Conditions: Classical Hodgkin Lymphoma
Keywords: Programmed Cell Death 1 (PD-1, PD1) Programmed Cell Death-Ligand 1 (PD-L1, PDL1) Programmed Cell Death-Ligand 2 (PD-L2, PDL2)
Allocation: NA | Intervention model: SEQUENTIAL
Enrollment: 146
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the safety and efficacy of pembrolizumab (MK-3475) monotherapy, followed by chemotherapy, followed by pembrolizumab consolidation. The primary hypothesis of the study is that the complete response (CR) rate at the end of study intervention according to Lugano 2014 response criteria is higher than conventional chemotherapy.

Detailed description:

Arms:
arm 1: After completing Positron Emission Tomography (PET) scan 1 during eligibility screening, participants received pembrolizumab monotherapy intravenous (IV) for three 3-week cycles followed by PET scan 2.

Participants next received 2 phases of chemotherapy. In chemotherapy phase 1, all participants received doxorubicin in combination with vinblastine \& dacarbazine (AVD) IV for two 4-week cycles followed by PET scan 3. In chemotherapy phase 2, participants who were PET scan 3 negative, or positive and age ≥60 years, received up to 4 additional cycles of AVD IV, while participants who were PET scan 3 positive and age \<60 years received up to four 3-week cycles of escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, \& prednisone (escBEACOPP) IV.

All participants then received pembrolizumab consolidation IV for four 6-week cycles followed by a final PET scan.

Interventions: intervention 1: Pembrolizumab intervention 2: Doxorubicin intervention 3: Vinblastine intervention 4: Dacarbazine intervention 5: Bleomycin intervention 6: Etoposide intervention 7: Cyclophosphamide intervention 8: Vincristine intervention 9: Procarbazine intervention 10: Prednisone
Intervention descriptions: intervention 1: 200 mg IV administered on Day 1 of each 3-week cycle for 3 cycles during pembrolizumab monotherapy.

400 mg IV administered on Day 1 of each 6-week cycle for 4 cycles as pembrolizumab consolidation. intervention 2: 25 mg/m\^2 IV administered as part of AVD chemotherapy on Days 1 and 15 of each 4-week cycle for 2 cycles in all participants after PET scan 2 and up to 4 additional cycles after PET scan 3 (participants who are PET scan 3 negative, or positive and ≥60 years of age).

35 mg/m\^2 IV administered as part of escBEACOPP chemotherapy on Day 1 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive, \<60 years of age). intervention 3: 6 mg/m\^2 IV administered as part of AVD chemotherapy on Days 1 and 15 of each 4-week cycle for 2 cycles after PET scan 2 (all participants) and up to 4 additional cycles after PET scan 3 (participants who are PET scan 3 negative, or positive and ≥60 years of age). intervention 4: 375 mg/m\^2 IV administered as part of AVD chemotherapy on Days 1 and 15 of each 4-week cycle for 2 cycles after PET scan 2 (all participants) and up to 4 additional cycles after PET scan 3 (participants who are PET scan 3 negative, or positive and ≥60 years of age). intervention 5: 10 units/m\^2 IV administered as part of escBEACOPP chemotherapy on Day 8 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive and \<60 years of age). intervention 6: 200 mg/m\^2 IV administered as part of escBEACOPP chemotherapy on Days 1-3 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive and \<60 years of age). intervention 7: 1250 mg/m\^2 IV administered as part of escBEACOPP chemotherapy on Day 1 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive and \<60 years of age). intervention 8: 1.4 mg/m\^2 IV administered as part of escBEACOPP chemotherapy on Day 8 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive and \<60 years of age). intervention 9: 100 mg/m\^2 orally (PO) administered as part of escBEACOPP chemotherapy on Days 1-7 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive and \<60 years of age). intervention 10: 40 mg/m\^2 PO administered as part of escBEACOPP chemotherapy on Days 1-14 of each 3-week cycle for up to 4 cycles after PET scan 3 (participants who are PET scan 3 positive and \<60 years of age).

Protocol document:
Prot_SAP_001.pdf: 
Official Protocol Title:
NCT number:
Document Date:
Phase 2 Study of Pembrolizumab and
Chemotherapy in Patients With Newly
Diagnosed Classical Hodgkin Lymphoma
(KEYNOTE-C11)
NCT05008224 
15-Dec-2023


