Phase 1 Trial of Single Agent MK-4166 and MK-4166 in Combination With Pembrolizumab in Subjects With Advanced Malignancies
Phase: PHASE1
Conditions: Solid Tumor
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02132754
21-May-2019
Document Date: 
Phase 1 Trial of Single Agent MK-4166 and MK-4166 in 
Combination with Pembrolizumab in Subjects with Advanced 
Malignancies

Product:  MK-4166 
1
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
Phase 1 Trial of Single Agent MK-4166 and MK-4166 in Combination with Pembrolizumab 
in Subjects with Advanced Malignancies
IND NUMBER:  120143
EudraCT NUMBER:  [Not Applicable]
 
 
057N3N

Product:  MK-4166 
2
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 13
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 15
Trial Design ........................................................................................................... 15
Trial Diagram........................................................................................................ 16
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 18
Primary Objective(s) & Hypothesis(es).............................................................. 18
Secondary Objective(s) & Hypothesis(es)........................................................... 18
Exploratory Objectives......................................................................................... 18
4.0
BACKGROUND & RATIONALE.......................................................................... 19
Background ........................................................................................................... 19
Pharmaceutical and Therapeutic Background .................................................... 19
4.1.1.1
MK-4166 Background ................................................................................. 19
4.1.1.2
Pembrolizumab (MK-3475) Background .................................................... 21
Pre-clinical and Clinical Trials ........................................................................... 22
4.1.2.1
MK-4166 Preclinical and Clinical Trials..................................................... 22
4.1.2.2
Pembrolizumab Preclinical and Clinical Trials ........................................... 23
4.1.2.3
MK-4166 with Pembrolizumab Combination Preclinical Trials................. 24
Ongoing Clinical Trials....................................................................................... 26
4.1.3.1
Ongoing Clinical Trials with MK-4166....................................................... 26
4.1.3.2
Ongoing Pembrolizumab Clinical Trials ..................................................... 26
Information on Other Trial-Related Therapy...................................................... 26
Rationale................................................................................................................ 26
Rationale for the Trial and Selected Subject Population .................................... 26
Rationale for Dose Selection/Regimen............................................................... 27
4.2.2.1
Starting Dose for This Trial......................................................................... 27
4.2.2.2
Rationale for Pembrolizumab dose.............................................................. 28
4.2.2.3
Maximum Dose/Exposure for This Trial..................................................... 29
4.2.2.4
Rationale for Dose Interval and Trial Design.............................................. 30
 
 
057N3N

Product:  MK-4166 
3
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
4.2.2.4.1
MK-4166 Monotherapy ........................................................................ 30
4.2.2.4.2
MK-4166 in Combination with Pembrolizumab .................................. 30
Rationale for Endpoints ...................................................................................... 30
4.2.3.1
Safety Endpoints.......................................................................................... 30
4.2.3.2
Efficacy Endpoints....................................................................................... 31
4.2.3.3
Pharmacodynamic Endpoints....................................................................... 31
4.2.3.3.1
Target Engagement: Receptor Availability on Peripheral Blood 
Lymphocytes......................................................................................... 31
4.2.3.3.2
Anti-Drug Antibody (ADA) Assay....................................................... 31
4.2.3.3.3
Serum Cytokines of Systemic Immune Activation............................... 32
4.2.3.4
Planned Exploratory Biomarker Research................................................... 32
4.2.3.5
Future Biomedical Research........................................................................ 32
5.0
METHODOLOGY ................................................................................................... 33
Entry Criteria........................................................................................................ 33
Diagnosis/Condition for Entry into the Trial ...................................................... 33
Subject Inclusion Criteria.................................................................................... 33
Subject Exclusion Criteria .................................................................................. 35
Trial Treatment(s) ................................................................................................ 36
Dose Selection/Modification .............................................................................. 38
5.2.1.1
Dose Selection (Preparation) ....................................................................... 38
5.2.1.2
Dose Escalation............................................................................................ 39
5.2.1.3
Accelerated Dose Escalation (MK-4166 Monotherapy).............................. 39
5.2.1.4
3+3 Dose Escalation .................................................................................... 39
5.2.1.5
Dose Confirmation (Arm 2 only)................................................................. 41
Definition of Dose Limiting Toxicity................................................................. 43
Guidelines for Dose Modification due to Adverse Events ................................. 44
5.2.3.1
Dose Modification and Toxicity Management for Adverse Events 
Associated with MK-4166 and/or Pembrolizumab ..................................... 44
5.2.3.2
Dose Interruption/Discontinuation and Toxicity Management Guidelines 
for Immune-Related Adverse Events Associated with Pembrolizumab...... 46
5.2.3.3
Toxicity Management of Infusion Reactions Related to Pembrolizumab... 50
Replacement of Subjects in DLT Evaluation Period .......................................... 51
Timing of Dose Administration.......................................................................... 52
 
 
057N3N

Product:  MK-4166 
4
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Trial Blinding/Masking....................................................................................... 52
Randomization or Treatment Allocation or Vaccine Allocation...................... 52
Stratification.......................................................................................................... 52
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 52
Acceptable Concomitant Medication.................................................................. 52
Prohibited Concomitant Medications.................................................................. 53
Rescue Medications & Supportive Care............................................................. 53
Diet/Activity/Other Considerations..................................................................... 54
Diet...................................................................................................................... 54
Contraception...................................................................................................... 54
Use in Pregnancy ................................................................................................ 54
Use in Nursing Women....................................................................................... 55
Subject Withdrawal/Discontinuation Criteria................................................... 55
Subject Replacement Strategy............................................................................. 56
Beginning and End of the Trial ........................................................................... 56
Clinical Criteria for Early Trial Termination ................................................... 56
6.0
TRIAL FLOW CHART ........................................................................................... 57
7.0
TRIAL PROCEDURES ........................................................................................... 63
Trial Procedures ................................................................................................... 63
Administrative Procedures.................................................................................. 63
7.1.1.1
Informed Consent......................................................................................... 63
7.1.1.1.1
General Informed Consent.................................................................... 63
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 64
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 64
7.1.1.3
Subject Identification Card .......................................................................... 64
7.1.1.4
Medical History ........................................................................................... 64
7.1.1.5
Prior and Concomitant Medications Review............................................... 64
7.1.1.5.1
Prior Medications.................................................................................. 64
7.1.1.5.2
Concomitant Medications..................................................................... 64
7.1.1.6
Disease Details and Treatments................................................................... 65
7.1.1.6.1
Disease Details...................................................................................... 65
 
 
057N3N

Product:  MK-4166 
5
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
7.1.1.6.2
Prior Oncology Treatment History ....................................................... 65
7.1.1.7
Assignment of Screening Number............................................................... 65
7.1.1.8
Assignment of Randomization Number....................................................... 65
7.1.1.9
Trial Compliance (Study Drug Administration).......................................... 65
Clinical Procedures/Assessments........................................................................ 66
7.1.2.1
Adverse Event (AE) Monitoring.................................................................. 66
7.1.2.2
Full Physical Examination........................................................................... 66
7.1.2.3
Vital Signs and Weight ................................................................................ 67
7.1.2.4
Electrocardiogram (ECG)............................................................................ 67
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 67
7.1.2.6
Tumor Imaging ............................................................................................ 67
7.1.2.7
Response Assessment .................................................................................. 67
7.1.2.7.1
Immune-related RECIST (irRECIST) .................................................. 67
7.1.2.8
Tumor Tissue Collection and Correlative Studies Blood Sampling............ 69
Laboratory Procedures/Assessments .................................................................. 70
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) .. 70
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 71
7.1.3.2.1
Blood Collection for Serum MK-4166 and Pembrolizumab................ 71
7.1.3.2.2
Blood Collection for Anti-MK-4166 Antibodies and Anti-
Pembrolizumab Antibodies................................................................... 72
7.1.3.2.3
Blood for Receptor Availability Assay................................................. 72
7.1.3.3
Future Biomedical Research........................................................................ 72
Other Procedures................................................................................................. 72
7.1.4.1
Withdrawal/Discontinuation........................................................................ 72
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 72
7.1.4.2
Blinding/Unblinding .................................................................................... 73
7.1.4.3
Calibration of Critical Equipment................................................................ 73
Visit Requirements.............................................................................................. 73
7.1.5.1
Screening...................................................................................................... 74
7.1.5.2
Treatment Period.......................................................................................... 74
7.1.5.3
Post-Treatment Visits................................................................................... 74
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 74
 
 
057N3N

Product:  MK-4166 
6
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
7.1.5.3.2
Follow-up Visits ................................................................................... 75
7.1.5.4
Survival Status ............................................................................................. 75
Assessing and Recording Adverse Events .......................................................... 75
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor ............................................................................................................... 76
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 77
Immediate Reporting of Adverse Events to the Sponsor.................................... 77
7.2.3.1
Serious Adverse Events ............................................................................... 77
7.2.3.2
Events of Clinical Interest............................................................................ 78
Evaluating Adverse Events................................................................................. 79
Sponsor Responsibility for Reporting Adverse Events ...................................... 82
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 82
Statistical Analysis Plan Summary ..................................................................... 82
Responsibility for Analyses/In-House Blinding ................................................. 82
Hypotheses/Estimation ......................................................................................... 83
Analysis Endpoints ............................................................................................... 83
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..................................... 83
Safety Endpoints ................................................................................................. 83
Derivations of Efficacy/Immunogenicity/Pharmacokinetics Endpoints............. 83
Derivations of Safety Endpoints ......................................................................... 84
Analysis Populations............................................................................................. 84
Safety Analysis Populations ............................................................................... 84
Efficacy Analysis Populations ............................................................................ 85
Statistical Methods................................................................................................ 85
Statistical Methods for Efficacy Analyses .......................................................... 85
Statistical Methods for Safety Analyses ............................................................. 85
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 86
8.6.3.1
Demographic and Baseline Characteristics ................................................. 86
8.6.3.2
Population PK Analyses .............................................................................. 86
Interim Analyses ................................................................................................... 86
Multiplicity ............................................................................................................ 86
Sample Size and Power Calculations .................................................................. 86
 
 
057N3N

Product:  MK-4166 
7
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Dose Escalation and Dose Confirmation ............................................................ 86
Subgroup Analyses and Effect of Baseline Factors ........................................... 88
Compliance (Medication Adherence).................................................................. 88
Extent of Exposure................................................................................................ 88
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 88
Investigational Product ........................................................................................ 88
Packaging and Labeling Information ................................................................. 89
Clinical Supplies Disclosure................................................................................. 89
Storage and Handling Requirements.................................................................. 89
Returns and Reconciliation.................................................................................. 90
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 90
Confidentiality....................................................................................................... 90
Confidentiality of Data ....................................................................................... 90
Confidentiality of Subject Records..................................................................... 90
Confidentiality of Investigator Information........................................................ 90
Confidentiality of IRB/IEC Information............................................................. 91
Compliance with Financial Disclosure Requirements....................................... 91
Compliance with Law, Audit and Debarment ................................................... 92
Compliance with Trial Registration and Results Posting Requirements ........ 93
Quality Management System............................................................................... 94
Data Management................................................................................................. 94
Publications ........................................................................................................... 94
11.0
LIST OF REFERENCES......................................................................................... 96
12.0
APPENDICES......................................................................................................... 101
Merck Code of Conduct for Clinical Trials...................................................... 101
Collection and Management of Specimens for Future Biomedical Research
.............................................................................................................................. 103
Understanding the Intent, Scope and Public Health Benefits of Exploratory 
Biomarker Research: A Guide for IRBs/IECs and Investigational Site Staff
.............................................................................................................................. 109
ECOG Performance Status................................................................................ 120
Common Terminology Criteria for Adverse Events V4.0 .............................. 121
 
 
057N3N

Product:  MK-4166 
8
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Criteria for Evaluating Response in Solid Tumors in Solid Tumors, 
RECIST 1.1.......................................................................................................... 122
13.0
SIGNATURES......................................................................................................... 123
Sponsor's Representative ................................................................................... 123
Investigator.......................................................................................................... 123
 
 
057N3N

Product:  MK-4166 
9
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values........................................................ 34
Table 2
Trial Treatment for MK-4166 Monotherapy (Arm 1) ............................................ 37
Table 3
Trial Treatment for MK-4166 with Pembrolizumab Combination (Arm 2) .......... 38
Table 4
Dose Confirmation Rules........................................................................................ 42
Table 5
MK-4166 Dose Modification and Treatment Discontinuation Guidelines for 
Drug-Related Adverse Events................................................................................ 45
Table 6
Pembrolizumab Dose Interruption/Treatment Discontinuation and Toxicity 
Management Guidelines for Immune-Related Adverse Events............................. 47
Table 7
Pembrolizumab Infusion Reaction Treatment Guidelines...................................... 50
Table 8
Laboratory Tests ..................................................................................................... 71
Table 9
Evaluating Adverse Events..................................................................................... 80
Table 10 Product Descriptions .............................................................................................. 89
 
 
057N3N

Product:  MK-4166 
10
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
LIST OF FIGURES
Figure 1
Trial Design .......................................................................................................... 17
Figure 2
Schematic Diagram of Immune Stimulatory Targets ........................................... 20
Figure 3
Efficacy of a Single Dose of mDTA-1 IgG2a in Established Syngeneic Mouse 
Tumor Model ........................................................................................................ 23
Figure 4
Efficacy of Combination Treatment with mDTA-1 IgG2a and xDX400 in 
Established Syngeneic Mouse Tumor Models...................................................... 25
 
 
057N3N

Product:  MK-4166 
11
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
4166-001-08
21-May-2019
Added language to allow ongoing study subjects to discontinue this 
study and transition into an extension study.
4166-001-07
06-Nov-2017
Added guidelines for dose interruption/treatment discontinuation and 
toxicity management in the event of myocarditis and intolerable or 
persistent Grade 2 drug-related toxicities
4166-001-06
02-Mar-2017
Expanded the dose confirmation phase of the study (Part E) to include 
all melanoma patients (treatment-naïve and pre-treated)
4166-001-05
17-Feb-2017
Removed the dose confirmation part (Part C) in the MK-4166 
monotherapy arm; modified study design to increase the number of 
subjects in the dose confirmation part (Part E) in the MK-4166 plus 
pembrolizumab combination therapy arm and to limit enrollment in this 
part to subjects with advanced malignant melanoma
4166-001-04
21-Jul-2016
Exclusion criterion 10 modified to add language excluding subjects with 
a history of pneumonitis; added language to allow subjects with 
confirmed radiologic progression to continue study treatment, after 
consultation with the Sponsor, in circumstances in which the 
investigator believes that the subject is experiencing clinical benefit 
from treatment
4166-001-03
17-Apr-2015
Added combination treatment (MK-4166 + pembrolizumab) arm; 
changed RECIST to iRECIST; added requirement for baseline tumor 
sample beginning in Part B; updated SAP to comply with new template
 
 
057N3N

Product:  MK-4166 
12
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Document
Date of Issue
Overall Rationale
4166-001-02
21-Oct-2014
Accommodation of FDA feedback
4166-001-01
09-Jun-2014
Accommodation of FDA feedback
4166-001-00
02-Apr-2014
First-in-human evaluation of MK-4166
 
 
057N3N

Product:  MK-4166 
13
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0;
2.1;
2.2;
5.8;
5.10;
7.1.5.3.2
Trial Summary;
Trial Design;
Trial Diagram;
Subject 
Withdrawal/
Discontinuation Criteria;
Beginning and End of the Trial;
Follow-up Visits
Language was added to allow 
ongoing 
study 
subjects 
to 
discontinue this study and 
transition into an extension 
study 
to 
continue 
protocol-defined 
assessments 
and treatment.
This change will allow this 
study to be closed.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
 
 
057N3N

Product:  MK-4166 
14
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
1.0 TRIAL SUMMARY
Abbreviated Title
Phase 1 Trial of MK-4166 Monotherapy and MK-4166 in Combination 
with Pembrolizumab in Subjects with Advanced Solid Tumors
Trial Phase
Phase 1
Clinical Indication
The treatment of subjects with advanced solid tumors
Trial Type
Interventional
Type of control
None
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups
Subjects will be allocated by non-random assignment to one of 2 treatment 
arms:
Treatment Arm 1: MK-4166 monotherapy
Treatment Arm 2: MK-4166 in combination with pembrolizumab
Number of trial subjects
Approximately 92 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 4.12 years
(see Section 8.9.1 for assumptions) from the time the first subject signs the 
informed consent until the last subject’s last visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs the 
Informed Consent Form (ICF) through the final contact. After a screening 
phase of up to 28 days, eligible subjects will be allocated by non-random 
assignment to one of 2 treatment arms and receive treatment with MK-
4166 alone or in combination with pembrolizumab. Study treatment in 
both arms will begin on Day 1 of each 21 day cycle. For subjects enrolled 
to Arm 1 and Arm 2, treatment with MK-4166 will end after 4 cycles of 
treatment; treatment with pembrolizumab in Arm 2 will continue for up to 
24 months of treatment. Treatment in both Arms will continue until 
disease progression, unacceptable adverse event(s), intercurrent illness 
that prevents further administration of treatment, Investigator’s decision 
to withdraw the subject, subject withdraws consent, pregnancy of the 
subject, noncompliance with trial treatment or procedure requirements, 
subject receives 4 cycles of treatment in Arm 1 or 24 months of study 
medication in Arm 2, or administrative reasons requiring cessation of 
treatment. After the end of treatment, each subject will be followed for 30 
days for adverse event monitoring (serious adverse events and events of 
clinical interest will be collected for 90 days after the end of treatment or 
30 days after the end of treatment if the subject initiates new anticancer 
therapy, whichever is earlier).
Subjects who discontinue for reasons other than disease progression will 
have post-treatment follow-up for disease status until disease progression, 
initiating a non-study cancer treatment, withdrawing consent, or becoming 
lost to follow-up.
Once subjects have achieved the study objectives or the study has ended, 
they will be discontinued from this study and will be enrolled into an 
extension study to continue protocol-defined assessments and treatment.
 
 
057N3N

Product:  MK-4166 
15
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
2.0 TRIAL DESIGN
Trial Design
This is a non-randomized, multi- site, 2-arm, open-label trial of MK-4166 monotherapy 
(Arm 1) and MK-4166 in combination with pembrolizumab (Arm 2) in subjects with a 
histologically or cytologically confirmed diagnosis of any type of solid tumor who have 
measurable disease.
This trial will use an adaptive design based on the pre-specified criteria of dose limiting toxicity 
(DLT). For Dose Escalation (Parts B and D), a 3+3 dose escalation design will be used (see 
Section 5.2.1.4). For dose confirmation in the combination arm only (Part E), the toxicity
probability interval (TPI) design [1] will be used to refine the estimate of maximum tolerated 
dose ([MTD]; see Section 5.2.1.5). The study will not proceed with dose confirmation in the 
monotherapy arm.
In Arm 1, MK-4166 monotherapy, an accelerated dose escalation in single subject cohorts 
(Part A) will proceed based on safety events to a dose of 10 mg. Starting at a 30 mg dose (or 
earlier as described in Section 5.2.1.3), the study will continue with a 3+3 design to identify a 
preliminary MTD (Part B). During 3+3 dose escalation, an initial cohort of 3 subjects will be 
enrolled to each dose level. If none of the 3 subjects experience a DLT, escalation to the next 
dose will occur. If one of the 3 subjects experiences a DLT, another 3 subjects will be enrolled 
at this dose level. If 1 DLT is observed among the 6 subjects, the dose escalation will continue. 
If >2/3 or >2/6 subjects at a dose level develop DLTs, dose escalation will be terminated. At 
least 2 days of observation will occur between each of the first 3 subjects at each dose level. 
Arm 2, MK-4166 in combination with pembrolizumab, will follow a 3+3 design to identify a 
preliminary MTD (Part D). The starting dose of MK-4166 in Arm 2 will be 1.1 mg and will be 
escalated as shown in Table 3; a fixed dose of 200 mg of pembrolizumab will be 
administered. During 3+3 dose escalation, at least 2 days of observation will occur between 
each of the first 3 subjects at each dose level. There will be a 1-week observation period 
between the first and second subjects treated with the combination in the first cohort of Arm 2. 
Dose confirmation in Part E will refine the estimate of tolerability of the MTD using a TPI
design. Part E will enroll approximately 20 subjects with advanced malignant melanoma only. 
Doses of MK-4166 used in combination will be 1 to 2 dose levels behind the monotherapy 
dose, and would not exceed the MTD for monotherapy. However, once the MTD for the 
monotherapy arm is established, the dose of MK-4166 in combination may continue escalation 
up to that dose.
When both treatment arms are open for enrollment, enrollment to both arms will occur in 
parallel with treatment allocation accomplished by non-random assignment to Arm 1 or Arm 2 
using an interactive voice response system / integrated web response system (IVRS/IWRS). 
Once dose escalation (Parts A and B) is completed in Arm 1, only the combination therapy 
arm (Arm 2) of the study will be open for enrollment.
 
