A Phase 1 Trial of MK-1248 as Monotherapy and in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors.
Phase: PHASE1
Conditions: Advanced Solid Tumor
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
NCT02553499
06-Nov-2017
Document Date: 
A Phase 1 Trial of MK-1248 as Monotherapy and in 
Combination with Pembrolizumab in Subjects with 
AdvancedSolid Tumors. 

Product:  MK-1248 
1
Protocol/Amendment No.: 001-03
MK-1248-001-03 Final Protocol
06-Nov-2017
Confidential
THIS PROTOCOL 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:
A Phase 1 Trial of MK-1248 as Monotherapy and in Combination with Pembrolizumab in 
Subjects with Advanced Solid Tumors.
IND NUMBER:  128971
EudraCT NUMBER:  Not Applicable
 
 
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TABLE OF CONTENTS
SUMMARY OF CHANGES.................................................................................................11
1.0
TRIAL SUMMARY...................................................................................................13
2.0
TRIAL DESIGN.........................................................................................................14
Trial Design .............................................................................................................14
2.1
Trial Diagram..........................................................................................................15
2.2
3.0
OBJECTIVE(S) & HYPOTHESIS(ES)...................................................................17
Primary Objective(s)...............................................................................................17
3.1
Secondary Objective(s)...........................................................................................17
3.2
Exploratory Objectives...........................................................................................17
3.3
4.0
BACKGROUND & RATIONALE...........................................................................18
Background..............................................................................................................18
4.1
Pharmaceutical and Therapeutic Background .....................................................18
4.1.1
4.1.1.1
MK-1248 Background ..................................................................................18
4.1.1.2
Pembrolizumab (MK-3475) Background .....................................................20
Preclinical and Clinical Trials..............................................................................21
4.1.2
4.1.2.1
MK-1248 Preclinical and Clinical Trials......................................................21
4.1.2.2
Pembrolizumab (MK-3475) Preclinical and Clinical Trials.........................22
4.1.2.3
MK-1248 with Pembrolizumab Combination Preclinical Trials ..................23
Ongoing Clinical Trials........................................................................................25
4.1.3
4.1.3.1
MK-1248 Ongoing Clinical Trials................................................................25
4.1.3.2
Pembrolizumab Ongoing Clinical Trials ......................................................25
Information on Other Trial-Related Therapy.......................................................25
4.1.4
Rationale ..................................................................................................................25
4.2
Rationale for the Trial and Selected Subject Population .....................................25
4.2.1
Rationale for Dose Selection/Regimen/Modification ..........................................25
4.2.2
4.2.2.1
Starting Dose for This Trial ..........................................................................26
4.2.2.2
Rationale for Pembrolizumab Dose..............................................................27
4.2.2.3
Maximum Dose/Exposure for This Trial......................................................28
4.2.2.4
Rationale for Dose Interval and Trial Design ...............................................28
4.2.2.4.1
MK-1248 Monotherapy .........................................................................28
 
 
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4.2.2.4.2
MK-1248 in Combination with Pembrolizumab ...................................28
Rationale for Endpoints .......................................................................................29
4.2.3
4.2.3.1
Efficacy Endpoints........................................................................................29
4.2.3.2
Safety Endpoints ...........................................................................................29
4.2.3.3
Pharmacokinetic Endpoints ..........................................................................29
4.2.3.4
Pharmacodynamic Endpoints........................................................................29
4.2.3.4.1
Target Engagement (TE): Receptor Availability on Peripheral 
Blood Lymphocytes...............................................................................29
4.2.3.5
Anti-Drug Antibody (ADA) Assay...............................................................30
4.2.3.6
Serum Cytokines...........................................................................................30
4.2.3.7
Planned Exploratory Biomarker Research....................................................30
4.2.3.8
Planned Genetic Analysis .............................................................................31
4.2.3.9
Future Biomedical Research.........................................................................31
Benefit/Risk..............................................................................................................31
4.3
5.0
METHODOLOGY ....................................................................................................32
Entry Criteria..........................................................................................................32
5.1
Diagnosis/Condition for Entry into the Trial .......................................................32
5.1.1
Subject Inclusion Criteria.....................................................................................32
5.1.2
Subject Exclusion Criteria ...................................................................................34
5.1.3
Trial Treatment(s)...................................................................................................36
5.2
Dose Selection/Modification ...............................................................................39
5.2.1
5.2.1.1
Dose Selection (Preparation) ........................................................................39
5.2.1.2
Dose Escalation.............................................................................................39
5.2.1.3
Accelerated Dose Escalation (MK-1248 Monotherapy)...............................39
5.2.1.4
3+3 Dose Escalation (MK-1248 Monotherapy and MK-1248 plus 
Pembrolizumab Combination)......................................................................40
5.2.1.5
Dose Confirmation........................................................................................41
Definition of Dose Limiting Toxicity ..................................................................43
5.2.2
Guidelines for Dose Modification due to Adverse Events ..................................44
5.2.3
5.2.3.1
Dose Modification and Toxicity Management for Adverse Events 
Associated with MK-1248 and/or Pembrolizumab ......................................44
5.2.3.2
Dose Interruption/Discontinuation and Toxicity Management 
Guidelines for Immune-Related Adverse Events Associated with 
Pembrolizumab.............................................................................................46
 
 
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5.2.3.3
Toxicity Management of Infusion Reactions Related to 
Pembrolizumab.............................................................................................50
Replacement of Subjects During DLT Evaluation Period ...................................51
5.2.4
Timing of Dose Administration ...........................................................................52
5.2.5
Trial Blinding/Masking........................................................................................52
5.2.6
Randomization or Treatment Allocation..............................................................52
5.3
Stratification............................................................................................................53
5.4
Concomitant Medications/Vaccinations (Allowed & Prohibited) ......................53
5.5
Acceptable Concomitant Medication...................................................................53
5.5.1
Prohibited Concomitant Medications...................................................................53
5.5.2
Rescue Medications & Supportive Care ...............................................................54
5.6
Diet/Activity/Other Considerations.......................................................................54
5.7
Diet.......................................................................................................................54
5.7.1
Contraception.......................................................................................................54
5.7.2
Use in Pregnancy .................................................................................................55
5.7.3
Use in Nursing Women........................................................................................55
5.7.4
Subject Withdrawal/Discontinuation Criteria .....................................................55
5.8
Subject Replacement Strategy ...............................................................................56
5.9
Beginning and End of the Trial .............................................................................56
5.10
Clinical Criteria for Early Trial Termination......................................................56
5.11
6.0
TRIAL FLOW CHART ............................................................................................57
7.0
TRIAL PROCEDURES ............................................................................................64
Trial Procedures......................................................................................................64
7.1
Administrative Procedures...................................................................................64
7.1.1
7.1.1.1
Informed Consent..........................................................................................64
7.1.1.1.1
General Informed Consent.....................................................................64
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.................................................................................................65
7.1.1.2
Inclusion/Exclusion Criteria .........................................................................65
7.1.1.3
Subject Identification Card ...........................................................................65
7.1.1.4
Medical History ............................................................................................65
7.1.1.5
Disease Details..............................................................................................65
7.1.1.6
Prior Oncology Treatment History ...............................................................65
 
 
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7.1.1.7
Prior and Concomitant Medications Review ................................................65
7.1.1.7.1
Prior Medications...................................................................................65
7.1.1.7.2
Concomitant Medications......................................................................66
7.1.1.8
Assignment of Screening Number................................................................66
7.1.1.9
Assignment of Randomization Number........................................................66
7.1.1.10 Trial Compliance (Study Drug Administration) ...........................................66
Clinical Procedures/Assessments.........................................................................67
7.1.2
7.1.2.1
Adverse Event (AE) Monitoring...................................................................67
7.1.2.2
Full Physical Examination ............................................................................67
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 ...........68
7.1.2.6
Tumor Imaging .............................................................................................68
7.1.2.7
Response Assessment ...................................................................................68
7.1.2.7.1
Immune-related RECIST (irRECIST) ...................................................68
Laboratory Procedures/Assessments ...................................................................69
7.1.3
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis).....................................................................................................70
7.1.3.2
Blood for Correlative DNA/RNA.................................................................71
Pharmacokinetic/Pharmacodynamic Evaluations ................................................71
7.1.4
7.1.4.1
Blood Collection for MK-1248 and Pembrolizumab PK .............................71
7.1.4.2
Blood Collection for Anti-MK-1248 Antibodies and Anti-
Pembrolizumab Antibodies (ADA) ..............................................................71
7.1.4.3
Blood for Receptor Availability Assay (PD) ................................................71
7.1.4.4
Tumor Tissue Collection...............................................................................71
Planned Genetic Analysis Sample Collection......................................................72
7.1.5
Future Biomedical Research ................................................................................72
7.1.6
Other Procedures..................................................................................................72
7.1.7
7.1.7.1
Withdrawal/Discontinuation.........................................................................72
7.1.7.1.1
Withdrawal From Future Biomedical Research ....................................72
7.1.7.2
Blinding/Unblinding .....................................................................................73
7.1.7.3
Calibration of Critical Equipment.................................................................73
Visit Requirements...............................................................................................73
7.1.8
 
 
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7.1.8.1
Screening.......................................................................................................73
7.1.8.2
Treatment Period...........................................................................................73
7.1.8.3
Post-Treatment Visits....................................................................................74
7.1.8.3.1
Safety Follow-Up Visit..........................................................................74
7.1.8.3.2
Follow-Up Visits....................................................................................74
7.1.8.4
Survival Status ..............................................................................................74
Assessing and Recording Adverse Events.............................................................74
7.2
Definition of an Overdose for This Protocol and Reporting of Overdose 
7.2.1
to the Sponsor ......................................................................................................75
Reporting of Pregnancy and Lactation to the Sponsor ........................................75
7.2.2
Immediate Reporting of Adverse Events to the Sponsor.....................................76
7.2.3
7.2.3.1
Serious Adverse Events ................................................................................76
7.2.3.2
Events of Clinical Interest.............................................................................77
Evaluating Adverse Events ..................................................................................78
7.2.4
Sponsor Responsibility for Reporting Adverse Events .......................................81
7.2.5
8.0
STATISTICAL ANALYSIS PLAN .........................................................................81
Statistical Analysis Plan Summary........................................................................81
8.1
Responsibility for Analyses/In-House Blinding....................................................82
8.2
Hypotheses/Estimation ...........................................................................................82
8.3
Analysis Endpoints..................................................................................................82
8.4
Efficacy/Immunogenicity/Pharmacokinetics Endpoints......................................82
8.4.1
Safety Endpoints ..................................................................................................82
8.4.2
Derivations of Efficacy/Immunogenicity/Pharmacokinetics Endpoints..............82
8.4.3
Derivations of Safety Endpoints ..........................................................................83
8.4.4
Analysis Populations...............................................................................................83
8.5
Safety Analysis Populations ................................................................................83
8.5.1
Efficacy Analysis Populations .............................................................................84
8.5.2
Statistical Methods..................................................................................................84
8.6
Statistical Methods for Efficacy Analyses ...........................................................84
8.6.1
Statistical Methods for Safety Analyses ..............................................................84
8.6.2
Summaries of Baseline Characteristics, Demographics, and Other 
8.6.3
Analyses...............................................................................................................85
8.6.3.1
Demographic and Baseline Characteristics ..................................................85
 
 
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8.6.3.2
Population PK Analyses ...............................................................................85
Interim Analyses .....................................................................................................85
8.7
Multiplicity ..............................................................................................................85
8.8
Sample Size and Power Calculations ....................................................................85
8.9
Dose Escalation and Dose Confirmation .............................................................85
8.9.1
Precision of the DLT rate at RP2D ......................................................................87
8.9.2
Subgroup Analyses and Effect of Baseline Factors..............................................88
8.10
Compliance (Medication Adherence)....................................................................88
8.11
Extent of Exposure..................................................................................................88
8.12
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF 
CLINICAL SUPPLIES .............................................................................................88
Investigational Product...........................................................................................88
9.1
Packaging and Labeling Information ...................................................................89
9.2
Clinical Supplies Disclosure ...................................................................................89
9.3
Storage and Handling Requirements ....................................................................89
9.4
Discard/Destruction/Returns and Reconciliation ................................................89
9.5
10.0
ADMINISTRATIVE AND REGULATORY DETAILS........................................90
Confidentiality.........................................................................................................90
10.1
Confidentiality of Data ........................................................................................90
10.1.1
Confidentiality of Subject Records ......................................................................90
10.1.2
Confidentiality of Investigator Information.........................................................90
10.1.3
Confidentiality of IRB/IEC Information..............................................................91
10.1.4
Compliance with Financial Disclosure Requirements.........................................91
10.2
Compliance with Law, Audit and Debarment......................................................91
10.3
Compliance with Trial Registration and Results Posting 
10.4
Requirements...........................................................................................................93
Quality Management System.................................................................................93
10.5
Data Management...................................................................................................93
10.6
Publications..............................................................................................................94
10.7
11.0
LIST OF REFERENCES..........................................................................................95
12.0
APPENDICES............................................................................................................99
Merck Code of Conduct for Clinical Trials..........................................................99
12.1
 
