A Phase 1 Study of MK-1697 in Participants With Advanced Solid Tumors
Phase: PHASE1
Conditions: Neoplasms, Colorectal Neoplasms, Head and Neck Neoplasms
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
A Phase 1 Study of MK-1697 in Participants with Advanced 
Solid Tumors
23-May-2019
NCT03515824

Product:  MK-1697 
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Title Page
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., NJ, U.S.A.
(MSD).
Protocol Title: A Phase 1 Study of MK-1697 in Participants with Advanced Solid Tumors
Protocol Number: 001-03
Compound Number: MK-1697
Sponsor Name and Legal Registered Address: 
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or MSD)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Regulatory Agency Identifying Number(s):
IND NUMBER:   141943
EudraCT NUMBER: To Be Determined
Approval Date:  23 May 2019
 
 
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Trial 
File Binder (or equivalent). 
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-1697-001-03
23-May-2019
To respond to FDA review comments
MK-1697-001-02
29-Nov -2018
To change the target population for the Part B expansion cohorts, and other minor 
changes as requested by regulatory authorities.
MK-1697-001-01
10-Jul-2018
To add a 24-hour inpatient observation period for participants treated at the first 
dose level of MK-1697 and other minor changes as requested by regulatory 
authorities.
MK-1697-001-00
21-Feb-2018
Original Protocol
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment 001-03
Overall Rationale for the Amendment:
This amendment was initiated to align with the response to FDA review comments.
Summary of Changes Table:
Section # and Name
Description of Change
Brief Rationale
1.3 Schedule of Activities
5.1 Inclusion Criteria
8.9 Biomarkers
8.11.1 Screening Phase
Removed the 90-day restriction for 
tumor tissue sample
Define tumor tissue collection as recent rather than new. 
4.2.1.6 Planned Exploratory 
Biomarker Research
Revised MSI testing description
Clarified biomarker collection for participants with CRC 
in Part B
6.6.1 Definition of Dose-
Limiting Toxicity
Revised to align with Merck standard 
DLT definition
Clarified that in order to be considered a DLT, a given 
AE must be attributed to study intervention.  
7.1 Discontinuation of Study 
Treatment
8.1.1.1 General Informed 
Consent
8.2.2 iRECIST Assessment of
Disease
Deleted text related to Sponsor-
approved treatment continuation and 
treatment beyond confirmed 
progressive disease.
Clarified that treatment beyond confirmed progression is 
not an option in this trial.
Clarified that an addendum informed consent form will 
be signed at the initial radiographic disease progression, 
and treatment will end if progression is confirmed.
 
 
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Table of Contents
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1.
Protocol Summary .....................................................................................................13
Synopsis....................................................................................................................13
Schema .....................................................................................................................16
Schedule of Activities (SoA) ...................................................................................17
2.
Introduction................................................................................................................29
Study Rationale .......................................................................................................29
Background..............................................................................................................30
Pharmaceutical and Therapeutic Background .....................................................30
Benefit/Risk Assessment.........................................................................................31
3.
Objectives/Hypotheses and Endpoints.....................................................................31
4.
Study Design...............................................................................................................32
Overall Design .........................................................................................................32
Scientific Rationale for Study Design....................................................................34
Rationale for Endpoints .......................................................................................34
Efficacy Endpoints........................................................................................34
Safety Endpoints...........................................................................................35
Pharmacokinetic Endpoints ..........................................................................35
Antidrug Antibody Endpoint ........................................................................35
Pharmacodynamic Endpoints........................................................................36
Target Engagement................................................................................36
Serum for Cytokine Testing...................................................................36
Planned Exploratory Biomarker Research....................................................36
Future Biomedical Research.........................................................................38
Justification for Dose ..............................................................................................38
Starting Dose for This Study................................................................................38
Maximum Dose/Exposure for This Study ...........................................................40
 
 
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Rationale for Dose Interval and Study Design.....................................................40
Dose Finding Using a Modified Toxicity Probability Interval 
Design ...........................................................................................................40
Beginning and End of Study Definition ................................................................43
Clinical Criteria for Early Study Termination .....................................................43
5.
Study Population........................................................................................................43
Inclusion Criteria....................................................................................................43
Exclusion Criteria ...................................................................................................46
Lifestyle Considerations .........................................................................................49
Meals and Dietary Restrictions............................................................................49
Contraception.......................................................................................................49
Pregnancy.............................................................................................................49
Use in Nursing Women........................................................................................50
Number of Participants ..........................................................................................50
Screen Failures ........................................................................................................50
Participant Replacement Strategy.........................................................................50
6.
Treatments..................................................................................................................51
Treatments Administered.......................................................................................51
Preparation/Handling/Storage/Accountability ....................................................53
Dose Preparation..................................................................................................53
Handling, Storage and Accountability.................................................................53
Measures to Minimize Bias: Randomization and Blinding.................................53
Method of Treatment Assignment .......................................................................53
Stratification..................................................................................................54
Blinding................................................................................................................54
Treatment Compliance...........................................................................................54
Concomitant Therapy.............................................................................................54
Supportive Care ...................................................................................................55
Dose Modification ...................................................................................................56
Definition of Dose-Limiting Toxicity..................................................................63
Treatment After the End of the Study ..................................................................64
Clinical Supplies Disclosure...................................................................................64
 
 
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7.
Discontinuation of Study Treatment and Participant Withdrawal ......................64
Discontinuation of Study Treatment.....................................................................64
Participant Withdrawal From the Study..............................................................65
Lost to Follow-up ....................................................................................................65
8.
Study Assessments and Procedures..........................................................................66
Administrative and General Procedures ..............................................................67
Informed Consent.................................................................................................67
General Informed Consent............................................................................67
Consent and Collection of Specimens for Future Biomedical 
Research........................................................................................................67
Inclusion/Exclusion Criteria ................................................................................67
Participant Identification Card.............................................................................68
Medical History ...................................................................................................68
Prior and Concomitant Medications Review .......................................................68
Prior Medications..........................................................................................68
Concomitant Medications.............................................................................68
Assignment of Screening Number.......................................................................68
Assignment of Treatment/Randomization Number.............................................69
Treatment Administration....................................................................................69
Timing of Dose Administration....................................................................69
Central Venous Access for MK-1697 Administration..................................69
Domiciling ...........................................................................................................70
Discontinuation and Withdrawal .........................................................................70
Withdrawal From Future Biomedical Research ...........................................70
Participant Blinding/Unblinding..........................................................................70
Calibration of Equipment.....................................................................................71
Efficacy Assessments...............................................................................................71
Tumor Imaging and Assessment of Disease........................................................71
Initial Tumor Imaging...................................................................................71
Tumor Imaging During the Trial ..................................................................71
iRECIST Assessment of Disease.........................................................................72
Medical Photography of Cutaneous Lesions .......................................................75
 
 
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ECOG Performance Status ..................................................................................75
Safety Assessments..................................................................................................75
Physical Examinations.........................................................................................75
Full Physical Exam .......................................................................................75
Directed Physical Exam................................................................................75
Vital Signs............................................................................................................75
Electrocardiograms ..............................................................................................75
Clinical Safety Laboratory Assessments..............................................................76
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis).....................................................................................................76
Pregnancy Testing.........................................................................................77
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Reportable Safety Events .......................................................................................77
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..................................................................77
Method of Detecting AEs, SAEs, and Other Reportable Safety Events..............79
Follow-up of AE, SAE and Other Reportable Safety Event Information............79
Regulatory Reporting Requirements for SAE .....................................................79
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as AEs or SAEs..................................................................................79
Pregnancy and Exposure During Breastfeeding ..................................................80
Events of Clinical Interest (ECIs) ........................................................................80
Treatment of Overdose...........................................................................................80
Pharmacokinetics....................................................................................................81
Antidrug Antibodies.............................................................................................81
Pharmacodynamics.................................................................................................81
Tumor Biopsies........................................................................................................81
Biomarkers ..............................................................................................................81
Future Biomedical Research Sample Collection..................................................82
Visit Requirements..................................................................................................82
Screening Phase ...................................................................................................83
Treatment Phase...................................................................................................83
Discontinued Participants Continuing to be Monitored in the Study ..................83
Posttreatment Phase .............................................................................................84
 
 
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Safety Follow-up Visit..................................................................................84
Imaging Follow-up Visits .............................................................................84
Survival Follow-up Visits.............................................................................84
Survival Status .....................................................................................................84
9.
Statistical Analysis Plan ............................................................................................84
Statistical Analysis Plan Summary........................................................................85
Responsibility for Analyses/In-house Blinding.....................................................86
Hypotheses/Estimation ...........................................................................................86
Analysis Endpoints..................................................................................................86
Efficacy/Immunogenicity/Pharmacokinetics Endpoints......................................86
Safety Endpoints ..................................................................................................87
Analysis Populations...............................................................................................87
Safety Analysis Populations ................................................................................87
Pharmacokinetic Analysis Populations................................................................87
Efficacy Analysis Populations .............................................................................87
Statistical Methods..................................................................................................88
Statistical Methods for Efficacy Analysis............................................................88
Statistical Methods for Safety Analysis...............................................................88
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses...............................................................................................................88
Demographic and Baseline Characteristics ..................................................88
Pharmacokinetic and Pharmacodynamic Modeling Analysis.......................88
Interim Analyses .....................................................................................................88
Multiplicity ..............................................................................................................89
Sample Size and Power Calculations ....................................................................89
Subgroup Analyses..................................................................................................90
Compliance (Medication Adherence)....................................................................90
Extent of Exposure..................................................................................................90
10.
Supporting Documentation and Operational Considerations...............................91
Appendix 1:  Regulatory, Ethical and Study Oversight Considerations ...........91
Code of Conduct for Clinical Trials.................................................................................91
Financial Disclosure.........................................................................................................93
 
 
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Data Protection.................................................................................................................93
Confidentiality of Data ....................................................................................................93
Confidentiality of Participant Records.............................................................................93
Confidentiality of IRB/IEC Information..........................................................................94
Publication Policy............................................................................................................94
Compliance with Study Registration and Results Posting Requirements .......................94
Compliance with Law, Audit, and Debarment ................................................................95
Data Quality Assurance ...................................................................................................95
Source Documents ...........................................................................................................96
Study and Site Closure.....................................................................................................96
Appendix 2:  Collection and Management of Specimens for Future 
Biomedical Research...............................................................................................97
Appendix 3:  Contraceptive Guidance and Pregnancy Testing........................101
Definitions......................................................................................................................101
Pregnancy Testing..........................................................................................................104
Appendix 4: Adverse Events:  Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting............................................105
Definition of AE ............................................................................................................105
Definition of SAE ..........................................................................................................106
Additional Events Reported in the Same Manner as SAE.............................................107
Recording AE and SAE .................................................................................................107
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor.............110
Appendix 5:  Clinical Laboratory Tests..............................................................112
Appendix 6:  Abbreviations .................................................................................113
Appendix 7: Description of the iRECIST Process for Assessment of 
Disease Progression...............................................................................................116
11.
References.................................................................................................................120
 
 
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LIST OF TABLES
    
Table 1
Predicted Pharmacokinetic Parameters in Humans at the Starting Dose 
and the Relative Fold Differences to these Parameters at the NOAEL in 
Rhesus Monkeys...................................................................................................39
Table 2
Whole Body Target Saturation Corresponding To Predicted Maximum 
Concentration upon MK-1697 Dosing in Human ................................................39
Table 3
Predicted Pharmacokinetic Parameters in Humans at the Highest 
Planned Dose and the Relative Fold Differences to these Parameters at 
the NOAEL in Rhesus Monkeys ..........................................................................40
Table 4
Dose-finding Rules per mTPI Design...................................................................42
Table 5
Adequate Organ Function Laboratory Values......................................................45
Table 6
Study Treatment....................................................................................................52
Table 7
Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with MK-1697................................................................57
Table 8
MK-1697 Infusion Reaction Dose Modification and Treatment 
Guidelines.............................................................................................................61
Table 9
Imaging and Treatment After First Radiologic Evidence of Progressive 
Disease..................................................................................................................74
Table 10
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events............................................................................78
Table 11
Estimate and 80%, 95% CI of ORR .....................................................................90
Table 12
Highly Effective Contraception Methods...........................................................103
Table 13
Protocol-Required Safety Laboratory Assessments ...........................................112
 
 
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LIST OF FIGURES
          
Figure 1
Study Diagram......................................................................................................16
 
 
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1. Protocol Summary
Synopsis
Protocol Title:
A Phase 1 Study of MK-1697 in Participants with Advanced Solid Tumors
Short Title:
A Phase 1 Study of MK-1697 in Participants with Advanced Solid Tumors
Objectives/Hypotheses and Endpoints:
In male/female participants with advanced solid tumors that have not responded to 
conventional therapies:
Objective/Hypothesis
Endpoint
Primary

Objective: To determine the safety and 
tolerability and to establish a 
preliminary recommended Phase 2 
(RP2D) dose of MK-1697

Dose-limiting toxicity (DLT)

Adverse event (AE)

Discontinuing study intervention due 
to an AE
Secondary

Objective: To evaluate the 
pharmacokinetics (PK) of MK-1697

PK parameters including area under 
the curve (AUC), maximum 
concentration (Cmax), and minimum 
concentration (Cmin) 

Objective: To evaluate the objective 
response rate (ORR) as assessed by the 
investigator based on Response 
Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST 1.1) and iRECIST 
following administration of MK-1697

Objective response is a confirmed 
complete response (CR) or partial 
response (PR)
 
 
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Overall Design:
Study Phase
Phase 1b
Clinical 
Indication
Treatment of advanced solid tumors
Population
Part A: Participants with advanced/metastatic solid tumor who
have received, or been intolerant to, or been ineligible for all 
treatments known to confer clinical benefit.
Part B: Participants with the following tumor types that are naïve 
to anti-PD-1/PD-L1 therapy:

HNSCC that is considered incurable by local therapies. 
Participants should have progressed after receiving platinum-
containing systemic therapy. Systemic therapy given as part 
of multimodal treatment for locally advanced disease is 
allowed. The eligible primary tumor locations are 
oropharynx, oral cavity, hypopharynx, and larynx. 
Participants may not have a primary tumor site of 
nasopharynx (any histology).

CRC originating in either the colon or rectum that is locally 
advanced unresectable or metastatic (ie, Stage IV) and that 
has received, and progressed on, all available standard-of-care 
therapies including fluoropyrimidine, oxaliplatin, and 
irinotecan. Participants with known MSI-high or MMR-
deficient CRC (as determined by PCR, IHC, or a validated 
NGS panel, eg. Foundation Medicine or MSKImpact) are 
excluded from participating in this study.
Study Type
Interventional
Type of 
Design
Single arm, multi-site, dose escalation and confirmation
Type of 
Control
No treatment control
Study Blinding
Unblinded Open-label
Estimated 
Duration of 
Study
The Sponsor estimates that the study will require approximately 4 
years from the time the first participant signs the informed consent 
until the last participant’s last study-related telephone call or visit. 
 
 
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Number of Participants:
A maximum of approximately 122 participants will be enrolled.
Treatment Groups and Duration:
Treatment Groups
Part A:
Dose Level 1 (DL1) – 20 mg of MK-1697 every 3 weeks 
(Q3W) as intravenous (IV) infusion
  DL2 – 65 mg of MK-1697 Q3W as IV infusion
  DL3 – 200 mg of MK-1697 Q3W as IV infusion
Part B: MK-1697 at the preliminary RP2D Q3W as IV 
infusion
Duration of 
Participation
Each participant will participate in the study from the time 
the participant signs the informed consent form (ICF) through 
the final protocol-specified contact.  
After a screening phase of 28 days, each participant will be 
assigned to receive study treatment until disease progression 
is radiographically documented and, when clinically 
appropriate, confirmed by the site per modified Response 
Evaluation Criteria in Solid Tumors 1.1 for immune-based 
therapeutics (iRECIST), unacceptable adverse event(s) 
(AEs), intercurrent illness that prevents further administration 
of treatment, investigator’s decision to withdraw the 
participant, noncompliance with study treatment or procedure 
requirements or administrative reasons requiring cessation of 
treatment, pregnancy of the participant, the participant 
withdraws consent, or until the participant has received 35 
administrations of MK-1697 (approximately 2 years).
After the end of treatment, each participant will be followed 
for the occurrence of AEs and spontaneously reported 
pregnancy as described under Section 8.4.  
Participants who discontinue for reasons other than 
radiographic disease progression will have post-treatment 
follow-up imaging for disease status until disease progression 
is documented radiographically per RECIST 1.1, and 
confirmed by the site per iRECIST, initiating a non-study 
cancer treatment, withdrawing consent, or becoming lost to 
follow-up.  All participants will be followed by telephone for 
overall survival until death, withdrawal of consent, or the end 
of the study.
 
 
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Study Governance:
Study Governance 
Committees
There are no governance committees in this study.
A list of abbreviations used in this document can be found in Appendix 6.
Schema
The study design is depicted in Figure 1.
Figure 1
Study Diagram
 
 
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Schedule of Activities (SoA)
Trial Period:
Screen-
ing 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treat-
ment / 
Discon-
tinuat-
ion
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screen-
ing
1
2
3
4 
5 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
All procedures and 
assessments are to 
be performed prior 
to administration of 
study treatment
unless otherwise 
indicated.
Cycle Day:
1
2
3
8
15
1
3
8
15
1
3
8
15
1
1
At time 
of 
treat-
ment 
discon.
30 days 
after 
last 
dose
Every 
12 
weeks
Every 
12 
weeks
Scheduling
Window (Days):
-28 to
-1
±3
±
3
+3
±3
±
3
±3
±3
±
3
±
3
±
3
+ 3
+ 14
± 7
± 7
Informed Consent
X
Informed Consent 
for Future 
Biomedical 
Research
X
Optional
Participant 
Identification 
Card
X
Inclusion/Exclus-
ion Criteria
X
Demographic and 
Medical History
X
Prior/Concomitant 
Treatment & 
Medication 
Review
X
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior Oncology 
Treatment History
X
Treatment 
Allocation
X
 
 
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Trial Period:
Screen-
ing 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treat-
ment / 
Discon-
tinuat-
ion
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screen-
ing
1
2
3
4 
5 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
All procedures and 
assessments are to 
be performed prior 
to administration of 
study treatment
unless otherwise 
indicated.
Cycle Day:
1
2
3
8
15
1
3
8
15
1
3
8
15
1
1
At time 
of 
treat-
ment 
discon.
30 days 
after 
last 
dose
Every 
12 
weeks
Every 
12 
weeks
Scheduling
Window (Days):
-28 to
-1
±3
±
3
+3
±3
±
3
±3
±3
±
3
±
3
±
3
+ 3
+ 14
± 7
± 7
Portacath (or 
similar device) 
Insertion*
X
* Applies only to
doses <65 mg, 
which require 
administration 
directly into a 
central vein. Only 
perform if 
participant does not 
have central 
venous access (eg, 
portacath, Hickman 
line, or PICC line) 
currently inserted.
Only perform after 
all other screening 
procedures/assess-
ments have been 
performed and 
participant has 
been determined to 
be eligible for the 
study.
 
 
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Trial Period:
Screen-
ing 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treat-
ment / 
Discon-
tinuat-
ion
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screen-
ing
1
2
3
4 
5 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
All procedures and 
assessments are to 
be performed prior 
to administration of 
study treatment
unless otherwise 
indicated.
Cycle Day:
1
2
3
8
15
1
3
8
15
1
3
8
15
1
1
At time 
of 
treat-
ment 
discon.
30 days 
after 
last 
dose
Every 
12 
weeks
Every 
12 
weeks
Scheduling
Window (Days):
-28 to
-1
±3
±
3
+3
±3
±
3
±3
±3
±
3
±
3
±
3
+ 3
+ 14
± 7
± 7
MK-1697
Administration
X
X
X
X
X
An optional 24-
hour inpatient 
observation period 
may be performed 
following MK-
1697 
administration on 
C1D1 for the first 
dose level.
Efficacy 
Procedures
Tumor Imaging 
and Response 
Assessment
X
X
X
X
X
Every 9 weeks (±7 
days) during 
Treatment Phase. 
After 54 weeks, 
every 12 weeks (±7 
days). Calculated 
from the first dose 
of study treatment 
and not adjusted 
for delays in 
treatment.
 
