A Phase 2, Open-label Study to Evaluate the Safety and Efficacy of MK-7684A (MK-7684 [Vibostolimab] With MK-3475 [Pembrolizumab] Coformulation) in Participants With Relapsed or Refractory Hematological Malignancies
Phase: PHASE2
Conditions: Hematological Malignancies
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 2, Open-label Study to Evaluate the
Safety and Efficacy of MK-7684A (MK-7684 
[Vibostolimab] with MK-3475 [Pembrolizumab] 
Coformulation) in Participants with Relapsed or 
Refractory Hematological Malignancies
NCT05005442
19-Dec-2023

PRODUCT: MK-7684A
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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 2, Open-label Study to Evaluate the Safety and Efficacy of MK-
7684A (MK-7684 [Vibostolimab] with MK-3475 [Pembrolizumab] Coformulation) in 
Participants with Relapsed or Refractory Hematological Malignancies
Protocol Number: 004-05 
Compound Number: MK-7684A
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):
NCT
154973
EU CT
Not applicable
EudraCT
2021-001700-15
JRCT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
154973
Approval Date: 19 December 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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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................15
1.1
Synopsis.................................................................................................................15
1.2
Schema ..................................................................................................................19
1.3
Schedule of Activities...........................................................................................20
1.3.1
21
1.3.1.1
21
1.3.1.2
33
1.3.2
46
1.3.3
46
1.3.3.1
.46
1.3.3.2
50
1.3.4
64
1.3.4.1
64
1.3.4.2
.67
2
INTRODUCTION..........................................................................................................70
2.1
Study Rationale....................................................................................................70
2.1.1
70
2.1.2
Rationale for Use in Hematological Malignancies......................................71
2.2
Background ..........................................................................................................74
2.2.1
Selected Hematological Malignancies.........................................................74
2.2.2
Pharmaceutical and Therapeutic Background .............................................76
2.2.2.1
Vibostolimab Background .................................................................76
2.2.2.2
Pembrolizumab Background..............................................................77
2.2.3
Preclinical and Clinical Studies ...................................................................77
2.2.3.1
77
2.2.3.2
Pembrolizumab Preclinical and Clinical Studies...............................77
2.2.4
Ongoing Clinical Studies.............................................................................77
2.2.4.1
Pembrolizumab Ongoing Clinical Trials ...........................................77
2.3
Benefit/Risk Assessment......................................................................................78
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................79
4
STUDY DESIGN............................................................................................................81
4.1
Overall Design......................................................................................................81
4.1.1
Signal Finding (Part 1).................................................................................82
4.1.2
Cohort Expansion (Part 2) ...........................................................................83
4.2
Scientific Rationale for Study Design.................................................................84
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4.2.1
Rationale for Endpoints ...............................................................................84
4.2.1.1
Efficacy Endpoints.............................................................................84
4.2.1.2
Safety Endpoints................................................................................85
4.2.1.3
85
4.2.1.3.1
86
4.2.1.3.2
86
4.2.1.4
.86
4.2.1.5
86
4.2.1.6
88
4.2.1.7
 
88
4.3
88
4.3.1
88
4.3.2
90
4.3.3
90
4.3.4
90
4.3.5
Maximum Dose Exposure for This Study ...................................................91
4.4
Beginning and End-of-Study Definition ............................................................91
4.4.1
Clinical Criteria for Early Study Termination .............................................91
5
STUDY POPULATION ................................................................................................93
5.1
Inclusion Criteria.................................................................................................93
5.2
Exclusion Criteria..............................................................................................101
5.3
Lifestyle Considerations....................................................................................103
5.3.1
Meals and Dietary Restrictions..................................................................103
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ............................................103
5.3.3
Activity Restrictions ..................................................................................104
5.4
Screen Failures...................................................................................................104
5.5
104
5.5.1
104
6
STUDY INTERVENTION..........................................................................................106
6.1
Study Intervention(s) Administered.................................................................106
6.1.1
Initial Treatment or First Course................................................................108
6.1.2
Second Course of Study Treatment ...........................................................108
6.2
Preparation/Handling/Storage/Accountability ...............................................108
6.2.1
Dose Preparation........................................................................................108
6.2.2
Handling, Storage, and Accountability......................................................108
6.3
Measures to Minimize Bias: Randomization and Blinding............................109
6.3.1
Intervention Assignment............................................................................109
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6.3.2
Stratification...............................................................................................109
6.3.3
Blinding......................................................................................................109
6.4
Study Intervention Compliance........................................................................109
6.5
Concomitant Therapy........................................................................................110
6.5.1
110
6.5.2
Rescue Medications and Supportive Care .................................................111
6.6
Dose Modification (Escalation/Titration/Other).............................................111
6.6.1
Dose Modification and Toxicity Management of Hematological AEs 
Related to MK-7684A................................................................................111
6.6.2
 
112
6.6.3
112
6.6.4
Dose Modification and Toxicity Management of Infusion Reactions 
Related to Pembrolizumab Monotherapy, Coformulations (MK-7684A), 
or IO Combinations....................................................................................118
6.6.5
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, 
Coformulations (MK-7684A), or IO Combinations..................................119
6.7
Intervention After the End of the Study..........................................................119
6.8
Clinical Supplies Disclosure..............................................................................119
6.9
Standard Policies................................................................................................120
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL..........................................................................................................121
7.1
Discontinuation of Study Intervention.............................................................121
7.2
Participant Withdrawal From the Study.........................................................122
7.3
Lost to Follow-up ...............................................................................................122
8
STUDY ASSESSMENTS AND PROCEDURES......................................................123
8.1
Administrative and General Procedures .........................................................123
8.1.1
Informed Consent.......................................................................................123
8.1.1.1
General Informed Consent...............................................................124
8.1.1.2
124
8.1.2
Inclusion/Exclusion Criteria ......................................................................124
8.1.3
Participant Identification Card...................................................................124
8.1.4
Medical History .........................................................................................125
8.1.5
Baseline Disease Characteristics................................................................125
8.1.6
Prior and Concomitant Medications Review.............................................126
8.1.6.1
Prior Medications.............................................................................126
8.1.6.2
Concomitant Medications................................................................126
8.1.7
Assignment of Screening Number.............................................................126
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8.1.8
Assignment of Treatment/Randomization Number...................................127
8.1.9
Study Intervention Administration ............................................................127
8.1.9.1
Timing of Dose Administration.......................................................127
8.1.10
Discontinuation and Withdrawal ...............................................................127
8.1.10.1
127
8.1.11
Participant Blinding/Unblinding................................................................128
8.1.12
Calibration of Equipment...........................................................................128
8.2
128
8.2.1
129
8.2.1.1
129
8.2.2
130
8.2.2.1
130
8.2.3
131
8.2.4
133
8.2.4.1
133
8.2.4.2
133
8.2.4.3
134
8.2.5
135
8.2.6
135
8.3
135
8.3.1
Physical Examinations...............................................................................135
8.3.1.1
Full Physical Examination...............................................................135
8.3.1.2
Directed Physical Examination........................................................136
8.3.2
Vital Signs..................................................................................................136
8.3.3
Eastern Cooperative Oncology Group Performance Scale........................136
8.3.4
Electrocardiograms ....................................................................................136
8.3.5
Lymphoma B Symptoms (Cohorts A to D, and F; cHL, PMBCL, FL, 
DLBCL, and NHL)....................................................................................136
8.3.6
Clinical Safety Laboratory Assessments ...................................................136
8.3.7
Pregnancy Testing......................................................................................137
8.3.8
138
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events..................................................................................................................138
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ........................................................139
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....140
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.140
8.4.4
Regulatory Reporting Requirements for SAE ...........................................141
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................141
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8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................141
8.4.7
.142
8.5
Treatment of Overdose......................................................................................142
8.6
Pharmacokinetics...............................................................................................142
8.6.1
Blood Collection for Plasma MK-7684A ..................................................142
8.7
Pharmacodynamics............................................................................................143
8.8
Biomarkers .........................................................................................................143
8.8.1
143
8.9
Future Biomedical Research Sample Collection.............................................144
8.10
Health Economics Medical Resource Utilization and Health Economics.....144
8.11
Visit Requirements.............................................................................................144
8.11.1
Screening....................................................................................................145
8.11.2
Treatment Period........................................................................................145
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ........145
8.11.4
Poststudy Visits..........................................................................................145
8.11.4.1
Safety Follow-up Visit.....................................................................145
8.11.4.2
Efficacy Follow-up Visits................................................................146
8.11.4.3
Survival Follow-up Contacts ...........................................................146
9
STATISTICAL ANALYSIS PLAN ...........................................................................147
9.1
Statistical Analysis Plan Summary...................................................................147
9.2
Responsibility for Analyses/In-house Blinding ...............................................148
9.3
Hypotheses/Estimation ......................................................................................148
9.4
Analysis Endpoints.............................................................................................148
9.4.1
Efficacy/Pharmacokinetics Endpoints .......................................................149
9.4.2
Safety Endpoints........................................................................................150
9.4.3
150
9.5
Analysis Populations..........................................................................................150
9.5.1
Efficacy Analysis Population.....................................................................150
9.5.2
Safety Analysis Population........................................................................150
9.5.3
PK Populations...........................................................................................151
9.5.4
PRO Analysis Population ..........................................................................151
9.6
Statistical Methods.............................................................................................151
9.6.1
Statistical Methods for Efficacy Analyses.................................................151
9.6.1.1
Objective Response Rate .................................................................151
9.6.1.2
Duration of Response.......................................................................151
9.6.1.3
Disease Control Rate........................................................................152
9.6.1.4
Analysis Strategy for Key Efficacy Variables.................................152
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9.6.2
Statistical Methods for Safety Analyses ....................................................153
9.6.3
153
9.6.4
Baseline Characteristics, Demographics, and Other Analyses ..................153
9.6.4.1
Demographic and Baseline Characteristics .....................................153
9.6.4.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis..........154
9.7
154
9.7.1
154
9.7.2
Efficacy Interim Reviews ..........................................................................155
9.7.2.1
Efficacy Futility Review..................................................................155
9.8
155
9.9
Sample Size and Power Calculations ...............................................................156
9.10
156
9.11
Compliance (Medication Adherence)...............................................................156
9.12
Extent of Exposure.............................................................................................156
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................157
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......157
10.1.1
Code of Conduct for Clinical Trials...........................................................157
10.1.2
Financial Disclosure...................................................................................160
10.1.3
Data Protection...........................................................................................161
10.1.3.1
Confidentiality of Data ....................................................................161
10.1.3.2
Confidentiality of Participant Records.............................................161
10.1.3.3
Confidentiality of IRB/IEC Information..........................................161
10.1.4
Committees Structure.................................................................................162
10.1.5
Publication Policy......................................................................................162
10.1.6
Compliance with Study Registration and Results Posting Requirements .162
10.1.7
Compliance with Law, Audit, and Debarment ..........................................162
10.1.8
Data Quality Assurance .............................................................................163
10.1.9
Source Documents .....................................................................................164
10.1.10
Study and Site Closure...............................................................................164
10.2
Appendix 2: Clinical Laboratory Tests............................................................165
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................167
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................167
10.3.2
Definition of AE ........................................................................................167
10.3.3
Definition of SAE ......................................................................................168
10.3.4
Additional Events Reported in the Same Manner as SAE.........................169
10.3.5
Recording AE and SAE .............................................................................170
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................173
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................175
10.5
Appendix 5: Contraceptive Guidance..............................................................176
10.5.1
Definitions..................................................................................................176
10.5.2
Contraception Requirements......................................................................177
10.6
178
10.7
182
10.7.1
182
10.7.2
182
10.7.3
183
10.8
Appendix 8: Response Criteria.........................................................................184
10.8.1
Lugano Classification (Cohorts A to D, and F).........................................184
10.8.2
IMWG Consensus Criteria for Response and MRD in MM (Cohort E) ...195
10.9
Appendix 9: Eastern Cooperative Oncology Group Performance Status....198
10.10 Appendix 10: Abbreviations .............................................................................199
11
REFERENCES.............................................................................................................205
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LIST OF TABLES
Table 1
 
21
Table 2
33
Table 3
46
Table 4
.50
Table 5
 
64
Table 6
67
Table 7
Efficacy Results With PD-1 Antibody as Monotherapy in Selected B-cell 
Malignancies and Multiple Myeloma..............................................................74
Table 8
100
Table 9
Study Interventions........................................................................................107
Table 10
 
112
Table 11
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated With Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .............................................................115
Table 12
Pembrolizumab Monotherapy, Coformulations (MK-7684A), or IO 
Combinations Infusion Reaction Dose Modification and Treatment 
Guidelines ......................................................................................................118
Table 13
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events...............................................................................140
Table 14
152
Table 15
Analysis Strategy for Key Efficacy Variables...............................................153
Table 16
154
Table 17
155
Table 18
155
Table 19
Hematology, Chemistry, and Urinalysis Laboratory Assessments................165
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LIST OF FIGURES
Figure 1
Signal Finding (Part 1).....................................................................................19
Figure 2
Cohort Expansion (Part 2) ...............................................................................20
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2, Open-label Study to Evaluate the Safety and Efficacy of MK-
7684A (MK-7684 [Vibostolimab] with MK-3475 [Pembrolizumab] Coformulation) in 
Participants with Relapsed or Refractory Hematological Malignancies
Short Title: A Phase 2 Study of MK-7684A in Relapsed/Refractory Hematological 
Malignancies
Acronym: MK-7684A-004
Hypotheses, Objectives, and Endpoints:
Formal hypothesis testing will not be performed in this protocol. In male and female 
participants who are 18 years of age or older with various relapsed/refractory hematological 
malignancies. 
Tertiary/exploratory endpoints will not be collected after the end of the study.
Primary Objective
Primary Endpoint
Part 1: To determine the safety and 
tolerability of MK-7684A (Cohorts A to F)
Dose-Limiting Toxicities
Adverse events
Discontinuation of study intervention due to 
an AE.
Secondary Objectives
Secondary Endpoints
Part 1: To evaluate ORR following 
administration of MK-7684A (Cohorts A to 
F) per disease-specific criteria as assessed 
by the investigator.
Objective response: CR or PR (for MM 
includes stringent CR, CR, and VGPR, PR)
Part 1: To evaluate the DOR following 
administration of MK-7684A (Cohorts A to 
F)
DOR, defined as the time from first 
documented evidence of CR or PR (for MM 
includes stringent CR, CR, and VGPR, PR) 
until disease progression per disease-
specific criteria as assessed by the 
investigator or death due to any cause, 
whichever occurs first.
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Part 1: To evaluate the DCR following 
administration of MK-7684A (Cohorts A to 
F)
DCR: CR, PR or SD (for MM, also 
including stringent CR, VGPR, MR) for at 
least 12 weeks prior to any evidence of 
progression.
Part 1: To characterize the PK profile of 
vibostolimab (Cohorts A to F)
Trough concentration (Ctrough)
Maximum concentration (Cmax)
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Haematological malignancy
Population
Participants with cHL or PMBCL, FL, 
DLBCL, MM, and NHL
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 5 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 180 participants with various hematological malignancies will be treated in 
the signal finding (Part 1) and approximately 150 participants may be treated in cohort 
expansion (Part 2), if initiated. Part 1 will involve 6 cohorts (Cohorts A to F 
relapsed/refractory: cHL or PMBCL not previously treated with an anti-PD-1/L1 agent, cHL 
or PMBCL previously treated with an anti-PD-1/L1 agent, FL, DLBCL, MM, and NHL) of 
approximately 30 participants per cohort treated with MK-7684A, a coformulation of 
vibostolimab and pembrolizumab. Part 2 may involve the expansion of Cohorts B to E (cHL 
or PMBCL previously treated with an anti-PD-1/L1, FL, DLBCL, and MM) of 
approximately 30 participants per cohort treated with MK-7684A and the addition of Cohort 
G (relapsed/refractory: may include cHL or PMBCL previously treated with an anti-
PD-1/L1, FL, DLBCL, and MM) of approximately 30 participants treated with vibostolimab 
monotherapy. The decision to open expansion cohorts in Part 2 will depend on the benefit 
and risk profile observed in Part 1.
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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: 
Cohorts A to 
F
MK-7684A
Vibostolimab 
200mg+ 
pembrolizumab 20 
mg/ 20mL vial
200 mg/ 200 
mg
IV Infusion
Q3W up to 
35 cycles
Test 
Product
Other current or former name(s) or alias(es) for study intervention(s) are as follows: 
MK-7684A is a coformulation of vibostolimab and pembrolizumab.
Total Number of Intervention Groups/Arms
Part 1: Cohorts A to F will be treated with 
MK-7684A coformulation
Duration of Participation
Each participant will participate in the study 
from the time that the participant provides 
documented informed consent through the 
final protocol-specified contact.
After a screening phase of 28 days, each 
participant will be assigned to receive study 
intervention until 1 of the conditions for 
discontinuation of study intervention is met 
(as defined in Section 7.1), or until the 
participant has received 35 administrations 
of MK-7684A.
All participants who achieve a CR may be 
eligible for a second course of treatment (up 
to an additional 17 cycles of MK-7684A) if 
there is an investigator-determined disease 
progression as per disease-specific criteria 
after initial treatment or first course has 
been completed or stopped for confirmed 
CR.
After the approval of Amendment 5, the 
study will end 90 days after the last 
participant completes 35 cycles of 
treatment, or terminates early, whichever 
comes first, and second course option for 
treatment is no longer available. Participants 
in the Imaging Follow-up or Survival 
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Follow-up phase will be discontinued from 
the study and no further imaging or 
participant contacts will be required.
After the end-of-study treatment, each 
participant will be followed for the 
occurrence of adverse events and 
spontaneously reported pregnancy as 
described under Section 8.4.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Steering Committee
No
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 10.
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1.2
Schema
The study design for Part 1 is depicted in Figure 1 and for Part 2 in Figure 2.
Figure 1
Signal Finding (Part 1)
In addition to the number of prior lines of therapies specified in the schema, requirements regarding stem cell 
transplant are described in Section 5.1.
Abbreviations: cHL=classic Hodgkin’s lymphoma; DLBCL=diffuse large B-cell lymphoma; FL=Follicular 
lymphoma; FU=follow-up; IV=intravenous; MM=multiple myeloma; NHL=non-Hodgkin’s lymphoma; PD-
1/L1=programmed cell death protein 1/ligand 1; PMBCL=primary mediastinal B‐cell lymphoma; Q3W=every 
3 weeks; Q12W=every 12 weeks.
Note: After approval of Amendment 5, participants will not be offered second course treatment. The study will 
end 90 days after the last participant completes 35 cycles of treatment, or terminates early, whichever comes 
first and second course option for treatment is no longer available. Participants in the Imaging Follow-up or 
Survival Follow-up phase will be discontinued from the study and no further imaging or participant contacts 
will be required.
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Figure 2
Cohort Expansion (Part 2)
The decision to open expansion cohorts in Part 2 will depend on the benefit and risk profile 
observed in Part 1.
In addition to the number of prior lines of therapies specified in the schema, requirements regarding stem cell 
transplant are described in Section 5.1.
Abbreviations: cHL=classic Hodgkin’s Lymphoma; DLBCL=Diffuse Large B-cell Lymphoma; FL=Follicular 
Lymphoma; FU=follow-up; IV=intravenous; MM=Multiple Myeloma; PD-1/L1=programmed cell death 
protein 1/ligand 1; PMBCL=Primary mediastinal B‐cell Lymphoma; Q3W=every 3 weeks; Q12W=every 12 
weeks.
Note: After approval of Amendment 5, participants will not be offered second course treatment. The study will 
end 90 days after the last participant completes 35 cycles of treatment, or terminates early, whichever comes 
first and second course option for treatment is no longer available. Participants in the Imaging Follow-up or 
Survival Follow-up phase will be discontinued from the study and no further imaging or participant contacts 
will be required.
1.3
Schedule of Activities
After approval of Amendment 5, participants will not be offered second course treatment. 
This will not affect participants already receiving the second course treatment.
The study will end 90 days after the last participant completes 35 cycles of treatment, or 
terminates early, whichever comes first and second course option for treatment is no longer 
available. Participants in the Imaging Follow-up or Survival Follow-up phase will be 
discontinued from the study and no further visits will be required.
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1.3.1
1.3.1.1
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1.3.1.2
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1.3.2
1.3.3
. 
1.3.3.1
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1.3.3.2
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1.3.4
 
