A Phase 1b Study to Evaluate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of MK-0482 in Participants With Relapsed or Refractory Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia
Phase: PHASE1
Conditions: Relapsed or Refractory Acute Myeloid Leukemia, Relapsed or Refractory Chronic Myelomonocytic Leukemia
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
Protocol/Amendment No.: 002-05 A Phase 1b Study 
to Evaluate the Safety, Tolerability, and 
Pharmacokinetics/Pharmacodynamics of MK0482 in 
Participants with Relapsed or Refractory Acute 
Myeloid Leukemia or Chronic Myelomonocytic 
Leukemia
NCT05038800
02-OCT-2023

PRODUCT: MK-0482
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02-OCT-2023
TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 1b Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics/Pharmacodynamics of MK-0482 in Participants with Relapsed or 
Refractory Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia
Protocol Number: 002-05 
Compound Number: MK-0482
Sponsor Name: Merck Sharp & Dohme LLC (hereafter called the Sponsor or MSD)
Legal Registered Address:
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Regulatory Agency Identifying Number(s):
EudraCT
2022-003740-27
IND
154224
EU CT
2023-503580-42
Approval Date: 02 October 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
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
Amendment 5
02-OCT-2023
To add the EU CT number to the list of Regulatory 
Agency Identifying Numbers
Amendment 4
22-MAY-2023
To add a new dose strength 750 mg/vial for MK-
0482
Amendment 3
07-DEC-2022
To add the Eudra CT number to the list of 
Regulatory Agency Identifying Numbers
Amendment 2
11-JUL-2022
To allow participants with relapsed/refractory 
CMML to participate in the dose escalation part of 
the study
Amendment 1
09-JUN-2021
Revisions based on FDA feedback
Original Protocol
02-APR-2021
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 05
Overall Rationale for the Amendment:
To add the EU CT number to the list of Regulatory Agency Identifying Numbers.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
Title Page
Updated Regulatory Agency Identifying 
Numbers
This change was made to address new 
regulatory guidance.
Section Number 
and Name
Description of Change
Brief Rationale
Other Changes in Amendment
Not applicable.
Not applicable.
Not applicable.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................15
1.3
Schedule of Activities...........................................................................................16
1.3.1
Dose Escalation and Expansion...................................................................16
2
INTRODUCTION..........................................................................................................26
2.1
Study Rationale....................................................................................................27
2.2
Background ..........................................................................................................28
2.2.1
Pharmaceutical and Therapeutic Background .............................................28
2.2.1.1
MK-0482 Pharmaceutical and Therapeutic Background...................28
2.2.2
Preclinical and Clinical Studies ...................................................................30
2.2.3
Ongoing Clinical Studies.............................................................................30
2.3
Benefit/Risk Assessment......................................................................................31
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................32
4
STUDY DESIGN............................................................................................................34
4.1
Overall Design......................................................................................................34
4.2
Scientific Rationale for Study Design.................................................................35
4.2.1
Rationale for Endpoints ...............................................................................35
4.2.1.1
Efficacy Endpoints.............................................................................35
4.2.1.2
Safety Endpoints................................................................................36
4.2.1.3
Pharmacokinetic Endpoints ...............................................................36
4.2.1.4
Antidrug Antibodies...........................................................................36
4.2.1.5
Pharmacodynamic Endpoints.............................................................36
4.2.1.6
Planned Exploratory Biomarker Research.........................................36
4.2.1.7
Future Biomedical Research..............................................................38
4.3
Justification for Dose...........................................................................................39
4.3.1
Starting Dose for This Study........................................................................39
4.3.1.1
Rationale for Starting and Maximum Dose of MK-0482..................39
4.3.1.2
Rationale for Dose Interval and Escalation Increments.....................39
4.3.1.3
Accelerated Titration Design.............................................................40
4.3.1.4
Dose Finding Using a Modified Toxicity Probability Interval 
Design ................................................................................................40
4.4
Beginning and End-of-Study Definition ............................................................42
4.4.1
Clinical Criteria for Early Study Termination .............................................42
5
STUDY POPULATION ................................................................................................43
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5.1
Inclusion Criteria.................................................................................................43
5.2
Exclusion Criteria................................................................................................45
5.3
Lifestyle Considerations......................................................................................47
5.3.1
Meals and Dietary Restrictions....................................................................47
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................47
5.3.3
Activity Restrictions ....................................................................................47
5.4
Screen Failures.....................................................................................................47
5.5
Participant Replacement Strategy......................................................................48
6
STUDY INTERVENTION............................................................................................49
6.1
Study Intervention(s) Administered...................................................................49
6.2
Preparation/Handling/Storage/Accountability .................................................51
6.2.1
Dose Preparation..........................................................................................51
6.2.2
Handling, Storage, and Accountability........................................................51
6.3
Measures to Minimize Bias: Randomization and Blinding..............................52
6.3.1
Intervention Assignment..............................................................................52
6.3.2
Stratification.................................................................................................52
6.3.3
Blinding........................................................................................................52
6.4
Study Intervention Compliance..........................................................................52
6.5
Concomitant Therapy..........................................................................................52
6.5.1
Acceptable Concomitant Medications .........................................................52
6.5.2
Prohibited Concomitant Medications ..........................................................53
6.5.3
Rescue Medications and Supportive Care ...................................................53
6.5.3.1
General Supportive Care....................................................................53
6.5.3.2
Tumor Lysis Prophylaxis...................................................................54
6.6
Dose Modification ................................................................................................54
6.6.1
Definition of Dose-limiting Toxicity...........................................................54
6.6.2
Dose Expansion ...........................................................................................55
6.6.3
Timing of Dose Administration...................................................................55
6.6.4
Guidelines for Dose Modification due to Adverse Events ..........................55
6.6.4.1
Dose Modification for MK-0482.......................................................55
6.7
Intervention After the End of the Study............................................................56
6.8
Clinical Supplies Disclosure................................................................................56
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................57
7.1
Discontinuation of Study Intervention...............................................................57
7.2
Participant Withdrawal From the Study...........................................................58
7.3
Lost to Follow-up .................................................................................................58
8
STUDY ASSESSMENTS AND PROCEDURES........................................................59
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8.1
Administrative and General Procedures ...........................................................59
8.1.1
Informed Consent.........................................................................................59
8.1.1.1
General Informed Consent.................................................................60
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................60
8.1.2
Inclusion/Exclusion Criteria ........................................................................60
8.1.3
Participant Identification Card.....................................................................60
8.1.4
Medical History ...........................................................................................61
8.1.5
AML or CMML-related Medical History....................................................61
8.1.6
Prior and Concomitant Medications Review...............................................61
8.1.6.1
Prior Medications...............................................................................61
8.1.6.2
Concomitant Medications..................................................................61
8.1.7
Assignment of Screening Number...............................................................61
8.1.8
Assignment of Treatment/Randomization Number.....................................62
8.1.9
Study Intervention Administration ..............................................................62
8.1.9.1
Timing of Dose Administration.........................................................62
8.1.10
Discontinuation and Withdrawal .................................................................63
8.1.10.1
Withdrawal From Future Biomedical Research ................................63
8.1.11
Participant Blinding/Unblinding..................................................................63
8.1.12
Calibration of Equipment.............................................................................63
8.2
Efficacy Assessments ...........................................................................................64
8.2.1
Disease Assessments....................................................................................64
8.2.1.1
AML or CMML Disease Assessments at Screening/ Baseline .........64
8.2.1.2
AML or CMML Disease Assessments During Study Treatments.....64
8.2.2
Eastern Cooperative Oncology Group Performance Scale..........................64
8.3
Safety Assessments...............................................................................................64
8.3.1
Physical Examinations.................................................................................65
8.3.1.1
Full Physical Examination.................................................................65
8.3.1.2
Directed Physical Examination..........................................................65
8.3.2
Vital Signs....................................................................................................65
8.3.3
Electrocardiograms ......................................................................................65
8.3.4
Clinical Safety Laboratory Assessments .....................................................65
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................66
8.3.5
Pregnancy Testing........................................................................................66
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................67
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................67
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......69
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...69
8.4.4
Regulatory Reporting Requirements for SAE .............................................69
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................69
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................70
8.4.7
Events of Clinical Interest............................................................................70
8.5
Treatment of Overdose........................................................................................71
8.6
Pharmacokinetics.................................................................................................71
8.6.1
Blood Collection for Plasma MK-0482 .......................................................71
8.6.2
Blood Collection for Antidrug Antibodies ..................................................71
8.7
Pharmacodynamics..............................................................................................71
8.8
Biomarkers ...........................................................................................................71
8.8.1
Planned Genetic Analysis Sample Collection..............................................72
8.9
Future Biomedical Research Sample Collection...............................................72
8.10
Health Economics.................................................................................................72
8.11
Visit Requirements...............................................................................................72
8.11.1
Screening......................................................................................................73
8.11.2
Study Intervention Period ............................................................................73
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................73
8.11.3.1
Safety Follow-up Visit.......................................................................74
8.11.3.2
Survival Follow-up Visits..................................................................74
8.11.4
Survival Status .............................................................................................74
9
STATISTICAL ANALYSIS PLAN .............................................................................75
9.1
Statistical Analysis Plan Summary.....................................................................75
9.2
Responsibility for Analyses/In-house Blinding .................................................76
9.3
Hypotheses/Estimation ........................................................................................76
9.4
Analysis Endpoints...............................................................................................76
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..............................76
9.4.2
Safety Endpoints..........................................................................................76
9.5
Analysis Populations............................................................................................77
9.5.1
Safety Analysis Populations ........................................................................77
9.5.2
Pharmacokinetic Analysis Populations........................................................77
9.5.3
Efficacy Analysis Populations.....................................................................77
9.6
Statistical Methods...............................................................................................77
9.6.1
Statistical Methods for Efficacy Analysis....................................................77
9.6.2
Statistical Methods for Safety Analysis.......................................................78
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9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................78
9.6.3.1
Demographic and Baseline Characteristics .......................................78
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis............78
9.7
Interim Analyses ..................................................................................................78
9.8
Multiplicity ...........................................................................................................78
9.9
Sample Size and Power Calculations .................................................................78
9.10
Subgroup Analyses...............................................................................................79
9.11
Compliance (Medication Adherence).................................................................79
9.12
Extent of Exposure...............................................................................................79
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................80
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........80
10.1.1
Code of Conduct for Interventional Clinical Trials .....................................80
10.1.2
Financial Disclosure.....................................................................................82
10.1.3
Data Protection.............................................................................................83
10.1.3.1
Confidentiality of Data ......................................................................83
10.1.3.2
Confidentiality of Participant Records...............................................83
10.1.3.3
Confidentiality of IRB/IEC Information............................................83
10.1.4
Publication Policy........................................................................................84
10.1.5
Compliance with Study Registration and Results Posting Requirements ...84
10.1.6
Compliance with Law, Audit, and Debarment ............................................84
10.1.7
Data Quality Assurance ...............................................................................85
10.1.8
Source Documents .......................................................................................86
10.1.9
Study and Site Closure.................................................................................86
10.2
Appendix 2: Clinical Laboratory Tests..............................................................87
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................89
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................89
10.3.2
Definition of AE ..........................................................................................89
10.3.3
Additional Events Reported in the Same Manner as SAE...........................91
10.3.4
Recording AE and SAE ...............................................................................91
10.3.5
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................94
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................96
10.4.1
Definitions....................................................................................................96
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions ....97
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10.5
Appendix 5: Contraceptive Guidance................................................................99
10.5.1
Definitions....................................................................................................99
10.5.2
Contraceptive Requirements......................................................................100
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................101
10.7
Appendix 7: Country-specific Requirements..................................................105
10.8