 
057N3N

Product:  MK-4166 
16
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
The final number of subjects enrolled in the dose escalation and confirmation parts of the study 
will depend on the empirical safety (DLT) observations, in particular, at what doses the 3+3 
design is triggered, and what dose is identified as the recommended Phase 2 dose (RP2D). For 
example, for MK-4166 monotherapy, in a scenario where no DLTs are encountered during the 
dose escalation part and Part B continues to the highest dose in Table 2, the sample size across 
Parts A and B would be 36 subjects (9 subjects in Part A plus 27 subjects across 9 doses in 
Part B). For MK-4166 with pembrolizumab, in a scenario where Arm 2 starts at 1.1 mg 
MK-4166 and 200 mg pembrolizumab and no DLTs are encountered during the dose escalation 
and confirmation parts so that Part D continues to the highest dose in Table 3, the sample size 
across Parts D and E would be 56 subjects (36 subjects across 12 doses in Part D plus 20
subjects at the RP2D in Part E). In this scenario, the total sample size would be 92 subjects.
The trial will be conducted in conformance with Good Clinical Practices. 
Adverse events (AEs) will be evaluated according to criteria outlined in the NCI Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Once subjects have achieved the study objectives or the study has ended, they will be 
discontinued from this study and will be enrolled into an extension study to continue 
protocol-defined assessments and treatment.
Trial Diagram
The trial design is depicted in Figure 1.
 
 
057N3N

Product:  MK-4166 
17
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Figure 1
Trial Design
In Arm 1, an accelerated dose escalation in single subject cohorts will proceed based on safety events in Part A 
to a dose of 10 mg. Starting at a 30 mg dose (or earlier as described in Section 5.2.1.4) in Part B, the study will 
continue with a 3+3 design to identify a preliminary maximum tolerated dose (MTD). The study will not proceed 
with dose confirmation in Arm 1.
In Arm 2 Part D, treatment with the combination will begin with 1.1 mg of MK-4166. The dose of pembrolizumab 
in Arm 2 will be 200 mg IV every 3 weeks. Combination dose escalation will follow a 3+3 design to identify a 
preliminary MTD. The MK-4166 dose in the combination arm will not exceed the MTD for monotherapy. Dose 
confirmation in Part E will refine the estimate of tolerability of the MTD using a toxicity probability interval [1].
Part E will enroll approximately 20 subjects with advanced malignant melanoma.
Once subjects have achieved the study objectives or the study has ended, they will be discontinued from this study 
and will be enrolled into an extension study to continue protocol-defined assessments and treatment.
 
 
057N3N

Product:  MK-4166 
18
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
(1) Objective: To determine the safety and tolerability of single agent MK-4166 and to 
establish a maximum tolerated dose (MTD) or maximum administered dose (MAD) in 
subjects with advanced solid tumors. Note: The MTD or MAD established during dose 
escalation will not be confirmed.
(2) Objective: To establish the safety and tolerability of intravenous (IV) MK-4166 and to 
establish a maximum tolerated dose (MTD) or maximum administered dose (MAD) when 
given in combination with pembrolizumab.
Secondary Objective(s) & Hypothesis(es)
(1) Objective: To characterize the PK profile of single agent MK-4166.
(2) Objective: To characterize the PK profile of MK-4166 and pembrolizumab following 
administration of MK-4166 and pembrolizumab in combination.
(3) Objective: To evaluate target engagement as measured by modulation in peripheral blood 
GITR receptor availability.
Exploratory Objectives 
(1) Objective: To evaluate the objective response rate (ORR), disease control rate (DCR), best 
overall response (BOR), best target lesion response, time to confirmed response, duration
of response (DOR), and progression-free survival (PFS) of subjects with advanced solid 
tumors treated with MK-4166 as monotherapy or MK-4166 in combination with 
pembrolizumab, by irRECIST 1.1 as assessed by investigator review.
(2) Objective: To investigate the relationship between candidate efficacy biomarkers and anti-
tumor activity of MK-4166 alone or in combination with pembrolizumab:
a.
To evaluate the relationship between GITR expression levels in tumor samples and 
anti-tumor activity of MK-4166 alone or in combination with pembrolizumab.
b.
To investigate other biomarkers in circulating blood cells or in tumor tissue (e.g. tumor 
infiltrating lymphocytes, GITR expression, FOXP3 expression, PD-L1 expression, T-
cell repertoire, T-cell immunophenotyping, ribonucleic acid [RNA] signature profiles, 
pharmacogenetic variation) that may correlate with tumor responses.
c.
To evaluate differences in tumor tissue characteristics in biopsies taken post treatment 
with MK-4166 alone or in combination with pembrolizumab versus baseline.
 
 
057N3N

Product:  MK-4166 
19
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
(3) Objective: To examine concordance between archival tumor tissues, and newly obtained
tumor tissues obtained during the trial period with respect to candidate efficacy biomarkers.
(4) Objective: To evaluate development of circulating anti-MK-4166 or anti-pembrolizumab 
antibodies.
4.0 BACKGROUND & RATIONALE
Background
Detailed background information on MK-4166 and pembrolizumab is available in the MK-
4166 Investigator’s Brochure (IB) and the Pembrolizumab IB.
Pharmaceutical and Therapeutic Background
4.1.1.1
MK-4166 Background
MK-4166 is a humanized IgG1 agonist monoclonal antibody (mAb) that targets 
Glucocorticoid-Induced Tumor necrosis factor Receptor -related protein (GITR). GITR is 
constitutively expressed at high levels on regulatory T-cells (Tregs) and at low levels on resting 
CD4+ and CD8+ T-cells, as well as NK cells and NK T cells [2]; [3].  Following T-cell 
activation, GITR expression is highly upregulated on CD4+ and CD8+ T-cells and NK cells, 
including tumor infiltrating lymphocytes [4]; [5].  The natural ligand for GITR, GITR ligand 
(GITRL), is expressed at low levels by antigen presenting cells (APCs) such as dendritic cells, 
macrophages and B cells, and is upregulated upon activation with stimuli such as Toll-like 
receptor (TLR) ligands [6].
GITR ligation by GITRL (or anti-GITR agonist antibodies) provides a costimulatory signal 
that enhances both CD4+ and CD8+ T-cell proliferation and effector functions leading to 
enhanced cellular and humoral immunity [2]; [7]; [8]; [9]; [10]. In contrast, blocking GITR-
GITRL signaling with antagonist anti-GITRL antibodies inhibits T lymphocyte activation [11].  
GITR ligation signaling enhances T-cell survival by up-regulating IL-2, IL-2R, IFN-and 
rescue of T-cells from anti-CD3 mediated apoptosis [12]; [3].  In addition, co-stimulation 
through GITR has been shown to render naive or effector T-cells (Teffs) resistant to the 
suppressive effects of Tregs [6]; [7]; [11]; [13].
MK-4166 is a humanized agonistic mAb of the IgG1 isotype that targets human GITR and is 
intended for treatment of multiple human cancers.  MK-4166 binds to a region on human GITR 
that is comparable to the region where a functionally active surrogate monoclonal antibody, 
DTA-1 (DTA-1), binds on mouse GITR.  DTA-1 has been shown to augment anti-tumor T-
cell responses and induce tumor rejection in several syngeneic mouse tumor models (see IB 
for details).
Effective antitumor immunity depends on presentation of a tumor antigen, activation of 
protective T-cell responses, and the ability to overcome tumor-based blockade of anti-tumor 
responses [14]. Approaches to antigen-induced promotion of anti-tumor response were
pharmacologically validated with the approval of PROVENGE™ (sipuleucel-T) in 2010. 
 
 
057N3N

Product:  MK-4166 
20
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Approaches to reversal of tumor-based immunosuppression were pharmacologically validated 
by approval of YERVOY™ (ipilimumab) in 2011, and KEYTRUDA® (pembrolizumab) and 
OPDIVO™ (nivolumab) in 2014. Following these milestones in immunotherapy, agonist 
stimulators of anti-tumor T-cell responses represent a next important frontier for development 
of pharmacologic agents promoting anti-tumor immunity. 
Figure 2
Schematic Diagram of Immune Stimulatory Targets
A broad range of immunostimulatory molecules have been identified and characterized [15]. 
Several antibodies that target these molecules have entered early pharmacologic development 
(Figure 2 – red highlighted molecules) [16]. Initial attempts to manipulate T-cell activation 
focused on CD28 as the prototypic costimulatory molecule; CD28 agonists showed promise in 
preclinical work [17]. Unfortunately, the anti-CD28 agonist TGN1412 demonstrated 
unexpected toxicity when evaluated in first-in-human (FIH) clinical studies [18], which urges 
caution for all ongoing and proposed agonist immunostimulatory antibodies. 
Five agonist immunostimulatory molecules have entered investigational studies in humans. In 
early phase studies, the RP2D for CD40 agonists was established from the MTD where
transaminitis was the main DLT. [19]; [20]. Early results for an anti-CD137 (41BB) presented 
in abstract form (ASCO) documented no MTD for one agonist compound (BMS-663513) [21]; 
these preliminary results further documented that <15% of subjects experienced grade 1-2 
events, and 6% of subjects showed objective responses. Both anti-OX40 and anti-CD27 
(NCT01460134) antibodies are in early phase clinical trials (NCT01644968). TRX-518 
(GITR, Inc.) is the only known anti-GITR mAb to enter clinical trials to date, other than MK-
4166. It is under evaluation in a single dose escalation study in adults with biopsy proven 
unresectable Stage III or Stage IV melanoma and other solid tumor malignancies. The 
completion date for this 40-patient trial was expected in Dec 2014. TRX-518 is an agonist anti-
hGITR mAb that contrasts with MK-4166 in that it contains a mutation in the Fc region of the 
molecule that abrogates binding to Fcγ receptors.
 
 
057N3N

Product:  MK-4166 
21
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
4.1.1.2
Pembrolizumab (MK-3475) Background
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress
immune control. The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune
responses, including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and CTLA-4 which has been shown to negatively
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD L2) [22];
[23]. The structure of murine PD-1 has been resolved [24]. PD-1 and family membersare type 
I transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible 
for ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM). Following T-cell stimulation, PD 1 recruits the tyrosine
phosphatases SHP-1 and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the
dephosphorylation of effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved 
in the CD3 T-cell signaling cascade [22]; [25]; [26]; [27]. The mechanism by which PD-1 
down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both
molecules regulate an overlapping set of signaling proteins [28]; [29]. PD-1 was shown to be
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, 
Tregs and Natural Killer cells [30]; [31]; CD4-CD8- (double negative) T-cells as well as subsets 
of macrophages and dendritic cells [32]. The ligands for PD-1 (PD-L1 and PD-L2) are 
constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors [33]; [34]; [35]; [28]. Both ligands are type 
I transmembrane receptors containing both IgV- and IgC-like domains in the extracellular 
region and contain short cytoplasmic regions with no known signaling motifs. Binding of either 
PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting cells 
found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought to control 
immune T-cell activation in lymphoid organs, whereas PD-L1 serves to dampen unwarranted 
T-cell function in peripheral tissues [28]. Although healthy organs express little (if any) PD-
L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. 
High expression of PD-L1 on tumor cells (and to a lesser extent of PD-L2) has been found to
correlate with poor prognosis and survival in various cancer types, including RCC [36],
pancreatic carcinoma [37], hepatocellular carcinoma [38], and ovarian carcinoma [39].  
Furthermore, PD-1 has been suggested to regulate tumor-specific T-cell expansion in subjects 
with melanoma (MEL) [40]. This suggests that the PD-1/PD-L1 pathway plays a critical role 
in tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention.
 
 
057N3N

Product:  MK-4166 
22
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Pre-clinical and Clinical Trials
4.1.2.1
MK-4166 Preclinical and Clinical Trials
Published and internal Merck preclinical observations showing that GITR ligation has potent 
immunostimulatory effects prompted evaluation of GITR modulation as an approach to 
enhancement of antitumor immunity.  Most of these studies used the rat anti-mouse agonist 
GITR mAb DTA-1 [41]; [42]; [43]; [44]. These studies have demonstrated that DTA-1 
treatment can augment anti-tumor T-cell responses and can induce tumor rejection in several 
murine tumor models.  In these studies, DTA-1 administration leads to an increased ratio of 
effector T cells (Teff) to regulatory T cells (Treg) (Teff:Treg ratio) and enhanced intra-tumor 
Teff activation and function.  Data from some models suggest that this shift in Teff:Treg ratio is 
dependent on direct DTA-1 interaction with both tumor-specific Teffs and Tregs. Recent studies 
demonstrated that the reduction in number of Tregs within the tumor after DTA-1 treatment 
was associated with decreased Treg migration to the tumor as well as loss of Foxp3 expression 
in Tregs within the tumor [44]. These effects of GITR ligation on Tregs were not observed in 
draining lymph node or spleen [43]; [44]. The effect of GITR modulation on intratumor Tregs, 
combined with the known co-stimulatory activity of GITR ligation on Teffs, provides a 
potentially novel dual immunomodulatory mechanism to enhance antitumor immunity. In 
addition, the apparent preservation of global Treg function following GITR stimulation [43];
[44] suggests that the loss of immune tolerance and the incidence of immune-related adverse 
events may be low.  Thus, targeted immunomodulation of GITR appears to be a promising 
new approach for treatment of cancer.
The results of studies conducted at Merck using the murinized version of DTA-1 (mouse 
IgG2a; mDTA-1) revealed that administration of a single dose of mDTA-1 leads to complete 
regressions of established (84 to 117 mm3 in volume) subcutaneous MC38, CT26, and CM3 
tumors in a large proportion of animals. The maximal effective dose of mDTA-1 in these 
models is in the dose range of approximately 1 to 3 mg/kg (Figure 3).
 
 
057N3N

Product:  MK-4166 
23
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Figure 3
Efficacy of a Single Dose of mDTA-1 IgG2a in Established Syngeneic Mouse 
Tumor Model
The CT26 colon adenocarcinoma (panel A), MC38 colon adenocarcinoma (panel B), and CM3 melanoma (panel 
C) mouse tumor cell lines were implanted subcutaneously into immune-competent BALB/cAnN, C57BL/6J, and 
DBA/2J mice, respectively.  Animals were randomized into treatment groups when the mean tumor volume 
reached 84 to 117 mm3.  Isotype control antibody mIgG2a or mDTA-1 IgG2a were administered as a single 
subcutaneous dose on Day 0.  Tumors were measured twice weekly.  Tumor volumes are presented as mean ± 
standard error of the mean.  There were 6 to 12 animals in each group.
GITR stimulation induces humoral immune responses resulting in mechanism-based anti-drug 
antibody (ADA) formation in murine models, which is also seen in non-human primates (NHP) 
(details in Investigator Brochure).  This ADA response has the potential to confound drug 
exposures at therapeutic doses, and potentially prime for subsequent infusion-related toxicity. 
Analysis of serum cytokines shows no evidence of cytokine storm associated with the ADA.  
However, in mice, IV bolus administration of mDTA-1 in the presence of pre-existing ADA 
leads to an acute infusion reaction.  Studies summarized in the IB suggest that the acute 
infusion reactions in mice may result from rapid immune complex formation leading to an 
“alternative” IgG1-mediated pathway of anaphylaxis [45].  No acute infusion reactions are 
observed in mice after multiple sub-cutaneous administrations of mDTA-1 or in monkeys after 
multiple 30-minute IV infusions of MK-4166 (at dose levels of 0.03 to 200 mg/kg), suggesting 
that anti-GITR antibodies can be safely administered even in the presence of ADA.
4.1.2.2
Pembrolizumab Preclinical and Clinical Trials
Therapeutic studies in mouse models have shown that administration of antibodies blocking
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads
ultimately to tumor rejection, either as a mono-therapy or in combination with other treatment 
modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor 
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
MEL and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted CD8+ T-
cell infiltration into the tumor and the presence of IFN-γ, granzyme B and perforin, indicating 
 
 
057N3N

Product:  MK-4166 
24
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
that the mechanism of action involved local infiltration and activation of effector T-cell 
function in vivo [40]; [46]; [47]; [48]. Experiments have confirmed the in vivo efficacy of PD-
1 blockade as a monotherapy as well as in combination with chemotherapy in syngeneic mouse 
tumor models (see the IB).
Pembrolizumab [KEYTRUDA® (US); previously known as lambrolizumab, MK-3475 and 
SCH 9000475] is a potent and highly selective humanized monoclonal antibody (mAb) of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2. KEYTRUDA® (pembrolizumab) is indicated for the treatment of patients 
across a number of indications. For more details on specific indications refer to the IB.
4.1.2.3
MK-4166 with Pembrolizumab Combination Preclinical Trials
As MK-4166 acts to stimulate effector immune cells while pembrolizumab acts to prevent 
immune suppression in tumors, it is conceivable that a combination of MK-4166 and 
pembrolizumab may result in further stimulation of the immune system against malignant 
disease and thereby greater anti-tumor efficacy.  This hypothesis was tested in preclinical 
models, the results of which provide support for the proposed clinical trial.
Studies have been conducted in MC38 and MB49 syngeneic mouse tumor models to assess the 
anti-tumor efficacy of treatment with mDTA-1 IgG2a (mouse surrogate for MK-4166) in 
combination with muDX400 (mouse surrogate for pembrolizumab). Due to the strong efficacy 
of monotherapy with mDTA-1 IgG2a or muDX400 in the standard established MC38 tumor 
model, an advanced MC38 tumor model with starting tumor volume 3 times larger than normal 
was used. mDTA-1 IgG2a or muDX400 were administered either as monotherapy or in 
combination twice with a 7-day interval at previously determined maximally effective
monotherapeutic doses. Administration of mDTA-1 IgG2a in combination with muDX400 
resulted in greater anti-tumor efficacy than administration of either antibody alone (Figure 4).
 
 
057N3N

Product:  MK-4166 
25
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Figure 4
Efficacy of Combination Treatment with mDTA-1 IgG2a and xDX400 in 
Established Syngeneic Mouse Tumor Models
The MC38 colon adenocarcinoma (panels A and B) and MB49 bladder carcinoma (panels C and D) mouse tumor cell lines 
were implanted subcutaneously (SC) into immune-competent C57BL/6J mice.  Animals were randomized into treatment 
groups when the mean tumor volume reached 300 mm3 (MC38) or 100 mm3 (MB49).  mIgG2a isotype control monoclonal 
antibody (mAb) and mDTA-1 IgG2a were administered SC.  mIgG1 isotype control mAb and muDX400 were administered 
intraperitoneally.  All test and control articles were administered on Days 0 and 7.  In panels A and C, animal survival curves 
are presented; (survival was defined as time to >2000 mm3 tumor volume). In panels B and D, mean group tumor volumes (± 
standard error of the mean) are presented. 
 
 
057N3N

Product:  MK-4166 
26
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Ongoing Clinical Trials
4.1.3.1
Ongoing Clinical Trials with MK-4166
This is the first clinical trial of MK-4166. As of 16-Jan-2017, data are available for a total of 
73 subjects: 41 subjects treated with MK-4166 monotherapy and 32 subjects treated with 
MK-4166 in combination with pembrolizumab. Dose escalation has reached 480 mg in the 
monotherapy treatment arm and 240 mg in the combination treatment arm; dose escalation is 
continuing per protocol. Treatment has been generally well tolerated. A total of 2 (2.7%) 
subjects have discontinued study treatment due to AEs, one in each treatment arm. The most 
common AEs reported to date by preferred term have been fatigue (32 out of 73 [44%] 
subjects), nausea (16 out of 73 [22%] subjects), abdominal pain and malignant neoplasm 
progression (14 out of 73 [19%] subjects each), anaemia, decreased appetite, and dyspnoea (13 
out of 73 [18%] subjects each), infusion related reaction and vomiting (12 out of 73 [16%] 
subjects each), and pruritus (11 out of 73 [15%] subjects each). In total, 1 DLT has been 
observed to date; this DLT was a Grade 3 Indiana Pouch perforation reported in a subject with 
metastatic urethral cancer. The subject received 30 mg MK-4166 monotherapy. The 
investigator determined the event to be possibly related to study treatment because of the low 
incidence of spontaneous perforation and no obvious explanation for the event.
4.1.3.2
Ongoing Pembrolizumab Clinical Trials
Ongoing clinical trials with pembrolizumab are being conducted in multiple solid tumors, 
including melanoma, non-small cell lung cancer, head and neck cancer, triple negative breast 
cancer, gastric cancer, and bladder cancer, as well as hematologic malignancies. For trial 
details please refer to the pembrolizumab IB.
Information on Other Trial-Related Therapy
No comparators are proposed for this trial. 
Rationale
Rationale for the Trial and Selected Subject Population
MK-4166 is being developed for treatment of solid tumors. This trial is the FIH trial designed 
to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of escalating doses 
of MK-4166 alone and in combination with pembrolizumab in subjects with advanced solid 
tumors that have failed standard therapy. The effect of MK-4166 on tumor size will also be 
explored. The trial will enroll subjects with solid tumors without regard to specific tumor type
during dose escalation. Dose confirmation will proceed only in the combination therapy arm 
and will enroll subjects with advanced malignant melanoma.
Subjects 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.
 