PRODUCT: MK-3475
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PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: Phase 2 Study of Pembrolizumab and Chemotherapy in Patients With Newly 
Diagnosed Classical Hodgkin Lymphoma (KEYNOTE-C11)
Protocol Number: C11-06
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
NCT05008224
EU CT
2022-501615-14
EudraCT
2021-001244-95
JRCT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
118604
Approval Date: 15 December 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 6
15-DEC-2023
To add language allowing eligible participants to 
enroll in an extension study, if available, 
following the end of MK-3475-C11.
Amendment 5
06-JUN-2023
To clarify participants’ continuation through the 
study and into pembrolizumab consolidation
regardless of positron emission tomography 2 and 
3 response.
Amendment 4
20-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.
Amendment 3
France-specific
25-FEB-2022
Based on France HA feedback, the duration of 
contraception use in study participants in France 
was increased to 12 months for females who 
receive cyclophosphamide and 9 months for 
males who receive cyclophosphamide.
Amendment 2
UK-specific 
01-SEP-2021
Based on MHRA feedback, the duration of 
contraception use in UK study participants was 
increased to 12 months for females who receive 
cyclophosphamide and was increased to 6 months 
for males who receive bleomycin, 
cyclophosphamide, dacarbazine, doxorubicin, 
etoposide, vincristine, vinblastine, or 
procarbazine.
Amendment 1
14-MAY-2021
To incorporate revisions based on health 
authority feedback, including modification of 
sample size, additional safety data monitoring, 
interim efficacy analysis for futility, only 
allowing participants <60 years of age to receive 
escBEACOPP, adding DurCR as a secondary 
objective, and moving modified PFS and OS 
from secondary to exploratory objectives.
Original Protocol
11-MAR-2021
Not applicable
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PROTOCOL AMENDMENT SUMMARY OF CHANGES
Amendment: 06
Overall Rationale for the Amendment: To add language allowing eligible participants to 
enroll in an extension study, if available, following the end of MK-3475-C11.
Summary of Changes Table:
Section Number 
and Name
Description of Change
Brief Rationale
Primary Reason for Amendment
4.4 Beginning and 
End-of-Study 
Definition
Added language regarding 
extension study.
Revision to allow eligible 
participants to enroll in an 
extension study, if available, 
following the end of MK-3475-
C11.
Section Number 
and Name
Description of Change
Brief Rationale
Additional Changes
8.11.4.2 Efficacy 
Follow-up Visits
Added clarification that an 
exception to beginning Efficacy 
Follow-up for participants who 
discontinue study intervention for 
a reason other than disease 
progression is based on 
investigator assessed disease 
progression.
To clarify that discontinuation 
of study intervention for a 
reason other than disease 
progression is based on 
investigator assessed disease 
progression.
10.1.7 Compliance 
with Law, Audit, 
and Debarment
Removed statement on country-
specific serious breach reporting.
Text was added in error in 
previous amendment.
Throughout 
document
Minor administrative, formatting, 
grammatical, and typographical 
changes were made throughout 
the document.
To ensure clarity and accurate 
interpretation of the intent of 
the protocol.
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................20
1.3
Schedule of Activities...........................................................................................21
1.3.1
All Participants – Screening, Pembrolizumab Monotherapy (3 Cycles), 
and AVD (Chemotherapy Phase 1) (2 Cycles)............................................21
1.3.2
Participants Who are PET-negative at PET3 Scan or PET-positive at 
PET3 Scan and ≥60 Years of Age – 4 Cycles of AVD (Chemotherapy 
Phase 2)........................................................................................................28
1.3.3
Participants Who are PET-positive at PET3 Scan and <60 Years of Age 
– 4 Cycles of escBEACOPP (Chemotherapy Phase 2)................................31
1.3.4
All Participants – Pembrolizumab Consolidation and Posttreatment..........34
2
INTRODUCTION..........................................................................................................41
2.1
Study Rationale....................................................................................................41
2.2
Background ..........................................................................................................42
2.2.1
Pembrolizumab ............................................................................................42
2.2.1.1
Pharmaceutical and Therapeutic Background ...................................42
2.2.1.2
Preclinical and Clinical Studies .........................................................43
2.2.1.3
Ongoing Clinical Studies...................................................................43
2.2.2
Treatment of Early Unfavorable and Advanced-stage Hodgkin 
Lymphoma...................................................................................................43
2.2.3
Role of 2-Fluorodeoxyglucose-positron Emission Tomography.................44
2.2.4
Incorporating Anti-PD-1 in Frontline Hodgkin Lymphoma........................45
2.2.5
Information on Other Study-related Therapy ..............................................46
2.3
Benefit/Risk Assessment......................................................................................46
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................48
4
STUDY DESIGN............................................................................................................51
4.1
Overall Design......................................................................................................51
4.2
Scientific Rationale for Study Design.................................................................53
4.2.1
Rationale for Endpoints ...............................................................................53
4.2.1.1
Efficacy Endpoints.............................................................................53
4.2.1.2
Safety Endpoints................................................................................54
4.2.1.3
Patient-reported Outcomes.................................................................54
4.2.1.3.1
EORTC QLQ-C30 ...................................................................54
4.2.1.3.2
EuroQoL EQ-5D-5L ................................................................55
4.2.1.4
Planned Exploratory Biomarker Research.........................................55
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4.2.1.5
Future Biomedical Research..............................................................57
4.3
Justification for Dose...........................................................................................57
4.3.1
Pembrolizumab ............................................................................................57
4.3.2
AVD and escBEACOPP..............................................................................58
4.4
Beginning and End-of-Study Definition ............................................................58
4.4.1
Clinical Criteria for Early Study Termination .............................................59
5
STUDY POPULATION ................................................................................................60
5.1
Inclusion Criteria.................................................................................................60
5.2
Exclusion Criteria................................................................................................63
5.3
Lifestyle Considerations......................................................................................65
5.3.1
Meals and Dietary Restrictions....................................................................65
5.4
Screen Failures.....................................................................................................65
5.5
Participant Replacement Strategy......................................................................65
6
STUDY INTERVENTION............................................................................................66
6.1
Study Intervention(s) Administered...................................................................66
6.1.1
Treatment .....................................................................................................70
6.2
Preparation/Handling/Storage/Accountability .................................................70
6.2.1
Dose Preparation..........................................................................................70
6.2.2
Handling, Storage, and Accountability........................................................70
6.3
Measures to Minimize Bias: Randomization and Blinding..............................71
6.3.1
Intervention Assignment..............................................................................71
6.3.2
Stratification.................................................................................................71
6.3.3
Blinding........................................................................................................71
6.4
Study Intervention Compliance..........................................................................71
6.4.1
Procarbazine and Prednisone Compliance...................................................72
6.5
Concomitant Therapy..........................................................................................72
6.5.1
Prohibited Concomitant Medications ..........................................................72
6.5.1.1
Systemic Corticosteroid Use..............................................................73
6.5.1.2
Cautions for Use of Chemotherapy....................................................73
6.5.2
Rescue Medications and Supportive Care ...................................................74
6.6
Dose Modification (Escalation/Titration/Other)...............................................74
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................74
6.6.2
AVD and escBEACOPP Dose Modification...............................................80
6.6.3
Additional Safety Data Monitoring .............................................................80
6.7
Intervention After the End of the Study............................................................81
6.8
Clinical Supplies Disclosure................................................................................81
6.9
Standard Policies..................................................................................................81
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DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................82
7.1
Discontinuation of Study Intervention...............................................................82
7.2
Participant Withdrawal From the Study...........................................................83
7.3
Lost to Follow-up .................................................................................................83
8
STUDY ASSESSMENTS AND PROCEDURES........................................................84
8.1
Administrative and General Procedures ...........................................................84
8.1.1
Informed Consent.........................................................................................84
8.1.1.1
General Informed Consent.................................................................85
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................85
8.1.2
Inclusion/Exclusion Criteria ........................................................................85
8.1.3
Participant Identification Card.....................................................................85
8.1.4
Medical History ...........................................................................................86
8.1.4.1
Classical Hodgkin Lymphoma Disease History ................................86
8.1.5
Prior and Concomitant Medications Review...............................................86
8.1.5.1
Prior Medications...............................................................................86
8.1.5.2
Concomitant Medications..................................................................86
8.1.5.3
Subsequent Antineoplastic Therapy Status........................................86
8.1.6
Assignment of Screening Number...............................................................87
8.1.7
Assignment of Treatment/Randomization Number.....................................87
8.1.8
Study Intervention Administration ..............................................................87
8.1.8.1
Timing of Dose Administration.........................................................88
8.1.9
Discontinuation and Withdrawal .................................................................89
8.1.9.1
Withdrawal From Future Biomedical Research ................................89
8.1.10
Participant Blinding/Unblinding..................................................................89
8.1.11
Calibration of Equipment.............................................................................89
8.1.12
Tumor Tissue for Biomarker Status.............................................................90
8.2
Efficacy Assessments ...........................................................................................90
8.2.1
Tumor Imaging and Assessment of Disease................................................90
8.2.1.1
Initial Tumor Scans............................................................................91
8.2.1.2
Tumor Scans During the Study..........................................................92
8.2.1.3
End-of-treatment and Follow-up Tumor Scans .................................92
8.2.1.4
Scan Evaluation .................................................................................93
8.2.1.5
Bone Marrow Biopsy/Aspirate ..........................................................93
8.2.2
Patient-reported Outcomes...........................................................................93
8.3
Safety Assessments...............................................................................................93
8.3.1
Physical Examinations.................................................................................94
8.3.1.1
Full Physical Examination.................................................................94
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8.3.1.2
Directed Physical Examination..........................................................94
8.3.1.3
Assessment of Lymphoma B Symptoms...........................................94
8.3.2
Vital Signs....................................................................................................94
8.3.3
Electrocardiograms ......................................................................................95
8.3.4
Echocardiography or Multigated Acquisition Scan.....................................95
8.3.5
Pulmonary Function Testing........................................................................95
8.3.6
Clinical Safety Laboratory Assessments .....................................................95
8.3.6.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................96
8.3.7
Pregnancy Testing........................................................................................96
8.3.8
International Prognostic Score.....................................................................97
8.3.9
Unfavorable Risk Factors ............................................................................97
8.3.10
Performance Assessments: Eastern Cooperative Oncology Group 
Performance Status ......................................................................................97
8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................97
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................98
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events....100
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information.100
8.4.4
Regulatory Reporting Requirements for SAE ...........................................100
8.4.5
Pregnancy and Exposure During Breastfeeding ........................................100
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs..........................................................................................101
8.4.7
Events of Clinical Interest..........................................................................101
8.5
Treatment of Overdose......................................................................................102
8.5.1
Pembrolizumab ..........................................................................................102
8.5.2
AVD and escBEACOPP............................................................................102
8.6
Pharmacokinetics...............................................................................................102
8.7
Pharmacodynamics............................................................................................102
8.8
Biomarkers .........................................................................................................103
8.8.1
Planned Genetic Analysis Sample Collection............................................103
8.9
Future Biomedical Research Sample Collection.............................................103
8.10
Medical Resource Utilization and Health Economics.....................................103
8.11
Visit Requirements.............................................................................................104
8.11.1
Screening....................................................................................................104
8.11.2
Treatment Period........................................................................................104
8.11.3
Discontinued Participants Continuing to be Monitored in the Study ........104
8.11.4
Posttreatment Visit.....................................................................................105
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8.11.4.1
Safety Follow-up Visit.....................................................................105
8.11.4.2
Efficacy Follow-up Visits................................................................105
8.11.4.3
Survival Follow-up Contacts ...........................................................105
8.11.5
Vital Status.................................................................................................105
9
STATISTICAL ANALYSIS PLAN ...........................................................................106
9.1
Statistical Analysis Plan Summary...................................................................106
9.2
Responsibility for Analyses/In-house Blinding ...............................................107
9.3
Hypotheses/Estimation ......................................................................................107
9.4
Analysis Endpoints.............................................................................................107
9.4.1
Efficacy Endpoints.....................................................................................107
9.4.2
Safety Endpoints........................................................................................108
9.5
Analysis Populations..........................................................................................108
9.5.1
Efficacy Analysis Populations...................................................................108
9.5.2
Safety Analysis Populations ......................................................................108
9.6
Statistical Methods.............................................................................................108
9.6.1
Statistical Methods for Efficacy Analyses.................................................108
9.6.1.1
Complete Response..........................................................................109
9.6.1.2
PET Negativity.................................................................................109
9.6.1.3
Duration of Complete Response......................................................109
9.6.1.4
Analysis Strategy for Key Efficacy Variables.................................110
9.6.2
Statistical Methods for Safety Analyses ....................................................111
9.6.3
Demographic and Baseline Characteristics ...............................................111
9.7
Interim Analyses ................................................................................................111
9.7.1
Interim Efficacy Analysis ..........................................................................111
9.7.2
Ongoing Safety Data Monitoring...............................................................112
9.8
Multiplicity .........................................................................................................112
9.9
Sample Size and Power Calculations ...............................................................113
9.10
Subgroup Analyses.............................................................................................113
9.11
Compliance (Medication Adherence)...............................................................113
9.12
Extent of Exposure.............................................................................................114
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS...................................................................................................115
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations......115
10.1.1
Code of Conduct for Clinical Trials...........................................................115
10.1.2
Financial Disclosure...................................................................................118
10.1.3
Data Protection...........................................................................................118
10.1.3.1
Confidentiality of Data ....................................................................119
10.1.3.2
Confidentiality of Participant Records.............................................119
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10.1.3.3
Confidentiality of IRB/IEC Information..........................................119
10.1.4
Committees Structure.................................................................................119
10.1.4.1
Internal Data Monitoring Committee...............................................119
10.1.5
Publication Policy......................................................................................119
10.1.6
Compliance with Study Registration and Results Posting Requirements .120
10.1.7
Compliance with Law, Audit, and Debarment ..........................................120
10.1.8
Data Quality Assurance .............................................................................121
10.1.9
Source Documents .....................................................................................122
10.1.10
Study and Site Closure...............................................................................122
10.2
Appendix 2: Clinical Laboratory Tests............................................................123
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................125
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................125
10.3.2
Definition of AE ........................................................................................125
10.3.3
Definition of SAE ......................................................................................126
10.3.4
Additional Events Reported.......................................................................127
10.3.5
Recording AE and SAE .............................................................................127
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................131
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................132
10.5
Appendix 5: Contraceptive Guidance..............................................................133
10.5.1
Definitions..................................................................................................133
10.5.2
Contraceptive Requirements......................................................................134
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................135
10.7
Appendix 7: Country-specific Requirements..................................................139
10.7.1
France-specific Requirements....................................................................139
10.8
Appendix 8: Description of the iRECIST Process for Assessment of 
Disease Progression............................................................................................141
10.9
Appendix 9: Application of the Lugano Classification for Treatment 
Response Assessment.........................................................................................142
10.9.1
Overview....................................................................................................142
10.9.2
Lugano Summary Table.............................................................................142
10.9.3
Anatomic Disease Assessment ..................................................................145
10.9.3.1
Screening (Baseline) Assessment ....................................................145
10.9.3.2
Post-baseline Assessment ................................................................147
10.9.4
Metabolic Response...................................................................................152
10.9.5
Clinical Data ..............................................................................................153
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10.9.6
Overall Response .......................................................................................154
10.10 Appendix 10: International Prognostic Score.................................................156
10.11 Appendix 11: Unfavorable Risk Factors – NCCN Guidelines.......................157
10.12 Appendix 12: Eastern Cooperative Performance Status ...............................158
10.13 Appendix 13: Abbreviations .............................................................................159
11
REFERENCES.............................................................................................................165
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values .............................................62
Table 2
Study Interventions......................................................................................67
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated With Pembrolizumab Monotherapy, 
Coformulations, or IO Combinations ..........................................................................75
Table 4
Pembrolizumab Infusion Reaction Dose Modification and Treatment 
Guidelines ....................................................................................................................79
Table 5
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.............................................................................................99
Table 6
.......................................................................110
Table 7
Analysis Strategy for Key Efficacy Variables...........................................110
Table 8
............................112
Table 9
Protocol-required Safety Laboratory Assessments....................................123
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LIST OF FIGURES
Figure 1
Study Diagram .............................................................................................20
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: Phase 2 Study of Pembrolizumab and Chemotherapy in Patients With Newly 
Diagnosed Classical Hodgkin Lymphoma (KEYNOTE-C11)
Short Title: Pembrolizumab and chemotherapy for newly diagnosed classical Hodgkin 
Lymphoma
Acronym: KEYNOTE-C11
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In males and females with newly diagnosed early unfavorable or advanced-stage classical 
Hodgkin Lymphoma:
Primary Objective
Primary Endpoint
To evaluate complete response (CR) rate at 
the end of study intervention in participants 
with newly diagnosed classical Hodgkin 
Lymphoma (cHL) assessed by independent 
central review according to Lugano 2014 
response criteria
CR
Secondary Objectives
Secondary Endpoints
To evaluate the CR rate at the end of study 
intervention in participants with newly 
diagnosed cHL by investigator assessment 
according to Lugano 2014 response criteria
CR
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PRODUCT: MK-3475
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PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
To evaluate the rate of Positron Emission 
Tomography (PET) negativity at PET2 
following 3 cycles of pembrolizumab 
monotherapy by independent central review 
according to the 2-fluorodeoxyglucose 
(FDG)-PET 5-point scale
PET negativity: a score of 1, 2, or 3 on the 
FDG-PET 5-point scale after 3 cycles of 
pembrolizumab monotherapy
To evaluate the rate of PET negativity at 
PET3 after completion of 3 cycles of 
pembrolizumab monotherapy followed by 
2 cycles of doxorubicin in combination with 
vinblastine and dacarbazine (AVD) by 
independent central review according to the
FDG-PET 5-point scale
PET negativity: a score of 1, 2, or 3 on the 
FDG-PET 5-point scale after 3 cycles of 
pembrolizumab monotherapy followed by 2 
cycles of AVD
To evaluate the safety and tolerability of 
initial pembrolizumab monotherapy 
followed by chemotherapy and 
pembrolizumab consolidation in 
participants with newly diagnosed cHL
-Adverse Events (AEs)
-Discontinuation of study intervention due 
to an AE
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PRODUCT: MK-3475
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Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
The treatment of participants with classical 
Hodgkin's lymphoma
Population
Participants with newly diagnosed early 
unfavorable or advanced-stage cHL
Study Type
Interventional
Intervention Model
Sequential
This is a multi site study.
Type of Control
No Treatment Control
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Number of Participants:
Approximately 140 participants will be enrolled in the study.
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Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
All 
participants
Pembrolizumab
25 mg/mL
200 mg
IV Infusion
Day 1 of each 
cycle, Q3W, 
3 cycles
Test 
Product
All 
participants
Doxorubicin
Variable
25 mg/m2
Per Local 
Guidelines
Days 1 and 
15 of each 
cycle, Q4W, 
2 cycles
Test 
Product
All 
participants
Vinblastine
Variable
6 mg/m2
Per Local 
Guidelines
Days 1 and 
15 of each 
cycle, Q4W, 
2 cycles
Test 
Product
All 
participants
Dacarbazine
Variable
375 mg/m2
Per Local 
Guidelines
Days 1 and 
15 of each 
cycle, 
Q4W, 2 
cycles
Test 
Product
PET3 
negative, or 
PET3 
positive and 
≥60 years of 
age
Doxorubicin
Variable
25 mg/m2
Per Local 
Guidelines
Days 1 and 
15 of each 
cycle, Q4W, 
4 cycles
Test 
Product
PET3 
negative, or 
PET3 
positive and 
≥60 years of 
age
Vinblastine
Variable
6 mg/m2
Per Local 
Guidelines
Days 1 and 
15 of each 
cycle, Q4W, 
4 cycles
Test 
Product
PET3 
negative, or 
PET3 
positive and 
≥60 years of 
age
Dacarbazine
Variable
375 mg/m2
Per Local 
Guidelines
Days 1 and 
15 of each 
cycle, Q4W, 
4 cycles
Test 
Product
PET3 
positive and 
<60 years of 
age
Bleomycin
Variable
10 units/m2
Per Local 
Guidelines
Day 8 of each 
cycle, Q3W, 
4 cycles
Test 
Product
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Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
PET3 
positive and 
<60 years of 
age
Etoposide
Variable
200 mg/m2
Per Local 
Guidelines
Days 1 to 3 
of each cycle, 
Q3W, 
4 cycles
Test 
Product
PET3 
positive and 
<60 years of 
age
Doxorubicin
Variable
35 mg/m2
Per Local 
Guidelines
Day 1 of each 
cycle, Q3W, 
4 cycles
Test 
Product
PET3 
positive and 
<60 years of 
age
Cyclophosphamide Variable
1250 mg/m2 Per Local 
Guidelines
Day 1 of each 
cycle, Q3W, 
4 cycles
Test 
Product
PET3 
positive and 
<60 years of 
age
Vincristine
Variable
1.4 mg/m2
Per Local 
Guidelines
Day 8 of each 
cycle, Q3W, 
4 cycles
Test 
Product
PET3 
positive and 
<60 years of 
age
Procarbazine
Variable
100 mg/m2
Oral
Days 1 to 7 
of each cycle, 
Q3W, 
4 cycles
Test 
Product
PET3 
positive and 
<60 years of 
age
Prednisone
Variable
40 mg/m2
Oral
Days 1 to 14 
of each cycle, 
Q3W, 
4 cycles
Test 
Product
All 
participants
Pembrolizumab
25 mg/mL
400 mg
IV Infusion
Day 1 of each 
cycle, Q6W, 
4 cycles
Test 
Product
AVD=doxorubicin in combination with vinblastine and dacarbazine; escBEACOPP=escalated bleomycin in combination 
with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; IV=intravenous; PET=positron 
emission tomography; Q3W=every 3 weeks; Q4W=every 4 weeks; Q6W=every 6 weeks.
Note: Age is based on age at screening.
For vincristine, maximum dose=2 mg.
For participants with early unfavorable, nonbulky disease will receive 2 cycles of AVD if PET3-negative, or if PET3-
positive and ≥60 years of age, or 2 cycles of escBEACOPP if PET3-positive and <60 years of age.
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MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
Other current or former name(s) or alias(es) for study intervention(s) are as follows: 
Pembrolizumab is also known as MK-3475. Doxorubicin is also known as adriamycin.
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 up to 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 any reason 
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.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
Yes
Clinical Adjudication Committee
No
Steering Committee
No
Study governance considerations are outlined in Appendix 1.
The DMC will be an internal DMC (see Sections 6.6.3 and 10.1.4.1).
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 13.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Diagram
-ve=negative; +ve=positive; AVD=doxorubicin in combination with vinblastine and dacarbazine; cHL=classical Hodgkin 
Lymphoma; CR=complete response; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EOT=end-of-
treatment; escBEACOPP=escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, 
procarbazine, and prednisone; FU=follow-up; N=number of participants; Pembro=pembrolizumab; PET=positron emission 
tomography; Q3W=every 3 weeks; Q4W=every 4 weeks; Q6W=every 6 weeks.
a
Each cycle of AVD consists of administration of study intervention on Days 1 and 15.
b
Participants with early unfavorable, nonbulky disease will receive 2 cycles of AVD (if PET3 -ve or if PET3 +ve and 
≥60 years of age) or 2 cycles of escBEACOPP (if PET3 +ve and <60 years of age).
c
Participants ≥60 years of age will continue to receive AVD in Chemotherapy Phase 2 regardless of their PET3 response, 
and will not receive escBEACOPP.
d
Each cycle of escBEACOPP consists of administration of study intervention according to the dosing schedule provided 
in Section 1.3.3.
Note: Age is based on age at screening. 
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15-DEC-2023
1.3
Schedule of Activities
1.3.1
All Participants – Screening, Pembrolizumab Monotherapy (3 Cycles), and AVD (Chemotherapy Phase 1) (2 Cycles)
Study Period
Screening
Intervention (Pembro) 
(Q3W Cycles)a
PET2
Intervention (AVD) 
(Q4W Cycles)a,b
PET3
Notes
Treatment Cycle
Screening
Pembro 
C1
Pembro 
C2
Pembro 
C3
AVD
C1
AVD
C2
AVD C1D1 should start 3 weeks 
(+3 days) after Pembrolizumab C3D1
Dosing Day
-28 to -1
D1
D1
D1
D1
D15
D1
D15
Administrative Procedures
Informed Consent
X
Informed Consent for 
Future Biomedical 
Research (optional)
X
Participant may participate in main 
study without signing Future Biomedical 
Research consent.
Consent for optional 
tissue collection
X
Optional Consent.
Inclusion/Exclusion 
Criteria
X
Participant 
Identification Card
X
X
Distribute at Screening and add the 
allocation number at the time of 
allocation.
Demographics and 
Medical History
X
cHL Disease History
X
Prior/Concomitant 
Medication Review
X
X
X
X
X
X
X
X
Record medications taken within 28 
days before the start of study 
intervention. Concomitant medications 
will be recorded during the study 
through the Safety Follow-up Visit 
(Section 1.3.4).
Survival Status
On Sponsor request, participants may be 
contacted for survival status at any time 
during the course of the study.
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Study Period
Screening
Intervention (Pembro) 
(Q3W Cycles)a
PET2
Intervention (AVD) 
(Q4W Cycles)a,b
PET3
Notes
Treatment Cycle
Screening
Pembro 
C1
Pembro 
C2
Pembro 
C3
AVD
C1
AVD
C2
AVD C1D1 should start 3 weeks 
(+3 days) after Pembrolizumab C3D1
Dosing Day
-28 to -1
D1
D1
D1
D1
D15
D1
D15
Intervention 
Allocation in IWRS
X
Treatment number: Obtain after all 
screening assessments are completed 
and ensuring participant meets all 
study-related eligibility criteria.
Pembrolizumab C1D1 dose should be 
administered within 3 days of allocation 
in IWRS.
Study Intervention Administration (Assessments/procedures to be performed before administration of study intervention at each visit unless 
otherwise specified)
Pembrolizumab 
X
X
X
200 mg by IV on Day 1 of each Q3W 
cycle for 3 cycles.
Doxorubicin 
X
X
X
X
25 mg/m2 by IV on Days 1 and 15 of 
each Q4W cycle for 2 cycles
Vinblastine 
X
X
X
X
6 mg/m2 by IV on Days 1 and 15 of each 
Q4W cycle for 2 cycles
Dacarbazine 
X
X
X
X
375 mg/m2 by IV on Days 1 and 15 of 
each Q4W cycle for 2 cycles
Efficacy Procedures
FDG-PET scan 
(Whole body)
X (PET1)
X
X
PET1 is required for eligibility and must 
be performed within 28 days before the 
first dose of study intervention.
PET2 must be performed 3 weeks (±3 
days) after pembrolizumab C3D1 and 
before AVD C1D1.
PET3 must be performed between AVD 
C2D26 and C2D29 and before starting 
additional chemotherapy (AVD or 
escBEACOPP) (Sections 1.3.2 and 
1.3.3).
Additional PET scans may be performed 
as clinically indicated.
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Study Period
Screening
Intervention (Pembro) 
(Q3W Cycles)a
PET2
Intervention (AVD) 
(Q4W Cycles)a,b
PET3
Notes
Treatment Cycle
Screening
Pembro 
C1
Pembro 
C2
Pembro 
C3
AVD
C1
AVD
C2
AVD C1D1 should start 3 weeks 
(+3 days) after Pembrolizumab C3D1
Dosing Day
-28 to -1
D1
D1
D1
D1
D15
D1
D15
Diagnostic Quality 
CT scan (Neck, 
Chest, Abdominal, 
Pelvic)
X
CT scan is required for eligibility and 
must be performed within 28 days 
before the first dose of study 
intervention.
If PET and CT scans at Screening are 
positive for disease of the neck, 
subsequent CT scans must include the 
neck. If PET and CT scans at Screening 
are negative for disease in the neck, 
subsequent CT scans may omit the neck.
Additional CT scans may be performed 
as clinically indicated.
If diagnostic quality CT scan cannot be 
performed due to medical 
contraindication or local practice, refer 
to Site Imaging Manual for alternative 
methods for anatomic imaging.
Lymphoma Disease 
Response 
Assessment by 
Lugano 
Classification 2014 
(see Appendix 9)
X
X
Symptom Assessment
Assessment of 
Lymphoma B 
Symptoms
X
X
Perform at screening and within 3 days 
before AVD C1D1 dosing.
Safety Procedures
Full Physical 
Examination 
X
Directed Physical 
Examination
X
X
X
X
X
Perform within 3 days before dosing on 
Day 1 of each cycle and as clinically 
indicated.
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Study Period
Screening
Intervention (Pembro) 
(Q3W Cycles)a
PET2
Intervention (AVD) 
(Q4W Cycles)a,b
PET3
Notes
Treatment Cycle
Screening
Pembro 
C1
Pembro 
C2
Pembro 
C3
AVD
C1
AVD
C2
AVD C1D1 should start 3 weeks 
(+3 days) after Pembrolizumab C3D1
Dosing Day
-28 to -1
D1
D1
D1
D1
D15
D1
D15
Vital Signs 
(temperature, blood 
pressure, respiratory 
rate, pulse rate, 
weight, height 
[height – Screening 
only])
X
X
X
X
X
X
X
X
Perform at Screening and within 3 days 
before dosing at each specified time 
point, and as clinically indicated.
12-lead ECG
X
Additional ECGs may be performed as 
clinically indicated.
ECHO or MUGA
X
X
Perform at Screening and at the end of 
AVD C2 (before starting additional 
chemotherapy [AVD or 
escBEACOPP]).
ECOG Performance 
Status
X
X
X
X
X
Perform screening assessment within 
7 days before C1D1 dose of 
pembrolizumab and all other 
assessments within 3 days before dosing 
on Day 1 of each subsequent cycle. 
IPS
X
Refer to Appendix 10 for prognostic 
factors used for scoring. 
Unfavorable Risk 
Factors
X
Refer to Appendix 11. Applicable only 
for participants with Stage I or II 
disease.
HIV / HBV / HCV 
Eligibility Testing
X
Required only when mandated by local 
health authority. 
Adverse Event 
Monitoring
X
X
X
X
X
X
X
X
Report all AEs through 30 days after the 
last dose. Report SAEs through 90 days 
after the last dose, or 30 days after the 
last dose if participant initiates a new 
anticancer treatment, whichever is 
earlier. Report SAEs outside the time 
specified above if considered related to 
study intervention.
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Study Period
Screening
Intervention (Pembro) 
(Q3W Cycles)a
PET2
Intervention (AVD) 
(Q4W Cycles)a,b
PET3
Notes
Treatment Cycle
Screening
Pembro 
C1
Pembro 
C2
Pembro 
C3
AVD
C1
AVD
C2
AVD C1D1 should start 3 weeks 
(+3 days) after Pembrolizumab C3D1
Dosing Day
-28 to -1
D1
D1
D1
D1
D15
D1
D15
Laboratory Procedures/Assessments (Performed by Local Laboratory)
Urine or Serum 
Pregnancy Test –
WOCBP Only
X
WOCBP require a negative pregnancy 
test within 24 hours for urine and 72 
hours for serum before C1D1 dose of 
pembrolizumab.
If a urine test cannot be confirmed as 
negative (eg, an ambiguous result), a 
serum pregnancy test is required.
In case of suspected false positive 
pregnancy test in participants with 
fertility preservation, consult Sponsor.
A pregnancy test must be performed 
every cycle (within 24 hours of study 
visit for urine and 72 hours for serum) 
during study intervention.
More frequent pregnancy testing may be 
performed if required by local 
regulations or if clinically indicated. 
Serum FSH – if 
needed to confirm 
postmenopausal state
X
May be used to confirm postmenopausal 
state in women not currently on HRT or 
hormonal contraception (see Appendix 
5). In absence of 12 months of 
amenorrhea, confirmation with 2 FSH 
measurements in the postmenopausal 
range is required.
PT/INR and 
aPTT/PTT
X
Screening: Perform within 7 days before 
C1D1 dose of pembrolizumab.
After Screening: Additional testing may 
be conducted as clinically indicated.
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Study Period
Screening
Intervention (Pembro) 
(Q3W Cycles)a
PET2
Intervention (AVD) 
(Q4W Cycles)a,b
PET3
Notes
Treatment Cycle
Screening
Pembro 
C1
Pembro 
C2
Pembro 
C3
AVD
C1
AVD
C2
AVD C1D1 should start 3 weeks 
(+3 days) after Pembrolizumab C3D1
Dosing Day
-28 to -1
D1
D1
D1
D1
D15
D1
D15
Hematology
X
X
X
X
X
X
Screening: perform within 7 days before 
C1D1 dose of pembrolizumab.
After Screening: perform within 3 days 
before dosing on Day 1 of every cycle.
There is no need to repeat assessments 
on pembrolizumab C1D1 if screening 
assessment is within 3 days before 
pembrolizumab C1D1 dose.
The laboratory criteria in Table 1 must 
be met before dosing on Day 1 of every 
cycle (the requirement for ANC is 
≥1000/µL from pembrolizumab C2 
onwards), with the exception of 
hematological parameters for AVD 
cycles.
Perform more frequently as clinically 
indicated.
Chemistry
X
X
X
X
X
X
Thyroid Function 
Tests (TSH, T3, T4)
X
X
X
X
X
X
Urinalysis
X
Perform within 7 days before C1D1 
dose of pembrolizumab.
ESR
X
LDH
X
Bone Marrow 
Biopsy/Aspirate
<Perform as clinically indicated >
Refer to Section 8.2.1.5 for details.
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood (Performed by Central Laboratory)
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Study Period
Screening
Intervention (Pembro) 
(Q3W Cycles)a
PET2
Intervention (AVD) 
(Q4W Cycles)a,b
PET3
Notes
Treatment Cycle
Screening
Pembro 
C1
Pembro 
C2
Pembro 
C3
AVD
C1
AVD
C2
AVD C1D1 should start 3 weeks 
(+3 days) after Pembrolizumab C3D1
Dosing Day
-28 to -1
D1
D1
D1
D1
D15
D1
D15
Biomarkers
Patient-reported Outcomes
AE=adverse event; ANC=absolute neutrophil count; aPTT=activated partial thromboplastin time; AVD=doxorubicin in combination with vinblastine and dacarbazine; C=cycle; cHL=classical 
Hodgkin Lymphoma; CT=computed tomography; 
; D=day; ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative 
Oncology Group; 
 