1.3.4.1
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1.3.4.2
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2
INTRODUCTION
This is a Phase 2 open-label, signal finding and cohort expansion study to evaluate the safety 
and efficacy of MK-7684A in participants with relapsed or refractory cHL or PMBCL, FL, 
DLBCL, MM, and NHL.
MK-7684A is a coformulation of vibostolimab (MK-7684) and pembrolizumab (MK-3475). 
MK-7684 is a humanized, antagonist IgG1 mAb that binds to the immune checkpoint 
receptor, TIGIT expressed on T-cells and NK cells, and blocks the interaction between 
TIGIT and its ligands. Preclinical data has showed that anti-mTIGIT antibodies on the 
mIgG2a backbone (with high affinity FcγR binding) are more efficacious than anti-mTIGIT 
antibodies on the IgG1 D265A backbone (without FcγR binding) as single agents and in 
combination with mDX400 (anti-mPD-1 antibody) in multiple preclinical tumor models. 
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Therefore, a strong 
rationale exists to develop anti-PD-1 and anti-TIGIT combination therapies. The single 
coformulation vial of MK-7684A will allow simplified preparation and reduced infusion 
times compared with separate formulations of vibostolimab and pembrolizumab administered 
sequentially. Effective antitumor immunity depends on presentation of a tumor antigen, 
activation of protective T-cell responses, and the ability to overcome tumor-based blockade 
of antitumor responses.
2.1
Study Rationale
Effective antitumor immunity depends on presentation of a tumor antigen, activation of 
protective T-cell responses, and the ability to overcome tumor-based blockade of antitumor 
responses. Immune checkpoint inhibitor blockade aims to reverse the immunosuppressive 
strategies implemented by tumors to avoid immune detection.
Enhancing the proven anti-PD-1 immune stimulatory mechanism with the T-cell 
stimulatory/inhibitory network TIGIT (PVRIG/TACTILE)-CD226 (DNAM1) pathway is an 
interesting scientific concept. TIGIT is highly coexpressed with PD-1 on both CD4+ and 
CD8+ T-cells during chronic inflammatory states, including viral infections and cancer 
[Chauvin, J. M., et al 2015] [Johnston, R. J., et al 2014]. Enhanced antitumor efficacy is 
observed in preclinical models when an anti-TIGIT antibody is used with an anti-PD-1 
antibody. In vitro PD-1 blockade causes up-regulation of TIGIT in tumor antigen-specific 
CD8+ T-cells, a potential mechanism of resistance. Dual blockade of TIGIT and PD-1 
increased IFN-γ, TNF, and T-cell proliferation [Chauvin, J. M., et al 2015a].
2.1.1
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2.1.2
Rationale for Use in Hematological Malignancies
As defined by the eligibility criteria, the following hematological malignancies were selected 
because each represents a significant unmet medical need despite recent advances in 
treatment options. In selected hematological malignancies, preliminary efficacy with PD-1 
inhibitor (as summarized in [Table 7]), coexpression of TIGIT and PD-1 on T-cells and NK 
cells, and preliminary efficacy data with anti-TIGIT antibody and anti-PD-1 antibody in 
preclinical setting were observed in published data, providing rationale to evaluate such 
combination in selected hematological malignancies.
Classic Hodgkin’s Lymphoma and Primary Mediastinal Large B-cell Lymphoma
Pembrolizumab as monotherapy has shown efficacy in adult patients with relapsed or 
refractory cHL in KEYNOTE-204 (median PFS 13.2 months, [95% CI: 10.9, 19.4]; ORR 
66%, [95% CI: 57, 73; CR 24.5%) and KEYNOTE-87 (ORR 71%, [95% CI: 64, 77; CR 
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27.6%). As one of the tumor types that is sensitive to PD-1 inhibition, coexpression of TIGIT 
and PD-1 were also found in cHL, including CD8+ cytotoxic T-cells, CD4+ helper T-cells 
and FOXP3+ regulatory T-cells [Li, W., et al 2018].
Gene expression profiling has revealed that the pattern of gene expression in PMBCL is more 
similar to cHL than DLBCL [Rosenwald, A., et al 2003] [Savage, K. J., et al 2003], and 
hence these participants are included in the same cohort as cHL. Pembrolizumab as 
monotherapy has shown efficacy in adult and pediatric participants with relapsed or 
refractory PMBCL in KEYNOTE-170 (ORR 45%, [95% CI: 32, 60]; CR 18.9%).
Diffuse Large B-cell Lymphoma
Coexpression of TIGIT and PD-1 in intratumoral CD3+ T-cells was observed in DLBCL 
patient samples [Josefsson, S. E., et al 2019]. Previously published data with nivolumab 
relapsed/refractory DLBCL showed an ORR of 10%, with a median PFS of 1.9 months 
[Ansell, S. M., et al 2019]. Unpublished internal data from KEYNOTE-013 had 41 
participants with relapsed or refractory DLBCL, of whom 5 showed remission. Retrospective 
analysis on DLBCL responders indicated several of them to be EBV+ or T-cell histiocyte-
rich subtypes. Although sample size was small, PD-1 inhibitor showed preliminary efficacy 
in this aggressive type of NHL.
Follicular Lymphoma
TIGIT has been identified as an important coinhibitory receptor on T-cells in FL patients, 
coexpressed with PD-1 on CD8+ T-cells. TIGIT expression was associated with T-cell 
dysfunction, which was reversible by removing its ligand via in vitro culture [Josefsson, S. 
E., et al 2018]. Data, presented at the Annual American Society of Hematology meeting in 
2017, from an investigator-initiated study with pembrolizumab monotherapy in relapsed or 
refractory indolent NHL (18 participants with FL) [Ding, W., et al 2017], reported that 2 of 
18 participants with FL (11%) experienced a PR with therapy ongoing at time of data cutoff. 
Unpublished internal data from KEYNOTE-013 is generally consistent with these findings; 2 
of 23 (9%) participants with relapsed or refractory FL showed a remission.
Non-Hodgkin’s Lymphoma
Besides DLBCL, FL and PMBCL, other types of NHL originating from B lymphocytes will 
also be evaluated in this study, which may include MCL, MZL. Although anti-PD-1 
monotherapy data in the other types of NHL remains incomplete, there is molecular evidence 
that TIGIT and PD-1 are likely to inhibit T-cell antitumor activity through interaction with 
tumor cells and/or endothelial cells expressing the ligands in MCL and MZL [Josefsson, S. 
E., et al 2019].
Multiple Myeloma
Similar to solid tumors, immune effector cells from MM patients are efficiently primed but 
become dysfunctional in several aspects like cytokine secretion defects, proliferative arrest, 
and expression of multiple coinhibitory receptors, including TIGIT and PD-1. Through 
assessing cytokine release by BM cells from patients with MM on stimulation, TIGIT 
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expression has been associated with a subset of exhausted CD8+ T-cells with severely 
impaired effector function [Guillerey, C., et al 2018] [Lozano, E., et al 2020]. In preclinical 
setting, MM progression is associated with high levels of TIGIT expression on CD8+ T-cells 
and impaired effector functions. CD8+ T-cells from the BM of MM-relapsed mice showed 
increased expression of TIGIT, PD-1, LAG-3 and TIM-3. In addition, anti-TIGIT mAbs 
treatment significantly reduced tumor burden and prolonged the survival in CD8+ T-cell-
dependent manner [Guillerey, C., et al 2018]. Lozano et al showed that TIGIT blockage 
depleted FoxP3+ Tregs while increasing proliferation of IFN--producing CD4+ T-cell from 
patients with multiple myeloma via in vitro experiment [Lozano, E., et al 2020]. These 
molecular and preclinical data provided scientific rationale in targeting both TIGIT and PD-1 
pathways in this disease.
Treatment effect with anti-PD-1 monotherapy in MM showed some preliminary efficacy 
with safety profile consistent with other cancers. A study with PD-1 monotherapy reported 1 
patient experienced a response to nivolumab among 27 MM participants and achieved CR 
after radiotherapy [Lesokhin, A. M., et al 2016]. In KEYNOTE-013 study, the best response 
among 30 relapsed or refractory MM participants was SD (DCR: 56.7%), and 2 participants 
had unconfirmed responses per laboratory assessment. Pembrolizumab was generally well 
tolerated in these participants after a median follow-up of 19.9 months. Most treatment-
related AE’s after pembrolizumab monotherapy were mild to moderate[Ribrag, V., et al 
2019].
In summary, the safety profile observed with anti-PD-1 monotherapy in MM patients, safety 
profile of vibostolimab and pembrolizumab combination in patients’ solid tumors 
(vibostolimab/MK-7684A IB), molecular evidence of TIGIT’s role in MM patients and 
preclinical data with anti-TIGIT mAbs support the rationale to evaluate this coformulation of 
vibostolimab and pembrolizumab in relapsed or refractory MM.
Efficacy with PD-1 monotherapy in selected B-cell malignancies and multiple myeloma is 
summarized in Table 7 below. These data provided context for assessing this coformulation, 
vibostolimab and pembrolizumab, in these hematological malignancies.
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Table 7
Efficacy Results With PD-1 Antibody as Monotherapy in Selected B-cell 
Malignancies and Multiple Myeloma
Disease 
Type
No. of 
Participants
ORR
CR
Median 
PFS 
(months)
Median 
OS 
(months)
Study 
Treatment
References
r/r cHL
151
66%
25%
13.2
-
Pembrolizumab 
monotherapy
Pembrolizumab 
USPI, 
KEYNOTE-
204 [U.S. 
Prescribing 
Information 
2020]
r/r PMBCL
53
45%
11%
-
-
Pembrolizumab 
monotherapy
Pembrolizumab 
USPI, 
KEYNOTE-
170 [U.S. 
Prescribing 
Information 
2020]
r/r DLBCL
87
10%
-
1.9
12.2
Nivolumab 
monotherapy
[Ansell, S. M., 
et al 2019]
(Failed ASCT 
in Checkmate 
139)
r/r FL
18
11%
-
-
-
Pembrolizumab 
monotherapy
[Ding, W., et al 
2017]
r/r MM
30
0a
0
2.7
20.2
Pembrolizumab 
monotherapy
[Ribrag, V., et 
al 2019]
Abbreviations: ASCT=autologous stem cell transplant; cHL=classic Hodgkin’s Lymphoma; CR=complete response; 
DLBCL=Diffuse Large B-cell Lymphoma; FL=Follicular Lymphoma; MM=Multiple Myeloma; No.=number; 
ORR=objective response rate; OS=overall survival; PFS=Progression-free survival; PMBCL=Primary Mediastinal 
Large B-cell Lymphoma; r/r=relapsed/refractory; USPI=United States Prescribing Information.
-: not reported
a: Two unconfirmed responses based on laboratory assessment. Response not confirmed because participants 
started subsequent anticancer therapy.
A more comprehensive review of nonclinical and clinical data is included in the MK-7684 
IB.
2.2
Background
2.2.1
Selected Hematological Malignancies
Hodgkin’s lymphoma accounts for approximately 11% of all lymphomas in western 
countries [Landgren, O. 2007], with an incidence of 2.3/100,000 and account for 
approximately 0.4/100,000 of all cancer deaths [Eichenauer, D. A., et al 2014]. Classical HL 
is divided into 4 histologic subtypes: nodular sclerosis, mixed cellularity, lymphocyte rich, 
and lymphocyte depleted [Landgren, O. 2007].
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Non-Hodgkin’s lymphomas are a heterogeneous group of lymphoproliferative disorders 
originated in B lymphocytes, T lymphocytes, or NK cells. Non-Hodgkin’s lymphomas is the 
fifth leading site of new cancer cases among men and women, accounting for 4% to 5% of 
new cancer cases and 3% of cancer-related deaths [National Comprehensive Cancer 
Network, Inc. 2008].
DLBCL is the most common type of adult NHL in both North America and Europe, making 
up 31% of NHL [National Comprehensive Cancer Network, Inc. 2008]. Patients with double-
hit lymphomas (rearrangement of BCL2 and/or BCL6 and MYC genes) have a poor 
prognosis compared with patients without. Four-year OS rate was 25% versus 61% in a 
retrospective review of 117 patients with relapsed or refractory double-hit lymphomas 
compared with DLBCL who underwent autologous SCT [Herrera, A. F., et al 2017].
FL is the second most common NHL, comprising 17% to 22% of cases. FL is incurable in 
most patients, and relapse generally occurs with poor outcomes after early relapse or 
chemoimmunotherapy-resistant disease [Gopal, A. K., et al 2018]. Some patients with 
relapse and resistant disease after standard therapies may have poor outcomes (2-year OS 
rate of 38% in POD24 study) [Freeman, C. L., et al 2019]. Data suggests that the tumor 
microenvironment may contribute to the development and progression of FL, and the 
interaction of FL cells with immune cells in the tumor may inﬂuence the clinical course and 
response to therapy [Gopal, A. K., et al 2018].
PMBCL is a distinct subtype of NHL that accounts for 2% to 4% of all cases [Steidl, C. 
2011]. PMBCL was considered a subtype of DLBCL; however, the WHO classiﬁcation listed 
PMBCL as a separate entity. PMBCL patients treated with multiagent chemotherapy appear 
to have a better survival compared with DLBCL [Steidl, C. 2011].
Besides DLBCL, FL, and PMBCL, other types of NHL originating from B lymphocytes will 
also be evaluated in this study, which may include MCL and MZL. Refer to eligibility 
criteria for detail.
Multiple myeloma is a malignant monoclonal plasma cell disorder that is characterized by 
end-organ damage, such as CRAB (calcium [elevated], renal failure, anemia, bone lesions) 
[Mahindra, A., et al 2012] [Palumbo, A., et al 2014]. Multiple myeloma accounts for 10% of 
all hematological malignancies and has an age-adjusted incidence of approximately 4 per 
100,000 [Mahindra, A., et al 2012]. The combination strategy of anti-PD-1 with standard 
therapy, IMiD was explored in MM; pembrolizumab in combination with pomalidomide or 
lenalidomide with dexamethasone. The combination failed to improve clinical outcomes 
compared with standard therapy alone for participants with relapsed/refractory multiple 
myeloma (KEYNOTE-183, pomalidomide as part of standard therapy) [Mateos, M. V., et al 
2019] and treatment-naïve multiple myeloma (KEYNOTE 185, lenalidomide as part of 
standard therapy) [Usmani, S. Z., et al 2019]. Data from an unplanned interim analyzes 
showed an imbalance in number of deaths between treatment groups. However, the interim 
analyses were underpowered and inconclusive because of the shortened follow-up at study 
termination. Median follow-up was 8.1 months in KEYNOTE 183 and 6.6 months in 
KEYNOTE 185. In addition, disease characteristics were generally not balanced between 
treatment groups at the time of early study termination. Specifically, a greater proportion of 
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those in the pembrolizumab plus standard therapy group than in the standard therapy group 
had risk factors associated with poorer prognosis. This imbalance might account for the 
difference in early death observed that led to early termination of KEYNOTE-183 and 
KEYNOTE 185.
2.2.2
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between TILs in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-
cells/FoxP3+ regulatory T-cells correlates with improved prognosis and long-term survival in 
solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma. TILs can be expanded ex vivo 
and reinfused, inducing durable objective tumor responses in cancers such as melanoma 
[Dudley, M. E., et al 2005] [Hunder, N. N., et al 2008].
2.2.2.1
Vibostolimab Background
Vibostolimab is a humanized, antagonist mAb that binds to the immune checkpoint receptor, 
TIGIT, and blocks the interaction between TIGIT and its ligands. This human IgG1 antibody 
is being developed as a cancer immunotherapeutic with the potential to be used as 
monotherapy or to be combined with pembrolizumab (a humanized anti-PD-1 receptor 
antibody) to increase benefit to patients with various tumor types.
TIGIT is an immunomodulatory receptor expressed primarily on activated CD4+ and CD8+ 
T-cells, NK cells, and NKT cells. TIGIT is one of multiple immune checkpoint molecules 
that maintain immune homeostasis and prevent uncontrolled immune activation. Its structure 
reveals a single extracellular immunoglobulin domain, a transmembrane region, an 
immunoglobulin tail tyrosine-like phosphorylation motif, and an immunoreceptor tyrosine-
based inhibitory motif.
TIGIT forms part of a costimulatory network that consists of a positive (CD226) and 
negative (TIGIT) immunomodulatory receptor on T-cells, and ligands (CD155 and CD112) 
expressed on tumor cells and antigen presenting cells [Levin, S. D., et al 2011]. Whereas 
CD226 is widely expressed on most immune cells, TIGIT is highly expressed on memory T-
cells, T regs, NK cells, and NKT cells [Dardalhon, V., et al 2005] [Stanietsky, N., et al 
2009]. CD155/PVR (poliovirus receptor) and CD112/PVRL-2 are 2 nectin family members 
that are widely expressed, both on cells of the hematopoietic system and on fibroblasts and 
endothelial cells. Functionally, these receptor ligands are involved in cell adhesion and 
motility. CD155 is reported to be overexpressed in several tumor types and has been found to 
be induced by Ras activation and genotoxic stress [Carlsten, M., et al 2007] [Hirota, T., et al 
2005] [Soriani, A., et al 2009] [Stanietsky, N., et al 2009].
In addition, TIGIT is highly coexpressed with PD-1 on both CD4+ and CD8+ TILs including 
T regs, in mouse and human tumors, and has been reported to be coexpressed with PD-1 and 
TIM-3 on the TILs with the most exhausted phenotype [Chauvin, J. M., et al 2015] 
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[Johnston, R. J., et al 2014]. Furthermore, enhanced antitumor efficacy is observed in 
preclinical models when an anti-TIGIT antibody is used with an anti-PD-1 antibody. We 
hypothesize, therefore, that combining vibostolimab with pembrolizumab will offer 
substantially augmented antitumor efficacy.
2.2.2.2
Pembrolizumab Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the PD 
1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. KEYTRUDA® (pembrolizumab) is 
indicated for the treatment of patients across a number of indications. For more details on 
specific indications refer to the IB.
2.2.3
Preclinical and Clinical Studies
2.2.3.1
2.2.3.2
Pembrolizumab Preclinical and Clinical Studies
Refer to the IB for preclinical and clinical study data for pembrolizumab.
2.2.4
Ongoing Clinical Studies
Refer to the IBs for detailed background information on vibostolimab/MK-7684A and 
pembrolizumab.
2.2.4.1
Pembrolizumab Ongoing Clinical Trials
Numerous interventional clinical studies involving pembrolizumab are currently ongoing in a 
number of advanced solid tumor indications, as well as in hematological malignancies.
Additional details regarding other ongoing studies of pembrolizumab in hematological 
malignancies may be found in the IB.
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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.
The existing data in available studies suggest that blockade of TIGIT with vibostolimab 
offers a new immunological mechanism, which has been shown to enhance the activity of 
pembrolizumab in preclinical and early clinical observations. Furthermore, since this 
pathway is independent of PD-L1 expression, it may offer a particular benefit to all patients, 
regardless of PD-L1 status. Inhibiting TIGIT in combination with PD-1 blockade is a 
therapeutic strategy being investigated for the first time in patients with a variety of 
hematologic malignancies with limited treatment options, and the benefit/risk assessment for 
patients in this study may be favorable.
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
Formal hypothesis testing will not be performed in this protocol. In male and female 
participants who are 18 years of age or older with various relapsed/refractory hematological 
malignancies. 
Tertiary/exploratory endpoints will not be collected after the end of the study.
Primary Objective
Primary Endpoint
Part 1: To determine the safety and 
tolerability of MK-7684A (Cohorts A to F)
Dose-Limiting Toxicities
Adverse events
Discontinuation of study intervention due to 
an AE
Secondary Objectives
Secondary Endpoints
Part 1: To evaluate ORR following 
administration of MK-7684A (Cohorts A to 
F) per disease-specific criteria as assessed 
by the investigator.
Objective response: CR or PR (for MM 
includes stringent CR, CR, and VGPR, PR)
Part 1: To evaluate the DOR following 
administration of MK-7684A (Cohorts A to 
F)
DOR, defined as the time from first 
documented evidence of CR or PR (for MM 
includes stringent CR, CR, and VGPR, PR) 
until disease progression per disease-
specific criteria as assessed by the 
investigator or death due to any cause, 
whichever occurs first.
Part 1: To evaluate the DCR following 
administration of MK-7684A (Cohorts A to 
F)
DCR: CR, PR or SD (for MM, also 
including stringent CR, VGPR, MR) for at 
least 12 weeks prior to any evidence of 
progression.
Part 1: To characterize the PK profile of 
vibostolimab (Cohorts A to F)
Trough concentration (Ctrough)
Maximum concentration (Cmax)
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2, open-label, nonrandomized study to evaluate the safety and efficacy of 
MK-7684A (a coformulation of vibostolimab and pembrolizumab) and vibostolimab 
monotherapy in participants with various hematological malignancies.
The study will be divided into 2 parts: signal finding (Part 1) and cohort expansion (Part 2). 
Overall, 330 participants may be enrolled into both parts of the study; Part 1 will include 
approximately 180 participants with relapsed/refractory disease in Cohorts A to F to be 
administered MK-7684A Q3W for up to 35 cycles; Part 2 may include approximately 120 
participants with relapsed/refractory disease in Cohorts B to E to be administered MK-7684A 
Q3W and approximately 30 participants in Cohort G to be administered vibostolimab 
monotherapy Q3W for up to 35 cycles. The decision to open expansion cohorts in Part 2 will 
depend on the benefit and risk profile observed in Part 1 and Sponsor’s development 
strategy.
AEs will be monitored throughout the study and graded in severity according to the 
guidelines outlined in the NCI CTCAE Version 5.0. Each participant will be monitored for 
AEs and SAEs for 30 days and 90 days, respectively, after discontinuation of study 
intervention.
After documenting the informed consent, suitable candidates will be screened to assess 
whether they meet all study eligibility criteria. Eligible participants will be assigned to 1 of 6 
cohorts in Part 1 (Cohorts A to F) according to their hematologic malignancy and prior 
therapy received. All participants will be dosed with MK-7684A. No dose titration is 
currently being planned in Part 1. For Part 2, eligible participants will be alternately assigned 
to Cohorts B to E, according to their hematologic malignancy, to receive MK-7684A or 
Cohort G, to receive vibostolimab monotherapy. The study will be conducted in conformance 
with GCP.
After approval of Amendment 5, participants will not be offered second course treatment.
The study will end 90 days after the last participant completes 35 cycles of treatment or 
terminates early, whichever comes first and second course option for treatment is no longer 
available. Participants in the Imaging Follow-up or Survival Follow-up phase will be 
discontinued from the study and no further imaging or participant contacts will be required.
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.
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4.1.1
Signal Finding (Part 1)
Approximately 180 participants may be enrolled in 1 of the 6 disease-specific cohorts 
(approximately 30 participants per cohort) in Part 1 of the study. The cohorts will include:
•
Cohort A: Participants with cHL or PMBCL who are relapsed or refractory to at least 1 
line of prior therapy (cHL) or at least 2 lines of prior therapies (PMBCL). Prior therapy 
must not include an anti-PD-1/L1 treatment.
•
Cohort B: Participants with cHL or PMBCL who are relapsed or refractory to at least 2 
lines of prior therapies (cHL) or at least 3 lines of prior therapies (PMBCL). These prior 
therapies must include a prior anti-PD-1/L1 treatment.
•
Cohort C: Participants with FL who are relapsed or refractory to at least 2 lines of prior 
therapy.
•
Cohort D: Participants with DLBCL who are relapsed or refractory to at least 2 lines of 
prior therapy.
•
Cohort E: Participants with MM who are relapsed or refractory to at least 3 lines of prior 
therapy and have exhausted all approved lines of therapy.
•
Cohort F: Participants with NHL who are relapsed or refractory to at least 2 lines of prior 
therapy.
Further details regarding prior treatment, including SCT requirements, are described in 
Section 5.1 per cohort.
The primary endpoints of Part 1 of the study are DLTs, AEs, and AEs resulting in treatment 
discontinuation with the aim to move to cohort expansion to determine effectiveness. The 
definition of DLTs is provided in Section 4.3.4.
In Part 1, safety data from the first 12 participants (from any cohort) treated with MK-7684A 
and deemed as DLT evaluable (see definition in Section 9.5.2 and replacement requirements 
in Section 5.5.1) will be reviewed to determine tolerability of MK-7684A. DLT observation 
period is defined as the first 2 cycles (first 6 weeks) of study treatment without 
discontinuation. DLTs will be monitored in the first 12 DLT evaluable participants on an 
ongoing basis, based on timely data entry and close communication between investigator 
sites and Sponsor’s study team. The Sponsor will formally evaluate the DLT rate when at 
least 12 DLT evaluable participants have completed the DLT observation period to confirm 
the safety of MK-7684A. If 4 or fewer participants have a DLT (DLT rate of ≤33.3%), the 
coformulation will be considered tolerable. If 5 or more of the first 12 participants have a 
DLT (DLT rate of ≥41.7%), enrollment will be paused to evaluate all available data and to 
determine whether or not to stop enrollment into Part 1 of the study due to unacceptable 
toxicity.
After the initial DLT review for the first 12 evaluable participants (from any cohort), all 
safety data will be reviewed every 6 months, thereafter, for all of the participants as 
described in Section 9.7.1. Enrollment will not be halted unless a potential safety signal 
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arises during the conduct of the study. Considerations may include, but not limited to, the 
number of DLT’s, the clinical course of the toxicities, and benefit/risk assessment in 
conjunction with treating physicians.
For Cohort B participants (relapsed or refractory cHL or PMBCL who have been previously 
treated with a PD-1/L1 inhibitor), pretrial scans are required to be reviewed by ICR to verify 
disease progression on prior therapy. If disease progression cannot be verified, additional 
participants may be enrolled to ensure approximately 30 eligible participants are enrolled.
One futility assessment is planned for each cohort, when the first 12 participants per cohort in 
Part 1 have completed at least 1 postbaseline efficacy assessment. Further details are 
provided in Section 9.7.2.
All participants who achieve a SD, PR, or CR may be eligible for up to an additional 17 
cycles of MK-7684A if there is an investigator-determined disease progression as per 
disease-specific criteria after initial treatment or first course has been completed or stopped 
for confirmed CR, PR, or SD. Further details are provided in Section 6.1.2 and Section 1.3.3.
4.1.2
Cohort Expansion (Part 2)
The decision to open expansion cohorts in Part 2 will depend on an interim review of Part 1 
data per cohort of approximately 30 participants to evaluate the benefit/risk of MK-7684A in 
each disease type. If a favorable profile is observed in any particular disease type, Part 2 
cohorts may be initiated.
Approximately 150 participants may be enrolled in 1 of the 5 cohorts (approximately 30 
participants per cohort) in Part 2 of the study. Participants enrolled in Cohorts B to E (PD-
1/L1 refractory, relapsed or refractory cHL or PMBCL; relapsed or refractory FL; relapsed or 
refractory DLBCL; and relapsed or refractory MM) will be treated with MK-7684A and 
those enrolled in Cohort G (PD-1/L1 refractory, relapsed or refractory cHL or PMBCL; 
relapsed or refractory FL; relapsed or refractory DLBCL; and relapsed or refractory MM) 
will be treated with vibostolimab monotherapy. Cohort allocation for Part 2 will be 
alternating with 1 participant for each disease type being enrolled into Cohort G first and the 
second into Cohort B to E, whichever is applicable. The cohorts will include:
•
Cohort B: Participants with cHL or PMBCL who are relapsed or refractory to at least 2 
lines of prior therapies (cHL) or at least 3 lines of prior therapies (PMBCL). These prior 
therapies must include an anti-PD-1/L1 treatment.
•
Cohort C: Participants with FL who are relapsed or refractory to at least 2 lines of prior 
therapy.
•
Cohort D: Participants with DLBCL who are relapsed or refractory to at least 2 lines of 
prior therapy.
•
Cohort E: Participants with MM who are relapsed or refractory to at least 3 lines of prior 
therapy and have exhausted all approved lines of therapy.
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•
Cohort G: The following hematological malignancies, with an initial limit of 7 
participants per disease type, will be included. Enrollment may be adjusted depending on 
opening of disease-specific cohort(s) in Part 2:
-
Participants with cHL or PMBCL who are relapsed or refractory to at least 2 line of 
prior therapy (cHL) or at least 3 lines of prior therapies (PMBCL). These prior 
therapies must include an anti-PD-1/L1 treatment,
-
Participants with FL who are relapsed or refractory to at least 2 lines of prior therapy,
-
Participants with DLBCL who are relapsed or refractory to at least 2 lines of prior 
therapy, AND
-
Participants with MM who are relapsed or refractory to at least 3 lines of prior 
therapy and have exhausted all approved lines of therapy.
Further details regarding prior treatment, including SCT requirements, are described in 
Section 5.1 per cohort.
4.2
Scientific Rationale for Study Design
This Phase 2, nonrandomized, open-label, signal finding and cohort expansion study will first 
establish the safety and tolerability of MK-7684A, and second, provide proof of concept in 
various relapsed or refractory hematological malignancies. The hematologic malignancies 
selected for this study are those disease types known to represent a significant unmet medical 
need as well as the expression of TIGIT and responses to anti-PD-1/L1 monotherapy, as 
summarized in Section 2.2.1.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Endpoint definitions are provided in Section 9.4. 
After the approval of Amendment 5, the study will end 90 days after the last participant 
completes 35 cycles of treatment or terminates early, whichever comes first, and second 
course option for treatment is no longer available. Participants in the Imaging Follow-up or 
Survival Follow-up phase will be discontinued from the study, and no further imaging or 
participant contacts will be required.
Objective Response Rate
ORR is a secondary efficacy endpoint for Part 1 of the study.
Treatment effect measured by ORR can represent direct clinical benefit based on the specific 
disease, context of use, magnitude of the effect, number of CRs, durability of response, 
disease setting, location of the tumors, available therapy, and risk-benefit relationship.
Each hematological malignancy has specific response criteria developed by experts that will 
be applied in the assessment of ORR (for Cohorts A to F) as summarized in Appendix 8.
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Duration of Response
DOR is a secondary efficacy endpoint for Part 1 of the study.
Improved DOR can result in a meaningful delay in disease progression as opposed to a 
temporary response without lasting benefit.
Disease Control Rate
DCR is a secondary efficacy endpoint for Part 1 of the study.
This includes participants who have achieved tumor response per relevant response criteria or 
have showed SD for at least 12 weeks before any evidence of progression. The proportion of 
participants with tumor response or SD can result in a meaningful delay in disease 
progression.
Progression-free Survival
PFS is an exploratory efficacy endpoint for Part 1 of the study.
PFS is a surrogate endpoint that reflects tumor growth and includes deaths and therefore 
correlates to OS.
Overall Survival
OS is an exploratory efficacy endpoint for Part 1 of the study.
OS is a precise and reliable measure of survival, a key clinical endpoint.
Minimal Residual Disease
MRD is an exploratory efficacy endpoint for participants with MM in Cohort E for Part 1.
MRD negativity is a surrogate endpoint that correlates with improved OS and PFS.
4.2.1.2
Safety Endpoints
The safety and tolerability of MK-7684A will be assessed by clinical evaluation of AEs and 
inspection of other study parameters including vital signs, physical examination, and 
laboratory safety tests at time points specified in the SoA. AEs will be assessed as defined by 
CTCAE, Version 5.0 and recorded according to Section 8.4 and Appendix 3. In addition, 
DLTs will be used to determine the safety and tolerability of MK-7684A. The definition of a 
DLT is provided in Section 4.3.4.
4.2.1.3
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4.2.1.3.1
4.2.1.3.2
4.2.1.4
 