 
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Trial Period:
Screen-
ing 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treat-
ment / 
Discon-
tinuat-
ion
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screen-
ing
1
2
3
4 
5 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
All procedures and 
assessments are to 
be performed prior 
to administration of 
study treatment
unless otherwise 
indicated.
Cycle Day:
1
2
3
8
15
1
3
8
15
1
3
8
15
1
1
At time 
of 
treat-
ment 
discon.
30 days 
after 
last 
dose
Every 
12 
weeks
Every 
12 
weeks
Scheduling
Window (Days):
-28 to
-1
±3
±
3
+3
±3
±
3
±3
±3
±
3
±
3
±
3
+ 3
+ 14
± 7
± 7
Medical
Photography 
(cutaneous 
lesions, if 
applicable)
X
X
X
X
X
Every 9 weeks (±7 
days) during 
Treatment Phase. 
After 54 weeks, 
every 12 weeks (±7 
days). Calculated 
from the first dose 
of study treatment 
and not adjusted 
for delays in 
treatment.
Survival Status
X
After investigator 
determined PD or
start of new 
anticancer 
treatment. In 
addition, upon 
Sponsor request, 
participants may be 
contacted for 
survival status at 
any time during the 
course of the study.
 
 
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Trial Period:
Screen-
ing 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treat-
ment / 
Discon-
tinuat-
ion
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screen-
ing
1
2
3
4 
5 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
All procedures and 
assessments are to 
be performed prior 
to administration of 
study treatment
unless otherwise 
indicated.
Cycle Day:
1
2
3
8
15
1
3
8
15
1
3
8
15
1
1
At time 
of 
treat-
ment 
discon.
30 days 
after 
last 
dose
Every 
12 
weeks
Every 
12 
weeks
Scheduling
Window (Days):
-28 to
-1
±3
±
3
+3
±3
±
3
±3
±3
±
3
±
3
±
3
+ 3
+ 14
± 7
± 7
Safety 
Procedures
Full physical 
examination
X
X
X
X
X
X
X
X
Every 3rd cycle 
after C4 (C7, C10, 
C13…)
Height
X
Weight
X
X
X
X
X
X
X
X
Directed Physical 
Examination
X
X
X
X
X
X
X
X
Symptom directed. 
When a full exam 
is not performed.
Vital Signs 
X
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Heart rate, 
respiratory rate,
blood pressure, and 
temperature.
12-lead 
electrocardio-
graph (ECG)
X
As clinically 
indicated after 
screening.
Tumor Markers
(as clinically 
indicated)
X
X
X
X
X
X
X
Specific tumor 
markers (eg, CEA,
CA-125, CA-19-9) 
are to be obtained 
as clinically 
indicated.
 
 
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Trial Period:
Screen-
ing 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treat-
ment / 
Discon-
tinuat-
ion
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screen-
ing
1
2
3
4 
5 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
All procedures and 
assessments are to 
be performed prior 
to administration of 
study treatment
unless otherwise 
indicated.
Cycle Day:
1
2
3
8
15
1
3
8
15
1
3
8
15
1
1
At time 
of 
treat-
ment 
discon.
30 days 
after 
last 
dose
Every 
12 
weeks
Every 
12 
weeks
Scheduling
Window (Days):
-28 to
-1
±3
±
3
+3
±3
±
3
±3
±3
±
3
±
3
±
3
+ 3
+ 14
± 7
± 7
Eastern 
Cooperative 
Oncology Group 
(ECOG)
Performance 
Status
X
X
X
X
X
X
X
X
Urine Pregnancy 
Test (Serum β-
Human Chorionic 
Gonadotropin [β-
hCG] if required) 
(WOCBP only)
X
X
X
X
Screening: perform 
within 72 hours 
prior to first dose 
of study treatment.
Human 
immunodefici-
ency virus (HIV), 
hepatitis B and C 
screen status (per 
site SOP)
X
Acceptable to be 
based on history 
unless testing is 
required by local 
regulation.
Urinalysis
X
X
X
X
X
Screening: perform 
within 7 days of 
treatment 
allocation.
 
 
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Trial Period:
Screen-
ing 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treat-
ment / 
Discon-
tinuat-
ion
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screen-
ing
1
2
3
4 
5 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
All procedures and 
assessments are to 
be performed prior 
to administration of 
study treatment
unless otherwise 
indicated.
Cycle Day:
1
2
3
8
15
1
3
8
15
1
3
8
15
1
1
At time 
of 
treat-
ment 
discon.
30 days 
after 
last 
dose
Every 
12 
weeks
Every 
12 
weeks
Scheduling
Window (Days):
-28 to
-1
±3
±
3
+3
±3
±
3
±3
±3
±
3
±
3
±
3
+ 3
+ 14
± 7
± 7
Hematology
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
Screening: perform 
within 7 days of 
treatment 
allocation.
Prothrombin 
(PT)/International 
Normalized Ratio 
(INR) and 
activated partial 
thromboplastin 
time (aPTT)
X
Consider ongoing 
testing for 
participants on 
routine warfarin 
treatment.
Perform within 7 
days of treatment 
allocation.
Comprehensive
Chemistry Panel
X
X X
X
X
X
X
X
X
X
X
X
X
X
X
Screening: perform 
within 7 days of 
treatment 
allocation.
Thyroid Function 
(triiodothyronine 
[T3] or free T3 
[FT3], free 
thyroxine [FT4], 
and thyroid 
stimulating 
hormone [TSH])
X
X
X
X
X
X
Every other cycle 
(C5, C7, C9…)
 
 
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Trial Period:
Screen-
ing 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treat-
ment / 
Discon-
tinuat-
ion
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screen-
ing
1
2
3
4 
5 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
All procedures and 
assessments are to 
be performed prior 
to administration of 
study treatment
unless otherwise 
indicated.
Cycle Day:
1
2
3
8
15
1
3
8
15
1
3
8
15
1
1
At time 
of 
treat-
ment 
discon.
30 days 
after 
last 
dose
Every 
12 
weeks
Every 
12 
weeks
Scheduling
Window (Days):
-28 to
-1
±3
±
3
+3
±3
±
3
±3
±3
±
3
±
3
±
3
+ 3
+ 14
± 7
± 7
Lipase and 
Amylase
X
X
X
X
X
X
X
X
Gamma-glutamyl 
transferase (GGT)
X
Perform within 7 
days of treatment 
allocation, and as 
clinically indicated 
after screening.
AE/SAE review
X
X
X
X
X
Cytokine Panel
X
X X
X
X
X
X
Cycles 1-6 only. 
Part A only.
 
 
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Trial Period:
Screen-
ing 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treat-
ment / 
Discon-
tinuat-
ion
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screen-
ing
1
2
3
4 
5 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
All procedures and 
assessments are to 
be performed prior 
to administration of 
study treatment
unless otherwise 
indicated.
Cycle Day:
1
2
3
8
15
1
3
8
15
1
3
8
15
1
1
At time 
of 
treat-
ment 
discon.
30 days 
after 
last 
dose
Every 
12 
weeks
Every 
12 
weeks
Scheduling
Window (Days):
-28 to
-1
±3
±
3
+3
±3
±
3
±3
±3
±
3
±
3
±
3
+ 3
+ 14
± 7
± 7
Pharmacokinetics/Pharmacodynamics/Future Biomedical Research/Biomarkers
Blood for Genetic 
Analysis
X
Blood for MSI 
Status Test 
X
Testing is 
applicable only for 
the Part B CRC 
expansion cohort.
Peripheral Blood 
for PD-1 Target 
Engagement
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Day 1 of Cycles 1-
4, 6, 8: Collect 
samples predose
(within 24 hours 
prior to dosing), 
after infusion (+10 
min), and 2h after 
start of infusion 
(±10 min).
Day 1 of every 4 
cycles thereafter 
(C12, C16…): 
Only collect 
predose (within 24 
hours prior to 
dosing).
Serum for Total 
sLAG-3
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum for MK-
1697 Pharmaco-
kinetics
X X X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
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Trial Period:
Screen-
ing 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treat-
ment / 
Discon-
tinuat-
ion
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screen-
ing
1
2
3
4 
5 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
All procedures and 
assessments are to 
be performed prior 
to administration of 
study treatment
unless otherwise 
indicated.
Cycle Day:
1
2
3
8
15
1
3
8
15
1
3
8
15
1
1
At time 
of 
treat-
ment 
discon.
30 days 
after 
last 
dose
Every 
12 
weeks
Every 
12 
weeks
Scheduling
Window (Days):
-28 to
-1
±3
±
3
+3
±3
±
3
±3
±3
±
3
±
3
±
3
+ 3
+ 14
± 7
± 7
Peripheral Blood 
for Immuno-
phenotyping
X
X
X
X
X
X
X
X
Blood for 
circulating tumor 
DNA
X
X
X
X
X
Serum for 
Anti-MK-1697
Antibodies 
X
X
X
X
X
X
Collected within 24 
hours prior to 
dosing of Cycles 1-
4, 6, 8, and every 4 
cycles thereafter 
(C12, C16…).
Blood for RNA 
Analysis
X
X
X
X
X
X
Cycles 1-5 and at 
treatment 
discontinuation.
Blood for Plasma 
Biomarker 
Analyses
X
X
X
X
X
X
Blood for Serum 
Biomarker 
Analyses
X
X
X
X
X
X
 
 
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Protocol/Amendment No.: 001-03 
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Confidential
Trial Period:
Screen-
ing 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treat-
ment / 
Discon-
tinuat-
ion
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screen-
ing
1
2
3
4 
5 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
All procedures and 
assessments are to 
be performed prior 
to administration of 
study treatment
unless otherwise 
indicated.
Cycle Day:
1
2
3
8
15
1
3
8
15
1
3
8
15
1
1
At time 
of 
treat-
ment 
discon.
30 days 
after 
last 
dose
Every 
12 
weeks
Every 
12 
weeks
Scheduling
Window (Days):
-28 to
-1
±3
±
3
+3
±3
±
3
±3
±3
±
3
±
3
±
3
+ 3
+ 14
± 7
± 7
Tumor Tissue Collection
Archival and/or 
Recently
Obtained Tumor 
Tissue Collection
X
This tumor sample 
may have been 
collected at any 
point prior to the 
first dose of 
treatment. For 
subjects in Part B 
with HNSCC (of 
oropharyngeal 
origin, only), HPV 
testing by p16 IHC, 
polymerase chain 
reaction (PCR), or 
fluorescent in situ 
hybridization is 
required before or 
during screening.
 
 
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Trial Period:
Screen-
ing 
Phase
Treatment Phase (3-Week Cycles)
End of 
Treat-
ment / 
Discon-
tinuat-
ion
Post-Treatment Phase
Notes
Treatment 
Cycle/Title:
Screen-
ing
1
2
3
4 
5 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
All procedures and 
assessments are to 
be performed prior 
to administration of 
study treatment
unless otherwise 
indicated.
Cycle Day:
1
2
3
8
15
1
3
8
15
1
3
8
15
1
1
At time 
of 
treat-
ment 
discon.
30 days 
after 
last 
dose
Every 
12 
weeks
Every 
12 
weeks
Scheduling
Window (Days):
-28 to
-1
±3
±
3
+3
±3
±
3
±3
±3
±
3
±
3
±
3
+ 3
+ 14
± 7
± 7
Tumor Biopsy
X
X
Required for first 
10 participants in 
each expansion 
cohort of Part B. 
Cycle 2 biopsy 
may be collected 
between Days 8 
and 15.
An optional biopsy 
will be performed 
within 4 weeks 
after disease 
progression for 
participants in each 
expansion cohort 
of Part B who 
achieved either a 
CR, PR, or SD 
while participating 
in the study.
 
 
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2. Introduction
MK-1697 is a novel small bispecific nanobody that binds to both programmed cell death 
protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3), inhibitory immuno-modulatory 
receptors (IMRs). This is a first-in-human, dose-escalation, and dose-finding study to assess 
the safety, tolerability, and preliminary efficacy of MK-1697.
Study Rationale 
Because of the roles of PD-1 and LAG-3 on both effector T-cell proliferation and activation, 
and on the suppressor activity of regulatory T cells (Tregs), the dual antagonism of these 
checkpoint molecules on both T cell populations may potentially increase antitumor activity
[Goldberg, M. V. 2011] [Huang, C. T., et al 2004]. Additionally, both LAG-3 and PD-1
monoclonal antibodies (mAbs) are under clinical evaluation for a wide variety of solid tumor 
indications, and PD-1/PD-L1 mAbs have been approved for the treatment of a number of 
solid tumor indications. Therefore, Part A of the study will enroll participants with advanced 
solid tumors. 
In Part B of the study, participants who are anti-PD-1/PD-L1 treatment-naïve and who have 
the following tumor types will be enrolled:
1) HNSCC that is considered incurable by local therapies. Participants should have 
progressed after receiving platinum-containing systemic therapy. Systemic therapy given 
as part of multimodal treatment for locally advanced disease is allowed. The eligible 
primary tumor locations are oropharynx, oral cavity, hypopharynx, and larynx. 
Participants may not have a primary tumor site of nasopharynx (any histology).
2) CRC originating in either the colon or rectum that is locally advanced unresectable or 
metastatic (ie, Stage IV) and that has received, and progressed on, all available standard-
of-care therapies including fluoropyrimidine, oxaliplatin, and irinotecan. Participants 
with known MSI high or MMR deficient CRC (as determined by PCR, IHC, or a 
validated NGS panel, eg. Foundation Medicine or MSKImpact) are excluded from 
participating in this study. 
These tumor types were selected based on the known expression of LAG-3 in these tumors
[Jie, H. B., et al 2013] as well as the Sponsor’s experience with co-administration of 
anti-PD-1 and anti-LAG-3 mAbs in participants with these tumor types. Additionally, since it 
is believed that therapies targeting LAG-3 might have potential antitumor activity in the MSS
setting, this study will enroll participants that are naïve to anti-PD-1/PD-L1 therapy in the 
HNSCC and CRC cohorts.
Squamous cell cancer of the head and neck (HNSCC) was chosen based on high expression 
of LAG-3 and known response to PD-1 therapy. An anti-PD-1/PD-L1 treatment-naïve 
population is being assessed for both expansion cohorts in Part B. There is scientific 
evidence that the expression of alternate immune checkpoints including LAG-3 may increase 
after PD-1 blockade, promoting resistance to PD-1 therapy [Huang, R. Y., et al 2017]. Co-
blockade with LAG-3 and PD-1 may overcome resistance in some tumors. 
 
 
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The intention of the anti-PD-1/PD-L1 treatment-naïve HNSCC expansion cohort is to 
determine if MK-1697 improves upon the response rates observed with pembrolizumab 
monotherapy in this population. Results from Keynote-055 demonstrated an objective 
response rate of 18% in anti-PD-1/PD-L1 treatment-naïve HNSCC patients that had 
progressed on at least 2 prior lines of therapy [Bauml, J., et al 2017].
MSS CRC was chosen based on high expression of LAG-3, little to no responsiveness to 
PD-1 monotherapy [O'Neil, B. H., et al 2017], and high unmet medical need. Response rates 
for regorafenib and TAS-102, approved agents in 3L CRC, have an OS benefit of 2 months 
and ~1-2% ORR. The intention of this expansion cohort is to determine if MK-1697 
improves on the response rates observed for 3L standard of care therapies. 
Background
Refer to the IB for detailed background information on MK-1697. This is a first-in-
participant study.
Pharmaceutical and Therapeutic Background
MK-1697 is a bispecific nanobody that binds to both PD-1 and LAG-3. A nanobody is a 
novel class of therapeutic proteins based on single-domain VHH antibody fragments that 
contain the unique structural and functional properties of naturally-occurring heavy chain 
only antibodies. The nanobody technology was developed following the discovery that 
camelidae (eg, camels, llamas, and alpacas) have functional antibodies constituted of heavy 
chains only and lack light chains. The cloned and isolated VHH have full antigen binding 
capacity and are very stable. The current bispecific PD-1/LAG-3 nanobody (MK-1697) is 
composed of an anti-PD-1 module, an anti-LAG-3 module, and an anti-albumin module (to 
extend the nanobody’s half-life) with all modules connected by linkers.  PD-1 and LAG-3 are 
inhibitory IMRs that modulate the magnitude of effector T cell proliferation and activation. 
Both also have a role in the suppressor activity of Tregs. PD-1 is expressed on activated CD8+ 
and CD4+ T cells, CD4+ Tregs, exhausted T cells, B-cells, and at lower levels on monocytes
[Francisco, L. M., et al 2010].  LAG-3 is expressed on activated CD8+ and CD4+ T-cells, 
CD4+ Tregs, exhausted T cells, as well as on natural killer cells and a subset of tolerogenic 
plasmacytoid dendritic cells [Gagliani, N., et al 2013] [Huard B, Gaulard P, Faure F, Hercend 
T, Triebel F. 1994] [Workman CJ, Wang Y, El Kasmi KC, Pardoll DM, Murray PJ 2009]. 
Due to their proposed roles on both effector T cells and Tregs, simultaneous blockade of PD-1
and LAG-3 on both cell populations has the potential to enhance anti-tumor immunity
[Goldberg, M. V. 2011] [Huang, C. T., et al 2004]. 
Nonclinical tumor model data and human tumor immunology data support a combination 
immunotherapy approach with dual blockade of both the PD-1 and LAG-3 checkpoints with 
a bispecific PD-1/LAG-3 nanobody candidate. Studies using surrogate nanobodies have 
demonstrated that the bispecific PD-1/LAG-3 nanobody candidate may have potential greater 
efficacy than the corresponding cocktail of two mAbs [Woo, S. R., et al 2010] [Goding, S. 
R., et al 2013].
 
 
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Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and ICF documents.
3. Objectives/Hypotheses and Endpoints
In male/female participants with advanced solid tumors that have not responded to 
conventional therapy:
Objective/Hypothesis
Endpoint
Primary

Objective:  To determine the safety 
and tolerability and to establish a 
RP2D of MK-1697

Dose-limiting toxicity (DLT)

Adverse event (AE)

Discontinuing study intervention due to 
an AE
Secondary

Objective: To evaluate the PK of 
MK-1697 

PK parameters including AUC, Cmax, and 
Cmin

Objective: To evaluate the ORR as 
assessed by the investigator based on 
RECIST 1.1 and iRECIST following 
administration of MK-1697

Objective response is a confirmed CR or 
PR
Tertiary/Exploratory

Objective: To evaluate the 
development of circulating 
anti-MK-1697 antibodies following 
administration of MK-1697

Antidrug antibody (ADA) levels

Objective: To evaluate target 
engagement and pharmacodynamics 
through biomarker evaluation

Total soluble LAG-3 (sLAG-3)

PD-1 receptor occupancy

Objective: To evaluate 
progression-free survival (PFS) as 
assessed by investigator based on 
RECIST 1.1 and iRECIST and 
overall survival (OS) following 
administration of MK-1697

PFS is time from the first dose of study 
medication to the first documented 
disease progression or death due to any 
cause, whichever occurs first

OS is the time from the first dose of 
study medication to death due to any 
cause
 
 
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Objective/Hypothesis
Endpoint

Objective: To identify molecular 
(genomic, metabolic and/or 
proteomic) biomarkers that may be 
indicative of clinical 
response/resistance, safety, 
pharmacodynamic activity, and/or the 
mechanism of action of MK-1697.