 
057N3N

Product:  MK-4166 
27
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Details regarding specific benefits and risks for subjects participating in this clinical trial may 
be found in the accompanying IB and Informed Consent documents.
Rationale for Dose Selection/Regimen
Since immunostimulatory agonists like MK-4166 are included in the group of compounds 
where there is potential for harm intrinsic to their mode of action, the starting dose of MK-4166 
for this trial is based on the minimum anticipated biological effect level (MABEL).
4.2.2.1
Starting Dose for This Trial
Upon MK-4166 binding to the GITR receptor, the GITR receptor becomes internalized.  Thus 
target engagement can be assessed by the disappearance of cell surface GITR receptors.  This 
receptor availability assay was used to assess target engagement.  Assuming that target binding 
is essential for drug effect [49], target engagement was used to predict the minimum level at 
which MK-4166 might exert a biological effect (MABEL) for the proposed FIH study. 
Cynomolgus monkeys were used for studies of PK and GITR engagement as a bridging species 
to human administration. Cynomolgus monkeys were chosen as the relevant pharmacological 
species for the conduct of preclinical safety studies since MK-4166 binds to and co-activates 
cynomolgus monkey GITR with similar affinity and potency to that of human GITR. A broad 
survey of tissues from normal human and cynomolgus monkey demonstrated that GITR is 
expressed at low levels primarily on lymphoid cells in the blood and in lymphoid tissues in 
both species.  In the blood, GITR expression on T cells is comparable.  However, a higher 
percentage of GITR-positive NKT cells is present in cynomolgus monkey blood, and a large 
but variable percentage of GITR-positive NK cells is present in human while none are present 
in cynomolgus monkey blood. Similar to studies in mice, non-linear PK properties were 
observed in cynomolgus monkeys at lower doses (0.0003 – 3 mg/kg). In line with changes in 
serum concentration-time profiles for MK-4166, a dose-dependent effect on GITR engagement 
in blood, as measured by a receptor (GITR) availability assay (RA assay described in IB), was 
observed in monkeys. Relationships between receptor (GITR) availability and MK-4166 
serum concentrations were described by an inhibitory Emax model, which provided a 
preliminary estimate of a potency value (EC50≈ 6 ng/ml) for blood GITR engagement.
To select doses for the initial clinical study, GITR+ T-cells in blood were evaluated for 
MK-4166 binding in cancer patients, normal healthy volunteers and Cynomolgus monkeys. 
Results from this experiment showed comparable binding potency and maximum binding 
capacity between humans and Cynomolgus monkeys under the in vitro experimental 
conditions employed. To determine the MK-4166 starting dose, binding to blood at maximum 
serum concentrations (Cmax) was projected. Using conservative scaling assumptions, a dose 
of 0.000025 mg/kg was projected to correspond to 10% GITR engagement on peripheral blood 
CD4+CD95+ cells. This level of peripheral blood engagement represents less than 1% 
engagement of total body antigen pool since GITR is widely expressed in multiple tissue 
compartments. This dose was planned as the initial dose, as it reflected a balance between 
potential risk and benefit for subjects being administered the lowest doses of MK-4166. 
 
 
057N3N

Product:  MK-4166 
28
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
A fixed dosing regimen was used for this FIH trial.  Recent publications show that both body 
weight adjusted dosing and fixed dosing approaches can lead to similar variability in human 
exposure depending on how clearance and volume of distribution are related to body weight.  
[50]; [51]. In the absence of this information for MK-4166, a fixed dose approach has been 
chosen.  A conservative initial fixed dose is proposed as 0.0015 mg determined based on a 60 
kg patient receiving a dose of 0.000025 mg/kg.  The effect of body weight on the 
pharmacokinetics (PK) of MK-4166 and GITR target engagement will be evaluated to inform 
whether future studies will continue with a fixed dose regimen or switch to weight based 
dosing.  
MK-4166 will be administered as a 30-minute IV infusion (+10/-5 minutes).  Additional 
information regarding drug preparation and administration can be found in the Procedures 
Manual.  
As of 16-Jan-2017, data are available for a total of 73 subjects: 41 subjects treated with 
MK-4166 monotherapy and 32 subjects treated with MK-4166 in combination with
pembrolizumab. In the monotherapy arm, dose escalation began at 0.0015 mg and has reached 
480 mg. In the combination therapy arm, dose escalation began at 1.1 mg and has reached 240
mg. Dose escalation is continuing per protocol. Treatment has been generally well tolerated. 
A total of 2 (2.7%) subjects have discontinued study treatment due to AEs, one in each 
treatment arm. The most common AEs reported to date by preferred term have been fatigue 
(32 out of 73 [44%] subjects), nausea (16 out of 73 [22%] subjects), abdominal pain and 
malignant neoplasm progression (14 out of 73 [19%] subjects each), anaemia, decreased 
appetite, and dyspnoea (13 out of 73 [18%] subjects each), infusion related reaction and 
vomiting (12 out of 73 [16%] subjects each), and pruritus (11 out of 73 [15%] subjects each). 
In total, 1 DLT has been observed to date; this DLT was a Grade 3 Indiana Pouch perforation 
reported in a subject with metastatic urethral cancer. The subject received 30 mg MK-4166 
monotherapy. The investigator determined the event to be possibly related to study treatment
because of the low incidence of spontaneous perforation and no obvious explanation for the 
event. See the IB for pharmacokinetic and pharmacodynamics results to date.
4.2.2.2
Rationale for Pembrolizumab dose
The planned dose of pembrolizumab for this study is 200 mg given once every 3 weeks. Based 
on the totality of data generated in the Keytruda development program, 200 mg given once 
every 3 weeks is the appropriate dose of pembrolizumab across all indications and regardless 
of tumor type. As outlined below, this dose is justified by: 
•
Clinical data from 8 randomized studies demonstrating flat dose-efficacy and 
exposure-efficacy relationships from doses of 2 mg/kg given once every 3 weeks to 
10 mg/kg given once every 2 weeks;
•
Clinical data showing meaningful improvement in benefit-risk including overall 
survival at 200 mg given once every 3 weeks across multiple indications; and
 
 
057N3N

Product:  MK-4166 
29
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from physiologically-based PK analysis) at 200 mg 
given once every 3 weeks.
Among the 8 randomized dose-comparison studies, a total of 2262 subjects with either 
melanoma or non-small cell lung cancer were enrolled, covering different disease settings (i.e., 
treatment-naïve, previously treated, PD-L1-enriched, and all-comers) and different treatment 
settings (i.e., monotherapy and in combination with chemotherapy). Five studies compared 
2 mg/kg given once every 3 weeks with 10 mg/kg given once every 3 weeks (KN001 B2, 
KN001 D, KN002, KN010, and KN021), and 3 studies compared 10 mg/kg given once every 
3 weeks with 10 mg/kg given once every 2 weeks (KN001 B3, KN001 F2, and KN006). All 
of these studies demonstrated flat dose-response and exposure-response relationships across 
the doses studied representing an approximate 5-fold to 7.5-fold difference in exposure. The 
2-mg/kg (or 200-mg fixed dose) given once every 3 weeks provided similar responses to the 
highest doses studied. Subsequently, flat dose-response and exposure-response relationships 
were also observed in other tumor types including head and neck cancer, bladder cancer, gastric 
cancer, and classical Hodgkin’s lymphoma, confirming 200 mg given once every 3 weeks as 
the appropriate dose independent of the tumor type. These findings are consistent with the 
mechanism of action of pembrolizumab, which acts by interaction with immune cells, and not 
by direct binding to cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg given once every 
3 weeks. First, PK data in KN001 evaluating target-mediated drug disposition conclusively 
demonstrated saturation of PD-1 in systemic circulation at doses much lower than 200 mg 
given once every 3 weeks. Second, a physiologically-based PK analysis was conducted to 
predict tumor PD-1 saturation over a wide range of tumor penetration and PD-1 expressions. 
This evaluation concluded that pembrolizumab at 200 mg given once every 3 weeks achieves 
full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab which characterized the influence of body 
weight and other subject covariates on exposure, has shown that fixed dosing provides similar 
control of PK variability as weight-based dosing, with considerable overlap in the distribution 
of exposures from the 200-mg given once every 3 weeks dose and the 2-mg/kg given once 
every 3 weeks dose. Supported by these PK characteristics, and given that fixed dose has
advantages of reduced dosing complexity and reduced potential of dosing errors, the 200-mg 
given once every 3 weeks fixed dose was selected for evaluation across all pembrolizumab 
protocols.
No dose reduction is allowed for pembrolizumab in this study.
4.2.2.3
Maximum Dose/Exposure for This Trial
Data from mouse efficacy studies and predictions of human target engagement suggest a 
human efficacious dose in the range of 60 to 330 mg for MK-4166. Although dose escalations
will depend on safety evaluations, a potential dose of up to 900 mg is planned. While the 
maximum clinical dose to be evaluated in this trial is 900 mg, studies in the appropriate safety 
 
 
057N3N

Product:  MK-4166 
30
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
species (Cynomolgus monkeys) showed no adverse effects at doses where the Cmax and AUC 
values were 20-fold and 5-fold higher, respectively, relative to the predicted human exposure.
4.2.2.4
Rationale for Dose Interval and Trial Design
4.2.2.4.1 MK-4166 Monotherapy
Maximal efficacy was achieved in mouse preclinical studies using single 1 to 3 mg/kg doses. 
In the rapidly progressing syngeneic tumor models, no improvement in efficacy was observed 
with weekly or every other week dosing (see IB).  Because preclinical data suggests that long-
term chronic dosing may not be necessary for full efficacy, we plan a limited number of MK-
4166 administrations. A single first dose will be followed by a 3-week (DLT) observation 
period during which time subjects will be monitored for toxicity (including signs of systemic 
cytokine release) and target engagement monitored by receptor availability. In the absence of 
limiting safety events, 3 additional doses will be administered at 21-day intervals. The 3-week 
dosing interval may be adjusted based on emerging data from the study, e.g., PK and receptor 
(GITR) availability. Subjects will also be monitored for anti-drug antibodies (ADA).
4.2.2.4.2 MK-4166 in Combination with Pembrolizumab
As described previously, the combination of MK-4166 and pembrolizumab showed greater 
efficacy in preclinical studies than either agent alone.  Therefore, the combination of MK-4166 
and pembrolizumab is planned for study in clinical trials to assess whether selected groups of 
cancer patients may also derive greater benefit from the combination.  As an initial step in 
testing the combination in clinical trials, this study will assess the safety and tolerability of the 
combination of MK-4166 and pembrolizumab, and determine a maximum tolerated dose and 
recommended Phase 2 dose for MK-4166 when used in combination with pembrolizumab.  In 
this trial, pembrolizumab will be administered at 200 mg every 3 weeks.  This is the 
pembrolizumab regimen currently being studied in multiple registration trials.  Similar to the 
preclinical studies, MK-4166 and pembrolizumab will be administered on the same day for the 
first 4 cycles in Arm 2 when both drugs are administered.  
Rationale for Endpoints
4.2.3.1
Safety Endpoints
The primary safety endpoint of this trial is to characterize the safety and tolerability of single 
agent MK-4166 and MK-4166 in combination with pembrolizumab in subjects with advanced 
solid tumors. The primary safety analysis will be based on subjects who experience toxicities 
as defined by CTCAE criteria. Safety will be assessed by quantifying the toxicities and grades 
experienced by subjects who have received MK-4166 alone and in combination with 
pembrolizumab, including serious adverse events (SAEs) and events of clinical interest (ECIs).
Safety will be assessed by reported adverse experiences using CTCAE, version 4. The 
attribution to drug, time-of onset, duration of event, its resolution, and any concomitant 
medications administered will be recorded. AEs will be analyzed including but not limited to 
 
 
057N3N

Product:  MK-4166 
31
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
all AEs, SAEs, fatal AEs, and laboratory changes. Furthermore, the occurrence of specific 
immune-related adverse events (irAEs) will be collected. 
4.2.3.2
Efficacy Endpoints
An exploratory endpoint for this trial is to evaluate the anti-tumor activity of MK-4166 and 
MK-4166 in combination with pembrolizumab in subjects with advanced solid malignancies. 
Tumor response will be accessed using irRECIST 1.1.
Immunotherapeutic agents such as MK-4166 and pembrolizumab may produce antitumor 
effects by potentiating endogenous cancer-specific immune responses. The response patterns 
seen with such an approach may extend beyond the typical time course of responses seen with 
typical cytotoxic agents, and can manifest a clinical response after an initial increase in tumor 
burden or even the appearance of new lesions. Standard response assessment criteria may not 
provide a comprehensive response assessment of immunotherapeutic agents such as MK-4166
and pembrolizumab. Therefore, the subject should not be discontinued from treatment unless 
the initial assessment of PD is confirmed at least 4 weeks later, provided the subject’s clinical 
condition is stable.
4.2.3.3
Pharmacodynamic Endpoints
As a required first step in pharmacologic activity, receptor engagement is fundamental to 
dosing strategies.  To evaluate GITR target engagement, a receptor availability (RA) assay that 
compares the availability of surface GITR pre- and post-administration of MK-4166 has been 
developed.  
Additional exploratory analyses will be performed to assess the effect of MK-4166 on immune 
cells in tumor tissues and in the circulation and are discussed in the following sections.
4.2.3.3.1 Target Engagement: Receptor Availability on Peripheral Blood Lymphocytes
Due to GITR internalization upon binding by MK-4166, direct measurement of GITR receptor 
occupancy is not feasible.  Therefore, to evaluate GITR target engagement, a receptor (GITR) 
availability (RA) assay designed to assess the availability of surface GITR following 
administration of MK-4166 was developed.  GITR is detected on CD4+CD25+ and 
CD4+CD95+ T-cell sub-populations using flow cytometry and compared to pre-dose baseline.  
GITR target engagement is calculated as 100% - (%) receptor (GITR) availability.
4.2.3.3.2 Anti-Drug Antibody (ADA) Assay
GITR stimulation results in an induction of humoral immune responses resulting in 
mechanism-based anti-drug antibody (ADA) formation.  This ADA response can potentially 
confound drug exposures at therapeutic doses, and prime for subsequent infusion-related
toxicity.  ADA response at the beginning of each cycle will be determined to understand drug 
metabolism, exposure and safety.  
 
 
057N3N

Product:  MK-4166 
32
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
4.2.3.3.3 Serum Cytokines of Systemic Immune Activation
Because of the immune stimulation by an agonistic antibody and resulting potential for 
cytokine release triggered by anti-GITR, serum cytokines will be monitored to provide 
supplementary information to assist in the evaluation of any safety events (for example TNF, 
IL-2, and IL-6).
4.2.3.4
Planned Exploratory Biomarker Research
Mechanistic pharmacodynamic markers of anti-GITR activity have been observed after 
administration of the surrogate mAb mDTA-1 in mouse syngeneic tumor efficacy models, 
including changes in intra-tumor CD8:Treg ratios and induction of gene expression changes of 
various immune mediators (e.g. IFNperforin and granzymes). These changes in candidate 
pathway biomarkers are predominantly seen within the tumor. Immunophenotyping and gene 
expression profiling of tumor biopsies will be performed to explore changes in lymphocyte
populations. These may include Treg markers (e.g. FoxP3, GITR) as well as measures of 
interferon--pathway 
genes, 
effector 
T-cell 
response 
genes, 
T-cell 
repertoire 
immunomodulatory receptors (IMRs) and other related markers of immune response.
In Arm 1 (Part B) and Arm 2 (Parts D and E) of the study, subjects will be required to provide
an archival tumor tissue sample and/or a fresh tumor biopsy for biomarker analysis before 
starting treatment. Subjects will also be asked to agree to an optional tumor biopsy for 
biomarker analysis after starting treatment.
Immune modulatory agents may alter populations of circulating immune cells in blood. To 
assess the effect of MK-4166 on these cell populations, peripheral blood samples will be 
obtained at designated times before and after MK-4166 administration. Changes in immune 
cell populations will be evaluated by comparing changes from baseline in expression of 
immune function genes or proteins after treatment, and by evaluating changes from baseline
in T-cell repertoire after treatment. 
Additional host genetic factors might predict for response to the treatments in this study. 
Therefore, an additional blood sample will be collected for exploratory pharmacogenetic 
studies. This research will evaluate whether genetic variation within the clinical trial 
population correlates with response to the treatment(s) or adverse events under evaluation.
4.2.3.5
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens routinely and specifically 
collected 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.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future Biomedical 
 
 
057N3N

Product:  MK-4166 
33
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Research is to explore and identify biomarkers that inform the scientific understanding of 
diseases and/or their therapeutic treatments. For instance, exploratory pharmacogenetic (PGt) 
studies may be performed if significant Pharmacokinetic/Pharmacodynamic (PK/PD) 
relationships are observed or adverse events are identified.  Genomic markers of disease may 
also be investigated.  Such retrospective pharmacogenetic studies will be conducted with 
appropriate biostatistical design and analysis and compared to PK/PD results or clinical 
outcomes. Any significant PGt relationships to outcome would require validation in future 
clinical trials. The overarching goal is to use such information to develop safer, more effective 
drugs/vaccines, and/or to ensure that subjects receive the correct dose of the correct 
drug/vaccine at the correct time.  The details of this Future Biomedical Research sub-trial are 
presented in Section 12.2 - Collection and Management of Specimens for Future Biomedical 
Research.  Additional informational material for institutional review boards/ethics committees 
(IRBs/ERCs) and investigational site staff is provided in Section 12.3.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with advanced solid tumors, of at least 18 years of age will be enrolled 
in this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Parts A, B, and D: Have a histologically- or cytologically-confirmed metastatic solid 
tumor for which there is no available therapy which may convey clinical benefit.
Solid tumors of any type are eligible for enrollment during dose escalation. Tumor 
types of greatest interest include, but are not limited to, malignant melanoma, renal cell 
carcinoma, non-small cell lung cancer, ovarian carcinoma, and colorectal carcinoma.
Part E: Have advanced malignant melanoma (treatment-naïve or pre-treated), 
excluding uveal melanoma.
2. Have measurable disease by RECIST 1.1 criteria (Appendix 12.6).
3. Be ≥18 years of age on day of signing informed consent.
4. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale (Appendix 12.4).
5. Demonstrate adequate organ function as defined by the following table (Table 1). All 
screening labs should be performed within 7 days of treatment initiation.
 
 
057N3N

Product:  MK-4166 
34
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
≥1,500/mcL
Platelets
≥100,00/mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L
Renal
Serum Creatinine or
Creatinine 
Clearance 
(CrCl) 
(measured or calculated)a or
Glomerular Filtration Rate (GFR) in 
place of CrCl
≤1.5 X ULN or
≥60 mL/min for subject with creatinine levels 
>1.5 X ULN
Hepatic
Total bilirubin (serum) 
≤1.5 X ULN or
Direct bilirubin ≤ULN for subjects with total 
bilirubin levels >1.5 X ULN
AST (SGOT) and ALT (SGPT)
≤2.5 X ULN 
Coagulation
International Normalized Ratio (INR) 
or Prothrombin Time (PT)
Activated 
Partial 
Thromboplastin 
Time (aPTT)
≤1.5 X ULN 
≤1.5 X ULN
a Creatinine clearance should be calculated per institutional standard
6. Voluntarily agreed to participate by giving written informed consent. The subject may 
also provide consent for Future Biomedical Research.  However, the subject may 
participate in the main trial without participating in Future Biomedical Research.
7. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test at Screening and again within 24 hours prior to receiving the first dose 
of study treatment.  If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.  The serum pregnancy test must be negative for 
the subject to be eligible.
8. Female subjects of childbearing potential must be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after last dose of study medication. Subjects of childbearing 
potential are those who have not been surgically sterilized or have not been free of 
menses for >1 year. Male subjects must agree to use an adequate method of 
contraception during sexual contact with females of childbearing potential starting with 
the first dose of study medication through 180 days after the last dose of study therapy.
 
 
057N3N

Product:  MK-4166 
35
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
9. Submit an evaluable tumor sample for analysis. If submitting unstained cut slides, 
freshly cut slides should be submitted to the testing laboratory within 14 days from 
when the slides are cut.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Has had chemotherapy, radiation, or biological cancer therapy within 4 weeks prior 
to the first dose of study therapy, or who has not recovered to CTCAE grade 1 or 
better from the adverse events due to cancer therapeutics administered more than 
4 weeks earlier.
2. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 28 days of administration of MK-4166.
3. Is expected to require any other form of antineoplastic therapy while on study.  
4. Is on chronic systemic steroid therapy in excess of replacement doses, or on any other 
form of immunosuppressive medication.
5. Has a history of a malignancy, unless potentially curative treatment has been 
completed, with no evidence of malignancy for 5 years.
a.
Note: The time requirement for no evidence of disease for 5 years does not 
apply to the tumor for which a subject is enrolled in the study.  The time 
requirement does not apply to subjects who underwent successful definitive 
resection of basal cell carcinoma of the skin, superficial bladder cancer or in 
situ cervical cancer.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate 
provided they are clinically stable for at least 8 weeks prior to study entry, have no 
evidence of new or enlarging brain metastases and are off steroids. 
7. Has had a severe hypersensitivity reaction to treatment with another monoclonal 
antibody.
8. Has an active autoimmune disease or a documented history of autoimmune disease, 
except vitiligo or resolved childhood asthma/atopy.
9. Has an active infection requiring therapy.
10. Has current pneumonitis, or a history of (non-infectious) pneumonitis that required 
steroids. 
 
 
057N3N

Product:  MK-4166 
36
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
11. Has had a prior stem cell or bone marrow transplant.
12. Is positive for Human Immunodeficiency Virus (HIV), Hepatitis B, or Hepatitis C.
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject’s participation 
for the full duration of the study, or is not in the best interest of the subject to 
participate, in the opinion of the treating Investigator.
14. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
15. Is a regular user (including “recreational use”) of any illicit drugs or had a recent 
history (within the last year) of substance abuse (including alcohol), at the time of 
signing informed consent.
16. Has symptomatic ascites or pleural effusion. A subject who is clinically stable 
following treatment for these conditions (including therapeutic thoracentesis or 
paracentesis) is eligible.
17. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study. 
18. Has clinically significant heart disease.
19. Has had major surgery in the past 16 weeks.
20. Has received a live vaccine within 30 days prior to first dose.
21. Is or has an immediate family member (spouse or children) who is investigational 
site or sponsor staff directly involved with this trial, unless prospective IRB approval 
(by chair or designee) is given allowing exception to this criterion for a specific 
subject.
Trial Treatment(s)
The treatments to be used in this trial are outlined below in Table 2 and Table 3.
In Arm 1, Part A, an accelerated dose escalation in single subject cohorts will proceed based 
on safety events to a dose of 10 mg. Starting at a 30 mg dose (or earlier as described in Section 
5.2.1.4) in Part B, the study will continue with a 3+3 design to identify a preliminary MTD.
In Arm 2, Part D, treatment in the combination arm will follow a 3+3 design during dose 
escalation to identify a preliminary MTD. Dose confirmation in Part E will refine the estimate 
of tolerability of the MTD in subjects with advanced malignant melanoma using a toxicity 
probability interval [1].
 