escBEACOPP=escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; ESR=erythrocyte sedimentation rate; FDG-PET=2-
fluorodeoxyglucose positron emission tomography; FSH=follicle-stimulating hormone; HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HRT=hormone 
replacement treatment; INR=international normalized ratio; IPS=international prognostic score; IV=intravenous; IWRS=interactive web response system; LDH=lactate dehydrogenase; 
MRI=magnetic resonance imaging; MUGA=multigated acquisition; PBMC=peripheral blood mononuclear cell; Pembro=pembrolizumab; PET=positron emission tomography; PRO=patient-reported 
outcome; PT=prothrombin time; PTT=partial thromboplastin time; Q3W=every 3 weeks; Q4W=every 4 weeks; SAE=serious adverse event; T3=triiodothyronine; T4=thyroxine; TCR=T-cell 
receptor; TSH=thyroid-stimulating hormone; WOCBP=woman of childbearing potential.
a.
A maximum of a 3-day delay is permitted from the scheduled start of each cycle.
b
For AVD, any delays of more than 3 days beyond the visit window not related to an adverse event should be discussed with Sponsor.
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1.3.2
Participants Who are PET-negative at PET3 Scan or PET-positive at PET3 Scan and ≥60 Years of Age – 4 Cycles of 
AVD (Chemotherapy Phase 2)
Note: 2 cycles of AVD in Chemotherapy Phase 2 in participants with early unfavorable, nonbulky disease.
Participants ≥60 years of age who are PET3 positive will continue to receive AVD in Chemotherapy Phase 2.
Age is based on age at screening.
Study Period
Intervention (AVD Chemotherapy) (Q4W 
Cycles)a,b
Notes
Treatment Cycle
AVD C3
AVD C4
AVD C5c
AVD C6c
PET-negative is defined as a score of 1, 2, or 3 on the FDG-PET 
5-point scale.
AVD C3D1 should start 4 weeks (+3 days) after AVD C2D1 (see 
Section 1.3.1)
Dosing Day
D1
D15
D1
D15
D1
D15
D1
D15
Administrative Procedures
Concomitant Medication 
Review
X
X
X
X
X
X
X
X
Concomitant medications will be recorded during the study through 
the Safety Follow-up Visit (Section 1.3.4).
Survival Status
On Sponsor request, participants may be contacted for survival 
status at any time during the course of the study.
Study Intervention Administration (Assessments/procedures to be performed before administration of study intervention at each visit unless 
otherwise specified)
Doxorubicin
X
X
X
X
X
X
X
X
25 mg/m2 by IV on Days 1 and 15 of each Q4W cycle for 4 cyclesc
Vinblastine 
X
X
X
X
X
X
X
X
6 mg/m2 by IV on Days 1 and 15 of each Q4W cycle for 4 cyclesc
Dacarbazine 
X
X
X
X
X
X
X
X
375 mg/m2 by IV on Days 1 and 15 of each Q4W cycle for 4 cyclesc
Symptom Assessment
Assessment of Lymphoma B 
Symptoms
X
Perform within 3 days before AVD C3D1 dosing.
Safety Procedures
Directed Physical 
Examination
X
X
X
X
Perform within 3 days before dosing on Day 1 of each cycle and as 
clinically indicated.
Vital Signs (temperature, 
blood pressure, respiratory 
rate, pulse rate, weight)
X
X
X
X
X
X
X
X
Perform within 3 days before dosing on Day 1 and Day 15 of each 
cycle and as clinically indicated.
12-lead ECG
<Perform as clinically indicated>
08GW9Y
08HFB4