4.2.1.5
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4.2.1.6
4.2.1.7
 
4.3
4.3.1
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4.3.2
 
4.3.3
 
 
4.3.4
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4.3.5
Maximum Dose Exposure for This Study
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 (Section 
7.3). 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.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
Recruitment in the study or at (a) particular study site(s) may be stopped due to insufficient 
compliance with the protocol, GCP and/or other applicable regulatory requirements, 
procedure-related problems or the number of discontinuations for administrative reasons is 
too high.
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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
2. Plans to modify or discontinue the development of the study medication
Ample notification will be provided in the event of Sponsor decision to no longer supply 
MK-7684A.
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5
STUDY POPULATION
Male/female participants at least 18 years of age with relapsed or refractory hematological 
malignancies will be enrolled in this study.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
Participants are required to have a confirmed diagnosis of:
1. Cohort A: relapsed or refractory cHL or PMBCL, not previously treated with an anti-
PD-1/L1 therapy
cHL
a) Diagnosis of cHL, according to the WHO classification of neoplasms of the 
hematopoietic and lymphoid tissues [Swerdlow, S. H., et al 2016].
b) Have relapsed*a or refractory*b cHL to at least 1 prior line of therapy and:
i.
Have failed to achieve a response or progressed after auto-SCT, OR
ii.
Were unable to achieve a CR or PR to salvage chemotherapy, and therefore 
did not proceed to auto-SCT, or were ineligible for auto-SCT due to 
age/comorbidities as judged by the treating physician.
*a Relapsed Disease: Progression of disease after achieving a remission to the 
most recent therapy
*b Refractory Disease: Failure to achieve CR or PR to the most recent therapy
Note: A planned treatment approach of induction therapy followed by auto-
SCT, followed by maintenance, is considered 1 line of therapy
c) Have not been previously treated with an anti-PD-1/L1 therapy.
Note: Refer to Appendix 7 for Italy-specific requirements related to Cohort A.
Note: Refer to Appendix 7 for France-specific requirements related to Cohort A.
PMBCL
d) Diagnosis of PMBCL, according to the WHO classification of neoplasms of the 
hematopoietic and lymphoid tissues [Swerdlow, S. H., et al 2016].
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e) Have relapsed*a or refractory*b PMBCL to at least 2 prior lines of therapies and:
i.
Have failed to achieve a response or progressed after auto-SCT, OR
ii.
Were unable to achieve a CR or PR to salvage chemotherapy, and therefore 
did not proceed to auto-SCT, or are ineligible for auto-SCT due to 
age/comorbidities as judged by the treating physician.
*a Relapsed Disease: Progression of disease after achieving a remission to the most 
recent therapy. *b Refractory Disease: Failure to achieve CR or PR to the most recent 
therapy.
Note: A planned treatment approach of induction therapy followed by auto-SCT, 
followed by maintenance, is considered 1 line of therapy.
f)
Participants must be relapsed or refractory to CAR-T-cell therapy or unable to receive 
it.
g) Must have received rituximab as part of prior treatment.
h) Have not been previously treated with an anti-PD-1/L1 therapy.
2. Cohort B: relapsed or refractory cHL or PMBCL previously treated with an anti-PD-
1/L1 therapy
cHL
a) Diagnosis of cHL, according to the WHO classification of neoplasms of the 
hematopoietic and lymphoid tissues [Swerdlow, S. H., et al 2016].
b) Have relapsed*a or refractory*b cHL to at least 2 prior lines of therapies (including 
prior PD-1/L1 therapy) and:
i.
Have failed to achieve a response or progressed after auto-SCT, OR 
ii.
Were unable to achieve a CR or PR to salvage chemotherapy, and therefore 
did not proceed to auto-SCT, or were ineligible for auto-SCT due to 
age/comorbidities as judged by the treating physician.
*a Relapsed Disease: Progression of disease after achieving a remission to the most 
recent therapy.
*b Refractory Disease: Failure to achieve CR or PR to the most recent therapy.
Note: A planned treatment approach of induction therapy followed by autologous 
SCT, followed by maintenance, is considered 1 line of therapy.
c) Have progressed on-treatment with an anti-PD-1/L1 mAb administered either as 
monotherapy or in combination with other checkpoint inhibitors or other therapies. 
Anti-PD-1/L1 treatment progression is defined by meeting all of the following 
criteria:
i. Have received at least 2 doses of an anti-PD-1/L1 mAb that has been approved in 
cHL and administered at the approved dose and schedule.
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ii. Have showed disease progression after an anti-PD-1/L1 mAb as defined by 
Lymphoma Disease Response criteria (Cheson or Lugano). This determination is 
made by the investigator.
i. Progressive disease has been documented within 12 weeks from the last dose of 
an anti-PD-1/L1 mAb or during therapy.
ii. Note: Intervening therapies are allowed in between last anti-PD-1/L1 dose and 
enrollment on-study if all other criteria are met.
iii. Have submitted pretrial imaging.
Note: The investigator site’s study team must have reviewed pretrial images that are of 
diagnostic quality from at least 2 dates (before treatment with anti-PD-1/L1 inhibitor 
and then on or after therapy) to determine that radiographic progression has occurred 
per Lymphoma Disease Response criteria (Cheson or Lugano) after initiation of a PD-
1/L1 inhibitor. Verification of progression by ICR will not be required before 
enrollment in the study; however, basic image quality review will be performed to 
ensure images are readable for potential ICR.
Note: Refer to Appendix 7 for France- and Germany-specific requirements related to Cohort 
B.
PMBCL
d) Diagnosis of PMBCL, according to the WHO classification of neoplasms of the 
hematopoietic and lymphoid tissues [Swerdlow, S. H., et al 2016].
e) Have relapsed*a or refractory*b PMBCL to at least 3 prior lines of therapies 
(including prior PD-1/L1 therapy) and:
i.
Have failed to achieve a response or progressed after auto-SCT, OR
ii.
Were unable to achieve a CR or PR to salvage chemotherapy, and therefore 
did not proceed to auto-SCT, or are ineligible for auto-SCT due to 
age/comorbidities as judged by the treating physician.
*a Relapsed Disease: Progression of disease after achieving a remission to the most 
recent therapy. 
*b Refractory Disease: Failure to achieve CR or PR to the most recent therapy.
Note: A planned treatment approach of induction therapy followed by auto-SCT, 
followed by maintenance, is considered 1 line of therapy.
f)
Must have previously received rituximab as part of prior treatment.
g) Participants must be relapsed or refractory to CAR-T-cell therapy or unable to receive 
it.
h) Have progressed on-treatment with an anti-PD-1/L1 mAb administered either as 
monotherapy or in combination with other checkpoint inhibitors or other therapies. 
Anti-PD-1/L1 treatment progression is defined by meeting all of the following 
criteria:
i. Have received at least 2 doses of an anti-PD-1/L1 for PMBCL treatment, and
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ii. Have showed disease progression after an anti-PD-1/L1 mAb as defined by 
Lymphoma Disease Response criteria (Cheson or Lugano). This determination is 
made by the investigator, and
iii. Progressive disease has been documented within 12 weeks from the last dose of 
an anti-PD-1/L1 mAb or during therapy, and
Note: Intervening therapies are allowed in between last anti-PD-1/L1 dose and 
enrollment on-study if all other criteria are met.
iv. Have submitted pretrial imaging.
Note: The investigator site’s study team must have reviewed pretrial images that 
are of diagnostic quality from at least 2 dates (before treatment with anti-PD-1/L1 
inhibitor and then on or after therapy) to determine that radiographic progression 
has occurred per Lymphoma Disease Response criteria (Cheson or Lugano) after 
initiation of a PD-1/L1 inhibitor. Verification by ICR of progression will not be 
required before enrollment in the study; however, basic image quality review will 
be performed to ensure images are readable for potential ICR.
Note: Refer to Appendix 7 for France-specific requirements related to Cohort B.
3. Cohort C: relapsed or refractory FL
1. Diagnosis of FL (all grades permitted; 1 to 3b), according to the WHO classification 
of neoplasms of the hematopoietic and lymphoid tissues [Swerdlow, S. H., et al 
2016].
2. Participants who are relapsed or refractory to at least 2 prior lines of therapy, 
chemoimmunotherapy and immunomodulatory agents (ie, lenalidomide + rituximab). 
Participants must have received and failed, been intolerant to, or determined by their 
treating physician to be a poor candidate or ineligible for a PI3K inhibitor per local 
(institution) guidelines. Participants who are ineligible for standard treatment or who 
have withdrawn from standard treatment due to unacceptable toxicity warranting 
discontinuation of that treatment and precluding retreatment with the same agent 
before progression of disease will also be eligible.
Note: A planned treatment approach of induction therapy followed by auto-SCT, 
followed by maintenance, is considered 1 line of therapy.
Participants must be relapsed or refractory to CAR-T-cell therapy or unable to receive 
it.
4. Cohort D: relapsed or refractory DLBCL
a) Diagnosis of DLBCL, according to the WHO classification of neoplasms of the 
hematopoietic and lymphoid tissues [Swerdlow, S. H., et al 2016]. Cell of Origin is 
known for DLBCL, NOS, germinal center B-cell type or activated B-cell type. 
DLBCL with over-expression of MYC, BCL2, and/or BCL6 proteins without 
rearrangement are also classified as DLBCL.
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b) Participants must have progressed after at least 2 lines of previous therapy, including 
progression after an auto-SCT, or are not a candidate (per institutional criteria) for an 
auto-SCT. Participants who are ineligible for standard treatment or who have 
withdrawn from standard treatment due to unacceptable toxicity warranting 
discontinuation of that treatment and precluding retreatment with the same agent 
before progression of disease will also be eligible.
Note: A planned treatment approach of induction therapy followed by auto-SCT, 
followed by maintenance, is considered 1 line of therapy.
c) Participants must be relapsed or refractory to CAR-T-cell therapy or unable to receive 
it.
d) Participants must have exhausted or be ineligible for or intolerant to all treatments, 
which in the opinion of the investigator are standard of care for their disease.
Note: Refer to Appendix 7 for Germany-specific requirements related to Cohort D.
5. Cohort E: relapsed or refractory MM
a) Have histologically or cytologically confirmed diagnosis of active MM as per 
IMWG criteria [Rajkumar, S. V., et al 2014].
b) Have measurable disease defined as meeting at least 1 of the following criteria:
c) Serum monoclonal protein (M-protein) levels ≥0.5 g/dL (≥5 g/L), OR
d) Urine monoclonal protein (M-protein) levels ≥200 mg/24 h, OR
e) For participants without measurable serum and urine M-protein levels, an abnormal 
serum-FLC ratio (FLC k/l <0.26 or >1.65) with involved FLC level ≥100 mg/L 
(normal serum FLC k/l value: 0.26-1.65).
f)
Must have undergone stem cell transplant and have relapsed after auto-SCT or have 
failed to achieve a CR or PR following auto-SCT, or is considered ineligible for 
auto-SCT
g) Note: A planned treatment approach of induction therapy followed by auto-SCT, 
followed by maintenance, is considered one line of therapy.
h) Participants must have received all regionally approved antimyeloma therapy 
including IMiD (pomalidomide, lenalidomide, or thalidomide), proteasome inhibitor 
(bortezomib, carfilzomib, or ixazomib), steroids, anti-CD38 monoclonal antibody, 
selinexor, and anti-BCMA therapies alone or in combination.
i)
Note: Exception in cases where an approved therapy is not available or not suitable 
for the participant.
j)
Participants must have failed their last line of therapy, defined as 1 of the following:
i. Refractory: Nonresponsive (ie, failure to achieve at least PR) while on primary or 
salvage therapy, or documented progressive disease on or within 60 days of 
completing treatment, OR
ii. Relapsed: disease progression following prior response to antimyeloma therapy, 
participants must have relapsed within 6 months after stopping treatment.
Note: Participants must be relapsed or refractory to CAR-T-cell therapy or unable 
to receive it.
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6. Cohort F: relapsed or refractory NHL
a) Have histologically confirmed diagnosis of B-cell lymphoma other than cHL, 
PMBCL, DLBCL (as described in inclusion criterion 4a), or FL, according to the 
WHO classification of neoplasms of the hematopoietic and lymphoid tissues 
[Swerdlow, S. H., et al 2016]. Examples include transformed indolent lymphoma, 
classical MCL, MZL (both nodal and extranodal), splenic MZL, 
lymphogranulomatosis, intravascular large B-cell lymphoma, T-cell/histiocyte-rich 
large cell lymphoma, high-grade B-cell lymphoma (with MYC, BCL2, and/or BCL6 
rearrangements), DLBCL with chronic inflammation, B-cell lymphoma 
unclassifiable, EBV+ DLBCL-NOS and ALK+ large B-cell lymphoma, or small 
lymphocytic lymphoma. For MCL, documentation of either over-expression of cyclin 
D1 or presence of t(11;14) is required.
b) Participants with MCL must have received prior Bruton’s tyrosine kinase inhibitor 
therapy.
c) Participants must have progressed after at least 2 lines of previous therapy. 
Participants must have received and failed, been intolerant to, or determined by their 
treating physician to be a poor candidate or ineligible for a PI3K inhibitor per local 
(institution) guidelines. Participants who are ineligible for standard treatment or who 
have withdrawn from standard treatment due to unacceptable toxicity warranting 
discontinuation of that treatment and precluding retreatment with the same agent 
before progression of disease will also be eligible. Participants with a indolent 
lymphoma are required to meet criteria for systemic therapy.
Note: A planned treatment approach of induction therapy followed by auto-SCT, 
followed by maintenance, is considered 1 line of therapy.
d) Participants must have exhausted or be ineligible for or intolerant to all standard of 
care treatment options for their disease per investigator’s judgment before enrollment.
7. Cohorts A, B, C, D, and F (non-FDG-avid lymphoma participants):
a) Have measurable disease, defined as at least 1 lesion that can be accurately measured 
in at least 2 dimensions with spiral CT scan. Minimum measurement must be >15 
mm in the longest diameter or >10 mm in the short axis.
Note: If a target lesion is selected for an excisional screening biopsy, the inclusion 
criterion for measurable disease must still be met after such biopsy.
b) Be able to provide newly obtained bone marrow biopsy material for tumor response 
assessment by local investigator sites.
8. Cohort E (MM participants): Be able to provide newly obtained (within 3 months) bone 
marrow biopsy or aspirate material for disease assessment at local institution and submit 
sample to Sponsor-designated central laboratory for biomarker analysis. If bone marrow 
biopsy or aspiration was performed within 3 months before screening but participant had 
anticancer treatment after biopsy, the bone marrow biopsy or aspiration should be 
repeated.
9. Participants who have received CAR T-cell therapy before study entry and have 
experienced disease progression post therapy may be considered for the study.
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Demographics
10. Is male or female, ≥18 years of age, at the time of providing the informed consent.
Female Participants
11. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies:
•
Is not a WOCBP
OR
•
Is a WOCBP and using a contraceptive method that is highly effective (with a failure 
rate of <1% per year), or be abstinent from heterosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long-term and persistent basis), as described in 
Appendix 5 during the intervention period and for at least 120 days after the last dose 
of study intervention. The investigator should evaluate the potential for contraceptive 
method failure (ie, noncompliance, recently initiated) in relationship to the first dose 
of study intervention.
-
A WOCBP must have a negative highly sensitive pregnancy test ([urine or serum] 
as required by local regulations) within 72 hours for serum sample and within 24 
hours for urine test 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 8.3.7.
-
The investigator is responsible for review of medical history, menstrual history, 
and recent sexual activity to decrease the risk for inclusion of a woman with an 
early undetected pregnancy.
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
12. The participant (or legally acceptable representative) has provided documented informed 
consent for the study. The participant may also provide consent for FBR. However, the 
participant may participate in the study without participating in FBR.
Additional Categories
13. Participants with endocrine-related conditions, including Type 1 Diabetes Mellitus, 
hyperglycemia, hyperthyroidism, hypothyroidism, adrenal insufficiency, or hypophysitis, 
are eligible if controlled with treatment (≤Grade 1).
14. Have a performance status of 0 or 1 on the ECOG PS.
15. Have adequate organ function as defined in Table 8. Specimens must be collected within 
7 days before the start of study intervention.
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16. Participants who are HBsAg positive are eligible if they have received HBV antiviral 
therapy for at least 4 weeks and have undetectable HBV viral load before allocation.
Note: Participants should remain on antiviral therapy throughout study intervention and 
follow local guidelines for HBV antiviral therapy post completion of study intervention.
Hepatitis B screening tests are not required unless:
a) Known history of HBV infection.
b) As mandated by local health authority.
17. Participants with history of HCV infection are eligible if HCV viral load is undetectable 
at screening.
Note: Participants must have completed curative antiviral therapy at least 4 weeks before 
allocation.
Hepatitis C screening tests are not required unless:
a.
Known history of HCV infection.
b. As mandated by local health authority.
CCI
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. For Cohort D and F (DLBCL and NHL): Has lymphoplasmacytic lymphomas, 
Waldenstrom’s macroglobulinemia, chronic lymphocytic leukemia (not associated with 
small lymphocytic lymphoma), Burkitt (-like) lymphoma, mature T-cell and NK cell 
neoplasms, immunodeficiency associated lymphoproliferative neoplasms, or histiocytic 
and dendritic cell neoplasms.
2. For Cohort E (MM):
a) Has oligo-secretory myeloma, plasma cell leukemia, smoldering multiple myeloma, 
monoclonal gammopathy of undetermined significance.
b) History of primary amyloidosis, hyperviscosity or POEMS syndrome (plasma cell 
dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, 
and skin changes).
3. For Cohort F (EBV+ DLBCL): For patients with EBV+ DLBCL should NOT be 
associated with a solid organ transplant.
4. Has known prior or current CNS involvement.
5. A WOCBP who has a positive urine pregnancy test within 72 hours before study 
intervention allocation (see Appendix 5). If the urine test is positive or cannot be 
confirmed as negative, a serum pregnancy test will be required.
Note: If 72 hours have elapsed between the screening pregnancy test and the first dose of 
study intervention, another pregnancy test (urine or serum) must be performed and must 
be negative in order for participant to start receiving study medication.
6. Has clinically significant cardiovascular disease within 12 months from first dose of 
study intervention, including New York Heart Association Class III or IV congestive 
heart failure, unstable angina, myocardial infarction, cerebral vascular accident, or 
cardiac arrhythmia associated with hemodynamic instability.
Note: Medically controlled arrhythmia would be permitted.
7. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
8. Has a history of a second malignancy, unless potentially curative treatment has been 
completed with no evidence of malignancy for 3 years.
Note: The time requirement does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, squamous-cell carcinoma of the 
skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers.
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Prior/Concomitant Therapy
9. Has received prior therapy with an mAb blocking TIGIT, an anti-TIGIT agent or an agent 
modulating the TIGIT axis, or an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (except 
where specified) or with an agent directed to another stimulatory or coinhibitory T-cell 
receptor (eg, CTLA-4, OX-40, CD137).
Note: Participants in Cohort B, relapsed or refractory cHL or PMBCL, must have been 
previously treated with an anti-PD-1/L1 agent.
Note: Participants with toxicities to prior anti-PD-1/L1 therapy will be excluded unless 
their toxicities have resolved to ≤Grade 1 and/or permanent discontinuation is mandated 
per Table 11. Exceptions include participants with Grade 1-4 hypothyroidism, 
Grade 2 hyperthyroidism, and Grade 2 hyperglycemia (in combination with evidence of 
β-cell failure).
10. Any PMBCL participants in Cohort A and B that require the use of urgent cytoreductive 
therapy.
11. Has received prior systemic anticancer therapy, including investigational agents, within 2 
weeks (small molecules like kinase inhibitors) or 4 weeks (chemotherapies and 
monoclonal antibodies) before cohort allocation.
Note: Participants must have recovered from all AEs due to previous therapies to ≤Grade 
1 or baseline. Participants with ≤Grade 2 neuropathy may be eligible. Participants with 
endocrine-related AEs ≤Grade 2 requiring treatment or hormone replacement may be 
eligible. For consideration of AEs related to previous treatment with anti-PD-1/L1 
therapies, see note below criterion #9 above.
12. If the participant had major surgery, the participant must have recovered adequately from 
the procedure and/or any complications from the surgery before starting study 
intervention.
13. Has received prior radiotherapy within 2 weeks of start of study intervention. Participants 
must not require ongoing corticosteroid use, and not have >Grade 1 radiation 
pneumonitis or other radiation-related toxicities. A 1-week washout is permitted for 
palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
14. Has received a live or live-attenuated vaccine within 30 days before the first dose of 
study intervention. Administration of killed vaccines is allowed. Refer to Section 6.5 for 
information on COVID-19 vaccine.
Prior/Concurrent Clinical Study Experience
15. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks before the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study may 
participate as long as it has been 4 weeks after the last dose of the previous 
investigational agent
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Diagnostic Assessments
16. Known severe hypersensitivity to MK-7684A, vibostolimab or pembrolizumab and/or 
any of its excipients.
17. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority. Refer to Appendix 7 for country-specific testing requirements.
18. Has an active autoimmune disease that has required systemic treatment in past 2 years 
(ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency) is not considered a form of systemic 
treatment and is allowed.
19. Has an active infection requiring systemic therapy.
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the participant's participation 
for the full duration of the study, or is not in the best interest of the participant to 
participate, in the opinion of the treating investigator.
21. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant's ability to cooperate with the requirements of the study.
22. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring 
drainage or diuretic drugs within 2 weeks before enrollment.
23. Has dual active HBV infection (HBsAg (+) and /or detectable HBV DNA) and HCV 
infection (anti-HCV Ab (+) and detectable HCV RNA) at study entry.
Other Exclusions
24. Participant, in the judgment of the investigator, is unlikely to comply with the study 
procedures, restrictions, and requirements of the study.
25. Has had an allogenic hematopoietic stem cell/solid organ transplantation within the last 5 
years. Participants who have had a transplant greater than 5 years ago are eligible as long 
as there are no symptoms of Graft versus Host Disease
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
No restrictions are required.
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5.3.3
Activity Restrictions
No restrictions are necessary.
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.
Participants who fail screening may be rescreened for eligibility after consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
5.5
5.5.1
CCI
CCI
CCI
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CCI
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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 MK-7684A coformulation will be packaged to support enrollment. Clinical 
supplies will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 9
All study interventions will be administered in the clinic setting.
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Table 9
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: 
Cohorts A 
to F
Experimental MK-7684A
Biological/Vaccine Injection, 
Solution
Vibostolimab 
200mg+ 
pembrolizumab 
20 mg/ 20mL 
vial
200 mg/ 
200 mg
IV Infusion
Q3W up to 
35 cycles
Test 
Product
IMP
Central
EEA=European Economic Area, IMP=investigational medicinal product; IV=intravenous; NIMP/AxMP=noninvestigational/auxiliary medicinal product; Q3W=every 3 weeks.
The classification of IMP and NIMP 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 may exist. In these circumstances, local legislation is followed.
MK-7684A = coformulated as 200 mg vibostolimab and 200 mg pembrolizumab
Only participants that achieved SD, PR, or CR after initial treatment or first course followed by an investigator-determined disease progression as per disease-specific criteria will be eligible for a second 
course of treatment.
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All supplies indicated in Table 9 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.
6.1.1
Initial Treatment or First Course
The initial treatment or first course of MK-7684A coformulation consists of 35 treatments, 
administered Q3W. Note: The number of treatments is calculated starting with the first dose.
For participants who have attained a CR (confirmation of CR is required for MM 
participants) and have been treated for at least 8 cycles (at least 24 weeks) beyond the initial 
CR date (initial CR confirmation date for MM participants), treatment may be stopped.
6.1.2
Second Course of Study Treatment
All participants who have SD, PR, or CR may be eligible for up to an additional 17 cycles of 
MK-7684A if there is investigator-determined disease progression as per disease-specific 
criteria (see Appendix 8) after initial treatment or first course has been completed or stopped 
for confirmed CR, PR or SD. This retreatment is the second course of this study.
Note: For participants in Cohort E (MM), confirmation of CR is required beyond the initial 
CR date.
Participants may enter the second course if all of the following criteria are met:
1. No new anticancer treatment was administered after the last dose of study 
intervention
2. The participant meets all of the inclusion criteria and none of the exclusion criteria
3. The study is ongoing
An objective response or disease progression that occurs during the second course will not be 
counted as an event for the primary analysis of either endpoint in this study.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of MK-7684A are provided in the 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.
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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.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Participants enrolled in Part 1 of the study will be assigned to receive study intervention 
within the appropriate cohort as described in Section 5.1.
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, the details of and reason for any 
interruption of study intervention will be documented in the participant’s medical record.
Refer to Section 6.6.2 for dose modification and toxicity management for irAEs associated 
with MK-7684A and for other allowed dose interruptions of MK-7684A.
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Participants will receive study intervention in the clinic setting directly from the investigator 
or designee, under medical supervision. The date and time of each dose administered in the 
clinic will be recorded in the source documents and recorded in the CRF. The dose of study 
intervention and study participant ID will be confirmed at the time of dosing by a member of 
the study-site staff other than the person administering the study intervention.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the treatment period. If there is a clinical indication for any medication or vaccination 
specifically prohibited, discontinuation from study therapy or vaccination may be required. 
The investigator should discuss any questions regarding this with the Sponsor's Clinical 
Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician. However, the decision to continue the 
participant on-study intervention requires the mutual agreement of the investigator, the 
Sponsor, and the participant.
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medications will be recorded on the eCRF including all 
prescriptions, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
6.5.1
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6.5.2
Rescue Medications and Supportive Care
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Suggested supportive care measures for the management of AEs with potential immunologic 
etiology are outlined along with the dose modification guidelines in Sections 6.6.1, 6.6.2, and 
6.6.3. Note: If after the evaluation of the event, it is determined not to be related to MK-
7684A, the investigator does not need to follow the treatment guidance. Refer to Table 10 in 
Section 6.6.2 and Table 11 in Section 6.6.3 for guidelines regarding dose modification and 
supportive care.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Dose Modification and Toxicity Management of Hematological AEs Related to 
MK-7684A
No dose modifications are required for ≤Grade 3 hematological AEs.
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In the event of Grade 4 hematological AE that is associated with study treatment 
(pembrolizumab monotherapy, coformulations, or IO combinations), MK-7684A will not be 
resumed until the AE has returned to ≤Grade 1.
6.6.2
 
