Clinical trial NCT04317066
Conditions: Lymphoma, B-Cell
Keywords: Programmed Cell Death-1 (PD1, PD-1) Programmed Death-Ligand 1 (PDL1, PD-L1)
Sponsor: Merck Sharp & Dohme LLC
Start date: 2020-06-26; Completion date: 2024-04-11
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the objective response, safety, and tolerability of pembrolizumab in Japanese participants who have refractory primary mediastinal large B-cell lymphoma.

Detailed description:

Arms: arm 1: Participants with relapsed or refractory primary mediastinal large B-cell lymphoma (rrPMBCL) receive Pembrolizumab 200 mg by intravenous (IV) infusion on day 1 of each 3-week cycle for up to 35 cycles (approximately 2 years).
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Pembrolizumab 200 mg by intravenous (IV) infusion, given on day 1 of each 3-week cycle.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title:
NCT number:
Document Date:
NCT04317066
28-Nov-2023
Protocol/Amendment No.: A33-03 A Phase 1
Clinical Study of Pembrolizumab (MK-3475) in
Participants with Relapsed or Refractory
Primary Mediastinal Large B-cell Lymphoma
(rrPMBCL) (KEYNOTE-A33)


PRODUCT: MK-3475
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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 1 Clinical Study of Pembrolizumab (MK-3475) in Participants with 
Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) 
(KEYNOTE-A33)
Protocol Number: A33-03
Compound Number: MK-3475
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
04317066
EU CT
Not applicable
EudraCT
Not applicable
JRCT
2080225167
WHO
Not applicable
UTN
Not applicable
IND
Not applicable
Approval Date: 28 November 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
A33-03
28-NOV-2023
To close the study since the primary objective of this 
study has been achieved and additional data is not 
required.
A33-02
09-SEP-2022
Merck Sharp & Dohme Corp. underwent an entity name 
and address change to Merck Sharp & Dohme LLC, 
Rahway, NJ, USA. This conversion resulted only in an 
entity name change and update to the address.
To update the dose modification and toxicity 
management guidelines for immune-related adverse 
events (irAEs).
A33-01
03-FEB-2020
To change the primary efficacy endpoint from 
investigator assessment to central assessment and to 
modify the statistical analysis.
Original 
Protocol
19-NOV-2019
Not applicable
PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment:03
Overall Rationale for the Amendment:
To close the study since the primary objective of this study has been achieved and additional 
data is not required.
Summary of Changes Table
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
1.1
Synopsis
4.1
Overall Design
8.9.3
Post treatment Visit
Added below sentences:
After the approval of Protocol amendment 03, the study will 
be completed at the Safety Follow-up visit (scheduled 30 
days after the last dose) or imaging assessment 120 weeks 
from the allocation date, of the last participant, whichever is 
later. If the study intervention is still ongoing at Week 120 of 
the last participant, further study intervention should be 
discontinued, and no further visits will be required after the 
Safety Follow-up visit which scheduled 30 days after the last 
dose. Participants in the Imaging Follow-up Phase or 
Survival Follow-up Phase will be discontinued from the 
study and no further visits will be required.
To close the study since the 
primary objective of this study 
has been achieved and additional 
data is not required.
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Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
Title page
Added NCT and jRCT numbers.
To provide updated information.
6.5.3
Rescue Medications 
and Supportive Care 
Updated text from “AEs with potential immunologic 
etiology” to “AEs associated with study intervention” which
follow dose modification guideline.
To clarify the applicable events 
of dose modification guidelines.
8.1.1
Informed Consent
Updated texts regarding informed consent.
Clarification.
8.1.1.1
General Informed 
Consent
Updated texts regarding informed consent and added that 
documented informed consent is required when study 
intervention is continued beyond disease progression.
Clarification and to obtain 
appropriate consent.
8.1.5.2
Concomitant 
Medications
Deleted “30 day”.
To clarify the end of 
concomitant medications
collection period.
8.4
Adverse Events, 
Serious Adverse 
Events, and Other 
Reportable Safety 
Events
Added “Investigators need to document if an SAE was 
associated with a medication error, misuse, or abuse.”
To adhere the requirement of EU
regulations.
8.4.7
Events of Clinical 
Interest
Updated text for overdose and potential DILI.
For overdose, to be consistent in 
terminology used throughout the 
document.
For potential DILI, to define 
what potential DILI is and to 
align with this acronym being 
used in Table 5.
10.3,
Appendix 3: 
Adverse Events: 
Definitions and 
Procedures for 
Recording,
Evaluating, Follow-
up, and Reporting
“Sponsor’s product” is replaced by “study intervention” 
throughout this section.
To be consistent in terminology 
used throughout the document.
10.3.1
Definitions of 
Medication Error, 
Misuse, and Abuse
Added definitions of medication error, misuse, and abuse.
To adhere the requirement of EU
regulations.
Throughout 
Document
Minor administrative, formatting, grammatical, and/or 
typographical changes were made throughout the document.
To ensure clarity and accurate 
interpretation of the intent of the 
protocol.
Throughout 
Document
After marketing approval of MK-3475 for rrPMBCL in 
Japan, the term of “clinical study” and “clinical trial” should 
be replaced with “post marketing clinical trial” and the study 
will be continued.
All applicable laws, rules and regulations related to the 
conduct of the clinical trial mentioned in these sections 
include Japan specific local regulation, Good Post-Marketing 
Study Practice (GPSP) in Japan.
To adhere the requirement of 
Japanese regulations.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................3
1
PROTOCOL SUMMARY ............................................................................................12
1.1
Synopsis.................................................................................................................12
1.2
Schema ..................................................................................................................16
1.3
Schedule of Activities...........................................................................................17
2
INTRODUCTION..........................................................................................................21
2.1
Study Rationale....................................................................................................21
2.2
Background ..........................................................................................................22
2.2.1
Pharmaceutical and Therapeutic Background .............................................22
2.2.1.1
Pembrolizumab (MK-3475) Pharmaceutical and Therapeutic 
Background........................................................................................22
2.2.2
Preclinical and Clinical Studies ...................................................................23
2.2.3
Ongoing Clinical Studies.............................................................................23
2.3
Benefit/Risk Assessment......................................................................................23
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................24
4
STUDY DESIGN............................................................................................................25
4.1
Overall Design......................................................................................................25
4.2
Scientific Rationale for Study Design.................................................................26
4.2.1
Rationale for Endpoints ...............................................................................26
4.2.1.1
Efficacy Endpoints.............................................................................26
4.2.1.2
Safety Endpoints................................................................................27
4.3
Justification for Dose...........................................................................................27
4.4
Beginning and End-of-Study Definition ............................................................27
4.4.1
Clinical Criteria for Early Study Termination .............................................27
5
STUDY POPULATION ................................................................................................28
5.1
Inclusion Criteria.................................................................................................28
5.2
Exclusion Criteria................................................................................................31
5.3
Lifestyle Considerations......................................................................................33
5.3.1
Meals and Dietary Restrictions....................................................................33
5.4
Screen Failures.....................................................................................................33
5.5
Participant Replacement Strategy......................................................................34
6
STUDY INTERVENTION............................................................................................35
6.1
Study Intervention(s) Administered...................................................................35
6.2
Preparation/Handling/Storage/Accountability .................................................37
6.2.1
Dose Preparation..........................................................................................37
6.2.2
Handling, Storage, and Accountability........................................................37
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6.3
Measures to Minimize Bias: Randomization and Blinding..............................37
6.3.1
Intervention Assignment..............................................................................37
6.3.2
Stratification.................................................................................................38
6.3.3
Blinding........................................................................................................38
6.4
Study Intervention Compliance..........................................................................38
6.5
Concomitant Therapy..........................................................................................38
6.5.1
Acceptable Concomitant Medications .........................................................38
6.5.2
Prohibited Concomitant Medications ..........................................................39
6.5.3
Rescue Medications and Supportive Care ...................................................40
6.6
Dose Modification (Escalation/Titration/Other)...............................................40
6.6.1
Dose Modification .......................................................................................40
6.7
Intervention After the End of the Study............................................................47
6.8
Clinical Supplies Disclosure................................................................................47
6.9
Standard Policies..................................................................................................47
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................48
7.1
Discontinuation of Study Intervention...............................................................48
7.2
Participant Withdrawal From the Study...........................................................49
7.3
Lost to Follow-up .................................................................................................49
8
STUDY ASSESSMENTS AND PROCEDURES........................................................50
8.1
Administrative and General Procedures ...........................................................50
8.1.1
Informed Consent.........................................................................................50
8.1.1.1
General Informed Consent.................................................................51
8.1.2
Inclusion/Exclusion Criteria ........................................................................51
8.1.3
Participant Identification Card.....................................................................51
8.1.4
Medical History ...........................................................................................51
8.1.5
Prior and Concomitant Medications Review...............................................52
8.1.5.1
Prior Medications...............................................................................52
8.1.5.2
Concomitant Medications..................................................................52
8.1.5.3
Prior Cancer Treatment......................................................................52
8.1.5.4
Subsequent Antineoplastic Therapy ..................................................52
8.1.6
Assignment of Screening Number...............................................................52
8.1.7
Assignment of Treatment/Randomization Number.....................................53
8.1.8
Study Intervention Administration ..............................................................53
8.1.8.1
Timing of Dose Administration.........................................................53
8.1.9
Discontinuation and Withdrawal .................................................................53
8.1.10
Participant Blinding/Unblinding..................................................................54
8.1.11
Calibration of Equipment.............................................................................54
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8.2
Efficacy Assessments ...........................................................................................54
8.2.1
Criteria for Assessment of Disease..............................................................54
8.2.1.1
Disease Assessment of Immunotherapeutic Agents ..........................54
8.2.2
Assessment of Disease and Tumor Response..............................................55
8.2.2.1
Initial Disease Assessment.................................................................55
8.2.2.2
Disease Assessment During the Study...............................................55
8.2.3
Disease Progression Assessments................................................................56
8.2.4
Bone Marrow Biopsy and Aspirate..............................................................57
8.3
Safety Assessments...............................................................................................57
8.3.1
Physical Examinations.................................................................................57
8.3.1.1
Full Physical Examination.................................................................57
8.3.1.2
Directed Physical Examination..........................................................58
8.3.2
Vital Signs....................................................................................................58
8.3.3
Electrocardiograms ......................................................................................58
8.3.4
Clinical Safety Laboratory Assessments .....................................................58
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and 
Urinalysis)..........................................................................................59
8.3.4.2
Pregnancy Test...................................................................................59
8.3.5
Eastern Cooperative Oncology Group Performance Status.........................59
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................59
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................60
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......62
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...62
8.4.4
Regulatory Reporting Requirements for SAE .............................................62
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................62
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................63
8.4.7
Events of Clinical Interest............................................................................63
8.4.7.1
Follow-Up Post-Allogeneic Stem Cell Transplantation ....................63
8.5