 
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Collection and Management of Specimens for Future Biomedical 
12.2
Research.................................................................................................................101
Understanding the Intent, Scope and Public Health Benefits of 
12.3
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff.......................................................................................105
ECOG Performance Status..................................................................................116
12.4
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ...............117
12.5
13.0
SIGNATURES..........................................................................................................118
Sponsor's Representative .....................................................................................118
13.1
Investigator............................................................................................................118
13.2
 
 
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values.........................................................33
Table 2
Trial Treatment for MK-1248 Monotherapy (Arm 1).............................................37
Table 3
Trial Treatment for MK-1248 and Pembrolizumab Combination (Arm 2) ............38
Table 4
Dose Confirmation Rules........................................................................................42
Table 5
MK-1248 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......................................................................................................70
Table 9
Evaluating Adverse Events .....................................................................................79
Table 10 Precision of the estimated DLT rates at RP2D........................................................88
Table 11 Product Descriptions ...............................................................................................89
 
 
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LIST OF FIGURES
Figure 1 Trial Design.............................................................................................................16
Figure 2 Schematic Diagram of Immune Stimulatory Targets..............................................19
Figure 3 Efficacy of a Single Dose of mDTA-1 IgG1 in Established Syngeneic 
Mouse Tumor Model...............................................................................................22
Figure 4 Efficacy of Combination Treatment with mDTA-1 IgG1 and muDX400 
in Established Syngeneic Mouse Tumor Model......................................................24
 
 
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SUMMARY OF CHANGES
PRIMARY REASON FOR THIS AMENDMENT:
Section Number
Section Title
Description of Change (s)
Rationale
5.2.3
Guidelines for Dose 
Modification due to Adverse 
Events
Added guidelines for dose 
interruption/treatment 
discontinuation 
and 
toxicity 
management in the event of 
myocarditis and intolerable or 
persistent Grade 2 drug-related 
toxicities.
To align with the most current 
label and safety information for 
pembrolizumab.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
4.2.2.2
Rationale for Pembrolizumab 
Dose
Updated to align with most 
current template text.
To ensure the most current 
information is included.
5.2.3; 5.6
Guidelines 
for 
Dose 
Modification due to Adverse 
Events; Rescue Medications & 
Supportive Care
These 
sections 
were 
re-distributed to align with the 
most current template text.
To align with the most current 
template text.
6.0; 7.1.8.4
Trial Flow Chart; Survival 
Status
Added 
text 
to 
allow 
the 
Sponsor to collect survival data 
throughout the study.
To allow the Sponsor to collect 
survival data throughout the 
study 
to 
support 
ongoing 
analyses of survival data as 
appropriate.
 
 
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Section Number (s)
Section Title (s)
Description of Change (s)
Rationale
7.1.4.1; 7.1.4.2
Blood Collection for MK-1248 
and Pembrolizumab PK; Blood 
Collection for Anti-MK-1248 
Antibodies 
and 
Anti-
Pembrolizumab 
Antibodies 
(ADA)
Updated to allow storage of PK 
and ADA samples collected 
and to allow the Sponsor to 
reduce or discontinue sample 
collections as needed.
To 
clarify 
that 
samples 
collected for PK and ADA may 
be stored and to allow the 
Sponsor flexibility to reduce or 
discontinue sample collections 
as needed.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
Phase 1 Trial of MK-1248 as Monotherapy and in Combination with 
Pembrolizumab in Subjects with Advanced Solid Tumors
Trial Phase
Phase 1
Clinical Indication
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:
Arm 1: MK-1248 as monotherapy
Arm 2: MK-1248 in combination with pembrolizumab
Number of trial subjects
Approximately 96 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 4 years
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, each subject will be allocated by 
non-random assignment into one of two arms and receive treatment 
with MK-1248 alone or in combination with pembrolizumab. Study 
treatment in both arms will begin on Day 1 of each 3-week cycle. For 
subjects enrolled in Arm 1 and Arm 2, treatment with MK-1248 will 
end after 4 cycles; treatment with pembrolizumab in Arm 2 will 
continue for up to 24 months. Treatment in both arms will continue 
until disease progression, unacceptable adverse event(s), intercurrent 
illness that prevents further administration of treatment, Investigators 
decision to withdraw treatment, subject withdraws consent, pregnancy 
of the subject, noncompliance with study treatment or procedure 
requirements, subject completes treatment, 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 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).
Enrollment into this study has been prematurely discontinued due to program prioritization 
and not related to any safety concerns. The cut-off date for enrollment is 31-Mar-2017.
Subjects who are ongoing in the study after that date and who do not yet meet established 
protocol discontinuation criteria, as outlined in Section 5.8, will continue to attend study 
visits and be followed per protocol.
Subjects who are ongoing in the study after that date and who do not yet meet established 
treatment discontinuation criteria, as outlined in Section 5.8, may continue to receive study 
treatment per protocol, provided the investigator feels such treatment is in the best interest of 
the subject.
 
 
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2.0 TRIAL DESIGN
Trial Design
2.1
This is a non-randomized, multi-site, 2-arm, open-label trial of MK-1248 monotherapy 
(Arm 1) and MK-1248 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 
utilized (See Section 5.2.1.4). For Dose Confirmation (Parts C and E) the toxicity probability 
interval (TPI) design [1] will be utilized to refine the estimate of maximum tolerated dose 
(MTD).
In Arm 1, MK-1248 monotherapy, dose escalation will begin with 2-subject cohorts (Part A) 
starting at a MK-1248 dose of 0.12 mg and will proceed based on adverse events to a dose of 
10.0 mg or until a DLT occurs. If a DLT occurs, an additional subject will be enrolled and 
the rules of 3+3 as described in Section 5.2.1.4 will apply. Starting at a 30.0 mg dose in 
Part B, the study will continue with a 3+3 design to identify a preliminary maximum 
tolerated dose (MTD). During 3+3 dose escalation in both arms, an initial cohort of 
3 subjects will be enrolled to a dose level. If none of the 3 subjects experiences 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, and the study will proceed to the dose confirmation stage at the 
previous dose level. At least 2 days of observation will occur between each of the first 
3 subjects at each dose level (for Part A this applies to the 2 subjects enrolled). In Part C, 
dose confirmation will refine the estimate of the tolerability of the MTD (or maximum 
administered dose), using a toxicity probability interval.
Treatment in Arm 2, (MK-1248 in combination with pembrolizumab) will begin once 
2 subjects complete 1 cycle of ≥3 mg dose level in Part A, and will follow a 3+3 design to 
identify a preliminary MTD in Part D. The starting dose of MK-1248 will be 0.12 mg and the 
dose of 200 mg pembrolizumab will be used in Arm 2.  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 one week observation period between the first and second subject 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 toxicity probability interval. 
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). Doses of MK-1248 used in 
combination will be at least 1-2 dose levels behind the monotherapy dose, and would not 
exceed the MTD for monotherapy. However, once the MTD or RP2D (recommended 
Phase 2 dose) for the monotherapy arm is established, the dose of MK-1248 in combination 
may continue escalation up to that dose.
The trial will be conducted in conformance with Good Clinical Practices. 
 
 
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Adverse Events (AEs) will be evaluated according to criteria outlined in the National Cancer 
Institute’s (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.
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.
Enrollment into this study has been prematurely discontinued due to program prioritization 
and not related to any safety concerns. The cut-off date for enrollment is 31-Mar-2017. 
Subjects who are ongoing in the study after that date and who do not yet meet established 
protocol discontinuation criteria, as outlined in Section 5.8, will continue to attend study 
visits and be followed per protocol. Subjects who are ongoing in the study after that date and 
who do not yet meet established treatment discontinuation criteria, as outlined in Section 5.8, 
may continue to receive study treatment per protocol, provided the investigator feels such 
treatment is in the best interest of the subject.
Trial Diagram
2.2
The trial design is depicted in Figure 1.
Note: Enrollment into this study has been prematurely discontinued due to program 
prioritization and not related to any safety concerns. The cut-off date for enrollment is 
31-Mar-2017. Subjects who are ongoing in the study after that date and who do not yet meet 
established protocol discontinuation criteria, as outlined in Section 5.8, will continue to 
attend study visits and be followed per protocol. Subjects who are ongoing in the study after 
that date and who do not yet meet established treatment discontinuation criteria, as outlined 
in Section 5.8, may continue to receive study treatment per protocol, provided the 
investigator feels such treatment is in the best interest of the subject.
 
 
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In Arm 1, Part A, dose escalation will begin with 0.12 mg in cohorts of 2 subjects each, and will proceed based on safety events to a dose of 
10.0 mg. During Part A, there will be at least 2 days observation between the first 2 subjects treated at each dose level. Starting at a 30.0 mg 
dose (or at a lower dose as described in Section 5.2.1.3) in Part B, the study will continue with a 3+3 design to identify a preliminary 
maximum tolerated dose (MTD). In Part C, dose confirmation will refine the estimate of the tolerability of the MTD (or maximum 
administered dose), using a toxicity probability interval.
Treatment in Arm 2, (MK-1248 in combination with pembrolizumab) will begin once 2 subjects complete 1 cycle of ≥3 mg dose level in 
Part A, and will follow a 3+3 design to identify a preliminary MTD in Part D. The starting dose of MK-1248 will be 0.12 mg and the dose 
of 200 mg pembrolizumab will be used in Arm 2. During 3+3 dose escalation in Part D, at least 2 days of observation will occur between 
each of the first 3 subjects at each dose level. There will be a one week observation period between the first and second subject treated with 
the combination in the first cohort of Arm 2. Doses of MK-1248 used in combination will be at least 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-1248 in combination may continue escalation up to that dose. Dose confirmation in Part E will refine the estimate of 
tolerability of the MTD using a toxicity probability interval.
Figure 1
Trial Design
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
In subjects with a histologically or cytologically confirmed diagnosis of any type of solid 
tumor having measurable disease:
Primary Objective(s)
3.1
1) Objective:  To determine the safety and tolerability of MK-1248 monotherapy and to 
establish a maximum tolerated dose (MTD) or maximum administered dose (MAD)
2) Objective: To determine the safety and tolerability of MK-1248 monotherapy and to 
establish a maximum tolerated dose (MTD) or maximum administered dose (MAD) 
when given in combination with pembrolizumab
Secondary Objective(s)
3.2
1) Objective:  To characterize the PK profile of MK-1248 alone and in combination 
with 
pembrolizumab
2) Objective: To characterize the PK profile of pembrolizumab following 
administration of MK-1248 and pembrolizumab in combination
3) Objective:  To evaluate target engagement as measured by modulation in peripheral 
blood GITR receptor availability alone and in combination with pembrolizumab
Exploratory Objectives
3.3
1) Objective: To evaluate the antitumor activity of MK-1248 alone and in combination 
with pembrolizumab as determined by irRECIST as assessed by investigator review
2) Objective: To investigate the relationship between candidate efficacy biomarkers and 
anti-tumor activity of MK-1248 alone and in combination with pembrolizumab
a.
To evaluate the relationship between GITR expression levels in tumor samples 
and anti-tumor activity
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, 
ribonucleic 
acid 
signature 
profiles, 
pharmacogenetic variation) that may correlate with tumor responses
c.
To evaluate differences in tumor tissue characteristics in biopsies taken pre- and 
post-treatment versus 
baseline
3) Objective:  To evaluate development of circulating anti-MK-1248 antibodies and 
anti-pembrolizumab antibodies, as appropriate, following administration of MK-1248 
alone and in combination with pembrolizumab
4) Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered.  Variation across the human genome will be analyzed for 
association with clinical data collected in this study
 
 
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4.0 BACKGROUND & RATIONALE
Background
4.1
Detailed background information on MK-1248 and pembrolizumab (MK-3475) is available 
in the MK-1248 Investigator’s Brochure (IB) and the Pembrolizumab IB.
Pharmaceutical and Therapeutic Background
4.1.1
4.1.1.1
MK-1248 Background
MK-1248 is a humanized IgG4 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-1248 is a humanized agonistic mAb of the IgG4 isotype that targets human GITR and is 
intended for treatment of multiple human cancers. MK-1248 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 
antitumor T-cell responses and induce tumor rejection in 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. 
Approaches to reversal of tumor-based immunosuppression were pharmacologically 
validated by approval of Yervoy™ (ipilimumab) in 2011, and Keytruda ® (pembrolizumab) 
and Opdivo™ (nivolumimab) 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.
 