 
6.6.3
 
 
 
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Table 11
Dose Modification and Toxicity Management Guidelines for Immune-related Adverse Events Associated With 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
General instructions:
1.   Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.   Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment.
3.   The corticosteroid taper should begin when the irAE is ≤Grade 1 and continue at least 4 weeks.
4.   If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Pneumonitis 
Grade 2
Withhold 
·   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
·   Add prophylactic antibiotics 
for opportunistic infections
·     Monitor participants for signs and symptoms of 
pneumonitis
·     Evaluate participants with suspected pneumonitis 
with radiographic imaging and initiate corticosteroid 
treatment
Recurrent 
Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
Diarrhea/Colitis 
Grade 2 or 3
Withhold
·   Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
·     Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (ie, peritoneal signs and ileus)
·     Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and performing 
endoscopy to rule out colitis
·     Participants with diarrhea/colitis should be advised 
to drink liberal quantities of clear fluids. If sufficient 
oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion
Recurrent Grade 
3 or Grade 4
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
b-cell failure
Withhold a
·   Initiate insulin replacement 
therapy for participants with 
T1DM
·   Administer 
antihyperglycemic in 
participants with hyperglycemia
·     Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes
Hypophysitis
Grade 2
Withhold
·   Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
·     Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hyperthyroidism
Grade 2
Continue
·   Treat with nonselective beta-
blockers (eg, propranolol) or 
thionamides as appropriate
·     Monitor for signs and symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinue a
Hypothyroidism
Grade 2, 3 or 4
Continue
·   Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyronine) per standard of 
care
·     Monitor for signs and symptoms of thyroid 
disorders
Nephritis:
grading according to 
increased creatinine 
or acute kidney 
injury
Grade 2
Withhold
·   Administer corticosteroids 
(prednisone 1 to 2 mg/kg or 
equivalent) followed by taper
·     Monitor changes of renal function
Grade 3 or 4
Permanently 
discontinue
Neurological 
Toxicities
Grade 2
Withhold
·   Based on severity of AE 
administer corticosteroids
·     Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 3 or 4
Permanently 
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Myocarditis
Asymptomatic 
cardiac enzyme 
elevation with 
clinical 
suspicion of 
myocarditis 
(which was 
previously 
myocarditis 
Grade 1 using 
CTCAE v4.0)
Withhold
·   Based on severity of AE 
administer corticosteroids
·     Ensure adequate evaluation to confirm etiology 
and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
Exfoliative 
Dermatologic 
Conditions
Suspected SJS, 
TEN, or DRESS
Withhold
·   Based on severity of AE 
administer corticosteroids
·     Ensure adequate evaluation to confirm etiology or 
exclude other causes
Confirmed SJS, 
TEN, or DRESS
Permanently 
discontinue
All Other irAEs
Persistent Grade 
2
Withhold
·   Based on severity of AE 
administer corticosteroids
·     Ensure adequate evaluation to confirm etiology or 
exclude other causes
Grade 3
Withhold or 
discontinue based on 
the event b 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue
AE(s)=adverse event(s); CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; 
IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
b
Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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6.6.4
Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab Monotherapy, Coformulations (MK-7684A), or IO 
Combinations
Pembrolizumab monotherapy, coformulations (MK-7684A), or IO combinations may cause 
severe or life-threatening infusion reactions including severe hypersensitivity or anaphylaxis. 
Signs and symptoms usually develop during or shortly after drug infusion and generally 
resolve completely within 24 hours of completion of infusion. Dose modification and toxicity 
management guidelines on pembrolizumab monotherapy, coformulations (MK-7684A), or 
IO combinations associated infusion reactions are provided in Table 12.
Table 12
Pembrolizumab Monotherapy, Coformulations (MK-7684A), or IO 
Combinations Infusion Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 h
Stop Infusion
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion 
may be restarted at 50% of the original 
infusion rate (eg, from 100 mL/h to 
50 mL/h). Otherwise, dosing will be 
held until symptoms resolve and the 
participant should be premedicated for 
the next scheduled dose.
Participants who develop Grade 2 
toxicity despite adequate premedication 
should be permanently discontinued 
from further study intervention.
Participant may be premedicated 1.5 h 
(±30 min) prior to infusion of study 
intervention with:
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine).
Acetaminophen 500 to 1000 mg po (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms after initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the participant 
is deemed medically stable in the 
opinion of the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Participant is permanently discontinued 
from further study intervention.
No subsequent dosing
CTCAE=Common Terminology Criteria for Adverse Events; h=hour; IV=intravenous; NCI=National Cancer 
Institute; NSAIDs=nonsteroidal anti-inflammatory drugs.
Note: Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the CTCAE v5.0 at http://ctep.cancer.gov
6.6.5
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, 
Coformulations (MK-7684A), or IO Combinations
Pembrolizumab monotherapy, coformulations (MK-7684A), or IO combinations may be 
interrupted for situations other than treatment-related AEs such as medical or surgical events 
and/or unforeseen circumstances not related to study intervention. However, study 
intervention is to be restarted within 3 weeks of the originally scheduled dose and within 84 
days of the previously administered dose, unless otherwise discussed with the Sponsor. The 
reason for study intervention interruption is to be documented in the participant's study 
record.
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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6.9
Standard Policies
Not applicable.
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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 
regimen will still continue to be monitored in this study and participate in the study visits and 
procedures as specified in Section 1.3 and Section 8.11.3 unless the participant has 
withdrawn from the study 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 6.6.1, 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, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Disease progression outlined in Section 8.2.4 (after obtaining informed consent 
addendum and Sponsor communication, the investigator may elect to continue treatment 
beyond disease progression).
•
Any occurrence of another malignancy that requires active 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.
•
Any prohibited medication listed in Section 6.5.1.
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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.
Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention
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 8.9.
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 (or dental) decisions must be made by an investigator who is a 
qualified physician (or dentist when appropriate).
•
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 procedures meet 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 
is outlined in the Laboratory Manual.
Repeat or unscheduled samples may be taken for safety reasons (where clinically indicated) 
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.
If the investigator recommends continuation of study intervention beyond disease 
progression, the participant or their legally acceptable representative will be asked to provide 
documented informed consent.
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
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 
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the participant provides documented informed consent. At the time of intervention allocation,
site personnel will add the treatment/randomization number to the participant identification 
card.
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.
General medical history will collect all active conditions and any condition diagnosed within 
the prior 10 years that the investigator considers to be clinically important. All other prior 
malignancies should be recorded, regardless of timeframe.
Details regarding the disease for which the participant has enrolled in this study, ie, 
hematological malignancy, will be recorded separately and not listed as general medical 
history.
8.1.5
Baseline Disease Characteristics
The investigator or qualified designee will obtain prior and current details regarding 
hematological malignancy under the study. Initial primary diagnosis, prior anticancer 
therapies, and known genetic alterations/mutational status will be recorded. If applicable, 
prior history of acute and/or chronic GVHD, maximum grade, and dates will be collected.
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8.1.6
Prior and Concomitant Medications Review
8.1.6.1
Prior Medications
The investigator or qualified designee will review before medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before first dose of study intervention/vaccination.
8.1.6.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study. Refer to Section 6.5.1 for prohibited medication.
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 allocation. Each 
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participant will 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 8.11.1.
8.1.8
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/randomization number. The treatment/randomization number identifies the 
participant for all procedures occurring after treatment allocation. 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.
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.
8.1.9.1
Timing of Dose Administration
MK-7684A will be administered using a 30-minute, IV infusion every 3 weeks. The 
Pharmacy Manual contains specific instructions for MK-7684A reconstitution, preparation of 
the infusion fluid, and administration. All study treatment will be dosed on Day 1 of each 
21-day cycle. For Cycle 1 Day 1, study medication must be administered within 3 days of 
randomization. After Cycle 1 Day 1, study medication may be administered up to 3 days 
before or after the scheduled Day 1 of each subsequent cycle for administrative reasons.
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
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8.1.11
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
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.
8.2
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8.2.1
8.2.1.1
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8.2.2
8.2.2.1
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8.2.3
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8.2.4
8.2.4.1
8.2.4.2
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8.2.4.3
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8.2.5
 