Objective: To understand the 
association of human leukocyte 
antigen (HLA) type to the 
development of immune response to 
MK-1697

Germline genetic variation, genetic 
(DNA) mutations from tumor, tumor and 
blood RNA variation, proteomics and 
IHC, and other biomarkers
4. Study Design 
Overall Design 
This is a first-in-human, multisite, worldwide, open-label study of MK-1697 in participants 
with a histologically or cytologically confirmed diagnosis of an advanced/metastatic solid 
tumor who have received, or been intolerant to, or been ineligible for all treatments known to 
confer clinical benefit (Part A) or with the specific tumor types described in Section 5.1 –
Inclusion Criteria (Part B).
This study will evaluate the safety, tolerability, and preliminary efficacy of MK-1697. There 
are 2 parts in this study: dose escalation and confirmation (Part A) and cohort expansion 
(Part B).
In Part A of the study, a modified Toxicity Probability Interval (mTPI) design [Ji, Y. and 
Wang, S.-J. 2013] will be used to identify a preliminary RP2D of MK-1697. Three 
predetermined dose levels of MK-1697 will be evaluated: 20 mg, 65 mg, and 200 mg. 
Intermediate or higher dose levels of MK-1697 may be explored depending on the combined 
safety, PK, and pharmacodynamics data available at each preplanned dose level.
During dose escalation, 3 to 6 participants will be initially enrolled to receive MK-1697. 
Treatment allocation will be accomplished by nonrandom assignment and controlled via an 
interactive voice response system/integrated web response system (IVRS/IWRS). Enrollment 
at the next dose level (DL) will begin once all participants in the current DL complete DLT 
evaluation and a dose-escalation decision has been made. Each subsequent dose level will 
proceed the same way. The final number of participants enrolled in Part A will depend on the 
safety data (number of DLTs observed), and what dose is ultimately identified as the 
preliminary RP2D using the mTPI design. 
During dose escalation, a minimum of 3 participants are required at each dose level, and up 
to 6 participants may be initially enrolled at each dose level. At least 72 hours must pass 
between when the first and second participants receive study treatment in Cycle 1 of each 
new dose level.  Additionally, participants treated at the first dose level may undergo, at the 
 
 
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investigator’s discretion, a 24-hour observation period following administration of MK-1697 
on Cycle 1, Day 1. This inpatient observation on Cycle 1, Day 1 may also be performed for 
participants treated at higher dose levels of MK-1697 at the discretion of the investigator 
and/or per local Institutional Review Board, Ethics Review Committee, and/or Health 
Authority requirement. As shown in Table 4, based on the mTPI design, the number of 
participants who are enrolled at a dose level, but are not yet fully evaluable for DLT 
assessment, may not exceed the number of remaining participants who are at risk of 
developing a DLT before the dose would be considered unacceptably toxic. 
Part A will end after 14 participants have been treated at any of the selected doses (which 
may include intermediate or higher dose levels) and the decision based on Table 4 is to stay 
(or escalate, if at the highest dose level). The pool adjacent-violators algorithm [Ji, Y. and 
Wang, S.-J. 2013] will be used to estimate the DLT rates across doses under the assumption 
of monotonicity between DLT rates and dose levels. The totality of the data (including 
safety, PK, pharmacodynamics, and efficacy) will be considered before deciding on the 
preliminary RP2D to carry forward to Part B. Either a fixed or weight-based dose may be 
chosen as the preliminary RP2D.
In Part B, participants with select advanced solid tumors will be enrolled in expansion 
cohorts based on tumor type to further evaluate the safety and efficacy of MK-1697 at the 
preliminary RP2D defined in Part A. Up to 40 participants will be enrolled into each 
tumor-type cohort as described in Section 5.1 – Inclusion Criteria. Additional doses of 
MK-1697 may also be explored in Part B. The final RP2D for future studies will be 
confirmed using all available safety information (including early and late toxicities from 
Parts A and B), as well as PK and pharmacodynamics data and preliminary efficacy 
assessments. Additional expansion cohorts may be added by the Sponsor at a later point, in 
which case the protocol will be amended to add these cohorts.
Preliminary efficacy will be evaluated using ORR assessed by the investigator based on 
RECIST 1.1 as a secondary objective. Progression-free survival based on RECIST 1.1 as 
assessed by the investigator and OS will be evaluated as exploratory objectives. ORR and 
PFS will be also assessed by iRECIST per investigator.
Although in this study there will not be any formal hypothesis testing, an interim look at the 
data may be conducted to enable future trial planning and dosing decisions. In Part B, the 
efficacy data will be assessed after the first ~15 participants become evaluable in each of the 
select solid tumor expansion cohorts. If no responses are observed in a given cohort, 
enrollment in this cohort may be stopped early.
Participants will be monitored carefully for the development of AEs, and for clinical and/or 
radiographic evidence of disease progression according to RECIST 1.1. However, iRECIST 
will be used by the investigator for treatment decisions. In participants who have initial 
evidence of radiological progressive disease (PD) by RECIST 1.1, it will be at the discretion 
of the investigator whether to continue a participant on study treatment until repeat imaging 
is obtained. This clinical judgment decision should be based on the participant’s overall 
clinical condition, including performance status, clinical symptoms, and laboratory data. 
Participants may continue to receive study treatment until tumor assessment is repeated 
≥4 weeks later in order to confirm progressive disease by iRECIST per site assessment.
 
 
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Adverse events will be evaluated by the investigator, according to criteria outlined in the 
National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE), 
version 4.0, to establish the safety and tolerability of MK-1697 as per the primary objective 
of this study.
There will be no intraparticipant dose escalation for participants enrolled in this study. The 
definition of DLTs and criteria for dose modification of MK-1697 are outlined in 
Section 6.6.1 and Section 6.6, respectively. 
Participants may receive study treatment for up to 35 cycles (approximately 24 months). 
Participants will be treated until PD, unacceptable toxicity, intercurrent illness that prevents 
further administration of treatment, investigator’s decision to withdraw treatment, participant 
withdrawal of consent, pregnancy of the participant, noncompliance with trial treatment or 
procedure requirements, participant completes treatment, or administrative reasons requiring 
cessation of treatment, at which point they will be discontinue study treatment.
Once a participant discontinues from any part of the study, they will be treated at the 
discretion of the physician.
All participants will be followed for at least 90 days after their last dose of MK-1697 for AE 
and SAE monitoring. Participants with an ongoing AE of Grade >1 at the time of treatment 
discontinuation will be followed until resolution of the AE to Grade 0-1, until considered 
stable by the treating physician, or until beginning a new anticancer therapy, whichever 
occurs first.
Participants who discontinue treatment for reasons other than confirmed PD will have 
posttreatment follow-up for disease status (including imaging) until PD, initiating a new 
anticancer therapy, withdrawing consent for study participation, or becoming lost to 
follow-up.
After confirmed PD, each participant will be contacted by telephone every 12 weeks 
(84±7 days) for survival until withdrawal of consent to participate in the study, becoming lost 
to follow up, death, or end of the study, whichever occurs first.
Specific procedures to be performed during the study, as well as their prescribed times and 
associated visit windows, are outlined in the Schedule of Activities (SoA), Section 1.3. 
Details of each procedure are provided in Section 8.
Scientific Rationale for Study Design 
Rationale for Endpoints
Efficacy Endpoints
Secondary and exploratory objectives for this trial are to evaluate the antitumor activity of 
MK-1697 in participants with several types of advanced solid malignancies, as detailed in 
Section 5.1 (Inclusion Criteria). Tumor response will be assessed using both RECIST 1.1 and 
iRECIST by investigator review. Antitumor activity will be measured through such endpoints 
as the ORR, PFS, and OS which are further described in Section 9.4.1.
 
 
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iRECIST accounts for the unique tumor response characteristics seen with 
immunotherapeutic agents. iRECIST was developed and published by the RECIST Working 
Group, with input from leading experts from industry and academia, along with participation 
from the US Food and Drug Administration and European Medicines Agency.
Immunotherapeutic agents such as MK-1697 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, thus, not provide an accurate response 
assessment of immunotherapeutic agents. These findings support the need to apply a 
modification to RECIST 1.1 that takes into account the unique patterns of atypical response 
in immunotherapy and enables treatment beyond initial radiographic progression, if the 
participant is clinically stable.
The unidimensional measurement of target lesions, qualitative assessment of nontarget 
lesions, and response categories are identical to RECIST 1.1, until progression is seen by 
RECIST 1.1. If a participant is clinically stable, additional imaging may be performed to 
confirm radiographic progression. In this study, iRECIST will be used by investigators to 
assess tumor response and progression and make treatment decisions. Additional information 
on iRECIST can be found in Section 8.2.2.
Safety Endpoints
The primary objective of this trial is to characterize the safety and tolerability of MK-1697 in 
participants with advanced solid tumors. The primary safety analysis will be based on 
participants who experience toxicities as defined by CTCAE Version 4.0 criteria and DLTs
further defined in Section 6.6.1. Safety will be assessed by quantifying the toxicities and 
grades of toxicities experienced by participants who have received MK-1697.
For AEs, attribution to drug, time-of-onset, duration of the event, its resolution, and any 
concomitant medications administered will be recorded. AEs that will be analyzed include, 
but are not limited to, all AEs, SAEs, fatal AEs, and laboratory changes.
Pharmacokinetic Endpoints
A secondary objective of this trial is to characterize the PK profile of MK-1697 following 
administration. The serum concentrations of these agents will serve as the primary readout 
for the PK, and these data will be used to derive PK parameters (such as AUC, Cmin, and 
Cmax) of MK-1697. Furthermore, the results of these analyses will be used in conjunction 
with the safety, pharmacodynamics, and other exploratory endpoint data to help assess future 
dosing strategies for MK-1697.
Antidrug Antibody Endpoint
An exploratory objective of this trial is to characterize the formation of ADAs against MK-
1697. The formation of ADAs can potentially confound drug exposures at therapeutic doses 
and prime for subsequent infusion-related toxicity. ADA response at the beginning of each 
cycle will be determined to understand drug metabolism, exposure, and safety. The incidence 
 
 
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of antidrug antibodies and neutralizing antidrug antibodies will be evaluated and summarized 
over time by dose. Correlations between the presence/absence of positivity for ADAs and PK 
and pharmacodynamics markers, activity, and safety of MK-1697 will be explored.
Pharmacodynamic Endpoints
Exploratory objectives in this trial are to evaluate receptor (target) engagement and serum 
cytokines.
Target Engagement
Target engagement of MK-1697 will be assessed through total soluble LAG-3 (sLAG-3) and 
PD-1 receptor occupancy. 
The frequency of surface LAG-3+ cells in human, NHP, and mouse peripheral blood is 
negligible by flow cytometry which precludes the use of cell surface LAG-3 receptor binding 
or receptor availability assays for target engagement. Soluble LAG-3 present in the serum, 
however, presents an alternative method to assess target engagement of the LAG-3 
component of MK-1697 by measuring total (free and bound) serum LAG-3 levels. 
Target engagement of the PD-1 portion of MK-1697 can be assessed by measuring the 
binding of MK-1697 to the PD-1 receptor in peripheral blood.
Serum for Cytokine Testing
Because treatment with MK-1697 can result in immune stimulation and resulting potential 
for cytokine release, serum cytokines will be monitored to provide supplementary 
information to assist in the evaluation of any safety events (eg, IFN-γ, IL-1β, IL-2, IL-4, IL-
6, IL-8, IL-10, IL-12p70, IL-13 and TNF-α).
Planned Exploratory Biomarker Research
Cancer immunotherapies represent an important and novel class of antitumor agents. 
However, the mechanism of action of these exciting new therapies is not completely 
understood and much remains to be learned regarding how best to leverage these new drugs 
in treating patients. Thus, to aid future patients, it is important to investigate the determinants 
of response or resistance to cancer immunotherapy and other treatments administered, as well 
as determinants of AEs in the course of our clinical studies. These efforts may identify novel 
predictive/PD biomarkers and generate information that may better guide single-agent and 
combination therapy with immuno-oncology drugs. To identify novel biomarkers, 
biospecimens (ie, blood components, tumor material) will be collected to support analyses of 
cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules. 
Investigations may include but are not limited to:
Germline (blood) genetic analyses (eg, SNP analyses, whole exome sequencing, whole 
genome sequencing)
This research may evaluate whether genetic variation within a clinical study population 
correlates with response to the treatment(s) under evaluation. If genetic variation is found to 
 
 
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predict efficacy or adverse events, the data might inform optimal use of therapies in the 
patient population. Furthermore, it is important to evaluate germline DNA variation across 
the genome in order to interpret tumor-specific DNA mutations. Finally, microsatellite 
instability (MSI) may be evaluated, as this is an important tumor type-agnostic biomarker 
predictive of response to PD-1 blockade. For all subjects with CRC enrolled in Part B, MSI 
testing may be performed to confirm local tumor testing results.
Genetic (DNA) analyses from tumor
The application of new technologies, such as next generation sequencing, has provided 
scientists the opportunity to identify tumor-specific DNA changes (ie, mutations, methylation 
status, microsatellite instability). Key molecular changes of interest to immuno-oncology 
drug development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes referred to as a ‘hyper-
mutated’ state) may generate neo-antigen presentation in the tumor microenvironment. To 
conduct this type of research, it is important to identify tumor-specific mutations that occur 
across all genes in the tumor genome. Thus, genome-wide approaches may be used for this 
effort. Note that in order to understand tumor-specific mutations, it is necessary to compare 
the tumor genome with the germline genome. Microsatellite instability may also be evaluated 
as this is an important biomarker for some cancers (ie, colorectal cancer). Circulating tumor 
DNA and/or RNA may also be evaluated from blood samples.
Tumor and blood RNA analyses
Both genome-wide and targeted messenger RNA (mRNA) expression profiling and 
sequencing in tumor tissue and in blood may be performed to define gene signatures that 
correlate to clinical response to treatment with immunotherapies and/or other treatments 
administered. Immunotherapies induce a response in tumors that likely reflects an 
inflamed/immune phenotype. Specific immune-related gene sets (ie, those capturing 
interferon-gamma transcriptional pathways) may be evaluated and new signatures may be 
identified. Individual genes related to the immune system may also be evaluated (eg, IL-10). 
MicroRNA profiling may also be pursued as well as exosomal profiling.
Proteomics and immunohistochemistry (IHC) using blood or tumor
Tumor and blood samples from this study may undergo proteomic analyses (eg, PD-L1 IHC). 
PD L1 protein level in tumor sections, assessed by IHC, has been shown to correlate with 
response to immunotherapy in patients with NSCLC, and an in vitro diagnostic (IVD) device 
has been developed for use with immunotherapy in NSCLC. Preliminary data indicates that 
this association may also be true in additional cancer types (ie, triple negative breast cancer, 
head and neck, and gastric). Additional tumor or blood-derived proteins may also correlate 
with response to immunotherapy. Therefore, tumor tissue may be subjected to proteomic 
analyses using a variety of platforms that could include but are not limited to immunoassays 
and liquid chromatography/mass spectrometry. This approach could identify novel protein 
biomarkers that could aid in patient selection for immunotherapy and/or treatments.
 
 
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Peripheral Blood Mononuclear Cell (PBMC) Phenotypic Analysis
Phenotypic characterization and enumeration of immune suppressive cells (eg, myeloid-
derived suppressor cells [MDSC], Tregs) and activated/proliferating T-cell subsets (eg, Ki67, 
human leukocyte antigen – antigen D related [HLA-DR]) circulating in blood collected at 
pre- and posttreatment time points may be assessed by flow cytometry as a potential 
pharmacodynamic biomarker downstream of target engagement.
Other biomarkers
In addition to expression on the tumor tissue, PD-L1 and other tumor derived proteins can be 
shed from tumor and released into the blood. Assays such as enzyme-linked immunoassay 
(ELISA) that measure proteins may also be evaluated from blood samples. Correlation of 
these biomarkers with response to immunotherapy and/or treatments may identify new 
approaches for predictive biomarkers in blood, representing a major advance from today’s 
reliance on assessing tumor biomarkers. This research would serve to develop such assays for 
future clinical use. 
Other molecular changes of interest include the subtype of T-cells in the tumor 
microenvironment. The T-cell repertoire from tumor tissue and blood components may be 
evaluated.
Future Biomedical Research
The Sponsor will conduct future biomedical research on specimens for which consent was 
provided during this study. This research may include genetic analyses (DNA), gene 
expression profiling (ribonucleic acid [RNA]), proteomics, metabolomics (serum, plasma) 
and/or the measurement of other analytes, depending on which specimens are consented for 
future biomedical research.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main study) and will only be conducted on specimens from 
appropriately consented participants. The objective of collecting/retaining specimens for 
future biomedical research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. The overarching goal is to use 
such information to develop safer, more effective drugs/vaccines, and/or to ensure that 
participants receive the correct dose of the correct drug/vaccine at the correct time. The 
details of this future biomedical research substudy are presented in Appendix 2.
Justification for Dose 
Starting Dose for This Study
The starting dose for this study is 20 mg (0.3 mg/kg in an approximately 70 kg participant) of 
MK-1697 Q3W. This dose was determined based on an integrated analysis approach of all 
nonclinical dosing data. More information can be found in the IB. A 2-compartment PK 
model with linear and nonlinear clearance components was used to predict the anticipated 
serum-exposure profiles of MK-1697 in humans for a variety of doses. These predicted 
 
 
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exposures were then compared to the exposures observed in the nonhuman primate (NHP)
toxicology studies The NOAEL in a 4-week toxicology study in Rhesus monkeys was 
estimated as 10 mg/kg given once weekly. The predicted maximum serum concentration 
(Cmax) of the starting 20 mg dose level in humans provides an approximately 31- to 60-fold 
safety margin relative to the Cmax observed in Rhesus monkeys in 2 independent studies at 
the NOAEL (Table 1). In addition, the anticipated exposure in humans at the 20 mg starting 
dose based on AUC comparison provides an approximately 20- to 44-fold safety margin to 
the AUC at steady state (AUC0-τ) observed in Rhesus monkeys at the NOAEL (Table 1).
Table 1
Predicted Pharmacokinetic Parameters in Humans at the Starting Dose and the 
Relative Fold Differences to these Parameters at the NOAEL in Rhesus Monkeys
PK 
parameter
Units
Rhesus 
monkey 
NOAEL 
(10 mg/kg
/week)
Study #1
Study #2
Human
(0.3 mg/kg)
Fold increase 
of human 
prediction 
over NOAEL 
in Rhesus 
monkeys
Human
(0.3 mg/kg)
Fold increase 
of human 
prediction 
over NOAEL 
in Rhesus 
monkeys
Cmax
nmol/L 
(nM)
7901
132
59.8
255
30.9
AUC3,4
nM day
23570
536
43.9
1210
19.4
Additionally, the 20 mg starting dose of MK-1697 is predicted to achieve >90% whole body 
occupancy in humans, as shown in Table 2. Based on previous Sponsor experience, this level 
of saturation is expected to be sufficient to elicit antitumor efficacy.
Table 2
Whole Body Target Saturation Corresponding To Predicted Maximum 
Concentration upon MK-1697 Dosing in Human
MK-1697 
dose
(mg/kg)
Predicted Cmax in humans
(nmol/L)
Predicted whole body target occupancy1
(%)
Study #1
Study #2
Study #1
Study #2
0.1
43.5
83.9
78.5
87.6
0.3
132
255
91.7
95.5
1
457
906
97.5
98.7
3
1460
2820
99.2
99.6
10
5000
9550
99.8
99.9
1
The % whole body target occupancy was calculated as (Cmax / (Cmax + Km)) * 100.
Additionally, results from the Sponsor’s MK-4280-001 study, combining an anti-LAG-3 
mAb (MK-4280) with pembrolizumab, have shown this combination to be well-tolerated. No 
DLTs were observed in any participants (N=47) treated with escalating doses of MK-4280 
(ranging from 7 mg to 700 mg) either as monotherapy or in combination with 
pembrolizumab.
 