 
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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-man clinical studies [18], which urges caution for all ongoing and 
proposed agonist immunostimulatory antibodies. 
Multiple agonist immunostimulatory molecules have entered investigational studies in 
humans. In early phase studies, the RP2D for CD40 agonists was established from the 
maximum tolerable toxicity dose (MTD) where transaminitis was the main dose-limiting 
toxicity (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). Other known 
anti-GITR mAbs in clinical trials include MK-4166 (Merck) and TRX-518 (GITR, Inc.).
MK-4166 is a humanized IgG1 agonist monoclonal antibody being evaluated in an ongoing 
Phase 1 trial in adults with advanced solid tumors. As of 01-Mar-2017, human safety data are 
available for a total of 81 patients: 45 patients treated with MK-4166 monotherapy and 
36 patients treated with MK-4166 in combination with pembrolizumab. Dose escalation has 
reached 670 mg in the monotherapy treatment arm and 480 mg in the combination treatment 
arm. Treatment has generally been well tolerated. One DLT was reported in the MK-4166 
monotherapy arm at the 30 mg dose: a patient with metastatic urethral cancer had a Grade 3
perforation of an Indiana Pouch which was considered possibly related to study drug, as the 
 
 
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rate of spontaneous perforation is extremely low and there is no other obvious explanation 
for the event. Dose escalation is continuing per protocol.
MK-1248 has a similar GITR binding region to MK-4166, while the framework for 
MK-1248 is an IgG4 class compared to the IgG1 class for MK-4166.  As such, MK-4166 has 
ADCC and CDC activity related to the IgG1 backbone while MK-1248 does not.  It is 
unknown whether the activity of the IgG1 in MK-4166 will result in increased efficacy, 
increased toxicity, or both.  If the IgG1 class molecule results in greater toxicity related to the 
backbone, then an IgG4 class molecule such as MK-1248 may have a greater therapeutic 
index.  By studying both MK-4166 and MK-1248 in clinical trials, the potential difference in 
therapeutic index based on the IgG subtype will be assessed and a determination made 
whether one subtype should be favored for further development.
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 members
are 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 
 
 
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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.
Preclinical and Clinical Trials
4.1.2
4.1.2.1
MK-1248 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 
mouse 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 T eff: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 
IgG1; mDTA-1 IgG1) revealed that administration of a single dose of mDTA-1 IgG1 leads to 
tumor growth inhibition of established (70 to 115 mm3 in volume) subcutaneous MC38 and  
CT26 tumors. The maximal effective dose of mDTA -1 in these models is in the dose range 
of approximately 3 mg/kg (Figure 3).
 
 
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The CT26 colon adenocarcinoma (Panel A) and MC38 colon adenocarcinoma (Panel B) mouse tumor cell lines were 
implanted subcutaneously into immunocompetent C57BL/6J and BALB/cAnN mice, respectively. Animals were assigned 
into treatment groups when the mean tumor volume reached approximately 74 to 110 mm3.and 70 to 115 mm3. Isotype 
control monoclonal antibody mIgG1 was administered as a single subcutaneous dose on Day 0. mDTA-1 IgG1 was 
administered as a single subcutaneous dose of 0.3, 3, or 30 mg/kg on Day 0, or up to 4 weekly doses of 3 mg/kg on Days 0, 
7, 14, and 21. Tumors were measured approximately once weekly. Tumor volumes are presented as group median tumor 
volumes normalized to starting tumor volume ± 68% CI.  There were 9 to 10 animals in each group.
Figure 3
Efficacy of a Single Dose of mDTA-1 IgG1 in Established Syngeneic Mouse 
Tumor Model
GITR stimulation induces humoral immune responses resulting in mechanism-based anti-
drug antibody (ADA) formation in mouse models, which is also seen in non-human primates 
(NHP) (details in IB). 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, intravenous (IV) bolus administration of mDTA-1 in the presence of preexisting 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 (SQ) administrations of mDTA-1 or in 
cynomolgus monkeys after multiple 30-minute IV infusions of MK-1248 (at dose levels of 
0.0005 to 200  mg/kg), suggesting that anti-GITR antibodies can be safely administered even 
in the presence of ADA.
4.1.2.2
Pembrolizumab (MK-3475) Preclinical and Clinical Trials
Efficacy studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction, either as a mono-therapy or in combination with other treatment 
modalities, enhances infiltration of tumor-specific CD8+ T-cells and leads ultimately to 
tumor rejection. 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, melanoma and colorectal carcinoma. Blockade of the PD-1 pathway effectively 
 
 
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promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-γ, granzyme B and 
perforin, indicating that the mechanism of action involved local infiltration and activation of 
effector T-cell function in vivo [40], [46], [45], [47]. Experiments have confirmed the in vivo 
efficacy of PD-1 blockade as a mono-therapy 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-1248 with Pembrolizumab Combination Preclinical Trials
As MK-1248 acts to stimulate effector immune cells while pembrolizumab acts to prevent 
immune suppression in tumors, it is conceivable that a combination of MK-1248 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 the CT26 syngeneic mouse tumor model to assess the 
anti-tumor efficacy of treatment with mDTA-1 IgG1 (mouse surrogate for MK-1248) in 
combination with muDX400 (mouse surrogate for pembrolizumab). mDTA-1 IgG1 or 
muDX400 were administered either as monotherapy or in combination twice with a seven 
day interval at previously determined maximally effective monotherapeutic doses. 
Administration of mDTA-1 IgG1 in combination with muDX400 resulted in greater 
anti-tumor efficacy than administration of either antibody alone (Figure 4).
 
 
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The CT26 colon adenocarcinoma cells were implanted into immunocompetent BALB/cAnN mice subcutaneously.  Animals 
were assigned into treatment groups when the tumor volume ranged from approximately 77 to 115 mm3.  mIgG1 isotype 
control monoclonal antibody (mIgG1) was administered SC or IP on Days 0 and 7.  muDX400 alone was administered IP on 
Days 0 and 7.  mDTA-1 IgG1 alone was administered SC on Day 0.  mDTA-1 IgG1 was administered SC in combination 
with muDX400 administered IP on Days 0 and 7.  In panel A, mean group tumor volumes (± standard error of the mean) are 
presented.  Statistical comparisons of tumor volume between groups are presented in panel B. In panel B, individual animal 
tumor volumes on Day 35 are presented.  Open symbols are measured values from Day 35; solid symbols are censored data 
(final measurement taken before Day 35).  In panel C, animal survival curves are presented.  Comparison of animal survival 
between groups was conducted using Log-rank with Mantel-Cox test analysis.  Comparisons with significant differences are 
shown in panel C. Tumor volumes presented are from Study 14-M320-6565.  There were 10 animals in each group.
Figure 4
Efficacy of Combination Treatment with mDTA-1 IgG1 and muDX400 in 
Established Syngeneic Mouse Tumor Model
 
 
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Ongoing Clinical Trials
4.1.3
4.1.3.1
MK-1248 Ongoing Clinical Trials
This is the first clinical trial with MK-1248. A Phase 1 clinical trial with MK-4166, an 
anti-GTIR humanized mAB of the IgG1 class, is ongoing as described previously in 
Section 4.1.1.1.
4.1.3.2
Pembrolizumab Ongoing 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 hematological malignancies. In 
addition, multiple combinations with pembrolizumab are also being investigated, including 
the combination of pembrolizumab with MK-4166 (anti-GITR).  For trial details please refer 
to the pembrolizumab IB.
Information on Other Trial-Related Therapy
4.1.4
No comparators are proposed for this trial.
Rationale
4.2
Rationale for the Trial and Selected Subject Population
4.2.1
MK-1248 is being developed for treatment of solid tumors.  This trial is the first-in-human 
trial designed to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of 
escalating doses of MK-1248 alone and in combination with pembrolizumab in subjects with 
advanced solid tumors that have failed standard therapy. The effect of MK-1248 on tumor 
size will also be explored.  The trial will enroll subjects with solid tumors without regard to 
specific tumor type.
Rationale for Dose Selection/Regimen/Modification
4.2.2
MK-1248 and MK-4166 are both monoclonal antibodies with similar binding to the GITR 
receptor and different Fc regions; MK-4166 has a functional IgG1 domain while MK-1248 
utilizes an IgG4 framework.  Therefore, the dose regimen proposed for this first-in-human 
trial of MK-1248 is based on the experience in the MK-4166 first-in-human trial.  
Specifically, doses of 0.0015 to 10 mg have been administered to single-dose cohorts of 
subjects in MK-4166 PN 001 and no DLTs have been reported in these subjects.  A dose of 
30 mg MK-4166 was administered to 3 subjects, with 1 subject reporting a DLT.  This DLT 
was a Grade 3 Indiana Pouch perforation reported in a subject with metastatic urethral cancer 
in which the investigator determined the event to be possibly related to study drug because of
the low incidence of spontaneous perforation and no obvious explanation for the event.  As 
of 01-Mar-2017, data are available for a total of 81 patients: 45 patients treated with 
MK-4166 monotherapy and 36 patients treated with MK-4166 in combination with 
pembrolizumab. Dose escalation has reached 670 mg in the monotherapy treatment arm and 
480 mg in the combination treatment arm; dose escalation is continuing per protocol.
 
 
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4.2.2.1
Starting Dose for This Trial
The starting dose of MK-1248 for this trial was determined by the following criteria:
1) MK-1248 has similar GITR binding epitope to MK-4166 while due to its IgG4 
domain MK-1248 is predicted to have lesser Fc-related activity compared to the
MK-4166, with its functional IgG1 domain.
2) Preclinically, cytokine release activity representing the minimum active biologic 
activity for MK-1248 is similar to MK-4166 (see below).
3) MK-4166 has been administered to subjects at doses ranging from 0.0015 mg to 
10 mg without any DLTs.  One DLT has been reported at a dose of 30 mg and dose 
escalation is ongoing.
4) The GITR receptor binding pharmacodynamic assay utilized in the MK-4166 
protocol indicates that saturation of GITR receptors in the periphery approaches 
saturation as doses of 0.37 mg and higher.
Therefore, the starting dose of MK-1248 in this trial is planned to be 0.12 mg.  The dose of 
0.12 mg MK-1248 was chosen because safety data from the closely related MK-4166 
molecule is available as doses approximately 100-fold higher than the 0.12 mg dose (i.e. at 
10 mg MK-4166) without DLTs.  Furthermore, while a starting dose of 0.12 mg is 
anticipated to have some GITR-binding pharmacodynamic activity, it is expected to be below 
the corresponding dose of MK-4166 at which full saturation of peripheral GITR receptors 
was approached (0.37 mg MK-4166).  
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-1248 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 NK T-cells is present in 
cynomolgus monkey blood relative to human, and a large but variable percentage of 
GITR-positive NK cells is present in human while none are present in cynomolgus monkey 
blood. Non-linear PK properties were observed in cynomolgus monkeys at lower doses 
(0.0005 – 3 mg/kg). In line with changes in serum concentration-time profiles for MK-1248, 
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-1248 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. It should be noted that MK-4166 has a similar 
estimated potency value in this same model.
GITR+ T-cells in blood were evaluated for MK-1248 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.
 
 
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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

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 
 
 
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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 mg to 330 mg for MK-1248.  Although dose 
escalations will depend on adverse events, a potential dose 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 species (cynomolgus monkey) showed no adverse effects at doses where the Cmax and 
AUC values were twenty-fold and five-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-1248 Monotherapy
Maximal efficacy was achieved in mouse preclinical studies using 3 mg/kg doses. In the 
rapidly progressing syngeneic tumor models, no improvement in efficacy was 
observed with weekly 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-
1248 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, three 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-1248 in Combination with Pembrolizumab
As described previously, the combination of the anti-mouse GITR and anti-mouse PD-1 
surrogate antibodies for MK-1248 and pembrolizumab showed greater efficacy in
preclinical studies than either agent alone. Therefore, the combination of MK- 1248 and
pembrolizumab is planned for study in clinical trials to assess whether selected groups
of patients with cancer 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-1248 and pembrolizumab, and determine a
recommended Phase 2 dose for MK-1248 when used in combination with pembrolizumab.
Similar to the preclinical studies, MK-1248 and pembrolizumab will be administered on
the same day for the first 4 cycles in Arm 2 when both drugs are administered, followed by 
administration  of pembrolizumab alone every 3 weeks for a total of 24 weeks or until a 
discontinuation criterion is met.
 