 
057N3N

Product:  MK-4166 
37
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
When both treatment arms are open for enrollment, enrollment to both arms will occur in 
parallel with treatment allocation accomplished by non-random assignment to Arm 1 or Arm 2 
using an interactive voice response system / integrated web response system (IVRS/IWRS).
Once dose escalation (Parts A and B) is completed in Arm 1, only the combination therapy 
arm (Arm 2) of the study will be open for enrollment.
If pharmacodynamic saturation at the tissue level and/or robust clinical efficacy is observed 
during the dose escalation phase in either the monotherapy or combination therapy arm, dose 
escalation in that arm of the trial may be stopped at a level below the maximum dose planned 
in the absence of safety findings and an MTD would not be determined for the respective 
regimen.  In this case an administrative letter will be used to document the preliminary 
completion of dose escalation and, in the combination arm, transition to the dose confirmation 
part (Part E).
Table 2
Trial Treatment for MK-4166 Monotherapy (Arm 1)  
Treatment during Part A: Accelerated Dose Escalation
Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Trea
tment Period
Use
MK-4166
0.0015 mg
0.0045 mg
0.014 mg
0.04 mg
0.12 mg
0.37 mg
1.1 mg
3.3 mg
10 mg
Every 21
days.
Intravenous
over 30 
minutes
Day 1 of each 
21-day 
cycle 
for 
up 
to 
4 cycles
Experimental
Treatment during Part B: Dose Finding
Drug
Dose/Potency
Dose 
Frequency
Route 
of 
Administration
Regimen/Trea
tment Period
Use
MK-4166
30 mg
60 mg
120 mg 
170 mg
240 mg
330 mg
460 mg
650 mg
900 mg
Every 21
days.
Intravenous
over 30 
minutes
Day 1 of each 
21-day 
cycle 
for 
up 
to 
4 cycles
Experimental
Note: Dose levels shown in Table 2 are proposed dose levels, with 3-fold increases between doses levels in 
Part A, and 100% increases at the 30 mg and 60 mg dose levels, followed by 40% increases at and after the 
120 mg dose level in Part B. Actual doses tested in the trial will depend on whether or not safety observations 
trigger the switch to 40 % dose level increases before the 120 mg dose.
 
 
057N3N

Product:  MK-4166 
38
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Table 3
Trial Treatment for MK-4166 with Pembrolizumab Combination (Arm 2)
Drug
Dose
Dose 
Frequency
Route of 
Administration
Regimen
Use
Treatment during Part D: Dose Finding
MK-4166
1.1 mg
3.3 mg
10 mg
30 mg
60 mg
120 mg
170 mg
240 mg
330 mg
460 mg
650 mg
900 mg
Every 21 
days
Intravenous 
over 30 
minutes
Day 1 of 
each 21-
day cycle 
up to 4 
cycles
Experimental
Pembrolizumab
200 mg
Every 21 
days
Intravenous 
over 30 
minutes
Day 1 of 
each 21 
day cycle 
up to 24 
months of 
treatment
Experimental
Note: Dose levels shown in Table 3 are proposed dose levels, actual doses of MK-4166 will depend on 
safety/tolerability experienced in the monotherapy arm. Doses of MK-4166 used in combination will be 1-
2 dose levels behind the monotherapy dose, and would not exceed the MTD for monotherapy. However, 
once the MTD for the monotherapy arm is established, the dose of MK-4166 in combination may continue 
escalation to that dose.  Combination dose escalation will follow 3 + 3 design to identify a preliminary 
maximum dose.
In Arm 2, pembrolizumab will be administered first, than after a 30 minutes interval, MK-4166 
will be administered.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1.1
Dose Selection (Preparation)
Details on dose calculation, preparation and administration of MK-4166 and pembrolizumab 
are provided in the Procedures Manual.
 
 
057N3N

Product:  MK-4166 
39
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
5.2.1.2
Dose Escalation
In Arm 1 (MK-4166 monotherapy), an accelerated dose escalation in single subject cohorts 
will proceed based on safety events in Part A to a dose of 10 mg. Beginning with the 30 mg 
dose (or earlier as described below), the study will continue with a 3+3 design to identify a 
preliminary MTD.
Enrollment to Arm 2, (MK-4166 with pembrolizumab) will begin at the 1.1 mg dose level. All 
dose levels in Part D will follow a 3+3 design. Doses of MK-4166 used in combination with 
pembrolizumab will be 1 to 2 dose levels behind the monotherapy dose, until the MTD in the 
monotherapy arm is determined. Once the MTD in the monotherapy arm is established, the 
dose of MK-4166 in the combination arm may continue escalation to that dose.  However, the 
dose of MK-4166 used in combination with pembrolizumab would not exceed the MTD for 
monotherapy. 
5.2.1.3
Accelerated Dose Escalation (MK-4166 Monotherapy)
During the accelerated dose escalation part (Part A), each cohort will enroll a single subject 
and dose escalation will proceed as designated in Table 2, until a DLT is observed, or a subject
experiences a Grade 2 or greater possibly, probably or definitely drug-related adverse event, 
or until the dose level of 10 mg is safely administered.
If a subject experiences a DLT, the study will convert to a 3+3 design starting at that level with 
40% dose increments. See Section 5.2.2 for definition of DLTs.
If a single subject at a given dose level experiences a Grade 2 or greater drug-related adverse 
event, this cohort will be expanded to 3 subjects. If no additional drug-related adverse events 
of Grade 2 or greater occur (1/3), accelerated dose escalation will continue. If an additional 
drug-related adverse event of Grade 2 or greater occurs at that dose level (>2/3), escalation 
will convert to the 3+3 design. This will signify the transition to Part B. Further dose 
escalations from that level will proceed in approximately 40% increments.
Starting with the 30 mg dose, 3 subjects will be enrolled to each dose level, and dose escalation 
will proceed as designated in Table 2. 
5.2.1.4
3+3 Dose Escalation
In Arm 1, once the 10 mg dose is safely administered in Part A, the study will proceed to Part 
B starting at the 30 mg dose, with 3 subjects enrolled at each new dose level and dose escalation 
continuing according to Table 2. Arm 2 will start with 3+3 dose escalation according to
Table 3.
During 3+3 dose escalation, at least 2 days of observation will occur between each of the first 
3 subjects at each dose level. There will be a 1-week observation period between the first and
second subject treated with the combination in the first cohort of Arm 2.
 
 
057N3N

Product:  MK-4166 
40
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Dose escalation will increase in increments of approximately 40% after either the 120 mg dose 
is safely administered, or starting with any dose where a DLT or 2 >Grade 2 treatment-related 
toxicities are observed.  
Intermediate lower dose levels, not specified in Table 2 or Table 3 may be investigated. This 
escalation schedule may be adjusted downward based on PD, PK, and safety data emerging 
throughout the Phase 1 study. 
The rules applied for the preliminary dose finding using the 3+3 design are as follows:
An initial cohort of 3 subjects is enrolled. 

If 0/3 subjects develop a DLT, escalation to the next dose will occur. 

If 1/3 subjects develops a DLT, another 3 subjects will be enrolled at this dose level. 

If 0 of the 3 new subjects develop a DLT (for a total of 1/6 subjects with a DLT at 
this dose level), escalation to the next dose level will occur. 

If 1 of the 3 new subjects develops a DLT (for a total of 2/6 subjects with a DLT at 
this dose level), the dose escalation part of the trial will be terminated. If the dose 
directly below the current dose had been studied in at least 3 subjects, the dose 
directly below the current dose will be considered the preliminary MTD. In the 
combination arm, the study will proceed to dose confirmation (Part E).

If >1 of the 3 new subjects develop a DLT (for a total of >2/6 subjects with a DLT 
at this dose level), the dose escalation part of the trial will be terminated. If the dose 
directly below the current dose had been studied in at least 3 subjects, the dose 
directly below the current dose will be considered the preliminary MTD. In the 
combination arm, the study will proceed to dose confirmation (Part E). If the dose 
directly below the current dose had been studied in <3 subjects, more subjects to a 
total of 3 will be enrolled at the dose directly below the current dose before 
declaring the preliminary MTD.

If ≥2/3 subjects develop a DLT, the dose escalation part of the trial will be terminated. 
If the dose directly below the current dose had been studied in at least 3 subjects, the 
dose directly below the current dose will be considered the preliminary MTD. In the 
combination arm, the study will proceed to dose confirmation (Part E). If the dose 
directly below the current dose had been studied in <3 subjects, more subjects to a total 
of 3 will be enrolled at the dose directly below the current dose before declaring the 
preliminary MTD.
It is conceptually acceptable to de-escalate to an intermediate, not pre-defined and not 
previously-studied dose, if evaluation of toxicity at such a dose is desired in lieu of proceeding 
directly to the dose confirmation part of the study in the combination arm. If this approach is 
taken, 3 new subjects should be enrolled at the new intermediate dose, and the aforementioned 
rules should be used to determine further enrollment at this dose level. 
 
 
057N3N

Product:  MK-4166 
41
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
If the highest candidate dose of MK-4166 in combination with pembrolizumab is studied 
during dose escalation, and 0/3 subjects or ≤2/6 subjects develop a DLT at that dose, then dose 
escalation will terminate with this finding and this dose will be taken to the confirmation part 
in the combination arm.
5.2.1.5
Dose Confirmation (Arm 2 only)
Dose confirmation will occur in the combination therapy arm (Arm 2) only and will be 
restricted to subjects with advanced malignant melanoma (Part E). The objective of dose 
confirmation is to refine the estimate of the MTD based on a TPI design [1] with a target 
toxicity rate <30%. Dose confirmation involves the expansion of at least 1 dose level studied 
in the dose escalation part of the study. 
Dose confirmation will begin with expansion of the preliminary MTD/MAD identified in the 
dose escalation part described above (Part D). As subjects become evaluable for DLT 
assessment, the number of subjects who are evaluable for DLT versus the number of subjects 
who developed a DLT will continuously be assessed and de-escalation and re-escalation to 
eligible doses will occur as shown in Table 4. If the MTD is the MAD, future subjects would 
stay at the current dose level even if Table 4 indicated an escalation. Dose confirmation will 
end when 20 subjects have been treated at a given dose. Note that while 30% has been the 
target toxicity rate used to generate the guidelines in Table 4 the observed rate of subjects with 
DLT at the MTD may be slightly above or below 30%.
 
 
057N3N

Product:  MK-4166 
42
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Table 4
Dose Confirmation Rules
Number of subjects treated at current dose
Number
of 
toxicities
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
0
S
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
S
S
S
E
E
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
S
S
S
E
E
E
E
E
E
3
D
U
D
D
S
S
S
S
S
S
S
S
S
S
S
S
S
E
4
D
U
D
U
D
U
D
D
D
S
S
S
S
S
S
S
S
S
S
S
5
D
U
D
U
D
U
D
U
D
U
D
D
S
S
S
S
S
S
S
S
S
6
D
U
D
U
D
U
D
U
D
U
D
U
D
D
D
S
S
S
S
S
S
7
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
D
D
D
S
S
S
8
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
D
D
D
9
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
10
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
11
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
12
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
13
D
U
D
U
D
U
D
U
D
U
D
U
D
U
D
U
14
D
U
D
U
D
U
D
U
D
U
D
U
D
U
15
D
U
D
U
D
U
D
U
D
U
D
U
16
D
U
D
U
D
U
D
U
D
U
17
D
U
D
U
D
U
D
U
18
D
U
D
U
D
U
19
D
U
D
U
20
D
U
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
DU = The current dose is unacceptably toxic
Target toxicity rate = 30%
a=1; b=1; k1=1; k2=1.5; pow=1 per [1].
Subjects may be enrolled continuously (i.e., without waiting for Cycle 1 completion of subjects 
who have received the first dose) unless a DLT is observed at the particular dose.  Once a DLT 
is observed, the number of subjects who are enrolled at that dose but are not yet fully evaluable 
for DLT assessment may not exceed the number of remaining subjects who are at risk of 
 
 
057N3N

Product:  MK-4166 
43
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
developing a DLT before the dose would be considered unacceptably toxic (denoted as DU in 
Table 4).  For example, if 3/7 subjects have experienced a DLT at a given dose level, no more 
than an additional 2 subjects should be enrolled at this dose level until additional DLT data are 
available. This is because this dose level would be considered unacceptably toxic if all 2 of the 
additional subjects experience a DLT (i.e., 5/9 subjects with DLT in Table 4). To find out how 
many more subjects can be enrolled, one can count steps in diagonal direction (down and to 
the right) from the cell (7 subjects, 3 toxicities) to the first cell marked DU.
Definition of Dose Limiting Toxicity
DLT’s will be defined from toxicities observed during the first cycle of treatment (21 days) for 
each dose level. See Section 5.2.4 for rules on replacement of subjects in the DLT period. The 
occurrence of any of the following toxicities during Cycle 1, if assessed by the Investigator to 
be possibly, probably or definitely related to MK-4166 in Arm 1 or the MK-4166 with 
pembrolizumab combination in Arm 2, will be considered a DLT:
1. Grade 4 non-hematologic 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 bleeding:
3. Grade 3 non-hematologic toxicity (not laboratory) lasting >3 days despite optimal 
supportive care.  Grade 3 nausea, vomiting or diarrhea will be considered a DLT if 
lasting more than 3 days despite optimal supportive care.
4. Any Grade 3 or Grade 4 non-hematologic laboratory abnormality, if
a.
medical intervention is required, or
b. the abnormality leads to hospitalization, or
c.
the abnormality persists for >1 week
5. Febrile neutropenia Grade 3 or Grade 4
6. Any drug-related AE which caused subject to discontinue treatment during Cycle 1
7. Grade 5 toxicity
8. Any treatment-related toxicity which causes a >2 week delay in initiation of Cycle 2
 
 
057N3N

Product:  MK-4166 
44
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Guidelines for Dose Modification due to Adverse Events
5.2.3.1
Dose Modification and Toxicity Management for Adverse Events Associated 
with MK-4166 and/or Pembrolizumab
The Common Terminology Criteria for Adverse Events version 4.0 (CTCAE 4.0) must be
used to grade the severity of adverse events.
The Investigator may attribute each toxicity event to MK-4166 alone, pembrolizumab alone,
or to the combination of both treatments and modify the dose as appropriate. If a dose
reduction for toxicity occurs with any agent, the dose may not be re-escalated. Dose
modifications are always based on the previous cycle.  Reduction or holding of 1 agent and 
not the other agent is appropriate if, in the opinion of the Investigator, the toxicity is clearly
related to one of the study drugs. For subject convenience in Arm 2, if 1 drug is delayed, the 
second drug can be delayed until both can be administered.  If, in the opinion of the 
Investigator, the toxicity is related to the combination of 2 agents, both drugs should be held 
according to the recommended dose modification guidelines.
Subjects may have 1 dose modification to MK-4166 throughout the course of the study, as
described in Table 5.  If further toxicity occurs or the criteria for resuming treatment are not
met, the subject must be discontinued from the agent. If a subject experiences several toxicities 
and there are conflicting recommendations, follow the most conservative dose adjustment
recommended (dose reduction appropriate to the most severe toxicity).
Exceptional circumstances to following the dose modification tables below may be considered
after consultation with the Sponsor.
Adverse events (both non-serious and serious) associated with MK-4166 and pembrolizumab
exposure may represent an immunologic etiology.  These adverse events may occur shortly 
after the first dose to several months after the last dose of treatment.
MK-4166 will be withheld for Grade 4 hematologic toxicities, non-hematological toxicity 
≥Grade 3 including laboratory abnormalities, and severe or life-threatening AEs as per Table 
5 below. Pembrolizumab treatment interruption/discontinuation and toxicity management
guidelines are described in Section 5.2.3.2 and Section 5.2.3.3.
 
 
057N3N

Product:  MK-4166 
45
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Table 5
MK-4166 Dose Modification and Treatment Discontinuation Guidelines for 
Drug-Related Adverse Events
Toxicity
Grade
Hold 
Treatment
Criteria for 
Restarting 
Treatment
Dose/Schedule 
for Restarting 
Treatment
Criteria for 
Discontinuation after 
Consultation with 
Sponsor
Hematologic 
toxicity
1, 2, 3
No 
N/A
N/A
N/A
4
Yes
Toxicity 
resolves to 
Grade 0-1, 
or to 
baseline
No change in 
dose. May 
increase dosing 
interval by 1 
week
Toxicity does not 
resolve within 12 
weeks of last dose.
Permanent 
discontinuation 
should be considered 
for any severe or life-
threatening event
Non-hematologic 
toxicity
Note: Exception to 
be treated similar 
to Grade 1 toxicity

Grade 2 
alopecia

Grade 2 
fatigue
1
No 
N/A
N/A
N/A
2
Consider 
holding for 
persistent 
symptoms 
Toxicity 
resolves to 
Grade 0-1 
or baseline
Clinical AE 
resolves within 
3 weeks: treat at 
same dose and 
schedule
Clinical AE 
does not resolve 
within 3` 
weeks: may 
increase the 
dose schedule 
by 1 week for 
each occurrence
Toxicity does not 
resolve within 12 
weeks of last dose.
3, 4
Yes
Toxicity 
resolves to 
Grade 0-1 
or baseline
May increase 
the dose 
schedule by 1 
week for each 
occurrence
Toxicity does not 
resolve within 12 
weeks of last dose. 
Permanent 
discontinuation 
should be considered 
for any severe or life-
threatening event
In case toxicity does not resolve to Grade 0-1 within 12 weeks after last infusion, trial treatment 
should be discontinued after consultation with the Sponsor. 
With Investigator and Sponsor agreement, subjects with a laboratory adverse event still at 
Grade 2 after 12 weeks may continue treatment in the trial only if asymptomatic and controlled.
 
 
057N3N

Product:  MK-4166 
46
Protocol/Amendment No.:  001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
After any Grade 4 drug-related adverse event, subjects should not restart trial treatment without 
consultation with the Sponsor; the toxicity must have resolved to Grade 0-1 or baseline prior 
to restarting 
5.2.3.2
Dose Interruption/Discontinuation and Toxicity Management Guidelines for 
Immune-Related Adverse Events Associated with Pembrolizumab
Adverse events associated with pembrolizumab exposure may represent an immunologic 
etiology. These irAEs may occur anywhere from shortly after the first dose to several months 
after the last dose of pembrolizumab treatment and may affect more than one body system 
simultaneously. 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 
dose interruptions and administration of corticosteroids and/or other supportive care. For 
suspected irAEs, ensure adequate evaluation to confirm etiology and/or exclude other causes. 
Additional procedures or tests such as bronchoscopy, endoscopy, and/or skin biopsy may be 
included as part of the evaluation. Dose interruption/discontinuation and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 6.
 
 
057N3N

Product:  MK-4166 
47
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Table 6
Pembrolizumab Dose Interruption/Treatment Discontinuation and Toxicity Management Guidelines for Immune-Related 
Adverse Events
General instructions:
1. Corticosteroid taper should be initiated after AE has improved to Grade 1 or less and continue over at least 4 weeks.
2. In situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has improved to Grade 1 or less and corticosteroid has been 
tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to 
≤10 mg prednisone or equivalent per day within 12 weeks.
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AE
Toxicity grade or 
condition 
(CTCAEv4.0)
Action taken with 
pembrolizumab
irAE management with corticosteroid 
and/or other therapy
Monitor guideline and follow-up
Pneumonitis
Grade 2
Withhold
Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms of 
pneumonitis

Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for opportunistic 
infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently 
discontinue
Diarrhea / Colitis
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus)

Participants with Grade ≥2 diarrhea suspicious 
for colitis should consider GI consultation and 
performing endoscopy to rule out colitis

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted by IV infusion
Grade 4
Permanently 
discontinue
 
 
057N3N

Product:  MK-4166 
48
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Immune-related 
AE
Toxicity grade or 
condition 
(CTCAEv4.0)
Action taken with 
pembrolizumab
irAE management with corticosteroid 
and/or other therapy
Monitor guideline and follow-up
AST / ALT 
elevation or 
Increased bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5-1 mg/kg prednisone or 
equivalent) followed by taper

Monitor liver function tests (consider weekly or 
more frequently) until liver enzyme values 
return to baseline or are stable
Grade 3 or 4
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
Newly onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell
failure
Withhold

Initiate insulin replacement therapy 
for participants with T1DM

Administer anti-hyperglycemic in 
participants with hyperglycemia

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold

Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue1 
Hyperthyroidism
Grade 2
Continue

Treat with non-selective 
beta-blockers (eg, propranolol) or 
thionamides as appropriate

Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue1
Hypothyroidism
Grades 2-4
Continue

Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders
Nephritis and 
Renal dysfunction
Grade 2
Withhold

Administer corticosteroids 
(prednisone 1-2 mg/kg or equivalent) 
followed by taper

Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE, administer 
corticosteroids

Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
 
 
057N3N

Product:  MK-4166 
49
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Immune-related 
AE
Toxicity grade or 
condition 
(CTCAEv4.0)
Action taken with 
pembrolizumab
irAE management with corticosteroid 
and/or other therapy
Monitor guideline and follow-up
All other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE, 
administer corticosteroids

Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3
Withhold or 
permanently 
discontinue based on 
the type of event. 
Events that require 
discontinuation 
include but are not 
limited to: 
Gullain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3
Permanently 
discontinue
1.
The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.
NOTE: For participants with Grade 3 or 4 immune-related endocrinopathy where pembrolizumab is withheld, pembrolizumab may be resumed when AE resolves 
to Grade ≤2 and is controlled with hormonal replacement therapy, or metabolic control is achieved (in case of T1DM).
 