 
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A fixed-dosing strategy, as opposed to weight-based dosing, is proposed for this study. Prior 
Sponsor experience has demonstrated that fixed-dosing can provide similar control of PK 
variability as weight-based dosing for monoclonal antibodies. Additionally, fixed-dosing has 
many advantages such as reduced dosing complexity and less potential for dosing errors.
Based on all of these assessments, the FIH starting dose of 20 mg (equivalent to 0.3 mg/kg in 
an approximately 70 kg participant) of MK-1697 Q3W is proposed.
Maximum Dose/Exposure for This Study
The higher planned doses for this study are 65 mg and 200 mg of MK-1697 Q3W. These 
were determined as half-log increases over the starting dose, rounded for ease of 
administration. These doses correspond approximately to 1 mg/kg and 3 mg/kg doses in a 70
kg participant.  As shown in Table 2, the maximum dose of 200 mg corresponds to a >99% 
predicted whole body target occupancy. The predicted whole-body target saturation appears 
to plateau at this dose and, as such, this is proposed as the highest dose for the study. 
Additionally, as shown in Table 3, this maximum dose still provides an approximately 2.8- to 
5.4-fold safety margin relative to the Cmax observed in Rhesus monkeys at the NOAEL.
Table 3
Predicted Pharmacokinetic Parameters in Humans at the Highest Planned Dose 
and the Relative Fold Differences to these Parameters at the NOAEL in Rhesus 
Monkeys
PK 
parameter
Units
Rhesus 
monkey 
NOAEL
(10 mg/kg
/week)
Study #1
Study #2
Human
(3 mg/kg)
Fold increase of 
human 
prediction over 
NOAEL in 
Rhesus 
monkeys
Human
(3 mg/kg)
Fold increase of 
human 
prediction over 
NOAEL in 
Rhesus monkeys
Cmax
nmol/L 
(nM)
7901
1460
5.4
2820
2.8
Rationale for Dose Interval and Study Design
The starting dose and dosing interval for MK-1697 are based on an integration of nonclinical, 
toxicological, PK and pharmacodynamics data. Dose escalation and confirmation will use a 
modified toxicity probability interval (mTPI) approach to identify a preliminary RP2D.
Dose Finding Using a Modified Toxicity Probability Interval Design
In Part A of this study, an mTPI design [Ji Y, Li Y, Bekele BN 2007] with a target toxicity 
rate of about 30% will be used to determine the RP2D of MK-1697.
Three predetermined dose levels of MK-1697 will be assessed: 20 mg (DL1), 65 mg (DL2), 
and 200 mg (DL3). Intermediate doses of MK-1697 may be used if one of the predetermined 
doses is deemed toxic and the immediate lower dose is deemed too low for potential efficacy. 
All dose-escalation decisions will be made based on the frequency of DLT(s) and will be 
 
 
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made in collaboration between the Sponsor and the investigators after the DLT observation 
period (ie, 21 days after the dose on Day 1 of the treatment cycle) of the last participant 
enrolled at each dose level is completed.
Treatment allocation will be accomplished by nonrandom assignment as described in Section 
6.3.1 – Method of Treatment Assignment. An observation period of at least 72 hours will 
occur between treatment initiation in the first 2 participants enrolled within each dose level.
Each new dose level will open for enrollment once the 21-day DLT observation period of the 
previous dose level is completed and decision is made to escalate the dose.
In Table 4, the number of participants treated is indicated in the columns and the number of 
participants who experience at least 1 DLT is indicated in the rows. Dosing decisions 
include: escalate to the next higher dose (E), stay at the current dose (S), deescalate to the 
next lower dose (D), and deescalate to a lower dose and never test this dose again (ie, 
unacceptably toxic dose; DU).
During dose escalation, a minimum of 3 participants are required at each dose. Depending on 
accrual rate, 3 to 6 participants may be initially enrolled at each new dose until the last of 
those participants completes the 21-day DLT observation period.
Based on the mTPI design, the number of participants who are enrolled at a dose but are not 
yet fully evaluable for DLT assessment may not exceed the number of remaining participants 
who are at risk of developing a DLT before the dose would be considered unacceptably toxic 
(DU). To determine how many more participants can be enrolled at a dose level, one can 
count steps in a diagonal direction (down and to the right) from the current cell to the first 
cell marked DU.
For example, if 3 participants are enrolled at a dose and none of them develops a DLT, then 
the dose can be escalated to the next level without further expansion. If 1 out of the first 3 
participants develops a DLT, no more than an additional 3 participants may be enrolled at 
this dose level until additional DLT data are available since this dose would be considered 
unacceptably toxic if all 3 of the additional participants experience a DLT (ie, 4 out of 6 total 
participants). If 2 out of the first 3 participants at a given dose level develop a DLT, the dose 
will be deescalated to the next lower level. If 3 out of the first 3 participants at a given dose 
level develop a DLT, this dose will be considered unacceptably toxic and the dose will be 
deescalated and never re-escalated to that dose again. These same principles (see Table 4) 
will be applied whether 3, 4, 5, or 6 participants are initially enrolled in that dose level.
Dose escalation and confirmation will end after 14 participants have been treated at any of 
the selected doses (including intermediate or higher dose levels) and the decision based on 
Table 4 is to stay (or escalate if at the highest pre-determined dose level). If dose escalation 
proceeds to the highest dose level, the dose will be considered acceptably safe (and therefore 
Part B enrollment may begin) once the DLT period has been completed for enough 
participants (out of 14 total) such that, even if all remaining participants experienced a DLT, 
the mTPI table would still call for a ‘stay’ or ‘escalate’ decision. For example, if there was 0 
DLTs with 12 participants enrolled at the highest dose, even if participants 13 and 14 both 
had DLTs, the mTPI decision would still be to stay at the highest dose.
 
 
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The pool-adjacent-violators algorithm that forces the DLT rate estimates to be nondecreasing 
with dose levels and pools adjacent violators for weighted estimates by sample size will be 
used to estimate the DLT rates for each dose level. 
The totality of the data will be considered when determining the preliminary RP2D to be 
used in Part B. In the event that a RP2D cannot be determined based on the totality of data 
collected from the dose escalation part of the study (ie, the MTD is not reached, high 
variability is seen with PK profiles, or target engagement cannot be confirmed), up to 2 doses 
of MK-1697 may be tested in a subset of the expansion part of the study, at the Sponsor’s 
discretion.
Note that while 30% was the target toxicity rate used to generate the guidelines in Table 
4, the observed rates of participants with DLTs at any given dose level may be slightly 
above or below 30%.
Table 4
Dose-finding Rules per mTPI Design
Number of Participants Evaluable for DLT at Current Dose
Number of 
Participants with 
at Least 1 DLT
3
4
5
6
7
8
9
10
11
12
13
14
0
E
E
E
E
E
E
E
E
E
E
E
E
1
S
S
S
E
E
E
E
E
E
E
E
E
2
D
S
S
S
S
S
S
S
E
E
E
E
3
DU
DU
D
S
S
S
S
S
S
S
S
S
4
DU
DU
DU
D
D
S
S
S
S
S
S
5
DU
DU
DU
DU
DU
D
S
S
S
S
6
DU
DU
DU
DU
DU
DU
D
S
S
7
DU
DU
DU
DU
DU
DU
DU
D
8
DU
DU
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
DU
DU
10
DU
DU
DU
DU
DU
11
DU
DU
DU
DU
12
DU
DU
DU
13
DU
DU
14
DU
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%
Flat non-informative prior Beta (1,1) is used as a prior and ε1=ε2=0.03[Ji Y, Li Y, Bekele BN 2007].
 
 
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Beginning and End of Study Definition
The overall study begins when the first participant signs the Informed Consent Form (ICF). 
The overall study ends when the last participant completes the last study-related telephone-
call or visit, withdraws from the study or is lost to follow-up (ie, the participant is unable to 
be contacted by the investigator).
Clinical Criteria for Early Study Termination
Early study termination will be the result of the criteria specified below:
1. Incidence or severity of adverse drug reactions in this or other trials suggest a potential 
health hazard to participants
2. Plans to modify or discontinue the development of the trial drug
3. Poor adherence to protocol and regulatory requirements
4. Quality or quantity of data recording is inaccurate or incomplete
Ample notification will be provided in the event of Sponsor decision to no longer supply 
MK-1697.
5. Study Population
Male/Female participants of at least 18 years of age with advanced solid tumors will be 
enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Type of Participant and Disease Characteristics
1. Part A - Have a histologically- or cytologically-confirmed advanced/metastatic solid 
tumor by pathology report and have received, or been intolerant to, or been ineligible 
for all treatments known to confer clinical benefit.
2. Part B – Have 1 of the following histologically or cytologically confirmed tumor 
types confirmed by pathology report and are anti-PD-1/PD-L1-treatment-naïve:
a.
HNSCC that is considered incurable by local therapies. Participants should 
have progressed after receiving platinum-containing systemic therapy. 
Systemic therapy given as part of multimodal treatment for locally advanced 
disease is allowed. The eligible primary tumor locations are oropharynx, oral 
cavity, hypopharynx, and larynx. Participants may not have a primary tumor 
site of nasopharynx (any histology).
 
 
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b. CRC originating in either the colon or rectum that is locally advanced 
unresectable or metastatic (ie, Stage IV) and that has received, and progressed 
on, all available standard-of-care therapies including fluoropyrimidine, 
oxaliplatin, and irinotecan. 
3. Have measurable disease by RECIST 1.1 as assessed by the local site 
investigator/radiology. Target lesions situated in a previously irradiated area are 
considered measurable if progression has been demonstrated in such lesions.
4. Submit an evaluable baseline tumor sample for analysis (either an archival or recently 
obtained tumor sample). Details pertaining to tumor tissue submission can be found 
in the Laboratory Manual.
5. Have a performance status of 0 or 1 on the ECOG Performance Scale
6. Have central venous access (eg, portacath, Hickman line, or peripherally inserted 
central catheter [PICC] line) currently inserted or be considered medically fit for (in 
the opinion of the investigator and/or treating surgeon) and willing to undergo the 
insertion of such a device.
Note: This Inclusion Criterion only applies to participants who are being 
considered for enrollment at a dose level that requires administration into a central 
vein. See the Laboratory Manual and Pharmacy Manual for more details on dose 
levels to which this applies.
7. Demonstrate adequate organ function as defined by Table 5 (labs to be obtained 
within 7 days of treatment initiation)
 
 
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Table 5
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥100 000/µL
Hemoglobin
≥9.0 g/dL or ≥5.6 mmol/L1
Renal
Creatinine OR
Measured or calculated2 creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 × ULN OR
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants with total bilirubin levels 
>1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases)
Coagulation
INR or PT
aPTT (PTT may be substituted)
≤1.5 × ULN unless participant is receiving
anticoagulant therapy as long as PT or aPTT is 
within therapeutic range of intended use of 
anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper 
limit of normal.
1 Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
2 Creatinine clearance (CrCl) should be calculated per institutional standard.
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations.
 
 
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Demographics
Male participants:
8. A male participant must agree to use a contraception as detailed in Appendix 3 of this 
protocol during the treatment period and for at least 120 days after the last dose of 
study treatment and refrain from donating sperm during this period.
Female participants:
9. A female participant is eligible to participate if she is not pregnant (see Appendix 3), 
not breastfeeding, and at least one of the following conditions applies: 
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 3
OR 
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during 
the treatment period and for at least 120 days after the last dose of study treatment.
Informed Consent
10. Be ≥18 years of age on the day of signing the ICF
11. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the study. The participant may also provide consent for future 
biomedical research. However, the participant may participate in the main study
without participating in future biomedical research.
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Has a history of a second malignancy, unless potentially curative treatment has been 
completed with no evidence of malignancy for 3 years.
Note: The time requirement does not apply to participants who underwent 
successful definitive resection of basal cell carcinoma of the skin, superficial 
bladder cancer or in situ cervical cancer, or other in-situ cancers.
2. Has clinically active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Participants with previously-treated brain or meningeal metastases may 
participate and be eligible for treatment provided they are stable and asymptomatic 
(without evidence of progression by magnetic resonance imaging (MRI) scan of the 
brain separated by at least 4 weeks after treatment), have no evidence of new or 
enlarging brain metastases, are evaluated within 4 weeks prior to first study treatment 
administration, and are off immunosuppressive doses of systemic steroids at least 2 
weeks prior to enrollment.
 
 
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3. Has had a severe hypersensitivity reaction to treatment with any monoclonal antibody 
and/or components of the study treatment.
4. Has an active infection requiring therapy.
5. Has a history of interstitial lung disease.
6. Has a history of (noninfectious) pneumonitis that required steroids or current 
pneumonitis.
7. Has an active autoimmune disease that has required systemic treatment in the past 2 
years (ie, with use of disease-modifying agents, corticosteroids, or 
immunosuppressive drugs) except vitiligo or resolved childhood asthma/atopy. 
Replacement therapy, such as thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, is not considered a form of 
systemic treatment and is allowed. Use of nonsystemic steroids is permitted.
8. Participants with known human immunodeficiency virus (HIV) and/or Hepatitis B or 
C infections, or known to be positive for Hepatitis B antigen (HBsAg)/ Hepatitis B 
virus (HBV) DNA or Hepatitis C Antibody or RNA.
9. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant’s 
participation for the full duration of the study, make administration of the study 
treatments hazardous or make it difficult to monitor adverse effects such that it is not 
in the best interest of the participant to participate, in the opinion of the treating 
investigator
10. Has a history or current evidence of severe cardiovascular disease, ie, arrhythmias 
requiring chronic treatment, congestive heart failure (New York Heart Association 
[NYHA] Class III or IV) or symptomatic ischemic heart disease.
11. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the trial.
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days 
after the last dose of study treatment.
13. Has not fully recovered from any effects of major surgery without significant 
detectable infection. Surgeries that required general anesthesia must be completed at 
least 2 weeks before first study treatment administration.  Surgery requiring 
regional/epidural anesthesia must be completed at least 72 hours before first study 
treatment administration and participants should be recovered.
 
 
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14. Has known MSI high or MMR deficient colorectal cancer (as determined by PCR, 
IHC, or a validated NGS panel [eg. Foundation Medicine or MSKImpact]). If a 
participant’s MSI status is unknown, a paired blood sample for MSI in addition to 
biomarker testing is required to determine MSI status retrospectively (for the CRC 
expansion cohort only).
15. A WOCBP who has a positive urine pregnancy test within 72 hours before the first 
dose of study treatment. If the urine test is positive or cannot be confirmed as 
negative, a serum pregnancy test will be required.
Note: In the event that 72 hours have elapsed between the screening pregnancy 
test and the first dose of study treatment, another pregnancy test (urine or serum) 
must be performed and must be negative in order for participant to start receiving 
study medication.
Prior/Concomitant Therapy
16. Has had chemotherapy, definitive radiation, or biological cancer therapy within 
4 weeks (2 weeks for palliative radiation) prior to the first dose of study therapy, or 
has not recovered to CTCAE Grade 1 or better from any adverse events that were due 
to cancer therapeutics administered more than 4 weeks earlier (this includes 
participants with previous immunomodulatory therapy with residual immune-related 
adverse events).  Participants receiving ongoing replacement hormone therapy for 
endocrine immune-related adverse events will not be excluded from participation in 
this study.
Note: Participants with ≤ Grade 2 neuropathy may be eligible after consultation 
with the Sponsor.
Note: If participant received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
study treatment.
17. Has received prior therapy with an anti-LAG-3 agent.
18. Has received a live vaccine within 30 days prior to the first dose of study drug.  
Examples of live vaccines include, but are not limited to, the following:  measles, 
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus 
Calmette–Guérin (BCG), and typhoid vaccine.  Seasonal influenza vaccines for 
injection are generally killed virus vaccines and are allowed; however, intranasal 
influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
19. Has undergone a prior stem cell or bone marrow transplant within the last 5 years.
Note: Participants who have had a transplant greater than 5 years ago are 
eligible as long as there are no symptoms of graft-versus-host disease (GVHD).
20. Is expected to require any other form of antineoplastic therapy while on study.
 
 
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Prior/Concurrent Clinical Study Experience
21. Is currently participating in or has participated in a study of an investigational agent 
or has used an investigational device within 4 weeks prior to the first dose of study 
treatment.
Note:  Participants who have entered the follow-up phase of an investigational
study may participate as long as it has been 4 weeks after the last dose of the 
previous investigational agent.
Lifestyle Considerations
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
Contraception
MK-1697 may have adverse effects on a fetus in utero.  Refer to Appendix 3 for approved 
methods of contraception.
Participants 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 this study, participants of childbearing potential must adhere to the 
contraception requirement (Appendix 3) from the day of study medication initiation (or 14 
days prior to the initiation of study medication for oral contraception) throughout the study
period up to 120 days after the last dose of study medication.  If there is any question that a 
participant of childbearing potential will not reliably comply with the requirements for 
contraception, that participant should not be entered into the study.
Pregnancy
If a participant inadvertently becomes pregnant while on treatment with MK-1697, the 
participant will be immediately discontinued from study treatment.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has 
been completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).  The study Investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor.  If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 8.4.
 
 
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Use in Nursing Women
It is unknown whether MK-1697 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, participants who are breastfeeding are not eligible for enrollment.
Number of Participants
The total number of participants enrolled will depend on the frequency of DLTs observed in 
Part A and on which expansion cohorts (if any) discontinue enrollment early in Part B. For 
planning purposes and under the assumption that 3 doses will be tested during Part A with up 
to 14 participants in each of the 3 dose levels, followed by 2 expansion cohorts in Part B with 
up to 40 participants each, we assume an approximate maximum sample size of 122 
participants. See Section 9.9 for a more thorough description of sample size and power 
calculations.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study. A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any adverse events (AEs) or serious adverse 
events (SAEs) meeting reporting requirements as outlined in the data entry guidelines.
Participant Replacement Strategy
In order to adequately evaluate the safety of the doses administered in this study, all 
participants enrolled in the dose escalation phase must meet the criteria for evaluability for 
Cycle 1.  Participants are considered nonevaluable and will be replaced if:

They are allocated 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 75% of the total MK-1697 infusion in Cycle 1 (eg, if the 
infusion had to be discontinued due to an infusion reaction) and did not experience a 
DLT
Participants who are nonevaluable will be replaced unless accrual to the expansion cohort has 
stopped.  Nonevaluable participants will not be counted toward the total number of 
participants in the expansion cohort for DLT evaluation.
If a participant experiences a DLT in Cycle 1, trial treatment may be discontinued following 
discussion between the sponsor and investigator. However, if the participant is deriving 
clinical benefit from the trial treatment, the participant may be allowed to continue after 
discussion between the Sponsor and the investigator.
 
 
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6. Treatments
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a study participant according to the study 
protocol.
Clinical supplies [study treatment(s) provided by the Sponsor] will be packaged to support 
enrollment as required. Clinical supplies will be affixed with a clinical label in accordance 
with regulatory requirements.
Treatments Administered
The study treatment to be used in this study is outlined below in Table 6.
 
 
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Table 6
Study Treatment
Study 
Treatment 
Name
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment Period
Use
IMP/NIMP
Sourcing
MK-1697
Solution for 
Infusion
10 mg/mL
Part A:
20 mg
65 mg
200 mg
Part B:
Preliminary 
RP2D
IV infusion
Q3W for up to 
35 cycles
Experimental
IMP
Provided centrally 
by the Sponsor
Definition Investigational Medicinal Product (IMP) and Non- Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
 
 
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All supplies indicated in Table 6 will be provided per the ‘Sourcing’ row depending upon 
local country operational requirements. Every attempt should be made to source these 
supplies from a single lot/batch number where possible (eg, not applicable in the case where 
multiple lots or batches may be required due to the length of the study etc.).
Refer to Section 8.1.8 for details regarding administration of the study treatment.
Preparation/Handling/Storage/Accountability
Dose Preparation
There are no specific calculations or evaluations required to be performed in order to 
administer the proper dose to each participant. The rationale for selection of doses to be used 
in this study is provided in Section 4.3.
Handling, Storage and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatment received and any discrepancies are reported 
and resolved before use of the study treatment.
Only participants enrolled in the study may receive study treatment and only authorized site 
staff may supply or administer study treatment. All study treatments must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (ie, 
receipt, reconciliation, and final disposition records).
For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of study 
treatments in accordance with the protocol and any applicable laws and regulations.
Measures to Minimize Bias: Randomization and Blinding
Method of Treatment Assignment 
Participants participating in this study will be allocated by nonrandom assignment.
 