 
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Rationale for Endpoints
4.2.3
4.2.3.1
Efficacy Endpoints
An exploratory endpoint for this trial is to evaluate the anti-tumor activity of MK-1248 and 
MK-1248 in combination with pembrolizumab in subjects with advanced solid malignancies. 
Tumor response will be accessed using irRECIST.
Immunotherapeutic agents such as MK-1248 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-1248 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, and irRECIST will thus be used to assess efficacy.
4.2.3.2
Safety Endpoints
The primary safety analysis of this trial is to characterize the safety and tolerability of MK -
1248 monotherapy and 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 
of toxicities experienced by subjects who have received MK-1248, including serious adverse 
events and events of clinical interest (ECIs).
Safety will be assessed by reported adverse experiences using CTCAE, version 4.0. The
attribution to drug, time-of-onset, duration of the event, its resolution, and any concomitant
medications administered will be recorded. AEs will be analyzed including but not limited to
all AEs, SAEs, fatal AEs, and laboratory changes. 
4.2.3.3
Pharmacokinetic Endpoints
A secondary objective of this trial is to characterize the pharmacokinetic (PK) profile of 
MK-1248 following administration as a single agent, and MK-1248 and pembrolizumab 
following administration of MK-1248 and pembrolizumab in combination. The serum 
concentrations of each antibody will serve as the primary readout for the PK, and these data 
will be used to derive PK parameters of the agents alone and in combination. Furthermore, 
the results of these analyses will be used in conjunction with the pharmacodynamics, safety 
and anti-drug antibody endpoints to help assess future dosing strategies for MK-1248.
4.2.3.4
Pharmacodynamic Endpoints
4.2.3.4.1 Target Engagement (TE): Receptor Availability on Peripheral Blood 
Lymphocytes
Due to GITR internalization upon binding by MK-1248, 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
 
 
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following administration of MK-1248 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.  
This assay is the primary pharmacodynamic assessment of MK-1248 target binding, and 
represents a secondary hypothesis for this trial.  As GITR binding and internalization in the 
periphery is likely to saturate, this assay may not be conducted at higher doses once 
saturation has been confirmed.
4.2.3.5
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. Anti-MK-1248 and anti-pembrolizumab ADA response at the beginning of each 
cycle will be determined to understand drug metabolism, exposure and safety.
4.2.3.6
Serum Cytokines 
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).
4.2.3.7
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.
For Arm 1, Parts B and C 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 biopsy of tumor before treatment for 
these biomarker analyses. Subjects will also be asked to agree to an optional biopsy of tumor 
after initiation of MK-1248 and to provide the acquired tissue for these biomarker analyses.
Immune modulatory agents may alter populations of circulating immune cells in blood. To
assess the effect of MK-1248 on these cell populations, peripheral blood samples will be
obtained at designated times before and after MK-1248 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.
 
 
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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.
4.2.3.8
Planned Genetic Analysis 
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
4.2.3.9
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
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 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 analysi s 
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.
Benefit/Risk
4.3
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination during participation, as clinical trials are designed to provide 
information about the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the accompanying IB and informed consent documents.
 
 
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5.0 METHODOLOGY
Entry Criteria
5.1
Diagnosis/Condition for Entry into the Trial
5.1.1
Enrollment into this study has been prematurely discontinued due to program prioritization 
and not related to any safety concerns. The cut-off date for enrollment is 31-Mar-2017. 
Subjects who are ongoing in the study after that date and who do not yet meet established 
protocol discontinuation criteria, as outlined in Section 5.8, will continue to attend study 
visits and be followed per protocol. Subjects who are ongoing in the study after that date and 
who do not yet meet established treatment discontinuation criteria, as outlined in Section 5.8, 
may continue to receive study treatment per protocol, provided the investigator feels such 
treatment is in the best interest of the subject. Male/Female subjects with advanced solid 
tumors, of at least 18 years of age will be enrolled in this trial.
Subject Inclusion Criteria
5.1.2
In order to be eligible for participation in this trial, the subject must:
1. Have histologically or cytologically-confirmed metastatic solid tumor for which there 
is no available therapy which may convey clinical benefit.
2. Have measureable disease by RECIST 1.1 criteria.
3. Be ≥18 years of age on the day of signing informed consent.
4. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group 
(ECOG) Performance Scale.
5. Demonstrate adequate organ function as defined in Table 1 (labs to be obtained 
within 7 days of initiation of treatment).
 
 
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
> 1500/mcL
Platelets
> 100,000/ mcL
Hemoglobin
≥9 g/dL or ≥5.6 mmol/L
Renal
Creatinine OR
Measured or calculated creatinine 
clearance
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 mL/min for subject with creatinine 
levels > 1.5 X institutional ULN
Note: 
Creatinine 
clearance 
should 
be 
calculated per institutional standard
Hepatic
Total Bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 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 
6. Female subjects of childbearing potential should 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 the last dose of study medication. Subjects of 
childbearing potential are those who have not been surgically sterilized, or have not 
been free from menses for > 1 year. Male subjects should agree to use an adequate 
method of contraception starting with the first dose of study therapy through 180 days 
after the last dose of study medication. Abstinence is acceptable if this is the 
established and preferred contraception for this subject.
7. Female subjects of childbearing potential should have a negative urine or serum 
pregnancy test at Screening and again within 24 hours prior to receiving the first dose 
of study medication. If urine test is positive, a negative serum pregnancy test will be 
required.
8. 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.
 
 
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9. Submit a baseline 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
5.1.3
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 (this includes subjects with previous immunomodulatory therapy with residual 
irAEs).
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 4 weeks of the first dose of study treatment.
3. Has received previous treatment with another agent targeting the GITR receptor (e.g., 
MK-4166).
4. Have received previous treatment with
an immunomudulatory therapy (e.g.,
anti-PD-1/PD-L1 or CTLA 4 agent) and was discontinued from that therapy due to an 
irAE.
5. Is expected to require any other form of antineoplastic therapy while on study.
6. Is on chronic systemic steroid therapy in excess of replacement doses, or on any other 
form of immunosuppressive medication.
7. Has a history of a previous, additional 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.
8. 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. 
9. Has had a severe hypersensitivity reaction to treatment with another monoclonal 
antibody.
 
 
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10. Has an active autoimmune disease or a documented history of autoimmune disease, 
except vitiligo or resolved childhood asthma/atopy, or endocrine deficiency following 
treatment with an immunomodulary agent.
11. Has an active infection requiring therapy.
12. Has active, or a history of non-infectious pneumonitis.
13. Has had a prior stem cell or bone marrow transplant.
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies), 
active chronic or acute Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV 
RNA [qualitative] is detected).
15. 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.
16. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
17. 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.
18. Has symptomatic ascites or pleural effusion. A subject who is clinically stable 
following treatment for these conditions (including therapeutic thoraco-
or 
paracentesis) is eligible.
19. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study.
20. Has had major surgery within 16 weeks prior to screening. Local surgery for 
melanoma is allowed. 
21. Has received a live vaccine within 30 days prior to first dose.
22. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or 
child) 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.
 
 
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Trial Treatment(s)
5.2
The treatment(s)to be used in this trial are outlined below in Table 2 and Table 3.
In Arm 1, Part A, dose escalation will begin with 0.12 mg in cohorts of 2 subjects each, and 
will proceed based on safety events to a dose of 10 mg. Starting at a 30 mg dose (or at a 
lower dose as described in Section 5.2.1.3) in Part B, dose escalation will continue with a 
3+3 design to identify a preliminary maximum tolerated dose (MTD). In Part C, dose 
confirmation will refine the estimate of the tolerability of the MTD (or maximum 
administered dose), using a toxicity probability interval [1].
Enrollment to Arm 2, (MK-1248 in combination with pembrolizumab) will begin once 
2 subjects complete 1 cycle of MK-1248 monotherapy at the ≥3 mg dose level in Part A, and 
will follow a 3+3 design to identify a preliminary MTD in Part D. The starting dose of 
MK-1248 will be 0.12 mg. Doses of MK-1248 will be escalated as described in Table 3 and 
the dose of pembrolizumab will be fixed at 200 mg.  During 3+3 dose escalation, at least 
2 days of observation will occur between each of the first 3 subjects at each dose level
(except for the first 2 subjects receiving the combination treatment at the first dose level for 
which at least 7 days of observation between dosing will occur). Dose confirmation in Part E 
will refine the estimate of tolerability of the MTD using a toxicity probability interval [1]. 
Enrollment to both arms will occur in parallel with treatment allocation accomplished by 
non-random assignment to Arm 1 or Arm 2 using an IVRS/IWRS.
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, 
initiation of the dose confirmation Parts C and E may begin. Depending on safety, efficacy 
and pharmacologic data, dose escalation in the monotherapy and combination therapy arms 
may continue concurrent with enrollment in Parts C and E. Up to a total of 14 subjects may 
be enrolled at a lower dose level where robust clinical activity is observed concurrent with 
the dose escalation phase.  In either of the above cases, an administrative letter will be used 
to document the initiation of a dose confirmation cohort (Part C or E for the monotherapy or 
combination treatment, respectively), or to allow enrollment of up to a total of 14 subjects at 
a given dose.
Note: Enrollment into this study has been prematurely discontinued due to program 
prioritization and not related to any safety concerns. The cut-off date for enrollment is 
31-Mar-2017. Subjects who are ongoing in the study after that date and who do not yet meet 
established protocol discontinuation criteria, as outlined in Section 5.8, will continue to 
attend study visits and be followed per protocol. Subjects who are ongoing in the study after 
that date and who do not yet meet established treatment discontinuation criteria, as outlined 
in Section 5.8, may continue to receive study treatment per protocol, provided the 
investigator feels such treatment is in the best interest of the subject.
 
 
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Table 2
Trial Treatment for MK-1248 Monotherapy (Arm 1)
Drug
Dose
Dose 
Frequency
Route of 
Administration
Regimen
Use
Treatment during Part A : Dose escalation
MK-1248
0.12 mg
0.6 mg
3 mg
10 mg
Q3 weeks
IV infusion
Day 1 of each 21 
day cycle
Experimental
Treatment during Part B : 3+3
MK-1248
30 mg
60 mg
120 mg
170 mg
240 mg
330 mg
460 mg
650 mg
900 mg
Q3 weeks
IV infusion
Day 1 of each 21 
day cycle
Experimental
Note: Dose levels shown in Table 2 are proposed dose levels. 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.
 
 
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Table 3
Trial Treatment for MK-1248 and Pembrolizumab Combination (Arm 2)
Drug
Dose
Dose 
Frequency
Route of 
Administration
Regimen
Use
Treatment during Part D: 3+3 
MK-1248
0.12 mg
0.6 mg
3 mg
10 mg
30 mg
60 mg
120 mg
170 mg
240 mg
330 mg
460 mg
650 mg
900 mg
Q3 weeks
IV infusion
Day 
1 
of 
each 21 day 
cycle
Experimental
Pembrolizumab
200 mg
Q3 weeks
IV infusion
Day 
1 
of 
each 21 day 
cycle
Experimental
Note: Dose levels shown in Table 3 are proposed dose levels. Actual doses of MK-1248 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.
In Arm 2, pembrolizumab will be administered first, then after a 30-minute observation 
period MK-1248 will be administered.
Based on preliminary safety information from the ongoing study, the Sponsor recommends 
that all subjects be prophylactically pre-medicated, 1.5 hours (± 30 minutes) before infusion 
with MK-1248, with the following:
(1) Dexamethasone, 8 mg intravenously;
(2) Acetaminophen, 1000 mg orally; and
(3) Loratadine, 10 mg orally.
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
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.
 
 
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Dose Selection/Modification
5.2.1
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background & Rationale.  
Details on preparation of administration of MK-1248 and pembrolizumab are provided in the 
Procedure Manual. 
5.2.1.2
Dose Escalation
In Arm 1 (MK-1248 monotherapy), dose escalation will begin with 0.12 mg in cohorts of 
2 subjects each, and will proceed based on safety events to a dose of 10 mg. Starting at a 
30 mg dose (or at a lower dose as described in Section 5.2.1.3) in Part B, dose escalation will 
continue with a 3+3 design to identify a preliminary maximum tolerated dose (MTD). In Part 
C, dose confirmation will refine the estimate of the tolerability of the MTD (or maximum 
administered dose), using a toxicity probability interval [1]. 
Enrollment to Arm 2, (MK-1248 in combination with pembrolizumab) will begin once 
2 subjects complete 1 cycle of MK-1248 monotherapy at the ≥3 mg dose level in Part A, and 
will follow a 3+3 design to identify a preliminary MTD in Part D. The starting dose of 
MK-1248 will be 0.12 mg. Doses of MK-1248 will be escalated as described in Table 3 and 
the dose of pembrolizumab will be fixed at 200 mg.  Dose confirmation in Part E will refine 
the estimate of tolerability of the MTD using a toxicity probability interval [1]. 
5.2.1.3
Accelerated Dose Escalation (MK-1248 Monotherapy)
During the accelerated dose escalation stage (Part A), each cohort will enroll two subjects
and dose escalation will proceed as designated in Table 2 and Table 3, until a DLT is 
observed or until the dose level of 10 mg is safely administered. 
At least 2 days of 
observation will occur between each of the first 2 subjects at each dose level.
If a DLT is observed during a 2-subject cohort, an additional subject will be enrolled at this 
dose level for a total of 3 subjects, and the rules of 3+3 dose escalation described in 
Section 5.2.1.4 will apply:

If the new subject does not develop a DLT (for a total of 1/3 subjects with a DLT 
at that dose level), three more subjects will be enrolled at this dose level and the 
rules of 3+3 design (Section 5.2.1.4) will be followed for a cohort of 6 subjects.
The 3+3 dose escalation design will be followed from then on with 40% 
increments in the dose level.