Treatment of Overdose........................................................................................64
8.6
Pharmacokinetics.................................................................................................64
8.7
Pharmacodynamics..............................................................................................64
8.8
Future Biomedical Research Sample Collection...............................................64
8.9
Visit Requirements...............................................................................................64
8.9.1
Screening......................................................................................................64
8.9.2
Treatment Period..........................................................................................65
8.9.3
Post Treatment Visit ....................................................................................65
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8.9.3.1
Discontinuation Visit .........................................................................65
8.9.3.2
Safety Follow-up Visit.......................................................................66
8.9.3.3
Imaging Follow-up Visits ..................................................................66
8.9.3.4
Survival Follow-up Visits..................................................................66
9
STATISTICAL ANALYSIS PLAN .............................................................................67
9.1
Statistical Analysis Plan Summary.....................................................................67
9.2
Responsibility for Analyses/In-house Blinding .................................................67
9.3
Hypotheses/Estimation ........................................................................................68
9.4
Analysis Endpoints...............................................................................................68
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints..............................68
9.4.2
Safety Endpoints..........................................................................................68
9.5
Analysis Populations............................................................................................69
9.5.1
Safety Analysis Populations ........................................................................69
9.5.2
Pharmacokinetic Analysis Populations........................................................69
9.5.3
Efficacy Analysis Populations.....................................................................69
9.6
Statistical Methods...............................................................................................69
9.6.1
Statistical Methods for Efficacy Analysis....................................................69
9.6.2
Statistical Methods for Safety Analysis.......................................................70
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses.......................................................................................................70
9.6.3.1
Demographic and Baseline Characteristics .......................................70
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis............70
9.7
Interim Analyses ..................................................................................................70
9.8
Multiplicity ...........................................................................................................71
9.9
Sample Size and Power Calculations .................................................................71
9.10
Subgroup Analyses...............................................................................................71
9.11
Compliance (Medication Adherence).................................................................71
9.12
Extent of Exposure...............................................................................................71
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................72
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........72
10.1.1
Code of Conduct for Clinical Trials.............................................................72
10.1.2
Financial Disclosure.....................................................................................74
10.1.3
Data Protection.............................................................................................75
10.1.3.1
Confidentiality of Data ......................................................................75
10.1.3.2
Confidentiality of Participant Records...............................................75
10.1.3.3
Confidentiality of IRB/IEC Information............................................75
10.1.4
Publication Policy........................................................................................76
10.1.5
Compliance with Study Registration and Results Posting Requirements ...76
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10.1.6
Compliance with Law, Audit, and Debarment ............................................76
10.1.7
Data Quality Assurance ...............................................................................77
10.1.8
Source Documents .......................................................................................78
10.1.9
Study and Site Closure.................................................................................78
10.2
Appendix 2: Clinical Laboratory Tests..............................................................79
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting...............................................................81
10.3.1
Definitions of Medication Error, Misuse, and Abuse..................................81
10.3.2
Definition of AE ..........................................................................................81
10.3.3
Definition of SAE ........................................................................................82
10.3.4
Additional Events Reported in the Same Manner as SAE...........................83
10.3.5
Recording AE and SAE ...............................................................................84
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ........................................................................................................87
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ..............................................................................................................89
10.5
Appendix 5: Contraceptive Guidance................................................................90
10.5.1
Definitions....................................................................................................90
10.5.2
Contraceptive Requirements........................................................................91
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research............................................................................................93
10.7
Appendix 7: Country-specific Requirements....................................................94
10.8
Appendix 8: Abbreviations .................................................................................95
10.9
Appendix 9: IWG Revised Response Criteria for Malignant Lymphoma.....99
10.10 Appendix 10: Lugano Classification ................................................................100
10.11 Appendix 11: Lymphoma B Symptoms and Constitutional Symptoms .......103
10.12 Appendix 12: ECOG Performance Status.......................................................104
11
REFERENCES.............................................................................................................105
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values ...........................................29
Table 2
Study Interventions....................................................................................36
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .........................................................41
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ..................................................................................................46
Table 5
Reporting Time Periods and Time Frames for Adverse Events and 
Other Reportable Safety Events.................................................................61
Table 6
Analysis Strategy for Key Efficacy Variables...........................................70
Table 7
Estimated ORR and 95% confidence interval (Clopper-Pearson 
interval)......................................................................................................71
Table 8
Protocol-required Safety Laboratory Assessments....................................80
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LIST OF FIGURES
Figure 1
Study Design..............................................................................................16
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 1 Clinical Study of Pembrolizumab (MK-3475) in Participants with 
Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) 
(KEYNOTE-A33)
Short Title: Phase 1 Study of MK-3475 in participants with rrPMBCL
Acronym: Not Applicable
Hypotheses, Objectives, and Endpoints:
All objectives and endpoints apply to Japanese participants with rrPMBCL: 
Primary Objective
Primary Endpoint
To evaluate objective response using IWG 
Revised Response Criteria for Malignant 
Lymphoma (Appendix 9) as assessed by 
independent central review.
Objective response: complete response 
(CR) or partial response (PR).
To evaluate the safety and tolerability of 
pembrolizumab.
-Adverse event
-Discontinuing study intervention due to an 
adverse event
Secondary Objectives
Secondary Endpoints
-To evaluate disease control using IWG 
Revised Response Criteria for Malignant 
Lymphoma (Appendix 9) as assessed by 
independent central review.
-To evaluate objective response and disease 
control using IWG Revised Response 
Criteria for Malignant Lymphoma
(Appendix 9) as assessed by the 
investigator.
-Disease control: CR, PR, or stable disease 
(SD).
-Objective response: CR or PR.
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Overall Design:
Study Phase
Phase 1
Primary Purpose
Treatment
Indication
Primary mediastinal large B-cell lymphoma
Population
Participants with rrPMBCL
Study Type
Interventional
Intervention Model
Single Group
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 5 participants will be enrolled.
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period
Use
N/A
Pembrolizumab 25 mg/mL
200 mg
IV Infusion
Q3W; Day 
1 in each 
cycle
up to 35 
cycles
Test 
Product
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Total Number of Intervention Groups/Arms
1
Duration of Participation
Each participant will participate in the study 
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 one of the conditions for 
discontinuation of study intervention is met.
After the-end-of treatment, each participant 
will be followed for the occurrence of 
adverse events and spontaneously reported 
pregnancy. 
Participants who discontinue for reasons 
other than radiographic disease progression
will have posttreatment follow-up imaging 
for disease status until any of the conditions 
for discontinuation of imaging are met. 
All participants will be followed for overall 
survival until death, withdrawal of consent, 
or the end of the study.
After the approval of Protocol amendment 
03, the study will be completed at the Safety 
Follow-up visit (scheduled 30 days after the 
last dose) or imaging assessment 120 weeks 
from the allocation date, of the last 
participant, whichever is later. If the study 
intervention is still ongoing at Week 120 of 
the last participant, further study 
intervention should be discontinued, and no 
further visits will be required after the 
Safety Follow-up visit which scheduled 30 
days after the last dose. Participants in the 
Imaging Follow-up Phase or Survival 
Follow-up Phase will be discontinued from 
the study and no further visits will be 
required.
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Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
Steering Committee
No
Study governance considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations used in this document can be found in Appendix 8.
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1.2
Schema
The study design is depicted in Figure 1.
Abbreviations: rrPMBCL = relapsed or refractory primary mediastinal large B-cell lymphoma, Q3W = every 3 weeks
Figure 1
Study Design
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1.3
Schedule of Activities
Study Period:
Screening 
Phase
Treatment Phase
(3-Week Cycles)
End of 
Treatment 
(EOT) / 
Discontinuation
Post-treatment Phase
Notes
Treatment 
Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
Treatment Days per 
Cycle:
1
1
1
1
At time of 
treatment 
discontinuation
30 days 
post last 
dose study 
medication
Every 
12 
weeks
Every 
12 
weeks
Scheduled Window
(Days):
-28 to -1
+3
±3
±3
±3
+7
±14
±14
Administrative Procedures
Informed Consent
X
Participant 
Identification Card
X
Inclusion/Exclusion 
Criteria
X
Demographic and 
Medical History 
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
Administration of 
Pembrolizumab
X
X
X
X
Post-study 
Anticancer Therapy 
Status
X
X
X
Survival Status
====================== X====================
X
Safety Procedures
Adverse Event (AE) 
Monitoring
X
X
X
X
X
Full Physical 
Examination
X
Directed Physical 
Examination 
X
X
X
X
X
X
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Study Period:
Screening 
Phase
Treatment Phase
(3-Week Cycles)
End of 
Treatment 
(EOT) / 
Discontinuation
Post-treatment Phase
Notes
Treatment 
Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
Treatment Days per 
Cycle:
1
1
1
1
At time of 
treatment 
discontinuation
30 days 
post last 
dose study 
medication
Every 
12 
weeks
Every 
12 
weeks
Scheduled Window
(Days):
-28 to -1
+3
±3
±3
±3
+7
±14
±14
Vital Signs and
Weight 
X
X
X
X
X
X
X
VS: pulse, respiratory rate, blood 
pressure, temperature.
Height
X
12-lead ECG
X
ECOG Performance 
Status
X
X
X
X
X
X
X
ECOG Performance Status at screening 
should be performed within 7 days 
prior to the first dose of study 
intervention.
Pregnancy Test -
Urine or Serum β-
hCG (WOCBP only)
X
X
X
Urinalysis
X
PT/INR and aPTT
X
CBC with 
Differential
X
X
X
X
X
X
Comprehensive 
Chemistry Panel
X
X
X
X
X
X
Thyroid Function 
Testing (T3, or FT3, 
FT4, and TSH)
X
X
X
X
X
Every 2 Cycles.
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Study Period:
Screening 
Phase
Treatment Phase
(3-Week Cycles)
End of 
Treatment 
(EOT) / 
Discontinuation
Post-treatment Phase
Notes
Treatment 
Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
Treatment Days per 
Cycle:
1
1
1
1
At time of 
treatment 
discontinuation
30 days 
post last 
dose study 
medication
Every 
12 
weeks
Every 
12 
weeks
Scheduled Window
(Days):
-28 to -1
+3
±3
±3
±3
+7
±14
±14
Efficacy Procedures
PET/CT [Neck, 
Chest, Abdomen, 
Pelvic]b
X
Xa
Xc
X
Lymphoma B symptom and disease 
response assessments should be 
performed at the same time as tumor 
imaging; disease assessments are not to 
be delayed for cycle delays.
a. Every 12 weeks (±7 days) from the 
time of allocation.
b. Perform PET/CT during screening. 
On-study, perform disease assessments 
using PET/CT if PET-avid at baseline; 
otherwise, CT may be used. See 
Sections 8.2.2 and 8.2.3 for detailed 
information on imaging.
c.  In participants who discontinue 
study therapy, imaging should be 
performed at the time of treatment 
discontinuation (ie, date of 
discontinuation ± 4 weeks).  If previous 
scan/ was obtained within 4 weeks 
prior to the date of discontinuation, 
then a scan at treatment discontinuation 
does not need to be performed.
Disease Response 
Assessment by IWG 
Revised Response 
Criteria for 
Malignant 
Lymphoma
Xa
Xc
X
Disease Response 
Assessment by 
Lugano 
Classification 
Xa
Xc
X
Assessment of 
Lymphoma B 
Symptoms
X
Xa
Xc
X
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Study Period:
Screening 
Phase
Treatment Phase
(3-Week Cycles)
End of 
Treatment 
(EOT) / 
Discontinuation
Post-treatment Phase
Notes
Treatment 
Cycle/Title:
Screening
(Visit 1)
1
2
3
4 to 
35
Safety 
Follow-
up
Imaging 
Follow-
up
Survival 
Follow-
up
Treatment Days per 
Cycle:
1
1
1
1
At time of 
treatment 
discontinuation
30 days 
post last 
dose study 
medication
Every 
12 
weeks
Every 
12 
weeks
Scheduled Window
(Days):
-28 to -1
+3
±3
±3
±3
+7
±14
±14
Bone Marrow Biopsy 
and Aspirate
X
X
All participants will have bone marrow 
biopsy and aspirate at baseline. 
Subsequent bone marrow assessments 
will only be performed in participants 