 
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Stratification
In Part A of the study, no stratification based on age, sex or other characteristics will be used.
In Part B of the study, treatment allocation/randomization will be stratified according to the 
following factors:
1. Tumor type
Blinding 
This study is an open-label study; therefore, the Sponsor, investigator and participant will 
know the treatment administered.
Treatment Compliance
Interruptions from the protocol specified treatment plan for ≥12 weeks require consultation 
between the investigator and the Sponsor and written documentation of the collaborative 
decision on participant management.
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccination
specifically prohibited, discontinuation from study treatment may be required. The 
investigator should discuss any questions regarding this with the Sponsor Clinical Director. 
The final decision on any supportive therapy or vaccination rests with the investigator and/or 
the participant's primary physician. However, the decision to continue the participant on 
study treatment requires the mutual agreement of the investigator, the Sponsor and the 
participant.
Listed below are specific concomitant therapies and vaccinations prohibited during the 
course of the study:

Antineoplastic systemic chemotherapy or biological therapy

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents not specified in this protocol

Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be 
allowed at the Investigator’s discretion.
 
 
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
Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, 
and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed 
virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) 
are live attenuated vaccines and are not allowed.

Prolonged therapy with systemic glucocorticoids (>7 days) for any purpose other than 
the management of AEs as described in Section 6.6.  Brief, limited use of systemic 
corticosteroids (≤7 days) are permitted where such use is considered standard of care 
(eg, for COPD exacerbation). The use of physiologic doses of corticosteroids (ie, 
prednisone 5 to 7.5 mg daily) may be approved after consultation with the Sponsor. 
The use of local steroids is allowed.
Participants who, in the assessment of the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  
All treatments that the Investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the Investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the eCRF including all 
prescription, over-the-counter (OTC) products, herbal supplements, and IV medications and 
fluids.  If changes occur during the study period, documentation of drug dosage, frequency, 
route, and date should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study treatment 
and up to 30 days after the last dose of study treatment should be recorded.  Concomitant 
medications administered 30 days after the last dose of study treatment should be recorded 
for SAEs and events of clinical interest (ECIs) as defined in Section 8.4.
Supportive Care
AEs associated with immunomodulatory agents such as MK-1697 may represent an 
immunologic etiology. These immune-related AEs (irAEs) may occur shortly after the first 
dose or several months after the last dose of MK-1697 treatment and may affect more than 
one body system simultaneously. Therefore, early recognition and initiation of treatment is 
critical to reduce complications.  Based on clinical study data for pembrolizumab, most 
irAEs were reversible and could be managed with interruptions of study treatment, 
administration of corticosteroids and/or other supportive care. For suspected irAEs, ensure 
adequate evaluation to confirm etiology or exclude other causes. Additional procedures or 
tests such as bronchoscopy, endoscopy, or skin biopsy may be included as part of the
evaluation.
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 6.6, Table 7.  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
 
 
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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 MK-1697. 
Note: If after the evaluation of the event, it is determined not to be related to MK-1697, the 
Investigator does not need to follow the treatment guidance.  Refer to Table 7 in Section 6.6
for guidelines regarding dose modification and supportive care. 
Dose Modification  
Dose modification and toxicity management guidelines for irAEs associated with MK-1697 
are provided in Table 7.
 
 
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Table 7
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with MK-1697
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where MK-1697 has been withheld, MK-1697 can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has been 
tapered. MK-1697 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 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
MK-1697
irAE management with 
corticosteroid and/or other 
therapies
Monitor 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 suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear fluids.  
If sufficient oral fluid intake is not feasible, fluid 
and electrolytes should be substituted via IV 
infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
MK-1697
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
AST / ALT 
elevation or 
Increased 
bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper
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
Grade 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
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
MK-1697
irAE management with 
corticosteroid and/or other 
therapies
Monitor and follow-up
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
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 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Guillain-Barre 
Syndrome, 
encephalitis
Grade 4 or 
recurrent Grade 3 
Permanently 
discontinue
1.
Withhold or permanently discontinue MK-1697 is at the discretion of the investigator or treating physician.  
NOTES: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of MK-1697 is required, MK-1697 may be resumed when AE resolves 
to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
All Grade 1 AEs should be treated with appropriate supportive care, but treatment should not be withheld or discontinued, unless stated otherwise.
 
 
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Dose modification and toxicity management of infusion-reactions related to MK-1697
Immuno-modulators such as MK-1697 may cause severe or life-threatening infusion-
reactions including severe hypersensitivity or anaphylaxis. Signs and symptoms usually 
develop during or shortly after drug infusion and generally resolve completely within 24 
hours of completion of infusion. Dose modification and toxicity management guidelines on 
MK-1697-associated infusion reaction are provided in Table 8. 
 
 
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Table 8
MK-1697 Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the 
investigator.
None
Grade 2
Requires therapy or infusion 
interruption but responds promptly 
to symptomatic treatment (eg, 
antihistamines, NSAIDs, narcotics, 
IV fluids); prophylactic medications 
indicated for ≤24 hrs
Stop Infusion.
Additional appropriate medical therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically indicated until the 
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 drug treatment.
Participant may be premedicated 1.5h (± 30 
minutes) prior to infusion of MK-1697 with:
Diphenhydramine 50 mg po (or equivalent 
dose of antihistamine).
Acetaminophen 500-1000 mg po (or equivalent 
dose of analgesic).
 
 
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(eg, renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may include but is not 
limited to:
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 drug 
treatment.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov
 
 
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Definition of Dose-Limiting Toxicity
All toxicities will be graded using NCI-CTCAE Version 4.0 based on the investigator 
assessment.
The DLT window of observation will be during Cycle 1.  
The occurrence of any of the following toxicities during Cycle 1 will be considered a DLT, if 
assessed by the investigator to be possibly, probably, or definitely related to study 
intervention administration:

Grade 4 non-hematologic toxicity (not laboratory)

Grade 4 hematologic toxicity lasting at least 7 days, except thrombocytopenia, 
which is a DLT as follows:
o
Grade 4 thrombocytopenia of any duration
o
Grade 3 thrombocytopenia if associated with clinically significant 
bleeding

Any Grade 3 or higher nonhematologic clinical AE should be considered a DLT, 
except for the following: Grade 3 fatigue lasting ≤3 days and Grade 3 rash 
without use of corticosteroids or anti-inflammatory agents per standard of care.
Grade 3 nausea, vomiting, or diarrhea lasting greater than 72 hours, despite use of 
anti-emetics, anti-diarrheals, or other supportive care, should be considered a 
DLT.

Any Grade 3 or Grade 4 non-hematologic laboratory value, if
o
Clinically significant medical intervention is required to treat the 
participant, or
o
The abnormality leads to hospitalization, or
o
The abnormality persists for more than 1 week, or
o
The abnormality results in a Drug-induced Liver Injury (DILI)

Grade 3 or Grade 4 febrile neutropenia
o
Grade 3 is defined as absolute neutrophil count (ANC) <1000/mm3 with a 
single temperature of >38.3 degrees C (101 degrees F) or a sustained 
temperature of ≥38 degrees C (100.4 degrees F) for more than 1 hour
 
 
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o
Grade 4 is defined as ANC <1000/mm3 with a single temperature of >38.3 
degrees C (101 degrees F) or a sustained temperature of ≥38 degrees C 
(100.4 degrees F) for more than 1 hour, with life-threatening consequences 
and urgent intervention indicated

Any treatment-related toxicity that caused the participant to discontinue treatment 
during Cycle 1

Missing >25% of the intended MK-1697 dose as a result of drug-related AE(s) 
during the first cycle

Grade 5 toxicity

Any treatment-related toxicity that causes a greater than 2-week delay in initiation 
of Cycle 2.
Treatment After the End of the Study 
There is no study-specified treatment following the end of the study.
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study site personnel, the Sponsor 
and/or designee are not blinded. Study treatment (name, strength or potency) is included in 
the label text; random code/disclosure envelopes or lists are not provided.
7. Discontinuation of Study Treatment and Participant Withdrawal
Discontinuation of Study Treatment 
Discontinuation of study treatment does not represent withdrawal from the study.
As certain data on clinical events beyond study treatment discontinuation may be important 
to the study, they must be collected through the participant’s last scheduled follow-up, even 
if the participant has discontinued study treatment. Therefore, all participants who 
discontinue study treatment prior to completion of the protocol-specified treatment period
will still continue to participate in the study as specified in Section 1.3 and Section 8.11.3.
Participants may discontinue study treatment at any time for any reason or be discontinued
from the study treatment at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study treatment by the investigator 
or the Sponsor if study treatment is inappropriate, the study plan is violated, or for 
administrative and/or other safety reasons. Specific details regarding procedures to be 
performed at study treatment discontinuation are provided in Section 8.1.9.
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons:
○
The participant or participant’s legally acceptable representative requests to discontinue 
study treatment.
 
 
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o
The participant interrupts study treatment administration for more than 12 consecutive 
weeks (unless Sponsor approval to continue – See Section 6.4)
o
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study treatment.
o
The participant has a confirmed positive serum pregnancy test.
o
The participant has confirmed radiographic disease progression as outlined in Section 
8.2.2.
o
The participant experiences any progression or recurrence of any malignancy, or any 
occurrence of another malignancy, that requires active treatment.
o
The participant demonstrates noncompliance with study treatment or procedure 
requirements.
o
The participant experiences recurrent Grade 2 pneumonitis.
o
The participant completes 35 treatments (approximately 2 years) with MK-1697.
o
The participant experiences an overdose, and after consultation with the Sponsor (Section 
8.5).
For participants who are discontinued from study treatment but continue to be monitored in 
the study, all visits and procedures, as outlined in the SoA, should be completed.
Discontinuation from study treatment is “permanent.” Once a participant is discontinued, 
he/she shall not be allowed to restart study treatment. 
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study treatment or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from future biomedical research are 
outlined in Section 8.1.9.1. The procedures to be performed should a participant repeatedly 
fail to return for scheduled visits and/or if the study site is unable to contact the participant
are outlined in Section 7.3.
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
●
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
 
 
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●
The investigator or designee must make every effort to regain contact with the 
participant at each missed visit (eg, telephone calls and/or a certified letter to the 
participant’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the participant’s medical record.
●
Note:  A participant is not considered lost to follow-up until the last scheduled visit 
for the individual participant. The missing data for the participant will be managed 
via the prespecified statistical data handling and analysis guidelines.
8. Study Assessments and Procedures
●
Study procedures and their timing are summarized in the SoA. 
●
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
●
The investigator is responsible for assuring that procedures are conducted by 
appropriately qualified or trained staff. Delegation of study site personnel 
responsibilities will be documented in the Investigator Trial File Binder (or 
equivalent).
●
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
●
Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of ICF may be utilized for screening or 
baseline purposes provided the procedure met the protocol-specified criteria and were 
performed within the time frame defined in the SoA.
●
Additional evaluations/testing may be deemed necessary by the investigator and or 
the Sponsor for reasons related to participant safety. In some cases, such 
evaluation/testing may be potentially sensitive in nature (eg, HIV, Hepatitis C, etc.), 
and thus local regulations may require that additional informed consent be obtained 
from the participant. In these cases, such evaluations/testing will be performed in 
accordance with those regulations.
The maximum amount of blood collected from each participant over the duration of the 
study, including any extra assessments that may be required, is described in detail in the 
accompanying Laboratory Manual.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
 
 
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Administrative and General Procedures
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
participant or each participant’s legally acceptable representative prior to participating in a 
clinical study or future biomedical research. If there are changes to the participant’s status 
during the study (eg, health or age of majority requirements), the investigator or qualified 
designee must ensure the appropriate consent is in place. 
General Informed Consent
Consent must be documented by the participant’s dated signature or by the participant’s 
legally acceptable representative’s dated signature on a consent form along with the dated 
signature of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the participant before 
participation in the study.
The initial ICF, any subsequent revised written ICF and any written information provided to 
the participant must receive the Institutional Review Board/Independent Ethics Committee’s
(IRB/IEC’s) approval/favorable opinion in advance of use. The participant or his/her legally 
acceptable representative should be informed in a timely manner if new information becomes 
available that may be relevant to the participant’s willingness to continue participation in the 
study. The communication of this information will be provided and documented via a revised 
consent form or addendum to the original consent form that captures the participant’s dated 
signature or by the participant’s legally acceptable representative’s dated signature. 
The participant or his/her legally acceptable representative will be asked to sign consent at 
the point of initial radiographic disease progression.
Specifics about a study and the study population will be added to the consent form template 
at the protocol level. 
The informed consent will adhere to IRB/IEC requirements, applicable laws and regulations 
and Sponsor requirements.
Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the future biomedical research consent to 
the participant, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the future biomedical research substudy. A copy of the 
informed consent will be given to the participant.
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the study.
 
 
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Participant Identification Card
All participants will be given a Participant Identification Card identifying them as 
participants in a research study. The card will contain study site contact information 
(including direct telephone numbers) to be utilized in the event of an emergency. The 
investigator or qualified designee will provide the participant with a Participant Identification 
Card immediately after the participant provides written informed consent. At the time of 
treatment allocation/randomization, site personnel will add the treatment/randomization 
number to the Participant Identification Card.
The participant identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about study 
treatment in emergency situations where the investigator is not available.
Medical History
A medical history will be obtained by the investigator or qualified designee.
Prior and Concomitant Medications Review
Prior Medications
The investigator or qualified designee will review prior medication use and record prior 
medication taken by the participant within 28 days before the first dose of study medication. 
Additionally, the investigator or qualified designee will review and record all prior treatment 
and medication the participant has received for the indication they are enrolled into the trial 
for.
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study.
Assignment of Screening Number
All consented participants will be given a unique screening number that will be used to 
identify the participant for all procedures that occur prior to treatment allocation. Each 
participant will be assigned only one screening number. Screening numbers must not be re-
used for different participants.
Any participant who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 8.11.1. 
 
 
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Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation/randomization.  Once a 
treatment/randomization number is assigned to a participant, it can never be re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
Treatment Administration
Administration of study medication will be witnessed by the investigator and/or study staff.
Study treatment should be given on the day of treatment allocation/randomization or as close 
as possible to the date on which the participant is allocated/assigned.
Timing of Dose Administration
MK-1697 will be administered as an IV infusion Q3W. The reason for any variability in 
administration of MK-1697 outside of the protocol-specified window should be documented 
in the participant’s chart and recorded on the electronic case report forms (eCRFs).
Every effort should be made to begin the first dose of study treatment on the day of 
allocation, but if this is not achieved, study treatment should be initiated no later than 3 days 
from the date of allocation. All subsequent cycles of study treatment may be administered up 
to 3 days before or 3 days after the scheduled Day 1 of each cycle due to administrative 
reasons per the investigator’s judgement (Cycle 2 treatment may be administered up to 
3 days after the scheduled Day 1, only). All study treatments will begin on Day 1 of each 
cycle after all predose study procedures and assessments have been completed except as 
otherwise indicated in Section 1.3 – Schedule of Activities.
Central Venous Access for MK-1697 Administration
All dose levels of MK-1697 below 65 mg require administration directly into a central vein
due to the concentration of the supplied drug product and acceptable rate of infusion. See the 
accompanying Laboratory Manual and Pharmacy Manual for more information. If an 
enrolled participant does not have central venous access (eg, portacath, Hickman line, or 
PICC line) currently inserted, the participant should undergo a procedure to have such a 
device inserted. This should be done in accordance with the standard operating procedures of 
the local site. This procedure should not be performed until the participant has completed all 
other screening procedures/assessments and they have been determined to be eligible for the 
study.
 
 
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Domiciling
An inpatient observation for at least 24 hours may be performed, at the Investigator’s 
discretion, on Cycle 1, Day 1 for participants treated at the first dose level of MK-1697.  If 
performed, participants will report to the clinical research unit on Cycle 1, Day 1 and will 
remain for inpatient observation for at least 24 hours. The inpatient observation period may 
also be extended to the higher dose levels of MK-1697 at the discretion of the Investigator, 
local Institutional Review Board, Ethics Review Committee, and/or Health Authority 
requirement.
Discontinuation and Withdrawal
Participants who discontinue study treatment prior to completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits.
When a participant withdraws from participation in the study, all applicable activities 
scheduled for the final study visit (ie, End of Treatment/Discontinuation as indicated in the 
SoA) should be performed (at the time of withdrawal). Any AEs which are present at the 
time of withdrawal should be followed in accordance with the safety requirements outlined in 
Section 8.4 .
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for future biomedical research. Participants may 
withdraw consent at any time by contacting the principal investigator for the main study. If 
medical records for the main study are still available, the investigator will contact the 
Sponsor using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's consent for future biomedical research will be withdrawn. A 
letter will be sent from the Sponsor to the investigator confirming the withdrawal. It is the 
responsibility of the investigator to inform the participant of completion of withdrawal. Any 
analyses in progress at the time of request for withdrawal or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
study data and results. No new analyses would be generated after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study records) 
or the specimens have been completely anonymized, there will no longer be a link between 
the participant’s personal information and their specimens. In this situation, the request for 
specimen withdrawal cannot be processed.
Participant Blinding/Unblinding
This is an open label study; there is no blinding for this study.
 