PRODUCT: MK-3475
29
PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
Study Period
Intervention (AVD Chemotherapy) (Q4W 
Cycles)a,b
Notes
Treatment Cycle
AVD C3
AVD C4
AVD C5c
AVD C6c
PET-negative is defined as a score of 1, 2, or 3 on the FDG-PET 
5-point scale.
AVD C3D1 should start 4 weeks (+3 days) after AVD C2D1 (see 
Section 1.3.1)
Dosing Day
D1
D15
D1
D15
D1
D15
D1
D15
ECHO or MUGA
X*
X
Perform at the end of the last cycle of chemotherapy (before starting 
pembrolizumab consolidation). Additional testing may be performed 
as clinically indicated.
*Only for participants with early unfavorable nonbulky disease.
ECOG Performance Status
X
X
X
X
Perform within 3 days before dosing on Day 1 of each cycle.
Adverse Event Monitoring
X
X
X
X
X
X
X
X
Report all AEs through 30 days after the last dose. Report SAEs 
through 90 days after the last dose, or 30 days after the last dose if 
participant initiates a new anticancer treatment, whichever is earlier. 
Report SAEs outside the time specified above if considered related 
to study intervention.
Laboratory Procedures/Assessments (Performed by Local Laboratory)
Urine or Serum Pregnancy 
Test – WOCBP Only
A pregnancy test must be performed every cycle (within 24 hours of 
study visit for urine and 72 hours for serum) during study 
intervention. More frequent pregnancy testing may be performed if 
required by local regulations or if clinically indicated.
In case of suspected false positive pregnancy test in participants with 
fertility preservation, consult Sponsor.
Hematology
X
X
X
X
Perform within 3 days before dosing on Day 1 of every cycle.
The laboratory criteria in Table 1 must be met before dosing on Day 
1 of every cycle, with the exception of hematological parameters.
Perform more frequently as clinically indicated.
Chemistry
X
X
X
X
Thyroid Function Tests (TSH, 
T3, T4)
X
X
X
X
Bone Marrow 
Biopsy/Aspirate
ß Perform as clinically indicated à
Refer to Section 8.2.1.5 for details.
Patient-reported Outcomes
08GW9Y
CCI
CCI
CCI
08HFB4