who have bone marrow involvement. A 
bone marrow assessment should be 
performed to confirm CR (if participant 
had bone marrow involvement) and as 
clinically indicated.
Abbreviations: CT = computed tomography; PET = positron emission tomography; PT/INR = prothrombin time/international normalized ratio; aPTT =activated partial 
thromboplastin time; T3 = total triiodothyronine; FT4 = free thyroxine; TSH = thyroid stimulating hormone.
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2
INTRODUCTION
This is a Phase 1 study to evaluate the efficacy and safety of pembrolizumab in participants 
with rrPMBCL.
2.1
Study Rationale
Non-Hodgkin’s lymphomas (NHL) are a heterogeneous group of lymphoproliferative 
disorders originated in B-lymphocytes, T-lymphocytes or natural killer cells.  It is estimated 
that in 2015 around 30,000 new malignant lymphoma cases were diagnosed in Japan 
[National Cancer Center, Japan 2015], and the majority is diagnosed as NHL, comprise over 
90% of all malignant lymphoma cases [Lymphoma Study Group of Japanese Pathologists 
2000].  Diffuse Large B-Cell lymphoma (DLBCL) is the most common type of adult NHL in 
Japan, making up about 30 to 40% of NHL.  PMBCL is a distinct subtype of NHL that 
histologically can be indistinguishable from DLBCL and account only for about 2.5% of all 
NHL cases [Jackson MW, et al 2016].  This subtype tends to occur in young adults with a 
median age of 35 years with a slight female predominance [Aisenberg AC 1999] [Faris JE, et 
al 2009] [Cazals-Hatem D, et al 1996].  Interestingly, gene expression profiling has revealed 
that the pattern of gene expression in PMBCL is more similar to classical Hodgkin’s 
lymphoma than DLBCL [Rosenwald A, et al 2003] [Savage KJ, et al 2003].
The optimal therapeutic approach to PMBCL is controversial due to the limited availability 
of prospective studies resulted from the rarity of the disease.  In the absence of randomized 
PMBCL clinical trials, the therapeutic approaches for PMBCL have been the same as the 
ones used for other subtypes of DLBCL, which is R-CHOP followed by +/- involved-field 
radiotherapy (IFRT) is the preferred options for front line treatment per the Japanese Society 
of Hematology (JSH) practical guidelines for hematological malignancies [Japanese Society 
of Hematology 2018].
There is currently very limited data available regarding the optimal treatment for relapsed or 
refractory PMBCL if there is a poor response to this first-line therapy.  The prognosis in 
patients who either do not respond to first-line therapy or relapse is dismal with OS at 2 years 
of 15% [Tomassetti S, et al 2019].  The current approach is to extrapolate from modalities 
commonly used in the relapsed and refractory setting for other DLBCL subtypes like high-
dose chemotherapy with autologous hematopoietic stem cell transplantation (auto-SCT) 
following front line or salvage chemotherapy regimens for auto-SCT ineligible subjects 
[Japanese Society of Hematology 2018].  Based on a systematic literature review of clinical 
outcomes in rrPMBCL in 2017 [Systematic Literature Review 2017], there is no published 
randomized controlled trial and only 2 single-arm clinical studies with limited size (6 and 15 
each) in participants with rrPMBCL who either failed or were ineligible for auto-SCT 
[Zinzani PL, et al 2017] [Jacobsen ED, et al 2015]. These studies evaluated the efficacy of 
brentuximab vedotin (anti-CD30 antibody) and the objective response rate was not favorable 
(13% and 17%, respectively).  The lack of randomized clinical trials as well as the limited 
ORR in the Phase 2 trials suggests the high unmet medical needs in rrPMBCL.
A phase 2 study (KEYNOTE-170) investigated the efficacy and safety of pembrolizumab in 
participants with rrPMBCL or relapsed or refractory Richter Syndrome (rrRS) in overseas.  
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In the rrPMBCL cohort of this study, 53 participants with rrPMBCL who have failed auto-
SCT or were ineligible for auto-SCT and have failed ≥ 2 lines of prior treatments were 
treated with pembrolizumab 200 mg Q3W.  In All Subject as Treated (ASaT) population 
(n=53), pembrolizumab showed ORR of 45.3% (24/53 participants; 95% CI, 31.6%-59.6%) 
per blinded independent central review, and median DOR was not reached (range, 1.1+ to 
22.0+ months) among the participants with objective response.  Pembrolizumab was 
generally well tolerated in the ASaT population.  On Jun-2018, the United States Food and 
Drug Administration (US FDA) granted approval to pembrolizumab for both adult and 
pediatric rrPMBCL patients who have progressed after 2 or more lines of prior therapy. 
Given the clinical benefit of pembrolizumab monotherapy in rrPMBCL and that there are 
high unmet medical needs in the treatment of rrPMBCL in Japan, we plan to conduct a multi-
center, phase 1 study of pembrolizumab in Japanese participants with rrPMBCL.
2.2
Background
Refer to the IB/approved labeling for detailed background information on MK-3475 IB for 
detailed background information on pembrolizumab.
2.2.1
Pharmaceutical and Therapeutic Background
2.2.1.1
Pembrolizumab (MK-3475) Pharmaceutical and Therapeutic 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.
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [Disis, M. L. 2010].  Accumulating evidence 
shows a correlation between tumor-infiltrating lymphocytes 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 (Tregs) correlates with improved 
prognosis and long-term survival in many solid malignancies, such as ovarian, colorectal, 
and pancreatic cancer; hepatocellular carcinoma; malignant melanoma; and renal cell 
carcinoma. Tumor-infiltrating lymphocytes 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].
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated T 
cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and cytotoxic T-lymphocyte-associated antigen-4 
(CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
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engagement of its ligands (PD-L1 and/or PD-L2) [Greenwald, R. J., et al 2005] [Okazaki, T., 
et al 2001].  
The structure of murine PD-1 has been resolved [Zhang, X., et al 2004].  PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig variable-type domain 
responsible for ligand binding and a cytoplasmic tail that is responsible for the binding of 
signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling 
motifs, an immunoreceptor tyrosine-based inhibition motif and an immunoreceptor tyrosine-
based switch motif (ITSM).  Following T-cell stimulation, PD-1 recruits the tyrosine 
phosphatases SHP-1 and SHP-2 to ITSM within its cytoplasmic tail, leading to the 
dephosphorylation of effector molecules such as CD3 zeta, protein kinase C-theta, and zeta-
chain-associated protein kinase, which are involved in the CD3 T-cell signaling cascade 
[Okazaki, T., et al 2001] [Chemnitz, J. M., et al 2004] [Sheppard, K-A, et al 2004] [Riley, J. 
L. 2009].  The mechanism by which PD-1 down modulates T-cell responses is similar to, but 
distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins [Parry, R. V., et al 2005] [Francisco, L. M., et al 2010].  As a consequence, the PD 
1/PD-L1 pathway is an attractive target for therapeutic intervention in rrPMBCL.
2.2.2
Preclinical and Clinical Studies
Refer to the respective pembrolizumab IB for additional preclinical and clinical study data 
for pembrolizumab.
2.2.3
Ongoing Clinical Studies
Ongoing clinical studies with pembrolizumab are being conducted in multiple solid tumors
and hematologic malignancies. In addition, multiple combinations with pembrolizumab are 
also being investigated. Refer to pembrolizumab IB for study details.
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.
As a result of global Phase 2 study (KEYNOTE-170), pembrolizumab treatment resulted in 
an ORR of 45.3%, and median DOR was not reached at the time of date cutoff (range, 1.1+ 
to 22.0+ months) in participants with rrPMBCL. In terms of safety, pembrolizumab was
generally well tolerated in participants with rrPMBCL.
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
All objectives and endpoints apply to Japanese participants with rrPMBCL: 
Primary Objective
Primary Endpoint
To evaluate objective response using IWG 
Revised Response Criteria for Malignant 
Lymphoma (Appendix 9) as assessed by 
independent central review.
Objective response: complete response 
(CR) or partial response (PR).
To evaluate the safety and tolerability of 
pembrolizumab.
-Adverse event
-Discontinuing study intervention due to an 
adverse event
Secondary Objectives
Secondary Endpoints
-To evaluate disease control using IWG 
Revised Response Criteria for Malignant 
Lymphoma (Appendix 9) as assessed by 
independent central review.
-To evaluate objective response and disease 
control using IWG Revised Response 
Criteria for Malignant Lymphoma
(Appendix 9) as assessed by the 
investigator.
-Disease control: CR, PR, or stable disease 
(SD).
-Objective response: CR or PR.
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
To evaluate duration of response (DOR), 
progression free survival (PFS) using IWG 
Revised Response Criteria for Malignant 
Lymphoma (Appendix 9) as assessed by 
independent central review and the 
investigator, and overall survival (OS).
-DOR: the time from the first documented 
evidence of CR or PR to the earliest date of 
PD or death due to any cause, whichever 
comes first, for individuals with a CR or 
PR.
-PFS: the time from the first dose of study 
treatment to the first documented disease 
progression or death due to any cause, 
whichever occurs first.
-OS: the time from the first dose of study 
treatment to death due to any cause.
To evaluate the objective response using the 
5-point scale according to the Lugano 
Classification (Appendix 10) as assessed by 
independent central review.
Objective response: CR or PR.
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4
STUDY DESIGN
4.1
Overall Design
This is a multicenter, open label, non-randomized Phase 1 study of pembrolizumab 
monotherapy in Japanese participants with rrPMBCL who have failed auto-SCT or relapsed 
after auto-SCT, or were ineligible for auto-SCT and have failed ≥ 2 lines of prior treatments 
or relapse after auto-SCT. This study will evaluate the efficacy and safety of pembrolizumab. 
This study is conducted in Japan.
The study design is shown in Figure 1. Five (5) participants will be enrolled in this study and 
will receive pembrolizumab 200 mg Q3W. The details about the eligible criteria are 
described in Sections 5.1 and 5.2. 
Five (5) participants will be enrolled in this study and the anti-tumor activity at the timing of 
the Week 12 of the 5th evaluable participant will be reviewed by independent central review. 
If only <5 participants are enrolled over 1 year from the initiation of the study, the enrollment
may possibly be stopped, and the efficacy/safety will be assessed based on the enrolled 
participants with 12 weeks follow-up data.
Participants will receive pembrolizumab 200 mg Q3W up to 35 cycles (approximately 2 
years) from the first dose of the study treatment, or until disease progression is confirmed by 
the investigator using IWG Revised Response Criteria for Malignant Lymphoma, 
unacceptable AEs, investigator’s decision to discontinue treatment, or other reasons requiring 
cessation of treatment (Section 7.1).  Because of the possibility of immunotherapy-related 
tumor flare, participants who show initial radiographic progression, if they are clinically 
stable, may be continued on therapy at the discretion of the investigator. A follow-up scan 
should be obtained at least 4 weeks later to confirm progression.
Adverse events will be monitored throughout the study and graded in severity according to 
the guidelines outlined in the National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v5.0.  The reporting period for adverse events is described in 
Section 8.4.
Participants who discontinue study treatment for reasons other than progressive disease will 
have post-treatment follow-up for disease status (including imaging) until disease 
progression is identified by the investigator, the start of new anticancer treatment, death, 
withdrawal of consent, or the end of the study, whichever occurs first (See Section 8.9.3).
There is no re-treatment period in this study.
Participants who experience disease progression or start a new anticancer therapy will move 
into the Survival Follow-up Phase and should be contacted by telephone approximately every 
12 weeks (84 ±14 days) to assess for survival status until death, withdrawal of consent, or the 
end of the study, whichever occurs first (See Section 8.9.3).
After the approval of Protocol amendment 03, the study will be completed at the Safety 
Follow-up visit (scheduled 30 days after the last dose) or imaging assessment 120 weeks 
from the allocation date, of the last participant, whichever is later. If the study intervention is 
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still ongoing at Week 120 of the last participant, further study intervention should be 
discontinued, and no further visits will be required after the Safety Follow-up visit which 
scheduled 30 days after the last dose. Participants in the Imaging Follow-up Phase or 
Survival Follow-up Phase will be discontinued from the study and no further visits 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.
4.2
Scientific Rationale for Study Design
There is currently very limited data available regarding the optimal treatment for rrPMBCL if 
there is a poor response to this first-line therapy. The prognosis in patients who either did not 
respond to first-line therapy or relapsed is poor with OS at 2 years of 15% [Tomassetti S, et 
al 2019]. PMBCL is very rare cancer and account only for about 2.5% of all NHL cases 
[Jackson MW, et al 2016]. The lack of randomized clinical trials as well as the limited ORR 
in the previous Phase 2 trials suggest the high unmet medical needs in rrPMBCL.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary efficacy objective of this study is to evaluate objective response using IWG 
Revised Response Criteria for Malignant Lymphoma (Appendix 9) [Cheson, B. D., et al 
2007] as assessed by independent central review. Disease control as assessed by the 
independent central review will be evaluated as a secondary endpoint. The secondary 
efficacy endpoints also include objective response and disease control using IWG Revised 
Response Criteria for Malignant Lymphoma (Appendix 9) as assessed by the investigator. 
DOR, PFS and OS will be evaluated as exploratory endpoints. Objective response using the 
5-point scale per the Lugano Classification (Appendix 10) [Cheson, B. D., et al 2014] will 
also be evaluated as an exploratory endpoint.
Objective response, disease control, DOR and PFS are acceptable measures of clinical 
benefit of a new antineoplastic therapy. The primary efficacy endpoint of objective response 
will be assessed by independent central review to minimize the bias in the response 
assessments. OS has been recognized as the gold standard for the demonstration of 
superiority of a new antineoplastic therapy in randomized clinical studies. In this study, 
DOR, PFS and OS will be measured as exploratory endpoint because of the small sample 
size.
IWG Revised Response Criteria for Malignant Lymphoma will be applied by the site as the 
primary measure for assessment of disease response and as a basis for all protocol guidelines 
related to participant status (eg, discontinuation of study intervention).
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4.2.1.2
Safety Endpoints
The primary safety objective of this study is to characterize the safety and tolerability of 
pembrolizumab in participants with rrPMBCL. Safety parameters commonly used for 
evaluating investigational systemic anticancer treatments are included as safety endpoints 
including, but not limited to, the incidence of, causality, and outcome of AEs/SAEs; and 
changes in vital signs and laboratory values. AEs will be assessed as defined by CTCAE, 
Version 5.0.
4.3
Justification for Dose
The planned dose of pembrolizumab for this study is 200 mg Q3W. Based on the totality of 
data generated in the KEYTRUDA development program, 200 mg Q3W is an appropriate 
dose of pembrolizumab for adults across all indications. As outlined below, this dose is 
justified by:
•
Clinical data from 8 randomized studies in melanoma and NSCLC indications 
demonstrating
 