If the new subject develops a DLT (for a total of 2/3 subjects with a DLT at this 
dose level), the dose escalation stage of the trial will be terminated. The third
subject will be enrolled in the dose directly below the current dose and the 3+3 
dose escalation design will be followed from then on with 40% increments in the 
dose level.
See Section 5.2.2 for definition of DLTs.
Starting with the 30 mg dose, 3 subjects will be enrolled to each dose level.
 
 
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5.2.1.4
3+3 
Dose 
Escalation 
(MK-1248 
Monotherapy 
and 
MK-1248 
plus 
Pembrolizumab Combination)
During MK-1248 monotherapy (Arm 1), once the 10 mg dose is safely administered, starting 
with the next dose the study will proceed to 3 subjects enrolled at each dose level and dose 
escalation continuing according to Table 2. During 3+3 dose escalation, at least 2 days of
observation will occur between each of the first 3 subjects at each dose level.
For MK-1248, intermediate lower dose levels, not specified in Table 2 and 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 for the preliminary MK-1248 dose finding during MK-1248 monotherapy (Arm 1) 
and during MK-1248 plus pembrolizumab combination treatment (Arm 2) using the 3+3 
design are as follows (all dose adjustments are made only to MK-1248):
An initial cohort of 3 subjects is enrolled.
If 0/3 subjects develops a DLT, escalation to the next dose of MK-1248 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 develops 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 develop a DLT (for a total of ≥2/6 subjects 
with a DLT at this dose level), the dose escalation stage 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, and the study will proceed to the 
confirmation stage. 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 proceeding to the confirmation 
stage.
If ≥2/3 subjects develop a DLT, the dose escalation stage 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, and the study will proceed to the confirmation stage. 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 
proceeding to the confirmation stage.
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 stage of the study. 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. This would be 
communicated to sites via administrative letter.
 
 
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If the highest candidate dose of MK-1248 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 level may be taken to the confirmation stage.
5.2.1.5
Dose Confirmation
The objective of dose confirmation in Part C and Part E is to refine the estimate of the
MK-1248 MTD based on TPI design [1] with target toxicity rate <30%.  Dose confirmation 
involves the expansion of at least 1 dose level studied in the dose escalation stage of the 
study. 
The toxicity probability interval (TPI) design [1] will be used at the dose confirmation stage. 
Based on the observed DLTs, the approach recommends actions of escalating, staying at, or 
de-escalating the dose level as presented in Table 4.
Dose confirmation will begin with expansion of the preliminary MTD/MAD identified in the 
dose escalation stage described above. The dose confirmation part will continue until 
14 subjects are studied at the selected dose (combined from dose escalation and dose 
confirmation) with ≤5 of 14 subjects experiencing a DLT.  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 be continuously assessed and de-escalation and 
re-escalation to eligible doses of MK-1248 will occur as shown in Table 4
The 200 mg dose of pembrolizumab will not be adjusted.
 
 
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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
0
S
E
E
E
E
E
E
E
E
E
E
1
S
S
S
S
S
S
E
E
E
E
E
2
D
S
S
S
S
S
S
S
S
S
S
3
DU
D
D
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
D
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
D
S
S
S
6
DU
DU
DU
DU
DU
DU
D
D
D
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
E = Escalate to the next higher dose
S = Stay at the current dose
D = De-escalate to the next lower dose
DU = The current dose is unacceptably toxic
Target toxicity rate = 30%
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 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.
 
 
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If enrollment expands to 14 subjects for a dose level, and ≤5 of the 14 subjects develop a 
DLT, then the dose confirmation will stop.  If enrollment expands to 14 subjects for a dose 
level and >5/14 subjects develop a DLT, then the next lower dose may be expanded to 
further explore the dose-response relationship. 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%.
Definition of Dose Limiting Toxicity
5.2.2
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 study drug (MK-1248 in Arm 1 
or the MK-1248 with pembrolizumab combination in Arm 2), will be considered a DLT:
1. Grade 4 non-hematological toxicity (not laboratory)
2. Grade 4 hematological 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. Any Grade 3 non-hematological toxicity (not laboratory), with the exception of 
Grade 3 nausea, vomiting or diarrhea, which will not be considered a DLT unless 
lasting more than 3 days despite optimal supportive care
4. Any Grade 3 or Grade 4 non-hematological laboratory abnormality, if

medical intervention is required, or

the abnormality leads to hospitalization, or

the abnormality persists for >1 week
5. Febrile neutropenia Grade 3 or Grade 4
6. Any drug-related AE which caused subject to discontinue treatment during Cycle 1
7. Grade 5 toxicity
8. Any treatment-related toxicity which causes a greater than 2 week delay in initiation 
of Cycle 2
 
 
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Guidelines for Dose Modification due to Adverse Events
5.2.3
5.2.3.1
Dose Modification and Toxicity Management for Adverse Events Associated 
with MK-1248 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-1248 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-1248 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-1248 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-1248 will be withheld for Grade 3 thrombocytopenia associated with bleeding, Grades 3 
and 4 febrile neutropenia, Grade 4 hematological toxicities lasting ≥7 days, Grade 4 
thrombocytopenia of any duration, Grade ≥3 non-hematological toxicities including 
laboratory abnormalities, and severe or life-threatening AEs as per Table 5.
Pembrolizumab treatment interruption/discontinuation and toxicity management guidelines
are described in Section 5.2.3.2 and Section 5.2.3.3.
 
 
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Table 5
MK-1248 Dose Modification and Treatment Discontinuation Guidelines for 
Drug-Related Adverse Events
Toxicity
Hold 
Treatment
Criteria for 
Restarting 
Treatment
Dose/Schedule for 
Restarting Treatment
Criteria for 
Discontinuation after 
Consultation with 
Sponsor
Hematological toxicities:
Any Grade 1, 2, or 3 
hematological toxicity 
except Grade 3 
thrombocytopenia 
associated with bleeding 
and Grade 3 febrile 
neutropenia
No 
N/A
N/A
N/A
Grade 3 
thrombocytopenia 
associated with bleeding
Grade 3 febrile 
neutropenia
Grade 4 hematological 
toxicities lasting ≥7 days
Grade 4 
thrombocytopenia of 
any duration
Grade 4 febrile 
neutropenia
Yes
Toxicity 
resolves to 
Grade 0-1, 
or to 
baseline
The dose may be reduced 
by one dose level upon 
discussion with Study 
Team. Intervals between 
treatments remain 
unchanged
Toxicity does not 
resolve within 12 
weeks of last dose.
Permanent 
discontinuation 
should be considered 
for any severe or 
life-threatening event
Non-hematological toxicities:
Any Grade 1 non-
hematological toxicity 
Grade 2 alopecia
Grade 2 fatigue
No 
N/A
N/A
N/A
Any Grade 2 non-
hematological toxicity 
except Grade 2 alopecia 
and Grade 2 fatigue
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: 
The dose may be reduced 
by one dose level upon 
discussion with Study 
Team. Intervals between 
treatments remain 
unchanged
Toxicity does not 
resolve within 12 
weeks of last dose.
Any Grade 3 or 4 non-
hematological toxicity
Yes
Toxicity 
resolves to 
Grade 0-1 or
baseline
The dose may be reduced 
by one dose level upon 
discussion with Study 
Team. Intervals between 
treatments remain 
unchanged
Toxicity does not 
resolve within 12 
weeks of last dose. 
Permanent 
discontinuation 
should be considered 
for any severe or 
life-threatening event
 
 
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In case toxicity does not resolve to Grade 0-1 within 12 weeks after last 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.
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.
 
 
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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
 
 
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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
 
 
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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).
 
 
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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)
 
 
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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 During DLT Evaluation Period
5.2.4
In order to determine safety, all subjects selected must meet the criteria for evaluability for 
Cycle 1. Subjects are considered non-evaluable for DLT assessment 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-1248 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, study treatment may be discontinued following 
discussion between the sponsor and Investigator. However, if the subject is deriving clinical 
 
 
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benefit from the study treatment, the subject may be allowed to continue after discussion 
between the sponsor and the Investigator.
Timing of Dose Administration
5.2.5
Study 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-1248 occurring approximately 30 minutes after completion of the 
pembrolizumab administration. 
Based on preliminary safety information from the ongoing study, the Sponsor recommends 
that all subjects be prophylactically pre-medicated, 1.5 hours (± 30 minutes) before infusion 
with MK-1248, with the following:
(1) Dexamethasone, 8 mg intravenously;
(2) Acetaminophen, 1000 mg orally; and
(3) Loratadine, 10 mg orally.
Trial Blinding/Masking
5.2.6
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
5.3
Treatment allocation by non-random assignment to Arm 1 or Arm 2 will occur centrally 
using an IVRS/IWRS. Allocation to a treatment arm will take into consideration whether or 
not a treatment arm is open to allocation based on minimizing enrollment time, ensuring 
minimum number of days between each study-wide allocated subject for a given dose, and 
sequencing Arm 2 relative to the study-wide results of Arm 1.
Note: Enrollment into this study has been prematurely discontinued due to program 
prioritization and not related to any safety concerns. The cut-off date for enrollment is 
31-Mar-2017. Subjects who are ongoing in the study after that date and who do not yet meet 
established protocol discontinuation criteria, as outlined in Section 5.8, will continue to 
attend study visits and be followed per protocol. Subjects who are ongoing in the study after 
that date and who do not yet meet established treatment discontinuation criteria, as outlined 
in Section 5.8, may continue to receive study treatment per protocol, provided the 
investigator feels such treatment is in the best interest of the subject.
 
 
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Stratification
5.4
No stratification based on age, sex or other characteristics will be used in this trial.
Concomitant Medications/Vaccinations (Allowed & Prohibited)
5.5
Acceptable Concomitant Medication
5.5.1
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.
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 study 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
5.5.2
Subjects are prohibited from receiving the following therapies during the Screening, and 
Treatment Phases of this trial:

Immunotherapy not specified in this protocol.

Antineoplastic systemic chemotherapy or biological therapy.

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 study 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.
 
 
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
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
5.6
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 
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-1248 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
5.7
Diet
5.7.1
Subjects should maintain a normal diet unless modifications are required to manage AEs 
such as diarrhea, nausea or vomiting.
Contraception
5.7.2
MK-1248 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, or 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. 
 
 
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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
5.7.3
If a subject inadvertently becomes pregnant while on treatment with MK-1248 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 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
5.7.4
It is unknown whether MK-1248 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
5.8
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.
 
 
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Note: Subjects who discontinue treatment for reasons other than PD will have post-treatment 
follow-up for disease status until PD, initiating a non-study cancer treatment, withdrawing 
consent, or becoming lost to follow-up.
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.

Confirmed disease progression
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

The subject withdraws consent for treatment

Confirmed disease progression

Unacceptable adverse events (See Dose Modification Section 5.2.3)

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw subject

Subject has confirmed positive serum pregnancy test

Noncompliance with study treatment or procedure requirements

Administrative reasons

Completed treatment as defined in this protocol
Click here to enter text.
Subject Replacement Strategy
5.9
A subject who discontinues from the trial will not be replaced except as described in Section 
5.2.4 Replacement of Subjects During DLT Evaluation Period.
Beginning and End of the Trial
5.10
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit,
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator).
Clinical Criteria for Early Trial Termination
5.11
There are no pre-specified criteria for terminating the trial early.
 