 
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Calibration of Equipment
The investigator or qualified designee has the responsibility to ensure that any device or 
instrument used for a clinical evaluation/test during a clinical study that provides information 
about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably 
calibrated and/or maintained to ensure that the data obtained is reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
Efficacy Assessments 
Tumor Imaging and Assessment of Disease
Tumor imaging should be acquired by computed tomography (CT, strongly preferred). 
Magnetic resonance imaging (MRI) should be used when CT is contraindicated or for 
imaging in the brain. The same imaging technique regarding modality and use of contrast 
should be used in a participant throughout the trial to optimize the visualization of existing 
and new tumor burden.  Required anatomical images as well as the process for image 
collection and transmission to the central imaging vendor can be found in the Site Imaging
Manual (SIM).
Although RECIST 1.1 references to a maximum of 5 target lesions in total and 2 per organ, 
Merck allows a maximum of 10 target lesions in total and 5 per organ, if clinically relevant to 
enable a broader sampling of tumor burden.
Initial Tumor Imaging
Initial tumor imaging at screening must be performed within 28 days prior to the date of 
allocation.
Scans performed as part of routine clinical management are acceptable for use as screening 
tumor imaging if they are of diagnostic quality and performed within 28 days prior to the 
date of allocation. 
Participants with previously-treated brain metastases may participate provided they have 
stable brain metastases, ie, without evidence of progression by imaging (confirmed by 
magnetic resonance imaging (MRI) if MRI was used at prior imaging or confirmed by 
computed tomography (CT) imaging if CT used at prior imaging) for at least 4 weeks prior to 
the first dose of trial treatment. Any neurologic symptoms must have returned to baseline and 
participants must have no evidence of new or enlarging brain metastases and have not used 
steroids for brain metastases for at least 2 weeks prior to trial initiation as per local site 
assessment. This exception does not include carcinomatous meningitis, as participants with 
carcinomatous meningitis are excluded regardless of clinical stability.
Tumor Imaging During the Trial
The first on-study imaging assessment should be performed at 9 weeks (63 days ±7 days) 
from the date of allocation. Subsequent tumor imaging should be performed every 9 weeks 
(63 days ±7 days) or more frequently if clinically indicated. After 54 weeks, participants who 
remain on treatment will have imaging performed every 12 weeks (84 ±7 days). Imaging 
 
 
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timing should follow calendar days and should not be adjusted for delays in cycle starts. 
Imaging should continue to be performed until disease progression, the start of new 
anticancer treatment, withdrawal of consent, or death, whichever occurs first. 
Per RECIST 1.1, partial and complete response should be confirmed by a repeat tumor 
imaging assessment not less than 4 weeks from the date the response was first documented. 
The tumor imaging for confirmation of response may be performed at the earliest 4 weeks 
after the first indication of response, or at the next scheduled scan (ie, 9 weeks later), 
whichever is clinically indicated. Participants will then return to regular scheduled imaging, 
starting with the next scheduled imaging time point. Participants who obtain a confirmation 
scan do not need to undergo the next scheduled tumor imaging if it is <4 weeks later; tumor 
imaging may resume at the subsequent scheduled imaging time point.
Per iRECIST, disease progression should be confirmed by the site at least 4 weeks after first 
radiologic evidence of PD in clinically stable participants. Participants who have 
unconfirmed disease progression may continue on treatment at the discretion of the 
investigator until progression is confirmed provided they have met the conditions detailed in 
Section 8.2.2. Participants who obtain a confirmation scan do not need to undergo the next 
scheduled tumor imaging if it is <4 weeks later; tumor imaging may resume at the 
subsequent scheduled imaging time point if clinically stable. Participants who have 
confirmed disease progression as assessed by the site will discontinue the treatment.
iRECIST Assessment of Disease
iRECIST is based on RECIST 1.1 but adapted to account for the unique tumor response seen 
with immunotherapeutic drugs. iRECIST will be used by investigator/local radiology 
reviewers to assess tumor response and progression, and to make treatment decisions. These 
data will be collected in the clinical database. 
When feasible, participants should not be discontinued until progression is confirmed by the 
local investigator/radiology assessment. This allowance to continue treatment despite initial 
radiologic progressive disease (PD) takes into account the observation that some participants 
can have a transient tumor flare in the first few months after the start of immunotherapy, and 
then experience subsequent disease response. Participants who are deemed clinically unstable 
are not required to have repeat tumor imaging for confirmation of PD. Tumor flare includes 
any of the following scenarios:

Worsening of existing target lesion(s)

Worsening of existing nontarget lesion(s)

Development of new lesion(s)
In participants who have shown initial evidence of radiological PD by RECIST 1.1 as 
determined by the site, it is at the discretion of the investigator whether to continue a 
participant on study treatment until repeat imaging is obtained (using iRECIST for 
participant management, see Table 9). This clinical judgment decision by the site investigator 
should be based on the participant’s overall clinical condition, including performance status, 
clinical symptoms, and laboratory data. Participants may receive study treatment and the 
 
 
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tumor assessment should be repeated ≥4 weeks later in order to confirm PD by iRECIST per 
site assessment. Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of 
disease, including worsening of laboratory values

No decline in ECOG performance status 

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites (eg, cord compression) 
requiring urgent alternative medical intervention 
Any participant deemed clinically unstable should be discontinued from trial treatment at 
site-assessed first radiologic evidence of PD and is not required to have repeat imaging for 
PD confirmation.
In determining whether or not the tumor burden has increased or decreased per iRECIST, the 
local site investigator should consider all target and nontarget lesions, as well as any 
incremental new lesion(s).
Scenarios in which PD is not confirmed at repeat imaging if ALL of the following occur by 
iRECIST: 

Target lesion sum of diameters is <20% or <5 mm absolute increase compared with 
nadir

Nontarget disease resulting in initial PD is stable or qualitatively improved

New lesion resulting in initial PD is stable or qualitatively improved 

No incremental new lesion(s) since last evaluation

No incremental new nontarget lesion progression since last evaluation
If repeat imaging does not confirm PD per iRECIST as assessed by the local site investigator 
and the participant continues to be clinically stable, treatment may continue and follow the 
regular imaging schedule. 
Scenarios in which PD is confirmed at repeat imaging if ANY of the following occur by 
iRECIST:

Target lesion sum of diameters remains ≥ 20% and at least 5 mm absolute increase 
compared to nadir

Nontarget disease resulting in initial PD is qualitatively worse

New lesion resulting in initial PD is qualitatively worse

Additional new lesion(s) since last evaluation
 
 
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
Additional new nontarget lesion progression since last evaluation
If repeat imaging confirms PD due to any of the scenarios listed above, participants will be 
discontinued from study therapy.
Additional details about iRECIST are referenced in Merck TIP Sheet for RECIST 1.1 and 
iRECIST.
Table 9
Imaging and Treatment After First Radiologic Evidence of Progressive Disease
Clinically Stable
Clinically Unstable
Imaging
Treatment
Imaging
Treatment
First radiologic 
evidence of PD 
by RECIST 1.1
Repeat 
imaging at >4 
weeks at site 
to confirm PD
May continue study 
treatment at the 
local site 
investigator’s 
discretion while 
awaiting 
confirmatory tumor 
imaging by site by 
iRECIST.
Repeat imaging at 
>4 weeks to 
confirm PD per 
physician 
discretion only
Discontinue 
treatment
Repeat tumor 
imaging 
confirms PD by 
iRECIST at the 
local site
No additional 
imaging 
required
Discontinue 
treatment 
No additional 
imaging required
N/A
Repeat tumor 
imaging shows 
iUPD by 
iRECIST per 
investigator 
assessment
Repeat 
imaging at >4 
weeks at site 
to confirm PD. 
May occur at 
next regularly 
scheduled 
imaging visit
Continue study 
treatment at the 
investigator’s 
discretion.
Repeat imaging at 
>4 weeks to 
confirm PD per 
investigator’s 
discretion only
Discontinue 
treatment
Repeat tumor 
imaging shows 
SD, PR, or CR 
by iRECIST at 
the local site
Continue 
regularly 
scheduled 
imaging 
assessments
Continue study 
treatment at the 
local site 
investigator’s 
discretion
Continue regularly 
scheduled imaging 
assessments
May restart study 
treatment if 
condition has 
improved and/or 
clinically stable per 
investigator’s 
discretion. Next 
tumor image should 
occur according to 
the regular imaging 
schedule outlined 
in the protocol
 
 
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Medical Photography of Cutaneous Lesions
For participants with cutaneous lesions where photography is clinically indicated, qualitative 
digital photography should be performed at the timepoints specified in the SoA. Cutaneous 
lesions are not considered measurable for the purposes of this trial but may be considered as
non-target lesions for tumor assessments by the investigator. Information regarding 
submission and/or retention of the digital photographs is included in the SIM.
ECOG Performance Status
The investigator or qualified designee will assess ECOG status at screening, prior to the 
administration of each dose of trial treatment, and during the follow-up period as specified in 
the SoA.
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of 
the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Laboratory
Manual.
Planned time points for all safety assessments are provided in the SoA.
Physical Examinations
Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exam are described in the SoA. After the first dose 
of trial treatment, new clinically significant abnormal findings should be recorded as AEs.
Directed Physical Exam
For visits that do not required a full physical exam per the SoA, the investigator or qualified 
designee will perform a directed physical exam as clinically indicated. New clinically 
significant abnormal findings should be recorded as AEs.
Vital Signs
The investigator or qualified designee will take vital signs at specified time points as 
indicated in the SoA. Vital signs include temperature, pulse, respiratory rate, and blood 
pressure. Additionally, height and weight will be measured as specified in the SoA.
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the SoA. Clinically significant abnormal findings from the screening 
ECG should be recorded as medical history.  Additional ECGs may be performed as 
 
 
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clinically necessary over the course of the study. Clinically significant abnormal findings for 
any ECGs performed after the first dose of study treatment should be recorded as AEs.
Clinical Safety Laboratory Assessments
Refer to Appendix 5 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
●
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the AE section of the 
case report form (CRF). The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those which are 
not associated with the underlying disease, unless judged by the investigator to be 
more severe than expected for the participant's condition.
●
All protocol-required laboratory assessments, as defined in Appendix 5, must be 
conducted in accordance with the Laboratory Manual and the SoA.
●
If laboratory values from nonprotocol specified laboratory assessments performed at 
the institution’s local laboratory require a change in study participant management or 
are considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
●
For any laboratory tests with values considered clinically significantly abnormal 
during participation in the study or within 30 days after the last dose of study 
treatment, every attempt should be made to perform repeat assessments until the 
values return to normal or baseline or if a new baseline is established as determined 
by the investigator. 
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 participant can be found in the Study 
Laboratory Manual. Refer to the SoA for the schedule of laboratory assessments.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 5. 
Laboratory tests for screening should be performed within 7 days prior to the first dose of 
study treatment. Exceptions are HIV, hepatitis and thyroid serologies, and lipase & amylase, 
which may be performed within 28 days prior to first dose. Predose laboratory safety tests 
can be conducted up to 72 hours prior to dosing. 
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of trial treatment. Unresolved abnormal 
laboratory values that are drug-related AEs should be followed until resolution. Laboratory 
tests do not need to be repeated after the end of treatment if laboratory results are within 
normal range.
 
 
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Pregnancy Testing
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy as described in the SoA. If a 
urine test is positive or not evaluable, a serum test will be required. Participants must be 
excluded/discontinued from the study in the event of a positive or borderline-positive serum 
test result.
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Reportable 
Safety Events 
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 4.
Progression of the cancer under study is not considered an AE as described in Section 8.4.5 
and Appendix 4.
AE, SAEs, and other reportable safety events will be reported by the participant (or, when 
appropriate, by a caregiver, surrogate, or the participant's legally authorized representative). 
The investigator, who is a qualified physician, and any designees are responsible for 
detecting, assessing, documenting, and reporting events that meet the definition of an AE or 
SAE as well as other reportable safety events. Investigators remain responsible for following 
up AE, SAEs, and other reportable safety events for outcome according to Section 8.4.3.
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
but before treatment allocation/randomization must be reported by the investigator if the 
participant is receiving placebo run-in or other run-in treatment, if the event causes the 
participant to be excluded from the study, or is the result of a protocol-specified intervention, 
including but not limited to washout or discontinuation of usual therapy, diet, or a procedure. 
●
All AEs from the time of treatment allocation/randomization through 90 days following 
cessation of study treatment must be reported by the investigator. 
●
All AEs meeting serious criteria, from the time of treatment allocation/randomization 
through 90 days following cessation of study treatment must be reported by the 
investigator. 
●
All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 30 
days following cessation of study treatment if the participant initiates new anticancer 
therapy  must be reported by the investigator. 
●
Additionally, any SAE brought to the attention of an investigator at any time outside of 
the time period specified above must be reported immediately to the Sponsor if the event 
is considered to be drug-related.
 
 
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Investigators are not obligated to actively seek AE or SAE or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study treatment or study participation, the 
investigator must promptly notify the Sponsor.
All initial and follow-up AEs, SAEs and other reportable safety events will be recorded and 
reported to the Sponsor or designee within the time frames as indicated in Table 10.
Table 10
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Time Period
Time Frame to 
Report Event and 
Follow-up 
Information to 
SPONSOR:
Consent to 
Randomization/ 
Allocation
Randomization/ 
Allocation through 
Protocol-Specified 
Follow-up Period
After the 
Protocol 
Specified 
Follow-up 
Period
Non-Serious 
Adverse Event 
(NSAE)
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE)
including 
Cancer and 
Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
-
drug/vaccine 
related.
(Follow 
ongoing to 
outcome)
Within 24 hours of 
learning of event
Pregnancy/Lact
ation Exposure
Report if:
- due to 
intervention
- causes exclusion
Report all
Previously 
reported –
Follow to 
completion/t
ermination; 
report 
outcome
Within 24 hours of 
learning of event
Event of 
Clinical Interest 
(require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- Potential drug-
induced liver injury 
(DILI)
- Require regulatory 
reporting
Not required
Within 24 hours of 
learning of event
Event of 
Clinical Interest 
(Do not require 
regulatory 
reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs and 
those not requiring 
regulatory reporting
Not required
Within 5 calendar 
days of learning of 
event
 
 
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Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AE and/or SAE and other reportable 
safety events. Open-ended and nonleading verbal questioning of the participant is the 
preferred method to inquire about AE occurrence.
Follow-up of AE, SAE and Other Reportable Safety Event Information 
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AE, SAE, and other reportable safety events 
including pregnancy and exposure during breastfeeding, events of clinical interest (ECIs), 
Cancer and Overdose will be followed until resolution, stabilization, until the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). In 
addition, the investigator will make every attempt to follow all nonserious AEs that occur in 
randomized participants for outcome. Further information on follow-up procedures is given 
in Appendix 4.
Regulatory Reporting Requirements for SAE
●
Prompt notification (within 24 hours) by the investigator to the Sponsor of SAE is 
essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study treatment under clinical investigation are met. 
●
The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study treatment under clinical 
investigation. All AEs will be reported to regulatory authorities, IRB/IECs and 
investigators in accordance with all applicable global laws and regulations, ie, per 
ICH Topic E6 (R2) Guidelines for GCP.
●
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy 
and forwarded to investigators as necessary.
●
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAE) from the Sponsor will file 
it along with the IB and will notify the IRB/IEC, if appropriate according to local 
requirements.
Disease-related Events and/or Disease-related Outcomes Not Qualifying as AEs 
or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1. 
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the participants in the study. Any suspected endpoint which upon review 
 
 
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is not progression of the cancer under study will be forwarded to Global Pharmacovigilance
as an SAE within 24 hours of determination that the event is not progression of the cancer 
under study.
Pregnancy and Exposure During Breastfeeding
Although pregnancy and infant exposure during breastfeeding are not considered AEs, any 
pregnancy or infant exposure during breastfeeding in a participant (spontaneously reported to 
the investigator or their designee) that occurs during the study are reportable to the Sponsor.
All reported pregnancies must be followed to the completion/termination of the pregnancy. 
Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, 
blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as 
serious events (Important Medical Events). If the pregnancy continues to term, the outcome 
(health of infant) must also be reported.
Events of Clinical Interest (ECIs)
Selected nonserious and serious adverse events are also known as ECIs and must be reported 
to the Sponsor.
Events of clinical interest for this study include: 
1.
an overdose of Sponsor's product, as defined in Section 8.5, 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 study site guidance for 
assessment and follow-up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-1697 by ≥20% of the indicated dose. No specific information is available on the 
treatment of overdose of MK-1697. In the event of overdose, MK-1697 therapy should be 
discontinued after discussion with the Sponsor and the participant should be observed closely 
for signs of toxicity. Appropriate supportive treatment should be provided if clinically 
indicated.
 
 
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Pharmacokinetics
To further evaluate MK-1697 immunogenicity and exposure in this indication, and also to 
evaluate exposure of the proposed dosing regimen, sample collections for analysis of 
antidrug antibodies (ADA) and PK are currently planned as shown in the SoA. Blood 
samples will be obtained to measure PK of serum MK-1697. The MK-1697 Cmax and Cmin at 
planned visits and times will be summarized. Sample collection, storage and shipment 
instructions will be provided in the Laboratory Manual.
Antidrug Antibodies
Sample collection, storage and shipment instructions for serum samples will be provided in 
the Laboratory Manual. Anti-MK-1697 antibody samples should be drawn according to the 
ADA collection schedule for all participants in the SoA. Every effort should be taken to 
collect samples at 30 days after end of study treatment for ADA. Simultaneous PK sampling 
is required for interpretation of ADA analysis. If additional samples are deemed necessary to 
evaluate the risk of immunogenicity (e.g. at early time points), the remaining content of a PK 
sample (after analysis for drug levels) may be used to perform the analysis for ADA.
Pharmacodynamics
Venous blood samples will be collected for measurement of sLAG-3 and PD-1 target 
engagement. Sample collection, storage and shipment instructions for blood samples will be 
provided in the Laboratory Manual.
Note: If ongoing PK, pharmacodynamic, and/or ADA sampling is deemed to be unnecessary 
by the Sponsor, it may be reduced or discontinued. This will be communicated to sites via an 
administrative letter.
Tumor Biopsies
Tumor biopsies will be collected pre-treatment and in Cycle 2 from the first 10 participants 
enrolled into the HNSCC or CRC expansion cohorts of Part B. An additional, optional biopsy 
will be performed within 4 weeks after disease progression for participants in the HNSCC or 
CRC cohorts of Part B who achieved either a CR, PR, or SD while participating in the study. 
Biopsies will be performed in keeping with local clinical practice. Additional details 
regarding the collection, storage, and shipment of tumor biopsies will be provided in the 
Laboratory Manual.
Biomarkers
To identify novel biomarkers, the following biospecimens to support exploratory analyses of 
cellular components (eg, protein, RNA, DNA, metabolites) and other circulating molecules 
will be collected from all participants in this study as specified in the SoA:

Blood for Genetic Analysis

Peripheral Blood for Immunophenotyping

Blood for circulating tumor DNA
 
 
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
Blood for RNA Analysis

Blood for plasma biomarker analyses

Blood for serum biomarker analyses

Archival and/or recently obtained tumor tissue

Tumor Biopsy
Note: Sampling for the above-mentioned biomarkers may be reduced or discontinued at any 
point during the trial based on collected data. This will be communicated to sites via an 
administrative letter.
Sample collection, storage and shipment instructions for the exploratory biomarker 
specimens will be provided in the laboratory manual.
The sample for genetic analysis will be drawn for HLA genotyping and for planned 
exploratory biomarker research. If the IRB/IEC does not approve of the exploratory genetic 
analysis, or if there is a local law or regulation prohibiting the same, data analysis will be 
limited to HLA. Leftover extracted DNA will be stored for future biomedical research if the 
participant signs the future biomedical research consent.
Future Biomedical Research Sample Collection 
If the participant signs the future biomedical research consent, the following specimens will 
be obtained as part of future biomedical research:

Leftover DNA

Leftover RNA

Leftover plasma from circulating tumor DNA

Leftover plasma from biomarker analyses

Leftover serum from biomarker analyses

Leftover main study tumor
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
above in Section 8.
 
 
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Screening Phase
Approximately 28 days prior to treatment allocation, potential participants will be evaluated 
to determine that they fulfill the entry requirements as set forth in Section 5.1 and Section 
5.2.  Screening procedures may be repeated after consultation with the Sponsor.
Written consent must be obtained prior to performing any protocol specific procedure. 
Results of a test performed prior to the participant signing consent as part of routine 
management are acceptable in lieu of a screening test if performed within the specified time
frame. Screening procedures are to be completed within 28 days prior to the first dose of trial 
treatment except for the following:

Laboratory tests (urinalysis, hematology, chemistry, GGT, and PT/INR & aPTT) are 
to be performed within 7 days prior to the first dose of trial treatment. Exceptions are
lipase & amylase, thyroid, HIV, and hepatitis serology testing, which may be done up 
to 28 days prior to the first dose of trial treatment.

For women of reproductive potential, a urine or serum pregnancy test will be 
performed within 72 hours prior to the first dose of trial treatment. If urine pregnancy 
results cannot be confirmed as negative, a serum pregnancy test will be required 
(performed by the local study site laboratory).

An archival or recently obtained tumor sample should be submitted during screening 
and may have been collected at any point prior to the first dose of treatment.
Treatment Phase
Visit requirements during the Treatment Phase of the study are outlined in Section 1.3 –
Schedule of Activities (SoA). Specific procedure-related details are provided above in 
Section 8 – Study Assessments and Procedures.
Discontinued Participants Continuing to be Monitored in the Study
The End of Treatment/Discontinuation Visit should occur at the time study treatment is 
discontinued for any reason. If the End of Treatment/Discontinuation Visit occurs 30 days 
from the last dose of study treatment, at the time of the mandatory Safety Follow up Visit, 
the Discontinuation Visit procedures and any additional Safety Follow-up procedures should 
be performed. Visit requirements are outlined in Section 1.3. Additional details regarding 
participant withdrawal and discontinuation are presented in Section 7.
Participants who discontinue study treatment but remain in the study should continue to be 
followed as described in the SoA and below in Section 8.11.4.
 