Appendix 8: Response Criteria for AML (Modified ELN 2017)...................106
10.9
Appendix 9: Response Criteria for CMML.....................................................109
10.10 Appendix 10: Classification of Tumor Lysis Syndrome.................................112
10.11 Appendix 11: Abbreviations .............................................................................113
11
REFERENCES.............................................................................................................120
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LIST OF TABLES
Table 1
Dose-finding Rules per mTPI Design..............................................................42
Table 2
Adequate Organ Function Laboratory Values .................................................44
Table 3
Study Interventions..........................................................................................50
Table 4
MK-0482 Dose Modification and Treatment Discontinuation Guidelines 
for Drug-related Adverse Events .....................................................................56
Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.................................................................................68
Table 6
Statistical Analysis Plan Summary..................................................................75
Table 7
Confidence Intervals for Different Observed Response Rates ........................79
Table 8
Protocol-required Clinical Laboratory Assessments .......................................87
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LIST OF FIGURES
Figure 1
Part 1 and Part 2 Study Schema.......................................................................15
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1b Study to Evaluate the Safety, Tolerability, and 
Pharmacokinetics/Pharmacodynamics of MK-0482 in Participants with Relapsed or 
Refractory Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia
Short Title: Phase 1b study to evaluate MK-0482 for Relapsed/Refractory AML/CMML
Acronym:
Hypotheses, Objectives, and Endpoints:
In the participant population with relapsed and refractory AML/CMML subtypes of acute 
and chronic myelomonocytic leukemia or acute monoblastic/monocytic leukemia:
Primary Objective
Primary Endpoint
To determine the safety and tolerability and 
to determine a preliminary recommended 
Phase 2 dose of MK-0482 monotherapy
Dose-limiting toxicity
Adverse Events (AEs)
Discontinuing study intervention due to an 
AE
Secondary Objectives
Secondary Endpoints
To characterize the pharmacokinetic (PK) 
profile of MK-0482 monotherapy
Noncompartmental PK parameters
To evaluate antileukemia activity of 
MK-0482 monotherapy in acute myeloid 
leukemia (AML)
The following response endpoints will be 
assessed per 2017 European Leukemia Net 
(ELN) AML response criteria: 
Complete remission (CR),
Composite CR: CR + CR with incomplete 
recovery (CRi)  
Objective response: CR + CRi + partial 
remission (PR)
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Acute myeloid leukaemia
Population
Relapsed/refractory acute myeloid leukemia 
with subtypes of acute myelomonocytic 
leukemia or acute monoblastic/monocytic 
leukemia, and relapsed/refractory chronic 
myelomonocytic leukemia
Study Type
Interventional
Intervention Model
Parallel
This is a multi site study.
Type of Control
No Treatment Control
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 3 years from the time 
the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 30 to 35 participants will be allocated as described in Section 9.9.
Intervention Groups and Duration:
Arm Name Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment Period/
Vaccination 
Regimen
Use
Part 1
MK-0482
100 mg/vial
750 mg/vial
7.5 mg, 25 
mg, 75 mg, 
225 mg, 750 
mg or higher 
if needed
IV Infusion
Q3W up to 35 
cycles
Test 
Product
Part 2
MK-0482
100 mg/vial
750 mg/vial
RP2D
IV Infusion
Q3W up to 35 
cycles
Test 
Product
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Total Number of Intervention Groups/Arms
1
Duration of Participation
Each participant will participate in the study 
for approximately 2 years from the time the 
participant provides documented informed 
consent through the final contact. After a 
screening phase of 21 days, each participant 
will receive assigned intervention for 
approximately 2 years. 
After the end of treatment each participant 
will be followed for 30 days for the 
occurrence of AEs and spontaneously 
reported pregnancy, as described in Section 
8.4. All participants will be followed by 
telephone for overall survival until death, 
withdrawal of consent, or end of the study.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Steering Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 11.
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1.2
Schema
Figure 1
Part 1 and Part 2 Study Schema
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1.3
Schedule of Activities
1.3.1
Dose Escalation and Expansion
Study Period
Screening
Intervention
EOT/  
Discon.
Safety 
FU
Survi-
val FU
Notes
Treatment Cycle
1
2
3
4 to 
35
Scheduled Day per 
Cycle
-21 to -1
1
2
4
8
15
1
8
1
8
1
At time of 
treatment
discon.
30 days 
after 
last 
dose
Q12W
Scheduling Window 
(Days):
-
+1
+1
±3
±3
±3
±
3
±3
±
3
±3
+7
±14
Administrative Procedures
Informed Consent
X
Informed Consent for 
Future Biomedical 
Research
X
If the participant (or their legally 
acceptable representative) provides 
documented informed consent for 
FBR, any leftover sample/tissue 
that would ordinarily be discarded 
will be retained for FBR.
Participation in FBR is optional. 
See Section 8.9.
Inclusion/Exclusion 
Criteria
X
Participant Identification 
Card
X
X
Update on C1D1.
Demographic and 
Medical History
X
Prior Oncology 
Treatment History
X
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Study Period
Screening
Intervention
EOT/  
Discon.
Safety 
FU
Survi-
val FU
Notes
Treatment Cycle
1
2
3
4 to 
35
Scheduled Day per 
Cycle
-21 to -1
1
2
4
8
15
1
8
1
8
1
At time of 
treatment
discon.
30 days 
after 
last 
dose
Q12W
Scheduling Window 
(Days):
-
+1
+1
±3
±3
±3
±
3
±3
±
3
±3
+7
±14
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior medications – Record all 
medications taken within 30 days 
of the first dose of study treatment.
Concomitant medications – Enter 
new medications started during the 
study through 30 days after the last 
dose of study treatment. See 
Section 8.1.6.
MK-0482 
Administration 
X
X
X
X
Study treatment administered on 
Day 1 of each cycle after all 
procedures/ assessments have been 
completed. A 24-hour or longer 
observation period may be 
mandated, if clinically indicated. 
See Section 8.1.9. 
Survival Status
X
X
X
X
X
X
X
X
X
X
X
X
X
Survival FU begins after 
investigator-determined disease 
progression or start of new 
anticancer treatment. In addition, 
on Sponsor request, participants 
may be contacted for survival status 
at any time during the course of the 
study.
Posttreatment 
Anticancer Therapy 
Status
X
X
Enter new medications and 
procedures for cancer therapy 
started after the EOT through 
Survival FU.
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Study Period
Screening
Intervention
EOT/  
Discon.
Safety 
FU
Survi-
val FU
Notes
Treatment Cycle
1
2
3
4 to 
35
Scheduled Day per 
Cycle
-21 to -1
1
2
4
8
15
1
8
1
8
1
At time of 
treatment
discon.
30 days 
after 
last 
dose
Q12W
Scheduling Window 
(Days):
-
+1
+1
±3
±3
±3
±
3
±3
±
3
±3
+7
±14
Disease Assessments and Safety Procedures 
Full Physical 
Examination and Heighta
X
Xb
To be performed by the investigator 
or qualified designee.
Directed Physical 
Examination
X
X
X
X
X
X
X
X
X
Symptom directed as needed. May 
be performed on Day 1 of Cycles 2 
to 4 and every third cycle thereafter 
(ie, Cycle 7, Cycle 10, Cycle 13).
Weight, Vital Signs 
(including oxygen 
saturation)
X
X
X
X
X
X
X
X
X
X
X
Weight to be measured at 
Screening and predose on Day 1 of 
each cycle.
Vital signs and oxygen saturation to 
be collected predose and 10, 30, 
and 60 minutes after MK-0482 
infusion.
For Cycle 1, vital signs and oxygen 
saturation may also be collected 
approximately 24 hours after the 
end of the MK-0482 infusion (see 
Section 8.3.2 for details).
12-lead ECG
X
-----------If clinically indicated-----------
Additional ECGs may be 
performed as clinically indicated.
Chest X-Ray 
X
-----------If clinically indicated-----------
For baseline and symptomatic 
evaluation of chest disease
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Study Period
Screening
Intervention
EOT/  
Discon.
Safety 
FU
Survi-
val FU
Notes
Treatment Cycle
1
2
3
4 to 
35
Scheduled Day per 
Cycle
-21 to -1
1
2
4
8
15
1
8
1
8
1
At time of 
treatment
discon.
30 days 
after 
last 
dose
Q12W
Scheduling Window 
(Days):
-
+1
+1
±3
±3
±3
±
3
±3
±
3
±3
+7
±14
Urine or Serum hCG 
Pregnancy Test 
(WOCBP only) – as per 
local SOP
X
X
(x)
(x)
(x)
X
Perform at Screening and within 
72 hours prior to the start of study 
treatment.
(x) Additional tests may also be 
performed if clinically warranted, 
or as defined by local regulations 
(Appendix 5).
If urine pregnancy test cannot be 
confirmed as negative, a serum 
pregnancy test is required.
Hematology 
(see also Table 8)
X
X
X
X
X
X
X
X
X
X
X
X
X
- Hematology is also part of 
efficacy evaluation in conjunction 
with bone marrow evaluation and 
in addition to CBC with 
differential. Immunoprofiling with 
AML and monocytic panels will be 
performed at screening and at visits 
when bone marrow evaluation is 
performed, when feasible.
- Screening samples must be 
collected within 72 hours prior to 
the start of study treatment (24 
hours for hematological values). If 
screening tests are performed 
within 72 hours prior to study 
treatment, C1D1 can be skipped 
with exception of hematology and 
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
Chemistry (includes 
ALT, AST, bilirubin, 
LDH, also see Table 8)
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation tests 
(PT/INR and aPTT/PTT)
X
X
X
X
X
X
X
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Study Period
Screening
Intervention
EOT/  
Discon.
Safety 
FU
Survi-
val FU
Notes
Treatment Cycle
1
2
3
4 to 
35
Scheduled Day per 
Cycle
-21 to -1
1
2
4
8
15
1
8
1
8
1
At time of 
treatment
discon.
30 days 
after 
last 
dose
Q12W
Scheduling Window 
(Days):
-
+1
+1
±3
±3
±3
±
3
±3
±
3
±3
+7
±14
coagulation tests. These tests must 
be repeated on C1D1 and 
participant meet eligibility prior to 
dosing.
- On subsequent Day 1 visits when 
dosing occurs, all laboratory tests 
must be performed within 72 hours 
prior to dosing.
- Laboratory testing for monitoring 
of TLS on C1D2 and C1D4 should 
be performed as appropriate. Please 
also refer to Appendix 10 for 
details.
- PTT may be performed if the 
local laboratory is unable to 
perform aPTT. Also refer to 
Table 8.
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Study Period
Screening
Intervention
EOT/  
Discon.
Safety 
FU
Survi-
val FU
Notes
Treatment Cycle
1
2
3
4 to 
35
Scheduled Day per 
Cycle
-21 to -1
1
2
4
8
15
1
8
1
8
1
At time of 
treatment
discon.
30 days 
after 
last 
dose
Q12W
Scheduling Window 
(Days):
-
+1
+1
±3
±3
±3
±
3
±3
±
3
±3
+7
±14
Bone Marrow Aspirate 
and Biopsy
X
X
X
X
Screening/baseline sampling to be 
performed within 14 days prior to 
C1D1. Postbaseline sampling to be 
performed prior to C3D1, C5D1, 
C7D1, and then Day1 visit of every 
3 Cycles (to be performed within 7 
days of the scheduled visit) until 
progression or achieving confirmed 
CR. Bone marrow sampling also 
can be performed as clinically 
indicated. Bone marrow 
assessments should include 
pathological assessment and 
immunoprofiling, and other 
assessments (such as cytogenetic) 
as appropriate.
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
Evaluate within 72 hours prior to 
the start of study treatment at 
Screening, pre-treatment on Day 1 
of each cycle and on designated 
days.
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Study Period
Screening
Intervention
EOT/  
Discon.
Safety 
FU
Survi-
val FU
Notes
Treatment Cycle
1
2
3
4 to 
35
Scheduled Day per 
Cycle
-21 to -1
1
2
4
8
15
1
8
1
8
1
At time of 
treatment
discon.
30 days 
after 
last 
dose
Q12W
Scheduling Window 
(Days):
-
+1
+1
±3
±3
±3
±
3
±3
±
3
±3
+7
±14
AE/SAE Review
X
X
X
X
X
X
X
X
X
X
X
X
X
Continuous reporting (see Section 
8.4). Record all AEs and ECIs 
occurring within 30 days after last 
dose of study treatment and SAEs 
for 90 days after the EOT or 
30 days after EOT if the participant 
initiates new anticancer therapy 
(whichever is earlier). Report 
treatment-related SAEs regardless 
of when they occur.
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Study Period
Screening
Intervention
EOT/  
Discon.
Safety 
FU
Survi-
val FU
Notes
Treatment Cycle
1
2
3
4 to 
35
Scheduled Day per 
Cycle
-21 to -1
1
2
4
8
15
1
8
1
8
1
At time of 
treatment
discon.
30 days 
after 
last 
dose
Q12W
Scheduling Window 
(Days):
-
+1
+1
±3
±3
±3
±
3
±3
±
3
±3
+7
±14
Pharmacokinetics/Pharmacodynamics/Future 
Biomedical Research/Biomarkers 
Serum for MK-0482 PK
X
X
X
X
X
X
X
X
X
X
X
Pre- and posttreatment on C1D1, 
C2D1, C3D1, C4D1, C6D1, C8D1, 
and every 4 cycle thereafter. All 
pretreatment should be drawn 
within 24 hours prior to start of 
MK-0482 infusion, and all 
posttreatment except C1D2 should 
be drawn within 30 minutes after 
the end of MK-0482 infusion. 
Additional posttreatment samples: 
C1D2 (22-26 hours after C1D1
dosing), C1D4 (± 1 day), C1D8 
(± 1 day), C1D15 (± 1 day), C2D8 
(± 1 day), and C3D8 (± 1 day) can 
be drawn anytime in the window. 
For EOT, PK can be drawn any 
time of the day. 
Note: PK and ADA samples may be 
used for neutralizing antibody 
assay development and/or 
validation.
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Study Period
Screening
Intervention
EOT/  
Discon.
Safety 
FU
Survi-
val FU
Notes
Treatment Cycle
1
2
3
4 to 
35
Scheduled Day per 
Cycle
-21 to -1
1
2
4
8
15
1
8
1
8
1
At time of 
treatment
discon.
30 days 
after 
last 
dose
Q12W
Scheduling Window 
(Days):
-
+1
+1
±3
±3
±3
±
3
±3
±
3
±3
+7
±14
Blood for Receptor 
Occupancy
X
X
X
X
X
X
X
X
X
X
X
Pretreatment on C1D1, C2D1, 
C3D1, C4D1, C6D1, C8D1, and 
then every 4 cycle thereafter. 
Samples can be drawn anytime on 
C1D2, C1D4, C1D8, C1D15, 
C2D8, C3D8, and EOT.
Serum for Anti-
MK-0482 Antibodies
X
X
X
X
X
Pretreatment on C1D1, C2D1, 
C3D1, C4D1, C6D1, C8D1, every 
4 cycle thereafter, and anytime on 
EOT.
CCI
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AE = adverse event; ALT = alanine aminotransferase; AML = acute myeloid leukemia; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; C1D1 = 
Cycle 1 Day 1; CBC = complete blood count; CR = complete remission; ctDNA = circulating tumor deoxyribonucleic acid; ECG = electrocardiogram; ECI = event of clinical 
interest; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FBR = future biomedical research; FU = follow-up; hCG = beta human chorionic gonadotropin; 
LDH = lactate dehydrogenase; PK = pharmacokinetic; PT/INR = prothrombin time/international normalized ratio; PTT = partial thromboplastin time; Q12W = every 12 weeks; 
SAE = serious adverse event; SOP = standard operating procedure; TLS = tumor lysis syndrome; WOCBP = women of childbearing potential.
a
Height will be measured at Screening only.
b
Full physical examination at C1D1 to be performed within 72 hours before dosing.
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2
INTRODUCTION
AML is a heterogenous hematologic malignancy characterized by the clonal expansion of 
myeloid blasts in the bone marrow, peripheral blood, and potentially other tissues [Dohner, 
H., et al 2015]. AML is the most common form of adult acute leukemia in the US [Carter, J. 
L., et al 2020] with a median age of around 68 years at the initial diagnosis [Shallis, R. M., et 
al 2019]. In 2021 in the US, the estimated number of new AML cases is ~20,240 and the 
estimated number of deaths due to AML is ~ 11,400 [Siegel, R. L., et al 2021]. Despite 
increasing understanding of the underlying biology of AML and the development of several 
new therapies, the 5-year relative survival rate remains low, at about 26% based on 2021 
estimate from SEER [American Cancer Society 2021].
The initial goal of AML treatment is attempting to achieve a CR via chemotherapy (ie, 
induction), followed by postremission treatment (ie, consolidation). The selection of initial 
treatment is multifactorial based on a patient’s age, comorbidity, performance status, 
cytogenetic risk category, molecular profiling, and other medical histories etc. The search for 
a matched sibling or alternative hematopoietic stem cell transplantation donor is an option in 
addition to participation in a clinical study. Younger and physically fit patients are generally 
treated with intensive chemotherapy represented by high-dose cytarabine-based regimens; 
while older and unfit patients will receive therapies with less intensity or opt to receive best 
supportive care only. In the past few years, several targeted therapies have received 
regulatory approval and been integrated into AML treatment regimens including tyrosine 
kinase inhibitors targeting FIL3 mutations, epigenetic modulators targeting IDH1/2 
mutations, anti-CD33 mAb drug conjugates, Bcl-2 inhibitors, and liposomal chemotherapy 
[National Comprehensive Cancer Network 2021]. Even though addition of these new agents 
has improved clinical benefits in subsets of patients, the rate of refractory to initial induction 
and rate of relapse within 1 year of remission are still high in both fit and unfit patients. The 
choice of treatments for refractory and relapsed AML is very limited, which is an area with 
significant unmet medical need.
CMML is a myeloid neoplasm characterized by dysplasia, abnormal production and 
accumulation of monocytic cells with an elevated risk of transforming into acute leukemia. It 
is characterized by 1) persistent monocytosis >1 × 109/L in the peripheral blood; monocytes 
≥10% of white blood cell count) along with dysplastic features in the bone marrow, lack of 
Philadelphia chromosome and BCR-ABL 1 fusion gene; 3) no rearrangement of PDGFRA or 
PDGFRB; 4) fewer than 20% blasts in peripheral blood and bone marrow; and 5) dysplasia 
involving one or more myeloid lineages [Arber, D. A., et al 2016] [Orazi, A., et al 2008]. 
Due to renewed evidence demonstrating clinical, morphological and molecular differences, 
the 2016 WHO classification recommended categorization of CMML into “proliferative” 
(MPN-CMML) and “dysplastic” (MDS-CMML) subtypes based on a white blood cell count 
of ≥13 × 109/L for MPN-CMML [Arber, D. A., et al 2016]. In addition, based on peripheral 
blood and bone marrow blast percentage, CMML can be classified into 3 subcategories; 
CMML-0, a category for cases with ˂2% blasts in peripheral blood and ˂5% blasts in bone 
marrow; CMML-1 for cases with 2 % to 4 % blasts in peripheral blood and/or 5% to 9% 
blasts in bone marrow; and CMML-2 for cases with 5% to 19% blasts in peripheral blood, 
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10% to 19% in bone marrow, and/or when any Auer rods are present [Arber, D. A., et al 
2016].
Therapeutic approaches in CMML have generally been the model for treating the other 
MDS/MPN, with hypomethylating agent treatment for intermediate- and higher-risk patients 
and using these agents as a bridge to allogeneic HCT for those patients deemed to be 
transplant eligible [National Comprehensive Cancer Network 2022] [Patnaik, M. M. 2018]. 
Allogeneic stem cell transplantation remains the only curative option for patients with 
CMML. This modality is however fraught with complications including, acute and chronic 
GVHD, nonrelapse mortality and posttransplant disease relapse [Patnaik, M. M. 2018]. 
Reported median survival time is 20 to 40 months and progression to AML occurs in 
approximately 15% to 30% [Orazi, A., et al 2017] [Geissler K 2021]. These patients have 
strong unmet medical need.
2.1
Study Rationale
Immunoglobulin-like transcript 3 (ILT3, also known as LILRB4), belongs to a family of 
inhibitory cell surface receptors, the LILRBs. The inhibitory ILT members signal via 
multiple cytoplasmic ITIM leading to negative regulations of immune cell activation [Kang, 
X., et al 2016] [van der Touw, W., et al 2017]. 
Expression of ILT3 has been reported on dendritic cells, monocytic myeloid cells, 
macrophages, progenitor mast cells, endothelial cells and osteoclasts. The expression of ILT3 
on myeloid cells and dendritic cells is thought to be involved in immune suppression and 
antigen-specific immune tolerance and is considered contributing to the immunosuppressive 
tumor microenvironments in various human cancers [Kang, X., et al 2016]. 
ILT3 has been found highly expressed in human AML with monocytic differentiations, ie, 
the M4 and M5 subtypes per French-American-British classification [Dobrowolska, H., et al