 
057N3N

Product:  MK-4166 
50
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
5.2.3.3
Toxicity Management of Infusion Reactions Related to Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of the infusion. 
Toxicity management guidelines for pembrolizumab-associated infusion reactions are 
provided in Table 7.
Table 7
Pembrolizumab 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 therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(eg, antihistamines, 
non-steroidal 
anti-inflammatory drugs 
[NSAIDs], narcotics, 
IV fluids); prophylactic 
medications indicated 
for ≤24 hours
Stop infusion
Additional appropriate medical therapy may 
include, but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, from 
100 mL/hr to 50 mL/hr). Otherwise dosing 
will be held until symptoms resolve and the 
participant should be premedicated for the 
next scheduled dose
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further 
study treatment
Participant may be 
premedicated 1.5 hous (± 30 
minutes) prior to infusion of
pembrolizumab with:
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine)
Acetaminophen 
500-1000 mg PO (or 
equivalent dose of 
analgesic)
 
 
057N3N

Product:  MK-4166 
51
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor 
or ventilatory support 
indicated
Stop infusion
Additional appropriate medical therapy may 
include, but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator
Hospitalization may be indicated
**In cases of anaphylaxis, epinephrine should 
be used immediately
Participant is permanently discontinued 
from further study treatment
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of study treatment administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 at 
http://ctep.cancer.gov
Replacement of Subjects in DLT Evaluation Period
In order to determine safety, all subjects selected must meet the criteria for evaluability for 
Cycle 1. Subjects are considered non-evaluable and will be replaced if:

They are enrolled but not treated

They discontinue from the trial prior to completing all the safety evaluations for reasons 
other than treatment-related adverse events

They receive less than 90% of the total MK-4166 or pembrolizumab infusion in Cycle 
1 (e.g., because the infusion had to be discontinued due to an infusion reaction) and did 
not experience a DLT
Non-evaluable subjects will not be counted toward the cohort total for DLT evaluation.
If a subject experiences a DLT in Cycle 1, trial treatment may be discontinued following 
discussion between the Sponsor and Investigator. However, if the subject is deriving clinical 
benefit from the trial treatment, the subject may be allowed to continue after discussion 
between the Sponsor and Investigator.
 
 
057N3N

Product:  MK-4166 
52
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Timing of Dose Administration
Trial treatment may be administered up to 3 days before or 5 days after the scheduled Day 1 
of each cycle, beginning in Cycle 3. Cycle 2 Day 1 may be administered up to 5 days after the 
scheduled day 1. In addition, dosing interruptions are permitted in the case of medical / surgical 
events or logistical reasons not related to study therapy (e.g., elective surgery, unrelated 
medical events, subject vacation, and/or holidays). Subjects should be placed back on study 
therapy within 2 weeks of the scheduled interruption, unless otherwise discussed with the 
Sponsor. The reason for interruption should be documented in the subject's study record.
In Arm 2, pembrolizumab will be administered first on Day 1 of each cycle, with 
administration of MK-4166 occurring approximately 30 minutes after completion of the 
pembrolizumab administration.
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation or Vaccine Allocation
Treatment allocation by non-random assignment to Arm 1 or Arm 2 will occur centrally using 
an interactive voice response system / integrated web response system (IVRS/IWRS). 
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
Acceptable Concomitant Medication
Drugs specifically prohibited in the exclusion criteria are not allowed during the ongoing trial.  
Listed below are some specific restrictions for concomitant therapy use during the course of 
the trial.  If there is a clinical indication for one of these or other medications specifically 
prohibited during the trial, discontinuation from trial therapy may be required.  The investigator 
should discuss any questions regarding this with the Sponsor.  The final decision on any 
supportive therapy rests with the investigator and/or the subject's primary physician.  However, 
the decision to continue the subject on trial therapy requires the mutual agreement of the 
investigator, the Sponsor and the subject. All treatments that the investigator considers 
necessary for a subject’s welfare may be administered at the discretion of the investigator in 
keeping with the community standards of medical care. All concomitant medication will be 
recorded on the case report form (CRF) including all prescription, over-the-counter (OTC), 
herbal supplements, and IV medications and fluids.  If changes occur during the trial period, 
documentation of drug dosage, frequency, route, and date will also be included on the CRF.
 
 
057N3N

Product:  MK-4166 
53
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Palliative and supportive care is permitted during the course of the trial for underlying medical 
conditions and management of symptoms. Surgery or radiotherapy for tumor control is not 
permitted during the study; however, radiotherapy or procedures for symptom management is 
allowed.
All concomitant medications received within 30 days before the first dose of trial treatment 
through the Safety Follow-up Visit should be recorded.  After the Safety Follow-up Visit 
record all medications taken for SAEs and ECIs as defined in Section 7.2.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening, and 
Treatment Phases of this trial:

Immunotherapy not specified in this protocol.

Antineoplastic systemic chemotherapy or biological therapy

Investigational agents not specified in this protocol.

Radiation therapy; radiotherapy for symptom management is allowed.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chickenpox, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed. However, intranasal influenza vaccines (e.g. FluMist®) are 
live attenuated vaccines, and are not allowed.

Glucocorticoids for any purpose other than to modulate symptoms from an event of 
clinical interest. Chronic systemic replacement doses of steroids are allowed. Inhaled 
steroids for management of asthma are allowed.
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary.  
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the follow-up visits.
Rescue Medications & Supportive Care
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined in Section 5.2.3.2, Table 6. 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 
 
 
057N3N

Product:  MK-4166 
54
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
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 study treatment.
Note: If after evaluation of the event, it is determined not to be related to MK-4166 and/or 
pembrolizumab, the investigator does not need to follow the treatment guidance.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of the evaluation of the event.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage AEs such 
as diarrhea, nausea, or vomiting.
Contraception
MK-4166 and pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is 
not known if either drug has transient adverse effects on the composition of sperm.  
Non-pregnant, non-breast-feeding women may be enrolled if they are considered highly 
unlikely to conceive.  Highly unlikely to conceive is defined as: (1) surgically sterilized, (2) 
postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 
1 year will be considered postmenopausal), or (3) not heterosexually active for the duration of 
the study.  The 2 birth control methods can be either 2 barrier methods or a barrier method plus 
a hormonal method to prevent pregnancy. 
The following are considered adequate barrier methods of contraception: diaphragm, condom 
(by the partner), copper intrauterine device, sponge, or spermicide.  Appropriate hormonal 
contraceptives will include any registered and marketed contraceptive agent that contains an 
estrogen and/or a progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents).
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study they must adhere to the contraception requirement (described above) for the duration 
of the study and during the follow-up period defined in Section 7.2.2-Reporting of Pregnancy 
and Lactation to the Sponsor.  If there is any question that a subject will not reliably comply 
with the requirements for contraception, that subject should not be entered into the study.
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with MK-4166 or 
pembrolizumab, the subject will immediately be removed from the study.  The site will contact 
the subject at least monthly and document the subject’s status until the pregnancy has been 
 
 
057N3N

Product:  MK-4166 
55
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the mother 
or newborn).  The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to the Sponsor.  If 
a male subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and followed as described above and 
in Section 7.2.2.
Use in Nursing Women
It is unknown whether MK-4166 or pembrolizumab is excreted in human milk.  Since many 
drugs are excreted in human milk, and because of the potential for serious adverse reactions in 
the nursing infant, subjects who are breast-feeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
In this trial, a subject may discontinue from treatment but continue to participate in the 
regularly scheduled activities, as long as the subject does not withdraw consent.  
Discontinuation from treatment is permanent.  Once a subject has discontinued treatment, even 
though he/she continues to be monitored in the trial, he/she shall not be allowed to begin 
treatment again.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
A subject must be discontinued from treatment (but may continue to be monitored in the trial) 
for any of the following reasons:

Confirmed disease progression per response assessment criteria (See Section 7.2.1.7)
A subject with confirmed radiologic progression may continue to receive study treatment, after 
consultation with the Sponsor, if the Investigator deems the subject is receiving clinical benefit 
or value from treatment. Subjects who continue to receive study treatment after confirmed 
radiologic progression will continue to be followed according to the procedures and 
assessments listed under Cycle 7 and beyond in the Trial Flow Chart (Section 6.0).
 
 
057N3N

Product:  MK-4166 
56
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential

Noncompliance with trial treatment or procedure requirements

Investigator’s decision to withdraw the subject

Clinical progression

Subject has a confirmed pregnancy test

Unacceptable adverse events 

Intercurrent illness that prevents further administration of treatment

Administrative reasons requiring cessation of treatment

Lost to follow-up
Once subjects have achieved the study objectives or the study has ended, they will be 
discontinued from this study and will be enrolled into an extension study to continue 
protocol-defined assessments and treatment.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The study begins when the first subject signs the informed consent.  The end of the study may 
be designated as the time point when all subjects have discontinued the study or are a minimum 
of 6 months post initial study medication administration.  
By the end of the study, if there are still subjects ongoing 6 months post initial study medication 
administration, they will be discontinued and enrolled into a pembrolizumab extension study.
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Incidence or severity of adverse drug reactions in this or other trials suggest a potential 
health hazard to subjects;
2. Plans to modify or discontinue the development of the trial drug
3. Poor adherence to protocol and regulatory requirements
4. Quality or quantity of data recording  is inaccurate or incomplete
Ample notification will be provided in the event of Sponsor decision to no longer supply MK-
4166 or pembrolizumab.
 
 
057N3N

Product:  MK-4166 
57
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
6.0 TRIAL FLOW CHART
Screening 
Phase
Treatment Phase1
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-4
Cycles 
5 and 6 
(Arm 2 
only)
Cycle 7 
and 
Beyond 
(Arm 2 
only)
Discon
Post 
Treat-
ment 
Safety 
Follow-
up
Follow-up 
Visits
Cycle Day
1
2
3
5
8
15
1
2
3
5
8
15
9 wks 
from 
1st
dose
1
1
At time of 
discon
30 days 
post 
discon
3 mos 
and 6 
mos 
after 
end 
of 
treat-
ment
Every 
9 
weeks 
until 
PD
Scheduling Window (Days):
-28 to -1
± 3 ± 3
± 3
± 3
± 7
± 7
± 7
± 7
Administrative Procedures
Informed Consent
X2
Informed Consent for 
Future Biomedical 
Research
X3
Inclusion/Exclusion 
Criteria
X
Subject Identification Card
X
Demographics and Medical 
History
X
Prior and Concomitant 
Medication Review4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior Oncology Treatment 
History
X
MK-4166 Drug 
Administration (Arm 1 & 
2)
X
X
Pembrolizumab Drug 
Administration (Arm 2)5
X
X
X
X
 
 
057N3N

Product:  MK-4166 
58
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Screening 
Phase
Treatment Phase1
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-4
Cycles 
5 and 6 
(Arm 2 
only)
Cycle 7 
and 
Beyond 
(Arm 2 
only)
Discon
Post 
Treat-
ment 
Safety 
Follow-
up
Follow-up 
Visits
Cycle Day
1
2
3
5
8
15
1
2
3
5
8
15
9 wks 
from 
1st
dose
1
1
At time of 
discon
30 days 
post 
discon
3 mos 
and 6 
mos 
after 
end 
of 
treat-
ment
Every 
9 
weeks 
until 
PD
Scheduling Window (Days):
-28 to -1
± 3 ± 3
± 3
± 3
± 7
± 7
± 7
± 7
Clinical Procedures/Assessments
Adverse Events Monitoring6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination
X
X7
X7
X
X
X
X
X
Vital signs and weight8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
X
12-Lead Electrocardiogram9
X
X7
X7
X
ECOG Performance Status
X
X7
X7
X
X
X
X
Tumor Imaging10
X
X
X
X
X
Response Assessment11
X
X
Survival Status12
Laboratory Procedures/Assessments to be performed by local laboratory
CBC with Differential13
X14
X7, 14
X
X
X
X7, 
14
X
X
X
X
X
X
C reactive protein13
X14
X7, 14
X
X
X
X7, 
14
X
X
X
PT/INR and aPTT
X14
Chemistry Panel13
X14
X7, 14
X
X
X
X7,
14
X
X
X
X
X
X
LDH, GGT
X14
X7
X7
X
Pregnancy test –Urine or 
Serum β-HCG15
X
X
Urinalysis
X14
Immunoglobulins (IgA, 
IgG, IgM)
X7
X7
X
 
 
057N3N

Product:  MK-4166 
59
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Screening 
Phase
Treatment Phase1
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-4
Cycles 
5 and 6 
(Arm 2 
only)
Cycle 7 
and 
Beyond 
(Arm 2 
only)
Discon
Post 
Treat-
ment 
Safety 
Follow-
up
Follow-up 
Visits
Cycle Day
1
2
3
5
8
15
1
2
3
5
8
15
9 wks 
from 
1st
dose
1
1
At time of 
discon
30 days 
post 
discon
3 mos 
and 6 
mos 
after 
end 
of 
treat-
ment
Every 
9 
weeks 
until 
PD
Scheduling Window (Days):
-28 to -1
± 3 ± 3
± 3
± 3
± 7
± 7
± 7
± 7
Thyroid function (T4, T3, 
TSH)16
X7
X7
X
X
X
HIV, Hepatitis B and C17
X
Laboratory Procedures/Assessments to be performed by a central laboratory
Humoral Immunity 
Assays18
X7
X7
X
Cytokine Panel19
X7
X
X
X7
X
X
X
Anti-MK-4166 Antibodies 
(Arms 1 & 2)20
X7
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics for MK-
4166 (Arms 1 & 2)21
X7
X
X
X
(require 
for 9 
lowest 
dose 
levels
in Arm 
1)
X
X
X
X
X
X
(require 
for 9 
lowest 
dose 
levels
in Arm 
1)
X
X
X
Anti-Pembrolizumab 
Antibodies (Arm 2 
only)22
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics for 
Pembrolizumab (Arm 2 
only)23
X
X
X
X
X
X
X
X
X
X
X
X
Blood for T-cell 
Immunophenotyping24
X
X
 
 
057N3N

Product:  MK-4166 
60
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Screening 
Phase
Treatment Phase1
Cycle = 21 days
End of 
Treatment
Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-4
Cycles 
5 and 6 
(Arm 2 
only)
Cycle 7 
and 
Beyond 
(Arm 2 
only)
Discon
Post 
Treat-
ment 
Safety 
Follow-
up
Follow-up 
Visits
Cycle Day
1
2
3
5
8
15
1
2
3
5
8
15
9 wks 
from 
1st
dose
1
1
At time of 
discon
30 days 
post 
discon
3 mos 
and 6 
mos 
after 
end 
of 
treat-
ment
Every 
9 
weeks 
until 
PD
Scheduling Window (Days):
-28 to -1
± 3 ± 3
± 3
± 3
± 7
± 7
± 7
± 7
Blood for RNA Correlative 
Studies25
X7
X7
Blood for DNA Correlative 
Studies25
X7
X7
Blood (DNA) for 
Genetics26
X
Tumor tissue collection 
(Parts B, D, and E
only)27
X
Post-treatment tumor 
biopsy(Parts B, D and E  
only)28
X
Pharmacodynamics 
(receptor availability 
flow cytometry assay)29
(Arms 1 & 2)
X
X7
X
X
(require 
for MK-
4166 
dose 
levels < 
30mg)
X
(require 
for 9 
lowest 
dose 
levels
in Arm 
1)
X
X
X
X
X
require 
for
MK-
4166 
dose 
levels 
< 
30mg)
X
(require 
for 9 
lowest 
dose 
levels
in Arm 
1
X
X
X
 
 
057N3N

Product:  MK-4166 
61
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
1.
In general, assessments/procedures are to be performed on Day 1 and prior to dosing for each cycle, unless otherwise specified.
2.
Written consent must be obtained prior to performing any protocol specific procedure. Tests performed prior to the subject signing consent as part of routine clinical management are acceptable 
in lieu of a screening test if performed within the specified time frame. 
3.
Signing the informed consent for future biomedical research (FBR) is optional, and may be signed at any time during the subjects participation in the trial. Detailed instructions for the collection 
and management of FBR specimens are provided in the Procedure Manual. 
4.
Prior medications-Record all medications taken within 28 days of the screening visit. Concomitant medication- Record all new medication started from the screening visit through the Safety 
Follow-up visit.
5.
In the Arm 2, pembrolizumab is administered first, then following a 30-minute interval, MK-4166 will be administered.
6.
Record all AEs occurring from signing of informed consent until 30 days after the last dose of MK-4166. Record all SAEs and ECIs through 90 days after last dose of treatment. Afterwards, 
report only SAEs and ECIs that are considered related to study treatment. See Section 7.2 for a full description of reporting requirements.
7.
These samples and procedures required predose Day 1 may be performed up to 72 hours prior to dosing.
8.
Vital signs (VS) to include temperature, pulse, respiratory rate and blood pressure. On Day 1 of Cycles 1-4 in Arm 1 and Arm 2, collect prior to dosing, at 2-hr, 4-hr and 6-hr after start of the 
MK-4166 infusion. In Arm 2, beginning with Cycle 5, collect VS prior to pembrolizumab dosing on Day 1 of each cycle. Weight to be obtained Day 1 of each cycle. Height to be recorded at 
Screening only.  
9.
12-lead ECG should be performed at screening for all subjects and repeated in Arm 1 prior to and within 30 minutes after the end of the MK-4166 infusion in Cycles 1-4, and at the 30 days post 
discon visit.
10.
Tumor imaging (CT scan or MRI) should be performed within 28 days of enrollment, 9 weeks after first dose, than every 9 weeks until disease progression. Imaging assessments should be 
repeated every 9 weeks and follow calendar days and should not be adjusted for delays in Cycle starts or extensions of dosing frequencies.  The same imaging technique should be used on a 
subject throughout the trial.  Scans used for tumor measurements may be requested for central review. 
11.
Response evaluation will be according to irRECIST version 1.1. Response will be assessed locally at the study site 9 weeks after the 1st dose, than every 9 weeks until disease progression. Disease 
progression, partial response and complete response to be confirmed at least 4 weeks after initial determination. Scans used for tumor measurements may be requested for central review.  The 
timing for imaging should follow calendar days and should not be adjusted for delays in Cycle starts or extension of cycle frequencies.  The same imaging technique should be used on a subject 
throughout the trial. 
12.
Upon Sponsor request, participants may be contacted for survival status at any time during the course of the study.
13.
In Arm 1 and Arm 2, on Day 1 in cycles 1-4, CBC with differential, CRP and chemistry panel should be drawn prior to dosing and repeated 4 hours after the start of the infusion, with results of 
the CBC and chemistry panel reviewed by the PI or appropriate designee before the subject is discharged from the clinic. In Arm 2, beginning with Cycle 5, CBC with differential, CRP and 
chemistry panel should be drawn prior to dosing.
14.
Laboratory tests at Screening are to be performed within 7 days prior to the first dose of study treatment.
15.
For women of reproductive potential, a urine pregnancy test will be performed at Screening and within 24 hours of receiving the first dose of study medication. If urine pregnancy test cannot be 
confirmed as negative, a serum pregnancy test is required.
16.
Thyroid function testing is to be performed starting in Cycle 1 and then every other cycle and at the Post treatment safety follow-up visit.
17.
Include HCV, RNA (qualitative) or Hepatitis C antibody, HBsAg, and HIV type 1 and type 2 (e.g., HIV-1/-2 antibody screening test and evaluation of HIV viral load as needed).
18.
Collect humoral immunity assays prior to dosing in Cycles 1-4 in Arm 1 and Cycles 1-6 in Arm 2 (specific assays designated in procedures manual).
19.
Collect cytokine panel on Day 1 predose, 1-hr, and 4-hr after the start of the infusion, and on Day 2, and Day 3 of Cycles 1-4 in Arm 1, and Cycles 1-6 in Arm 2. (Specific assays designated in 
procedures manual.)
20.
MK-4166 anti-drug antibody (ADA) will be drawn in Arm 1, predose on Day 1, Day 2, Day 3, Day 8 and Day 15 of Cycles 1-4. In Arm 2, MK-4166 ADA will be obtained predose on Day 1, 
Day 2, Day 3, Day 8 and Day 15 of Cycles 1-4, and predose on Day 1 of Cycles 5 and 6.
21.
MK-4166 pharmacokinetic (PK) samples will be drawn in each cycle on Day 1 predose, at the end of infusion (+ 10 minutes), 2h after the start of the infusion (+/- 10 minutes), and on Day 2, 
Day 3, Day 5, Day 8, and Day 15 for subjects treated at the 9 lowest dose levels in Arm 1. Starting at the 10th dose level in Arm 1 and all dose levels in Arm 2, PK samples will be drawn in each 
cycle on Day 1 predose, at the end of MK-4166 infusion (+ 10 minutes), 2h after the start of the MK-4166 infusion (+/- 10 minutes), on Day 2, Day 3, Day 8, and Day 15 of Cycles 1-4. In 
addition, in Arm 2, MK-4166 PK will be drawn predose in Cycles 5 and 6. If the sample day falls on a weekend or holiday, please consult the Sponsor for alternate sample collection times.
22.
Pembrolizumab anti-drug antibody (ADA) will be drawn in Arm 2 only predose on Day 1, Day 2, Day 3, Day 8 and Day 15 in Cycles 1-4, predose in Cycles 5, 6, 8 and every 4 cycles thereafter.
23.
Pembrolizumab  pharmacokinetic (PK) samples will be drawn in Arm 2 only, Cycles 1-4 Day 1 predose, at the end of the pembrolizumab infusion (+10 minutes), at the end of MK-4166 infusion 
(+ 10 minutes), 2h after the start of the MK-4166 infusion (+/- 10 minutes), and on Day 2, Day 3,  Day 8, and Day 15, predose in Cycles 5, 6, 8 and every 4 cycles thereafter. If the sample day 
falls on a weekend or holiday, please consult the Sponsor for alternate sample collection times.
24.
Blood for T-cell immunophenotyping will be drawn prior to dosing on Day 1 of Cycles 1-4. Detailed instructions for the collection and management of these samples are provided in the Procedure 
Manual.
 