PRODUCT: MK-3475
30
PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
Study Period
Intervention (AVD Chemotherapy) (Q4W 
Cycles)a,b
Notes
Treatment Cycle
AVD C3
AVD C4
AVD C5c
AVD C6c
PET-negative is defined as a score of 1, 2, or 3 on the FDG-PET 
5-point scale.
AVD C3D1 should start 4 weeks (+3 days) after AVD C2D1 (see 
Section 1.3.1)
Dosing Day
D1
D15
D1
D15
D1
D15
D1
D15
AE=adverse event; AVD=doxorubicin in combination with vinblastine and dacarbazine; C=cycle; D=day; ECG=electrocardiogram; ECHO=echocardiogram; 
ECOG=Eastern Cooperative Oncology Group; 
 
FDG-PET=2-fluorodeoxyglucose positron emission tomography; IV=intravenous; 
MUGA=multigated acquisition; PET=positron emission tomography; 
; Q4W=every 4 weeks; SAE=serious adverse event; 
T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WOCBP=woman of childbearing potential.
a
A maximum of a 3-day delay is permitted from the scheduled start of each cycle.
b
For AVD, any delays of more than 3 days beyond the visit window not related to an adverse event should be discussed with Sponsor.
c Participants with early unfavorable, nonbulky disease will not receive AVD Cycles 5 and 6; therefore, assessments and procedures scheduled during AVD 
Cycles 5 and 6 are not applicable to these participants.
08GW9Y
CCI
CCI
CCI
08HFB4


PRODUCT: MK-3475
31
PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
1.3.3
Participants Who are PET-positive at PET3 Scan and <60 Years of Age – 4 Cycles of escBEACOPP (Chemotherapy 
Phase 2)
Note: 2 cycles of escBEACOPP in Chemotherapy Phase 2 in participants with early unfavorable, nonbulky disease. 
Participants ≥60 years of age who are PET3 positive will not receive escBEACOPP in Chemotherapy Phase 2 and should continue to 
receive AVD according to Section 1.3.2. 
Age is based on age at screening.
Study Period:
Intervention (escBEACOPP Chemotherapy) 
(Q3W Cycles)a
Notes
Treatment Cycle
escB C1
escB C2
escB C3b
escB C4b
PET-positive is defined as a score of 4 or 5 on the FDG-PET 
5-point scale. escBEACOPP C1D1 should start 4 weeks 
(+7 days) after AVD C2D1 (see Section 1.3.1)
Dosing Day
D1
D8
D1
D8
D1
D8
D1
D8
Administrative Procedures
Concomitant Medication 
Review
X
X
X
X
X
X
X
X
Concomitant medications will be recorded during the study through 
the Safety Follow-up Visit (Section 1.3.4).
Survival Status
On Sponsor request, participants may be contacted for survival 
status at any time during the course of the study.
Study Intervention Administration (Assessments/procedures to be performed before administration of study intervention at each visit unless 
otherwise specified)
Bleomycin 
X
X
X
X
10 units/m2 by IV on Day 8 of each Q3W cycle for 4 cyclesb
Etoposide 
X
X
X
X
200 mg/m2 by IV on Days 1 to 3 of each Q3W cycle for 4 cyclesb
Doxorubicin 
X
X
X
X
35 mg/m2 by IV on Day 1 of each Q3W cycle for 4 cyclesb
Cyclophosphamide 
X
X
X
X
1250 mg/m2 by IV on Day 1 of each Q3W cycle for 4 cyclesb
Vincristine 
X
X
X
X
1.4 mg/m2 (maximum 2 mg) by IV on Day 8 of each Q3W cycle for 
4 cyclesb
Procarbazine
X
X
X
X
100 mg/m2 PO on Days 1 to 7 of each Q3W cycle for 4 cyclesb
Prednisone
X
X
X
X
X
X
X
X
40 mg/m2 PO on Days 1 to 14 of each Q3W cycle for 4 cyclesb
Symptom Assessment
Assessment of Lymphoma B 
Symptoms
X
Perform within 3 days before escBEACOPP C1D1 dosing.
Safety Procedures
Directed Physical 
Examination
X
X
X
X
Perform within 3 days before dosing on Day 1 of each cycle and as 
clinically indicated.
08GW9Y
08HFB4