2013] [Deng M, Gui X, Kim J, Xie L, Chen W, Li Z, et al. 2018]. An in vivo study using 
NSG mouse model inoculated with human monocytic AML THP-1 cells and in vitro study 
using human monocytic AML cell lines THP-1 and MV4-11 showed that ILT3 signaling in 
monocytic AML cells mediates T-cell suppression and promotes tumor cell tissue infiltration 
[Deng M, Gui X, Kim J, Xie L, Chen W, Li Z, et al. 2018]. Furthermore, these functional 
activities of ILT3 could be inhibited by anti-ILT3 antibodies or be abolished in THP-1 and 
MV4-11 cells with the LILRB4 gene being knocked out. APOE has been identified as an 
extracellular binding protein of ILT3 [Deng M, Gui X, Kim J, Xie L, Chen W, Li Z, et al. 
2018].  
Further evaluation by Li et al. [Li, Z., et al 2020] suggested that the intracellular ITIM 
domain of activated ILT3 recruits SHP-2, which activates NFκB. Activation of NFκB results 
in regulations of downstream effectors including uPAR and ARG1, leading to inhibition of 
T-cell proliferation and infiltration of AML cells into tissues. Gui et al. developed a 
humanized antibody to ILT3 h128-3. Disrupting ILT3/APOE interaction using h128-3 could 
reverse T-cell suppression and block AML development in mouse models [Gui, X., et al 
2019]. This research indicates that ILT3 can be a useful target for monocytic AML.
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MK-0482 is a novel humanized IgG4 mAb that binds to ILT3 and, an inhibitory receptor 
expressed on the surface of myeloid immune cells. Based on the preclinical research from the 
Sponsor laboratories, the following were observed: 
1. In vitro assay showed that anti-ILT3 enhanced interferon gamma production in THP-1 
and T-cell coculture assay; 
2. In vivo experiment showed that anti-ILT3 mAb (a mice surrogate of MK-0482 clone 
c52B8) eliminated systemic MV-4-11 growth; 
3. Using PBMC from AML patients, clone 52B8 reduced tumor blast cells and modulated 
Treg in these ILT3 high AML PBMC (unpublished data). 
In non-AML cells, in vitro studies of MK-0482 provide evidence that ILT3 blockade leads to 
dendritic cell activation, T-cell activation in combination with pembrolizumab, and reduction 
of the suppressive function of MDSCs (MK-0482 IB). 
Based on research from the Sponsor and others on the role of ILT3 in monocytic AMLs, 
MK-0482 may play a role as a treatment for the monocytic subtypes of AML.
As for the CMML, it is a myeloid neoplasm characterized by dysplasia, abnormal production 
and accumulation of monocytic cells with ~ 30% to 40% risk of transforming into AML. 
Expression of ILT3 and role in CMML and MDS are unknown. However, Chien et al [Chien, 
K. S., et al 2020] recently investigated LILRB4 expression in 19 CMML, 27 MDS patients, 
and a few healthy volunteers. The study team found that LILRB4 RNA expression was 
increased in CMML patients when compared with MDS patients and healthy controls and 
slightly increased in patients who responded to hypomethylating agents. This study also 
showed that interferon gamma response and CTLA4 signaling genes positively correlated 
with LILRB4 expression in CMML patients. Given that there are no effective treatments 
available for CMML patients with refractory or relapsed disease, exploring clinical effects of 
anti-ILT3 mAb MK-0482 in this this myeloid malignancy is justified.
2.2
Background
Refer to the IB for detailed background information on MK-0482.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
MK-0482 Pharmaceutical and Therapeutic Background 
MK-0482 is a novel, first-in-class, humanized IgG4 mAb with high specificity of binding to 
ILT3, an inhibitory receptor expressed on the surface of myeloid immune cells. Based on in 
vitro data, MK-0482 has high affinity for ILT3, is selective for ILT3 versus other ILT family 
members, and is a potent antagonist of ILT3. MK-0482 has an acceptable preclinical safety 
profile and is in clinical development as an IV immunotherapy for advanced solid tumors, to 
be used as monotherapy or in combination with pembrolizumab to increase antitumor 
efficacy in participants with various tumor indications.
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The ILT family of proteins, also called the leukocyte immunoglobulin-like receptor family, 
contains both activating and inhibitory signaling domains with varying cellular expression 
profiles.
In humans, ILT3 is only expressed in the monocytic myeloid lineage of the immune system 
[Brown, D., et al 2004] [Kang, X., et al 2016] [Cella, M., et al 1997]. Internal mRNA data 
confirm this expression at both the tissue and immune cell level.
In organ transplant studies, expression of ILT3 on DCs is associated with induction of 
antigen-specific tolerance [Chang, C. C., et al 2002] [Brenk, M., et al 2009] [Vlad, G., et al 
2008] [Suciu-Foca, N., et al 2007] [Svajger, U., et al 2008] [Brown, D. P., et al 2009] [Kim-
Schulze, S., et al 2006] [Steinbrink, K., et al 2002] [Penna, G., et al 2005] [Manavalan, J. S., 
et al 2004] [Manavalan, J. S., et al 2003]. Antibody blockade of ILT3 has been shown to 
rescue the T-cell priming capacity of otherwise tolerogenic DCs [Manavalan, J. S., et al 
2003] [Brenk, M., et al 2009] and block the action of allo-specific CD8+ T suppressor cells 
[Chang, C. C., et al 2002].
Elevated levels of a sILT3 has been detected in the serum of patients with NSCLC, 
melanoma, colorectal, and pancreatic cancer compared with healthy controls [Suciu-Foca, 
N., et al 2007] [de Goeje, P. L., et al 2015]. Using a validated sandwich ELISA, internal data 
shows increased sILT3 levels in patient serum samples in the following cancer cohorts: 
multiple myeloma, NSCLC, pancreatic cancer, and colon cancer. It is hypothesized that ILT3 
is overexpressed in MDSCs infiltrating these types of tumors and is shed from the surface of 
these cells into the blood stream.
ILT3 in myeloid cell-driven immune suppression in the tumor microenvironment 
MDSCs are recognized as critical players in the tumor microenvironment [Marvel, D. 2015]. 
Numerous studies have documented the infiltration of tumors with myeloid cells and an 
association of that feature with immunosuppression and resistance to checkpoint inhibitors 
[Kumar V, Patel S, Tcyganov E, Gabrilovich DI. 2016] [Solito, S., et al 2014] [Messmer, M. 
N., et al 2015]. Similarly, elevated numbers of immature “MDSCs” in the peripheral blood of 
cancer patients has been widely reported. Indeed, in patients with previously treated 
metastatic bladder cancer, a high baseline circulating monocytic MDSC count was associated 
with a shorter OS after treatment with nivolumab compared with patients with a low MDSC 
count [Sharma, P., et al 2017]. A role for myeloid cells in the molecular epidemiology of 
resistance to checkpoint inhibitors, including pembrolizumab, has been reported, and ILT3 is 
strongly associated with that myeloid signature. Furthermore, De Goeje et al. have observed 
an inverse correlation between the level of ILT3 expression on circulating MDSCs and 
patient survival in NSCLC [de Goeje, P. L., et al 2015].
Nonclinical studies of an analog of MK-0482 in NOD scid gamma humanized mouse model 
systems reveal its ability to reduce tumor burden and shift cellular phenotypes to a more 
activated state. 
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Study MK-0482-002 will be the first clinical study to evaluate MK-0482 in an AML 
population. Data from in-house preclinical studies have shown the following:  
1. In an in vivo MV-4-11 model, luciferase labeled MV-4-11 cells were injected 
intravenously in female NSG mice and tumor growth was assessed via whole body 
bioluminescence (of note, MV-4-11 is a human monocytic AML cell line). In this 
experiment, mice treated with anti-ILT3 antibody clone c52B8, the parental clone of 
MK-0482, produced significant tumor growth inhibition compared with mice treated with 
a huIgG4 isotype. In the same experiment setting, MV-4-11 cells and human PBMCs 
were injected together in the mice. Mice treated with anti-ILT3 mAb c52B8 also showed 
significant tumor growth inhibition compared with mice treated with the huIgG4 isotype. 
These results indicated that there is likely a direct effect of tumor cell growth inhibition 
by anti-ILT3 on MV-4-11 cells.  
4. In an in vitro assay, human PBMC samples from patient with monocytic AML were 
treated with anti-ILT3 mAb c52B8 and huIgG4. C52B8 reduced tumor blasts and Treg in 
these ILT3 high AML PBMC compared with samples treated with huIgG4. 
Based on in-house preclinical data and those that were published from others (see Section 2 
Introduction), we hypothesized that MK-0482 may have direct effect to control the growth of 
monocytic AML cells.
2.2.2
Preclinical and Clinical Studies
See the MK-0482 IB.
2.2.3
Ongoing Clinical Studies
MK-0482 is currently being evaluated in Study MK-0482-001, an ongoing FIH, Phase 1 
clinical study that includes a dose escalation and confirmation phase in participants with 
advanced solid tumors of any type and a cohort expansion part in participants with select 
tumor types. Study objectives during dose escalation and confirmation include assessing the 
safety, tolerability, PK, and pharmacodynamics, and identifying a preliminary RP2D for 
MK-0482 when used as monotherapy and in combination with the anti PD-1 mAb 
pembrolizumab. 
Based on preliminary data from the Part I dose escalation in study MK-0482-001 (data cutoff 
20-JAN-2021), MK-0482 monotherapy is well tolerated up to doses of 2250 mg Q3W with 
no drug-related Grade 4 or 5 adverse events and no DLTs observed. Of 29 participants who 
received at least 1 dose of MK-0482 monotherapy, 9 participants (31.0%) experienced at 
least 1 treatment-related AE. Most of these AEs were Grade 1 or Grade 2. The treatment-
related AE of pyrexia was observed in 3 of 29 participants (10.3%), the only treatment-
related AE with an incidence ≥5%. No CRS or TLS has been reported for participants who 
have received either MK-0482 as monotherapy or in combination with pembrolizumab.
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2.3
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.
MK-0482 is being studied in study MK-0482-001 in solid tumors as monotherapy and in 
combination with pembrolizumab. MK-0482 monotherapy up to 2250 mg Q3W dosing has 
been well tolerated based on data from 29 participants with advanced solid tumor and no 
clinically significant safety concerns.
MK-0482-002 is the first study of MK-0482 in the refractory/relapsed AML subpopulation 
with monocytic differentiations or refractory/relapsed CMML. Based on preclinical data, 
blocking ILT3 in monocytic AML cells via anti-ILT3 mAb could control monocytic AML 
cell growth, prevent tissue infiltration and reverse suppression of T-cell activity. Therefore, 
there is potential benefit. Given CMML is a myeloid neoplasm with high accumulation of 
monocytic cells, it may also benefit from an anti-ILT3 agent like MK-0482. The safety 
profile of MK-0482 in the monocytic AML or CMML population may be different from that 
in the advanced solid tumor population. Therefore, the initial dose in the MK-0482 002 dose 
escalation is considerably lower, at 7.5 mg. Safety of participants will be closely monitored 
via clinical visits with physical examinations and laboratory tests. Due to the nature of this 
disease, participants are also monitored clinically for the occurrence of TLS and CRS. 
Since effective treatment for refractory and relapsed AML or CMML is very limited, patients 
are encouraged to participate in clinical studies for novel therapies. Participation in this study 
is justified. Benefit and risk will be further evaluated.  
Additional details regarding specific benefits and risks for participants participating in this 
clinical study may be found in the accompanying IB and informed consent documents.
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3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS
In the participant population with relapsed and refractory AML/CMML subtypes of acute 
and chronic myelomonocytic leukemia or acute monoblastic/monocytic leukemia:
Primary Objective
Primary Endpoint
To determine the safety and tolerability and 
to determine a preliminary recommended 
Phase 2 dose of MK-0482 monotherapy
Dose-limiting toxicity
Adverse Events (AEs)
Discontinuing study intervention due to an 
AE
Secondary Objectives
Secondary Endpoints
To characterize the pharmacokinetic (PK) 
profile of MK-0482 monotherapy
Noncompartmental PK parameters
To evaluate antileukemia activity of 
MK-0482 monotherapy in acute myeloid 
leukemia (AML)
The following response endpoints will be 
assessed per 2017 European Leukemia Net 
(ELN) AML response criteria: 
Complete remission (CR),
Composite CR: CR + CR with incomplete 
recovery (CRi)  
Objective response: CR + CRi + partial 
remission (PR)
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
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To evaluate antileukemia activity of 
MK-0482 monotherapy in chronic 
myelomonocytic leukemia (CMML)
Response criteria for CMML: evaluated per 
2015 International Consortium Proposal of 
Uniform Response Criteria for 
Myelodysplastic Syndromes 
(MDS)/Myeloproliferative Neoplasms 
(MPN) in Adults with endpoints including 
CR, PR, complete cytogenetic remission, 
marrow response and clinical benefit as 
appropriate
To evaluate the duration of response (DOR)
For participants who demonstrate CR, CRi, 
or PR, DOR is defined as the time from the 
first documented evidence of CR, CRi, or 
PR until disease progression or death due to 
any cause, whichever occurs first
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4
STUDY DESIGN
4.1
Overall Design
This is a multicenter, open-label, Phase 1b study to evaluate safety, tolerability, PK and 
pharmacodynamics of MK-0482 in participants with relapsed/refractory AML or CMML.  
There are 2 parts in this study: Dose Escalation (Part 1) and Dose Expansion (Part 2).
For Part 1, initial dose escalation will follow an ATD to evaluate 2 low DLs: DL1 of 7.5 mg 
and DL2 of 25 mg, with each group enrolling 1 to 3 participants. Once the study passes DL2, 
further dose escalation will follow the mTPI design [Ji, Y. and Wang, S.-J. 2013] to evaluate 
dose levels of 75 mg, 225 mg, and 750 mg MK-0482, respectively, in accordance with dose 
levels evaluated in the MK-0482-001 study. During this study, a higher dose level up to 
2250 mg may be explored depending on the combined safety, PK, and pharmacodynamics 
data available. Each dose level under mTPI will enroll 3 to 6 participants initially (with at 
least 2 participants with AML) with potential expansion to a maximum of 10 participants 
(with at least 5 participants with AML). 
Progression from one DL to the next higher DL is based on the evaluation of DLT. The ATD 
cohort will end early if a Grade 2 or higher treatment-related toxicity occurs. In that situation, 
the dose level will be evaluated per mTPI. During dose escalation, a higher dose level cannot 
be initiated until the previous lower dose level has cleared DLT. 
Dose finding in Part 1 will end after 10 participants have been treated at any dose level. The 
pool-adjacent-violators algorithm [Ji, Y. and Wang, S.-J. 2013] will be used to estimate the 
DLT rates across doses in each treatment arm under the assumption of monotonicity between 
DLT rates and dose levels. The totality of the data including safety events that occur within 
or beyond the DLT window, tolerability, preliminary antitumor activity, PK, and 
pharmacodynamics across all the dose levels will be considered before deciding a 
preliminary RP2D for carrying forward to Part 2. Approximately 20 participants will be 
enrolled in Part 1. 
Once a preliminary RP2D is identified in Part 1, approximately 10 to 15 additional 
participants with R/R AML will be enrolled at the RP2D for Part 2. The study will enroll 
approximately 30 to 35 participants in total. 
Study will include a screening period of maximum of 21 days. Eligible participants will 
receive study treatment and be monitored carefully via physical examinations and laboratory 
tests for safety. AEs will be evaluated by the investigator per NCI CTCAE 5.0.
Clinical activities will be evaluated for the changes in AML blasts in bone marrow as well as 
in peripheral blood in accordance with ELN 2017 response criteria (Appendix 8). Clinical 
activities for CMML will be evaluated per 2015 International Consortium Proposal of 
Uniform Response Criteria for MDS/MPN in Adults (Appendix 9).
Clinical PK, receptor occupancy, and biomarker sampling will be performed per the 
schedules outlined in the SoA. 
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Intraparticipant dose escalation is allowed for participants who are enrolled into the first 
2 dose levels of Part 1 once they have completed DLT evaluation and once a higher dose 
level has been cleared for DLT if the participants have not progressed. The definition of 
DLTs and criteria for dose modification of MK-0482 are outlined in Section 4.3.1.3 and 
Section 6.6. 
MK-0482 will be administered via IV infusion in a 3-week cycle. Participants will be treated 
until progressive disease, 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 study intervention 
or procedure requirements, participant completes treatment, or administrative reasons 
requiring cessation of treatment. Participants may receive study treatment for up to 35 cycles 
(24 months). In addition, if a participant has not achieved a PR or CR after 6 months of study 
treatment, the investigator should discuss the lack of response to the study treatment and 
other treatment options with the participant. If other alternative treatments with potential 
clinical benefits are available for the participant at that time, study treatment should be 
discontinued.  
Participants who discontinue treatment for reasons other than confirmed progressive disease 
will be followed for disease status until disease progression, initiating a new anticancer 
therapy, withdrawing consent for study participation, or becoming lost to follow-up. 
After confirmed progressive disease, each participant will be contacted by telephone every 
12 weeks (84 ± 14 days) for survival follow-up 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, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Since this is a Phase 1b study, clinical responses are included for efficacy evaluations as 
secondary endpoints, including rate of CR, rate of composite CR (CR + CRi) and objective 
response rate (CR + CRi and PR). The response criteria for AML as defined in the 2017 ELN 
international expert panel recommendations (Appendix 8) are well adapted in the clinical 
field worldwide, which also include response parameters suitable for clinical studies such as 
definition of stable disease, progressive disease, and relapse, etc. The assessments of these 
parameters are developed in accordance with the 2016 WHO classification of myeloid 
neoplasms and acute leukemia [Arber, D. A., et al 2016]. The response criteria for CMML 
will be evaluated per 2015 International Consortium Proposal of Uniform Response Criteria 
for MDS/MPN in Adults as outlined in Appendix 9.
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4.2.1.2
Safety Endpoints
The primary objective of this study is to characterize the safety and tolerability of MK-0482 
as monotherapy. The primary safety analysis will be based on participants who experience 
toxicities as defined by NCI CTCAE 5.0 criteria. Safety will be assessed by quantifying the 
toxicities and grades of toxicities experienced by participants who have received MK-0482 as 
monotherapy.
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.
4.2.1.3
Pharmacokinetic Endpoints
A secondary objective of this study is to characterize the PK profile of MK-0482 after 
administration as a single agent. The serum concentration of this agent will serve as the 
primary readout for the PK, and these data will be used to derive PK parameters of the agent. 
Furthermore, the results of these analyses will be used in conjunction with the 
pharmacodynamics, and safety and exploratory endpoint data to help assess future dosing 
strategies for MK-0482.
4.2.1.4
Antidrug Antibodies
Formation of ADA can potentially confound drug exposures at therapeutic doses and prime 
for subsequent infusion-related toxicity. Antidrug antibody response at the beginning of each 
cycle will be determined to understand drug metabolism, exposure, and safety. The incidence 
of ADA and neutralizing ADA will be evaluated and summarized over time by dose. 
Correlations between the presence/absence of positivity for ADAs and PK and 
pharmacodynamic markers, activity, and safety of MK-0482 will be explored.
4.2.1.5
Pharmacodynamic Endpoints
 