 
•
Population PK analysis showing that both fixed dosing and weight-based dosing provides 
similar control of PK variability with considerable overlap in the distributions of 
exposures, supporting suitability of 200 mg Q3W 
•
Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications
•
Pharmacology data showing full target saturation in both systemic circulation (inferred 
from PK data) and tumor (inferred from PBPK analysis) at 200 mg Q3W
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (ie, the 
participant is unable to be contacted by the investigator). For purposes of analysis and 
reporting, the overall study ends when the Sponsor receives the last laboratory result or at the 
time of final contact with the last participant, whichever comes last.
4.4.1
Clinical Criteria for Early Study Termination
The clinical study may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the study population 
as a whole is unacceptable. In addition, further 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.
CCI
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5
STUDY POPULATION
Male/Female participants with rrPMBCL and who are at least 18 years of ages on the day of 
signing informed consent 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
A participant will be eligible for inclusion in the study if the participant:
Type of Participant and Disease Characteristics
1. Have diagnosis of PMBCL, according to the World Health Organization (WHO) 
classification of neoplasms of the hematopoietic and lymphoid tissues (WHO Criteria, 
2008 [Swedlow SH, et al 2008]) by local pathological review.
2. Have relapsed*a or refractory*b PMBCL and:
•
Have relapsed after auto-SCT or have failed to achieve a CR or PR within 60 days of 
auto-SCT.  Subjects may have received intervening therapy after auto-SCT for 
relapsed or refractory disease, in which case they must have relapsed after or be 
refractory to their last treatment.
OR
•
For subjects who are ineligible for auto-SCT, have received at least ≥ 2 lines of prior 
therapy and have failed to respond to or relapsed after their last line of treatment.  For 
subjects who received consolidative local radiotherapy after systemic therapy, local 
radiotherapy will not be considered as a separate line of treatment.
*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
3. Have been previously exposed to rituximab as part of prior lines of treatment.
4. Have radiographically measurable disease by local institutional review, defined as at least 
one lesion that can be accurately measured in at least two dimensions with appropriate 
anatomic imaging (CT scan or magnetic resonance imaging [MRI]).  Minimum 
measurement must be > 15 mm in the longest diameter.
5. Have a performance status of 0 or 1 on the ECOG Performance Status.
Note: evaluation of ECOG Performance Status is to be performed within 7 days prior to 
the first dose of study intervention.
6. Have a life expectancy of at least 3 months.
7. Demonstrate adequate organ function as defined in Table 1. Specimens must be collected 
within 7 days prior to the first day of study intervention.
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
≥1,000/mcL
Platelets
≥75,000/mcL
Hemoglobin
≥8 g/dL or ≥5.0 mmol/L
Renal
Serum creatinine or 
creatinine clearance (CrCl) (measured or 
calculated) a or
Glomerular Filtration Rate (GFR) in place 
of CrCl
≤1.5 X ULN or 
≥60 mL/min for participants with 
creatinine levels >1.5 X ULN
Hepatic
Total bilirubin (serum) 
≤1.5 X ULN or 
Direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 X ULN
AST (SGOT) and ALT (SGPT)
≤2.5 X ULN or  
≤5 X ULN for participants with liver 
metastases
Coagulation
International Normalized Ratio (INR) or 
Prothrombin Time (PT)
Activated Partial Thromboplastin Time 
(aPTT)
≤1.5 X ULN unless participant is receiving 
anticoagulant therapy as long as PT or 
aPTT is within therapeutic range of 
intended use of anticoagulants
ALT (SGPT) = alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT) = 
aspartate aminotransferase (serum glutamic oxaloacetic transaminase); GFR = glomerular 
filtration rate; ULN = upper limit of normal.
a
Creatinine clearance (CrCl) should be calculated per institutional standard.
Demographics
8. Is male or female, at least 18 years of age at the time of signing the informed consent.
Male Participants
9. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least 120 days after the last dose of study intervention:
•
Refrain from donating sperm
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PLUS either:
•
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent
OR
•
Must agree to use contraception unless confirmed to be azoospermic (vasectomized or 
secondary to medical cause [Appendix 5]) as detailed below:
-
Agree to use a male condom plus partner use of an additional contraceptive method 
when having penile-vaginal intercourse with a WOCBP who is not currently 
pregnant. Note: Men with a pregnant or breastfeeding partner must agree to remain 
abstinent from penile-vaginal intercourse or use a male condom during each episode 
of penile-vaginal penetration.
•
Male participants must also agree to use male condom when engaging in any activity that 
allows for passage of ejaculate to another person of any sex.
Female Participants
10. A female participant is eligible to participate if she is not pregnant or breastfeeding, and 
at least one of the following conditions applies: 
•
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) within 
72 hours before the first dose of study intervention.
•
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive.
•
Additional requirements for pregnancy testing during and after study intervention are 
located in Appendix 5.
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•
Abstains from breastfeeding during the study intervention period and for at least 120 days 
after study intervention.
•
Medical history, menstrual history, and recent sexual activity has been reviewed by the 
investigator to decrease the risk for inclusion of a woman with an early undetected 
pregnancy.
Informed Consent
The participant (or legally acceptable representative if applicable) provides written informed 
consent for the study.
5.2
Exclusion Criteria
The participant must be excluded from the study if the participant:
Medical Conditions
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to 
randomization or treatment allocation (see Appendix 5). If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.
Note: In the event that 72 hours have elapsed between the screening pregnancy test 
and the first dose of study intervention, another pregnancy test (urine or serum) must 
be performed and must be negative in order for subject to start receiving study 
medication.
Prior/Concomitant Therapy
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an 
agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-
40, CD137).
3. Has received CAR T-cell therapy.
4. Has received a monoclonal antibody or radiation therapy within 4 weeks prior to the first 
dose of study intervention; has received prior chemotherapy or targeted small molecule 
therapy within 2 weeks prior to the first dose of study intervention; OR has not recovered 
(i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent
above. 
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study.
Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the inclusion 
requirements for laboratory parameters defined in Table 1.
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5. Has had major surgery within 3 weeks prior to first dose of study intervention. 
Note: Adequate wound healing after major surgery must be assessed clinically, 
independent of time elapsed for eligibility.
6. Has received a live vaccine within 30 days prior to the first dose of study drug (See 
Section 6.5.2)
Prior/Concurrent Clinical Study Experience
7. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks prior to the first dose of study 
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.
Diagnostic Assessments
8. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent, refer to Section 6.5.2) or any 
other form of immunosuppressive therapy within 7 days prior the first dose of study drug.
9. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.
Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have 
undergone potentially curative therapy are not excluded.
10. Has known active CNS metastases and/or carcinomatous meningitis. Participants with 
previously treated brain metastases may participate provided they are radiologically 
stable, (ie, without evidence of progression) for at least 4 weeks by repeat imaging (note 
that the repeat imaging should be performed during study screening), clinically stable and 
without requirement of steroid treatment for at least 14 days prior to first dose of study 
intervention.
11. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
12. 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.
13. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
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14. Has an active infection requiring systemic therapy.
15. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority.
16. Has a known history of Hepatitis B (defined as HBsAg reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is detected) infection.
Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local 
health authority
17. 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.
18. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
Other Exclusions
19. Is pregnant or breastfeeding or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after 
the last dose of study intervention.
20. Has had an allogeneic hematopoetic 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.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
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5.5
Participant Replacement Strategy
If a participant discontinues from study intervention before the first on-study disease 
assessment, a replacement participant may be enrolled if deemed appropriate by the 
investigator and Sponsor. The replacement participant will be assigned a unique 
treatment/randomization number. The study site should contact the Sponsor for the 
replacement participant’s treatment/randomization number.
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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 provided by the Sponsor will be packaged to support enrollment and 
replacement participants as required. When a replacement participant is required, the Sponsor 
or designee needs to be contacted before dosing the replacement supplies. Clinical supplies 
will be affixed with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study intervention to be used in this study is outlined in Table 2.
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Table 2
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
Use
IMP/NIMP Sourcing
N/A
Experimental Pembrolizumab Drug
Solution
25 mg/mL
200 mg
IV Infusion
Q3W; Day 
1 in each 
cycle
up to 35 
cycles
Test 
Product
IMP
Central
Definition Investigational Medicinal Product (IMP) and Non-Investigational Medicinal Product (NIMP) is based on guidance issued by the European 
Commission. Regional and/or Country differences of the definition of IMP/NIMP may exist. In these circumstances, local legislation is followed.
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All supplies indicated in Table 2 will be provided per the "Sourcing" column depending upon 
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 8.1.8 for details regarding administration of the study intervention.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab 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.
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 in this study will be allocated by nonrandom assignment.
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6.3.2
Stratification
No stratification based on age, sex, or other characteristics will be used in this study.
6.3.3
Blinding
This is an open-label study; therefore, the Sponsor, investigator, and participant will know 
the intervention administered.
6.4
Study Intervention Compliance
If there are interruptions in the study intervention schedule or infusion/injection was stopped, 
the details of and reason for any interruption or infusion/injection cessation of study 
intervention will be documented in the participant’s medical record.
Refer to Section 6.6.1 for Dose Modification and Toxicity Management Guidelines for irAEs 
associated with pembrolizumab monotherapy, coformulations, or IO combinations and for 
other allowed dose interruptions.
6.5
Concomitant Therapy
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study. If there is a clinical indication for any medication or vaccinations 
specifically prohibited, discontinuation from study intervention 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 vaccinations 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 concomitant medications received within 28 days before 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
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. Surgery or radiotherapy for tumor control is not permitted during the study; 
however, radiotherapy or procedures for symptom management are allowed with sponsor 
approval. All concomitant medication will be recorded on the CRF including all prescription, 
OTC, herbal supplements, and IV medications and fluids. If changes occur during the study 
period, documentation of drug dosage, frequency, route, and date may also be included on 
the CRF.
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6.5.2
Prohibited Concomitant Medications
The following medications and vaccinations are prohibited during the study:
•
Antineoplastic systemic chemotherapy, biological therapy, or immunotherapy not 
specified in this protocol
•
Investigational agents other than pembrolizumab
•
Radiation therapy
o
Note:  Radiation therapy to a symptomatic soft tissue lesion, bone lesions, or 
to the brain may be allowed after consultation with Sponsor.
o
Note: Radiation therapy is not allowed within 4 weeks prior to the first dose of 
study intervention.
•
Live or live attenuated vaccines within 30 days prior to the first dose of study 
intervention and while participating in the study. Examples of live vaccines include, but 
are not limited to the following: measles, mumps, rubella, varicella/zoster, yellow fever, 
rabies, BCG, and typhoid vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, 
FluMist®) are live attenuated vaccines and are not allowed.
•
Systemic glucocorticoids except when used for the following purposes:. 
o
To modulate symptoms of an AE that is suspected to have an immunologic 
etiology
o
For the prevention of emesis
o
To premedicate for IV contrast allergies
o
To treat COPD exacerbations (only short-term oral or IV use in doses >10 
mg/day prednisone equivalent)
o
For chronic systemic replacement not to exceed 10 mg/day prednisone 
equivalent
•
Other glucocorticoid use except when used for the following purposes:
o
For topical use or ocular use
o
Intraarticular joint use
o
For inhalation in the management of asthma or chronic obstructive pulmonary 
disease
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6.5.3
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 
associated with study intervention are outlined along with the dose modification guidelines in 
Section 6.6.1. Where appropriate, these guidelines include the use of oral or IV treatment 
with corticosteroids, as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids. Note that several courses of steroid tapering 
may be necessary as symptoms may worsen when the steroid dose is decreased. For each 
disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care. The treatment 
guidelines are intended to be applied when the investigator determines the events to be 
related to pembrolizumab.
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance. Refer to Table 3 in Section 
6.6.1 for guidelines regarding dose modification and supportive care.
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Dose Modification
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation.
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 3.
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Table 3
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