PRODUCT: MK-3475
32
PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
Study Period:
Intervention (escBEACOPP Chemotherapy) 
(Q3W Cycles)a
Notes
Treatment Cycle
escB C1
escB C2
escB C3b
escB C4b
PET-positive is defined as a score of 4 or 5 on the FDG-PET 
5-point scale. escBEACOPP C1D1 should start 4 weeks 
(+7 days) after AVD C2D1 (see Section 1.3.1)
Dosing Day
D1
D8
D1
D8
D1
D8
D1
D8
Vital Signs (temperature, 
blood pressure, respiratory 
rate, pulse rate, weight)
X
X
X
X
X
X
X
X
Perform within 3 days before dosing on Day 1 and Day 8 of each 
cycle and as clinically indicated.
12-lead ECG
<Perform as clinically indicated >
ECHO or MUGA
X*
X
Perform at the end of the last cycle of chemotherapy (before starting 
pembrolizumab consolidation). Additional testing may be performed 
as clinically indicated.
*Only for participants with early unfavorable nonbulky disease.
ECOG Performance Status
X
X
X
X
Perform within 3 days before dosing on Day 1 of each cycle.
Pulmonary function testing
X
X*
X
Perform within 7 days before C1D1 dose and at the end of the last 
cycle of chemotherapy (before starting pembrolizumab 
consolidation). Additional testing may be performed as clinically 
indicated.
*Only for participants with early unfavorable nonbulky disease.
Adverse Event Monitoring
X
X
X
X
X
X
X
X
Report all AEs through 30 days after the last dose. Report SAEs 
through 90 days after the last dose, or 30 days after the last dose if 
participant initiates a new anticancer treatment, whichever is earlier. 
Report SAEs outside the time specified above if considered related 
to study intervention.
Laboratory Procedures/Assessments (Performed by Local Laboratory)
Urine or Serum Pregnancy 
Test – WOCBP Only
A pregnancy test must be performed every cycle (within 24 hours of 
study visit for urine and 72 hours for serum) during study 
intervention. More frequent pregnancy testing may be performed if 
required by local regulations or if clinically indicated.
In case of suspected false positive pregnancy test in participants with 
fertility preservation, consult Sponsor.
Hematology
X
X
X
X
Perform within 3 days before dosing on Day 1 of every cycle.
The laboratory criteria in Table 1 must be met before dosing on Day 
1 of every cycle (the requirement for ANC is ≥1000/µL).
Perform more frequently as clinically indicated.
Chemistry 
X
X
X
X
Thyroid function tests (TSH, 
T3, T4)
X
X
X
X
Bone Marrow 
Biopsy/Aspirate
ß Perform as clinically indicated à
Refer to Section 8.2.1.5 for details.
08GW9Y
08HFB4


PRODUCT: MK-3475
33
PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
Study Period:
Intervention (escBEACOPP Chemotherapy) 
(Q3W Cycles)a
Notes
Treatment Cycle
escB C1
escB C2
escB C3b
escB C4b
PET-positive is defined as a score of 4 or 5 on the FDG-PET 
5-point scale. escBEACOPP C1D1 should start 4 weeks 
(+7 days) after AVD C2D1 (see Section 1.3.1)
Dosing Day
D1
D8
D1
D8
D1
D8
D1
D8
Patient-reported Outcomes
AE=adverse event; ANC=absolute neutrophil count; AVD=doxorubicin in combination with vinblastine and dacarbazine; C=cycle; D=day; 
ECG=electrocardiogram; ECHO=echocardiogram; ECOG=Eastern Cooperative Oncology Group; 
 
; escB/escBEACOPP=escalated bleomycin in 
combination with etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone; FDG-PET=2-fluorodeoxyglucose positron emission 
tomography; IV=intravenous; MUGA=multigated acquisition; PET=positron emission tomography; PO=by mouth;
 
Q3W=every 3 weeks; SAE=serious adverse event; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WOCBP=woman of childbearing 
potential.
a
A maximum of a 7-day delay is permitted from the scheduled start of each cycle.
b
Participants with early unfavorable, nonbulky disease will not receive escBEACOPP Cycles 3 and 4; therefore, assessments and procedures scheduled 
during escBEACOPP Cycles 3 and 4 are not applicable to these participants.
08GW9Y
CCI
CCI
CCI
CCI
CCI
CCI
08HFB4


PRODUCT: MK-3475
34
PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
1.3.4
All Participants – Pembrolizumab Consolidation and Posttreatment
Note: before starting pembrolizumab consolidation, any toxicity from chemotherapy must have resolved to ≤Grade 1 or baseline. Non-
clinically significant toxicities (such as: alopecia, low lymphocyte count) may not need dose delays.
Study Period
Pembro Consolidation
(Q6W Cycles)a
Posttreatment
Notes
Treatment Cycle
C1
C2
C3
C4
Safety 
Follow-up 
(by 
phone)
EOT
Efficacy 
Follow-up
Survival 
Follow-up
Pembrolizumab consolidation C1D1 should start 
4 weeks (+3 days) after Day 1 of the last cycle of 
chemotherapy (see Sections 1.3.2 and 1.3.3).
For participants who complete study intervention, 
EOT assessments, including imaging, must be 
performed 6 weeks (±7 days) after the 
pembrolizumab consolidation C4D1 dose.
For participants who discontinue study intervention 
early, EOT assessments should occur within 7 weeks 
after the last dose of study intervention.
Dosing Day
D1
D1
D1
D1
30 days 
(+7 d) 
after last 
dose
6 
weeks 
(±7 d) 
after 
last 
dose
Q12W
(± 7 d)
Q12W
(± 14 d)
Administrative Procedures
Concomitant 
Medication Review
X
X
X
X
X
X
Concomitant medications will be recorded during the 
study through the Safety Follow-up Visit.
All concomitant medications received within 28 days 
prior to the first dose of study intervention and up to 30 
days after the last dose of study intervention should be 
recorded.
Subsequent 
Anticancer 
Treatment
X
X
X
X
Participants should be contacted by telephone to 
monitor new anticancer treatment if there is no 
corresponding clinic visit. 
Survival status
X
On Sponsor request, participants may be contacted for 
survival status at any time during the course of the 
study.
Study Intervention Administration (Assessments/procedures to be performed before administration of study intervention at each visit unless 
otherwise specified)
Pembrolizumab 
X
X
X
X
400 mg by IV Day 1 of each Q6W cycle for 4 cycles 
(note different dosing regimen relative to 
pembrolizumab monotherapy in Section 1.3.1).
08GW9Y
08HFB4


PRODUCT: MK-3475
35
PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
Study Period
Pembro Consolidation
(Q6W Cycles)a
Posttreatment
Notes
Treatment Cycle
C1
C2
C3
C4
Safety 
Follow-up 
(by 
phone)
EOT
Efficacy 
Follow-up
Survival 
Follow-up
Pembrolizumab consolidation C1D1 should start 
4 weeks (+3 days) after Day 1 of the last cycle of 
chemotherapy (see Sections 1.3.2 and 1.3.3).
For participants who complete study intervention, 
EOT assessments, including imaging, must be 
performed 6 weeks (±7 days) after the 
pembrolizumab consolidation C4D1 dose.
For participants who discontinue study intervention 
early, EOT assessments should occur within 7 weeks 
after the last dose of study intervention.
Dosing Day
D1
D1
D1
D1
30 days 
(+7 d) 
after last 
dose
6 
weeks 
(±7 d) 
after 
last 
dose
Q12W
(± 7 d)
Q12W
(± 14 d)
Efficacy Procedures
FDG-PET scan 
(Whole body)
X 
(PET 
EOT)
X*
For participants who complete study intervention, the 
PET EOT scan must be performed 6 weeks (±7 days) 
after the pembrolizumab consolidation C4D1 dose. For 
participants who discontinue before completing study 
intervention, the PET EOT scan should be performed 
within 6 weeks (±7 days) after the last dose of study 
intervention.
*During Efficacy Follow-up: FDG-PET only required if 
CT scan suggests progression or clinical suspicion of 
progression.
08GW9Y
08HFB4