 
 
 
4.2.1.6
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 
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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/pharmacodynamic 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 
predict efficacy or AEs, the data might inform optimal use of therapies in the patient 
population. Furthermore, it is important to evaluate germline DNA variation across the 
genome to interpret tumor-specific DNA mutations.
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 oncology drug 
development include the mutational burden of tumors and the clonality of T-cells in the 
tumor microenvironment. Increased mutational burden (sometimes called a ‘hyper-mutated’ 
state) may generate neoantigen 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 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 cells and blood RNA analyses
Both genome-wide and targeted mRNA expression profiling and sequencing in AML and 
CMML cells, cells from bone marrow, and in blood may be performed to define gene 
signatures that correlate to clinical response to treatment with MK-0482 or other 
immunotherapies. Specific immune-related gene sets (ie, those capturing interferon gamma 
transcriptional pathways, or signatures of genes associated with populations of immune cells) 
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. In addition, genomic translocations, rearrangements, and 
deletions may be assessed, as some of these types of genomic alterations are prognostic 
markers in AML and CMML, and would be important to assess to determine the genomic 
complexity of the disease.
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4.2.1.7
Future Biomedical Research
 
 
 
 
 
 
 
 
 
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4.3
Justification for Dose
4.3.1
Starting Dose for This Study
4.3.1.1
Rationale for Starting and Maximum Dose of MK-0482
MK-0482 Q3W has been evaluated in advanced solid tumors as monotherapy at dose levels 
ranging from 0.2 mg to 2250 mg; and in combination with pembrolizumab 200 mg Q3W in 
dose levels ranging from 7.5 mg to 2250 mg during MK-0482-001. MK-0482 was well 
tolerated in all the dose levels in monotherapy and had an acceptable safety profile in 
combination with pembrolizumab. 
Preliminary PK data show target mediated drug disposition at lower MK-0482 doses while 
linear PK was observed at tested doses ≥75 mg. Near complete receptor occupancy was also 
observed in blood samples from participants treated with MK-0482 at dose levels ≥75 mg. 
Even with stringent assumptions, 750 mg MK-0482 Q3W is likely to maintain complete 
receptor occupancy in the tumor. The terminal t1/2 of MK-0482 at the 750 mg MK-0482 dose 
was 19.5 days when given as monotherapy and 13.7 days when given in combination with 
200 mg pembrolizumab.
While ADA was observed in 16 of 62 participants with evaluable data treated with MK-0482 
doses between 0.2 mg and 750 mg, there was no clear impact of ADA on PK or receptor 
occupancy. A dose-dependent increase in total soluble ILT3 concentration was seen in blood 
samples; however, based on internal investigations, there was no confirmed 
immunosuppressive activity for soluble ILT3.
ILT3 target expression levels in AML/CMML patient blood, relative to patients in other solid 
tumors is unknown. In AML/CMML patients, the safety profile resulting from ILT3 target 
binding is also unknown as this point. Therefore, dose escalation will start at 7.5 mg to rule 
out any unforeseen AEs. In patients with solid tumors, this dose yields minimal target 
engagement in blood at trough concentration (~ 20%). The study will enroll 3 to 6 
participants initially for each cohort at 75 mg, 225 mg, and 750 mg dose levels and will 
increase up to 10 participants as needed per mTPI design (see Table 1). Trough target 
engagement increases substantially between 7.5 and 75 mg in patients with solid tumors, and 
thus safety evaluations in more participants is warranted beyond 25 mg.  
Based on the collective evaluation of data from safety, PK, and receptor occupancy, the 
750 mg dose of MK-0482 was selected as the RP2D in combination with pembrolizumab for 
further evaluation in advanced solid tumors. Complete target engagement is expected to be 
achieved by this dose; however, based on actual data from the dose escalation, a higher dose 
level may be evaluated, if warranted.
4.3.1.2
Rationale for Dose Interval and Escalation Increments
Once complete target engagement is achieved, MK-0482 exhibits a PK profile that is 
consistent with that of other monoclonal antibodies. Preliminary data from MK-0482-001 
suggests that MK-0482 has a half-life of approximately 17 days. A 3-week dose interval is 
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expected to be adequate to maintain complete target engagement at trough in AML/CMML 
patients. A 3-week dosing interval is also being explored in MK-0482-001.
Approximately 3-fold dose escalation increments will be used. While the extent of 
population variability in exposure in AML/CMML patients is not known, a 3-fold difference 
between doses is expected to produce nonoverlapping exposures across doses. The 3-fold 
escalation increments are also being used in MK-0482-001.
4.3.1.3
Accelerated Titration Design
The initial dose escalation will follow an ATD to minimize the number of participants treated 
at potentially subtherapeutic doses of MK-0482. Single participants will be enrolled 
sequentially into the escalating dose levels 7.5 mg and 25 mg, respectively. The transition 
from ATD to mTPI is planned at the next dose level of 75 mg. 
Intraparticipant dose escalation will be allowed for participants in the ATD. Participants may 
undergo dose escalation up to the 75 mg dose level. Intermediate dose levels may be 
evaluated, if warranted. The dose to be tested in each group of participants will be 
communicated to the investigators or designees after the dose-escalation decision meeting for 
the previous dose. Enrollment of up to 3 participants per dose level at ATD is permitted on 
approval by the Sponsor’s medical monitor or designee provided that the first 2 participants 
will receive MK-0482 treatment at least 3 days apart. All participants enrolled at each dose 
level must complete the DLT period before the next dose level is initiated.
The ATD will end when at least 1 of the following occurs:
•
The highest dose level (up to 75 mg) has completed the DLT evaluation period and 
MK-0482 has been determined to be safe and well tolerated in this cohort.
•
Occurrence of a Grade 2 or higher treatment-related toxicity according to 
NCI CTCAE 5.0 during Cycle 1 (ATD ends at that current dose level).
Any time a DLT occurs in the ATD phase, the dose level in which the DLT occurred will be 
expanded at this dose per mTPI guidelines below. If no DLT occurs in the ATD phase, then 
the ATD phase will proceed to the mTPI phase once 1 of the above triggers is met.
4.3.1.4
Dose Finding Using a Modified Toxicity Probability Interval Design
Further dose finding will follow the mTPI design [Ji, Y., et al 2007] with a target DLT rate of 
25%. Dose-escalation and deescalation decisions are based on the mTPI design and depend 
on the number of participants enrolled and number of DLTs observed at the current dose 
level.
A minimum of 3 participants are required at each dose. However, depending on the accrual 
rate, 3 to 6 participants may be enrolled to an open dose level providing that the first 
2 participants receive the first dose at least 3 days apart. In Table 1, the columns indicate the 
numbers of participants treated at the current dose level, and the rows indicate the numbers of 
participants experiencing DLT. The entries of the table are the dose-finding decisions: E, S, 
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D, and DU represent escalating the dose, staying at the same dose, deescalating the dose, and 
excluding the dose from the study due to unacceptable toxicity, respectively. For example, if 
0 of 3 participants at a given dose level develop a DLT, then the dose can escalate to the next 
level. If 2 participants of 3 develop a DLT, the dose will be deescalated to the next lower 
dose level. If 3 of 3 participants develop a DLT, this indicates an unacceptable toxicity at this 
dose. The dose should be deescalated and the current dose will not be explored further. If 1 
of 3 participants at a given dose level develop a DLT, then additional participants should be 
enrolled at that dose level following the rules below.
When adding participants to a dose level in response to a “stay” decision, the number of 
additional participants to be enrolled is capped to minimize the exposure to a dose that may 
be unacceptably toxic (denoted as DU in Table 1). Second, to determine how many more 
participants can be enrolled at the 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 1 of 
3 participants experienced a DLT at a given dose level, no more than an additional 
3 participants should be enrolled at this dose level until additional DLT data are available. 
This dose level would be considered unacceptably toxic if all 3 of the additional participants 
experience a DLT (ie, 4/6 participants with DLT in Table 1). The same principles will be 
applied whether 3, 4, 5, or 6 participants are initially enrolled at that dose level.
A D or DU decision at the lowest dose level will stop the study. An E decision at the highest 
dose level will result in staying at that level. During dose finding, it may be acceptable to 
deescalate to an intermediate dose that was not predefined and not previously studied if 
evaluation of toxicity at such a dose is desired. If this approach is taken, 3 to 6 new 
participants may be enrolled at the new intermediate dose, and the aforementioned rules 
should be used to determine further enrollment at this dose level.
After 10 participants have been enrolled at any of the tested doses (including intermediate
doses), dose finding will stop if the mTPI table indicates “S” for staying at current dose. 
Otherwise, up to 10 new participants may be enrolled at a lower dose if “D” or “DU” is 
indicated, or at a higher dose if “E” is indicated.
The pool-adjacent-violators algorithm [Ji, Y. and Wang, S.-J. 2013] will be used to estimate 
the DLT rates across doses. The dose with an estimated DLT rate closest to 25% will be 
treated as a preliminary MTD. However, the totality of the data will be considered before 
deciding on the dose to carry forward to Part 2, and the escalation schedule may be adjusted 
based on pharmacodynamic, PK, and safety data emerging throughout the study. 
Note that although 25% was the target toxicity rate used to generate the guidelines in 
Table 1, the observed rates of participants with DLTs at the MTD may be slightly above or 
below 25%.
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Table 1
Dose-finding Rules per mTPI Design
Number of Participants With 
At Least 1 DLT
Number of Participants Evaluable for DLT at Current Dose
3
4
5
6
7
8
9
10
0
E
E
E
E
E
E
E
E
1
S
S
S
S
E
E
E
E
2
D
S
S
S
S
S
S
S
3
DU
DU
DU
D
S
S
S
S
4
DU
DU
DU
DU
DU
D
S
5
DU
DU
DU
DU
DU
DU
6
DU
DU
DU
DU
DU
7
DU
DU
DU
DU
8
DU
DU
DU
9
DU
DU
10
DU
D=Deescalate to the next lower dose; DLT=dose-limiting toxicity; DU=The current dose is unacceptably toxic; E=Escalate to the next 
higher dose; mTPI=modified toxicity probability interval; S=Stay at the current dose.
Target toxicity rate = 25%
Flat noninformative prior Beta (1,1) is used as a prior and ε1=ε2=0.03[Ji, Y., et al 2007] [Ji, Y. and Wang, S.-J. 2013] [Ji, Y., et al 
2010].
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator). For purposes of analysis and 
reporting, the overall study ends when the Sponsor receives the last laboratory test result or at 
the time of final contact with the last participant, whichever comes last.
4.4.1
Clinical Criteria for Early Study Termination
Recruitment in the study or at a particular study site may be stopped due to insufficient 
compliance with the protocol, GCP and/or other applicable regulatory requirements, 
procedure-related problems, or if the number of discontinuations for administrative reasons is 
too high.
Early study termination will be the result of the criteria specified below:
1. Incidence or severity of adverse drug reactions in this or other studies suggest a potential 
health hazard to participants
5. Plans to modify or discontinue the development of the study intervention
Ample notification will be provided in the event of Sponsor decision to no longer supply 
MK-0482.
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5
STUDY POPULATION
Male/female participants at least 18 years of age with relapsed or refractory AML or CMML 
will be enrolled in this study.
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Has confirmed diagnosis of AML with myelomonocytic or monoblastic/monocytic 
differentiation per WHO 2016 criteria[Arber, D. A., et al 2016] and with confirmed 
refractory or relapsed disease (ie, ≥5% blast in bone marrow or in peripheral blood) after 
treatment with available therapies known to benefit participant’s AML subtypes.
OR
Has known diagnosis of CMML per WHO criteria [Orazi, A., et al 2017] with confirmed 
refractory or relapsed disease after treatment with available therapies known to be active 
for CMML.
6. Has a WBC count ≤20 × 109/L within 24 hours prior to the first dose of study treatment. 
Note: Hydroxyurea should be used to keep the WBC count maintained ≤20 × 109/L until 
the first dose of study treatment, to the extent that this is possible.
7. Has ECOG performance status of 0 to 2 as assessed within 72 hours prior to the first dose 
of study treatment. 
8. Has adequate organ function as defined in Table 2 and as assessed within 72 hours prior 
to the first dose of study treatment.
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Table 2
Adequate Organ Function Laboratory Values 
System
Laboratory Value
Renal
Measured or calculateda CrCl 
(GFR can also be used in place of CrCl)
≥40 mL/min
Hepatic
Total bilirubin
≤1.5 × ULN or direct bilirubin ≤ULN or
≤3 × ULN if deemed elevated due to 
Gilbert’s disease or leukemia
AST (SGOT) and ALT (SGPT)
≤3 × ULN or 
≤5 × ULN if deemed elevated due to 
leukemia
ALT = alanine aminotransferase; AST = aspartate aminotransferase; CrCl = creatinine clearance; GFR = glomerular filtration rate; 
SGOT = serum glutamic oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; ULN = upper limit of normal.
a
CrCl should be calculated per Cockcroft-Gault formula, as below:
CrCl (male) = ([140-age in years] × weight in kg)/(serum creatinine in mg/dL × 72)
CrCl (female) = CrCl (male) × 0.85
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value requirements should be 
adapted according to local regulations and guidelines for the administration of specific chemotherapies.
Demographics
9. Is male or female, at least 18 years at the time of providing the informed consent.
Female Participants
10. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Not a WOCBP
OR
•
A WOCBP and:
-
Uses a contraceptive method that is highly effective (with a failure rate of <1% per 
year), or be abstinent from heterosexual intercourse as their preferred and usual 
lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 5
during the intervention period and for at least 90 days after the last dose of study 
intervention. The investigator should evaluate the potential for contraceptive method 
failure (ie, noncompliance, recently initiated) in relationship to the first dose of study 
intervention. Contraceptive use by women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies.
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-
Has a negative highly sensitive pregnancy test (urine as required by local regulations) 
within 72 hours before the first dose of study intervention. If a urine test cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. 
In such cases, the participant must be excluded from participation if the serum 
pregnancy result is positive. Additional requirements for pregnancy testing during 
and after study intervention are in Section 8.3.5.
-
Abstains from breastfeeding during the study intervention period and for at least 
90 days after study intervention MK-0482.
-
Medical history, menstrual history, and recent sexual activity has been reviewed by 
the investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
11. The participant (or legally acceptable representative) has provided documented informed
consent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Additional Categories
12. A bone marrow aspirate and biopsy sample will be performed within 14 days of treatment 
start date. Details pertaining to bone marrow biopsy submission can be found in the 
Laboratory Manual.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. Has active CNS leukemia.
Note: Participants with clinical signs of CNS involvement or with suspected CNS 
involvement must have CSF testing to confirm leukemic involvement.
13. Has isolated extramedullary disease, ie, no leukemic involvement in bone marrow or 
peripheral blood.
14. Has diagnosis of acute promyelocytic leukemia or participants with known Ph+ AML.  
15. Has received previous allogeneic stem cell transplant or organ transplant within 60 days 
of the start of study treatment.
Note: Participants with relapsed AML or CMML after allogeneic SCT, including those 
who have received donor lymphocyte infusions, are eligible if they have no active GVHD 
and are off immunosuppression therapy or are taking a maintenance dose of <10 mg daily 
prednisone or equivalent.
Note: Receipt of previous autologous transplant for AML or non-AML condition is 
allowed.
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16. Has a history of a second malignancy, unless potentially curative treatment has been 
completed with no evidence of malignancy for 1 year.
Note: The time requirement does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, superficial bladder cancer, or carcinoma in situ (eg, breast cancer in situ, cervical 
cancer in situ).
17. Has a history of any of the following cardiovascular conditions within 6 months of 
screening: myocardial infarction, unstable angina, cerebrovascular accident, transient 
ischemic attack, coronary artery bypass graft, or pulmonary embolism; has NYHA Class 
III or IV congestive heart failure.
18. Has had a severe hypersensitivity reaction to treatment a mAB and or any components of 
the study intervention, MK-0482.
19. Has an active uncontrolled infection requiring directed therapy.
20. Has immediately life-threatening, severe complications of leukemia such as uncontrolled 
bleeding, pneumonia with hypoxia or shock, or disseminated intravascular coagulation.
21. Has known HIV and/or hepatitis B or C infections or is known to be positive for 
HBsAg/HBV DNA or hepatitis C antibody or RNA. Active hepatitis C is defined by a 
known positive Hep C Ab result and known quantitative HCV RNA results greater than 
the lower limits of detection of the assay. 
22. Has known psychiatric or substance abuse disorders (verbally reported) that would 
interfere with the participant’s ability to cooperate with the requirements of the study.
23. Is pregnant or breast feeding 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 intervention.
Prior/Concomitant Therapy
24. Has received systemic anticancer therapy, radiotherapy, or surgery within 2 weeks before 
the start of study treatment.
Note: Participants must have recovered from all AEs due to previous therapies to 
≤Grade 1 or baseline.
25. Has received hematopoietic cytokines (G-CSF, GM-CSF, or erythropoietin) within 2 
weeks prior to start of study treatment.
26. Has received a live or live attenuated vaccine within 30 days before the first dose of study 
medication. 
Note: Killed vaccines are allowed. Refer to Section 6.5 for information on COVID-19 
vaccines.
27. Has received prior treatment(s) with another agent targeting ILT3.
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Prior/Concurrent Clinical Study Experience
28. Is currently participating and receiving study intervention in a study of an investigational 
agent or has participated and received study intervention in a study of an investigational 
agent or has used an investigational device within 14 days of administration of MK-0482.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 2 weeks since the last dose of the previous 
investigational agent.
Diagnostic Assessments
29. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study medication.
Note: Participants who require intermittent use of nonsystemic steroids such as ocular, 
inhaled, intranasal, topical steroids, or local steroid injections are not excluded from the 
study.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
There are no caffeine, alcohol, or tobacco restrictions.
5.3.3
Activity Restrictions
There are no activity restrictions during participation in this study.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
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5.5
Participant Replacement Strategy
To adequately evaluate the safety of the doses administered in this study, all participants 
enrolled must meet the criteria for evaluability for Cycle 1. Participants are considered 
non-evaluable for DLT evaluation if:
•
They are allocated, but not treated.
•
They discontinue from the study before completing all the safety evaluations for reasons 
other than treatment-related AEs.
•
They receive <75% of the total MK-0482 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 non-evaluable for DLT evaluation will be replaced unless accrual at the 
dose level has stopped. Non-evaluable participants will not be counted toward the total 
number of participants at the dose level for DLT evaluation.
If a participant experiences a DLT in Cycle 1, study intervention may be discontinued; 
however, if the participant is deriving clinical benefit from the study intervention, the 
participant may be allowed to continue after discussion with and approval by the Sponsor.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies will be packaged to support enrollment and replacement participants as 
required. When a replacement participant is required, the Sponsor or designee needs to be 
contacted before dosing the replacement participant. Clinical supplies will be affixed with a 
clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in Table 3.
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Table 3
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Part 1
Experimental MK-0482
Biological/Vaccine Solution
100 mg/vial
750 mg/vial
7.5 mg, 
25 mg, 
75 mg, 
225 mg, 
750 mg 
or higher 
if 
needed
IV Infusion
Q3W up to 
35 cycles
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
Part 2
Experimental MK-0482
Biological/Vaccine Solution
100 mg/vial
750 mg/vial
RP2D
IV Infusion
Q3W up to 
35 cycles
Test 
Product
IMP
Provided 
centrally 
by the 
Sponsor
EEA=European Economic Area; IMP=investigational medicinal product; IV=intravenous; NIMP/AxMP =noninvestigational/auxiliary medicinal product; Q3W=every 3 weeks; RP2D=recommended 
Phase 2 dose.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the 
definition/classification of IMP/NIMP/AxMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 3 will be provided per the “Sourcing” column depending on 
local country operational requirements. If local sourcing, every attempt should be made to 
source these supplies from a single lot/batch number.
Refer to Section 8.1.9 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of MK-0482 are provided in the appropriate 
Pharmacy Manual.
6.2.2
Handling, Storage, and Accountability
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received, and any discrepancies are 
reported and resolved before use of the study intervention.
Only participants enrolled in the study may receive study intervention, and only authorized 
site staff may supply or administer study intervention. All study interventions 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 intervention 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 
interventions in accordance with the protocol and any applicable laws and regulations.
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6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
In Part 1 of the study, treatment will be allocated by nonrandom assignment using an 
IVRS/IWRS based on the dose level evaluated at the time. C1D1 treatment for the first and 
second enrolled participants should be at least 3 days apart. A new dose level group will not 
start until the previous dose level group has been evaluated for DLT and is indicated for dose 
escalation. Part 2 enrollment will be initiated after the RP2D dose is determined and 
treatment will be allocated by nonrandom assignment using an IVRS/IWRS.
6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Refer to Section 6.6.4 for dose modification and toxicity management for irAEs associated 
with MK-0482 and for other allowed dose interruption of MK-0482.
6.5
Concomitant Therapy
Medications specifically prohibited in the exclusion criteria are not allowed during the 
ongoing study. If there is a clinical indication for any medication specifically prohibited, 
discontinuation from study intervention may be required. The investigator should discuss any 
questions regarding this with the Sponsor. The final decision on any supportive therapy rests 
with the investigator and/or the participant’s primary physician; however, the decision to 
continue the participant on study intervention requires the mutual agreement of the 
investigator, the Sponsor, and the participant.
6.5.1
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care except for those that are prohibited as described in Section 6.5.2. All 
concomitant medication will be recorded on the CRF including all prescription, OTC, herbal 
supplements, and IV medications and fluids. If changes occur during the study period, 
documentation of drug dosage, frequency, route, and date may also be included on the CRF.
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All concomitant medications received within 30 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. If 
participants experience an SAE or ECI, all concomitant medications administered after 
30 days after the last dose of study intervention are to be recorded as defined in Section 8.4.
6.5.2
Prohibited Concomitant Medications
•
Participants are prohibited from receiving the following therapies during the screening 
and treatment phases of this study:
•
Antineoplastic systemic chemotherapy or biological therapy
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents 
•
Radiation therapy
Note: Radiation therapy to a symptomatic solitary lesion or to the brain may be allowed 
at the investigator’s discretion with Sponsor consultation after the DLT observation 
period for the participant to be considered evaluable for DLT.
•
Live or attenuated vaccines within 30 days before the first dose of study intervention 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.
Note: Any licensed COVID-19 vaccine (including for Emergency Use) in a particular 
country is allowed in the study as long as they are mRNA vaccines, replication-
incompetent adenoviral vaccines, or inactivated vaccines. These vaccines will be treated 
just as any other concomitant therapy.
•
Systemic glucocorticoids for any purpose other than to modulate symptoms from an AE 
of suspected immunologic etiology. The use of physiologic doses of corticosteroids may 
be approved after consultation with the Sponsor.
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be discontinued from study 
intervention. Participants may receive other medications that the investigator deems to be 
medically necessary.
6.5.3
Rescue Medications and Supportive Care
6.5.3.1
General Supportive Care
Supportive care for managing AML should be given as needed per institution standard such 
as transfusion of leukocyte-depleted blood products (eg, RBC, platelets), prophylaxis and 
treatment for infections. Hydroxyurea can be given in an attempt to maintain WBC to 
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≤20 × 109/L. Growth factors (GM-CSF, G-CSF) may be considered as a part of supportive 
care for postremission therapy; however, it may confound bone marrow evaluation and 
therefore should be off for a minimum of 7 days before obtaining bone marrow for 
evaluation.
6.5.3.2
Tumor Lysis Prophylaxis
Participants with risk for developing TLS should receive prophylaxis treatment, such as with 
allopurinol, extra hydration, and diuretics, etc. per institution standard as clinically indicated. 
Hydroxyurea can be given in an attempt to maintain WBC to <20 × 109/L during treatment 
(see Section 6.5.3.1 and Appendix 10).
6.6
Dose Modification
6.6.1
Definition of Dose-limiting Toxicity
All toxicities will be graded using NCI CTCAE 5.0 based on the investigator assessment.
The DLT window of observation will be 21 days since the first dose of study intervention 
(ie, 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.
1. Grade 4 nonhematologic toxicity (not laboratory).
30. Any Grade 3 nonhematologic toxicity.
Exceptions to the DLT definition: 
-
Grade 3 fatigue lasting ≤3 days
-
Grade 3 diarrhea, nausea, or vomiting without requiring tube feeding, total parenteral 
nutrition, or prolonged hospitalization
-
Grade 3 hypersensitivity reaction that is successfully managed and resolved within 
72 hours
31. Any Grade 3 or Grade 4 nonhematologic laboratory value if:
-
Clinically significant medical intervention is required to treat the participant, or
-
The abnormality leads to hospitalization, or
-
The abnormality persists for >1 week, or
-
Electrolyte imbalances lasting more than 48 hours despite optimal therapy, or
-
The abnormality results in a DILI (see Section 8.4.7 for criteria).
Exceptions to the DLT definition: Grade 3 or Grade 4 isolated abnormalities 
without clinical consequences that is resolved with or without intervention to less 
than Grade 2 in <72 hours.
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32. Grade 4 neutropenia and/or thrombocytopenia, in the absence of active leukemia, lasting 
for more than 14 days.
33. Prolonged delay (>2 weeks) in initiating Cycle 2 due to intervention-related toxicity.
34. Any intervention-related toxicity that causes the participant to discontinue intervention 
during Cycle 1.
35. Missing >25% of MK-0482 dose as a result of drug-related AEs during the first cycle.
36. Grade 5 toxicity.
6.6.2
Dose Expansion
In Part 2 of the study, approximately 10 additional participants with AML will be enrolled 
with preliminary RP2D identified from Part 1.
6.6.3
Timing of Dose Administration
MK-0482 will be administered Q3W as an IV infusion. The reason for any variability in 
administration of MK-0482 outside the protocol-specified window should be documented in 
the participant’s medical record and recorded on the eCRFs.
Every effort should be made to begin the first dose of study intervention on the day of 
allocation or within 3 days of allocation. Subsequent doses will be administered on Day 1 of 
each cycle with a window of ± 3 days. Study intervention should be administered after all 
predose study procedures and assessments have been completed as detailed in Section 1.3.
The Pharmacy Manual contains specific instructions for MK-0482 dose calculation, 
reconstitution, preparation, and administration.
6.6.4
Guidelines for Dose Modification due to Adverse Events
6.6.4.1
Dose Modification for MK-0482
The NCI CTCAE 5.0 must be used to grade the severity of AEs. The investigator may 
attribute each toxicity event to MK-0482 and modify the dose according to Table 4. If a 
participant experiences several toxicities and there are conflicting recommendations, follow 
the most conservative recommendations. Exceptional circumstances to following the dose 
modification tables below may be considered after consultation with the Sponsor.
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Table 4
MK-0482 Dose Modification and Treatment Discontinuation Guidelines for 
Drug-related Adverse Events
Hold/Discontinue
Treatment
Criteria for 
Restarting 
Treatment
Toxicity Management
Hematological Toxicities:

