notification to the sponsor. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
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●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
trial?
●
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 ADVERSE EVENT WHICH 
WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S 
PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES 
ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE PARTICIPANT THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE 
PROTOCOL, AND IF REQUIRED, THE INSTITUTIONAL REVIEW 
BOARD/INDEPENDENT ETHICS COMMITTEE.
●
Consistency with Study 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.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product.  The temporal sequence of 
the AE onset relative to the administration of the Sponsor's product is reasonable.  
The AE is more likely explained by the Sponsor's product than by another cause. 
●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product.  (Also 
entered for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
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12.5
Appendix 5: Contraceptive Guidance and Pregnancy Testing
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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Contraception Requirements
Male Participants:
Male participants are eligible to participate if they agree to the following during the 
intervention period with MK-2118 and for at least 120 days after the last dose of MK-2118:

Refrain from donating sperm
PLUS either:

Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent

Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.

Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Female Participants:
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 24
during the protocol-defined time frame in Section 6.1. 
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Table 24
Highly Effective Contraception Methods
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.

Progestogen-only subdermal contraceptive implantb,c

IUSc,d

Non-hormonal IUD

Bilateral tubal occlusion

Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used. A spermatogenesis cycle is 
approximately 90 days.
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study 
and the preferred and usual lifestyle of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the 
use of contraceptive methods for participants of clinical studies.
b
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are 
limited to those which inhibit ovulation.
c
Male condoms must be used in addition to hormonal contraception.
d
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal 
(coitus interruptus), spermicides only, and LAM.
-
Male condom with cap, diaphragm, or sponge with spermicide.
-
Male and female condom should not be used together (due to risk of failure with friction).
Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test and in accordance with local requirements. When applicable, this test should be repeated 
within 24 hours before the first dose. 
Following initiation of treatment additional pregnancy testing will be performed per the SoA 
during the treatment period, at 30 days after the last dose of study treatment, and/or as 
required locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
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12.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this trial as outlined in Section 9.8 Future 
Biomedical Research Sample Collection9.8 Future Biomedical Research Sample 
Collection 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.
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3. Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants 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 participants 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 participants on the visit designated in 
the trial flow chart.  If delayed, present consent at next possible Participant Visit.  
Consent forms signed by the participant will be kept at the clinical trial site under 
secure storage for regulatory reasons.  
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 participant consent for Future Biomedical Research will be 
captured in the eCRFs. Any specimens for which such an informed consent cannot be 
verified will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the 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 participant is having blood drawn for other trial purposes.
4. Confidential Participant Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing participant 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
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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 participant 
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 (eg, a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third-party analyses 
will conform to the specific scope of analysis outlined. Future Biomedical Research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Participants may withdraw their consent for Future Biomedical Research and ask that 
their biospecimens not be used for Future Biomedical Research.  Participants may 
withdraw consent at any time by contacting the 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@MSD.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for Future Biomedical Research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable.  
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research 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 (eg, 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 participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
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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 Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants.  Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the participant have been minimized.
The Sponsor has developed strict security, policies and procedures to address participant 
data privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
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12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt biomarker
2. International Conference on Harmonisation: 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/
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12.7
Appendix 7: Prioritization of IT Lesion Injection
The selection and prioritization of lesions for IT 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 IT 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 (e.g. 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 IT 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.
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 IT
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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 IT immunotherapeutic, and a subsequent improved systemic antitumor response. New 
lesions may contain novel tumor antigens compared to previously injected lesions.
Source: [Goldmacher, G. V., et al 2020]
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12.8
Appendix 8: itRECIST Supplementary Figures
Figure 3
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 five lesions should be classified as 
target injected, and between one and five 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).
Source: [Goldmacher, G. V., et al 2020]
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Figure 4
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. 
Source: [Goldmacher, G. V., et al 2020]
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Figure 5
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 sum of diameters (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, sum of diameters.
Source: [Goldmacher, G. V., et al 2020]
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Figure 6
Example of Iterative Assessment of Injected Lesion Response During Treatment
Abbreviations: iPR = immunotherapeutic partial response; NE = not evaluable; NT-I = nontarget injected; NT-
NI = nontarget noninjected; PD = progressive disease; PR = partial response; iRECIST 1.1 =  
immunotherapeutic Response Evaluation Criteria in Solid Tumors; SD =  stable disease; SOD = sum of 
diameters (longest diameters for extranodal lesions, short axis for lymph nodes); T-I = target injected; T-NI = 
target noninjected.
This is an illustration of overall, injected, and noninjected response assessment, with a 
particular focus on the iterative assessment of injected lesions. All lesions from a single 
patient are displayed in simple schematic form and are not meant to be anatomically 
adjacent. For purposes of this illustration, the yellow and green lesions were selected at 
baseline as target injected, and the purple and blue lesions were selected as target 
noninjected; there are no nontarget lesions. In this simplified example, a full imaging 
assessment is performed at each treatment visit just before the decision about which lesions 
to inject at that visit. The overall response at each visit was based on the change in SODs for 
all the target lesions together (because there are no nontarget lesions in this example). Once 
progressive disease is observed (in this case, because of a new lesion), the overall response 
assessment thereafter is similar to that of iRECIST. The injected response is based on the 
change in SOD of the injected lesions from the assessment immediately before this one. The 
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noninjected response is based on the changes in SOD from baseline and nadir and is 
considered nonevaluable once any lesion that was initially selected as T-NI is subsequently 
injected, as happens in this case with the blue lesion. If this lesion were to grow later, it could 
contribute to an overall response of PD.
Source: [Goldmacher, G. V., et al 2020]
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