PRODUCT: MK-3475
36
PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
Study Period
Pembro Consolidation
(Q6W Cycles)a
Posttreatment
Notes
Treatment Cycle
C1
C2
C3
C4
Safety 
Follow-up 
(by 
phone)
EOT
Efficacy 
Follow-up
Survival 
Follow-up
Pembrolizumab consolidation C1D1 should start 
4 weeks (+3 days) after Day 1 of the last cycle of 
chemotherapy (see Sections 1.3.2 and 1.3.3).
For participants who complete study intervention, 
EOT assessments, including imaging, must be 
performed 6 weeks (±7 days) after the 
pembrolizumab consolidation C4D1 dose.
For participants who discontinue study intervention 
early, EOT assessments should occur within 7 weeks 
after the last dose of study intervention.
Dosing Day
D1
D1
D1
D1
30 days 
(+7 d) 
after last 
dose
6 
weeks 
(±7 d) 
after 
last 
dose
Q12W
(± 7 d)
Q12W
(± 14 d)
Diagnostic quality 
CT scan (Neck, 
Chest, Abdominal, 
Pelvic)
X (CT 
EOT)
X*
For participants who complete study intervention, the 
CT EOT scan must be performed 6 weeks (±7 days) 
after the pembrolizumab consolidation C4D1 dose. For 
participants who discontinue before completing study 
intervention, the CT EOT scan should be performed 
within 6 weeks (±7 days) after the last dose of study 
intervention.
*During Efficacy Follow-up: CT scans will be 
performed Q24W (±7 days) for 2 years after EOT 
imaging, then at investigator’s discretion until the end 
of the study or meeting other criteria specified in 
Section 8.2.1.3. MRI can be considered in place of CT 
if MRI was performed at EOT for comparison.
Additional CT scans can be performed as clinically 
indicated.
If PET and CT scans at Screening are positive for 
disease of the neck, subsequent CT scans must include 
the neck. If PET and CT scans at Screening are negative 
for disease in the neck, subsequent CT scans may omit 
the neck.
If diagnostic quality CT scan cannot be performed due 
to medical contraindication or local practice, refer to 
Site Imaging Manual for alternative methods for 
anatomic imaging.
08GW9Y
08HFB4


PRODUCT: MK-3475
37
PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
Study Period
Pembro Consolidation
(Q6W Cycles)a
Posttreatment
Notes
Treatment Cycle
C1
C2
C3
C4
Safety 
Follow-up 
(by 
phone)
EOT
Efficacy 
Follow-up
Survival 
Follow-up
Pembrolizumab consolidation C1D1 should start 
4 weeks (+3 days) after Day 1 of the last cycle of 
chemotherapy (see Sections 1.3.2 and 1.3.3).
For participants who complete study intervention, 
EOT assessments, including imaging, must be 
performed 6 weeks (±7 days) after the 
pembrolizumab consolidation C4D1 dose.
For participants who discontinue study intervention 
early, EOT assessments should occur within 7 weeks 
after the last dose of study intervention.
Dosing Day
D1
D1
D1
D1
30 days 
(+7 d) 
after last 
dose
6 
weeks 
(±7 d) 
after 
last 
dose
Q12W
(± 7 d)
Q12W
(± 14 d)
Lymphoma Disease 
Response 
Assessment by 
Lugano 
Classification 2014 
(see Appendix 9)
X
X*
*During Efficacy Follow-up: response assessment will 
be performed Q24W (±7 days) for 2 years after EOT 
imaging, then at investigator’s discretion until the end 
of the study or meeting other criteria specified in 
Section 8.2.1.3.
Symptom Assessment
Assessment of 
Lymphoma B 
Symptoms
X
X*
*During Efficacy Follow-up: assessment of Lymphoma 
B symptoms should occur with each disease response 
assessment. 
Safety Procedures
Full Physical 
Examination 
X
Directed Physical 
Examination
X
X
X
X
X
During pembrolizumab consolidation: perform within 
3 days before dosing on Day 1 of each cycle and as 
clinically indicated.
During Efficacy Follow-up: perform Q12W for 2 years 
after EOT imaging and then at investigator’s discretion.
Vital Signs 
(temperature, blood 
pressure, respiratory 
rate, pulse rate, 
weight)
X
X
X
X
X
X
During pembrolizumab consolidation: perform within 
3 days before dosing on Day 1 of each cycle and as 
clinically indicated.
During Efficacy Follow-up: perform Q12W for 2 years 
after EOT imaging and then at investigator’s discretion.
12-lead ECG
<Perform as clinically indicated>
08GW9Y
08HFB4


PRODUCT: MK-3475
38
PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
Study Period
Pembro Consolidation
(Q6W Cycles)a
Posttreatment
Notes
Treatment Cycle
C1
C2
C3
C4
Safety 
Follow-up 
(by 
phone)
EOT
Efficacy 
Follow-up
Survival 
Follow-up
Pembrolizumab consolidation C1D1 should start 
4 weeks (+3 days) after Day 1 of the last cycle of 
chemotherapy (see Sections 1.3.2 and 1.3.3).
For participants who complete study intervention, 
EOT assessments, including imaging, must be 
performed 6 weeks (±7 days) after the 
pembrolizumab consolidation C4D1 dose.
For participants who discontinue study intervention 
early, EOT assessments should occur within 7 weeks 
after the last dose of study intervention.
Dosing Day
D1
D1
D1
D1
30 days 
(+7 d) 
after last 
dose
6 
weeks 
(±7 d) 
after 
last 
dose
Q12W
(± 7 d)
Q12W
(± 14 d)
ECOG Performance 
Status
X
X
X
X
X
During pembrolizumab consolidation: perform within 
3 days before dosing on Day 1 of each cycle.
Adverse Event 
Monitoring
X
X
X
X
X
X
X
Report all AEs through 30 days after the last dose. 
Report SAEs through 90 days after the last dose, or 
30 days after the last dose if participant initiates a new 
anticancer treatment, whichever is earlier. Report SAEs 
outside the time specified above if considered related to 
study intervention.
08GW9Y
CCI
CCI
08HFB4


PRODUCT: MK-3475
39
PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
Study Period
Pembro Consolidation
(Q6W Cycles)a
Posttreatment
Notes
Treatment Cycle
C1
C2
C3
C4
Safety 
Follow-up 
(by 
phone)
EOT
Efficacy 
Follow-up
Survival 
Follow-up
Pembrolizumab consolidation C1D1 should start 
4 weeks (+3 days) after Day 1 of the last cycle of 
chemotherapy (see Sections 1.3.2 and 1.3.3).
For participants who complete study intervention, 
EOT assessments, including imaging, must be 
performed 6 weeks (±7 days) after the 
pembrolizumab consolidation C4D1 dose.
For participants who discontinue study intervention 
early, EOT assessments should occur within 7 weeks 
after the last dose of study intervention.
Dosing Day
D1
D1
D1
D1
30 days 
(+7 d) 
after last 
dose
6 
weeks 
(±7 d) 
after 
last 
dose
Q12W
(± 7 d)
Q12W
(± 14 d)
Laboratory Procedures/Assessments (Performed by Local Laboratory)
Urine or Serum 
Pregnancy Test –
WOCBP Only
X
X
X
A pregnancy test must be performed every cycle (within 
24 hours of study visit for urine and 72 hours for serum) 
during study intervention. More frequent pregnancy 
testing may be performed if required by local 
regulations or if clinically indicated. After 
discontinuation of study intervention, pregnancy testing 
should be conducted at the EOT visit and 120 days after 
the last dose of pembrolizumab or 180 days after the 
last dose of chemotherapy, whichever comes last.
In case of suspected false positive pregnancy test in 
participants with fertility preservation, consult Sponsor.
Hematology
X
X
X
X
X
X*
During pembrolizumab consolidation: perform within 
3 days before dosing on Day 1 of every cycle.
The laboratory criteria in Table 1 must be met before 
dosing on Day 1 of every cycle (the requirement for 
ANC is ≥1000/µL).
Perform more frequently as clinically indicated.
*During Efficacy Follow-up: perform as clinically 
indicated.
Chemistry 
X
X
X
X
X
X*
Thyroid function 
tests (TSH, T3, T4)
X
X
X
X
X
X*
Bone Marrow 
Biopsy/Aspirate
<Perform as clinically indicated>
Refer to Section 8.2.1.5 for details.
08GW9Y
08HFB4


PRODUCT: MK-3475
40
PROTOCOL/AMENDMENT NO.: C11-06
MK-3475-C11-06 FINAL PROTOCOL
15-DEC-2023
Study Period
Pembro Consolidation
(Q6W Cycles)a
Posttreatment
Notes
Treatment Cycle
C1
C2
C3
C4
Safety 
Follow-up 
(by 
phone)
EOT
Efficacy 
Follow-up
Survival 
Follow-up
Pembrolizumab consolidation C1D1 should start 
4 weeks (+3 days) after Day 1 of the last cycle of 
chemotherapy (see Sections 1.3.2 and 1.3.3).
For participants who complete study intervention, 
EOT assessments, including imaging, must be 
performed 6 weeks (±7 days) after the 
pembrolizumab consolidation C4D1 dose.
For participants who discontinue study intervention 
early, EOT assessments should occur within 7 weeks 
after the last dose of study intervention.
Dosing Day
D1
D1
D1
D1
30 days 
(+7 d) 
after last 
dose
6 
weeks 
(±7 d) 
after 
last 
dose
Q12W
(± 7 d)
Q12W
(± 14 d)
AE=adverse event; AVD=doxorubicin in combination with vinblastine and dacarbazine; C=cycle; CT=computed tomography; 
; D=day; 
ECG=electrocardiogram; ECI=event of clinical interest; ECOG=Eastern Cooperative Oncology Group; 
 