Any Grade 4 
neutropenia or 
thrombocytopenia, in 
the absence of active 
leukemia, lasting for 
more than 14 days
Discontinue
N/A
Symptomatic treatment and 
supportive care at 
investigator’s discretion
Nonhematological Toxicities:

Any Grade 1 
nonhematological 
toxicity 
No 
N/A
N/A

Any Grade 2 
intolerant 
nonhematological 
toxicity except Grade 
2 fatigue
Dose interrupt
If treatment held, 
may be restarted 
when AE resolves 
back to baseline or 
to Grade 1
Symptomatic treatment at 
investigator’s discretion 

Any Grade 3 
nonhematological 
toxicity, clinically 
significant Grade 3 or 
4 laboratory
Dose interrupt 
Treatment may be 
restarted when AE 
resolves back to 
baseline or to Grade 
1 and after Sponsor 
consultation 
Symptomatic treatment at 
investigator’s discretion

Any Grade 4, or 
recurrent Grade 3 
nonhematological 
toxicity 
Discontinue
N/A
Symptomatic treatment at 
investigator’s discretion
AE=adverse event; N/A = not applicable
Participants with dose interruption of more than 2 cycles (>6 weeks + 3 days) should be 
discontinued from study treatment, unless otherwise approved by the Sponsor.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
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7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL
7.1
Discontinuation of Study Intervention
Discontinuation of study intervention does not represent withdrawal from the study.
As certain data on clinical events beyond study intervention 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 intervention. Therefore, all participants 
who discontinue study intervention before completion of the protocol-specified treatment 
period will still continue to be monitored in the study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.1.10 unless the participant has 
withdrawn from the study as specified in Section 7.2.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, 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 intervention.
•
Any prolonged interruption of study intervention beyond the permitted periods, for irAE
management or other allowed dose interruptions, as noted in Section 6.6.4, require 
Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, places the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Unacceptable adverse experiences as described in Section 8.4.
•
Progression or recurrence of any malignancy, or any occurrence of another malignancy 
that requires active treatment.
•
Lack of response (ie, no PR or CR), after 6 months of study treatment.
Note: The investigator should discuss the lack of response to study treatment with the 
Sponsor and the alternative options. If other alternative treatments with potential clinical 
benefits are available for the participant at that time, treatment with MK-0482 should be 
discontinued.
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•
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
•
Investigator’s decision to discontinue treatment.
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6.
For participants who are discontinued from study intervention, but continue to be monitored 
in the study, all visits and procedures, as outlined in the SoA, should be completed.
7.2
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 intervention 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 FBR, are outlined in 
Section 8.1.9. 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.
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.
•
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.
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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 ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
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 used 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), 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 
will be defined in the Procedure Manual and will not exceed what is recommended by
regulatory agencies, IRBs or ethical committees.
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the 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 or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
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 used 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 documented informed consent. At the time of intervention, site 
personnel will add the treatment/randomization number to the participant identification card.
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The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically important by the investigator. Details regarding the disease for 
which the participant has enrolled in the study will be recorded separately and not listed as 
medical history.
8.1.5
AML or CMML-related Medical History
Detailed medical history related to the participant’s AML or CMML should be obtained, 
including, but not limited to date of initial diagnosis, AML or CMML subtype at initial 
diagnosis, identified cytogenetic and molecular genetic aberrations, risk category, initial and 
subsequent treatments for AML or CMML (including history of hematopoietic stem cell 
transplant) and outcomes, date of most recent relapse, etc.
8.1.6
Prior and Concomitant Medications Review
8.1.6.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 30 days before the first dose of study intervention.
8.1.6.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 8.4.
All new anticancer therapy initiated after the study start must be recorded in the eCRF. If a 
participant initiates another anticancer therapy other than the assigned study intervention, the 
study intervention should be discontinued and the participant will move into the Survival 
Follow-up Phase; if a participant initiates a new anticancer therapy within 30 days after the 
last dose of the study intervention, the 30-day Safety Follow-up Visit should occur before the 
first dose of the new therapy.
8.1.7
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 before intervention. Each participant will 
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be assigned only 1 screening number. Screening numbers must not be reused 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/rescreening visit 
requirements are in Section 8.10.1.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be randomly allocated and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. Once a 
treatment/randomization number is assigned to a participant, it can never be reassigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
In a situation where rerandomization of the participants is planned (eg, study extension 
periods), the rerandomization will be based on a new randomization schedule; however, each 
participant will retain his/her original treatment/randomization number. Only the study 
intervention regimen associated with the rerandomization period or phase may change.
8.1.9
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to
the specifications within the Pharmacy Manual. 
Allocation by nonrandom assignment will be done using an IVRS/IWRS. 
Administration of study medication will be witnessed by the investigator and/or study staff.
The total volume of study intervention infused will be compared with the total volume 
prepared to determine compliance with each dose administered.
Refer to Section 6 for dose and treatment details.
8.1.9.1
Timing of Dose Administration
Dosing and schedules are described in Section 6.1.
After the first cycle, study intervention may be administered up to 3 days before or after the 
scheduled dosing date for each infusion due to administrative reasons.
On Day 1 of each cycle, MK-0482 will be administered Q3W at the assigned dose level. 
Sites should make every effort to target infusion timing to be as close to 30 minutes as 
possible. Given the variability of infusion pumps form site to site, a window of minus (-) 
5 minutes and plus (+) 10 minutes is allowed (ie, infusion time is 
30 minutes, -5 min/+10 min). 
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Details on the preparation and administration of MK-0482 is provided in the Pharmacy 
Manual. 
8.1.10
Discontinuation and Withdrawal
Participants who discontinue study intervention before completion of the treatment period
should be encouraged to continue to be followed for all remaining study visits as outlined in 
the SoA and Section 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the final study visit at the time of withdrawal. Any AEs that are 
present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.10.1
Withdrawal From Future Biomedical Research
Participants may withdraw their consent for FBR. Participants may withdraw consent at any 
time by contacting the 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@MSD.com). Subsequently, the participant’s consent for 
FBR will be withdrawn. A letter will be sent from the Sponsor to the investigator confirming 
the withdrawal. It is the responsibility of the investigator to inform the participant of 
completion of withdrawal. Any analyses in progress at the time of request for withdrawal or 
already performed before 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.
If 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.
8.1.11
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.12
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 are reliable and/or reproducible. 
Documentation of equipment calibration must be retained as source documentation at the 
study site.
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8.2
Efficacy Assessments
8.2.1
Disease Assessments
8.2.1.1
AML or CMML Disease Assessments at Screening/ Baseline
Disease status of participant’s AML/CMML will be assessed by the investigator based on 
local laboratory reports. At screening/baseline, bone marrow aspirate and biopsy, peripheral 
blood samples will be collected for CBC and differentials, histopathology evaluation, and 
immunophenotyping (primarily focusing on acute myeloid and monocytic leukemic or 
CMML panels per institutional standard).
Participants with AML must have ≥5% blasts in bone marrow or peripheral blood at baseline 
to be eligible for the study. Blasts count will include myeloblasts, monoblasts, promonocytes, 
and/or megakaryoblasts per WHO criteria for AML [Dohner, H., et al 2017].
Extramedullary disease should be evaluated as clinically indicated per institutional guideline. 
Participants with CNS leukemia or isolated extramedullary lesion (ie, without bone marrow 
or peripheral disease as required per-protocol) should be excluded. For eligible participants, 
locations of extramedullary lesions should be recorded in the CRF.
8.2.1.2
AML or CMML Disease Assessments During Study Treatments
Disease status during the study treatment period will be evaluated by the investigator based 
on local laboratory reports of bone marrow and peripheral blood assessments. 
Extramedullary disease will be evaluated or followed as clinically indicated. Response 
evaluation criteria for AML and CMML as provided in Appendix 8 and Appendix 9, 
respectively will be followed for evaluating disease status at each protocol-specified 
timepoint or as clinically indicated. Details in disease assessment will be recorded in the 
CRF.
8.2.2
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG status at screening, before the 
administration of each dose of study intervention on the day of study treatment, and during 
the follow-up period as specified in the SoA (Section 1.3).
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn 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 Section 8.
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Physical Examinations
A complete physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard during the screening 
period. Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings should be recorded 
as AEs.
8.3.1.2
Directed Physical Examination
For cycles that do not required a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs at screening, before the 
administration of each dose of study intervention, and during the follow-up period as 
specified in the SoA. Vital signs include temperature, resting pulse, resting respiratory rate, 
weight, oxygen saturation, and blood pressure. Height will be measured at Visit 1 only.
8.3.3
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 should be recorded as 
medical history. Additional ECGs may be performed as clinically necessary.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
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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 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (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 intervention, 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.
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
Laboratory tests for screening should be performed within 3 days before the first dose of 
study intervention. After Cycle 1, predose laboratory safety tests can be conducted up to 72 
hours before dosing (24 hours for hematological values) unless otherwise noted on the flow 
charts.
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable before administration of each dose of study intervention. Unresolved 
abnormal laboratory values that are drug-related AEs should be followed until resolution. 
Laboratory tests within the normal range do not need to be repeated after the end of 
treatment.
8.3.5
Pregnancy Testing
• Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing ([urine] as required by local regulations) should be conducted 
within 72 hours of each cycle of study intervention and 30 days posttreatment during 
intervention.
• If a urine test is positive or not evaluable, a serum test will be required.
• Pregnancy testing ([urine] as required by local regulations) should be conducted at the 
end of relevant systemic exposure.
-
Additional serum or urine pregnancy tests may be performed, as determined 
necessary by the investigator or required by local regulation, to establish the absence 
of pregnancy at any time during the participant's participation in the study.
-
Participants must be excluded/discontinued from the study in the event of a positive 
or borderline-positive test result.
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8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6 
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
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 participant provides 
documented informed consent, but before intervention allocation, must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the 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 intervention allocation through 30 days after cessation of study 
intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation through 90 days 
after cessation of study intervention or 30 days after cessation of study intervention if the 
participant initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation through 120 days after cessation of study intervention, or 30 days after 
cessation of study intervention 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 the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
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Investigators are not obligated to actively seek AEs or SAEs 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 the investigator 
considers the event to be reasonably related to the study intervention 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 5.
Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-
specified Follow-
up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
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
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/
Lactation 
Exposure
Report if:
- participant has been 
exposed to any 
protocol-specified 
intervention (eg, 
procedure, washout or 
run-in treatment 
including placebo run-
in)
Report all
Previously 
reported – Follow 
to completion/
termination; 
report outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (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
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse event.
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, 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 3.
8.4.4
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 toward the safety of participants and the 
safety of a study intervention 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 intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements and global laws and 
regulations relating to safety reporting to regulatory authorities, IRB/IECs, and investigators.
Investigator safety reports must be prepared for 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 SAEs) from the Sponsor will file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.4.5
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.
Any pregnancy complication will be reported as an AE or SAE.
The medical reason (example: maternal health or fetal disease) for an elective termination of 
a pregnancy will be reported as an AE or SAE. Prenatal testing showing fetus will be born 
with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
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Pregnancy outcomes of ectopic pregnancy, 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.
8.4.6
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 ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs 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.
2. An elevated AST or ALT laboratory value that is greater than or equal to 3× the ULN and 
an elevated total bilirubin laboratory value that is greater than or equal to 2× the ULN 
and, at the same time, an alkaline phosphatase laboratory value that is less than 2× the 
ULN, as determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing.*
*Note: These criteria are based on 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 Study File Binder (or 
equivalent).
For the time period beginning when the consent form is signed until treatment allocation, any 
ECI, or follow-up to an ECI, that occurs to any participant must be reported within 24 hours 
to the Sponsor if it 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.
For the time period beginning at study intervention allocation through 30 days after cessation 
of study intervention, any ECI, or follow-up to an ECI, whether or not related to the 
Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
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guidelines. Paper reporting procedures can be found in the Investigator Study File Binder (or 
equivalent).
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as any dose exceeding the prescribed 
dose for MK-0482 by ≥20% of the indicated dose. No specific information is available on the 
treatment of overdose of MK-0482. In the event of overdose, MK-0482 may be discontinued 
and the participant should be observed closely for signs of toxicity. Appropriate supportive 
treatment should be provided if clinically indicated.
8.6
Pharmacokinetics
To further evaluate MK-0482 immunogenicity and exposure in this indication, and also to 
evaluate exposure of the proposed dosing regimen, sample collections for analysis of ADA 
and PK are currently planned as shown in Section 1.3. Blood samples will be obtained to 
measure PK of serum MK-0482. The MK-0482 serum Cmax and Ctrough at planned visits and 
times will be summarized. 
8.6.1
Blood Collection for Plasma MK-0482
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Laboratory Manual. 
Pharmacokinetic samples should be drawn according to the PK collection schedule for all 
participants.
8.6.2
Blood Collection for Antidrug Antibodies
Sample collection, storage, and shipment instructions for serum samples will be provided in 
the Laboratory Manual. Anti-MK-0482 samples should be drawn according to the ADA 
collection schedule for all participants (Section 1.3). Simultaneous PK sampling is required 
for interpretation of ADA analysis.
8.7
Pharmacodynamics
Sample collection, storage, and shipment instructions for pharmacodynamic samples will be 
in the Laboratory Manual.
8.8
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 as specified in the SoA:
•
Blood for serum biomarker analysis
•
Blood for receptor occupancy
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•
Blood for exploratory immune cell analyses 
•
Blood for genetic analysis
•
Blood for ctDNA analysis
•
Bone marrow aspirate
Sample collection, storage, and shipment instructions for the exploratory biomarker 
specimens will be in the Laboratory Manual.
8.8.1
Planned Genetic Analysis Sample Collection
The planned genetic analysis sample should be drawn for planned analysis of the association 
between genetic variants in DNA and drug response. This sample will not be collected at the 
site if there is either a local law or regulation prohibiting collection, or if the IRB/IEC does 
not approve the collection of the sample for these purposes. If the sample is collected, 
leftover extracted DNA will be stored for FBR if the participant provides documented 
informed consent for FBR. If the planned genetic analysis is not approved, but FBR is 
approved and consent is given, this sample will be collected for the purpose of FBR.
Sample collection, storage, and shipment instructions for planned genetic analysis samples 
will be provided in the Laboratory Manual. Samples should be collected for planned analysis 
of associations between genetic variants in germline/tumor DNA and drug response. If a 
documented law or regulation prohibits (or local IRB/IEC does not approve) sample 
collection for these purposes, then such samples should not be collected at the corresponding 
sites. Leftover DNA extracted from planned genetic analysis samples will be stored for FBR 
only if participant signs the FBR consent.
8.9
Future Biomedical Research Sample Collection
If the participant provides documented informed consent for FBR, the following specimens 
will be obtained as part of FBR:
•
Leftover DNA for future research
•
Leftover RNA for future research 
•
Leftover blood/serum/plasma
•
Leftover bone marrow
8.10
Health Economics 
Health economics are not evaluated in this study.
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
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8.11.1
Screening
Approximately 21 days before treatment allocation/randomization, potential participants will 
be evaluated to determine that they fulfill the entry requirements as set forth in Section 5.1. 
Screening procedures may be repeated after consultation with the Sponsor.
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame.
Screening procedures are to be completed within 3 days before the first dose of study 
intervention except for the following: 
•
Laboratory tests are to be performed within 72 hours before the first dose of study 
intervention, with the exception of CBC with differential, which must be collected within 
24 hours prior to the first dose of study treatment.
•
Evaluation of ECOG is to be performed within 72 hours before the first dose of study 
intervention.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 72 hours before the first dose of study intervention. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed by 
the local study-site laboratory).
•
A bone marrow aspirate and biopsy sample will be performed within 14 days of treatment 
start date. Details pertaining to bone marrow biopsy submission can be found in the 
Laboratory Manual.
8.11.2
Study Intervention Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, 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.
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8.11.3.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
All AEs that occur before the Safety Follow-up Visit should be recorded (up to 30 days after 
the end of treatment).
8.11.3.2
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 (± 14 days) to assess for survival status until death, withdrawal of consent, or the 
end of the study, whichever occurs first.
The Sponsor may request survival status be assessed at additional time points during the 
course of the study. For example, these additional time points may be requested before an 
efficacy interim analysis, and/or final analysis. All participants who are not known to have 
died before the request for these additional survival status time points will be contacted at 
that time.
8.11.4
Survival Status
To ensure current and complete survival data are 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 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).
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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 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 
after the protocol has been finalized, but before the conduct of any analyses, will be 
documented in the sSAP as needed and referenced in the CSR for the study. Post hoc 
exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
A summary of the SAP is provided in Table 6. Full details are in the SAP, Section 9.2 to 
9.12.
Table 6
Statistical Analysis Plan Summary
Study Design Overview
Phase 1b study to evaluate the safety, tolerability, and 
pharmacokinetics/pharmacodynamics of MK-0482 in participants with 
relapsed or refractory acute myeloid leukemia or chronic myelomonocytic 
leukemia. The study applies an accelerated titration design followed with a 
mTPI design for dose finding.
Intervention Assignment
Participants will be allocated centrally through IRT by nonrandom 
assignment. 
Analysis Populations
Safety (Primary): All Participants as Treated (APaT)
PK (Secondary): Per-Protocol (PP)
Efficacy (Secondary): Full Analysis Set (FAS) 
Primary Endpoint(s)