 
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6.0 TRIAL FLOW CHART
Note: Enrollment into this study has been prematurely discontinued due to program prioritization and not related to any safety 
concerns. The cut-off date for enrollment is 31-Mar-2017. Subjects who are ongoing in the study after that date and who do not yet 
meet established protocol discontinuation criteria, as outlined in Section 5.8, will continue to attend study visits and be followed per 
protocol. Subjects who are ongoing in the study after that date and who do not yet meet established treatment discontinuation criteria, 
as outlined in Section 5.8, may continue to receive study treatment per protocol, provided the investigator feels such treatment is in the 
best interest of the subject.
Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5 and 
6 
(Arm 
2 
only)1
Cycle 7 
and 
Beyond 
(Arm 2 
only)1
Discon
Safety 
Follow-
up
Follow-up
Cycle Day
1
2
3
5
8
15
1
2
3
5
8
15
9 
weeks 
after 
1st
dose
1
1
30 days 
after 
last 
dose
3 and 6 
months 
after 
last 
dose
Every 9 
weeks 
until 
PD
Scheduling Window
(Days)
-28 to -1
+/- 3
+/-
3
+/-
3
+/- 3
+/-
3
+/-
3
+/- 7
+/- 7
+/- 7 
+/- 7 
Administrative 
Procedures
Informed Consent2
X
Informed 
Consent 
for 
Future 
Biomedical 
Research3
X
Inclusion/Exclusion 
Criteria
X
Subject 
Identification 
Card
X
Demographics 
and 
Medical History
X
Concomitant Medication 
Review 
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior Oncology Treatment 
X
 
 
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Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5 and 
6 
(Arm 
2 
only)1
Cycle 7 
and 
Beyond 
(Arm 2 
only)1
Discon
Safety 
Follow-
up
Follow-up
Cycle Day
1
2
3
5
8
15
1
2
3
5
8
15
9 
weeks 
after 
1st
dose
1
1
30 days 
after 
last 
dose
3 and 6 
months 
after 
last 
dose
Every 9 
weeks 
until 
PD
Scheduling Window
(Days)
-28 to -1
+/- 3
+/-
3
+/-
3
+/- 3
+/-
3
+/-
3
+/- 7
+/- 7
+/- 7 
+/- 7 
History
MK-1248 
Drug 
Administration (Arms 1 & 
2)4
X
X
Pembrolizumab 
Drug 
Administration
(Arm 2 
only)5
X
X
X
X
Clinical 
Procedures/Assessments
Adverse 
Events 
Monitoring 
X
X
X
X
X
X
X
X
X
X
X
X
X
Full Physical Examination 
X
X6
X6
X6
X6
X
X
X
Height
X
Weight
X
X
X
X
X
X
X
Vital Signs (temperature, 
pulse, 
respiratory 
rate, 
blood pressure)7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-Lead 
Electrocardiogram8
X
X6
X6
ECOG 
Performance 
Status
X
X6
X6
X6
X6
X
X
Tumor 
Imaging 
and 
irRECIST 
Response 
Assessment9
X
X
X
X
X
Survival Status10
 
 
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Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5 and 
6 
(Arm 
2 
only)1
Cycle 7 
and 
Beyond 
(Arm 2 
only)1
Discon
Safety 
Follow-
up
Follow-up
Cycle Day
1
2
3
5
8
15
1
2
3
5
8
15
9 
weeks 
after 
1st
dose
1
1
30 days 
after 
last 
dose
3 and 6 
months 
after 
last 
dose
Every 9 
weeks 
until 
PD
Scheduling Window
(Days)
-28 to -1
+/- 3
+/-
3
+/-
3
+/- 3
+/-
3
+/-
3
+/- 7
+/- 7
+/- 7 
+/- 7 
Laboratory 
Procedures/Assessments 
–Analysis by Local Lab
CBC with differential
X11
X6, 
12
X
X
X
X6,12
X
X
X6, 12
X6, 12
X
X
C Reactive Protein
X11
X6, 
12
X
X
X
X6, 
12
X
X
X6, 12
PT/INR and aPTT
X11
Chemistry Panel
X11
X6, 
12
X
X
X
X6,
12
X
X
X6, 12
X6, 12
X
X
LDH, GGT
X11
X6
X6
X6
Pregnancy Test – Urine or 
Serum 
β-hCG, 
if 
applicable13
X
X13
Immunoglobulins 
(IgA, 
IgG, IgM)
X6
X6
X6
Urinalysis
X11
Thyroid Function (T4, T3, 
TSH)14
X6
X6
X6
X6
X
HIV, Hepatitis B and C15
X
 
 
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Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5 and 
6 
(Arm 
2 
only)1
Cycle 7 
and 
Beyond 
(Arm 2 
only)1
Discon
Safety 
Follow-
up
Follow-up
Cycle Day
1
2
3
5
8
15
1
2
3
5
8
15
9 
weeks 
after 
1st
dose
1
1
30 days 
after 
last 
dose
3 and 6 
months 
after 
last 
dose
Every 9 
weeks 
until 
PD
Scheduling Window
(Days)
-28 to -1
+/- 3
+/-
3
+/-
3
+/- 3
+/-
3
+/-
3
+/- 7
+/- 7
+/- 7 
+/- 7 
Laboratory 
Procedures/Assessments-
Analysis 
to 
be 
Performed by Central 
Lab
Humoral 
Immunity 
Assays16
X6
X
X
Cytokine Panel17
X6
X
X
X
X
X
X
Anti-MK-1248 Antibodies 
(Arms 1 & 2)18
X6
X
X
X
X
X
X
X
X
X
X
X
X
Pharmacokinetics for MK-
1248 (Arms 1 & 2)19
X6
X
X
X
(require 
for 4 
lowest 
dose 
levels 
in Arm 
1)
X
X
X
X
X
X
(require 
for 4 
lowest 
dose 
levels 
in Arm 
1)
X
X
X
X
X
Anti-MK-3475 Antibodies 
( Arm 2 only)20
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab/MK-3475 
PK (Arm 2 only)21
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood 
for 
DNA 
Correlative Studies22
X
X
 
 
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Screening 
Phase
Treatment Phase
Cycle = 21 days
End of 
Treatment Post Treatment Phase
Treatment Cycle/Title
Screening
(Visit 1)
Cycle 1
Cycles 2-41
Cycles 
5 and 
6 
(Arm 
2 
only)1
Cycle 7 
and 
Beyond 
(Arm 2 
only)1
Discon
Safety 
Follow-
up
Follow-up
Cycle Day
1
2
3
5
8
15
1
2
3
5
8
15
9 
weeks 
after 
1st
dose
1
1
30 days 
after 
last 
dose
3 and 6 
months 
after 
last 
dose
Every 9 
weeks 
until 
PD
Scheduling Window
(Days)
-28 to -1
+/- 3
+/-
3
+/-
3
+/- 3
+/-
3
+/-
3
+/- 7
+/- 7
+/- 7 
+/- 7 
Blood 
for 
RNA 
Correlative Studies 22
X
X
Blood 
for 
Genetic 
Analysis 23
X
Tumor Tissue Collection24
X
Post 
Treatment 
Tumor 
Biopsy25
X
Pharmacodynamic 
(receptor availability flow 
cytometry assay (Arms 1 
& 2)26
X
X6
X
X
(require 
for 
MK-
1248 
dose 
levels 
<30mg)
X
(require 
for 4 
lowest 
dose 
levels 
in Arm 
1)
X
X
X
X
X
require 
for 
MK-
1248 
dose 
levels 
<30mg)
X
(require 
for 4 
lowest 
dose 
levels 
in Arm 
1
X
X
X
1.
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. 
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 subject’s participation in the trial. Detailed 
instructions for the collection and management of FBR specimens are provided in the Procedure Manual. 
4.
The Sponsor recommends that all subjects be prophylactically pre-medicated with 8 mg dexamethasone, intravenously, 1000 mg acetaminophen, orally, and 10 mg loratadine,
orally, 1.5 hours (±30 minutes) before infusion with MK-1248.
5.
In the Arm 2, pembrolizumab is administered first, then following a 30-minute interval, MK-1248 will be administered.
 
 
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6.
These samples and procedures required predose Day 1 may be performed up to 72 hours prior to dosing.
7.
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-1248 infusion.  In Arm 2, beginning with Cycle 5, collect VS prior to pembrolizumab dosing on Day 1 of each cycle. 
8.
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-1248 infusion in Cycles 1-4.
9.
Tumor imaging (CT scan or MRI) should be performed within 28 days of enrollment. Tumor imaging and response assessment to be performed 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. 
10.
Upon Sponsor request, participants may be contacted for survival status at any time during the course of the study.
11.
Laboratory tests at Screening are to be performed within 7 days prior to the first dose of study treatment.
12.
In Arm 1 and Arm 2, on Day 1 in cycles 1-4, CBC with differential, CRP and chemistry profile should be drawn prior to dosing and repeated 4 hours after the start of the 
MK-1248 infusion, with results of the CBC and chemistry profile 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 profile should be drawn prior to dosing.
13.
For women of reproductive potential, a urine pregnancy test will be performed at Screening and within 24 hours prior to the first dose of study treatment.  If a urine pregnancy 
test cannot be confirmed as negative, a serum pregnancy test is required.
14.
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
15.
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).
16.
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).
17.
For Arm 1, collect cytokine panels for cycles 1-4 on day 1 predose, 1 hour and 4 hours post infusion, and on day 2 and day 3. For Arm 2, collect cytokine panels for cycles 1-
4 on day 1 predose, 1 hour and 4 hours post infusion, and on day 2 and day 3.   For Cycles 5 and 6, collect samples on day 1 Predose, 1hour and 4 hour post infusion. 
18.
MK-1248 Anti-drug antibody (ADA) will be drawn in Arm 1, predose MK-1248 on Day 1, Day 2, Day 3, Day 8 and Day 15 of Cycles 1-4, and at the Safety visit 30 days 
post discontinuation and at 3 months and 6 months after the last dose . In Arm 2 MK-1248 ADA will be obtained predose MK-1248 on Day 1, on Day 2, Day 3, Day 8 and 
Day 15 of Cycles 1-4, predose pembrolizumab Cycles 5, and 6, and at the Safety visit 30 days post discontinuation and at 3 months and 6 months after the last dose .
19.
MK-1248 Pharmacokinetic (PK) samples will be drawn in each cycle on Day 1 predose MK-1248, at the end of the MK-1248 infusion (+ 10 minutes), 2h after the start of the 
MK-1248 infusion (+/- 10 minutes), and on Day 2, Day 3, Day 5, Day 8, and Day 15 and at the Safety visit 30 days post discon and at 3 months and 6 months after the last 
dose for subjects treated at the 4 lowest dose levels in Arm 1. Starting at the 30 mg dose in Arm 1 and all dose levels in Arm 2, PK samples will be drawn in each cycle on 
Day 1 predose MK-1248, at the end of MK-1248 infusion (+ 10 minutes), 2h after the start of the MK-1248 infusion (+/- 10 minutes), on Day 2, Day 3, Day 8, and Day 15 in 
Cycles 1-4 and the Safety visit 30 days post discon and at 3 months and 6 months after the last dose. In addition, in Arm 2, MK-1248 PK will be drawn predose 
pembrolizumab in Cycles 5, and 6. If the sample day falls on a weekend or holiday, please consult the sponsor for alternate sample collection times.
20.
Pembrolizumab Anti-drug antibody (ADA) will be drawn in Arm 2 at the following timepoints: predose pembrolizumab on Day 1, on Day 2, Day 3, Day 8 and Day 15 in 
Cycles 1-4, predose in Cycles 5, 6, 8 and every 4 cycles thereafter, and at the Safety visit 30 days post discontinuation and at 3 months and 6 months after the last dose.
21.
Pembrolizumab  Pharmacokinetic (PK) samples will be drawn  in Arm 2, Cycles 1-4 Day 1 predose pembrolizumab, at the end of the Pembrolizumab infusion (+10 minutes) 
at the end of MK-1248 infusion (+ 10 minutes), 2h after the start of the MK-1248 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, at the Safety visit 30 days post discon and at 3 months and 6 months after the last dose.. If the sample day falls on a weekend or holiday, 
please consult the sponsor for alternate sample collection times.
 