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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
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
AST or ALT Elevation 
or Increased Bilirubin
Grade 2 a
Withhold
Administer corticosteroids 
(initial dose of 0.5 to 
1 mg/kg prednisone or 
equivalent) followed by 
taper
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
Grade 3 b or 4 c
Permanently 
discontinue
Administer corticosteroids 
(initial dose of 1 to 
2 mg/kg prednisone or 
equivalent) followed by 
taper
T1DM or 
Hyperglycemia
New onset T1DM or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure
Withhold d
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
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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
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 d
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 d
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 
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
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
Hematological toxicity 
(cHL or PMBCL only)
Grade 4
Withhold
Based on severity of AE 
administer corticosteroids
Ensure adequate evaluation to confirm etiology 
or exclude other causes
Can be resumed when ≤ Grade 1
All Other irAEs
PersistentGrade2
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 e
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
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; cHL=classical Hodgkin lymphoma; 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; 
PMBCL=primary mediastinal B-cell lymphoma; SJS=Stevens-Johnson Syndrome; T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit 
of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a
AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b
AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal
c
AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d
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.
e
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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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated 
infusion reaction are provided in Table 4.
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines
NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator
None
Grade 2
Requires therapy or infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic medications 
indicated for ≤24 hrs
Stop Infusion
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within 1 hour of 
stopping drug infusion, the infusion may be 
restarted at 50% of the original infusion rate 
(eg, from 100 mL/hr to 50 mL/hr). Otherwise 
dosing will be held until symptoms resolve 
and the participant should be premedicated 
for the next scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug intervention.
Participant may be 
premedicated 1.5 h (±30 
minutes) prior to infusion 
of study intervention with:
Diphenhydramine 50 mg 
PO (or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 
mg PO (or equivalent dose 
of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial improvement; 
hospitalization indicated for 
other clinical sequelae (eg, 
renal impairment, pulmonary 
infiltrates)
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as 
medically indicated until the participant is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine 
should be used immediately.
Participant is permanently discontinued from 
further study drug intervention.
No subsequent dosing
Appropriate resuscitation equipment should be available at the bedside and a physician readily available 
during the period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 
(CTCAE) at http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the Sponsor. The reason for interruption should be documented in 
the participant's study record.
6.7
Intervention After the End of the Study
There is no study-specified intervention following 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.
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 
period 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 8.9.3 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. Specific details regarding procedures to be 
performed at study intervention discontinuation are provided in Section 8.1.9 and 
Section 8.9.3.
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.
•
Radiographic disease progression outlined in Section 8.2 (exception if the Sponsor 
approves treatment continuation).
•
Progression or recurrence of any malignancy, or occurrence of another malignancy that 
requires active treatment.
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•
Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.
•
Investigator’s decision to discontinue treatment.
•
Completion of 35 treatments with pembrolizumab.
Note: 35 cycles are calculated from the first dose.
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, he/she 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, are outlined in Section 8.1.9. The procedures to be 
performed should a participant repeatedly fail to return for scheduled visits and/or if the 
study site is unable to contact the participant are outlined in Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of ICF may be used for screening or baseline purposes 
provided the 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.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements. The 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.
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 their legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated ICF should be given to the participant (or their legally 
acceptable representative) before participation in the study.
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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. 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.
8.1.1.1
General Informed Consent
Specifics about the study and the study population are to be included in the ICF.
The participant (or their 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.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention 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. The medical 
history will collect all active conditions and any condition diagnosed within the prior 
10 years that the investigator considers to be clinically important. Details regarding the 
disease for which the participant has enrolled in this study will be recorded separately and 
not listed as medical history.
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If a medical condition is diagnosed at the time of screening due to the physical examination, 
laboratory tests, radiologic assessment, other assessment, and/or a combination of these 
evaluations, the medical condition is to be recorded as a baseline condition along with the 
participant’s other medical history unless due to any protocol-specified intervention (eg, 
procedure, washout, or run-in treatment including placebo run-in).
8.1.5
Prior and Concomitant Medications Review
8.1.5.1
Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before the first dose of study intervention.
8.1.5.2
Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the participant 
during the study through the Safety Follow-up Visit.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 8.4.
8.1.5.3
Prior Cancer Treatment
The investigator or qualified designee will review all prior cancer treatments including but 
not limited to systemic treatments, prior transplantation, radiation, and surgeries and record 
in the study database.
Prior SCT details and acute and/or chronic Graft versus Host Disease, maximum grade, and 
dates will be collected.
8.1.5.4
Subsequent Antineoplastic Therapy
The investigator or qualified designee will review all new antineoplastic therapy initiated 
after the last dose of study intervention.  
Collect transplant parameters after study intervention to include the conditioning regimen, 
date, and type of transplant.
If a participant initiates a new antineoplastic therapy within 30 days after the last dose of 
study intervention, the 30-day Safety Follow-up visit must occur before the first dose of the 
new therapy.  Once new antineoplastic therapy has been initiated, the participant will move 
into survival follow-up.
8.1.6
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 provided in Section 8.9.1.
8.1.7
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 re-assigned to 
another participant.
A single participant cannot be assigned more than 1 treatment/randomization number.
8.1.8
Study Intervention Administration
Study intervention(s) will be administered by the investigator and/or study staff according to 
the specifications within the pharmacy manual.
8.1.8.1
Timing of Dose Administration
Dosing and schedules of the study intervention is described in Section 6.1.
First study treatment should begin within 3 days of intervention allocation. After the first 
cycle, study intervention may be administered ± 3 days of the scheduled dosing date for each 
infusion due to administrative reasons.
On Day 1 of each cycle, pembrolizumab will be administered at a dose of 200 mg using a 30-
minute IV infusion. Sites should make every effort to target infusion timing to be as close to 
30 minutes as possible. Given the variability of infusion pumps form site to site, a window of 
minus (-) 5 minutes and plus (+) 10 minutes is allowed (ie, infusion time is 30 minutes -
5min/+10 min).
Details on the preparation and administration of pembrolizumab is provided in the Pharmacy 
Manual.
8.1.9
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 8.9.3.
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 
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present at the time of withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.4.
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study.
8.1.11
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
Efficacy Assessments
8.2.1
Criteria for Assessment of Disease
Antitumor activity of pembrolizumab will be evaluated using IWG Revised Response 
Criteria for Malignant Lymphoma (Appendix 9).
Lymphoma response assessment by CT/PET, based on the IWG response criteria for 
malignant lymphoma [Cheson, B. D., et al 2007], will be applied by the site as a basis for all 
protocol guidelines related participant eligibility and for participant management (eg, 
discontinuation of study intervention). Assessment of lymphoma B symptoms (Appendix 11) 
should occur with each lymphoma disease response assessment.
All scheduled imaging for all study participants will be submitted to independent central 
review for primary efficacy assessment. In addition, imaging that is obtained at an 
unscheduled time point, for any reason (including suspicion of progression or other clinical 
reason), should also be submitted to independent central review if it shows progression, or if 
it is used to support a response assessment. A detailed description regarding tumor imaging 
procedures is provided in the Site Imaging Manual.
Antitumor activity of pembrolizumab will also be evaluated as part of exploratory analyses 
using the Lugano Classification (Appendix 10).
Refer to central review charter for independent central imaging review for both IWG 
response criteria and Lugano Classification.
8.2.1.1
Disease Assessment of Immunotherapeutic Agents
Immunotherapeutic agents such as pembrolizumab produce antitumor effects by potentiating 
endogenous cancer-specific immune responses, which may be functionally anergic.  The 
response patterns seen with such an approach may extend beyond the typical time course of 
responses seen with cytotoxic agents, and can manifest a clinical response after an initial 
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increase in tumor burden or even the appearance of new lesions. Standard response 
assessment criteria may not provide a complete response assessment of immunotherapeutic 
agents such as pembrolizumab.  Therefore, in the setting where a participant’s assessment 
shows progressive disease, study intervention may be continued at the discretion of the 
investigator until the next disease response assessment provided that the participant’s clinical 
condition is stable.  However, imaging should occur at any time when there is clinical 
suspicion of progression. 
Refer to Section 8.2.3 for confirmation assessment requirements when a participant’s disease 
response assessment shows progressive disease.
8.2.2
Assessment of Disease and Tumor Response
Disease assessments should be performed per the frequency defined in the SoA (Section 1.3).  
CT is the modality of choice for anatomic imaging, and will be the term used in this protocol 
when anatomic imaging is required. However, if CT with IV contrast is contraindicated, or if 
dictated by local practice guidelines, MRI may be performed instead.
For tumor burden assessment, CT must be of diagnostic quality. If a combination PET/CT is 
obtained, and the CT component is of diagnostic quality with IV contrast, that can be used. If 
the CT component is not of diagnostic quality, a separate diagnostic quality scan must be 
performed.
8.2.2.1
Initial Disease Assessment
Initial disease assessment or tumor imaging at Screening (CT and PET scans) must be 
performed within 28 days prior to Cycle 1 Day 1. The site study team must review screening 
images to confirm the participant has measurable disease per the disease-specific criteria.
Disease assessments or scans performed as part of routine clinical management are 
acceptable for use as the screening scan if they are of diagnostic quality and performed 
within 28 days prior to Cycle 1 Day 1. 
CT and PET scans should be used throughout the study at time-points designated in Section 
1.3-SoA. For lymphomas that are not FDG-avid at Screening, PET scans do not need to be 
repeated at follow-up assessments.
8.2.2.2
Disease Assessment During the Study
The first on-study imaging assessment should be performed at 12 weeks (±7 days) from the 
date of allocation. Subsequent tumor imaging by CT-scan should be performed every 
12 weeks (±7 days) or more frequently if clinically indicated; PET scan should be performed 
at Week 12, Week 24, and subsequently as clinically indicated if relapse or recurrence is 
suspected. Imaging timing should follow calendar days and should not be adjusted for delays 
in cycle starts. Imaging should continue to be performed until disease progression is 
identified by the investigator (unless the investigator elects to continue study intervention), 
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the start of new anticancer treatment, death, withdrawal of consent, or the end of the study,
whichever occurs first. 
If PET and CT scans at Screening are positive for disease involvement of the neck, 
subsequent CT scans must include the neck. If PET and CT scans at Screening are negative 
for disease involvement in the neck, subsequent CT scans are not required to include the 
neck, unless enlarged lymph nodes are detected during the physical examination, or if 
otherwise clinically indicated, and at the discretion of the treating physician.
For participants who discontinue study intervention without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used while on treatment (every 12 weeks) to monitor 
disease status until disease progression is identified by the investigator, the start of new 
anticancer treatment, death, withdrawal of consent, or the end of the study, whichever occurs 
first.
Response assessment by CT or PET/CT is based on IWG Revised Response Criteria for 
Malignant Lymphoma described in Appendix 9. If CR is documented by both CT and FDG-
PET, subsequent assessments may be by CT only, with PET used only if relapse or 
recurrence is suspected.  Assessment of lymphoma B symptoms (Appendix 11) should occur 
with each lymphoma disease response assessment.
8.2.3
Disease Progression Assessments
Treatment response assessments are conducted at the protocol-specified time points, but an 
additional assessment should occur at any time where there is clinical suspicion of 
progression.
If a participant has radiographic progression of disease documented at a treatment response 
assessment, the investigator should determine whether the participant is clinically stable. 
Clinical stability means:

Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression

No decline in ECOG performance status

Absence of rapid progression of disease 

Absence of progressive tumor at critical anatomical sites 
If the participants is clinically unstable, study intervention must be discontinued. Participants 
who are deemed clinically unstable are not required to have repeat imaging for confirmation.  
However, it is requested that participants who discontinue due to clinical progression without 
radiographic progression undergo a tumor imaging scan if they have not had one in the prior 
4 weeks.
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Participants who are clinically stable may continue study intervention, at the discretion of the 
investigator, until the next response assessment, which should occur no later than 4 to 
6 weeks after the initial determination of progression. If a participant is clinically stable and 
study intervention is to continue, notification to the sponsor is required and opinion of the 
participant to continue study intervention should be confirmed.
If, at the confirmatory assessment, the radiographic evidence of progression (enlargement of 
target lesions above the threshold specified in the criteria, unequivocal progression of non-
target lesions, or presence of new lesions) is still present or worsening, progression is 
considered confirmed. These participants should be discontinued from study intervention, but 
the investigator, upon consultation with the Sponsor, may keep a clinically stable participant 
on study intervention as long as the participant is deriving clinical benefit.
If, at the confirmatory assessment, the radiographic evidence of progression is no longer 
present, the progression is not confirmed, and the participant may continue on treatment 
provided that they remain clinically stable.
8.2.4
Bone Marrow Biopsy and Aspirate
For all participants, collect bone marrow biopsy and aspirate at baseline.  Bone marrow 
biopsy and aspirate performed as part of routine clinical management are acceptable for use 
as baseline data if they are performed within 28 days prior to Cycle 1 Day 1. Repeat bone 
marrow biopsy and aspirate as needed to confirm CR (if subject has baseline bone marrow 
involvement), and as clinically indicated. Local results of bone marrow biopsy and aspirate 
will be used for baseline and to confirm CR (or other reason).
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided.
Planned time points for all safety assessments are provided in the SoA.
8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a complete physical examination during 
the Screening period. Clinically significant abnormal findings should be recorded as medical 
history. The time points for full physical exams are described in Section 1.3. After the first 
dose of study intervention, new clinically significant abnormal findings should be recorded 
as AEs.
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 required a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination as clinically 
indicated prior to study intervention administration. New clinically significant abnormal 
findings should be recorded as AEs.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.2
Vital Signs
The investigator or qualified designee will take vital signs at the timing specified in the SoA. 
Vital signs include temperature, pulse, respiratory rate, weight and blood pressure. Height 
will be measured at Screening only.
8.3.3
Electrocardiograms
A standard 12-lead ECG will be performed using local standard procedures. The timing of 
ECGs is specified in the SoA. Clinically significant abnormal findings at screening should be 
recorded as medical history. Additional ECGs may be performed as clinically necessary.
Clinically significant abnormal findings seen on all ECGs performed after the first dose of 
study intervention should be recorded as adverse events.
8.3.4
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
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 SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
considered clinically significant by the investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the appropriate CRF (eg, SLAB).
•
For any laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention, every 
attempt should be made to perform repeat assessments until the values return to normal or 
baseline or if a new baseline is established as determined by the investigator.
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8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
Laboratory tests for screening should be performed within 7 days prior to the first dose of 
study intervention. After Cycle 1, predose laboratory safety tests can be conducted up to 3 
days prior to dosing unless otherwise noted on the flow charts.
Laboratory test results must be reviewed by the investigator or qualified designee and found 
to be acceptable prior to administration of each dose of study intervention.
8.3.4.2
Pregnancy Test
All women who are being considered for participation in the study, and who are not 
surgically sterilized or postmenopausal, must be tested for pregnancy within 72 hours of 
Cycle 1 Day 1. If a urine test is positive or not evaluable, a serum test will be required. 
Participants must be excluded/discontinued from the study in the event of a positive or 
borderline-positive test result. Pregnancy testing should be conducted at the end of treatment 
and 30 days follow-up after the last dose of study intervention.
8.3.5
Eastern Cooperative Oncology Group Performance Status
The ECOG Performance Status is standardized criteria to measure how cancer impacts level 
of functioning (performance status) in terms of ability to care for oneself, daily activity, and 
physical ability (walking, working, etc.) with grades 0 to 5.
The Investigator or qualified designee will assess ECOG Performance Status (see 
Appendix 12) at timing specified in the SoA.
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety Events
The definitions of an AE or SAE, as well as the method of recording, evaluating, and 
assessing causality of AE and SAE and the procedures for completing and transmitting AE, 
SAE, and other reportable safety event reports can be found in Appendix 3.
Progression of the cancer under study is not considered an AE as described in Section 8.4.6
and Appendix 3.
Adverse events, SAEs, and other reportable safety events will be reported by the participant 
(or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized 
representative).
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as well as other reportable safety events. 
Investigators need to document if an SAE was associated with a medication error, misuse, or 
abuse.
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Investigators remain responsible for following up AEs, SAEs, and other reportable safety 
events for outcome according to Section 8.4.3. The investigator, who is a qualified physician, 
will assess events that meet the definition of an AE or SAE as well as other reportable safety 
events with respect to seriousness, intensity/toxicity, and causality.
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other Reportable 
Safety Event Information
All AEs, SAEs, and other reportable safety events that occur after the consent form is signed 
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 following cessation of 
study intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation through 90 days 
following cessation of study intervention or 30 days following 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 following cessation of study intervention, or 30 days 
following 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 of 
the time period 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 5.
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Table 5
Reporting Time Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation through 
Protocol-specified 
Follow-up Period
Reporting Time 
Period:
After the 
Protocol-specified 
Follow-up Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
Nonserious 
Adverse Event 
(NSAE) 
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Not required
Per data entry 
guidelines
Serious Adverse 
Event (SAE) 
including Cancer 
and Overdose
Report if:
- due to protocol-
specified intervention
- causes exclusion
- participant is 
receiving placebo run-
in or other run-in 
treatment
Report all
Report if:
- drug/vaccine 
related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
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
Event of Clinical 
Interest 
(requiring
regulatory 
reporting)
Report if:
- due to intervention
- causes exclusion
Report
- potential drug-
induced liver injury 
(DILI)
- requiring
regulatory reporting
Not required
Within 24 hours 
of learning of 
event
Event of Clinical 
Interest (does 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
ECI=event of clinical interest.
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. SAEs and other reportable safety events, including 
pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be followed 
until resolution, stabilization, until the event is otherwise explained, or the participant is lost 
to follow-up (as defined in Section 7.3). The investigator will also make every attempt to 
follow 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.
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Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of study intervention as defined in Section 8.5.
2. Potential DILI events defined as: an elevated AST or ALT lab value that is greater than 
or equal to 3X the upper limit of normal and an elevated total bilirubin lab value that is 
greater than or equal to 2X the upper limit of normal and, at the same time, an alkaline 
phosphatase lab value that is less than 2X the upper limit of normal, as determined by 
way of protocol-specified laboratory testing or unscheduled laboratory testing.*.
*Note: These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The study site guidance for 
assessment and follow up of these criteria can be found in the Investigator Study File 
Binder (or equivalent).
3. Post-transplant complications (see Section 8.4.7.1) that occurred within 18 months from 
the date of the allogeneic transplant, for subject who were previously exposed to 
pembrolizumab.
8.4.7.1
Follow-Up Post-Allogeneic Stem Cell Transplantation
For participants who have an allogeneic SCT within 24 months of last dose of 
pembrolizumab, transplant parameters will be collected, and specific ECIs will be collected 
for 18 months from the date of the allogeneic transplant, to include graft-versus-host-disease, 
hepatic veno-occlusive disease or sinusoidal syndrome, febrile syndrome (a steroid-requiring 
febrile illness without an infectious cause), pulmonary complications, immune-mediated 
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AEs, critical illness, and transplant-related mortality for all grades, and regardless of 
relationship to study intervention. 
Additional medically important AEs post-allogeneic SCT may be submitted at the 
investigator’s discretion. If available and relevant to an event post-allogeneic SCT, 
concomitant medications and/or laboratory results may also be reported.
Post-allogenic SCT ECIs that occur after the normal safety follow-up period must be 
assessed for seriousness and causality and reported to the sponsor as follows: 
•
within 24 hours if serious regardless of causality or if non-serious and considered to be 
drug-related; and 
•
within 5 calendar days if non-serious and not considered to be drug-related.
8.5
Treatment of Overdose
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater (≥5 times the indicated dose).
No specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, the participant should be observed closely for signs of toxicity. 
Appropriate supportive treatment should be provided if clinically indicated.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
8.8
Future Biomedical Research Sample Collection
Future biomedical research samples will not be collected in this study.
8.9
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.9.1
Screening
Documented informed consent must be provided prior to performing any protocol-specific 
procedure. Results of a test performed prior to the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the
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specified time frame. Screening procedures are to be completed within 28 days prior to the 
first dose of study intervention except for the following:
•
Laboratory tests are to be performed within 7 days prior to the first dose of study 
intervention. 
•
Evaluation of ECOG Performance Status is to be performed within 7 days prior to the 
first dose of study intervention.
•
For women of reproductive potential, a urine or serum pregnancy test will be performed 
within 72 hours prior to the first dose of study intervention. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required (performed by 
the local study site laboratory).
Participants may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments during the initial screening period are acceptable in lieu of a repeat 
screening test if performed within the specified time frame and the corresponding 
inclusion/exclusion criteria is met. Participants who are rescreened will retain their original 
screening number.
8.9.2
Treatment Period
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
above in Section 8.
8.9.3
Post Treatment Visit
After the approval of Protocol amendment 03, the study will be completed at the Safety 
Follow-up visit (scheduled 30 days after the last dose) or imaging assessment 120 weeks 
from the allocation date, of the last participant, whichever is later. If the study intervention is 
still ongoing at Week 120 of the last participant, further study intervention should be 
discontinued, and no further visits will be required after the Safety Follow-up visit which 
scheduled 30 days after the last dose. Participants in the Imaging Follow-up Phase or 
Survival Follow-up Phase will be discontinued from the study and no further visits will be 
required.
8.9.3.1
Discontinuation Visit
The Discontinuation Visit should occur at the time study intervention is discontinued for any 
reason. If the Discontinuation Visit occurs 30 days from the last dose of study intervention, at 
the time of the mandatory Safety Follow-up Visit, the Discontinuation Visit procedures and 
any additional Safety Follow-up procedures should be performed. Visit requirements are 
outlined in Section 1.3. Additional details regarding participant withdrawal and 
discontinuation are presented in Section 7.
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8.9.3.2
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted approximately 30 days after the 
last dose of study intervention or before the initiation of a new anticancer treatment, 
whichever comes first.
8.9.3.3
Imaging Follow-up Visits
Participants who discontinue study intervention for reasons other than verified PD should 
continue with imaging assessments per the protocol-defined schedule until disease 
progression is identified by the investigator, the start of new anticancer treatment, death, 
withdrawal of consent, or the end of the study, whichever occurs first.
8.9.3.4
Survival Follow-up Visits
Participants who experience confirmed disease progression or start a new anticancer therapy 
will move into the Survival Follow-up Phase and should be contacted by telephone every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first.
The Sponsor may request survival status be assessed at additional time points during the 
course of the study. For example, these additional time points may be requested prior to an 
efficacy interim analysis, and/or final analysis. All participants who are not known to have 
died prior to the request for these additional survival status time points will be contacted at 
that time.
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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, but prior to database lock, will be 
documented in a supplemental SAP (sSAP) and referenced in the Clinical Study Report 
(CSR) for the study.  Post hoc exploratory analyses will be clearly identified in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2-9.12.
Study Design Overview
A Phase 1 clinical study of Pembrolizumab (MK-3475) in participants 
with relapsed or refractory primary mediastinal large B-cell lymphoma 
(rrPMBCL)
Intervention Assignment
This is a single arm, non-randomized and open label study.
Analysis Populations
Safety: All-Participants-as-Treated (APaT)
Efficacy: All-Participants-as-Treated (APaT)
Primary Endpoint(s)
The primary efficacy endpoint is objective response (CR or PR) as 
assessed by independent central review using IWG Revised Response 
Criteria for Malignant Lymphoma. The safety endpoints are adverse 
event and discontinuing study intervention due to an adverse event.
Secondary Endpoints
Disease control (SD, CR or PR) as assessed by independent central 
review using IWG Revised Response Criteria for Malignant Lymphoma 
will be the secondary efficacy endpoint.
Objective response and disease control as assessed by investigator using 
IWG Revised Response Criteria for Malignant Lymphoma will also be 
the secondary efficacy endpoints.
Statistical Methods for 
Efficacy/Immunogenicity/ 
Pharmacokinetic Analyses
ORR and DCR will be estimated together with its 95% confidence 
interval using an exact method based on the binomial distribution 
(Clopper-Pearson interval).
Statistical Methods for 
Safety Analyses
Adverse events will be listed and summarized by counts and 
frequencies. Laboratory tests, vital signs, and other safety endpoints will 
be summarized as appropriate.
Interim Analyses
No interim analysis will be performed.
Multiplicity
No multiplicity adjustment is planned since no formal hypothesis testing 
is planned.
Sample Size and Power
The sample size for this study is expected to be 5 for feasibility.
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.
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This study is being conducted as a non-randomized and open-label study, i.e., participants, 
investigators, and sponsor personnel will be aware of participant intervention assignment 
after each participant is enrolled and treatment is assigned.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are outlined in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Objective response as assessed by independent central review using IWG Revised Response 
Criteria for Malignant Lymphoma will be the primary efficacy endpoint.  Objective response 
is defined as a CR or PR. Objective response rate (ORR) is the proportion of participants in 
the analysis population with objective response.
Disease control defined as a response of CR, PR or SD as assessed by independent central 
review using IWG Revised Response Criteria for Malignant Lymphoma will be the 
secondary efficacy endpoint. Disease control rate (DCR) is the proportion of participants in 
the analysis population with disease control.
Objective response and disease control as assessed by investigator using IWG Revised 
Response Criteria for Malignant Lymphoma will also be the secondary endpoints.
DOR as assessed by independent central review and investigator, PFS as assessed by 
independent central review and investigator, OS and objective response using the 5-point 
scale according to the Lugano Classification as assessed by independent central review are 
the exploratory endpoints.
DOR is defined as the time from the first documented evidence of CR or PR to the earliest 
date of PD or death due to any cause, whichever comes first, for individuals with a CR or PR.
PFS is defined as the time from the first dose of study treatment to the first documented 
disease progression or death due to any cause, whichever occurs first.
OS is defined as the time from the first dose of study treatment to death due to any cause. 
Participants who do not die will be censored on the date of the last study assessment or 
contact.
A description of efficacy measures is provided in Section 4.2.1.1.
9.4.2
Safety Endpoints
The primary safety endpoints are adverse event and discontinuing study intervention due to 
an adverse event. In addition, safety and tolerability will be assessed by clinical review of all 
relevant parameters including AEs, laboratory tests, and vital signs.
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9.5
Analysis Populations
9.5.1
Safety Analysis Populations
The All Participants as Treated (APaT) population will be used for the analysis of safety data 
in this study. The APaT population consists of all participants who received at least 1 dose of 
study intervention.
At least 1 laboratory or vital sign measurement obtained subsequent to at least 1 dose of 
study intervention is required for inclusion in the analysis of each specific parameter. To 
assess change from baseline, a baseline measurement is also required.
9.5.2
Pharmacokinetic Analysis Populations
No pharmacokinetic analysis is planned in this study.
9.5.3
Efficacy Analysis Populations
The APaT population will be used for the analysis of efficacy data in this study. The APaT 
population consists of all participants who received at least 1 dose of study intervention.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to exploratory endpoints will be described in the sSAP.
9.6.1
Statistical Methods for Efficacy Analysis
ORR and DCR will be estimated using an exact method based on the binomial distribution 
together with its 95% confidence interval (Clopper-Pearson interval). Table 6 summarizes the 
key efficacy analyses.
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Table 6
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data Approach
Primary efficacy endpoint
ORR as assessed by 
independent central review 
based on IWG Revised 
Response Criteria for 
Malignant Lymphoma
Exact method based on 
binomial distribution
APaT
Participants with missing data 
are considered non-
responders
Secondary efficacy endpoints
DCR as assessed by 
independent central review
based on IWG Revised 