DLTs

AEs

Discontinuations of study intervention due to an AE 
Secondary Endpoints

Noncompartmental PK parameters

CR rate, composite CR rate, ORR in AML
Statistical Methods for 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
PK parameters of study medicines will be summarized by planned visit and 
time for each dose separately.
Point estimates and the corresponding 95% CIs will be provided for CR rate, 
composite CR rate, and ORR using the Clopper and Pearson method 
[Clopper, C. J. 1934].
Exploratory efficacy analyses are documented in the sSAP.
Statistical Methods for Safety 
Analyses
Summary statistics will be provided for the safety endpoints as appropriate. 
The pool-adjacent-violators algorithm [Ji, Y., et al 2007] will be used to 
estimate the DLT rates across doses. The estimate of the DLT rate among 
participants treated at RP2D of MK-0482 and the 80% Bayesian credible 
intervals for the estimate will be provided.
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Interim Analyses
There are no planned interim analyses for this study.
Multiplicity
No multiplicity adjustment is planned in this Phase 1 study.
Sample Size and Power
The overall sample size for this study depends on the observed DLT profiles 
of MK-0482. A target sample size of 30 to 35 participants will be used for 
study planning purposes.
APaT = All Participants as Treated; CI = confidence interval; DLT = Dose-Limiting Toxicity; FAS = Full 
Analysis Set; PP = Per-Protocol; sSAP = supplemental Statistical Analysis Plan. 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analyses of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
The study is open-label, ie, participants, investigators, and Sponsor personnel will be aware 
of participant intervention assignment after each participant is enrolled and treatment is 
assigned. Participants will be allocated by nonrandom assignment.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
For AML participants, complete remission rate, composite CR rate, and ORR as evaluated by 
investigator per 2017 ELN AML response criteria (Appendix 8) are the secondary efficacy 
endpoints. A composite CR is a CR or CR with CRi. An objective response is a CR, CRi, or 
PR. For CMML participants, CR rate, PR rate, marrow response, cytogenetic remission, and 
clinical benefit as evaluated by investigator per 2015 International Consortium Proposal of 
Uniform Response Criteria for MDS/MPN in Adults (Appendix 9) are exploratory efficacy 
endpoints.
PK endpoints include serum concentrations of MK-0482, as well as derived PK parameters.
9.4.2
Safety Endpoints
The primary safety endpoint is the incidence of DLTs. 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.
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9.5
Analysis Populations
9.5.1
Safety Analysis Populations
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all participants who received at least 1 dose of study intervention.
The DLT evaluable population includes APaT participants in Part 1 (dose escalation) that 
meet the criteria for DLT evaluability (eg, finished Cycle 1 without a DLT or experienced a 
DLT in Cycle 1). See Section 6.6 for details.
At least 1 laboratory or vital sign measurement obtained after at least 1 dose of study 
intervention is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.5.2
Pharmacokinetic Analysis Populations
The per-protocol population will be used for the analysis of PK and target engagement data 
in this study. The per-protocol population consists of the subset of participants who complied 
with the protocol sufficiently to ensure that their data will be likely to show 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 will be included in the per-protocol analysis dataset.
9.5.3
Efficacy Analysis Populations
The FAS population will be used for the analyses of efficacy data in this study. It consists of 
all participants with a baseline assessment, and who were administered at least 1 dose of 
study intervention in the dose expansion part. Participants who were treated at the determined 
RP2D from the dose-escalation part will be included in the analysis population. Efficacy for 
AML and CMML participants will be summarized separately.
9.6
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.
9.6.1
Statistical Methods for Efficacy Analysis
CR rate, composite CR rate, and ORR estimates will be reported along with the 95% CI 
using the Clopper and Pearson method [Clopper, C. J. 1934]. 
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9.6.2
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, and physical examinations.
AEs will be summarized by counts and frequencies for each dose level. Laboratory tests, 
vital signs, and other safety endpoints will be summarized as appropriate.
DLTs will be listed and summarized by dose level. The pool-adjacent-violators algorithm [Ji, 
Y., et al 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) for the estimate will be provided.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis
Peripheral blood ILT3 receptor occupancy and noncompartmental PK parameters will be 
summarized by planned visit and time for each dose separately.
PK and pharmacodynamics modeling analyses will be documented in the sSAP.
9.7
Interim Analyses
An interim analysis may be conducted to enable future study planning at the Sponsor’s 
discretion and data will be examined on a continuous basis to allow for dose-finding 
decisions.
9.8
Multiplicity
There will be no multiplicity control in this study.
9.9
Sample Size and Power Calculations
With approximately 2 to 6 total participants in the ATD stage and approximately 3 to 
6 participants with a maximum of 10 participants at each dose level in the mTPI stage, the 
sample size in the dose-escalation part is expected to be approximately 20 AML and CMML 
participants. The dose expansion part will enroll an additional 10 to 15 AML participants at 
the determined RP2D. Thus, the total sample size for the study is approximately 30 to 
35 participants. The actual sample size depends on the safety profiles and number of doses 
studied.
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The 20 AML participants treated at the RP2D will be available for efficacy analysis. Table 7
presents confidence intervals for different observed response rates.
Table 7
Confidence Intervals for Different Observed Response Rates
Total Sample Size per 
Group
Observed # of Responses
Observed Response Rate
95% CI
20
4
20%
(6%, 44%)
20
6
30%
(12%, 54%)
20
9
45%
(23%, 68%)
CI = confidence interval
9.10
Subgroup Analyses
Subgroup analyses of efficacy endpoints will be documented in the sSAP.
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
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
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Interventional Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease-related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
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clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the prespecified plans for data analysis. To the 
extent scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important 
to patients, physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather 
than hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be 
underpowered and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named 
authors must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in 
publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority 
acceptance/authorization prior to implementation of the trial or amendment, in compliance with local and/or 
national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance 
with local and/or national regulations. Changes to the protocol that are required urgently to eliminate an 
immediate hazard and to protect participant safety may be enacted in anticipation of ethics committee approval. 
MSD will inform regulatory authorities of such new measures to protect participant safety, in compliance with 
local and/or national regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At 
a minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is 
obtained. Participants may withdraw from an MSD trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all 
applicable data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on 
behalf of MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records 
that might identify the participant by name.
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D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an 
ethics committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to 
enroll participants in its trials. However, when enrollment is particularly challenging, additional payments may be 
made to compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent 
on chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may 
wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As 
noted above, all publications resulting from MSD trials will indicate MSD as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
10.1.2
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, frequently 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.
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10.1.3
Data Protection
The Sponsor will conduct this study in compliance with all applicable data protection 
regulations.
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 that 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.
10.1.3.1
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.
10.1.3.2
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 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 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before 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.
10.1.3.3
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.
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10.1.4
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 ICMJE authorship 
requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the 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 trials 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 study-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.
10.1.6
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, ICH GCP: 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.
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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.
10.1.7
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 
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 participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
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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.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). 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/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
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 or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 8 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.2 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.
•
Investigators must document their review of each laboratory safety report.
Table 8
Protocol-required Clinical Laboratory Assessments
Hematology
Comprehensive 
Chemistry Panel
Urinalysis
Other
Hematocrit
Hemoglobin
Platelet count
RBC
WBC (total and 
differential)
Myeloblasts
Monoblasts
Megakaryoblasts
Promyelocytes 
Myelocytes 
Metamyelocytes
Promonocytes
Prolymphocytes
Segmented neutrophils
Band neutrophils
Lymphocytes
Monocytes
Eosinophil
Basophil
Plasma cells
Absolute lymphocyte count b
Absolute neutrophil count b
Total blasts c
Coagulation
PT or INR
aPTT/PTT
Fibrinogen d
Albumin
Alkaline phosphatase
ALT
AST
Bicarbonate
BUN
Calcium
Chloride
Creatinine
Glucose (nonfasting)
LDH
Phosphorus 
Potassium 
Sodium
Magnesium
Total bilirubin (Note: 
Direct bilirubin is required 
if total bilirubin is elevated 
above 2 × ULN)
Total protein 
Uric acid
Blood
Glucose
Protein
Specific gravity 
Microscopic 
examination if abnormal 
results are noted d
Pregnancy test 
(serum or urine) a
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Hematology
Comprehensive 
Chemistry Panel
Urinalysis
Other
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; INR = international 
normalized ratio; LDH = lactate dehydrogenase; PT = Prothrombin time; PTT = partial thromboplastin time; 
RBC=red blood cell; ULN = upper limit of normal; WBC=white blood cell. 
a
Perform on women of childbearing potential only 72 hours before Day 1 of Cycle 1. Additional tests may also be 
performed if clinically warranted, or as defined by local regulations.
b
Report % and absolute results, as necessary. Report the results in the same manner throughout the study. When 
neutrophils are reported separately as segmented and band neutrophils, absolute neutrophils should be the sum of the 
two. 
c
Total blasts (in percentage) should include the following cell types: monoblasts, myeloblasts, megakaryoblasts and 
promonocytes.
d
As clinically indicated.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication Error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
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 intervention.
•
Note: For purposes of AE definition, study intervention (also referred to as Sponsor’s 
product) includes any pharmaceutical product, biological product, vaccine, diagnostic 
agent, medical device, combination product, or protocol-specified procedure whether 
investigational or marketed (including placebo, active comparator product, or run-in 
intervention), 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, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention 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 
intervention 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 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
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 preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 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 preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
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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) that may interfere with or prevent 
everyday life functions, but do not constitute a substantial disruption.
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 1 
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 department or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.3
Additional Events Reported in the Same Manner as SAE
Additional events that 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.
•
Is a new cancer (that is not the cancer under study) as noted in Section 8.4.1.
•
Is associated with an overdose.
10.3.4
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.
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•
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.
Assessment of intensity/toxicity
•
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.
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 IMP)?
-
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.
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◦
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 1 time.)
-
Rechallenge: Was the participant reexposed 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; (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 1 time.)
NOTE: IF A RECHALLENGE IS PLANNED FOR AN AE THAT WAS SERIOUS AND 
MAY HAVE BEEN CAUSED BY THE SPONSOR’S PRODUCT, OR IF REEXPOSURE 
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 intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the Sponsor’s product or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
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•
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 their 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 1 of the criteria used when determining regulatory reporting 
requirements.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
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.
10.3.5
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 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.
•
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.
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•
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 Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email 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 Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
The recording and follow-up procedures described in this protocol apply to all medical 
devices as described below. For purposes of this section, medical devices in scope for device 
information collection include devices intended to be used by a study participant according to 
the study protocol that are manufactured by the Sponsor or for the Sponsor by a third party, 
licensed by the Sponsor for human use and/or drug-device combination products as listed in 
Section 6.1.1. Product Quality Complaints/Malfunctions must be reported to the Sponsor.
10.4.1
Definitions
Combination Product – A product comprised of 2 or more regulated components (ie, a drug 
and a device; a biologic and device; a biologic and a drug; or a drug, a device, and a 
biologic). Combination products can be single entity, copackaged, or colabeled.
Complaint – Any written, electronic, or oral communication that alleges deficiencies related 
to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device 
after it is released for distribution. This would include PQC, AE, and customer feedback.
A complaint does not necessarily need to involve a user or any other person. 
Constituent Part – A drug, device, or biological product that is part of a combination 
product.
Customer Feedback – A report that does not allege a PQC or defect and has no relevant 
safety information/untoward event associated with it (eg, goodwill or courtesy replacement, 
consumer preference or suggestion, remark that may suggest an improvement in the 
functionality or quality of a medical device, or device like features of a drug delivery 
system).
Malfunction – The failure of a device to meet its performance specifications or otherwise 
perform as intended.
Medical Device – Any instrument, apparatus, appliance, material, or other article, whether 
used alone or in combination, including the software necessary for its proper application 
intended by the MANUFACTURER to be used for human beings for the purpose of: 
•
diagnosis, prevention, monitoring, treatment, or alleviation of disease,
•
diagnosis, monitoring, treatment, alleviation of, or compensation for an injury or 
handicap,
•
investigation, replacement, or modification of the anatomy or of a physiological process,
•
control of conception,
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and which does not achieve its principal intended action in or on the human body by 
pharmacological, immunological, or metabolic means, but which may be assisted in its 
function by such means.
PQC – Any communication that describes a potential defect related to the identity, strength, 
quality, purity, or performance of a product identified by external customers. This includes 
potential device or device component malfunctions. Note: A report of Lack or Limited 
Efficacy is considered an AE rather than a PQC.
Serious Injury – An injury or illness that:
1. Is life-threatening,
2. Results in permanent impairment of a body function or permanent damage to a body 
structure, or
3. Necessitates medical or surgical intervention to preclude permanent impairment of a 
body function or permanent damage to a body structure.
Permanent means irreversible impairment or damage to a body structure or function, 
excluding trivial impairment or damage.
10.4.2
Recording, Assessing Causality, and Follow-up of PQCs/Malfunctions
Recording
When a complaint including PQC/malfunction occurs it is the responsibility of the 
investigator to review all documentation (eg, hospital progress notes, laboratory reports, and 
diagnostic reports) related to the event.
Events occurring during the study will be recorded in the participant’s medical records, in 
accordance with the investigator’s normal clinical practice, and on the appropriate CRF 
(paper or electronic) as per instructions provided in the data entry guidelines. Medical 
device/device constituent part of drug-device combination product information will be 
collected and reported to the Sponsor in the same time frame as SAEs as per Section 8.4.1
via CRF (paper or electronic). PQCs/malfunctions must be reported to the Sponsor.
Assessing Causality
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship.
The investigator will use clinical judgment to determine the relationship.
Alternative causes such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study intervention administration should 
be considered and investigated.
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Follow-up
The investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the Sponsor to elucidate the 
nature and/or causality of the event as complete as possible.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
-
Documented hysterectomy
-
Documented bilateral salpingectomy
-
Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Müllerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonhormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependencyb
Failure rate of <1% per year when used consistently and correctly.
Progestogen-only subdermal contraceptive implantc, d
IUSc,e
Nonhormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
Highly Effective Contraceptive Methods That Are User Dependentb
Failure rate of <1% per year when used consistently and correctly.
Combined (estrogen- and progestogen- containing) hormonal contraceptionc,d
- Oral
- Intravaginal
- Transdermal
- Injectable
Progestogen-only hormonal contraceptionc,d
- Oral
- Injectable
Sexual Abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study intervention. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
a
Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive 
methods for participants of clinical studies.
b
Typical use failure rates are higher than perfect-use failure rates (ie, when used consistently and correctly).
c
Male condoms must be used in addition to female participant hormonal contraception.
d
If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those 
which inhibit ovulation.
e
IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), 
spermicides only, and LAM.
Male condom with cap, diaphragm, or sponge with spermicide.
Male and female condom should not be used together (due to risk of failure with friction).
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10.6
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
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 Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
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 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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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 Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ 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 sex, age, medical history, and intervention outcomes is
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 that 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 Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using 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 future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, 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 before 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.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the 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 Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the 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 used 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 Security3, 4
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.
9. Reporting of Future Biomedical Research Data to Participants3, 4
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.
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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 Population3, 4
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 Research3, 4
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 emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [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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10.7
Appendix 7: Country-specific Requirements
Not applicable.
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10.8
Appendix 8: Response Criteria for AML (Modified ELN 2017)
Category
Definition
Comment
Response
Complete 
remission (CR)
Bone marrow blasts <5%; absence of circulating 
blasts and blasts with Auer rods; absence of 
extramedullary disease; ANC ≥1.0 × 109/L 
(1000/µL); platelet count ≥100 × 109/L (100,000/µL)
MRD+ or unknown
CR with 
incomplete 
hematologic 
recovery (CRi)
All CR criteria except for residual neutropenia (<1.0 
× 109/L [1000/µL]) or thrombocytopenia (<100 × 
109/L [100,000/µL])
Morphologic 
leukemia-free 
state (MLFS)
Bone marrow blasts <5%; absence of blasts with 
Auer rods; absence of extramedullary disease; no 
hematologic recovery required
Marrow should not merely be 
“aplastic”; at least 200 cells 
should be enumerated or 
cellularity should be at least 10%
Partial 
remission (PR)
All hematologic criteria of CR; decrease of bone 
marrow blast percentage to 5% to 25%; and decrease 
of pretreatment bone marrow blast percentage by at 
least 50%
Especially important in the 
context of Phase 1-2 clinical trials
Treatment 
Failure
Primary 
Refractory 
Disease
No CR or CRi after 2 courses of intensive induction 
treatment; excluding patients with death in aplasia or 
death due to indeterminate cause
Regimens containing higher 
doses of cytarabine are generally 
considered as the best option for 
patients not responding to a first 
cycle of 7+3; the likelihood of 
responding to such regimens is 
lower after failure of a first
Death in aplasia
Deaths occurring ≥7 days following completion of 
initial treatment while cytopenic; with an aplastic or
hypoplastic bone marrow obtained within 7 days of 
death, without evidence of persistent leukemia
Death from 
indeterminate 
cause
Deaths occurring before completion of therapy, or 
<7 days following its completion; or deaths 
occurring ≥7 days following completion of initial 
therapy with no blasts in the blood, but no bone 
marrow examination available
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Category
Definition
Comment
Response 
criteria for 
clinical trials 
only
Stable disease
Absence of CR, CRi, PR, MLFS; and criteria for 
Progressive Disease not met
Period of stable disease should 
last at least 3 months.
Progressive 
disease (PD)a,b
Evidence for an increase in bone marrow blast 
percentage and/or increase of absolute blast counts in 
the blood:
Category mainly applies for older 
participants given low-intensity 
or single-agent “targeted 
therapies” in clinical trials
• >50% increase in marrow blasts over baseline (a 
minimum 15% point increase is required in cases 
with <30% blasts at baseline); or persistent marrow 
blast percentage of >70% over at least 3 months.; 
without at least a 100% improvement in ANC to an 
absolute level (>0.5 × 109/L [500/µL], and/or platelet 
count to >50 × 109/L [50,000/µL] nontransfused) or
In general, at least 2 cycles of a 
novel agent should be 
administered
• >50% increase in peripheral blasts (WBC × % 
blasts) to >25 × 109/L (>25,000/μL) (in the absence 
of differentiation syndrome)b or
Some protocols may require blast 
increase in 2 consecutive marrow 
assessments at least 4 weeks 
apart; the date of progression 
should then be defined as of the 
first observation date
• New extramedullary disease
Some protocols may allow 
transient addition of hydroxyurea 
to lower blast counts
Progressive disease is usually 
accompanied by a decline in 
ANC and platelets and increased 
transfusion requirement and 
decline in performance status or 
increase in symptoms
Relapse
Bone marrow blasts ≥5%; or reappearance of blasts 
in the blood; or development of extra medullary 
disease.
ANC = absolute neutrophil count; CR = complete remission; CRi = complete remission without hematologic recovery; 
IDH = isocitrate dehydrogenase; MLFS = morphologic leukemia-free state; PR = partial remission; WBC = white blood 
cell.
a
The authors acknowledge that this new provisional category is arbitrarily defined; the category aims at harmonizing 
the various definitions used in different clinical trials.
b
Certain targeted therapies, for example, those inhibiting mutant IDH proteins, may cause a differentiation 
syndrome, that is, a transient increase in the percentage of bone marrow blasts and an absolute increase in blood 
blasts; in the setting of therapy with such compounds, an increase in blasts may not necessarily indicate progression 
of disease.
Source: [Dohner, H., et al 2017]
Outcome measures for clinical studies in AML
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Category
Definition
Overall survival
Defined for all participants of a trial measured from the date of entry into a 
clinical trial or from the date of diagnosis (eg, for correlative science studies) to 
the date of death from any cause, patients not known to have died at last follow-
up are censored on the date they were last known to be alive
Source: [Dohner, H., et al 2017]
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10.9
Appendix 9: Response Criteria for CMML
Criteria for measurement of treatment response in adult MDS/MPN
CR (presence of all of the following improvements)a
Bone marrow: ≤5% myeloblasts (including monocytic blast equivalent in case of CMML) with normal 
maturation of all cell lines and return to normal cellularitya
Osteomyelofibrosis absent or equal to “mild reticulin fibrosis” (≤Grade 1 fibrosis)b
Peripheral bloodc
WBC ≤10 × 109 cells/L
Hgb ≥11 g/dL
Platelets ≥100 × 109/L; ≤450 × 109/L
Neutrophils ≥1.0 × 109/L
Blasts 0%
Neutrophil precursors reduced to ≤2%
Monocytes ≤1 × 109/L
Extramedullary disease: Complete resolution of extramedullary disease present before therapy (eg, cutaneous 
disease, disease-related serous effusions), including palpable hepatosplenomegaly
Provisional category of CR with resolution of symptoms:c CR as described above, and complete resolution of 
disease-related symptoms as noted by the MPN-SAF TSS
Persistent low-level dysplasia is permitted given subjectivity of assignment of dysplasiaa
Complete cytogenetic remission
Resolution of previously present chromosomal abnormality (known to be associated with myelodysplastic, 
syndrome myeloproliferative neoplasms, or MDS/MPN), as seen on classic karyotyping with minimal of 
20 metaphases or FISHd
Partial remission
Normalization of peripheral counts and hepatosplenomegaly with bone marrow blasts (and blast equivalents) 
reduced by 50%, but remaining >5% of cellularity except in cases of MDS/MPN with ≤5% bone marrow 
blasts at baseline
Marrow response
Optimal marrow response: Presence of all marrow criteria necessary for CR without normalization of 
peripheral blood indices as presented above
Partial marrow response: Bone marrow blasts (and blast equivalents) reduced by 50%, but remaining >5% of 
cellularity, or reduction in grading of reticulin fibrosis from baseline on at least 2 bone marrow evaluations 
spaced at least 2 months apart
Clinical benefit
Requires 1 of the following in the absence of progression or CR/partial response and independent of marrow 
response (cord blood response must be verified at ≥8 wk) to be considered a clinical benefit
Erythroid response
Hgb increase by ≥2.0 g/dL
TI for ≥ 8wk for patients requiring at least 4 packed red blood cell transfusions in the previous 8 wk
Only red blood cell transfusions given based on physician’s judgment for a pretreatment Hgb of 
≤8.5 g/dL will count in the red blood cell TI response evaluatione
Platelet response
Transfusion independence when previously requiring platelet transfusions of at least a rate of 4 platelet 
transfusions in the previous 8 wk
Pretreatment ≤20 × 109/L: increase from <20 × 109/L to >20 × 109/L and by at least 100%
Pretreatment >20 × 109/L but ≤ 100 × 109/L: absolute increase of ≥30 × 109/Le
Neutrophil response
Pretreatment ≤0.5 × 109/L at least 100% increase and an absolute increase ≥0.5 × 109/L
Pretreatment, >0.5 × 109/L and ≤1.0 × 109/L At least 50% increase and an absolute increase
≥0.5 × 109/Le
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Criteria for measurement of treatment response in adult MDS/MPN
Spleen response
Either a minimum 50% reduction in palpable splenomegaly of a spleen that is at least 10 cm at baseline 
or a spleen that is palpable at more than 5 cm at baseline becomes not palpable
Symptom response
Improvement in symptoms as noted by decrease of ≥50% as per the MPN-SAF TSS scoring <20 were 
not considered eligible for measuring clinical benefit.f
CMML=chronic myelomonocytic leukemia; CR=complete response; FISH= fluorescence in situ hybridization; 
Hgb=hemoglobin; MDS/MPN=myelodysplastic syndromes/myeloproliferative neoplasms; MPN-
SAF=myeloproliferative neoplasm symptom assessment form; TI=transfusion independence; TSS=total symptom score; 
WBC=white blood cell; wk=weeks
a.
Presence of dysplastic changes, which may be interpreted within the scope of normal range of dysplastic changes, 
may still exist in the presence of CR as allowed in MDS IWG. Marrow should show age-adjusted normocellularity 
in CR.
b.
If there is no significant fibrosis present on the initial bone marrow biopsy, a second biopsy is not required to prove 
resolution of fibrosis. Grading of fibrosis in measurement of treatment response should be according to the 
European Consensus System. 
c.
Given the current lack of a validated tool to assess complete resolution of symptoms in MDS/MPN, “CR with 
resolution of symptoms” (a complete resolution of disease-related symptoms as noted by the MPN-SAF TSS in 
presence of CR) will be a provisional category of disease response.
d.
Loss of cytogenetic burden of disease by (via FISH or classic karyotyping) known to adversely affect prognosis is 
required to reach complete cytogenetic remission. Decrease in the cytogenetic burden of disease must be by ≥50% 
(via FISH or classic karyotyping) to be indicative of a partial cytogenetic response. Given variability of fluorescent 
probes used in FISH, cytogenetic normalization via FISH will depend on the performance characteristics of the 
specific probes used.
e.
Resolution of abnormal peripheral blood counts must persist for at least 2 separate analyses over at least 8 wk. In the 
case of proliferative MDS/MPN, CR will include resolution of thrombocytosis to a normal platelet count (150-450 × 
109/L) and resolution of leukocytosis to WBC ≤10 × 109 cells/L but ≥1.5 × 109/L. Hgb should be maintained >11 
g/dL and platelets ≥100 × 109/L without the support of transfusions. Clinical benefit may occur when these changes 
occur in absence of other changes required for CR or marrow response. Platelet and packed red blood cell TI would 
be considered for clinical benefit, and duration of TI should be monitored. Reduction in myeloid precursors 
(promyelocytes, myelocytes, metamyelocytes, nucleated red blood cells) to less than appreciable levels (≤2-3%) 
and/or 1 × 109/L monocytosis in the absence of infection, cytokine treatment, or other reactive causes.
f.
MPN-SAF TSS validation among patients with MDS/MPN is currently under way (R.A. Mesa, personal 
communication, 2014).
Source: Adapted from [Savona, M. R., et al 2015]
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Criteria for measurement of treatment response in adult MDS/MPN
Combination of 2 major criteria, 1 major and 2 minor criteria, or 3 minor criteria from list
Major criteria
Increase in blast counta
<5% blasts: ≥50% increase and to >5% blasts
5-10% blasts: ≥50% increase and to >10% blasts
10-20% blasts: ≥50% increase and to >20% blasts
20-30% blasts: ≥50% increase and to >30% blastsb
Evidence of cytogenetic evolutionc
Appearance of a previously present or new cytogenetic abnormality in complete cytogenetic remission 
via FISH or classic karyotyping
Increase in cytogenetic burden of disease by ≥50% in partial cytogenetic remission via FISH or classic 
karyotyping
New extramedullary disease
Worsening splenomegaly
Progressive splenomegaly that is defined by IWG-MRT: the appearance of a previously absent 
splenomegaly that is palpable at >5 cm below the left costal margin or a minimum 100% increase in 
palpable distance for baseline splenomegaly of 5-10 cm or a minimum 50% increase in palpable 
distance for baseline splenomegaly of >10 cm
Extramedullary disease outside the spleen
To include new/worsening hepatomegaly, granulocytic sarcoma, skin lesions, etc.
Minor criteria
Transfusion dependenced
Significant loss of maximal response on cytopenias ≥50% decrement from maximum remission/response in 
granulocytes or platelets
Reduction in Hgb by ≥1.5 g/dL from best response or from baseline as noted on complete blood count
Increasing symptoms as noted by increase in ≥50% as per the MPN-SAF TSSe
Evidence of clonal evolution (molecular)f
FISH=fluorescence in situ hybridization; Hgb=hemoglobin; IWG-MRT=International Working Group for Myelofibrosis 
Research and Treatment; MDS/MPN=myelodysplastic syndromes/myeloproliferative neoplasms; MPN-
SAF=myeloproliferative neoplasm symptom assessment form; TSS=total symptom score
a.
Blasts as measured from the bone marrow.
b.
Patients with development of acute myeloid leukemia from MDS/MPN; 20-30% blasts may be allowed on some 
clinical trials for patients with MDS/MPN.
c.
Increase in cytogenetic burden of disease by ≥50% (via FISH or classic karyotyping). Given variability of 
fluorescent probes used in FISH, cytogenetic normalization via FISH will depend on specific probes used.
d.
Transfusion dependency is defined by a history of at least 2 U of red blood cell transfusions in the past month for a 
hemoglobin level <8.5 g/dL that was not associated with clinically overt bleeding. Cytopenias resulting from 
therapy should not be considered in assessment of progression.
e.
MPN-SAF TSS validation among patients with MDS/MPN is currently under way (R.A. Mesa, personal 
communication, 2014).
f.
The identification of new abnormalities using single nucleotide polymorphism arrays or sequencing or a clearly 
significant increase in mutational burden of a previously detected abnormality. Precise criteria for defining new 
abnormalities and what exactly constitutes a significant increase in mutational burden are open to interpretation; we 
suggest that this criterion should be used conservatively based on current evidence.
Source: Adapted from [Savona, M. R., et al 2015]
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10.10 Appendix 10: Classification of Tumor Lysis Syndrome
Metabolic Abnormality
Laboratory TLS Classification 
Criteriaa
Clinical TLS Classification 
Criteriab
Hyperuricemia
Uric acid ≥8 mg/dL
N/A
Hyperkalemia
Potassium ≥6 mmol/liter
Cardiac dysrhythmia or sudden 
death probably or definitely 
caused by hyperkalemia
Hyperphosphatemia
Phosphorous ≥4.5 mg/dL
N/A
Hypocalcemia
Corrected calcium ≤7.0 mg/dL or 
ionized calcium <1.12 mg/dLc
Cardiac dysrhythmia, sudden 
death, seizure, neuromuscular 
irritability (tetany, paresthesia, 
muscle twitching, carpopedal 
spasm, Trousseau's sign, 
Chvostek's sign, laryngospasm, or 
bronchospasm), hypotension, or 
heart failure probably or definitely 
caused by hypocalcemia
Acute Kidney Injuryd
N/A
Increase in the serum creatinine 
level of 0.3 mg/dL or the presence 
of oliguria (average urine output 
of <0.5 mL/kg/h over a 6-hour 
period)
N/A = not available; TLS = tumor lysis syndrome
a.
Laboratory TLS requires 2 or more metabolic abnormalities must be present during the same 24-hour period within 
3 days before the start of therapy or up to 7 days afterward.
b.
Clinical TLS requires the presence of Laboratory TLS plus one or more findings from the Clinical TLS column.
c.
Corrected calcium = measured calcium level in mg/dL + 0.8 × (4 – albumin in g/dL).
d.
Acute kidney injury, unless attributable to another cause, represents clinical TLS even if criteria for laboratory TLS 
are not satisfied.
Source: [Howard, S. C., et al 2011]
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10.11 Appendix 11: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibodies
ADL
activities of daily living
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AML
acute myeloid leukemia
ANC
absolute neutrophil count
APaT
All-Participants-as-Treated
APL
acute promyelocytic leukemia
APOE
apolipoprotein E
aPTT
activated partial thromboplastin time
AR
adverse reaction
AST
aspartate aminotransferase
ATD
accelerated titration design
ATP
adenosine triphosphate
AUC
area under the curve
BCG
Bacillus Calmette–Guérin
bid
twice daily
BMI
body mass index
BP
blood pressure
C1D1
Cycle 1 Day 1
CAC
Clinical Adjudication Committee
CBC
complete blood count
CD
cluster of differentiation
CG
Cockcroft-Gault
CI
confidence interval
CL
clearance
Cmax
maximum plasma concentration
CML
chronic myelogenous leukemia
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Abbreviation
Expanded Term
CMML
chronic myelomonocytic leukemia
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CrCl
creatinine clearance
CR
complete remission
CRF
Case Report Form 
CRi
complete remission with incomplete recovery
CRS
Cytokine Release Syndrome
CRU
clinical research unit
CSF
Cerebrospinal fluid
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
ctDNA
circulating tumor deoxyribonucleic acid
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CTMS
Clinical Trial Management System
Ctrough
trough plasma concentration
CYP
cytochrome P450
DC
dendritic cell
DILI
drug-induced liver injury
DL
dose level
DLT
dose-limiting toxicity
DNA
deoxyribonucleic acid 
DOR
duration of response
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
eCTA
exploratory Clinical Trial Application
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Abbreviation
Expanded Term
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
eDMC
external Data Monitoring Committee
eGFR
estimated glomerular filtration rate
ELISA
enzyme-linked immunosorbent assay
ELN
European Leukemia Net
EMA
European Medicines Agency
EOC
Executive Oversight Committee 
EOT
end of treatment
FDA
Food and Drug Administration
FAS
Full Analysis Set
FBR
future biomedical research
FFPE
formalin-fixed, paraffin embedded
FIH
first in human
FSH
follicle-stimulating hormone 
FU
follow-up
GCP
Good Clinical Practice 
G-CSF
granulocyte-colony stimulating factor
GM-CSF
granulocyte-macrophage colony stimulating factor
GVHD
graft versus host disease
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
hCG
human chorionic gonadotropin
HCT
hematopoietic cell transplantation
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HR
heart rate
IB
Investigator’s Brochure 
08FSN5