 
057N3N

Product:  MK-4166 
62
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
25.
Blood for correlative studies (RNA and DNA samples) will be drawn prior to dosing on Cycle 1 Day 1 and prior to dosing on Cycle 2 Day 1 or Cycle 1 Day 22 for subjects who do not receive a 
second dose of MK-4166. Detailed instructions for the collection and management of these samples are provided in the Procedure Manual.
26.
Blood for genetics sample will be collected to explore host genetics and to identify genetic predictors which may have a role in therapeutic response to MK-4166. Detailed instructions for the 
collection and management of the genetics sample are provided in the Procedure Manual. Blood for genetics will be retained for Future Biomedical Research if the subject signs the Future 
Biomedical Research informed consent.
27.
Tumor tissue (archival or newly obtained biopsy) will be required in Parts B, D, and E. Leftover tissue may also be saved for future biomedical research if the subject signs the Future Biomedical 
Research consent.
28.
Tumor biopsy will be requested in Parts B, D and E, in Cycle 1 between Day 8 and Day 15. Leftover tissue may also be saved for future biomedical research if the subject signs the Future 
Biomedical Research consent.
29.
Blood sample for Pharmacodynamic (PD) will be drawn in Screening, in Cycles 1-4 on Day 1 pre-dose, at the end of MK-4166 infusion (+ 10 minutes), 2h after the start of the MK-4166 infusion 
(+/- 10 minutes), on Day 2, Day 3, Day 5, Day 8, and Day 15 for subjects treated at the 9 lowest dose levels in Arm 1. Starting at the 10th dose level in Arm 1 and all dose levels in Arm 2, PD 
samples will be drawn in Screening, in Cycles 1-4 on Day 1 pre-dose, at the end of the MK-4166 infusion (+ 10 minutes), 2h after the start of the MK-4166 infusion (+/- 10 minutes), on Day 2, 
Day 3, Day 8, and Day 15. In addition, in Arm 2, PD samples will be drawn predose in Cycles 5-6. In both Arms, the following 2 timepoints -Day 1 2hr after start of infusion and Day 3 - PD 
samples will not be collected once the dose level off MK-4166 is >30 mg.  If the sample day falls on a weekend or holiday, please consult the Sponsor for alternate sample collection times. If 
the data from the receptor availability assay indicates saturation of the receptor at a given dose, then the Sponsor may eliminate collection of blood for and assessment of this pharmacodynamic 
assay at higher doses.  This will be indicated in an administrative memo.
 
 
057N3N

Product:  MK-4166 
63
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing may 
be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial.
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
057N3N

Product:  MK-4166 
64
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent to 
the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Details regarding the disease for 
which the subject has been enrolled in this trial will be recorded separately and should not be 
listed in medical history. Smoking history will be obtained.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before starting the trial. Treatment for the disease for which the subject has 
been enrolled in this trial will be recorded separately and should not be listed in prior 
medications.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record all medication, if any, taken by the subject 
during the trial and through the 30-day Safety Follow-up visit. After the Safety visit, record all 
medications related to reportable SAEs and ECIs.
 
 
057N3N

Product:  MK-4166 
65
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
7.1.1.6
Disease Details and Treatments
7.1.1.6.1 Disease Details
The Investigator or qualified designee will obtain prior and current details regarding disease
status.
7.1.1.6.2 Prior Oncology Treatment History
The Investigator or qualified designee will record all prior cancer treatments including 
systemic treatments, radiation and surgeries.
7.1.1.7
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or allocation.  Each subject will 
be assigned only one screening number.  Screening numbers must not be re-used for different 
subjects.  
Any subject who is screened multiple times will retain the original screening number assigned 
at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.  
7.1.1.8
Assignment of Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
randomization number.  The randomization number identifies the subject for all procedures 
occurring after treatment allocation.  While the subjects are being “allocated” to their 
treatment, and not in fact “randomized”, this unique number is termed a randomization number 
throughout the protocol for operational purposes. Beginning with Amendment #3, the 
randomization number will be assigned by an IVRS at time of enrollment. Allocation of 
subjects between the 2 arms will be managed by the Sponsor through the IVRS. Once a 
randomization number is assigned to a subject, it can never be re-assigned to another subject.
A single subject cannot be assigned more than 1 randomization number.
In a situation where rerandomization of the subject is planned (eg, study extension periods), 
the rerandomization will be based on a new randomization schedule; however, each subject 
will retain his/her original treatment/randomization number. Only the study intervention 
regimen associated with the rerandomization period or phase may change.
7.1.1.9
Trial Compliance (Study Drug Administration)
All doses of MK-4166 and pembrolizumab will be administered under the supervision of a 
qualified physician and/or designee experienced in the use of anticancer agents.
 
 
057N3N

Product:  MK-4166 
66
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
The instructions for preparing and administering MK-4166 and pembrolizumab are provided 
in the Procedure Manual. 
Interruptions from the protocol specified treatment for 28 days require consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
subject management.
Clinical Procedures/Assessments
7.1.2.1
Adverse Event (AE) Monitoring
The Investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated. 
Adverse events will be graded according to NCI CTCAE Version 4. Toxicities will be 
characterized in terms of seriousness, causality, toxicity grade and action taken with regard to 
trial treatment. 
All AEs of unknown etiology associated with MK-4166 and pembrolizumab exposure should 
be evaluated to determine if it is possibly an event of clinical interest (ECI) of a potential 
immunologic etiology (irAE). See Section 5.2.3.2 regarding the identification, evaluation and 
management of AEs of a potential immunological etiology.
This is a dose escalation trial to establish the MTD of MK-4166 alone and in combination with 
pembrolizumab; therefore, each dose escalation will be based on the safety and tolerability 
experienced by subjects at each dose level. The safety and tolerability of each cohort for the 
DLT evaluation period will be reviewed prior to the start of the next cohort. The Sponsor and 
the Principal Investigators will review the safety and tolerability of each trial treatment, the 
appropriateness of dose escalation, when each cohort is completed and the next cohort is 
opened for enrollment. Frequency of these communications will depend on the enrollment of 
each cohort, as well as any potential new information regarding a safety concern in this trial or 
other relevant trials.
As a Phase 1 trial, there is no plan for an external safety reviewer. Data from individual subjects 
will be closely followed on an ongoing basis by the Principal Investigator and the Sponsor.
7.1.2.2
Full Physical Examination
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant findings from the screening exam should be recorded 
as medical history. 
A full physical exam should be repeated according to the frequency defined in the Study Flow 
Chart (Section 6.0). After the first dose of study treatment, new clinically significant abnormal 
findings should be recorded as AEs.
 
 
057N3N

Product:  MK-4166 
67
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
7.1.2.3
Vital Signs and Weight
Vital signs should include temperature, pulse, respiratory rate, blood pressure and weight at 
the frequency defined in the Study Flow Chart (Section 6.0).
Height will be obtained at Screening only.
7.1.2.4
Electrocardiogram (ECG)
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 timepoints for ECGs are according to the Study Flow Chart (Section 6.0). Clinically 
significant abnormal findings seen on all ECGs performed after Screening should be recorded 
as AEs.
7.1.2.5
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess the ECOG performance status as the 
timepoints specified in the Study Flow Chart (Section 6.0).
7.1.2.6
Tumor Imaging
The initial CT scan or MRI for tumor imaging must be performed within 28 days prior to
enrollment, and the site study team must confirm the subject has measurable disease as defined 
by RECIST version 1.1 to confirm eligibility. 
Tumor imaging performed should be repeated every 9 weeks from the first dose of treatment 
until confirmed disease progression, the start of new anti-cancer therapy, withdrawal of 
consent, death or end of the study, whichever comes first. 
The same imaging technique should be performed at each timepoint.
Scans used for tumor measurements may be requested for central review.
7.1.2.7
Response Assessment
7.1.2.7.1 Immune-related RECIST (irRECIST)
RECIST 1.1 will be adapted to account for the unique tumor response characteristics seen with 
treatment with pembrolizumab and MK-4166. 
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-4166. Immune-related RECIST (irRECIST) is 
 
 
057N3N

Product:  MK-4166 
68
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
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 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 
≥4 weeks later in order to confirm PD with the option of continuing treatment per below while 
awaiting radiologic confirmation of progression.  
If repeat imaging shows <20% tumor burden compared to nadir, stable or improved previous 
new lesion (if identified as cause for initial PD), and stable/improved non-target disease (if 
identified as cause for initial PD), PD is not confirmed.  Treatment may be continue and 
subsequently follow regular imaging schedule.  
If repeat imaging confirms PD due to any of the scenarios list below, subjects will be 
discontinued from study therapy. A subject with confirmed radiologic progression may 
continue to receive study treatment, after consultation with the Sponsor, if the Investigator 
deems the subject is receiving clinical benefit or value from treatment. Subjects who continue 
to receive study treatment after confirmed radiologic progression will continue to be followed 
according to the procedures and assessments listed under Cycle 7 and beyond in the Trial Flow 
Chart (Section 6.0).
In determining whether or not the tumor burden has increased or decreased, the Investigator 
should consider all target lesions as well as non-target lesions.
Scenarios where PD is confirmed at repeat imaging:

Tumor burden remains ≥ 20% and at least 5 mm absolute increase compared to nadir

Non-target 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 non-target progression since last evaluation
 
 
057N3N

Product:  MK-4166 
69
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
In subjects who have initial evidence of radiological PD, it is at the discretion of the PI whether 
to continue a subject on study treatment until repeat imaging is obtained.  This clinical 
judgment decision should be based on the subject’s overall clinical condition, including 
performance status, clinical symptoms, and laboratory data.  Subjects may receive study
treatment while waiting for confirmation of PD if they are clinically stable as defined by the 
following criteria:

Absence of symptoms and signs indicating clinically significant progression of disease, 
including worsening of laboratory values

No decline in ECOG performance status

Absence of rapid progression of disease

Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention
When feasible, subjects should not be discontinued until progression is confirmed.  This 
allowance to continue treatment despite initial radiologic progression takes into account the 
observation that some subjects can have a transient tumor flare in the first few months after the 
start of immunotherapy, but with subsequent disease response.  Subjects that are deemed 
clinically unstable are not required to have repeat imaging for confirmation of progressive 
disease. 
NOTE:  In subjects who discontinue study therapy without documented disease progression, 
every effort should be made to continue monitoring their disease status by radiologic imaging 
every 9 weeks (± 7 days) until: (1) the start of new anti-cancer treatment, (2) disease 
progression (3) death, or (4) the end of the study, whichever occurs first.
Confirmation of partial response (PR) and complete response (CR) is required at least 4 weeks 
after the initial response assessment of PR and CR.
7.1.2.8
Tumor Tissue Collection and Correlative Studies Blood Sampling
In Arm 1 (Part B) and Arm 2 (Parts D and E) of the study, subjects will be required to provide 
an archival tumor tissue sample and/or a fresh tumor biopsy for biomarker analysis before 
starting treatment. Subjects will also be asked to agree to an optional tumor biopsy for 
biomarker analysis after starting treatment. Samples will be sent to a central laboratory.
Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are preferred; if 
submitting unstained slides, the slides should be freshly cut and submitted to the testing 
laboratory within 14 days from site slide sectioning date otherwise a new specimen will be 
requested.
 
 
057N3N

Product:  MK-4166 
70
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
If the subject signs the Future Biomedical Research (FBR) consent, any leftover tissue that 
would ordinarily be discarded at the end of the main study will be retained for FBR. Details 
regarding time points for collection of tumor tissue are outlined in the Study Flow Chart –
Section 6.0.
Blood for correlative studies (RNA and a separate DNA sample) will be obtained prior to 
dosing in Cycle 1 and prior to dosing in Cycle 2, or Cycle 1 Day 22 for subjects who do not 
receive a second dose of MK-4166.
Sample collection, storage, and shipment instructions for archival tumor tissue samples, newly 
obtained biopsy specimens, and blood for correlative studies are provided in the Procedure 
Manual.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of the 
trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject are provided in the Procedure Manual.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 8.
 
 
057N3N

Product:  MK-4166 
71
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Table 8
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic gonadotropin 
(β-hCG)
Hemoglobin
Alkaline phosphatase
Glucose
Hepatitis B (HBsAg)
Platelet count
Alanine aminotransferase 
(ALT)
Protein
Hepatitis C (HCV RNA) or Hepatitis C 
antibody
WBC (total and 
differential)
Aspartate aminotransferase 
(AST)
Specific gravity 
HIV
Red 
Blood 
Cell 
Count
Carbon dioxide (CO2 or 
Bicarbonate
Microscopic exam, 
if abnormal results 
are noted
PT (INR)
Absolute 
Neutrophil Count
Calcium
Urine pregnancy test
aPTT
Absolute 
lymphocyte count
Chloride
IgA
C reactive protein
Creatinine
IgG
Glucose
IgM
Lactate 
dehydrogenase 
(LDH)
Free thyroxine (T4)
Phosphorus
Thyroid Stimulating Hormone (TSH)
Potassium
Total Triiodothyronine (T3)
Sodium
Anti-MK-4166 antibodies
Total Bilirubin  
Humoral Immunity Assay
Direct Bilirubin, if total 
bilirubin is elevated above 
the upper limit of normal
Anti-MK-3475/pembrolizumab 
antibodies
Total protein
Cytokines
Blood Urea Nitrogen
Uric acid
Gamma Glutamyl 
transpeptidase (GGT)
Laboratory tests for Screening should be performed within 7 days prior to the first dose of MK-
4166 or pembrolizumab. After Cycle 1, pre-dose laboratory tests can be performed up to 72 
hours prior to dosing. Results must be reviewed by the investigator of qualified designee and 
found to be acceptable prior to each dose of MK-4166 or pembrolizumab.
7.1.3.2
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2.1 Blood Collection for Serum MK-4166 and Pembrolizumab
To evaluate the exposure of MK-4166 and pembrolizumab in this indication, sample 
collections for analysis of PK are currently planned as shown in the Trial Flow Chart. Blood 
samples for PK collected may be stored. Analysis will be performed only if required. If 
ongoing PK sampling is deemed to be unnecessary by the Sponsor, it may be reduced or 
discontinued.
 
 
057N3N

Product:  MK-4166 
72
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
7.1.3.2.2 Blood Collection for Anti-MK-4166 Antibodies and Anti-Pembrolizumab 
Antibodies
To evaluate the immunogenicity of MK-4166 and pembrolizumab in this indication, sample 
collections for analysis of ADAs are currently planned as shown in the Trial Flow Chart. Blood 
samples for ADA collected may be stored. Analysis will be performed only if required. If 
ongoing ADA sampling is deemed to be unnecessary by the Sponsor, it may be reduced or 
discontinued.
7.1.3.2.3 Blood for Receptor Availability Assay
Sample collection, storage, and shipment instructions for receptor availability flow cytometry 
assay samples are provided in the Procedure Manual. 
The timepoints for PD sampling are described in Section 6.0-Trial Flow Chart.
Once the PD Receptor Availability Assay indicates saturation of the receptor, then the Sponsor
may elect to not collect samples for this PD assay at higher doses.  In this case, the Sponsor
will notify study sites by administrative memo that this sample no longer will be collected.  
Decision to stop collection of blood for the receptor Availability Assay will be made 
independently for Arms 1 and 2.
7.1.3.3
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover blood for genomics use

Leftover archival tumor tissue or leftover newly obtained biopsy samples
Other Procedures
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from treatment prior to completion of the treatment/ 
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the discontinuation visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their specimens 
and all derivatives destroyed.   Subjects may withdraw consent at any time by contacting the 
 
 
057N3N

Product:  MK-4166 
73
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
principal investigator for the main trial.  If medical records for the main trial are still available, 
the 
investigator 
will 
contact 
the 
Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the subject's 
specimens will be removed from the biorepository and be destroyed.  A letter will be sent from 
the Sponsor to the investigator confirming the destruction. It is the responsibility of the 
investigator to inform the subject of completion of destruction.  Any analyses in progress at 
the time of request for destruction or already performed prior to the request being received by 
the Sponsor will continue to be used as part of the overall research trial data and results.   No 
new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for specimen 
destruction cannot be processed.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
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 with the study 
documentation as source documentation at the trial site.
Critical Equipment for this trial includes:

Laboratory equipment – as required for inclusion labs and trial assessments

Imaging equipment – as required for study objectives

ECG equipment – as required for trial assessments

Infusion syringe and/or pump – used to administer study treatment
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
 
 
057N3N

Product:  MK-4166 
74
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
7.1.5.1
Screening
Approximately 28 days prior to the first dose of treatment, potential subjects will be evaluated 
to determine that they fulfill the entry requirements as set forth in Section 5.1. 
Screening procedures may be repeated after consultation with the Sponsor.
Written consent must be obtained prior to performing any protocol specific procedure. Results 
of a test performed prior to the subject signing consent as part of routine clinical management 
are acceptable in lieu of a screening test if performed within the specified time frame. 
Screening procedures are to be completed within 28 days prior to the first dose of trial treatment 
except for the following:

Screening laboratory tests are to be performed within 7 days prior to the first dose of 
trial treatment.

For women of reproductive potential, a urine pregnancy test will be performed within 
24 hours prior to first dose of trial treatment. If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test, performed by the local study site 
laboratory, will be required.
7.1.5.2
Treatment Period
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related
details are provided above in Section 7.1 - Trial Procedures.
After a screening phase of up to 28 days, eligible subject will be assigned to one of 2 Arms 
and a dose level of MK-4166 by the Sponsor. In Arms 1 and 2, MK-4166 treatment will be 
administered on Day 1 of each 21-day cycle for up to a maximum of 4 cycles. In Arm 2, 
pembrolizumab will be administered on Day 1 of each 21 day cycle for up to 24 months of 
treatment.
Subjects will be followed until confirmed disease progression, unacceptable adverse event(s), 
intercurrent illness that prevents further administration of treatment, investigator’s decision to 
withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance 
with trial treatment or procedure requirements, or administrative reasons requiring cessation 
of treatment.
7.1.5.3
Post-Treatment Visits
7.1.5.3.1 Safety Follow-up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the
last dose of trial treatment or before the initiation of a new antineoplastic treatment, whichever 
comes first. Subjects with an AE of Grade >1 will be further followed until the resolution of 
the AE to Grade 0-1 or until beginning of a new antineoplastic therapy, whichever occurs first. 
 
 
057N3N

Product:  MK-4166 
75
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.
7.1.5.3.2 Follow-up Visits
Subjects who complete treatment or who discontinue trial treatment for a reason other than 
disease progression, will move into the Follow-Up Phase and should be assessed every 9 weeks 
(± 7 days) by radiologic imaging to monitor disease status. Every effort should be made to 
collect information regarding disease status until the start of new anti-neoplastic therapy, 
disease progression, death, or end of the study.
Once subjects have achieved the study objectives or the study has ended, they will be 
discontinued from this study and will be enrolled into an extension study to continue 
protocol-defined assessments and treatment.
7.1.5.4
Survival Status
To ensure current and complete survival data is available, updated survival status may be 
requested during the course of the study by the Sponsor. Upon Sponsor notification, all 
participants who do not/will not have a scheduled study visit or study contact during the 
Sponsor-defined time period will be contacted for their survival status (excluding participants 
who have a previously recorded death event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by the Sponsor for human use.
Adverse events may occur during the course of the use of the Sponsor's product in clinical 
trials or within the follow-up period specified by the protocol, or prescribed in clinical practice, 
from overdose (whether accidental or intentional), from abuse and from withdrawal.
 
 
057N3N

Product:  MK-4166 
76
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Adverse events may also occur in screened subjects during any pre-allocation baseline period 
as a result of a protocol-specified intervention, including washout or discontinuation of usual 
therapy, diet, placebo treatment or a procedure.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before 
randomization/treatment allocation must be reported by the investigator if they cause the 
subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.
From the time of randomization/treatment allocation through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be recorded 
at each examination on the Adverse Event case report forms/worksheets.  The reporting 
timeframe for adverse events meeting any serious criteria is described in section 7.2.3.1. The 
investigator will make every attempt to follow all subjects with non-serious adverse events for 
outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-4166 by 20%, or a pembrolizumab dose of 1000mg (5x the indicated dose). 
No specific information is available on the treatment of overdose of MK-4166 or 
pembrolizumab. In the event of overdose, treatment should be discontinued and the subject 
should be observed closely for signs of toxicity.  Appropriate supportive treatment should be 
provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor either by electronic media or paper.  Sponsor Contact information can be found in 
the Investigator Trial File Binder (or equivalent).
 