Response Criteria for 
Malignant Lymphoma
Exact method based on 
binomial distribution
APaT
Participants with missing data 
are considered non-
responders
ORR as assessed by 
investigator based on IWG 
Revised Response Criteria 
for Malignant Lymphoma
Exact method based on 
binomial distribution
APaT
Participants with missing data 
are considered non-
responders
DCR as assessed by 
investigator based on IWG 
Revised Response Criteria 
for Malignant Lymphoma
Exact method based on 
binomial distribution
APaT
Participants with missing data 
are considered non-
responders
9.6.2
Statistical Methods for Safety Analysis
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, SAEs, laboratory tests, vital signs, and physical examinations. Adverse events will be 
listed and summarized by counts and frequencies. Laboratory tests, vital signs, and other 
safety endpoints will be summarized as appropriate.
9.6.3
Summaries of Baseline Characteristics, Demographics, and Other Analyses
9.6.3.1
Demographic and Baseline Characteristics
Demographic variables, baseline characteristics, primary and secondary diagnoses, and prior 
and concomitant therapies will be summarized.
9.6.3.2
Pharmacokinetic and Pharmacodynamic Modeling Analysis
No pharmacokinetic analysis is planned in this study.
9.7
Interim Analyses
No interim analysis will be performed.
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9.8
Multiplicity
There will be no multiplicity control in this study since no formal hypothesis testing is 
planned.
9.9
Sample Size and Power Calculations
The sample size for this study is expected to be 5 for feasibility. Table 7 shows the ORR 
estimate and the 95% confidence interval (Clopper-Pearson interval) for N=5.
Table 7
Estimated ORR and 95% confidence interval (Clopper-Pearson interval).
Number of objective responses (CR/PR)
ORR (95% CI) %
0
0.0 (0.0, 52.2)
1
20.0 (0.5, 71.6)
2
40.0 (5.3, 85.3)
3
60.0 (14.7, 94.7)
4
80.0 (28.4, 99.5)
5
100.0 (47.8, 100.0)
9.10
Subgroup Analyses
No subgroup analyses will be performed.
9.11
Compliance (Medication Adherence)
Drug accountability data for study intervention will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I. Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials 
in compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted 
in compliance with local and/or national regulations (including all applicable data protection laws and 
regulations), and International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in 
accordance with the ethical principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or 
which are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the 
full control of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD 
may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to 
determine patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities 
and staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, 
sites are evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to 
successfully conduct the trial.
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Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts 
to raise awareness of clinical trial opportunities in various communities. MSD will seek to engage 
underrepresented groups and those disproportionately impacted by the disease under study. MSD will support 
clinical trial investigators to enroll underrepresented groups and expand access to those who will ultimately 
use the products under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus 
source documentation according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related 
Significant Quality Issues are reported, such matters are investigated. When necessary, appropriate corrective 
and/or preventative actions are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the 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.
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.
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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.
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
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect 
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.5
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trials Regulation 536/2014, 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, https://euclinicaltrials.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 
Regulation 536/2014 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 Regulation 536/2014, or other locally mandated registries 
are that of the Sponsor and agrees not to submit any information about this study or its results 
to those registries.
10.1.6
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
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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.
10.1.7
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
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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.
10.1.8
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.9
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 8 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 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.
•
Pregnancy testing:
-
Pregnancy testing requirements for study inclusion are described in Section 5.1.
-
Pregnancy testing (urine or serum as required by local regulations) should be 
conducted at the end of treatment and 30 days follow-up after the last dose of study 
intervention.
-
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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Table 8
Protocol-required Safety Laboratory Assessments
Hematology
Comprehensive 
Chemistry Panel
Urinalysis
Other
Hematocrit
Albumin
Blood
Pregnancy test (serum or 
urine)a
Hemoglobin
Alkaline phosphatase
Glucose
PT/INR
Platelet count
Alanine aminotransferase
Protein
aPTT or PTT
WBC (total and differential)
c
Aspartate aminotransferase
Specific gravity 
Total T3 (or Free T3 
[FT3])b, Free T4 [FT4]
and TSH
RBC
Calcium
Microscopic exam, if 
abnormal results are 
noted
Absolute lymphocyte count
Chloride
Absolute neutrophil count
Creatinine
Glucose
LDH
Magnesium
Phosphorus
Potassium
Sodium
Total bilirubin  
Direct bilirubin (if total 
bilirubin is > ULN)
Total protein
Blood urea nitrogen
Amylase
Lipase
CRP
a  Perform on women of childbearing potential only at 72 hours prior to Day 1 of Cycle 1, discontinue visit, and 30-day 
follow-up visit. 
b  T3 is preferred; if not available, Free T3 may be tested.
c  Report % or absolute results per standard of practice. Report the results in the same manner throughout the study.
Investigators must document their review of each laboratory safety report.
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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 a reportable event. Refer to Section 8.4.6 for additional details.
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:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
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c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
worsened is not an SAE.) A preexisting condition is a clinical condition that is 
diagnosed prior to the use of an MSD product and is documented in the participant’s 
medical history.
d. Results in persistent or significant disability/incapacity
-
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
-
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) that may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
-
In offspring of participant taking the product regardless of time to diagnosis.
f.
Other important medical events
-
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 1 
of the other outcomes listed in the above definition. These events should usually be 
considered serious.
-
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency 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.
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Assessment of causality
•
Did the study intervention cause the AE?
•
The determination of the likelihood that the study intervention 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 
study intervention and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely the study 
intervention caused the AE:
-
Exposure: Is there evidence that the participant was actually exposed to the study 
intervention 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 study intervention? Is the time of onset of the AE compatible 
with a drug-induced effect (applies to studies with investigational medicinal 
product)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the study intervention 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 study 
intervention; (3) the study is a single-dose drug study; or (4) study intervention(s) 
is/are only used 1 time.)
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-
Rechallenge: Was the participant re-exposed to the study intervention 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) study 
intervention(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 STUDY INTERVENTION, OR IF RE-
EXPOSURE TO THE STUDY INTERVENTION POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE PARTICIPANT THEN THE RECHALLENGE MUST BE 
APPROVED IN ADVANCE BY THE SPONSOR CLINICAL DIRECTOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL, AND IF REQUIRED, THE 
INIRB/IEC.
•
Consistency with study intervention profile: Is the clinical/pathological presentation of 
the AE consistent with previous knowledge regarding the study intervention or drug class 
pharmacology or toxicology?
•
The assessment of relationship will be reported on the case report forms/worksheets by 
an investigator who is a qualified physician according to their best clinical judgment, 
including consideration of the above elements.
•
Use the following scale of criteria as guidance (not all criteria must be present to be 
indicative of a study intervention relationship).
-
Yes, there is a reasonable possibility of study intervention relationship:
◦
There is evidence of exposure to the study intervention. The temporal sequence 
of the AE onset relative to the administration of the study intervention is 
reasonable. The AE is more likely explained by the study intervention than by 
another cause.
-
No, there is not a reasonable possibility of study intervention relationship:
◦
Participant did not receive the study intervention OR temporal sequence of the 
AE onset relative to administration of the study intervention is not reasonable 
OR the AE is more likely explained by another cause than the study 
intervention. (Also entered for a participant with overdose without an associated 
AE.)
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•
The investigator must review and provide an assessment of causality for each AE/SAE 
and document this in the medical notes.
•
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the Sponsor.
•
The investigator may change their opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment.
•
The causality assessment is 1 of the criteria used when determining regulatory reporting 
requirements.
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.
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•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
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 nonhormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to 
allow confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
Male Participants
Male participants with female partners of childbearing potential are eligible to participate if
they agree to 1 of the following during the protocol defined time frame in Section 5.1:
•
Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent.
•
Use a male condom plus partner use of an additional contraceptive method when having 
penile-vaginal intercourse with a WOCBP who is not currently pregnant.
-
The following are not acceptable methods of contraception:
•
Periodic abstinence (calendar, symptothermal, postovulation methods), 
withdrawal (coitus interruptus), spermicides only, and LAM.
•
Male condom with cap, diaphragm, or sponge with spermicide.
•
Male and female condom cannot be used together.
-
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration.
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Female Participants
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
• 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 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
Appendix 6: Collection and Management of Specimens for Future Biomedical 
Research
Not Applicable.
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10.7
Appendix 7: Country-specific Requirements
Not Applicable.
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10.8
Appendix 8: Abbreviations
Abbreviation
Expanded Term
AE
adverse event 
ALT
alanine aminotransferase
APaT
All-Participants-as-Treated
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
BCG
Bacillus Calmette–Guérin
β-hCG
β-human chorionic gonadotropin
CD28
cluster of differentiation 28
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
CrCl
creatinine clearance
CR
complete response/remission
CRF
Case Report Form 
CRP
C-reactive protein
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
DCR
disease control rate
DILI
drug-induced liver injury
DLBCL
Diffuse Large B-Cell lymphoma
DOR
duration of response
ECG
electrocardiogram 
ECI
event of clinical interest
eCRF
electronic Case Report Form
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data collection 
EMA
European Medicines Agency
FDG
fluorodeoxyglucose
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Abbreviation
Expanded Term
FDAAA
Food and Drug Administration Amendments Act
FSH
follicle stimulating hormone 
GCP
Good Clinical Practice 
GFR
glomerular filtration rate
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
human immunodeficiency virus
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council on Harmonization
IEC
Independent Ethics Committee
IFRT
involved-field radiotherapy
Ig
immunoglobulin
IgG4
immunoglobulin G4
IHC
immunohistochemistry
INR
international normalized ratio
irAEs
immune-related AEs
IRB
Institutional Review Board
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
JSH
the Japanese Society of Hematology
LAM
lactational amenorrhoea method
LDH
lactate dehydrogenase
LDi
longest transverse diameter of a lesion
mAb
monoclonal antibody
MRI
magnetic resonance imaging
NCI
National Cancer Institute
NHL
Non-Hodgkin’s lymphomas
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Abbreviation
Expanded Term
ORR
objective response rate
OS
overall survival
OTC
over-the-counter
PD
disease progression
PD-1
programmed cell-death 1
PD-L1/ PD-L2
programmed cell death ligand 1/ programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression free survival
PK
pharmacokinetic
PPD
cross product of the LDi and perpendicular diameter
PR
partial response/remission
PT
prothrombin time
PTT
partial thromboplastin time
Q2W/ Q3W
every 2 weeks/ every 3 weeks
RBC
red blood cell
RNA
ribonucleic acid
rrPMBCL
relapsed or refractory primary mediastinal large B-cell lymphoma
SAE
serious adverse event 
SAP
Statistical Analysis Plan
SCT
stem cell transplantation
SD
stable disease
SDi
shortest axis perpendicular to the LDi
SoA
schedule of activities
SPD
sum of the product of the perpendicular diameters for multiple lesions
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
TMDD
target-mediated drug disposition
T3
total triiodothyronine
T4
total thyroxine
TSH
thyroid stimulating hormone
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Abbreviation
Expanded Term
ULN
upper limit of normal
VS
vital sign
WBC
white blood cell
WHO
World Health Organization
WOCBP
woman/women of childbearing potential 
5PS
5-point scale
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10.9
Appendix 9: IWG Revised Response Criteria for Malignant Lymphoma
Cheson et al.  Revised Response Criteria for Malignant Lymphoma.  J Clin Oncol.  2007;
25:579-586.
Refer to central review charter for independent central imaging review.
Criteria for lymphoma disease assessment:
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10.10 Appendix 10: Lugano Classification
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, 
and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification, 
J Clin Oncol. 2014; Sep 20;32(27):3059-68.
Refer to central review charter for independent central imaging review.
Revised Criteria for Response Assessment
Response and Site
PET-CT Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all 
of the following)
     Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3* with or without a 
residual mass on 5PS†
It is recognized that 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, 
complete metabolic response 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.
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi
No extralymphatic sites of disease
     Nonmeasured lesion
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, IHC negative
Partial
Partial metabolic response
Partial remission (all of the 
following)
     Lymph nodes and 
extralymphatic sites
Score 4 or 5† with reduced uptake 
compared with baseline and 
residual mass(es) of any size
At interim, these findings suggest 
responding disease
At end of treatment, these 
findings indicate residual disease
≥ 50% decrease in SPD of up to 6 
target measurable nodes and 
extranodal sites
When a lesion is too small to 
measure on CT, assign 5 mm × 5 
mm as the default value
When no longer visible, 0 × 0 mm
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation
     Nonmeasured lesions
Not applicable
Absent/normal, regressed, but no 
increase
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Response and Site
PET-CT Based Response
CT-Based Response
     Organ enlargement
Not applicable
Spleen must have regressed by 
> 50% in length beyond normal
     New lesions
None
None
     Bone marrow
Residual uptake higher than 
uptake in normal marrow but 
reduced compared with baseline 
(diffuse uptake compatible with 
reactive changes from 
chemotherapy allowed). 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
Not applicable
No response or stable disease
No metabolic response
Stable disease
     Target nodes/nodal masses, 
extranodal lesions
Score 4 or 5 with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment
< 50% decrease from baseline in 
SPD of up to 6 dominant, 
measurable nodes and extranodal 
sites; no criteria for progressive 
disease are met
     Nonmeasured 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
Progressive disease
Progressive metabolic disease
Progressive disease requires at 
least 1 of the following
     Individual target nodes/nodal 
masses
     Extranodal lesions
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or
New FDG-avid foci consistent 
with lymphoma at interim or end-
of-treatment assessment
PPD progression
An individual node/lesion must be 
abnormal with:
LDi > 1.5 cm and
Increase by ≥ 50% from PPD 
nadir and
An increase in LDi or SDi from 
nadir
0.5 cm for lesions ≤ 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the 
splenic length must increase by 
> 50% of the extent of its prior 
increase beyond baseline (eg, a 
15-cm spleen must increase to 
> 16 cm). If no prior 
splenomegaly, must increase by at 
least 2 cm from baseline.
New or recurrent splenomegaly.
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Response and Site
PET-CT Based Response
CT-Based Response
     Nonmeasured lesions
None
New or clear progression of 
preexisting nonmeasured lesions
     New lesions
New FDG-avid foci consistent 
with lymphoma rather than 
another etiology (eg, infection, 
inflammation). If uncertain 
regarding etiology of new lesions, 
biopsy or interval scan may be 
considered.
Regrowth of previously resolved 
lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, 
its presence must be unequivocal 
and must be attributable to 
lymphoma
Assessable disease of any size 
unequivocally attributable to 
lymphoma
     Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
•Abbreviations: 5PS - 5-point scale; CT - computed tomography; FDG - fluorodeoxyglucose; IHC -
immunohistochemistry; LDi - longest transverse diameter of a lesion; MRI - magnetic resonance imaging; PET - positron 
emission tomography; PPD - cross product of the LDi and perpendicular diameter; SDi - shortest axis perpendicular to 
the LDi; SPD - sum of the product of the perpendicular diameters for multiple lesions.
•* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim 
scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 
as inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of the largest dominant nodes, 
nodal masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be 
from disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-
nodal lesions include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those 
noted on palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable 
disease should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not 
selected as dominant or measurable or that do not meet the requirements for measurability but are still considered 
abnormal, as well as truly assessable disease, which is any site of suspected disease that would be difficult to follow 
quantitatively with measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal 
masses, and other lesions that cannot be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites 
(eg, GI tract, liver, bone marrow), FDG uptake may be greater than in the mediastinum with complete metabolic 
response, but should be no higher than surrounding normal physiologic uptake (eg, with marrow activation as a result of 
chemotherapy or myeloid growth factors).
•† PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related
to lymphoma
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10.11 Appendix 11: Lymphoma B Symptoms and Constitutional Symptoms
Lymphoma B Symptoms:
Lymphoma B symptoms are a set of clinical criteria used in the initial diagnosis and 
treatment of Hodgkin Lymphoma. These criteria are used in this study as part of the initial 
assessment of Lymphoma disease staging and as a measure of the response to study
treatment.
The criteria are as follows: 