8.2.6
8.3
8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
A full physical examination will be conducted by an investigator or medically qualified 
designee (consistent with local requirements) per institutional standard at screening only. 
Height will be measured and recorded at screening only and weight will be measured and 
recorded according to the SoA in Section 1.3.
Other system-based examinations should be included if clinically indicated.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
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8.3.1.2
Directed Physical Examination
For cycles that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated. New clinically significant abnormal findings should be recorded as AEs.
Other system-based examinations should be included if clinically indicated.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
Vital signs will be measured after 5 minutes rest and will include temperature, systolic and 
diastolic blood pressure, pulse, and respiration rate.
8.3.3
Eastern Cooperative Oncology Group Performance Scale
The investigator or qualified designee will assess ECOG PS (see Appendix 9) as specified in 
the SoA (Section 1.3). Screening assessment is required to be performed within 7 days of 
treatment allocation.
8.3.4
Electrocardiograms
12-lead ECG will be obtained and reviewed by an investigator or medically qualified 
designee (consistent with local requirements) as outlined in Section 1.3, using an ECG 
machine that automatically calculates the heart rate and measures pulse rate, QRS, QT, and 
QTc intervals.
8.3.5
Lymphoma B Symptoms (Cohorts A to D, and F; cHL, PMBCL, FL, DLBCL, 
and NHL)
These symptoms include the following:
•
Unintentional weight loss ≥10% within the previous 6 months.
•
Signiﬁcant fatigue (ie, ECOG PS 2 or worse; cannot work or unable to perform usual 
activities).
•
Fever of 100.5°F or 38.0°C for 2 or more weeks without evidence of infection.
•
Night sweats for ≥1 month without evidence of infection.
8.3.6
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.
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•
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 
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 (90 days if considered an SAE) 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.
For all cohorts (A to F), thyroid function tests (T3, T4, and TSH) are required at Screening 
and as per SoA in Section 1.3. Free T3 and free T4 are acceptable.
For Cohorts A to D, and F (cHL, PMBCL, FL, DLBCL, and NHL), LDH and beta-2 
microglobulin parameters will be included as per SoA in Section 1.3.
For Cohort E (MM) screening LDH and beta-2 microglobulin levels will be recorded and 
IgG, IgM, IgA will be monitored. IgD/E is only required for participants with IgD/E 
myeloma, where serum M-protein cannot be followed otherwise, as per SoA in Section 1.3.
8.3.7
Pregnancy Testing
•
Pregnancy testing:
•
Pregnancy testing requirements for study inclusion are described in Section 5.1. 
WOCBP require negative serum test within 72 hours or negative urine test within 24 
hours before each dose of study intervention. The definition of WOCBP is provided 
in Appendix 5.1.
•
Pregnancy testing (serum as required by local regulations) should be conducted every 
cycle (Q3W) during intervention.
•
Pregnancy testing (serum as required by local regulations) should be conducted at the 
end of relevant systemic exposure (ie, 120 days after the last dose of MK-7684A).
•
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 subject's participation in the study.
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8.3.8
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 unless it results in 
hospitalization or death as described in Section 8.4 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.
Adverse events will not be collected for participants during the prescreening period (for 
determination of archival tissue status) as long as that participant has not undergone any 
protocol-specified procedure or intervention. If the participant requires a blood draw, fresh 
tumor biopsy, etc, the participant is first required to provide consent to the main study, and 
AEs will be captured according to guidelines for standard AE reporting.
Refer to Section 4.3.4 for DLT definition.
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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/randomization 
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.
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 13.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 13
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)
Exception: A positive 
pregnancy test at the time 
of initial screening is not a 
reportable event.
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.
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 
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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 allocated 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.
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
Progression of the cancer under study is not considered a reportable event unless it results in 
hospitalization or death.
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8.4.7
8.5
Treatment of Overdose
For purposes of this study, an overdose will be defined as ≥3 times the protocol-specified 
dose for MK-7684A. No specific information is available on the treatment of overdose of 
MK-7684A. In the event of overdose, study intervention should be discontinued, and the 
participant should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated.
All reports of MK-7684A overdose with and without an AE must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper.
Reports of either MK-7684A overdose without any associated clinical symptoms or 
abnormal laboratory results, should be reported using the terminology “accidental or 
intentional overdose without adverse effect.”
8.6
Pharmacokinetics
To further evaluate MK-7684A immunogenicity and exposure in various hematological 
malignancies, sample collections for analysis of ADA and PK are currently planned as shown 
in Section 1.3. Predose blood samples will be obtained to measure PK of serum vibostolimab 
and pembrolizumab and postdose blood samples will measure PK of serum MK-7684A. 
Serum Cmax and Ctrough at planned visits and times will be summarized.
8.6.1
Blood Collection for Plasma MK-7684A
Sample collection, storage, and shipment instructions for plasma samples will be provided in 
the Laboratory Manual.
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8.7
Pharmacodynamics
Sample collection, storage, and shipment instructions for pharmacodynamic samples will be 
in Laboratory Manual.
8.8
Biomarkers
8.8.1
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8.9
Future Biomedical Research Sample Collection
8.10
Health Economics Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data, associated with medical encounters, 
will be collected in the CRF by the investigator and study-site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.
The data collected may be used to conduct exploratory economic analyses and will include:
•
Number and duration of medical care encounters, including surgeries, and other selected 
procedures (inpatient and outpatient)
•
Duration of hospitalization (total days or length of stay, including duration by wards [eg, 
intensive care unit])
•
Number and type of diagnostic and therapeutic tests and procedures
•
Outpatient medical encounters and treatments (including physician or emergency room 
visits, tests and procedures, and medications).
8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
After the approval of Amendment 5, the follow up, survival follow up and ongoing 
assessments per original SoA are amended.
The study will end 90 days after the last participant completes 35 cycles of treatment or 
terminates early, whichever comes first, and second course option for treatment is no longer 
available. Participants in the Imaging Follow-up or Survival Follow-up phase will be 
discontinued from the study, and no further imaging or participant contacts will be required.
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8.11.1
Screening
Approximately 28 days before intervention allocation, potential participants will be evaluated 
to determine that they fulfill the entry requirements as set forth in Section 5. Screening 
procedures may be repeated after consultation with the Sponsor. Visit requirements are 
outlined in the SoA (Section 1.3.1).
8.11.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.
For participants eligible for a second course of treatment (see Section 6.1.2), visit 
requirements are outlined in the SoA (Section 1.3.3).
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
Participants who discontinue study treatment due to disease recurrence or start of a new 
anticancer therapy will have Safety Follow-up and then proceed directly to Survival Follow 
up Phase as outlined in the SoA (Section 1.3.4) and in Section 8.11.4.
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.
8.11.4
Poststudy Visits
After approval of Amendment 5, participants will not be offered second course treatment. 
This will not affect participants already receiving the second course treatment.
The study will end 90 days after the last participant completes 35 cycles of treatment or 
terminates early, whichever comes first, and second course option for treatment is no longer 
available. Participants in the Imaging Follow-up or Survival Follow-up phase will be 
discontinued from the study, and no further visits will be required.
8.11.4.1
Safety Follow-up Visit
Safety Follow-up Visits can be at clinic or telephone visit.
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before initiation of a new anticancer treatment, whichever 
comes first.
Participants who are eligible for a second course of treatment with MK-7684A may have up 
to 2 Safety Follow-up Visits: 1 after the initial treatment or first course and 1 after the second 
course.
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8.11.4.2
Efficacy Follow-up Visits
Efficacy Follow-up Visits are required for participants who withdraw from treatment without 
disease progression and have not received new anticancer therapy. Participants who complete 
the protocol-required cycles of study intervention or who discontinue study intervention for a 
reason other than disease progression will begin Efficacy Follow-up and should be assessed 
Q12W to monitor disease status for Cohorts A to D, and F (cHL, PMBCL, FL, DLBCL, and 
NHL), Q4W for Cohort E (MM). Every effort should be made to collect information 
regarding disease status until the start of new anticancer therapy, disease progression, death, 
end-of-study or if the participant begins retreatment with MK-7684A as detailed in Section 
6.1.2. Information regarding poststudy anticancer treatment will be collected if new treatment 
is initiated. Participants who completed all efficacy assessments and/or will not have further 
efficacy assessments must enter Survival Follow-up.
Participants who are eligible to receive retreatment with MK-7684A according to the criteria 
in Section 6.1.2 will move from Efficacy Follow-up to second course when they experience 
disease progression. Details are provided in the SoA (Section 1.3.3) for retreatment with 
MK-7684A.
8.11.4.3
Survival Follow-up Contacts
Survival Follow-up Visits are required for participants that withdraw from treatment for 
disease progression or have started other anticancer therapy.
Participant Survival Follow-up status will be assessed approximately every 12 weeks to 
assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
The first Survival Follow-up assessment should be scheduled as described below:
1. For participants who discontinue treatment intervention and who will not enter 
Efficacy Follow-up, the first Survival Follow-up contact will be scheduled 12 weeks 
after the Discontinuation Visit and/or Safety Follow-up Visit (whichever is last).
2. For participants who completed assessments in Efficacy Follow-up, the first Survival 
Follow-up contact will be scheduled 12 weeks after the last efficacy assessment 
follow-up visit has been performed.
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized will be documented in a sSAP 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
Key elements of the SAP are summarized below. The comprehensive plan is provided in 
Section 9.2 through Section 9.12.
Study Design Overview
A Phase 2, open-label, nonrandomized study to evaluate the safety and efficacy 
of MK-7684A and vibostolimab monotherapy in participants with various 
hematological malignancies.
The study will be divided into 2 parts: signal finding (Part 1) and cohort 
expansion (Part 2). 
Primary Endpoints
Part 1:
Safety assessed by number of participants with and/or rates of:

Dose-limiting Toxicities

Adverse Events

Discontinuation of study intervention due to an AE
Secondary Endpoints
Part 1:

Objective response rate assessed per disease criteria by investigator

Duration of response as assessed by investigator per relevant disease 
response criteria (Appendix 8)

Disease control rate as assessed by investigator per relevant disease 
response criteria (Appendix 8)

Pharmacokinetic endpoints including: Ctrough and Cmax
Note: CR, PR, and PD in lymphoma participants do not require confirmation. 
Stringent CR, CR, VGPR, PR, and PD in MM participants require confirmation 
via 2 consecutive laboratory assessments.
Statistical Methods for 
Key Efficacy Analyses
Separately for each disease cohort, the point estimate of ORR and DCR will be 
provided, together with 95% CI using exact binomial method proposed by 
Clopper and Pearson (1934)[Clopper, C. J. and Pearson, E. S. 1934]. Time to 
event analyses (DOR) will be based on Kaplan-Meier estimation and 
corresponding 95% CIs.
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Statistical Methods for 
Key Safety Analyses
Counts and percentages of participants with AEs will be provided. The estimate 
of the DLT rate among participants treated with MK-7684A in the DLT 
assessment period and the 95% confidence interval for the estimate will be 
provided.
Interim Analyses
In Part 1, safety data will be examined on a continuous basis during the DLT 
evaluation window. The first interim safety review will be performed when there 
are 12 DLT evaluable subjects who have completed at least 2 cycles of 
treatment.
For efficacy data, each cohort will be reviewed individually to assess efficacy 
signal.
Details are provided in Section 9.7.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power
Overall, approximately 330 participants may be enrolled into both parts of the 
study; the planned sample in Part 1 may include approximately 180 participants 
with relapsed/refractory disease in Cohorts A to F to be administered MK-
7684A; the planned sample size in Part 2 may include approximately 120 
participants with relapsed/refractory disease in Cohorts B to E to be administered 
MK-7684A and approximately 30 participants in Cohort G to be administered 
vibostolimab monotherapy. A target sample size of approximately 390
participants will be used for study planning purposes. 
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.
This study is being conducted as a nonrandomized, open-label study, ie, participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned.
9.3
Hypotheses/Estimation
There are no hypotheses to be tested in this study. Objectives of the study are outlined in 
Section 3.
9.4
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below, followed by the 
descriptions of the derivations of selected endpoints.
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9.4.1
Efficacy/Pharmacokinetics Endpoints
After the approval of Amendment 5, the tertiary/exploratory endpoints will not be pursued 
after the study ends.
Secondary (Part 1)

Objective Response Rate
The ORR is defined as the percentage of participants who achieve a CR or PR (for MM 
this includes stringent CR, CR, and VGPR), as assessed by investigator per disease-
specific criteria (see Appendix 8).

Duration of Response
For participants who show an objective response, as assessed by investigator per disease-
specific criteria, duration of response is defined as the time from the first documented 
evidence of an objective response (CR or PR [for MM this includes stringent CR, CR, and 
VGPR]) until disease progression or death due to any cause, whichever occurs first.

Disease Control Rate
The DCR is defined as the percentage of participants who have achieved stringent CR, 
CR, PR (for MM, also including VGPR, MR), or have showed SD for at least 12 weeks 
before any evidence of progression, per disease-specific criteria (see Appendix 8) as 
assessed by investigator.

Pharmacokinetic endpoints
PK endpoints will include vibostolimab Ctrough and Cmax parameters.
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9.4.2
Safety Endpoints
The primary endpoint of Part 1 is the number and proportion of participants with DLTs, with 
AEs, and who discontinue study treatment due to AEs. 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.
9.4.3
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
Efficacy analyses will be conducted in the APaT population, which consists of all allocated 
participants who received at least 1 dose of study treatment.
9.5.2
Safety Analysis Population
Safety analyses will be conducted in the APaT population, which consists of all allocated 
participants who received at least 1 dose of study treatment.
In Part 1, the DLT evaluable population includes the first 12 participants who meet the 
criteria for DLT evaluability of at least 2 cycles of treatment without discontinuation from 
study treatment, further detailed in Section 5.5.1. Section 4.3.4 describes the definition of 
DLTs.
At least 1 laboratory, vital sign, or ECG measurement obtained after at least 1 dose of study 
treatment is required for inclusion in the analysis of the respective safety parameter. To 
assess change from baseline, a baseline measurement is also required.
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9.5.3
PK Populations
PK analyses will be conducted in the APaT, which consists of all allocated participants who 
received at least 1 dose of study treatment, who have a valid Ctrough and/or Cmax measurement, 
within the permissible visit window.
9.5.4
PRO Analysis Population
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the secondary objectives. The 
efficacy analyses for ORR, DCR, and DOR will include responses and documented 
progression events that occur before second course treatment. Methods related to exploratory 
objectives will be described in the supplemental SAP.
Efficacy analyses will be performed for Part 1 and for combined data of Part 1 and Part 2.
9.6.1.1
Objective Response Rate
The assessment of the ORR by investigator is a secondary endpoint for Part 1. Estimation of 
the ORR based on disease-specific criteria will be conducted; Lugano 2014 criteria for 
Cohorts A to D and F (participants with lymphoma), and IWMG 2016 criteria for Cohort E
(participants with MM). The point estimate of ORR will be provided per cohort, together 
with 95% CI using exact binomial method proposed by Clopper and Pearson (1934)
[Clopper, C. J. and Pearson, E. S. 1934]. Participants with missing data will be considered 
nonresponders.
9.6.1.2
Duration of Response
The secondary efficacy endpoint of DOR as assessed by investigator will be summarized by 
cohort. If sample size permits, DOR will be summarized descriptively using Kaplan-Meier 
medians and quartiles. Only the subset of participants who achieve an objective response will 
be included in this analysis. Censoring rules for DOR are summarized in Table 14; additional 
details on disease-specific censoring, where needed, will appear in the sSAP. For each DOR 
analysis, a corresponding summary of the reasons responding participants are censored will 
also be provided. Responding participants who are alive, have not progressed, have not 
initiated new anticancer treatment, have not been determined to be lost to follow-up, and 
have had a disease assessment within ~5 months of the data cutoff date are considered 
ongoing responders at the time of analysis. If a participant meets multiple criteria for 
censoring, the censoring criterion that occurs earliest will be applied.
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9.6.1.3
Disease Control Rate
The assessment of the DCR by investigator is a secondary endpoint. Estimation of the DCR
based on disease-specific criteria will be conducted; Lugano 2014 criteria for Cohorts A to D 
and F (participants with lymphoma), and IWMG 2016 criteria for Cohort E (participants with 
MM). The point estimate of DCR will be provided per cohort, together with 95% CI using 
exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. J. and Pearson, 
E. S. 1934] .
Participants with missing data will be considered nonresponders.
9.6.1.4
Analysis Strategy for Key Efficacy Variables
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 15.
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Table 15
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
(Estimation)
Analysis 
Population
Missing Data Approach
Primary Analyses
ORR per disease-specific 
criteria a by investigator 
Summary statistics 
with 95% CI using 
Exact method based 
on binomial 
distribution
APaT
Participants with missing data 
are considered nonresponders
Key Secondary Analyses
DOR per disease-specific 
criteria a by investigator 
Summary statistics 
using Kaplan-Meier 
method
Responders 
in APaT 
population
See Table 14 for censoring 
rules
DCR per disease-specific 
criteriaa by investigator 
Summary statistics 
with 95% CI using 
Exact method based 
on binomial 
distribution
APaT
Participants with missing data 
are considered nonresponders
Abbreviations: APaT=all participants as treated; CI=confidence interval; DCR=disease control rate; 
DOR=duration of response; ORR=objective response rate.
a see Section 8.2.
9.6.2
Statistical Methods for Safety Analyses
Adverse events will be summarized by counts and frequencies for each cohort and/or pooled 
across cohorts. In addition, the broad AE categories consisting of the percentage of 
participants with any AE, a drug-related AE, a SAE, an AE, which is both drug-related and 
serious, and who discontinued due to an AE will be summarized in the same manner. 
Laboratory tests, vital signs, and other safety endpoints will be summarized as appropriate.
Safety data from second course of treatment will be excluded from the primary analyses.
For Part 1 (signal finding), the estimate of the DLT rate among the first 12 evaluable 
participants treated in Part 1 and the 95% confidence interval for the estimate will be 
provided.
9.6.3
9.6.4
Baseline Characteristics, Demographics, and Other Analyses
9.6.4.1
Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized. The number and percentage of participants 
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screened and randomized and the primary reasons for screening failure and discontinuation 
will be displayed. These analyses will be performed by cohort and overall.
9.6.4.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis
Pharmacokinetic parameters will be summarized by planned visit and time.
9.7
9.7.1
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9.7.2
Efficacy Interim Reviews
9.7.2.1
Efficacy Futility Review
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9.9
Sample Size and Power Calculations
Part 1 (signal finding) Sample Size:
Approximately 30 participants may enroll per cohort (Cohorts A to F). With 30 participants 
in each cohort, the maximum half-width of the two-sided 95% exact confidence interval for 
ORR within each cohort is 18.7%.
Part 2 (cohort expansion) Sample Size:
Approximately 30 participants may enroll per cohort (Cohorts B to E and G) and this is the 
target sample size used for study planning purposes. 
Since this study does not have formal hypotheses to be tested, no power calculations will be 
incorporated.
9.10
 
9.11
Compliance (Medication Adherence)
Study intervention is administered at the investigational institution. Drug accountability data 
for study treatment will be collected during the study. Any deviation from protocol-directed 
administration will be reported.
9.12
Extent of Exposure
Extent of Exposure for a participant is defined as the number of cycles in which the 
participant receives the study medication. Summary statistics will be provided on the Extent 
of Exposure for the APaT population.
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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 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 
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protection rights of all participants, trial site staff and, where applicable, third 
parties. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate 
participants, adequacy of facilities and staff, previous performance in clinical 
trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess 
the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis-generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
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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.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
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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 
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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.
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 
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and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
Not applicable.
10.1.5
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.
10.1.6
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.
10.1.7
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.
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The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority. 
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
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.
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Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
10.1.9
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.
10.1.10
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
•
Hematology, chemistry, and urinalysis testing detailed in Table 19 will be performed by 
the local laboratory.
•
Additional individual laboratory assessments, including INR/PT/aPTT, LDH, beta-2 
microglobulin, FSH (see Appendix 5), thyroid function, and serum immunoglobulin 
levels, as well as pregnancy test (see Appendix 5) and infection tests (HCV, HBV and 
HIV), are described in SoA.
•
Biochemical assessment for MM participants as detailed in SoA (Section 1.3) will also be 
performed by the local laboratory. If investigative sites do not have the capability to 
perform the required parameters listed in the protocol, samples may be submitted for 
central laboratory analysis. Investigators should contact the Sponsor to request this.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations.
Table 19
Hematology, Chemistry, and Urinalysis Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
RBC Indices (optional):
MCV
MCH
Reticulocytes (optional)
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUN (urea for sites 
that do not perform 
BUN)
Potassium
AST/SGOT
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is above 
the ULN)
Albumin
Bicarbonate
Chloride
Phosphorous
CrCl OR GFR
Sodium
ALT/SGPT
Total Protein
Glucose 
(Investigator should 
specify if sample is 
fasting or 
nonfasting)
Calcium
Alkaline 
phosphatase
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Laboratory 
Assessments
Parameters
Routine 
Urinalysis
Specific gravity
pH, glucose, protein, blood, ketones, leukocyte (esterase)
Bilirubin, urobilinogen, nitrite are optional by UA or dipstick
Abnormal urine dipstick will trigger microscopic examination/full urine analysis 
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; MCH=mean corpuscular 
hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; SGOT=serum glutamic oxaloacetic transaminase; 
SGPT=serum glutamic pyruvic transaminase; UA=urinalysis; ULN=upper limit of normal.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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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 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.”
Any new cancer (that is not a condition of the study). Progression of the cancer under study 
is not considered a reportable event unless it results in hospitalization or death.
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.
10.3.3
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:

Results in death

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.
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
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.

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.

Is a congenital anomaly/birth defect

In offspring of participant taking the product regardless of time to diagnosis.