 
057N3N

Product:  MK-4166 
77
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before 
randomization/treatment allocation must be reported by the investigator if they cause the 
subject to be excluded from the trial, or are the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, placebo 
treatment or a procedure.  
Pregnancies and lactations that occur from the time of randomization/treatment allocation 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator.  All reported pregnancies must be followed to the completion/termination 
of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor 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).
Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
 
 
057N3N

Product:  MK-4166 
78
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Refer to (Table 9) for additional details regarding each of the above criteria.
Progression of the cancer under study is not considered an adverse event unless it results in 
hospitalization or death.
For the time period beginning when the consent form is signed until randomization/treatment 
allocation, any serious adverse event, or follow up to a serious adverse event, including death 
due to any cause other than progression of the cancer under study (reference Section 7.2.3.3 
for additional details), that occurs to any subject must be reported within 24 hours to the 
Sponsor if it causes the subject to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure.
For the time period beginning at randomization/treatment allocation through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study (reference Section 7.2.3.3 for additional details), whether or not related to the Sponsor's 
product, must be reported within 24 hours to the Sponsor either by electronic media or paper. 
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent)
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph also 
must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until randomization/treatment 
allocation, any ECI, or follow up to an ECI, that occurs to any subject must be reported within 
24 hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of 
a protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at randomization/treatment allocation through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry guidelines. 
Paper reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
057N3N

Product:  MK-4166 
79
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the 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).
A separate guidance document has been provided entitled “MK-4166 and Pembrolizumab
Events of Clinical Interest and Immune-Related Adverse Event Guidance Document.” This 
document can be found in the administrative binder and provides guidance regarding 
identification, evaluation and management of ECIs and irAEs. Subjects should be assessed for 
possible ECIs prior to each dose. Laboratory results should be evaluated and subjects should 
be asked for signs and symptoms suggestive of an immune-related event. Subjects who develop 
an ECI thought to be immune-related should have additional testing to rule out other etiological 
causes. If laboratory results or symptoms indicated a possible immune-related ECI then 
additional testing should be performed to rule out other etiologic causes. If no other cause was 
found, then it is assumed to be immune-related. 
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
 
 
057N3N

Product:  MK-4166 
80
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Table 9
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer; (that is not a condition of the study) or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
test drug 
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, 
ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below 
are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor’s product?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
057N3N

Product:  MK-4166 
81
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR CLINICAL 
DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's product 
is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR there is another obvious cause of the AE.  (Also entered for a subject with overdose without an associated AE.)
 
 
057N3N

Product:  MK-4166 
82
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  Changes to 
analyses made after the protocol has been finalized, but prior to unblinding, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report (CSR) 
for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan is 
provided in Section 8.2 to Section 8.12.
Study Design Overview
Phase 1 trial of single agent MK-4166 and MK-4166 in combination with 
pembrolizumab in subjects with advanced malignancies
Analysis Populations
Safety: All Subjects as Treated (ASaT)
Efficacy (exploratory): Single agent MK-4166: Full Analysis Set (FAS1); 
MK-4166 in combination with pembrolizumab: Full Analysis Set (FAS2)   
Primary Endpoint(s)
Safety: DLT   
Key Secondary Endpoints
PK parameters of single agent MK-4166 and MK-4166 in combination with 
pembrolizumab
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Serum concentrations of MK-4166 in the MK-4166 Arm and serum 
concentrations of MK-4166 and pembrolizumab in the MK-4166 administered 
with pembrolizumab Arm will be summarized by planned visit and time for 
each dose separately; PK parameters will be summarized by dose
Treatment Assignment
Subjects are allocated to increasing doses of  single agent MK-4166 and MK-
4166 co-administered with pembrolizumab without randomization; the study 
is open-label
Statistical Methods for Key 
Safety Analyses
Summary statistics (counts, percentage, mean, standard deviation, etc.) will be 
provided for the safety endpoints as appropriate
Interim Analyses
Study has no interim analyses
Multiplicity
No multiplicity adjustment is planned in this Phase 1/1b study.
Sample Size and Power 
The sample size of the dose acceleration, dose escalation, and dose 
confirmation parts of the study depends on the observed DLT profiles of 
MK-4166 monotherapy and MK-4166 co-administered with pembrolizumab.  
The sample size of 92 subjects will be used for study planning purposes.
Responsibility for Analyses/In-House Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
 
 
057N3N

Product:  MK-4166 
83
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
This trial is conducted as an open-label trial, i.e., subjects, investigators, and Sponsor personnel 
will be aware of subject treatment assignments after each subject is enrolled and treatment is 
assigned. Allocation to treatment will not be randomized.
The database will be locked for analysis 6 months after the enrollment of the last subject. 
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy and safety endpoints are listed below, followed by the descriptions of the derivations 
of selected endpoints.
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Efficacy endpoints and their definitions are presented in Section 8.4.3.
Safety Endpoints
The primary safety endpoint is DLT.  Safety will be monitored by cumulative data reviews 
throughout the trial.  The toxicities and grades experienced by subjects who have received 
study treatment, including adverse events (AEs), serious adverse events (SAEs) and events of 
clinical interest (ECIs) will be summarized.  Other safety measures evaluated in all parts of the 
study include laboratory safety assessments, ECGs, vital signs, and physical examinations.
Derivations of Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Exploratory efficacy endpoints and their definitions are presented below.
Objective Response Rate (ORR): is defined as the percentage of subjects who have achieved 
confirmed complete response (CR) or partial response (PR) according to irRECIST 1.1 by the 
investigator review. Subjects with missing outcome on objective response will be considered 
non-responders. This endpoint is used to evaluate 2 primary efficacy hypotheses.
Disease Control Rate (DCR): is defined as the percentage of subjects who have achieved 
stable disease or confirmed complete response (CR) or confirmed partial response (PR) 
according to irRECIST 1.1 by the investigator review. Subjects with missing outcome on 
objective response will be considered non-responders. 
Duration of Response (DOR): is defined as the time interval between the date of the first 
confirmed response (CR/PR) (the response prior to confirmation) and the date of first 
documented disease progression based upon irRECIST 1.1 by the investigator review. 
Response duration will be only determined for confirmed responses.
 
 
057N3N

Product:  MK-4166 
84
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Best Overall Response per irRECIST 1.1 [Appendix 12.6]: the best response attained during 
the study with 4 categories based upon irRECIST 1.1 by the investigator review:  Complete 
Response (CR), Partial Response (PR), Stable Disease (SD), and Progressive Disease (PD).  
Categories of CR and PR need to be confirmed in this endpoint.
Progression-free Survival (PFS): is defined as the time from the start of treatment to 
progressive disease (PD) or death, whichever occurs earlier, based upon irRECIST 1.1 by the 
investigator review. Subjects without documented PD/death will be censored at the last disease 
assessment date. 
Best Target Lesion Response: is defined as the maximum percent reduction in tumor line 
length over target lesions by the investigator review.
Time to Confirmed Response: is defined only for subjects with confirmed response by the 
investigator review as the time interval between the start of treatment allocation and the date 
of the first confirmed response (CR/PR) (the response prior to confirmation).
Additional supportive analyses of these endpoints based on RECIST 1.1 criteria and, if needed, 
central review might be conducted.   
PK endpoints: serum concentrations of MK-4166 and pembrolizumab and derived PK 
parameters.
Target engagement endpoints: to be used in descriptive analyses
Biomarker endpoints: to be used in descriptive analyses
Derivations of Safety Endpoints
Description of safety measures is provided in Section 7.0.
Analysis Populations
Safety Analysis Populations
The All-Subjects-as-Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all subjects who received at least 1 dose of study 
treatment.  In case of treatment administration errors, subjects will be analyzed according to 
the treatment they actually received. For DLT evaluation, ASaT subjects that were observed 
for safety for 21 days after the first dose of assigned treatment or experienced a DLT prior to 
21 days after the first dose of assigned treatment will be used.
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.
 
 
057N3N

Product:  MK-4166 
85
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Efficacy Analysis Populations
The full analysis set populations FAS1 and FAS2 are defined as all subjects with a baseline 
scan with measurable disease by investigator assessment who were administered MK-4166 
(Arm 1; FAS1) or MK-4166 and pembrolizumab (Arm 2; FAS2). These populations will be 
used for exploratory analyses of efficacy.
Analysis of response duration is based on all confirmed responders.
Statistical Methods
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the exploratory efficacy objectives.  
For the subset of FAS1 subjects treated at the RP2D or MTD for MK-4166 monotherapy and 
the subset of FAS2 subjects treated at the RP2D for combination MK-4166 plus
pembrolizumab therapy, the estimates of the ORR and DCR and the 95% confidence intervals
for the estimates based on the Clopper-Pearson method will be provided. For PFS, DOR, and 
time to confirmed response Kaplan-Meier plots will be provided. The waterfall plots will be 
provided for the best target lesion response and the swimmer plots will be provided for DOR.
The ORR, DCR, BOR, DOR, PFS, best target lesion response, and time to confirmed response 
in subjects treated with doses below the RP2D will be listed along with baseline characteristics. 
For PFS, subjects without documented PD/death will be censored at the last disease assessment 
date or, if they started new anti-cancer treatment, at the last disease assessment before initiation 
of the new anticancer treatment. 
Descriptive statistics will be provided for other exploratory efficacy parameters.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, ECG measurements and physical examinations.
DLTs will be listed.  DLTs and adverse experiences will be summarized as counts and 
frequencies for each MK-4166 (Arm 1) or MK-4166 in combination with pembrolizumab dose 
level that had at least 3 subjects treated and listed for other dose levels. Laboratory assessments, 
vital signs, and other safety endpoints will be summarized as appropriate.
Immune-related ECIs (irECIs) that are designated as AEs of special interest will be 
summarized in separate tables from other AEs.  Any AE of unknown etiology associated with 
MK-4166 or MK-4166 in combination with pembrolizumab exposure will be evaluated to 
determine if it is possibly an event of clinical interest (ECI) of a potentially immunologic 
etiology (irECI) (see Section 7.2.3.2).  
 
 
057N3N

Product:  MK-4166 
86
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
In addition, the broad clinical and laboratory AE categories consisting of the percentage of 
subjects with any AE, a drug related AE, a serious AE, an AE which is both drug-related and 
serious, and who discontinued due to an AE will be summarized for dose levels with at least 3 
subjects treated and listed for other doses.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3.1
Demographic and Baseline Characteristics
The number and percentage of subjects screened, randomized/allocated, the primary reasons 
for screening failure, and the primary reason for discontinuation will be displayed.  
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized either by descriptive statistics or categorical 
tables for ASaT population (by Arm), the set of subjects treated with the recommended 
MK-4166 Phase 2 dose or MTD, and the set of subjects treated with the recommended Phase 2
dose for combination of MK-4166 with pembrolizumab.
8.6.3.2
Population PK Analyses
Serum concentrations of MK-4166 in the MK-4166 Arm and serum concentrations of 
MK-4166 and pembrolizumab in the MK-4166 administered with pembrolizumab Arm will be 
summarized by planned visit and time for each dose separately; PK parameters will be 
summarized by dose. Descriptive statistics will be provided for each dose with at least 
3 subjects; for other doses, the results will be listed.
The data from the study will be used to quantitatively explore the relationships among 
pharmacokinetics, target engagement, exploratory biomarkers and tumor response 
measurements.
Interim Analyses
No interim analyses are planned for this study.
Multiplicity
There will be no multiplicity control in this study.
Sample Size and Power Calculations
Dose Escalation and Dose Confirmation
The primary purpose of the dose escalation and dose confirmation parts of the trial is to 
investigate the safety and tolerability of MK-4166 monotherapy and MK-4166 
co-administered with pembrolizumab in adult subjects with advanced solid tumors and to 
establish the MTD/RP2D for MK-4166 monotherapy and MK-4166 co-administered with 
pembrolizumab. 
 
 
057N3N

Product:  MK-4166 
87
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
The final number of subjects enrolled in the dose escalation and confirmation parts of the study 
will depend on the empirical safety (DLT) observations, in particular, at what doses the 3+3 
design is triggered, and what doses are identified as the RP2Ds. Sample sizes for a few possible 
scenarios as well as the estimated time required to enroll all subjects and the time required to 
determine the MTD are provided below.  The time required to estimate the MTD is the time 
from the first subject’s first dose to the end of the 3-week observation period following the 
first dose of the last subject enrolled in the dose confirmation part.  The study duration is 
derived as the time from the first subject’s first dose in Part A to the end of the 2-year treatment 
period following enrollment of the last subject in Part E.
The enrollment time was conservatively estimated assuming that during dose acceleration a 
subject can be enrolled every 3 weeks and during the 3+3 parts and the dose confirmation a 
subject can be enrolled every week. 
Scenario 1:  No DLTs during Parts A, B, D, and E.  For MK-4166 monotherapy, in a scenario 
where no DLTs are encountered during the dose escalation part and Part B continues to the 
highest dose in Table 2, the sample size across Parts A and B would be 36 subjects (9 subjects 
in Part A plus 27 subjects across 9 doses in Part B).  For MK-4166 with pembrolizumab, in a 
scenario where Arm 2 starts at 1.1 mg MK-4166 and 200 mg pembrolizumab and no DLTs are 
encountered during the dose escalation and confirmation parts so that Part D continues to the 
highest dose in Table 3, the sample size across Parts D and E would be 56 subjects (36 subjects 
across 12 doses in Part D plus 20 subjects at the RP2D in Part E).  In this scenario, the total 
sample size would be 92 subjects.  
It would take 27 weeks to enroll 9 MK-4166 monotherapy subjects in Part A and proceed to 
Part B enrolment; it would take an additional 83 weeks to enroll 83 subjects (27 in Part B and 
56 in Parts D and E). Thus, in this scenario the enrollment time would be 110 weeks and the 
time required to determine the 2 MTDs would be 113 weeks. The study duration then would 
be approximately 110 weeks + 2 years or 4.12 years. If dose escalation stops at a dose below 
the highest dose in either treatment arm, the study might require less than 92 subjects and the 
enrollment duration might be less than 110 weeks. Also, with no DLTs observed, it might be 
possible to enroll subjects faster than 1 subject every week during the 3+3 dose escalation parts 
(Parts B and D) and the dose confirmation part (Part E) which would shorten the study duration.
Scenario 2: Flat DLT dose response.  Suppose no DLTs are observed in Part A, and dose 
escalation in Parts B and D continues to the highest dose with flat dose response so that in Arm 
1, 4 doses are given to 3 subjects each and 5 doses (including the highest one) are given to 
6 subjects each in Part B, while in Arm 2, 6 doses are given to 3 subjects each and 6 doses 
(including the highest one) are given to 6 subjects each in Part D.  Also suppose that the top 
dose is confirmed as the RP2D dose without de-escalation in Part E.  Thus, the sample size in 
Arm 1 would be 51 subjects (9 subjects in Part A plus 42 subjects in Part B) and the sample 
size in Arm 2 would be 74 subjects (54 subjects in Part D plus 20 subjects in Part E). In this 
scenario, the total sample size would be 125 subjects. 
It would take 27 weeks to enroll 9 MK-4166 monotherapy subjects in Part A and proceed to 
Part B enrolment; it would take an additional 116 weeks to enroll 116 subjects (42 in Part B 
 
 
057N3N

Product:  MK-4166 
88
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
and 74 in Parts D and E). Thus, in this scenario the enrollment time would be 143 weeks and 
the time required to determine the 2 MTDs would be 146 weeks. The study duration then 
would be approximately 143 weeks + 2 years or 4.75 years.
Scenario 3: Early start of 40% dose increments for Arm 2.  If in Arm 2, 40% increments in 
the 3+3 design doses are triggered at the 1.1 mg dose and dose escalation continues in 21 steps 
to the 900 mg dose, with 3 subjects per dose in the 3+3 design, the sample size across Parts D 
and E in Arm 2 would be 83 subjects (63 subjects in Part D plus 20 subjects in Part E).  Suppose 
that dose escalation in Arm 1 proceeds without DLTs as in Scenario 1, and thus, the sample 
size of Arm 1 is 36 subjects (9 subjects in Part A plus 27 subjects across 9 doses in Part B). In 
this scenario, the total sample size would be 119 subjects.  
It would take 27 weeks to enroll 9 MK-4166 monotherapy subjects in Part A and proceed to 
Part B enrolment; it would take an additional 110 weeks to enroll 110 subjects (27 in Part B 
and 83 in Parts D and E). Thus, in this scenario the enrollment time would be 137 weeks and 
the time required to determine the 2 MTDs would be 140 weeks. The study duration then 
would be approximately 137 weeks + 2 years or 4.6 years.
The plausible sample size of approximately 92 subjects and the enrollment time of 110 weeks
that correspond to the first described scenario are used for operational purposes.
Subgroup Analyses and Effect of Baseline Factors
No subgroup analyses will be performed.
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study.  Percent 
compliance with drug administration may be calculated for each subject for MK-4166 and 
pembrolizumab separately.
Extent of Exposure
A subject’s extent of exposure to MK-4166 is defined as the total number of doses of MK-4166 
the subject received.  A subject’s extent of exposure to pembrolizumab is defined as the total 
number of doses of pembrolizumab the subject received.
Extent of Exposure will be summarized for all MK-4166 and MK-4166 in combination with 
pembrolizumab dose levels with at least 3 subjects enrolled and listed for other dose levels.
9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
 
 
057N3N

Product:  MK-4166 
89
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 10.
Clinical supplies will be packaged to support enrollment and replacement subjects as required.  
When a replacement subject is required, the Sponsor or designee needs to be contacted prior 
to dosing the replacement supplies.
Table 10
Product Descriptions
Product Name & Potency
Dosage Form
MK-4166 100 mg
Injection
MK-3475 100 mg
Injection
All other supplies not indicated in Table 10 above will be provided centrally by the Sponsor 
or locally by the trial site, subsidiary or designee, depending on local country operational or 
regulatory requirements.
For any commercially available product that is provided by the trial site, subsidiary or designee 
every attempt will be made to source these supplies from a single lot/batch number. The trial 
site will be responsible for recording the lot number, manufacturer and expiry date of any 
locally purchased product.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Sites will receive open label kits of MK-4166 as directed in the protocol.  Each kit will contain 
1 vial.
Sites will also receive open label vials of MK-3475.
Clinical Supplies Disclosure
The trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. The product identification (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
 
 
057N3N

Product:  MK-4166 
90
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial sites, the local country Sponsor 
personnel or designee will provide appropriate documentation that must be completed for drug 
accountability and return, or local discard and destruction if appropriate.   Where local discard 
and destruction is appropriate, the investigator is responsible for ensuring that a local 
discard/destruction procedure is documented.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will be 
divulged to the institutional review board, ethics review committee (IRB/ERC) or similar or 
expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and regulations.
Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
 
 
057N3N

Product:  MK-4166 
91
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
may be used and disclosed for trial management purposes, as part of a regulatory submissions, 
and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  Additionally, 
the investigator’s name and business contact information may be included when reporting 
certain serious adverse events to regulatory authorities or to other investigators.  By signing 
this protocol, the investigator expressly consents to these uses and disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating investigators 
upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that reviews 
and approves this trial.  The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names and 
qualifications of the IRB/IEC members and to make these records available for regulatory 
agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  The 
investigator/subinvestigator(s) 
further 
agree 
to 
provide 
this 
information 
on 
a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor or through a secure password-protected electronic portal provided by the Sponsor.  
The investigator/subinvestigator(s) also consent to the transmission of this information to the 
Sponsor in the United States for these purposes.  This may involve the transmission of 
information to countries that do not have laws protecting personal data.
 
 
057N3N

Product:  MK-4166 
92
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of Good Clinical 
Practice (e.g., International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all applicable 
federal, state and local laws, rules and regulations relating to the conduct of the clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access to 
all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local laws, 
rules and regulations; and, for each subject participating in the trial, provide all data, and, upon 
completion or termination of the clinical trial, submit any other reports to the Sponsor as 
required by this protocol or as otherwise required pursuant to any agreement with the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the conduct 
of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, correspondence 
with regulatory authorities and IRBs/ERCs, consent forms, investigator’s curricula vitae, 
monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory director curriculum vitae.  By signing this protocol, the investigator 
agrees that documentation shall be retained until at least 2 years after the last approval of a 
marketing application in an ICH region or until there are no pending or contemplated 
marketing applications in an ICH region or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  Because the clinical 
development and marketing application process is variable, it is anticipated that the retention 
 
 
057N3N

Product:  MK-4166 
93
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
period can be up to 15 years or longer after protocol database lock. The Sponsor will determine 
the minimum retention period and notify the investigator when documents may be destroyed.  
The sponsor also recognizes that documents may need to be retained for a longer period if 
required by local regulatory requirements. All trial documents shall be made available if 
required by relevant regulatory authorities. The investigator must consult with and obtain 
written approval by the Sponsor prior to discarding trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator will 
immediately disclose in writing to the Sponsor if any person who is involved in conducting the 
trial is debarred or if any proceeding for debarment is pending or, to the best of the 
investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site is 
open in an EU country, Merck, as the Sponsor, will designate, per country, a national principal 
coordinator (Protocol CI), responsible for coordinating the work of the principal investigators 
at the different trial sites in that Member State, according to national regulations.  For a single-
center trial, the Protocol CI is the principal investigator.  In addition, the Sponsor must 
designate a principal or coordinating investigator to review the trial report that summarizes the 
trial results and confirm that, to the best of his/her knowledge, the report accurately describes 
the conduct and results of the trial [Clinical Study Report (CSR) CI].  The Sponsor may 
consider one or more factors in the selection of the individual to serve as the Protocol CI and 
or CSR CI (e.g., availability of the CI during the anticipated review process, thorough 
understanding of clinical trial methods, appropriate enrollment of subject cohort, timely 
achievement of trial milestones).  The Protocol CI must be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as Sponsor 
of this trial, will review this protocol and submit the information necessary to fulfill these 
requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. Information 
posted will allow subjects to identify potentially appropriate trials for their disease conditions 
 
 
057N3N

Product:  MK-4166 
94
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
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 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and functional 
area standard operating procedures (SOPs) to ensure that trials are conducted and data are 
generated, documented, and reported in compliance with the protocol, accepted standards of 
Good Clinical Practice, and all applicable federal, state, and local laws, rules and regulations 
relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her electronic 
signature is the legally binding equivalent of a written signature.  By entering his/her electronic 
signature, the investigator confirms that all recorded data have been verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be provided 
separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided the 
complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also include 
 
 
057N3N

Product:  MK-4166 
95
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
the protocol and statistical analysis plan to facilitate the peer and editorial review of the 
manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will allow 
the journal, if it so desires, to post on its website the key sections of the protocol that are 
relevant to evaluating the trial, specifically those sections describing the trial objectives and 
hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, the 
efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, due 
to statistical concerns.  In rare cases, publication of single trial site data prior to the main paper 
may be of value.  Limitations of single trial site observations in a multicenter trial should 
always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, or 
acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it 
critically for important intellectual content; and 3) final approval of the version to be published. 
Authors must meet conditions 1, 2 and 3.  Significant contributions to trial execution may also 
be taken into account to determine authorship, provided that contributions have also been made 
to all three of the preceding authorship criteria.  Although publication planning may begin 
before conducting the trial, final decisions on authorship and the order of authors’ names will 
be made based on participation and actual contributions to the trial and writing, as discussed 
above. The first author is responsible for defending the integrity of the data, method(s) of data 
analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. Any 
information identified by the Sponsor as confidential must be deleted prior to submission; this 
confidentiality does not include efficacy and safety results. Sponsor review can be expedited 
to meet publication timelines.
 