 
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Posttreatment Phase
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anticancer treatment, whichever 
comes first.  
All AEs that occur prior to the Safety Follow-Up Visit should be recorded (up to 30 days 
following end of treatment). Participants with an AE of Grade >1 will be followed until the 
resolution of the AE to Grade 0 to 1 or until the beginning of a new anticancer therapy, 
whichever occurs first.  SAEs that occur within 90 days of the end of treatment, 30 days if
the participant initiates new anticancer therapy less than 30 days after end of treatment, or the 
day new anticancer therapy is initiated if between 30 days and 90 days after end of treatment 
should also be followed and recorded.
Imaging Follow-up Visits
Participants who discontinue treatment for reasons other than verified PD should continue 
with imaging assessments per the protocol-defined schedule until: (1) PD is verified or 
further confirmed by the investigator, (2) initiation of a new anticancer treatment, (3) death, 
(4) withdrawal of consent, or (5) study conclusion or early termination, whichever occurs 
first.
Survival Follow-up Visits
Participants, who experience confirmed disease progression or start a new anticancer therapy 
will move into the Survival Follow-Up Phase and should be contacted by telephone every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the 
study, whichever occurs first.
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor. For 
example, updated survival status may be requested prior to but not limited to an external Data 
Monitoring Committee (eDMC) review, interim and/or final analysis. Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the Sponsor defined time period will be contacted for their survival status (excluding 
participants that have a previously recorded death event in the collection tool).
9. Statistical Analysis Plan 
This section outlines the statistical analysis strategies and procedures for the primary and 
secondary analyses of the study. Exploratory and other nonconfirmatory analyses will be 
outlined in a separate supplemental Statistical Analysis Plan (sSAP).
If, after the study has begun, changes are made to primary and/or secondary objectives, or the 
statistical methods related to those objectives, then the protocol will be amended (consistent 
with ICH Guideline E9). Changes to exploratory or other nonconfirmatory analyses made 
 
 
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after the protocol has been finalized, but prior to final database lock, will be documented in 
the sSAP as needed and referenced in the Clinical Study Report (CSR) for the study. Post 
hoc exploratory analyses will be clearly identified in the CSR.
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full details are 
in the Statistical Analysis Plan (SAP), Section 9.2 through 9.12.
Study Design Overview
Phase 1 trial of MK-1697 in participants with advanced solid 
tumors. The study applies a modified TPI design for dose 
finding.
Treatment Assignment
Participants will be allocated centrally through IVRS/IWRS to 
MK-1697 dose levels.
Analysis Populations
Safety (Primary): All-Subjects-as-Treated (ASaT) and DLT 
evaluable population
PK (Secondary): Per-Protocol (PP)
Efficacy: (Secondary and Exploratory): Full Analysis Set 
(FAS) 
Primary Endpoint(s)

Dose-limiting toxicity (DLT)

Adverse event (AE)

Discontinuing study intervention due to an AE
Secondary Endpoints

Objective response

PK parameters of MK-1697 including AUC, Cmax, and Cmin
Statistical Methods for 
Efficacy/ 
Immunogenicity/ 
Pharmacokinetic 
Analyses
ORR will be estimated using an exact method based on the 
binomial distribution (Clopper-Pearson interval) together with 
its 95% confidence interval. 
Methods for the rest of efficacy analyses are documented in the 
sSAP.
PK parameters of study medicines will be summarized by 
planned visit and time for each dose separately.
Target engagement parameters will be summarized by planned 
visit and time for each dose separately.
Statistical Methods for 
Safety Analyses
Summary statistics will be provided for the safety endpoints as 
appropriate (e.g. counts, percentages). The pool-adjacent-
violators-algorithm [Ji Y, Li Y, Bekele BN 2007] will be used 
to estimate the DLT rates across doses. The estimate of the 
DLT rate among participants treated at RP2D of MK-1697 and 
the 80% Bayesian credible intervals for the estimate will be 
provided for each treatment arm.
 
 
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Interim Analyses
An interim analysis may be conducted to enable future trial 
planning at the Sponsor’s discretion and data will be examined 
on a continuous basis to allow for dose-finding decisions.
For the CRC expansion cohort in Part B, if there are no 
responders among approximately the first 15 evaluable 
participants, the cohort may be stopped early. For the HNSCC 
expansion cohort in Part B, if there are 1 or fewer responders 
among approximately the first 15 evaluable participants, the 
cohort may be stopped early.
Multiplicity
No multiplicity adjustment is planned in this Phase 1 trial.
Sample Size and Power The overall sample size for this study depends on the observed 
DLT profiles of MK-1697. A maximum target sample size of 
122 participants will be used for study planning purposes. 
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The trial is open-label, ie, participants, investigators, and Sponsor personnel will be aware of 
participant treatment assignment after each participant is enrolled and treatment is assigned.  
Allocation to treatment will not be randomized.
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3 – Objectives/Hypotheses 
and Endpoints.
Analysis Endpoints
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Objective response rate is the secondary endpoint in this study. Objective response rate is 
defined as the proportion of participants in the analysis population who experience complete 
response (CR) or partial response (PR) using RECIST 1.1 and iRECIST criteria as assessed 
by investigator review. 
Other efficacy endpoints (e.g., PFS, OS) are exploratory endpoints in this trial and details of 
the analysis plan will be documented in the sSAP. Progression-free survival (PFS) is defined 
as the time from the first dose of study medication to the first documented PD, using 
RECIST 1.1 criteria as assessed by investigator review, or death due to any cause, whichever 
occurs first. Overall survival (OS) is defined as the time from the first dose of study 
medication to death due to any cause. Participants who did not die will be censored on the 
date of last study assessment or contact.
Pharmacokinetic endpoints include serum concentrations of MK-1697, as well as derived PK 
parameters (AUC, Cmax, Cmin).
 
 
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Target engagement of MK-1697 will be measured by total sLAG-3 and PD-1 receptor 
occupancy.
Safety Endpoints
The primary safety endpoint is the number/proportion of participants with DLT(s), AE(s), 
and who discontinue study treatment due to AE(s).  In addition, safety and tolerability will be 
assessed by clinical review of all relevant parameters including AEs, laboratory tests, and 
vital signs.
A description of safety measures is provided in Section 8.3 – Safety Assessments.
Analysis Populations
Safety Analysis Populations
The All-Subjects-as-Treated (ASaT) population will be used for the analysis of safety data in 
this study. The ASaT population consists of all participants who received at least 1 dose of 
study treatment. 
The DLT evaluable population includes ASaT participants that meet the criteria for DLT 
evaluability (eg, finished Cycle 1 without a DLT or experienced a DLT in Cycle 1).
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
Pharmacokinetic Analysis Populations
The Per-Protocol (PP) population will be used for the analysis of PK and target engagement 
data in this study. The PP population consists of the subset of participants who complied with 
the protocol sufficiently to ensure that their data will be likely to exhibit the effects of 
treatment, according to the underlying scientific model. Compliance includes such 
considerations as exposure to treatment, availability of measurements, and the absence of 
major protocol violations. Any participants or data values excluded from the analyses will be 
identified, along with the reasons for exclusion, in the CSR. At the end of the study, all 
participants who were compliant with the study procedures and have available data from at 
least 1 treatment may be included in the PP analysis dataset.
Efficacy Analysis Populations
For the expansion cohorts in Part B, the Full Analysis Set (FAS) population will be used for 
the analyses for both secondary (ORR) and exploratory efficacy data (PFS, OS) in this study. 
It consists of all participants with a baseline scan that demonstrated measurable disease by 
the investigator’s assessment, and who were administered at least 1 dose of study medicine. 
There will be no formal efficacy analysis during dose escalation in Part A, though 
participants in Part A that meet the inclusion criteria for the respective Part B tumor type and 
received the same dose level may be pooled as part of the FAS population.
 
 
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Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives.  Methods related to exploratory endpoints will be described in the sSAP.
Analyses for each Part B expansion cohort will pool Part A participants who meet the 
inclusion criteria for the respective Part B tumor type and received the same dose level.
Statistical Methods for Efficacy Analysis
The statistical methods for efficacy analyses of exploratory nature (PFS, OS) will be 
documented in the sSAP. ORR, along with the confidence interval, will be estimated using 
an exact method based on the binomial distribution [Clopper-Pearson].
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
DLTs, AEs, SAEs, laboratory tests, vital signs, ECG measurements, and physical 
examinations.
Adverse events will be summarized by counts and frequencies for each dose level.  
Laboratory tests, vital signs, and other safety endpoints will be summarized as appropriate 
(eg, counts, percentages).
DLTs will be listed and summarized by dose level. The pool-adjacent-violators algorithm 
(PAVA) [Ji Y, Li Y, Bekele BN 2007], which forces the DLT rate estimates to be 
nondecreasing with increasing dose levels and pools adjacent violators for weighted 
estimates by sample size, will be used to estimate the DLT rates across doses in each 
treatment arm. The estimate of the DLT rate among participants treated at the RP2D and the 
80% Bayesian credible interval based on a prior distribution of Beta (1,1) will be provided.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Demographic and Baseline Characteristics
Demographic variables and baseline characteristics will be summarized.
Pharmacokinetic and Pharmacodynamic Modeling Analysis
PD-1 receptor availability and total s-LAG3 will be summarized by planned visit and time 
for each dose separately.
Pharmacokinetic parameters of study medicines will be summarized by planned visit and 
time for each dose separately. 
Pharmacokinetics and pharmacodynamics modeling analyses will be documented in the 
sSAP.
Interim Analyses
An interim analysis (eg for efficacy) may be conducted to enable future trial planning at the 
Sponsor’s discretion. Data will be examined on a continuous basis to allow for 
dose-escalation decisions and at the end of Part A to make dose-finding decisions.
 
 
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For the CRC expansion cohort in Part B, if there are no responders among approximately the 
first 15 evaluable participants, the cohort may be stopped early. For the HNSCC expansion 
cohort in Part B, if there are 1 or less responders among approximately the first 15 evaluable 
participants, the cohort may be stopped early. An evaluable participant has at least one 
posttreatment tumor assessment that is evaluable. The estimated response rate for the CRC 
expansion cohort in Part B is approximately 1% to 2%, and for the HNSCC expansion
cohort, the estimated response rate is 18% (based on data from KEYNOTE-055). For the 
CRC expansion cohort, if the true response rate is 10%, then there is a ~21% chance of 
declaring futility; if the true response rate is 15%, then there is a ~9% chance of declaring 
futility. For the HSNCC expansion cohort, if the true response rate is 18%, then there is a 
~19% chance of declaring futility. These bars are not binding, and the totality of the data will 
be evaluated before making a decision to discontinue enrollment. The data will be analyzed 
on a continuous basis and enrollment will not be paused in the time between when the 15th
participant in a particular cohort is enrolled and when the interim analysis is performed.
Multiplicity
There will be no multiplicity control in this study.
Sample Size and Power Calculations
For study planning purposes and under the assumption that 3 doses will be tested during dose 
escalation, with up to 14 participants in each of the 3 dose levels, we assume an approximate 
maximum sample size for Part A of 42 participants. In Part B, 2 expansion cohorts will enroll 
up to 40 participants each so we assume an approximate maximum sample size of 80 
participants. The total maximum enrollment for the study across Part A and Part B is 
approximately 122 participants.
The actual sample size will depend on the safety profiles and the number of doses studied as 
well as which expansion cohorts (if any) are discontinued early. 
In Part B, approximately 80 participants (40 in each expansion cohort) are expected to be 
enrolled. The key efficacy endpoint will be the objective response rate based on the 
investigator assessment per RECIST 1.1. Table 11 shows the ORR estimate and its 
associated 80% and 95% CIs (Clopper-Pearson intervals).
 
 
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Table 11
Estimate and 80%, 95% CI of ORR
Sample Size
Number of Responses 
(PR/CR)
ORR
95% CI
80% CI
40
8
20%
(9.1%, 35.6%)
(12.0%, 30.4%)
9
22%
(10.8%, 38.5%)
(14.1%, 33.2%)
10
25%
(12.7%, 41.2%)
(16.2%, 35.9%)
11
28%
(14.6%, 43.9%)
(18.3%, 38.5%)
12
30%
(16.6%, 46.5%)
(20.5%, 41.2%)
20
50%
(33.8%, 66.2%)
(38.8%, 61.2%)
25
62%
(45.8%, 77.3%)
(51.1%, 72.9%)
Subgroup Analyses
Subgroup analyses of efficacy endpoints will be documented in the sSAP. Subgroups of 
interest for this study may include:
1.  Participants with PD-L1 positive tumors
2.  Participants with LAG-3 expression in tumors
3. Participants by HPV status in the HNSCC expansion cohort
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the trial.  Any deviation 
from protocol-directed administration will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
 
 
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10. Supporting Documentation and Operational Considerations
Appendix 1: Regulatory, Ethical and Study Oversight Considerations
Code of Conduct for Clinical Trials
Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc. (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design of clinical trials. In all cases, MSD clinical trials will be conducted in compliance 
with local and/or national regulations (e.g., International Council for Harmonisation Good Clinical Practice [ICH-
GCP]) and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials which are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the full 
control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial. Participants must meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate participants, adequacy of 
facilities and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial 
initiation, sites are evaluated by MSD personnel to assess the ability to successfully conduct the trial. 
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and general principles of Good 
Clinical Practice (GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified 
versus source documentation according to standard operating procedures. Per MSD policies and procedures, if 
fraud, scientific/research misconduct or serious GCP-non-compliance is suspected, the issues are investigated. 
When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review 
committees notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important to 
patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather than 
hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be underpowered 
and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
 
 
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conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics Committee [IEC])
All clinical trials will be reviewed and approved by an IRB/IEC before being initiated at each site. Significant 
changes or revisions to the protocol will be approved by the ethics committee prior to implementation, except 
changes required urgently to protect participant safety that may be enacted in anticipation of ethics committee 
approval. For each site, the ethics committee and MSD will approve the participant informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care. 
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, Sponsor (or representative), ethics committee, and/or regulatory authorities will have access to 
confidential medical records that might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to enroll 
participants in its trials. However, when enrollment is particularly challenging, additional payments may be made to 
compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent on 
chart review to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish 
to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted 
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices. 
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
 
 
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Financial Disclosure
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required. It is the investigator's/subinvestigator's 
responsibility to comply with any such request. 
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
Data Protection
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant names 
or any information which would make the participant identifiable will not be transferred. 
The participant must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee; affiliated institution and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents in 
order to verify worksheet/CRF data. By signing the consent form, the participant agrees to 
this process. If study documents will be photocopied during the process of verifying 
 
 
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worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules 
and regulations.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.
Compliance with Study Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
of the study is solely responsible for determining whether the study and its results are subject
to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD
entries are not limited to FDAAA or the EMA clinical trial directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and site contact information. 
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
 
 
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Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of GCP
(eg, International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline and other 
generally accepted standards of GCP); and all applicable federal, state and local laws, rules 
and regulations relating to the conduct of the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers or from government programs for procedures included as part of the study
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection, and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
 
 
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requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period. No records may be destroyed during 
the retention period without the written approval of the Sponsor. No records may be 
transferred to another location or party without written notification to the Sponsor. 
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available.
Study and Site Closure
The Sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 
In the event the Sponsor prematurely terminates a particular study site, the Sponsor will 
promptly notify that study site’s IRB/IEC.
 
 
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Appendix 2: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease. A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens consented and/or collected in this study as outlined in Section 8.10 will be 
used in various experiments to understand:
o
The biology of how drugs/vaccines work
o
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
o
Other pathways drugs/vaccines may interact with
o
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in the 
future biomedical research substudy.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all participants or legal guardians, at a 
study visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
 
 
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signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons. 
A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research 
In order to optimize the research that can be conducted with future biomedical research
specimens, it is critical to link participant' clinical information with future test results. In 
fact little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like gender, age, medical history and 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 study site, unique codes will be placed on the future biomedical research
specimens. This code is a random number which does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube. 
5. Biorepository Specimen Usage
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses utilizing the future biomedical research specimens may be performed 
by the Sponsor, or an additional third party (eg, a university investigator) designated by 
the Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy 
and confidentiality requirements. Any contracted third party analyses will conform to the 
specific scope of analysis outlined in this substudy. Future biomedical research 
specimens remaining with the third party after specific analysis is performed will be 
reported to the Sponsor.
 
 
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6. Withdrawal From Future Biomedical Research 
Participants may withdraw their consent for future biomedical research and ask that their 
biospecimens not be used for future biomedical research. Participants may withdraw 
consent at any time by contacting the principal investigator for the main study. If medical 
records for the main study are still available, the investigator will contact the Sponsor 
using the designated mailbox (clinical.specimen.management@merck.com). 
Subsequently, the participant's specimens will be flagged in the biorepository and 
restricted to main study use only. If specimens were collected from study participants 
specifically for future biomedical research, these specimens will be removed from the 
biorepository and destroyed. Documentation will be sent to the investigator confirming 
withdrawal and/or destruction, if applicable. It is the responsibility of the investigator to 
inform the participant of completion of the withdrawal and/or destruction, if applicable. 
Any analyses in progress at the time of request for withdrawal/destruction or already 
performed prior to the request being received by the Sponsor will continue to be used as 
part of the overall research study data and results. No new analyses would be generated 
after the request is received.
In the event that the medical records for the main study are no longer available (eg, if the 
investigator is no longer required by regulatory authorities to retain the main study
records) or the specimens have been completely anonymized, there will no longer be a 
link between the participant’s personal information and their specimens. In this situation, 
the request for withdrawal of consent and/or destruction cannot be processed. 
7. Retention of Specimens 
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
 
 
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9. Reporting of Future Biomedical Research Data to Participants
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include: Lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Conference on Harmonization [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
 
 
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Appendix 3:  Contraceptive Guidance and Pregnancy Testing
Definitions 
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below) 
Women in the following categories are not considered WOCBP:
●
Premenarchal
●
Premenopausal female with 1 of the following:
○
Documented hysterectomy
○
Documented bilateral salpingectomy
○
Documented bilateral oophorectomy
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
●
Postmenopausal female
○
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
▪
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). However, in the absence 
of 12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required. 
○
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
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Male Participants
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in Section 5.1: 
●
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
●
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
o
The following are not acceptable methods of contraception:
▪
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea 
method (LAM).
▪
Male condom with cap, diaphragm or sponge with spermicide.
▪
Male and female condom cannot be used together.
○
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
 
 
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Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 12
during the protocol-defined time frame in Section 5.1. 
Table 12
Highly Effective Contraception Methods
Highly Effective Contraceptive Methods That Are User Dependent a
Failure rate of <1% per year when used consistently and correctly.
●
Combined (estrogen- and progestogen- containing ) hormonal contraception b, c
○
Oral 
○
Intravaginal 
○
Transdermal 
○
Injectable
●
Progestogen-only hormonal contraception b, c
○
Oral 
○
Injectable 
Highly Effective Methods That Have Low User Dependency 
Failure rate of <1% per year when used consistently and correctly.
●
Progestogen-only contraceptive implant b, c 
●
Intrauterine hormone-releasing system (IUS) b
●
Intrauterine device (IUD)
●
Bilateral tubal occlusion
●
Vasectomized partner 
A vasectomized partner is a highly effective contraception method provided that the 
partner is the sole male sexual partner of the WOCBP and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
●
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining 
from heterosexual intercourse during the entire period of risk associated with the study 
treatment. The reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the study and the preferred and usual lifestyle of the participant.
Notes: 
Use should be consistent with local regulations regarding the use of contraceptive methods for participants of 
clinical studies. 
a) Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly). 
b) If hormonal contraception efficacy is potentially decreased due to interaction with study treatment, 
condoms must be used in addition to the hormonal contraception during the treatment period and for at least 
120 days after the last dose of study treatment.
c) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable 
hormonal contraceptives are limited to those which inhibit ovulation. 
 