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 room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
10.3.4
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 in the same time frame as SAEs to 
meet certain local requirements. Therefore, these events are considered serious by the 
Sponsor for collection purposes.
•
Is a new cancer (that is not a condition of the study).
•
Is associated with an overdose.
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10.3.5
Recording AE and SAE
AE and SAE recording
•
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory, and diagnostics reports) related to 
the event.
•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
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.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the Sponsor’s product cause the AE?
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•
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.
◦
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 re-exposed to the Sponsor’s product in this study?
◦
If yes, did the AE recur or worsen?
◦
If yes, this is a positive rechallenge.
◦
If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or 
permanent disability, or (2) the study is a single-dose drug study; or (3) Sponsor’s 
product(s) is/are used only 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 RE-EXPOSURE 
TO THE SPONSOR’S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT 
RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE APPROVED IN 
ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
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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 his/her best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a Sponsor’s product relationship).
-
Yes, there is a reasonable possibility of Sponsor’s product relationship:
◦
There is evidence of exposure to the Sponsor’s product. The temporal sequence of 
the AE onset relative to the administration of the Sponsor’s product is reasonable. 
The AE is more likely explained by the Sponsor’s product than by another cause.
-
No, there is not a reasonable possibility of Sponsor’s product relationship:
◦
Participant did not receive the Sponsor’s product OR temporal sequence of the 
AE onset relative to administration of the Sponsor’s product is not reasonable OR 
the AE is more likely explained by another cause than the Sponsor’s product. 
(Also entered for a participant with overdose without an associated AE.)
•
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 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.
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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.
10.3.6
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.
•
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.
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•
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
Not applicable.
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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, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
-
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required.
-
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraception 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
IUSd
Non-hormonal IUD
Bilateral tubal occlusion
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method 
of contraception should be used. A spermatogenesis cycle is approximately 90 days.
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
-
Oral
-
Intravaginal
-
Transdermal
-
Injectable
Progestogen-only hormonal contraceptionc
-
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   If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to those which 
inhibit ovulation.
d   IUS is a progestin releasing IUD.
Note: The following are not acceptable methods of contraception:
-  Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides 
only, and LAM.
-  Male condom with cap, diaphragm, or sponge with spermicide.
-  Male and female condom should not be used together (due to risk of failure with friction).
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10.6
 
CCI
CCI
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CCI
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CCI
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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/
CCI
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10.7
10.7.1
10.7.2
CCI
CCI
CCI
CCI
CCI
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10.7.3
CCI
CCI
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10.8
Appendix 8: Response Criteria
10.8.1
Lugano Classification (Cohorts A to D, and F)
Lugano Classification 2014 [Cheson, B. D., et al 2014].
This appendix describes the process for assessing treatment response according to the 
Lugano Classification [Cheson, B. D., et al 2014] (“Lugano” from now on) for malignant 
lymphoma. This assessment includes anatomic imaging with CT or MRI (size assessments of 
lymph nodes, extranodal lesions, spleen, and liver), metabolic imaging (whole body 
assessment with FDG-PET), and clinical findings (physical examination and bone marrow 
biopsy results), when these are available and appropriate.
Anatomic imaging may include CT, MRI or some combination of the 2, with details 
specified in the Site Imaging Manual. CT is the most common modality used, and for the 
purposes of this document the term “CT” will be used to represent all anatomic imaging, no 
matter which imaging modality is used.
Before treatment (“baseline”), on CT all focal lesions (nodal and extranodal) will be 
classified as “target” (selected for quantitative assessment) and “nontarget” (selected for 
qualitative assessment). The spleen will be assessed quantitatively (by measuring the vertical 
length), and the liver will be assessed qualitatively. The FDG-PET will be assessed using the 
5-point scale (a method similar to the older Deauville criteria [Barrington, S. F., et al 2014]). 
If bone marrow biopsy is performed, or if there are any physical examination findings that 
cannot be evaluated by imaging, these should be documented.
After therapy has begun, response assessment will include anatomic response based on CT 
(when a CT is available), which includes target, nontarget, and new focal lesions, as well as 
spleen and liver size assessment. Metabolic response, when an FDG-PET is available, will be 
based on the 5-point scale along with qualitative assessment of changes in FDG uptake from 
preceding timepoints. Anatomic response, metabolic response, and clinical information will 
be combined to produce the overall response for each timepoint. The criteria are summarized 
in the table below, and detailed in the following sections.
Lugano Summary Table
The following tables summarize the assessments based on both CT and PET, as described in 
the summary table in the original publication [Cheson, B. D., et al 2014]. For details about 
implementation, please see the sections following the tables. LDi – Longest diameter, SDi –
Short axis diameter, PPD – product of perpendicular diameters, SPD – sum of products of 
diameters.
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Complete Response (CR)
CR
PET-Based Response –
CMR
CT/MRI-Based Response - CR
Target lesions
Score 1, 2, or 3
Target nodes/nodal masses regress 
to <1.5 cm in LDi; no extranodal 
sites of disease remain
Nontarget lesions
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid disease in 
marrow
Normal by morphology; if 
indeterminate, negative by 
immunohistochemistry
CMR = complete metabolic response; CR = complete response; CT = computed tomography; FDG = 
2-fluorodeoxyglucose; LDi = longest diameter; MRI = magnetic resonance imaging; PET = positron emission 
tomography.
Partial Response (PR)
PR
PET-Based Response – PMR
CT/MRI-Based Response - PR
Target lesions
Score 4 or 5 without new lesions
Reduced overall uptake (extent and/or 
intensity) compared with baseline 
≥50% decrease from baseline 
in SPD of target lymph nodes 
and extranodal sites (up to 6)
Nontarget lesions
Not applicable
Anything other than 
progression 
Organ enlargement
Not applicable
Spleen must have regressed by 
≥50% in excess length 
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with baseline.
If there are persistent focal changes in the 
marrow in the context of a nodal response 
and without recent growth factor use, 
perform biopsy, or consider MRI, or an 
interval scan.
Not applicable 
CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography; PMR = partial 
metabolic response; PR = partial response; SPD = sum of products of diameters.
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Stable Disease (SD)
SD 
PET- Based Response – SMD
CT/MRI-Based Response - SD
Target lesions
Score 4 or 5 (without new lesions)
No significant change in FDG uptake 
from baseline or nadir 
<50% decrease from baseline in 
SPD of target lesions.
No lesion shows progression
Nontarget lesions
Not applicable
No increase consistent with 
progression 
Organ enlargement
Not applicable
No increase consistent with 
progression 
New lesions
None
None
Bone marrow
No change from baseline 
Not applicable 
CT = computed tomography; FDG = 2-fluorodeoxyglucose; MRI = magnetic resonance imaging; PET = positron 
emission tomography; SD = stable disease; SMD = stable metabolic disease; SPD = sum of products of diameters.
Progressive Disease (PD)
PD
PET-Based Response – PMD
CT/MRI-Based Response - PD
Target lesions
Score 4 or 5 with an increase in overall 
uptake (extent and/or intensity) from 
baseline 
Growth of any target lesion:
Increase ≥50% from nadir PPD 
and
Increase in LDi or SDi from nadir 
of:
≥0.5 cm for lesions <2 cm
≥1.0 cm for lesions ≥2 cm
and
Current LDi >1.5 cm for a lymph 
node or ≥1.0 cm for an extranodal 
lesion
Nontarget lesions 
Not applicable
Clear progression of preexisting 
nontarget lesions 
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another cause (eg, 
infection, inflammation).
If uncertain regarding cause of new 
lesions, biopsy or interval scan may be 
considered
Regrowth of previously resolved 
lesions
A new node >1.5 cm in LDi
A new extranodal site of any size, 
as long as its presence is 
unequivocal and attributable to 
lymphoma 
Organ enlargement
When splenomegaly was already 
present, the excess length must 
increase by >50% (≥1 cm absolute 
increase) from nadir.
If no prior splenomegaly, or prior 
splenomegaly had resolved, spleen 
length must increase by ≥2 cm to 
>13 cm.
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PD
PET-Based Response – PMD
CT/MRI-Based Response - PD
Bone marrow
New or recurrent FDG-avid foci, 
confirmed by biopsy 
New or recurrent involvement 
CT = computed tomography; FDG = 2-fluorodeoxyglucose; LDi = longest diameter; MRI = magnetic resonance 
imaging; PET = positron emission tomography; PD = progressive disease; PMD = progressive metabolic disease; PPD = 
product of perpendicular diameters; SDi = short axis diameter.
Anatomic Disease Assessment
Anatomic assessment specifically refers to the size of focal lesions or organs, assessed using 
computed tomography or magnetic resonance imaging. As stated previously, for simplicity 
the term “CT” will be used to represent all anatomic imaging.
Screening (Baseline) Assessment
Documentation of focal lesions
All focal lesions caused by lymphoma are identified at baseline and classified as measurable 
or nonmeasurable. Up to 6 of the measurable lesions are selected to serve as “target” lesions, 
which are then followed quantitatively throughout the study. All other focal lesions are 
documented as “nontarget” lesions, and evaluated qualitatively thereafter.
Measurable and nonmeasurable lesions
Malignant lymph nodes (nodal lesions) are considered measurable if they are consistent with 
lymphoma, clearly and reproducibly measurable in 2 dimensions on an axial slice, and 
measure >1.5 cm in LDi when assessed by CT/MRI scan, irrespective of scanner type and 
slice thickness/interval. Extranodal lesions are considered measurable if they are consistent 
with lymphoma, clearly and reproducibly measurable in 2 dimensions on an axial slice, and 
are ≥1.0 cm in both LDi and SDi when assessed by CT/MRI scan, regardless of slice 
thickness. In lymphomas that are FDG-avid, a lesion must be PET-positive (show FDG 
uptake greater than the surrounding tissue) to be measurable.
Lesions considered nonmeasurable include:
•
Lymph nodes and nodal masses that are PET-positive and considered consistent with 
lymphoma, but that do not meet the size and reproducibility requirements to be 
considered measurable, and lesions visible on PET but not CT
•
PET-negative lesions which meet the size criteria for measurability, and are considered 
consistent with lymphoma, in lymphoma that shows FDG avidity in other lesions
•
Uni-dimensionally measurable lesions (clearly measurable in only one dimension)
•
Extranodal lesions which do not meet the requirements for measurability, but are 
considered to be clearly due to lymphoma
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•
Truly nonmeasurable/assessable sites of disease, including:
-
Effusions and ascites
-
Bone lesions
-
Brain lesions, CNS lesions, leptomeningeal disease
-
Mucosal lesions in the gastrointestinal tract
-
Pleural, peritoneal or bowel wall thickening
Target and Nontarget Lesions
Up to up to 6 target lesions will be selected from among the measurable lesions and
documented as target nodal and target extranodal lesions. Target lesions should be selected 
based on their size (largest lesions preferred) and suitability for reproducible measurements. 
Measurements of the LDi and SDi should be made in the axial plane on the slice of the tumor 
with the longest in-plane diameter. Calculate the PPD for each target lesion and the SPD for 
all target lesions.
Nontarget lesions will be all focal (nodal and extranodal) lesions that are consistent with 
lymphoma, but not chosen as target lesions, whether they were measurable or not.
Once lesions are designated as target or nontarget, those designations may not change during 
later assessments.
Spleen Assessment at Baseline
Splenic involvement will be assessed quantitatively, as a separate category from the 
assessment of measurable or nonmeasurable focal lesions. The spleen length will be 
measured from cranial to caudal. All spleen measurements referred to hereafter will refer to 
this cranio-caudal measurement. The spleen is considered normal if it is less than 13 cm, or if 
the spleen has been removed surgically. It is considered enlarged if it is greater than 13 cm in 
length. The portion of the measurement that exceeds 13 cm will be considered the abnormal 
portion.
Liver Assessment at Baseline
Hepatic involvement will be assessed qualitatively, separately from the assessment of 
measurable or nonmeasurable disease. At baseline, the liver will be assessed qualitatively as 
either normal or enlarged, and should only be documented as enlarged if there is clear 
evidence (based on biopsy or imaging) that the enlargement is due to lymphoma, and not to 
benign causes.
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Anatomic Response (CT-based postbaseline assessment)
Target lesions
At every timepoint after screening, each target lesion is measured. Calculate the PPD for 
each target lesion and the SPD for all target lesions together. Response categories are as 
defined below:
•
Complete Response: All target lymph nodes must have regressed to normal size defined 
as ≤1.5 cm in LDi. Target extranodal sites must be absent (0 by 0 cm).
•
Partial Response: ≥50% decrease in SPD of target lesions from baseline, and no 
individual lesion meets the criteria for progression.
•
Progressive Disease: Target lesion progression is based on the progression of any single 
lesion (not a change in the SPD), which meets all of the following requirements:
-
The lesion must have increased by ≥50% from its nadir in PPD.
-
For a lymph node, it must be >1.5 cm in LDi, and for an extranodal lesion it must be 
≥1.0 cm in LDi.
-
And one of the following:
◦
For lesions <2 cm at nadir, the lesion’s LDi or SDi must have increased by ≥0.5 
cm at the current timepoint from its nadir.
◦
For lesions ≥2 cm at nadir, the lesion’s LDi or SDi must have increased by ≥1 cm 
at the current timepoint from its nadir.
•
Stable Disease: A target lesion assessment of SD requires all of the following:
-
Target lesions do not meet the criteria for CR or PR
-
No individual lesion meets the criteria for progression
•
Not Evaluable: When a target lesion identified at baseline cannot be evaluated at a 
postbaseline timepoint due to missing imaging, poor image quality, changes in the lesion 
or background that precludes assessment, or focal therapy or other procedures that 
change the lesion size, the target lesion assessment will be NE, unless progression is 
assessed in another target lesion.
Nontarget lesions
Nontarget lesions will be assessed at each post baseline timepoint individually and as a 
group. Response categories are as defined below:
•
Absent/Normalized (CR): All individual nontarget nodal lesions must have returned to 
normal size. All extranodal lesions must have disappeared.
•
Unequivocal Progression (PD): Any individual nontarget lesion must unequivocally 
progress in the context of the overall disease burden to be assessed as PD. For increased 
thickening of the wall of a hollow viscus, the reviewer will use their cautious judgment to 
determine whether the increase is most likely caused by disease progression.
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•
PD should not be called based on enlarging pleural effusions or ascites, or enlarging lytic 
bone lesions, and rather, the overall assessment should be based on the rest of the disease 
burden.
•
Stable Disease: At least one nontarget lesion is still present, or a node enlarged, without 
any individual lesions showing unequivocal progression.
•
Not Evaluable: When an individual nontarget lesion lymph node, extranodal lesion, or 
nonmeasurable disease cannot be assessed at a postbaseline timepoint due to missing 
imaging, poor image quality, changes in the lesion or background that precludes 
assessment, or focal therapy to a lesion, the individual nontarget lesion will be assessed 
as NE. The assessment of the nontarget lesions as a whole will be NE if any of the 
nontarget lesions are NE and none are PD.
New lesions
Lesions will be considered new if they were not present at the baseline timepoint but are 
visible at the current timepoint.
A node consistent with lymphoma will be recorded as a new lesion if it was previously 
normal in size and is now >1.5 cm in LDi. An unequivocal, new extranodal lesion consistent 
with lymphoma of any size is considered a new lesion. If multiple new extranodal lesions are 
noted, at least one should be recorded as a new lesion.
New lesions must be consistent with lymphoma rather than another etiology (eg, infection, 