 
057N3N

Product:  MK-4166 
96
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
11.0 LIST OF REFERENCES
[1]
Ji Y, Li Y, Bekele BN. Dose-finding in phase l clinical trials based on toxicity 
probability intervals. Clin Trials 2007;4:235-44.
[2]
Tone M, Tone Y, Adams E, Yates SF, Frewin MR, Cobbold SP, et al. Mouse 
glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory 
for T cells. Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15059-64.
[3]
Nocentini G, Ronchetti S, Petrillo MG, Riccardi C. Pharmacological 
modulation of GITRL/GITR system: therapeutic perspectives. Br J 
Pharmacol 2012;165:2089-99.
[4]
Miller AM, Lundberg K, Ozenci V, Banham AH, Hellstrom M, Egevad L, et 
al. CD4+CD25high T cells are enriched in the tumor and peripheral blood of 
prostate cancer patients. J Immunol 2006;177:7398-405.
[5]
Pedroza-Gonzalez A, Verhoef C, Ijzermans JNM, Peppelenbosch MP, 
Kwekkeboom J, Verheij J, et al. Activated tumor-infiltrating CD4+ 
regulatory T cells restrain antitumor immunity in patients with primary or 
metastatic liver cancer. Hepatology 2013;57(1):183-94.
[6]
Suvas S, Kim B, Sarangi PP, Tone M, Waldmann H, Rouse BT. In vivo 
kinetics of GITR and GITR ligand expression and their functional 
significance 
in 
regulating 
viral 
immunopathology. 
J 
Virol 
2005;79(18):11935-42.
[7]
Ronchetti S, Zollo O, Bruscoli S, Agostini M, Bianchini R, Nocentini G, et 
al. GITR, a member of the TNF receptor superfamily, is costimulatory to 
mouse T lymphocyte subpopulations. Eur J Immunol 2004;34:613-22.
[8]
Kanamaru F, Youngnak P, Hashiguchi M, Nishioka T, Takahashi T, 
Sakaguchi S, et. al. Costimulation via glucocorticoid-induced TNF receptor 
in both conventional and CD25+ regulatory CD4+ T cells.  J Immunol. 
2004;172:7306-7314.
[9]
Ronchetti S, Nocentini G, Bianchini R, Krausz LT, Migliorati G. Riccardi C. 
Glucocorticoid-induced TNFR-related protein lowers the threshold of CD28 
costimulation in CD8+ T cells. J Immunol 2007;179:5916-26.
[10]
Ponte JF, Ponath P, Gulati R, Slavonic M, Paglia M, O'Shea A, et al. 
Enhancement of humoral and cellular immunity with an anti-glucocorticoid-
induced tumour necrosis factor receptor monoclonal antibody. Immunology. 
2010 Jun;130(2):231-42.
 
 
057N3N

Product:  MK-4166 
97
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
[11]
Stephens GL, McHugh RS, Whitters MJ, Young DA, Luxenberg D, Carreno 
BM, et al. Engagement of glucocorticoid-induced TNFR family-related
receptor on effector T cells by its ligand mediates resistance to suppression 
by CD4+CD25+ T cells. J Immunol 2004;173:5008-20.
[12]
Nocentini G, Ronchetti S, Cuzzocrea S, Riccardi C. GITR/GITRL: more than 
an effector T cell co-stimulatory system. Eur J Immunol 2007;37:1165-9.
[13]
Shimizu J, Yamazaki S, Takahashi T, Ishida Y, Sakaguchi S. Stimulation of 
CD25(+)CD4(+) regulatory T cells through GITR breaks immunological 
self-tolerance. Nat Immunol. 2002 Feb;3(2):135-42.
[14]
Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. 
Nature 2011;480:480-9.
[15]
Chen Y-L, Chen Y-S, Lin H-H, Chan C-W, Chen S-C, Chen C-H. 
Immunostimulatory flagellin from Burkholderia pseudomallei effects on an 
increase in the intracellular calcium concentration and up-regulation of TNF-
alpha by mononuclear cells. Microbiol Immunol 2007;51(1):81-6.
[16]
Hellstrom KE, Hellstrom I, Chen L. Can co-stimulated tumor immunity be 
therapeutically efficacious? Immunol Rev 1995;145:123-45.
[17]
U.S. Prescribing Information: PROVENGE (sipuleucel-T) Suspension for 
Intravenous Infusion: 2011.
[18]
Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner 
MD, et al. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal 
antibody TGN1412. N Engl J Med 2006;355(10):1018-28.
[19]
Vonderheide RH, Dutcher JP, Anderson JE, Eckhardt SG, Stephans KF, 
Razvillas B, et al. Phase I study of recombinant human CD40 ligand in cancer 
patients. J Clin Oncol 2001;19(13):3280-7.
[20]
Vonderheide RH, Flaherty KT, Khalil M, Stumacher MS, Bajor DL, Hutnick 
NA, et al. Clinical activity and immune modulation in cancer patients treated 
with CP-870,893, a novel CD40 agonist monoclonal antibody. J Clin Oncol 
2007;25(7):876-83.
[21]
Molckovsky A, Siu LL. First-in-class, first-in-human phase I results of 
targeted agents: highlights of the 2008 American society of clinical oncology 
meeting. J Hematol Oncol 2008;1:20.
[22]
Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: 
Jekyll or Hyde. Cancer Metastasis Rev 2007;26(3-4):373-400.
 
 
057N3N

Product:  MK-4166 
98
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
[23]
Usubütün A, Ayhan A, Uygur MC, Özen H, Toklu C, Ruacan S. Prognostic 
factors in renal cell carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81.
[24]
Al-Shibli K, Al-Saad S, Andersen S, Donnem T, Bremnes RM, Busund L-T. 
The prognistic value of intraepithelial and stromal CD3-, CD117- and 
CD138-positive cells in non-small cell lung carcinoma. APMIS 
2010;118:371-82.
[25]
Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen P, Lardon 
F, et al. Tumor infiltrating lymphocytes: an intriguing player in the survival 
of colorectal cancer patients. BMC Immunol 2010;11:19.
[26]
Diez M, Pollán M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et 
al. Histopathologic prognostic score in colorectal adenocarcinomas. 
Anticancer Res 1998;18(1B):689-94.
[27]
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-
Pagès C, et al. Type, density, and location of immune cells within human 
colorectal tumors predict clinical outcome. Science 2006;313(5795):1960-4.
[28]
Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: 
molecular biology. Int J Clin Oncol 2010;15(6):544-51.
[29]
Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. 
Prolonged survival of a patient affected by pancreatic adenocarcinoma with 
massive lymphocyte and dendritic cell infiltration after interleukin-2 
immunotherapy. Report of a case. Tumori 2008;94(3):426-30.
[30]
Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating 
lymphocytes. J Cutan Pathol 2010;37(Suppl 1):48-53.
[31]
Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
Oncol. 2009 Sep;10(9):840-1.
[32]
Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are 
parameters of aggressiveness in primary cutaneous melanoma. Cancer 
Immunol Immunother 2008;57(1):97-106.
[33]
Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic 
implications of type and density of tumour-infiltrating lymphocytes in gastric 
cancer. Br J Cancer 2008;99(10):1704-11.
 
 
057N3N

Product:  MK-4166 
99
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
[34]
Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, 
Hollema H, et al. Prognostic significance of tumor-infiltrating T-
lymphocytes in primary and metastatic lesions of advanced stage ovarian 
cancer. Cancer Immunol Immunother 2009;58(3):449-59.
[35]
Nishimura H, Honjo T, Minato N. Facilitation of beta selection and 
modification of positive selection in the thymus of PD-1-deficient mice. J 
Exp Med. 2000 Mar 6;191(5):891-8.
[36]
Oble DA, Loewe R, Yu P, Mihm MC Jr. Focus on TILs: prognostic 
significance of tumor infiltrating lymphocytes in human melanoma. Cancer 
Immun. 2009 Apr 2;9:3.
[37]
Pölcher M, Braun M, Friedrichs N, Rudlowski C, Bercht E, Fimmers R, et al. 
Foxp3(+) cell infiltration and granzyme B(+)/Foxp3(+) cell ratio are 
associated with outcome in neoadjuvant chemotherapy-treated ovarian 
carcinoma. Cancer Immunol Immunother 2010;59(6):909-19.
[38]
Suzuki H, Chikazawa N, Tasaka T, Wada J, Yamasaki A, Kitaura Y, et al. 
Intratumoral CD8+ T/FOXP3+ cell ratio is a predictive marker for survival 
in patients with colorectal cancer. Cancer Immunol Immunother 
2010;59:653-61.
[39]
Chew V, Tow C, Teo M, Wong HL, Chan J, Gehring A, et al. Inflammatory 
tumor microenvironment is associated with superior survival in 
hepatocellular carcinoma patients. J Hepatol 2010;52:370-9.
[40]
Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency 
of regulatory T cells in peripheral blood and in tumour-infiltrating 
lymphocytes correlates with poor prognosis in renal cell carcinoma. BJU Int 
2011;107(9):1500-6.
[41]
Ko K, Yamazaki S, Nakamura K, Nishioka T, Hirota K, Yamaguchi T, et al. 
Treatment of advanced tumors with agonistic anti-GITR mAb and its effects 
on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells. J Exp Med. 
2005 Oct 3;202(7):885-91.
[42]
Cohen AD, Diab A, Perales MA, Wolchok JD, Rizzuto G, Merghoub T, et 
al. Agonist anti-GITR antibody enhances vaccine-induced CD8(+) T-cell 
responses and tumor immunity. Cancer Res. 2006 May 1;66(9):4904-12.
[43]
Zhou P, L'italien L, Hodges D, Schebye XM. Pivotal roles of CD4+ effector 
T cells in mediating agonistic anti-GITR mAb-induced-immune activation 
and tumor immunity in CT26 tumors. J Immunol. 2007 Dec 1;179(11):7365-
75.
 
 
057N3N

Product:  MK-4166 
100
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
[44]
Cohen AD, Schaer DA, Liu C, Li Y, Hirschhorn-Cymmerman D, Kim SC, et 
al. Agonist anti-GITR monoclonal antibody induces melanoma tumor 
immunity in mice by altering regulatory T cell stability and intra-tumor 
accumulation. PLoS One. 2010 May 3;5(5):e10436.
[45]
Murphy JT, Burey AP, Beebe AM, Gu D, Presta LG, Merghoub T, et al. 
Anaphylaxis caused by repetitive doses of a GITR agonist monoclonal 
antibody in mice. Blood. 2014 Apr 3;123(14):2172-80.
[46]
Ropponen KM, Eskelinen MJ, Lipponen PK, Alhava E, Kosma V-M. 
Prognostic value of tumour-infiltrating lymphocytes (TILs) in colorectal 
cancer. J Pathol 1997;182(3):318-24.
[47]
Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, 
et al. Adoptive cell transfer therapy following non-myeloablative but 
lymphodepleting chemotherapy for the treatment of patients with refractory 
metastatic melanoma. J Clin Oncol 2005;23(10):2346-57.
[48]
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. 
Treatment of metastatic melanoma with autologous CD4+ T cells against 
NY-ESO-1. N Engl J Med 2008;358(25):2698-703.
[49]
Lowe PJ, Tannenbaum S, Wu K, Lloyd P, Sims J. On setting the first dose in 
man: 
quantitating 
biotherapeutic 
drug-target 
binding 
through 
pharmacokinetic and pharmacodynamic models. Basic Clin Pharmacol 
Toxicol 2009;106:195-209.
[50]
Bai S, Jorga K, Xin Y, Jin D, Zheng Y, Damico-Beyer LA, et. al. A Guide to 
Rational Dosing of Monoclonal Antibodies.  Clin Pharmacokinet. 
2012;51(2):119-135.
[51]
Wang DD, Zhang S, Zhao H, Men AY, Parivar K.  Fixed dosing versus body 
size-based dosing of monoclonal antibodies in adult clinical trials.  J Clin 
Pharmacol. 2009;49:1012-1024.
 
 
057N3N

Product:  MK-4166 
101
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in the 
design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or national 
regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy and/or 
pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine subject 
preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose of 
the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, misconduct 
or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, the clinical 
site will be closed, the responsible regulatory authorities and ethics review committees notified and data disclosed 
accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of results 
may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues of 
multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice guidelines. 
In summary, authorship should reflect significant contribution to the design and conduct of the trial, performance or 
interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to defend the trial 
results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
057N3N

Product:  MK-4166 
102
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC approval. 
For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or receipt 
of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by an 
Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
057N3N

Product:  MK-4166 
103
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease.  A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The leftover DNA and leftover archival tumor tissue or leftover newly obtained biopsy
specimen(s) collected in the current trial will be used to study various causes for how 
subjects may respond to a drug/vaccine.  The leftover DNA and leftover archival tumor 
tissue or leftover newly obtained biopsy specimen(s) will be stored to provide a resource 
for future trials conducted by Merck focused on the study of biomarkers responsible for 
how a drug/vaccine enters and is removed by the body, how a drug/vaccine works, other 
pathways a drug/vaccine may interact with, or other aspects 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 Merck or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the Future 
Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained during 
screening for protocol enrollment from all subjects or legal guardians, at a trial visit by 
the investigator or his or her designate.  Informed consent for Future Biomedical 
Research should be presented to the subjects on Visit 1.  If delayed, present consent at 
next possible Subject Visit. Informed consent must be obtained prior to collection of 
all Future Biomedical Research specimens.  Consent forms signed by the subject will 
be kept at the clinical trial site under secure storage for regulatory reasons.  Information 
 
 
057N3N

Product:  MK-4166 
104
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
contained on the consent form alone cannot be traced to any specimens, test results, or 
medical information once the specimens have been rendered de-identified.
Subjects are not required to participate in the Future Biomedical Research sub-trial in 
order to participate in the main trial.  Subjects who decline to sign the Future 
Biomedical Research informed consent will not have the specimen collected nor will 
they be discontinued from the main trial.
A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.  Each consent will be assessed for appropriate 
specimen permissions.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for this sub-trial's research purposes. Any specimens for 
which such an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the Merck 
approved policies and procedures for specimen handling and preparation.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All specimens 
will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
 
 
057N3N

Product:  MK-4166 
105
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is now 
double coded.  Specimens with the second code are sometimes referred to as de-identified 
specimens. The use of the second code provides additional confidentiality and privacy 
protection for subjects over the use of a single code.  Access to both keys would be needed 
to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen will 
be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by the 
Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would be 
directly linked to the full clinical data set would be those situations mandated by regulatory 
authorities (e.g., EMEA, FDA), whereby this information would be directly transferred to 
the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the highly 
validated conditions usually associated with regulatory approval of diagnostics.  The scope 
of research performed on these specimens is limited to the investigation of the variability 
in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
Merck, or an additional third party (e.g., a university investigator) designated by Merck. 
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in this sub-trial.  Future Biomedical Research 
specimens remaining with the third party after the specific analysis is performed will be 
returned to the sponsor or destroyed and documentation of destruction will be reported to 
Merck.
 
 
057N3N

Product:  MK-4166 
106
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter will 
be sent from Merck to the investigator confirming the destruction. It is the responsibility 
of the investigator to inform the subject of completion of destruction.  Any analyses in 
progress at the time of request for destruction or already performed prior to the request 
being received by the Sponsor will continue to be used as part of the overall research trial 
data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the subject’s personal information and their specimens. In this situation, the request for 
specimen destruction can not 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 acquisition.  Specimens may be stored for longer if a 
regulatory or governmental authority has active questions that are being answered.  In this 
special circumstance, specimens will be stored until these questions have been adequately 
addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to the 
Merck 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 Merck policies and procedures and this destruction will be 
documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from the Future Biomedical 
Research sub-trial will be maintained by Merck.  This is done to separate the future 
exploratory test results (which include genetic data) from the clinical trial database thereby 
maintaining a separation of subject number and these results.  The separate databases are 
accessible only to the authorized Sponsor 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 in international standards 
(e.g., ISO17799) to protect against unauthorized access.  The Merck Entrusted Keyholder 
maintains control over access to all specimen data.  These data are collected for future 
biomedical research purposes only as specified in this sub-trial will not be used for any 
other purpose.
 
 
057N3N

Product:  MK-4166 
107
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported to 
the subject or family, and this information will not be entered into the clinical database 
maintained by Merck on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in exploratory 
research typically used for diagnostic testing.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information as 
to how to offer clinical diagnostic  testing (paid for by Merck) to subjects enrolled and will 
be advised that counseling should be made available for all who choose to participate in 
this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for public 
access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on Merck clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens from 
subjects and controls to represent the ethnic and gender population representative of the 
disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. Risks include 
those associated with venipuncture to obtain the whole blood specimen.  This specimen 
will be obtained at the time of routine blood specimens drawn in the main trial. 
Merck has developed strict security, policies and procedures to address subject data privacy 
concerns.  Data privacy risks are largely limited to rare situations involving possible breach 
of confidentiality.  In this highly unlikely situation there is risk that the information, like 
all medical information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data
analysis.  These subject data will be kept in a separate, secure Merck database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
 
 
057N3N

Product:  MK-4166 
108
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
14. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
057N3N

Product:  MK-4166 
109
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for IRBs/IECs 
and Investigational Site Staff
 
 
057N3N

Product:  MK-4166 
110
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
 
 
057N3N

Product:  MK-4166 
111
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
 
 
057N3N

Product:  MK-4166 
112
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
 
 
057N3N

Product:  MK-4166 
113
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
 
 
057N3N

Product:  MK-4166 
114
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
 
 
057N3N

Product:  MK-4166 
115
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
 
 
057N3N

Product:  MK-4166 
116
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
 
 
057N3N

Product:  MK-4166 
117
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
 
 
057N3N

Product:  MK-4166 
118
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
 
 
057N3N

Product:  MK-4166 
119
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
 
 
057N3N

Product:  MK-4166 
120
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to 
carry out any work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any selfcare.  Totally 
confined to bed or chair.
5
Dead
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E.,
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., 
Group Chair.
 
 
057N3N

Product:  MK-4166 
121
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Common Terminology Criteria for Adverse Events V4.0
The descriptions and grading scales found in the revised NCI Common Terminology Criteria
for Adverse Events (CTCAE) version 4.0 will be used for adverse event reporting.  
(http://ctep.cancer.gov/reporting/ctc.html)
 
 
057N3N

Product:  MK-4166 
122
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
Criteria for Evaluating Response in Solid Tumors in Solid Tumors, RECIST 1.1
RECIST version 1.1* will be used in this study for assessment of tumor response. While either 
CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in this 
study.
* As published in the European Journal of Cancer:
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J., et al. New 
response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1). Eur J 
Cancer. 2009 Jan;45(2):228-47.
 
 
057N3N

Product:  MK-4166 
123
Protocol/Amendment No.: 001-08 
MK-4166-001-08 Final Protocol
21-May-2019
Confidential
13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol and 
to abide by all provisions of this protocol (including other manuals and documents referenced 
from this protocol).  I agree to conduct the trial in accordance with generally accepted standards 
of Good Clinical Practice.  I also agree to report all information or data in accordance with the 
protocol and, in particular, I agree to report any serious adverse events as defined in Section 
7.0 – Assessing and Recording Adverse Events.  I also agree to handle all clinical supplies 
provided by the Sponsor and collect and handle all clinical specimens in accordance with the 
protocol.  I understand that information that identifies me will be used and disclosed as 
described in the protocol, and that such information may be transferred to countries that do not 
have laws protecting such information.  Since the information in this protocol and the 
referenced Investigator’s Brochure is confidential, I understand that its disclosure to any third 
parties, other than those involved in approval, supervision, or conduct of the trial is prohibited.  
I will ensure that the necessary precautions are taken to protect such information from loss, 
inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
057N3N