 
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22.
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-1248. Detailed instructions for the collection and management of these samples are provided in the Procedure Manual.
23.
This sample should be drawn for planned analysis of the association between genetic variants in DNA and drug response. If there is either a documented law or regulation 
prohibiting collection, or if the IRB/IEC does not approve the collection of the sample for these purposes, then this sample will not be collected at that site. If the sample is 
collected, leftover extracted DNA will be stored for future biomedical research if the subject signs the FBR consent. If the planned genetic analysis is not approved, but FBR 
is approved and consent is given, this sample will be collected for the purpose of FBR
24.
Tumor tissue (archival or newly obtained biopsy) will be required at Screening in Parts B, C, D, and E. Leftover tissue may also be saved for future biomedical research if the 
subject signs the Future Biomedical Research consent.
25.
Post treatment tumor biopsy is optional, but strongly encouraged in Parts B, C, 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.
26.
In Arm 1, blood sample for pharmacodynamic (PD) will be drawn in Screening, in Cycles 1-4 on Day 1 pre-dose MK-1248, at the end of MK-1248 infusion (+ 10 minutes), 
2h after the start of the MK-1248 infusion (+/- 10 minutes), on Day 2, Day 8, and Day 15; on Day 3 dose level <30 mg, Day 5 required for 4 lowest dose levels.  In case of 
DLT, starting at the 5th dose level in Arm 1, PD samples will be drawn in Screening, in Cycles 1-4 on Day 1 pre-dose MK-1248, at the end of the MK-1248 infusion (+ 10 
minutes), 2h after the start of the MK-1248 infusion (+/- 10 minutes), on Day 2, Day 3, Day 8, and Day 15. For all dose levels in Arm 2, PD samples will be drawn at 
screening , in Cycles 1-4 on Day 1 pre-dose pembrolizumab, at the end of the MK-1248 infusion (+ 10 minutes), 2h after the start of the MK-1248 infusion (+/- 10 minutes), 
on Day 2, Day 3, Day 8, and Day 15.  In Arm 2, Day 5 will not be drawn for any dose levels. Day 3 will be drawn for MK-1248 doses <30 mg. In addition, in Arm 2 PD 
samples will be drawn pre-dose pembrolizumab in Cycles 5-6.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
7.1
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
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. If there are changes to the subject’s status during the 
trial (e.g., health or age of majority requirements), the investigator or qualified designee must 
ensure the appropriate consent is in place. 
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised 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.
 
 
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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.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
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 clinically significant by the Investigator. Details regarding the disease for 
which the subject has been enrolled in the trial will be recorded separately and should not be 
listed in medical history.
7.1.1.5
Disease Details
The Investigator or qualified designee will obtain prior and current details regarding disease 
status. 
7.1.1.6
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
Prior and Concomitant Medications Review
7.1.1.7.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 30 days before starting the trial. Treatment for the disease for which the subject has 
 
 
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been enrolled in this trial will be recorded separately and should not be listed in prior 
medications.
7.1.1.7.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial and through the 30-day Safety Follow-up Visit. After the Safety Visit, record 
all medications related to reportable SAEs and ECIs.
7.1.1.8
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. 
7.1.1.9
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 ‘randomized’, this unique number is termed a randomization number throughout the 
protocol for operational purposes. Allocation of subjects between the two arms will be 
managed by the Sponsor through an 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.
7.1.1.10 Trial Compliance (Study Drug Administration)
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.
All doses of MK-1248 and pembrolizumab will be administered under the supervision of a 
qualified physician and/or designee experienced in the use of anticancer agents. 
Instructions for preparing and administering study drugs will be provided in the Procedure 
Manual.
 
 
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Clinical Procedures/Assessments
7.1.2
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 4.0. Toxicities 
will be characterized in terms of seriousness, causality, toxicity grade and action taken with 
regard to study treatment. 
All AEs of unknown etiology associated with MK-1248 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-1248 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 or Sub-Investigators will review the safety and 
tolerability of each study 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.
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. 
 
 
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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 is earlier. 
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-2148. 
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-1248. Immune-related RECIST (irRECIST) is 
RECIST 1.1 adapted as described below to account for the unique tumor response seen with 
immuno-therapeutics. irRECIST will be used by site investigators to assess tumor response 
and progression, and 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% increase in 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 and the initial date of Progression recorded as the PD date.
 
 
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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 increase 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
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 is earlier.
Confirmation of partial response (PR) and complete response (CR) is required at least 
4 weeks after the initial response assessment of PR and CR.
Laboratory Procedures/Assessments
7.1.3
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedure 
Manual.
 
 
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7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 8.
Table 8
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Hemoglobin
Alkaline phosphatase
Glucose
Serum β-human chorionic 
gonadotropin (β-hCG)
Platelet count
Alanine aminotransferase (ALT)
Protein
Hepatitis HBsAg
WBC (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Hepatitis C (HCV RNA) or 
Hepatitis C antibody
RBC
Bicarbonate or carbon diaoxide 
(CO2)
Microscopic 
exam, 
if 
abnormal 
results 
are 
noted
HIV
PT or INR
Calcium
Urine pregnancy test, if 
required
IgA, IgG, IgM
aPTT
Chloride
Free thyroxine ( T4)
Creatinine
Thyroid 
Stimulating 
Hormone ( TSH)
Glucose
Total Triiodothyronine (T3)
Gamma Glutamyl transpeptidase 
( GGT)
C reactive protein (CRP)
Lactate dehydrogenase (LDH)
Phosphorus
Potassium
Sodium
Total Bilirubin  
Direct Bilirubin, if total bilirubin 
is elevated above the upper limit 
of normal
Total protein
Blood Urea Nitrogen
Uric Acid
Laboratory safety tests for screening should be performed within 7 days prior to first dose of 
study medication. After Cycle 1, predose laboratory tests can be performed up to 72 hours 
prior to dosing. Results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to dosing. 
 
 
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7.1.3.2
Blood for Correlative DNA/RNA
Blood for correlative studies (RNA and a separate DNA sample) will be obtained as 
indicated in Section 6.0.
Sample collection, storage and shipment instructions for correlative study samples will be 
provided in the Procedure Manual. 
Pharmacokinetic/Pharmacodynamic Evaluations
7.1.4
7.1.4.1
Blood Collection for MK-1248 and Pembrolizumab PK
To evaluate the exposure of MK-1248 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.
7.1.4.2
Blood Collection for Anti-MK-1248 Antibodies and Anti-Pembrolizumab 
Antibodies (ADA)
To evaluate the immunogenicity of MK-1248 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.
7.1.4.3
Blood for Receptor Availability Assay (PD)
Sample collection, storage and shipment instructions for PD blood samples will be provided 
in the Procedure Manual.
The timepoints for PD sampling are described in Section 6.0-Trial Flow Chart. If the sample 
day falls on a holiday or weekend, please consult the sponsor for alternate collection day.
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 sties by administrative memo that this sample will no longer 
be collected.  Decision to stop collection of blood for the receptor Availability Assay will be 
made independently for Arms 1 and 2.
7.1.4.4
Tumor Tissue Collection
All subjects will be required to provide a tumor sample (archival or newly obtained sample) 
at Screening in Parts B, C, D, and E. Samples will be sent to a central lab. 
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.
 
 
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Post treatment tumor biopsy is optional, but strongly encouraged in Parts B, C, 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.
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.
Detailed instructions for tissue collection, processing and shipment are provided in the 
Procedures Manual.
Planned Genetic Analysis Sample Collection
7.1.5
Sample collection, storage and shipment instructions for Planned Genetic Analysis samples 
will be provided in the Procedure Manual.
Future Biomedical Research
7.1.6
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover tumor for future research 

Leftover main study DNA from Blood for Genetic Analysis stored for future research 
Other Procedures
7.1.7
7.1.7.1
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 final trial 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 .
7.1.7.1.1 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 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.
 
 
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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.
7.1.7.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.7.3
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 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 pump and/or syringe pump used to administer study treatment
Visit Requirements
7.1.8
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.8.1
Screening
Approximately 28 days prior to randomization, 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.
7.1.8.2
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-1248 by IVRS. In Arms 1 and 2, MK-1248 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 
 
 
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to withdraw the subject, subject withdraws consent, pregnancy of the subject, noncompliance 
with study treatment or procedure requirements, or administrative reasons.
7.1.8.3
Post-Treatment Visits
7.1.8.3.1 Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new antineoplastic treatment, 
whichever is earlier. 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 is earlier. 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.
7.1.8.3.2 Follow-Up Visits
Subjects who complete treatment or who discontinue study 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.
7.1.8.4
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
7.2
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 
 
 
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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 clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
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 
7.2.1
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-1248 by 20%, or a pembrolizumab dose of ≥1000mg (≥5x the indicated dose). 
No specific information is available on the treatment of overdose of
MK-1248 or 
pembrolizumab. In the event of overdose, MK-1248 or pembrolizumab should be 
discontinued and the subject should be observed closely for signs of toxicity.  Appropriate 
supportive treatment should be provided if clinically indicated.
If an 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 by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
7.2.2
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 
 
 
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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
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.
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, 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.
 
 
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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, 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).
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).
 
 
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Evaluating Adverse Events
7.2.4
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.
For studies in which multiple agents are administered as part of a combination regimen, the 
investigator may attribute each adverse event causality to the combination regimen or to a 
single agent of the combination.  In general, causality attribution should be assigned to the 
combination regimen (i.e., to all agents in the regimen). However, causality attribution may 
be assigned to a single agent if in the investigator’s opinion, there is sufficient data to support 
full attribution of the adverse experience to the single agent.
 
 
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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 cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for 
collection purposes. 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?
 
 
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Relationship to 
Sponsor’s 
Product
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
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 the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
7.2.5
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
Click here to enter text.
8.0 STATISTICAL ANALYSIS PLAN
Statistical Analysis Plan Summary
8.1
This section contains a brief summary of the statistical analyses for this trial. Full details are 
provided in the remainder of Section 8.
Study Design Overview
Phase 1 Trial of Single Agent MK-1248 and MK-1248 in combination 
with Pembrolizumab in Subjects With Advanced Solid Tumors
Analysis Populations
Safety: All Subjects as Treated (ASaT)
Efficacy (exploratory): Single Agent MK-1248  Full Analysis Set 
(FAS1), MK-1248 in combination with Pembrolizumab Full Analysis 
Set (FAS2)   
Primary Endpoint(s)
Safety: DLT
Key Secondary Endpoints
PK parameters
of single agent MK-1248
and MK-1248
in 
combination 
with 
pembrolizumab
and 
PK 
parameters 
of 
pembrolizumab for subjects treated with MK-1248 in combination 
with pembrolizumab; target engagement as measured by modulation 
in peripheral blood GITR receptor availability alone and in 
combination with pembrolizumab
Statistical Methods for Key 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
Serum concentrations of MK-1248 in the MK-1248 monotherapy arm 
and serum concentrations of MK-1248 and pembrolizumab in the 
MK-1248 and pembrolizumab combination 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-1248
and 
MK-1248
co-administered 
with 
pembrolizumab 
without 
randomization centrally through IVRS; 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. The 
estimate of the DLT rate among subjects treated with the 
recommended MK-1248 Phase 2 dose and the 95% Bayesian 
Probability Interval (PI) for the estimate will be provided.
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 A-E) depends on the observed DLT profiles of 
MK-1248
monotherapy 
and 
MK-1248
co-administered 
with 
pembrolizumab.  The sample size of 96 subjects that will be obtained 
if no DLTs are observed will be used for study planning purposes. In 
certain low probability scenarios, more than 96 subjects will be 
needed.
 
 
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Responsibility for Analyses/In-House Blinding
8.2
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the SPONSOR.
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 when all subjects who have not discontinued due to 
progression, death or withdrawal of consent are at least 6 months after their first dose.
Hypotheses/Estimation
8.3
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
8.4
Efficacy and safety endpoints are listed below, followed by the descriptions of the 
derivations of selected endpoints.
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
8.4.1
Efficacy endpoints and their definitions are presented in Section 8.4.3.
Safety Endpoints
8.4.2
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
8.4.3
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
by the investigator review. Subjects with missing outcome on objective response will be 
considered non-responders.
Disease Control Rate (DCR): is defined as the percentage of subjects who have achieved 
stable disease for at least 8 weeks or confirmed complete response (CR) or confirmed partial 
response (PR) according to irRECIST by the investigator review. Subjects with missing 
response will be considered not to have achieved DCR. 
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 by the investigator review. Response 
duration will be only determined for confirmed responses.
 
 
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Best Overall Response per irRECIST [Appendix 12.6]: the best response attained during the 
study with 4 categories based upon irRECIST 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 by the 
investigator review. Subjects without documented PD/death will be censored at the last 
disease assessment date. 
Best Target Lesion Response - maximum percent reduction in tumor line length over target
lesions by the investigator review.
Time to Confirmed Response - defined only for subjects with confirmed response by the 
investigator review - 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 criteria and, if needed, 
central review might be conducted.   
PK endpoints- serum concentrations of MK-1248 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
8.4.4
Description of safety measures is provided in Section 7.
Analysis Populations
8.5
Safety Analysis Populations
8.5.1
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 one dose of 
study treatment.  In case of treatment administration errors, subjects will be analyzed 
according to the treatment they actually received.
However, in the MK-1248 and 
pembrolizumab combination arm (i.e. Arm 2), if some subjects
received only 
pembrolizumab, but did not receive any dose of MK-1248, these subjects will be included in 
the ASaT population, but their safety data will be presented separately. 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 
(subjects evaluable for DLT as described in Section 5.2.4) will be used.
At least one laboratory or vital sign measurement obtained subsequent to at least one 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.
 