inflammation) and must be PET-positive, if PET is available. New lesions will be treated as 
PET-positive when PET is not available to confirm avidity.
Some types of truly nonmeasurable lesions generally require further verification that they are 
attributable to lymphoma through biopsy or cytology. These include ascites, pleural or 
pericardial effusions, and lytic bone lesions. They may be recorded as new lesions only when 
there is other evidence of progression.
Other truly nonmeasurable lesions will not require verification to be considered a new lesion, 
as long as their appearance is unequivocal in the judgment of the reviewer:
•
Nonmeasurable lesions such as brain and CNS lesions including leptomeningeal disease 
attributable to lymphoma
•
Nonmeasurable nodal masses such as infiltrative mesenteric masses or retroperitoneal 
masses
Extranodal lesions which disappeared and then reappeared at a later timepoint will have the 
same effect as a new lesion, but are not designated “new”.
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Spleen response
The spleen will be measured in the craniocaudal length as at baseline, and the enlarged 
portion calculated by subtracting 13 cm. Response categories for the spleen are as defined 
below:
•
Normal (CR): Spleen was enlarged at baseline and has regressed to ≤13 cm at the current 
timepoint or the spleen was assessed as normal at baseline and is still normal, or there is 
radiological evidence of splenectomy at baseline.
•
Partial Response (PR): Spleen was assessed as enlarged at baseline, and its excess length 
has decreased by ≥50%.
•
Stable Splenomegaly (SD): No decrease consistent with PR and no increase consistent 
with progression.
•
Unequivocal increase (PD): The spleen is assessed as PD if any of the following are true:
-
Recurrent splenomegaly: A spleen which was abnormal at baseline (>13 cm) first 
returned to normal, but at the current timepoint the spleen increases by >2 cm from its 
nadir and the length is >13 cm.
-
New splenomegaly: No prior splenomegaly and spleen increases by >2 cm from 
baseline and the length is >13 cm.
-
Progression of existing splenomegaly: A spleen which is abnormal at baseline has the 
enlarged portion increase by >50%, and by ≥1 cm in absolute measurement, at the 
current timepoint from its nadir value.
Liver response
The liver will be assessed qualitatively. Response categories are as defined below:
•
Normal (CR): Liver was assessed as enlarged at baseline and has regressed to a normal 
size or still enlarged but without evidence of lymphoma involvement, OR the liver was 
assessed as normal at baseline and continues to be normal.
•
Stable Disease (SD): Liver is considered stable if there is persistent liver involvement 
with evidence based on imaging (CT or MRI) or biopsy that there is infiltration by 
lymphoma of the entire organ.
•
Unequivocal increase (PD): New hepatomegaly, recurrent hepatomegaly, or definite 
growth from prior liver size, and there is evidence that this is due to lymphoma 
infiltration.
Anatomic Response
The anatomic response should be assessed at each postbaseline timepoint based on the 
criteria below. Liver size alone should never be the basis for response determination by itself, 
but only support the assessment as supplemental information.
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Target
Nontarget
Spleen
New Lesions
Anatomic 
Response
CR
CR
CR
No
CR*
CR
CR
PR
No
PR**
CR
SD
CR
No
PR**
PR
CR/SD
CR/PR
No
PR
PR
CR/SD
SD
No
SD
SD
CR/SD
CR/PR
No
SD
SD
CR/SD
CR/PR/SD
No
SD
Any non-PD
NE
CR/PR/SD
No
NE
NE
Any non-PD
CR/PR/SD
No
NE
PD
Any 
Any
Any
PD
Any
PD
Any
Any
PD
Any
Any
PD
Any
PD
Any
Any
Any
Yes
PD
CR = complete response; NE = not evaluable; PD = progressive disease; PR = partial response; SD = stable 
disease.
*if the liver shows lymphoma involvement, it must resolve to allow CR
**Spleen can drive PR on its own if no target lesions were identified at baseline
Metabolic Response
In addition to anatomic imaging, metabolic imaging using FDG-PET can contribute to the 
assessment, if it is available, or may form the sole basis for response if no anatomic imaging 
is performed at a time point. An FDG-PET is required at screening. Subsequent time points 
that require PET are shown in the schedule of assessments. If lesions are not FDG-avid at 
baseline, PET is not required at follow-up timepoints unless clinically indicated.
PET Assessment
For every FDG-PET scan, a 5-point scale score is obtained by comparing the SUVmax of the 
lesion that shows the greatest tracer uptake (the “hottest” lesion) to surrounding normal 
tissue, to a region of interest (ROI) placed over blood in the heart or major vessels of the 
mediastinum (the “mediastinal blood pool”) and to an ROI placed over normal liver.
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Depending on the uptake, a score between 1-5 will be assigned as follows:
Score
Definition
1
No uptake above background
2
Uptake above background, but below mediastinal blood pool
3
Uptake > mediastinal blood pool, but ≤ uptake in liver
4
Uptake moderately higher than liver
5
Uptake markedly higher than liver (SUVmax >2 × normal liver)
OR (after treatment has started)
New FDG-positive lymphoma lesions
FDG = fluorodeoxyglucose; SUVmax = maximum standardized uptake value.
After screening, in addition to the 5-point scale score the assessment of the FDG-PET also 
involves an assessment of the overall uptake (a combination of extent and intensity) by tissue 
consistent with lymphoma, and comparison of this uptake to the baseline and to the scan on 
which the overall uptake was lowest (nadir).
Metabolic response determination
Metabolic response categories are defined as follows:
Metabolic Response
Definition
Complete metabolic response (CMR)
A score of 1, 2, or 3
Partial metabolic response (PMR)
A score of 4 or 5 (without new lesions), AND
Overall uptake decreased compared with baseline
Stable metabolic disease
(SMD)
A score of 4 or 5 (without new lesions), AND
Overall uptake unchanged compared with baseline and nadir
Progressive metabolic disease
(PMD)
A score of 4 or 5 with overall uptake increased compared with 
nadir, OR with new FDG-positive lesions consistent with 
lymphoma
In Waldeyer’s ring or extranodal sites with high physiologic uptake or with activation within 
spleen or marrow (eg, with chemotherapy or myeloid colony-stimulating factors), uptake 
may be greater than normal mediastinum and/or liver. In this circumstance, CMR may be 
inferred if uptake at sites of initial involvement is no greater than surrounding normal tissue, 
even if the tissue has high physiologic uptake.
Clinical Data
Bone marrow assessment
To allow an overall response of CR, the bone marrow must be clear of lymphoma (negative 
for lymphoma).
Lugano allows assessment of bone marrow based on FDG-PET, if the lymphoma type is 
FDG-avid. Bone marrow on FDG-PET may be normal, may show diffuse uptake (clinical 
judgment is required because this is also compatible with reactive changes due to 
chemotherapy or colony-stimulating factors), or may show focal increased uptake that is 
strongly indicative of lymphoma.
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A negative PET allows the bone marrow to be declared negative, even without biopsy, and 
would support a CR overall (diffuse uptake compatible with reactive changes from 
chemotherapy or growth factor use can fall into this category). A PR may occur with residual 
uptake higher than uptake in normal marrow but reduced compared with baseline. If there are 
persistent focal changes in the marrow in the context of a nodal response, consideration 
should be given to further evaluation with MRI or biopsy or an interval scan.
Bone marrow aspirate or biopsy is required only as clinically indicated, or if FDG-PET 
evaluation of bone marrow is judged inconclusive. For lymphoma that is shown at baseline to 
be non-FDG-avid, aspiration or biopsy is required to declare marrow to be negative. If bone 
marrow biopsy is performed and shows lymphoma, the bone marrow is considered positive, 
regardless of the results of the PET.
Physical examination findings
On rare occasions, lesions may be present on physical examination that are not seen on 
imaging at all. An example might be lymphadenopathy in the popliteal fossa, when the 
“whole body” imaging includes only anatomy to the midfemur. Such lesions should be 
documented as nontarget lesions in study forms. They can contribute to progression if new 
lesions appear this way, and if any were present at baseline, they must disappear for an 
overall response of CR.
Other clinical data
Information on the use of hematopoietic growth factors and other medications can affect the 
response assessment as described above.
At certain protocol-specified time points, additional tissue biopsies may be collected and 
incorporated into the response assessment.
Overall Response
Overall response at each timepoint is determined by combining the anatomic response, 
metabolic response, and clinical data.
When both CT and FDG-PET are available, the overall response is driven primarily by the 
metabolic response. When only one imaging modality is available at a given timepoint, that 
modality is the main determinant of overall response.
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Metabolic 
Response
Anatomic Response
Bone 
Marrow
Physical Examination
Overall Response
CMR
CR, PR, or SD
Negative
No lesions
CR
PMR
CR, PR, or SD
Any
No new lesions
PR
SMD
CR, PR, or SD
Any
No new lesions
SD
PMD
Any
Any
Any
PD
Any
PD
Any
Any
PD
CMR = complete metabolic response; CR = complete response; PD = progressive disease; PMD = progressive metabolic 
disease; PMR = partial metabolic response; PR = partial response; SD = stable disease; SMD = stable metabolic disease.
During determination of overall response, if no FDG-PET was performed at the timepoint in 
question, the results of a preceding PET may be “carried forward”, unless there has been 
worsening of disease on the CT. For example, if a postbaseline assessment shows a CMR on 
the PET, and PR on the CT, the overall response is CR. If the next timepoint shows 
continued PR on the CT, but there is no PET available, the overall response for that visit is 
still CR.
If there is PR based on either anatomic or metabolic imaging, but a biopsy demonstrates that 
the tissue in question is not malignant, the response can be upgraded to a CR.
10.8.2
IMWG Consensus Criteria for Response and MRD in MM (Cohort E)
IMWG response criteria 2016 [Kumar, S., et al 2016].
Response assessments for Cohort E will be performed according to the IMWG criteria. The 
response assessment will include imaging assessments (including plasmacytoma and skeletal 
assessments), bone marrow results, MRD assessment, serum and urine protein results, serum 
FLC, and laboratory results.
Overall Response Category Definitions
IMWG MRD criteria (requires a CR as deﬁned below):
•
Sustained MRD-negative: MRD negativity in the marrow (NGF or NGS, or both) and by 
imaging as deﬁned below, conﬁrmed minimum of 1 year apart. Subsequent evaluations 
can be used to further specify the duration of negativity (eg, MRD-negative at 5 years).
•
Flow MRD-negative: Absence of phenotypically aberrant clonal plasma cells by NGF on 
bone marrow aspirates using the EuroFlow standard operation procedure for MRD 
detection in multiple myeloma (or validated equivalent method) with a minimum 
sensitivity of 1 in 10⁵ nucleated cells or higher.
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•
Sequencing MRD-negative: Absence of clonal plasma cells by NGS on bone marrow 
aspirate in which presence of a clone is deﬁned as less than 2 identical sequencing reads 
obtained after DNA sequencing of bone marrow aspirates using the LymphoSIGHT 
platform (or validated equivalent method) with a minimum sensitivity of 1 in 10⁵
nucleated cells or higher.
•
Imaging plus MRD-negative: MRD negativity as deﬁned by NGF or NGS plus 
disappearance of every area of increased tracer uptake found at baseline or a preceding 
PET/CT or decrease to less mediastinal blood pool SUV or decrease to less than that of 
surrounding normal tissue.
Standard IMWG response criteria
•
Stringent CR: CR as deﬁned below plus normal FLC ratio and absence of clonal cells in 
bone marrow biopsy by immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for κ and λ 
patients, respectively, after counting ≥100 plasma cells).
•
Complete response: Negative immunoﬁxation on the serum and urine and disappearance 
of any soft tissue plasmacytomas and <5% plasma cells in bone marrow aspirates.
•
Very good PR: Serum and urine M-protein detectable by immunoﬁxation but not on 
electrophoresis or ≥90% reduction in serum M-protein plus urine M-protein level <100 
mg per 24 h.
•
Partial response:
-
≥50% reduction of serum M-protein plus reduction in 24 h urinary M-protein by 
≥90% or to <200 mg per 24 h.
-
If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the diﬀerence
between involved and uninvolved FLC levels is required in place of the M-protein 
criteria;
-
If serum and urine M-protein are unmeasurable, and serum-free light assay is also 
unmeasurable, ≥50% reduction in plasma cells is required in place of M-protein, 
provided baseline bone marrow plasma cell percentage was ≥30%. In addition to 
these criteria, if present at baseline, a ≥50% reduction in the size (SPD) of soft tissue 
plasmacytomas is also required.
•
Minimal response: ≥25% but ≤49% reduction of serum M-protein and reduction in 24-h 
urine M-protein by 50–89%. In addition to the above listed criteria, if present at baseline, 
a ≥50% reduction in the size (SPD) of soft tissue plasmacytomas is also required.
•
Stable disease: Not recommended for use as an indicator of response; stability of disease 
is best described by providing the time-to-progression estimates. Not meeting criteria for 
CR, VGPR, PR, minimal response, or PD.
•
Progressive disease: Any one or more of the following criteria:
-
Increase of 25% from lowest conﬁrmed response value in one or more of the 
following criteria:
◦
Serum M-protein (absolute increase must be ≥0·5 g/dL);
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◦
Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL; 
Urine M-protein (absolute increase must be ≥200 mg/24 h);
◦
In participants without measurable serum and urine M-protein levels, the 
diﬀerence between involved and uninvolved FLC levels (absolute increase must 
be >10 mg/dL);
◦
In participants without measurable serum and urine M-protein levels and without 
measurable involved FLC levels, bone marrow plasma cell percentage 
irrespective of baseline status (absolute increase must be ≥10%);
-
Appearance of a new lesion(s), ≥50% increase from nadir in SPD of >1 lesion, or 
≥50% increase in the longest diameter of a previous lesion >1 cm in short axis;
-
≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the 
only measure of disease.
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10.9
Appendix 9: Eastern Cooperative Oncology Group Performance Status
Grade
Performance Status
0
Normal activity. Fully active, able to carry on all predisease performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able 
to perform work of a light or sedentary nature (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any 
work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
Adapted from [ECOG ACRIN Cancer Research Group 2016]
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10.10 Appendix 10: Abbreviations
Abbreviation
Expanded Term
ADA
antidrug antibodies
ADR
adverse drug reaction
AE
adverse event 
AEOSI
adverse event of special interest
ALK+
anaplastic lymphoma kinase-positive
ALT
alanine aminotransferase
APaT
All Participants as Treated
AST
aspartate aminotransferase
AUC
area under the curve
BM
bone marrow
CAR
Chimeric antigen receptor
CD
cluster of differentiation 
cHL
classical Hodgkin’s Lymphoma
CI
confidence interval
CL
clearance
Cmax
maximum plasma concentration
CMR
complete metabolic response
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CR
complete response
CRF
Case Report Form 
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
ctDNA
circulating tumor DNA
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
Ctrough
lowest plasma concentration
DCR
Disease control rate
DLBCL
Diffuse Large B-cell lymphoma
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Abbreviation
Expanded Term
DLT
dose-limiting toxicity
DLTe
dose-limiting toxicity evaluable
DNA
deoxyribonucleic acid 
DOR
duration of response
EBV
Epstein Barr virus
EC
Ethics Committee
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
ECOG PS
Eastern Cooperative Oncology Group Performance Score
EDC
electronic data collection 
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EORTC
European Organization for the Research and Treatment of Cancer 
ePROs
electronic patient-reported outcomes
EQ-5D-5L
EuroQoL 5D-5L
EuroQoL
European quality of life
FBR
future biomedical research
FcγR
Fc-gamma receptor
FDAAA
Food and Drug Administration Amendments Act
FDG
fluorodeoxyglucose
FISH
fluorescent in situ hybridization
FL
Follicular Lymphoma
FLC
free light chain
FLIPI
Follicular Lymphoma International Prognostic Index
FOXP3
forkhead box P3 protein
FSH
follicle-stimulating hormone 
GCP
Good Clinical Practice 
GVHD
graft versus host disease
HBsAg
hepatitis B surface antigen
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Abbreviation
Expanded Term
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HL
Hodgkin’s Lymphoma
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
ICR
independent central review
ID
identification
IEC
Independent Ethics Committee
IFN-γ
interferon-gamma
Ig
immunoglobulin
IgG4
immunoglobulin G4
IHC
immunohistochemistry
IMiD
immunomodulatory drugs
IMP
investigational medicinal product
IMWG
International Myeloma Working Group
IND
Investigational New Drug 
IO
immuno-Oncology
IPI
International Prognostic Index
irAEs
immune-related AEs
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
LAG
lymphocyte activation gene
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PRODUCT: MK-7684A
202
PROTOCOL/AMENDMENT NO.: 004-05
MK-7684A-004-05 FINAL PROTOCOL
19-DEC-2023
Abbreviation
Expanded Term
LAM
lactational amenorrhea method
LDi
longest diameter
mAb
monoclonal antibody
MCL
Mantle Cell Lymphoma
MIPI
Mantle Cell Lymphoma International Prognostic Index 
MIPI-c
MIPI + Ki-67 index
MM
Multiple Myeloma
mPD-1
murine programmed cell death 1 protein
MR
Minor response
MRD
minimal residual disease
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MTD
maximum tolerated dose 
mTIGIT
murine TIGIT
MYC
myelocytomatosis
MZL
marginal zone lymphoma
n
number
NCI
National Cancer Institute
NGF
next generation flow
NGS
next generation sequencing
NHL
Non-Hodgkin’s Lymphoma
NK
natural killer cell
NKT
natural killer T-cell
NOS
not otherwise specified
NSCLC
non–small cell lung cancer
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PBMC
peripheral blood mononuclear cells
08ZH2F