 
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Pregnancy Testing
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test. 
Pregnancy testing will be performed at the timepoints indicated in the SoA and as required 
locally.
Pregnancy testing will be performed whenever an expected menstrual cycle is missed or 
when pregnancy is otherwise suspected.
 
 
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Appendix 4: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definition of AE
AE definition
●
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study treatment, whether or not considered 
related to the study treatment.
●
NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study treatment.
●
NOTE: for purposes of AE definition, study treatment (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, device, 
diagnostic agent or protocol specified procedure whether investigational (including 
placebo or active comparator product) or marketed, manufactured by, licensed by, 
provided by or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
●
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, or are considered clinically significant in the 
medical and scientific judgment of the investigator.
●
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
●
New conditions detected or diagnosed after study treatment administration even though 
it may have been present before the start of the study.
●
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
●
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication. 
●
For all reports of overdose (whether accidental or intentional) with an associated AE, 
the AE term should reflect the clinical symptoms or abnormal test result. An overdose 
of study treatment without any associated clinical symptoms or abnormal laboratory 
results is reported using the terminology “accidental or intentional overdose without 
adverse effect.”
●
Any new cancer (that is not a condition of the study). 
Note: Progression of the cancer under study is not a reportable event. Refer to 
Section 8.4.5 for additional details.
 
 
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Events NOT meeting the AE definition 
●
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE.
●
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
●
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
●
Surgery planned prior to informed consent to treat a pre-existing condition that has not 
worsened.
●
Refer to Section 8.4.5 for protocol specific exceptions
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met 
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
●
The term 'life-threatening' in the definition of 'serious' refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
●
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not an SAE. A pre-existing condition is a clinical condition that is diagnosed 
prior to the use of an MSD product and is documented in the patient’s medical history.
d. Results in persistent or significant disability/incapacity
●
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
●
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, sprained ankle) which may interfere with or prevent everyday life 
functions but do not constitute a substantial disruption.
 
 
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e.
Is a congenital anomaly/birth defect
●
in offspring of participant taking the product regardless of time to diagnosis
f.
Other important medical events:
●
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious.
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
Additional Events Reported in the Same Manner as SAE
Additional events which require reporting in the same manner as SAE
●
In addition to the above criteria, AEs meeting either of the below criteria, although not 
serious per ICH definition, are reportable to the Sponsor in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Recording AE and SAE
AE and SAE recording
●
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related 
to the event.
●
The investigator will record all relevant AE/SAE information on the AE
CRFs/worksheets at each examination.
●
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
●
There may be instances when copies of medical records for certain cases are requested 
by the Sponsor. In this case, all participant identifiers, with the exception of the 
participant number, will be blinded on the copies of the medical records before 
submission to the Sponsor.
●
The investigator will attempt to establish a diagnosis of the event based on signs,
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
 
 
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Assessment of intensity
●
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe.
●
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0. Any AE which changes CTCAE grade over the 
course of a given episode will have each change of grade recorded on the AE
CRFs/worksheets.
●
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
●
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living (ADL).
●
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
●
Grade 4: Life threatening consequences; urgent intervention indicated.
●
Grade 5: Death related to AE.
Assessment of causality
●
Did the Sponsor's product cause the AE?
●
The determination of the likelihood that the Sponsor's product caused the AE will 
be provided by an investigator who is a qualified physician. The investigator’s 
signed/dated initials on the source document or worksheet that supports the 
causality noted on the AE form, ensures that a medically qualified assessment of 
causality was done. This initialed document must be retained for the required 
regulatory time frame. The criteria below are intended as reference guidelines to 
assist the investigator in assessing the likelihood of a relationship between the test 
product and the AE based upon the available information
●
The following components are to be used to assess the relationship between the 
Sponsor's product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the 
Sponsor's product caused the AE:
●
Exposure:  Is there evidence that the participant was actually exposed to the 
Sponsor's product such as:  reliable history, acceptable compliance assessment 
(pill count, diary, etc.), expected pharmacologic effect, or measurement of 
drug/metabolite in bodily specimen?
●
Time Course:  Did the AE follow in a reasonable temporal sequence from 
administration of the Sponsor's product? Is the time of onset of the AE 
compatible with a drug-induced effect (applies to studies with investigational 
medicinal product)?
 
 
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●
Likely Cause:  Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental 
factors
●
Dechallenge: Was the Sponsor's product discontinued or 
dose/exposure/frequency reduced?
●
If yes, did the AE resolve or improve?
●
If yes, this is a positive dechallenge. 
●
If no, this is a negative dechallenge.
(Note:  This criterion is not applicable if:  (1) the AE resulted in death or 
permanent disability; (2) the AE resolved/improved despite continuation of the 
Sponsor's product; (3) the study is a single-dose drug study); or (4) Sponsor's 
product(s) is/are only used one time.)
●
Rechallenge:  Was the participant re-exposed to the Sponsor's product in this 
study?
●
If yes, did the AE recur or worsen?
●
If yes, this is a positive rechallenge. 
●
If no, this is a negative rechallenge.
(Note:  This criterion is not applicable if:  (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study); or (3) 
Sponsor's product(s) is/are used only one time.)
NOTE:  IF A RECHALLENGE IS PLANNED FOR AN AE WHICH WAS SERIOUS 
AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S PRODUCT, OR IF 
RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER 
DOSE MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, 
THE INIRB/IEC.
●
Consistency with Study treatment Profile:Is the clinical/pathological 
presentation of the AE consistent with previous knowledge regarding the 
Sponsor's product or drug class pharmacology or toxicology?
●
The assessment of relationship will be reported on the CRFs/worksheets by an 
investigator who is a qualified physician according to his/her best clinical judgment, 
including consideration of the above elements.
●
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor's product relationship).
●
Yes, there is a reasonable possibility of Sponsor's product relationship:
There is evidence of exposure to the Sponsor's product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor's product is reasonable. 
The AE is more likely explained by the Sponsor's product than by another cause. 
 
 
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●
No, there is not a reasonable possibility of Sponsor's product relationship:
Participant did not receive the Sponsor's product OR temporal sequence of the AE 
onset relative to administration of the Sponsor's product is not reasonable OR the 
AE is more likely explained by another cause than the Sponsor’s product. (Also 
entered for a participant with overdose without an associated AE.)
●
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
●
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it is very 
important that the investigator always make an assessment of causality for every event 
before the initial transmission of the SAE data to the Sponsor.
●
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
●
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements
Follow-up of AE and SAE
●
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
●
New or updated information will be recorded in the CRF.
●
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
●
The primary mechanism for reporting to the Sponsor will be the electronic data 
collection (EDC) tool. 
●
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
●
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form. 
●
Reference Section 8.4.1 for reporting time requirements 
●
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
 
 
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●
After the study is completed at a given site, the EDC tool will be taken off-line to 
prevent the entry of new data or changes to existing data.
●
If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the EDC tool has been taken off-line, then the 
site can report this information on a paper SAE form or by telephone (see next section).
●
Contacts for SAE reporting can be found in the Investigator Trial File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
●
If the EDC tool is not operational, facsimile transmission or secure e-mail of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
●
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
●
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
●
Contacts and instructions for SAE reporting and paper reporting procedures can be 
found in the Investigator Trial File Binder (or equivalent).
 
 
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Appendix 5: Clinical Laboratory Tests 

The tests detailed in Table 13 will be performed by the local laboratory at the 
frequencies specified in Section 1.3 - Schedule of Activities.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 13
Protocol-Required Safety Laboratory Assessments
Hematology
Comprehensive
Chemistry Panel
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (urine or 
serum)a
Hemoglobin
Alkaline phosphatase
Glucose
PT/INR
Platelet count
Alanine aminotransferase
Protein
aPTT or PTT
WBC (total and 
differential)d
Aspartate aminotransferase
Specific gravity 
Total T3 (or FT3), Total T4 
(or FT4), and TSHb,c
RBC
Bicarbonate
Microscopic exam, if 
abnormal results are 
noted
Anti-HCV
Absolute 
lymphocyte countd
Calcium
HCV viral loadc
Absolute 
neutrophil countd
Chloride
HCV genotypec
Creatinine (or 
measured/calculated 
Creatinine Clearance)
anti-HBsc
Glucose
HBsAg 
Phosphorus
Anti-HBc (total and IgM)c
Potassium
HBeAgc
Sodium
anti-HBec
Total bilirubin  
HBV viral loadc
Direct bilirubin
Anti-HDV c
Total protein
GGT
Blood urea nitrogen
Tumor markers (eg, CEA, 
CA-125, CA-19-9)
Cytokine panel
Lipase and Amylase
a.
Perform on women of childbearing potential only. Perform urine pregnancy test first; if it cannot be confirmed as
negative, a serum pregnancy test is required.
b.
T3 is preferred; if not available, Free T3 may be tested. 
c.
If the local laboratory is unable to perform these tests, the site should submit the sample to the central laboratory for 
testing. Details are provided in the Laboratory Manual.
d. 
Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
Investigators must document their review of each laboratory safety report.
 
 
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Appendix 6: Abbreviations
Abbreviation
Definition
ADA
Antidrug antibody
AE
Adverse event
AFP
Alpha-ferroprotein
ALT (SGPT)
Alanine aminotransferase (serum glutamic pyruvic 
transaminase)
ANC
Absolute neutrophil count
aPTT
Activated partial thromboplastin time
AST (SGOT)
Aspartate aminotransferase (serum glutamic oxaloacetic 
transaminase)
AUC
Area under the curve
β-HCG
β-Human Chorionic Gonadotropin
Cmax
Maximum concentration
Cmin
Minimum concentration
CNS
Central nervous system
CR
Complete response
CRC
Colorectal cancer
CrCl
Creatinine clearance
CRP
C-reactive protein
CT
Computed tomography
CTFG
Clinical Trial Facilitation Group
DILI
Drug-induced liver injury
DL
Dose level
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
ECG
Electrocardiograph
ECI
Event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
FT3
Free triiodothyronine
FT4
Free thyroxine
GFR
Glomerular filtration rate
GGT
Gamma-Glutamyl transferase
GVHD
Graft-versus-host disease
HBsAG
Hepatitis B antigen
HBV
Hepatitis B virus
HER-2
Human epidermal growth factor receptor 2
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HNSCC
Head and neck squamous cell cancer
IB
Investigator’s Brochure
ICF
Informed consent form
iCPD
Confirmed progressive disease (by iRECIST)
 
 
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Abbreviation
Definition
IHC
Immunohistochemistry
IMR
Immuno-modulatory receptor
INR
International normalized ratio
irAE
Immune-related AE
iRECIST
modified Response Evaluation Criteria in Solid Tumors 1.1 for 
immune-based therapeutics (iRECIST)
iSD/iPR/iCR
Stable disease/partial response/complete response (by 
iRECIST)
IUD
Intrauterine device
iUPD
Unconfirmed progressive disease (by iRECIST)
IUS
Intrauterine hormone-releasing system
IV
Intravenous
IVRS/IWRS
Interactive voice response system / interactive web response 
system
LAG-3
Lymphocyte activation gene 3
LAM
Lactational amenorrhea method
mAb
Monoclonal antibody
MMR
(DNA) mismatch repair genes 
MRI
Magnetic resonance imaging
mRNA
Messenger RNA
MSI
microsatellite instability
MSS
Microsatellite stable
mTPI
Modified toxicity probability interval
NCI CTCAE
National Cancer Institute Common Terminology Criteria for 
Adverse Events
NHP
Nonhuman primate
NOAEL
No-observed-adverse-effect-level
NSAID
Non-steroidal anti-inflammatory drugs
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
OTC
Over the counter
PD
Progressive disease
PD-1
Programmed cell death protein 1
PD-L1
Programmed death-ligand 1
PFS
Progression-free survival
PICC
Peripherally inserted central catheter
PK
Pharmacokinetics
PR
Partial response
pRBC
Packed red blood cell
PT
Prothrombin
Q3W
Every 3 weeks
RECIST 1.1
Response Evaluation Criteria in Solid Tumors, version 1.1
RNA
Ribonucleic acid
 
 
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Abbreviation
Definition
RP2D
Recommended Phase 2 dose
SAE
Serious adverse event
sLAG-3
Soluble LAG-3
SIM
Site Imaging Manual
SoA
Schedule of Activities
sSAP
Supplemental Statistical Analysis Plan
T1DM
Type 1 diabetes mellitus
T3
Triiodothyronine
Treg
Regulatory T cell
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
WOCBP
Woman of child bearing potential
 
 
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Appendix 7: Description of the iRECIST Process for Assessment of Disease 
Progression
Assessment at Screening and Prior to RECIST 1.1 Progression
Until radiographic disease progression based on RECIST 1.1, there is no distinct iRECIST 
assessment.
Assessment and Decision at RECIST 1.1 Progression
For participants who show evidence of radiological PD by RECIST 1.1 as determined by the 
investigator, the investigator will decide whether to continue a participant on study treatment 
until repeat imaging is obtained (using iRECIST for participant management). This decision 
by the investigator should be based on the participant’s overall clinical condition.
Clinical stability is defined as the following: 

Absence of symptoms and signs indicating clinically significant progression of
disease

No decline in ECOG performance status 

No requirements for intensified management, including increased analgesia, 
radiation, or other palliative care
Any participant deemed clinically unstable should be discontinued from study treatment at 
site-assessed first radiologic evidence of PD and is not required to have repeat tumor imaging 
for confirmation of PD by iRECIST.
If the investigator decides to continue treatment, the participant may continue to receive 
study treatment and the tumor assessment should be repeated 4 to 8 weeks later to confirm 
PD by iRECIST, per investigator assessment. Images should continue to be sent in to the 
central imaging vendor for potential retrospective BICR.
Tumor flare may manifest as any factor causing radiographic progression per RECIST 1.1, 
including:

Increase in the sum of diameters of target lesion(s) identified at baseline to ≥20% and 
≥5 mm from nadir
o
Note: the iRECIST publication uses the terminology “sum of measurements”, but 
“sum of diameters” will be used in this protocol, consistent with the original 
RECIST 1.1 terminology.

Unequivocal progression of non-target lesion(s) identified at baseline

Development of new lesion(s)
iRECIST defines new response categories, including unconfirmed progressive disease 
(iUPD) and confirmed progressive disease (iCPD). For purposes of iRECIST assessment, the 
first visit showing progression according to RECIST 1.1 will be assigned a visit (overall) 
response of iUPD, regardless of which factors caused the progression.
 
 
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At this visit, target and non-target lesions identified at baseline by RECIST 1.1 will be 
assessed as usual.
New lesions will be classified as measurable or non-measurable, using the same size 
thresholds and rules as for baseline lesion assessment in RECIST 1.1. From measurable new 
lesions, up to 5 lesions total (up to 2 per organ), may be selected as New Lesions – Target.  
The sum of diameters of these lesions will be calculated and kept distinct from the sum of 
diameters for target lesions at baseline.  All other new lesions will be followed qualitatively 
as New Lesions – Non-target.
Assessment at the Confirmatory Imaging
On the confirmatory imaging, the participant will be classified as progression confirmed 
(with an overall response of iCPD), or as showing persistent unconfirmed progression (with 
an overall response of iUPD), or as showing disease stability or response (iSD/iPR/iCR).
Confirmation of Progression
Progression is considered confirmed, and the overall response will be iCPD, if ANY of the 
following occurs:

Any of the factors that were the basis for the iUPD at the previous visit show 
worsening
o
For target lesions, worsening is a further increase in the sum of diameters of 
≥5 mm, compared to any prior iUPD time point
o
For non-target lesions, worsening is any significant growth in lesions overall, 
compared to a prior iUPD time point; this does not have to meet the 
“unequivocal” standard of RECIST 1.1
o
For new lesions, worsening is any of these:

An increase in the new lesion sum of diameters by ≥5 mm from a prior iUPD 
time point 

Visible growth of new non-target lesions 

The appearance of additional new lesions

Any new factor appears that would have triggered PD by RECIST 1.1
Persistent iUPD
Progression is considered not confirmed, and the overall response remains iUPD, if:

None of the progression-confirming factors identified above occurs AND

The target lesion sum of diameters (initial target lesions) remains above the initial PD 
threshold (by RECIST 1.1)
 
 
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Additional imaging for confirmation should be scheduled 4 to 8 weeks from the imaging on 
which iUPD is seen. This may correspond to the next visit in the original visit schedule.  The 
assessment of the subsequent confirmation imaging proceeds in an identical manner, with 
possible outcomes of iCPD, iUPD, and iSD/iPR/iCR.
Resolution of iUPD
Progression is considered not confirmed, and the overall response becomes iSD/iPR/iCR, if:

None of the progression-confirming factors identified above occurs, AND

The target lesion sum of diameters (initial target lesions) is not above the initial PD 
threshold. 
The response is classified as iSD or iPR (depending on the sum of diameters of the target 
lesions), or iCR if all lesions resolve.
In this case, the initial iUPD is considered to be pseudo-progression, and the level of 
suspicion for progression is “reset”. This means that the next visit that shows radiographic 
progression, whenever it occurs, is again classified as iUPD by iRECIST, and the 
confirmation process is repeated before a response of iCPD can be assigned.
Management Following the Confirmatory Imaging
If repeat imaging does not confirm PD per iRECIST, as assessed by the investigator, and the 
participant continues to be clinically stable, study treatment may continue and follow the 
regular imaging schedule. If PD is confirmed, participants will be discontinued from study 
treatment.
NOTE: If a participant has confirmed radiographic progression (iCPD) as defined above, but 
the participant is achieving a clinically meaningful benefit, an exception to continue study 
treatment may be considered following consultation with the Sponsor. In this case, if study 
treatment is continued, tumor imaging should continue to be performed following the 
intervals as outlined in Section 1.3 – Schedule of Activities and submitted to the central 
imaging vendor.
Detection of Progression at Visits After Pseudo-progression Resolves
After resolution of pseudo-progression (ie, achievement of iSD/iPR/iCR), iUPD is indicated 
by any of the following events:

Target lesions
o
Sum of diameters reaches the PD threshold (≥20% and ≥5 mm increase from 
nadir) either for the first time, or after resolution of previous pseudo-progression. 
The nadir is always the smallest sum of diameters seen during the entire trial, 
either before or after an instance of pseudo-progression.
 
 
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
Non-target lesions
o
If non-target lesions have never shown unequivocal progression, their doing so for 
the first time results in iUPD.
o
If non-target lesions have shown previous unequivocal progression, and this 
progression has not resolved, iUPD results from any significant further growth of 
non-target lesions, taken as a whole.

New lesions
o
New lesions appear for the first time
o
Additional new lesions appear
o
Previously identified new target lesions show an increase of ≥5 mm in the new 
lesion sum of diameters, from the nadir value of that sum
o
Previously identified non-target lesions show any significant growth
If any of the events above occur, the overall response for that visit is iUPD, and the iUPD 
evaluation process (see Assessment at the Confirmatory Imaging above) is repeated. 
Progression must be confirmed before iCPD can occur.
The decision process is identical to the iUPD confirmation process for the initial PD, with 
one exception:  if new lesions occurred at a prior instance of iUPD, and at the confirmatory 
imaging the burden of new lesions has increased from its smallest value (for new target 
lesions, the sum of diameters is ≥5 mm increased from its nadir), then iUPD cannot resolve 
to iSD or iPR. It will remain iUPD until either a decrease in the new lesion burden allows 
resolution to iSD or iPR, or until a confirmatory factor causes iCPD.
Additional details about iRECIST are provided in the iRECIST publication [Seymour, L., et 
al 2017].
 
 
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