Unexplained weight loss of more than 10% of the body weight during the 6 months 
before initial staging investigation; 

Unexplained, persistent, or recurrent fever with temperatures above 38°C during the 
previous month; and 

Recurrent drenching night sweats during the previous month.
Source:  Lister TA, Crowther D, Sutcliffe, SB, et al. Report of a committee convened to discuss the evaluation and staging 
of participants with Hodgkin's disease: Cotswolds meeting. J Clin Oncol 1989;7:1630-1636.
Constitutional Symptoms:
Constitutional symptoms, defined as any one or more of the following disease-related 
symptoms or signs:

Unintentional weight loss of 10% or more within the previous 6 months;

Significant fatigue (ie, ECOG Performance Status 2 or worse; inability to work or 
perform usual activities);

Fevers higher than 100.5°F or 38.0°C for 2 or more weeks without other evidence of 
infection; or

Night sweats for more than 1 month without evidence of infection.
Source: Hallek M, Cheson BD, Catovsky D, et al.  Guidelines for the diagnosis and treatment of chronic lymphocytic 
leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer 
Institute–Working Group 1996 guidelines. Blood. 2008 Jun 15; 111(12): 5446–5456.
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10.12 Appendix 12: ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but ambulatory and able to carry out work of a light or sedentary nature 
(e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis M.D., 
Group Chair.
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11
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