PRODUCT: MK-0482
116
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Abbreviation
Expanded Term
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
IDH
isocitrate dehydrogenase
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
ILT3
immunoglobulin-like transcript 3
IMP
investigational medicinal product
IND
Investigational New Drug 
INR
international normalized ratio 
IO
immune-oncology
irAEs
immune-related AEs
IRB
Institutional Review Board
IRT
interactive response technology
ITIM
immunoreceptor tyrosine based inhibitory motifs
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IVRS
interactive voice response system
IWG
International Working Group
IWRS
integrated web response system
KPS
Karnofsky performance status
LAM
lactational amenorrhea method
LDH
lactate dehydrogenase
LILRB
leukocyte immunoglobulin-like receptor Bs
LLN
lower limit of normal
LLOQ
lower limit of quantitation
08FSN5

PRODUCT: MK-0482
117
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02-OCT-2023
Abbreviation
Expanded Term
mAb
monoclonal antibody
MAD
maximum administered dose
MDS
myelodysplastic syndromes
MDSC
myeloid-derived suppressor cell
MedDRA
Medical Dictionary for Regulatory Activities
MLFS
morphologic leukemia-free state
MPN
myeloproliferative neoplasms
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
mTPI
modified Toxicity Probability Interval
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NCS
not clinically significant
NSCLC
non–small cell lung cancer
NDA
New Drug Application 
NOAEL
no observed adverse effect level 
NOD
nonobese diabetic
NSG
NOD scid gamma
NYHA
New York Heart Association
OR
objective response
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PB
peripheral blood
PBMC
peripheral blood mononuclear cell
PBPK
physiologically based PK
PD-1
programmed cell death 1 protein
PDGFRA
platelet-derived growth factor receptor A
08FSN5

PRODUCT: MK-0482
118
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02-OCT-2023
Abbreviation
Expanded Term
PDGFRB
platelet-derived growth factor receptor B
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression-free survival
Ph+
Philadelphia chromosome positive
PK
pharmacokinetic
PKCθ
protein kinase C-theta
po
orally
PP
per-protocol
PQC
product quality complaint
PR
partial remission
PRO
patient-reported outcome
PT
prothrombin time
PTT
partial thromboplastin
Q2W
every 2 weeks
Q3W
every 3 weeks
QoL
quality of life
QP2
Department of Quantitative Pharmacology and Pharmacometrics
RNA
ribonucleic acid
RP2D
recommended Phase 2 dose
R/R
relapsed/refractory
SAC
Scientific Advisory Committee
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SCT
stem cell transplant
scid
severe combined immunodeficient
SD
standard deviation
sILT3
soluble inactive form of ILT3
SLAB
supplemental laboratory test(s)
08FSN5

PRODUCT: MK-0482
119
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02-OCT-2023
Abbreviation
Expanded Term
SoA
schedule of activities
SOC
standard of care
SOP
Standard Operating Procedures
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TEA
Treatment Eligibility Assessment (form)
TIL
tumor infiltrating lymphocytes
TLS
Tumor Lysis Syndrome
Tmax
Time to maximum plasma concentration
TME
tumor microenvironment
TPI
Toxicity Probability Interval
t1/2
half-life
UDS
urine drug screen
ULN
upper limit of normal
Vd
volume of distribution
VS
vital signs
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
WONCBP
woman/women of nonchildbearing potential
08FSN5

PRODUCT: MK-0482
120
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02-OCT-2023
11
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