PRODUCT: MK-7684A
203
PROTOCOL/AMENDMENT NO.: 004-05
MK-7684A-004-05 FINAL PROTOCOL
19-DEC-2023
Abbreviation
Expanded Term
PBPK
Physiologically based PK
PD
progressive disease
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
Progression-free survival
PI3K
phosphoinositide 3-kinase
PK
pharmacokinetic
PMBCL
Primary mediastinal B-cell lymphoma
PO
by mouth
PPD
product of perpendicular diameters
PR
partial response
PRN
as needed
PRO
patient-reported outcome
PVRL-2
poliovirus receptor-related 2
Q2W
every 2 weeks
Q3W
every 3 weeks
Q12W
every 12 weeks
Q24W
every 24 weeks
QLQ
quality of life questionnaire
QoL
quality of life
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
ribonucleic acid
SAE
serious adverse event 
SAP
Statistical Analysis Plan 
SCT
stem cell transplant
SD
stable disease
SDi
short axis diameter
SLL
Small Lymphocytic Lymphoma
08ZH2F

PRODUCT: MK-7684A
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PROTOCOL/AMENDMENT NO.: 004-05
MK-7684A-004-05 FINAL PROTOCOL
19-DEC-2023
Abbreviation
Expanded Term
SNP
single-nucleotide polymorphism
SoA
schedule of activities
SPD
sum of the product of diameters
SPEP
serum protein electrophoresis
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
SUV
standardized uptake value
SUVmax
maximum standardized uptake value
T3
Triiodothyronine
T4
Thyroxine
TIGIT
T-cell immunoreceptor with Ig and ITIM domains
TILs
Tumor-infiltrating lymphocytes
TIM-3
T-cell immunoglobulin and mucin-domain containing-3
TNF
Tumor necrosis factor
TPS
Tumor proportion score
T-reg
Regulatory T-cell
TSH
Thyroid-stimulating hormone
ULN
upper limit of normal
UPEP
urine protein electrophoresis
US
United States
VAS
Visual Analog Scale
Vc
central volume of distribution
VGPR
very good partial response
WHO
World Health Organization
WOCBP
woman/women of childbearing potential
08ZH2F

PRODUCT: MK-7684A
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MK-7684A-004-05 FINAL PROTOCOL
19-DEC-2023
11
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08ZH2F

PRODUCT: MK-7684A
208
PROTOCOL/AMENDMENT NO.: 004-05
MK-7684A-004-05 FINAL PROTOCOL
19-DEC-2023
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08ZH2F

PRODUCT: MK-7684A
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PROTOCOL/AMENDMENT NO.: 004-05
MK-7684A-004-05 FINAL PROTOCOL
19-DEC-2023
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08ZH2F

PRODUCT: MK-7684A
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MK-7684A-004-05 FINAL PROTOCOL
19-DEC-2023
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08ZH2F

PRODUCT: MK-7684A
211
PROTOCOL/AMENDMENT NO.: 004-05
MK-7684A-004-05 FINAL PROTOCOL
19-DEC-2023
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PRODUCT: MK-7684A
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MK-7684A-004-05 FINAL PROTOCOL
19-DEC-2023
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19-DEC-2023
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MK-7684A-004-05 FINAL PROTOCOL
19-DEC-2023
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U.S. Prescribing Information: KEYTRUDA 
(pembrolizumab) injection, for intravenous 
use: Nov 2020.
[05Q5QF]
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PRODUCT: MK-7684A
215
PROTOCOL/AMENDMENT NO.: 004-05
MK-7684A-004-05 FINAL PROTOCOL
19-DEC-2023
[Usmani, S. Z., et al 2019]
Usmani SZ, Schjesvold F, Oriol A, Karlin L, 
Cavo M, Rifkin RM, et al. Pembrolizumab 
plus lenalidomide and dexamethasone for 
patients with treatment-naive multiple 
myeloma (KEYNOTE-185): a randomised, 
open-label, phase 3 trial. Lancet Haematol. In 
press 2019.
[0597DD]
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