 
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Efficacy Analysis Populations
8.5.2
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-1248
(Arm 1; FAS1) or MK-1248 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
8.6
Statistical Methods for Efficacy Analyses
8.6.1
This section describes the statistical methods that address the exploratory efficacy objectives.  
For the subset of FAS1 subjects treated with the RP2D dose of MK-1248 and the subset of 
FAS2 subjects treated with the RP2D for combination of MK-1248 with pembrolizumab, the 
estimates of the ORR and DCR and the 95% confidence intervals for the estimates based on 
the Clopper-Pearson method [48] will be provided. For PFS, DOR, and time to confirmed 
response Kaplan-Meier plots will be provided. Graphic displays will be provided for the best 
target lesion response DOR.
The ORR, DCR, BOR, DOR, PFS, best target lesion response, and time to confirmed 
response in subjects treated with doses below the RP2 doses 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
8.6.2
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-1248 (Arm 1) or MK-1248 in combination with pembrolizumab 
dose level that had at least three subjects treated and listed for other dose levels.  The 
estimate of the DLT rate among subjects treated with the RP2D and the 95% Bayesian 
probability interval for the estimate will be provided.
Laboratory assessments, vital signs, and other safety endpoints will be summarized as 
appropriate.
Immune-related AEs (irAEs) will be summarized in separate tables from other AEs.  Any AE 
of unknown etiology associated with MK-1248 or MK-1248 in combination with 
pembrolizumab exposure will be evaluated to determine if it is possibly an AE of a 
potentially immunologic etiology).  
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 
 
 
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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.  Percentages of subjects in these categories 
among subjects treated with RP2D and 95% confidence intervals for the estimated 
percentages calculated using the Clopper-Pearson method [48] will be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3
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 MK-1248
Recommended Phase 2 Dose (RP2D), and the set of subjects treated with the RP2D for 
combination of MK-1248 with pembrolizumab.
8.6.3.2
Population PK Analyses
Serum concentrations of MK-1248 in the MK-1248 arm and serum concentrations of MK-
1248 and pembrolizumab in the MK-1248 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
8.7
No interim analyses are planned for this study.
Multiplicity
8.8
There will be no multiplicity control in this study.
Sample Size and Power Calculations
8.9
Dose Escalation and Dose Confirmation
8.9.1
The primary purpose of the dose escalation and dose confirmation parts of the trial is to 
investigate the safety and tolerability of MK-1248 monotherapy and MK-1248 co-
administered with pembrolizumab in adult subjects with advanced solid tumors (Parts A-E) 
and to establish RP2Ds for MK-1248 monotherapy and MK-1248 co-administered with 
pembrolizumab.  
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 dose the 
3+3 design is triggered and what dose is identified as the RP2D. Sample sizes for a few 
possible scenarios as well as the estimated time required to enroll all subjects and the time 
 
 
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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 to the end of 2-year treatment 
period following the enrollment of the last Part E subject.
The enrollment time was conservatively estimated assuming that during dose acceleration 
part it will take 4 weeks to proceed from one dose to the next and during 3+3 parts and that 
during the dose confirmation a subject can be enrolled every week.
Scenario 1.  No DLTs during Parts A-E.  For MK-1248 monotherapy, in a scenario where no 
DLTs are encountered during the dose escalation and confirmation parts and thus Part B 
continues to the highest dose in Table 2, the sample size across Parts A-C is 46 subjects (8
subjects in Part A, 27 subjects across 9 doses in Part B, and 11 subjects on RP2D in Part C).  
For MK-1248 with pembrolizumab, in a scenario where Arm 2 starts at 0.12mg MK-1248
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 2, the sample size 
across Parts D and E is 50 subjects (39 subjects across 13 doses in Part D, and 11 subjects on 
RP2D in Part E).  The total sample size across Parts A-E is 96 subjects.  
It will take 16 weeks to enroll and observe for DLTs the 8 MK-1248 monotherapy subjects in 
Part A and proceed to Part B enrolment; it will take additional 88 weeks to enroll 88 subjects 
(38 in Parts B and C and 50 in Parts D and E). Thus, in this scenario the enrollment time 
across Parts A-E is 104 weeks and the time required to determine the two MTDs is 107
weeks. The study duration then is approximately 104 weeks + 2 years or 4.0 years.
If dose escalation stops at a dose below the highest dose for either arm, the study might 
require less than 96 subjects and the enrollment duration shorter than 120 weeks. For 
example, if, in absence of DLTs, it is decided based on >95% receptor occupancy in tissue 
samples for multiple consecutive dose levels to stop MK-1248 escalation at 330mg dose and 
not explore the top three MK-1248 doses in Parts B and D, the sample size across Parts A-E 
will be 96-18=78 subjects. The enrollment duration will be 104-18=86 weeks and the total 
study duration will be 86 weeks+2 years or 3.6 years.
Also, with no DLTs observed, it might be possible to enter Part C and Part E subjects faster 
than one subject every week which will 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 dose levels are studied in 3 subjects each and 5 dose levels (including the top one) 
are studied in 6 subjects each in Part B, while in Arm 2, 6 dose levels are studied in 3 
subjects each and 7 dose levels (including the top one) are studied in 6 subjects each in Part 
D.  Also suppose that the top dose is confirmed as the RP2D dose without de-escalation in 
Parts C and E.  Thus, the sample size in Arm 1 is 58 subjects (8 in Part A, 42 in Part B, and 8 
in Part C) and the sample size in Arm 2 is 68 subjects (60 in Part D and 8 in Part E). Total 
sample size is 118 subjects. 
It will take 16 weeks to enroll 8 MK-1248 monotherapy subjects in Part A and proceed to 
Part B enrolment; it will take additional 118 weeks to enroll 118 subjects (50 in Parts B and 
C, and 68 in Parts D and E). Thus, in this scenario the enrollment time across parts A-E is 
 
 
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134 weeks and the time required to determine the two MTDs is 137 weeks. The study 
duration then is approximately 137 weeks + 2 years or 4.6 years.
Any dose de-escalations in Part C will increase the sample size in this example. 
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 3 mg dose and dose escalation continues in 18 steps to 
915 mg dose, with 3 subjects per dose in 3+3 design and 11 subjects in Part C, the sample 
size of Arm 2 across Parts D and E is 65 (54 in Part D and 11 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 across Parts A-C is 46 subjects (8 subjects in Part A, 27 subjects across 9 doses in Part 
B, and 11 subjects on RP2D in Part C). The total sample size across Parts A-E is 111 
subjects.  
It will take 16 weeks to enroll 8 MK-1248 monotherapy subjects in Part A and proceed to 
Part B enrolment; it will take additional 103 weeks to enroll 103 subjects (38 in Parts B and 
C and 65 in Parts D and E). Thus, in this scenario the enrollment time across Parts A-E is 135
weeks and the time required to determine the two MTDs is 122 weeks. The study duration 
then is approximately 125 weeks + 2 years or 4.3 years.
The plausible sample size of approximately 96 subjects and the enrollment time of 104 weeks
(study duration of 4 years) that correspond to the first described scenario are used for 
operational purposes.
Precision of the DLT rate at RP2D
8.9.2
The TPI design [1] will be used at the dose confirmation stage.  This design assumes the 
toxicity rate at each dose level follows a beta-binomial hierarchical model. Based on the 
distance between the toxicity rate of the current dose and a pre-specified targeted toxicity 
rate, it assigns the current dose level to one of three toxicity intervals (i.e.  under-dosing 
interval, proper-dosing interval, and over-dosing interval), which recommend actions of 
escalating, staying, or de-escalating the dose level, respectively. One of its attractive 
properties is that all possible dose-escalation decisions for a given trial can be pre-calculated, 
and tabulated in a spreadsheet, thus allowing investigators to easily implement and monitor 
the trial without subsequent statistical input. The dose confirmation rules using TPI design 
for this trial are presented in Table 4, Subsection 5.2.1.5.
Since the TPI approach will be used during the dose confirmation Parts C and E, the 
estimated DLT rate, and its 95% Bayesian Probability Interval (PI) will be calculated from 
the posterior distribution of the DLT rate at RP2D using the model specified in the TPI 
approach. A uniform distribution between 0 and 1 is used as the prior when calculating the 
PIs in Table 10. If 14 subjects are finally dosed at RP2D during the dose confirmation stage, 
the estimated DLT rate and its 95% PI should be similar to one of the rows in Table 10.
 
 
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Table 10
Precision of the estimated DLT rates at RP2D
Number of Subjects 
dosed at RP2D
Number of DLT
Events
Estimated 
DLT Rate
Lower Bound 
of 95% PI
Upper Bound of 95% PI
14
2
0.143
0.027
0.373
14
3
0.214
0.068
0.460
14
4
0.286
0.106
0.533
14
5
0.357
0.158
0.609
Subgroup Analyses and Effect of Baseline Factors
8.10
No subgroup analyses will be performed.
Compliance (Medication Adherence)
8.11
Drug accountability data for trial treatment will be collected during the study.  Percent 
compliance with drug administration will be calculated for each subject for MK-1248 and 
pembrolizumab separately.
For MK-1248 and pembrolizumab, percent compliance will be calculated as following: 
x 100.
For MK-1248, “Number of Doses that Should have been Taken” will be calculated as the 
minimum of the two numbers: 4 and (1 plus the number (integer) of 3-week intervals that fit 
between the date of the first dose and the date of the last dose of MK-1248).
For pembrolizumab, “Number of Doses that Should have been Taken” will be calculated as 1 
plus the number (integer) of 3-week intervals that fit between the date of the first dose and
the date of the last dose of pembrolizumab.
Extent of Exposure
8.12
A subject’s extent of exposure to MK-1248 is defined as the total number of doses of MK-
1248 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-1248 and MK-1248 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
9.1
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Taken
been 
have
Should
that 
Doses
of
Number 
Taken
Doses
of
Number 
Compliance
Percent 

 
 
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Clinical Supplies will be provided by the Sponsor as summarized in Table 11.
Table 11
Product Descriptions
Product Name & Potency
Dosage Form
MK-1248 100 mg
Injection
MK-3475 100 mg
Injection
All other supplies not indicated in Table 11 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
9.2
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Sites will receive open label kits of MK-1248 and MK-3475/pembrolizumab as outlined. 
Each kit will contain one vial.
Clinical Supplies Disclosure
9.3
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
9.4
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
Discard/Destruction/Returns and Reconciliation
9.5
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.
 
 
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10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
10.1
Confidentiality of Data
10.1.1
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
10.1.2
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
10.1.3
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
 
 
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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
10.1.4
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
10.2
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.
Compliance with Law, Audit and Debarment
10.3
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.
 
 
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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 period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
when documents may be destroyed. The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
 
 
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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
10.4
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 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
10.5
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
10.6
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.
 
 
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Publications
10.7
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 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.
 
 
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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.
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.
[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.
 
 
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[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]
Zhu Y, Yao S, Chen L. Cell surface signaling molecules in the control of immune 
responses: a tide model. Immunity 2011;34:466-78.
[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.
[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.
 
 
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[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.
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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.
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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.
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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.
[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.
 
 
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[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.
[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]
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.
[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]
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.
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Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the 
case of binomial. Biometrika 1934;26(4):404-13.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
12.1
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. 
 
 
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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."
 
 
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Collection and Management of Specimens for Future Biomedical Research
12.2
1. Definitions
a. Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c. Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e. RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.3 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine. Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor 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 the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a. Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in 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. 
 
 
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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. 
c. eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to 
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens 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 
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. 
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices. Analyses utilizing the Future Biomedical Research specimens may be 
performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and 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 the Sponsor using the designated 
 
 
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mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent 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 the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
through appropriate mechanisms (e.g., scientific publications and/or presentations). 
 
 
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Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. 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. 
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
12.3
IRBs/IECs and Investigational Site Staff
 
 
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ECOG Performance Status
12.4
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.
 
 
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Common Terminology Criteria for Adverse Events V4.0 (CTCAE)
12.5
The descriptions and grading scales found in the revised NCI Common Terminology Criteria
for Adverse Events (CTCAE), version 4.0 will be utilized for adverse event reporting.
(http://ctep.cancer.gov/reporting/ctc.htm)
 
 
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06-Nov-2017
Confidential
13.0 SIGNATURES
Sponsor's Representative
13.1
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
13.2
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
 
 
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