; EOT=end-of-treatment; escBEACOPP=escalated bleomycin in combination with etoposide, doxorubicin, cyclophosphamide, vincristine, 
procarbazine, and prednisone; EQ-5D-5L=EuroQoL 5-dimension, 5-level scale; FDG-PET=2-fluorodeoxyglucose positron emission tomography; IV=intravenous; MRI= magnetic resonance 
imaging; PBMC=peripheral blood mononuclear cell; pembro=pembrolizumab; PET=positron emission tomography; 
; Q6W=every 6 weeks; Q12W=every 12 weeks; 
SAE=serious adverse event; SCT=stem cell transplant; T3=triiodothyronine; T4=thyroxine; TCR=T-cell receptor; TSH=thyroid-stimulating hormone; WOCBP=woman of childbearing potential.
a.
After C1D1 of pembrolizumab consolidation, a ±3-day window is permitted is permitted from the scheduled start of each cycle.
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2
INTRODUCTION
2.1
Study Rationale
cHL has an excellent prognosis with 5-year survival exceeding 75% to 80% [Roy, P., et al
2000] [Brenner, H., et al 2008]. Despite many advances in the field, patients, although often 
cured of disease, may experience late effects from therapy, reducing length and QoL. As 
such, multiple efforts have focused on identifying more tolerable treatment combinations or 
de-escalation of therapy and elimination of the radiotherapy consolidation. Some approaches 
to limiting toxicity include the elimination of bleomycin from ABVD treatment (doxorubicin 
in combination with bleomycin, vinblastine, and dacarbazine) [Allen, P. B., et al 2020], 
treatment with an abbreviated course of chemotherapy [Radford, J., et al 2015], and
combining novel drugs with more tolerable side effects. One such class of drugs that has 
shown promise and tolerability in cHL includes checkpoint inhibitors. The advent of 
immunotherapy has transformed the therapeutic landscape, changing the standard of care 
across the field and raising questions of how best to use and assess response to this novel 
class of drugs. Checkpoint inhibitors, such as pembrolizumab, have shown efficacy and 
tolerability in relapsed HL, however their efficacy in the frontline setting combined with 
chemotherapy has not been widely studied.
In a recent study by Allen et al [Allen, P. B., et al 2020], pembrolizumab monotherapy 
followed by AVD proved both highly effective and safe in patients with newly diagnosed 
early unfavorable (n=12) or advanced (n=18) stage cHL, including those with bulky disease. 
In this study, a brief course of pembrolizumab monotherapy, previously unstudied in patients 
with newly diagnosed cHL, proved to be a powerful induction strategy in early unfavorable 
and advanced-stage disease. While 37% of patients achieved complete metabolic responses 
with only 3 doses of pembrolizumab, 100% of patients achieved a complete metabolic 
response after 2 cycles of chemotherapy, and all patients maintained their responses through 
the EOT. The complete metabolic response rate was 100%, both at interim PET and at EOT. 
At a median follow-up of 22.5 months, the PFS and OS were 100%, and no patient required 
salvage therapy or radiotherapy. No patient was treated with radiation therapy. The authors 
concluded that sequential administration of a short course of pembrolizumab monotherapy 
followed by AVD chemotherapy is safe and highly effective in newly diagnosed early 
unfavorable and advanced-stage cHL, including many patients with bulky disease, with all 
patients completing the prescribed course of therapy [Allen, P. B., et al 2020].
The study by Allen et al [Allen, P. B., et al 2020] was performed at US sites only, with most 
patients enrolled at a single institution. KEYNOTE-C11 is built on similar concepts and will 
use sequential administration of pembrolizumab followed by PET-guided chemotherapy 
treatment without radiotherapy. With the promising results of sequential pembrolizumab 
followed by chemotherapy shown by Allen et al [Allen, P. B., et al 2020], this strategy is 
expected to minimize the treatment toxicity associated with conventional chemotherapy and 
radiotherapy while improving the therapeutic efficacy. This single-arm study aims to 
evaluate whether administration of sequential pembrolizumab followed by chemotherapy to 
participants with newly diagnosed early unfavorable and advanced cHL achieves a CR rate 
similar to that of Allen et al, in a larger number of participants enrolled across a broader 
range of institutions. Specifically, it is hypothesized that the study achieves a CR rate of 
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greater than 80%. A CR rate of 80% was selected as a conservative CR rate based on data 
from previous studies with conventional chemotherapy [Connors, J. M., et al 2018] 
[Eichenauer, D. A., et al 2017], in which CR rates ranged from 70% to 86%, and the study of 
sequential pembrolizumab followed by chemotherapy [Allen, P. B., et al 2020] in which a 
100% CR rate was achieved.
2.2
Background
2.2.1
Pembrolizumab
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 several indications. For more details on specific 
indications refer to the IB.
2.2.1.1
Pharmaceutical and Therapeutic Background
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, M. L. 2010]. Accumulating evidence 
shows a correlation between 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 (T-regs) correlates with improved 
prognosis and long-term survival in solid malignancies, such as ovarian, colorectal, and 
pancreatic cancer, hepatocellular carcinoma, malignant melanoma, and renal cell carcinoma. 
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 CTLA-4 that has been shown to negatively 
regulate antigen receptor signaling on 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 its family 
members are type I transmembrane glycoproteins containing an IgV–type domain 
responsible for ligand binding and a cytoplasmic tail 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. After T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and 
SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, 
leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ, and ZAP70, 
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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, 
because 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 cHL.
2.2.1.2
Preclinical and Clinical Studies
Refer to the pembrolizumab IB for a summary of preclinical and clinical study data.
2.2.1.3
Ongoing Clinical Studies
Refer to the pembrolizumab IB for a summary of ongoing clinical study data.
2.2.2
Treatment of Early Unfavorable and Advanced-stage Hodgkin Lymphoma
Early stage HL is defined as Ann Arbor Stage I to II disease. Patients with bulky mediastinal 
masses, B symptoms, elevated ESR, or multiple nodal sites are generally classified as 
early unfavorable HL. Advanced-stage disease generally refers to patients with Ann Arbor 
Stage III/IV disease [Lister, T. A., et al 1989]. The population in this study will include early 
unfavorable and advanced disease. Although excellent outcomes in early favorable disease 
are achieved with existing therapies, there is continued need for therapeutic optimization in 
early unfavorable and advanced disease.
Combined-modality treatment consisting of chemotherapy and consolidation radiotherapy 
has been the standard of care for patients with early-stage unfavorable cHL. The most 
frequently used initial regimen in early unfavorable HL is ABVD × 4 to 6 cycles followed by 
involved-site radiation therapy to 30 Gy [Engert, A., et al 2003]. However, the use of 
radiotherapy has long-term sequelae, particularly cardiovascular disease and secondary 
malignancies. While randomized clinical trials have shown that chemotherapy alone leads to 
a higher recurrence rate and shorter PFS, this has not translated into an inferior OS compared 
with addition of radiotherapy to chemotherapy. This is mainly due to a higher number of 
deaths in patients receiving consolidation radiotherapy. The major focus in frontline cHL is 
thus the development of various strategies aimed at identifying the optimal balance between 
maintaining high cure rates and avoiding the long-term toxicity associated with radiation, 
especially in early-stage disease. Recent studies have been designed to reduce or eliminate 
radiotherapy, by incorporating novel agents into the treatment and using a PET-guided 
approach.
The large GHSG HD17 study showed that, in the setting of an appropriate chemotherapy 
backbone, radiotherapy can be successfully omitted from standard combined-modality 
treatment without a clinically relevant loss of tumor control in patients with a negative PET 
after systemic treatment with the 2+2 regimen of ABVD and escBEACOPP [Borchmann, P., 
et al 2021]. Additionally, in a study examining the use of combination chemotherapy alone in 
patients perceived to be at low risk of treatment failure but at high risk of radiation-induced 
toxicity, patients with nonbulky Stage I, II, and IIIA disease receiving 6 cycles of ABVD 
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with or without consolidation involved-field radiotherapy showed no significant difference in 
outcome among 152 patients [Straus, D. J., et al 2004].
One of the largest studies to make a direct comparison of chemotherapy alone with a 
combined modality approach was the intergroup study HD.6 in 399 patients with nonbulky 
Stage I and II disease. The early report of this study, with a median follow-up of 4.2 years, 
showed that OS was not significantly different between the combined modality approach and 
ABVD alone (94% vs 96%, respectively) [Meyer, R. M., et al 2005], but a subsequent 
reanalysis with median follow-up of 11.3 years showed a different picture, with inferior 
survival among the patients who had received radiotherapy (87% vs 94%, respectively; 
p=0.04) [Meyer, R. M., et al 2005]. The risk of death from HL was not different between the 
arms, but the risk of death from other causes was more than 3-fold higher among those 
irradiated, with much of the excess attributable to second cancers [Meyer, R. M., et al 2012].
The above results suggest that chemotherapy alone may be an appropriate treatment strategy 
in a subset of patients. In advanced disease, treatment continues to evolve. Guidelines 
generally recommend treatment with chemotherapy alone, starting with either ABVD or 
escBEACOPP [Engert, A., et al 2009] [Merli, F., et al 2016]. However, ABVD alone fails to 
cure 15% to 30% of patients. In contrast to early stage disease in which long-term cure 
exceeds 90%, only approximately 65% to 75% of patients with advanced-stage HL remain 
disease free at 10 years [Engert, A., et al 2009] [Carde, P., et al 2016] [Merli, F., et al 2016].
In addition, both ABVD and escBEACOPP are associated with acute and chronic toxicities 
including bleomycin lung toxicity [Boll, B., et al 2016] [Evens, A. M., et al 2013]. 
Bleomycin-free strategies that improve long-term remission rates without incorporating 
radiotherapy are needed.
Although PET-guided approaches might help to individualize chemotherapy and 
radiotherapy exposure, implementation of novel agents such as the anti–PD-1 therapies will 
help further optimize the therapy. The investigation of novel drugs is warranted to reduce 
upfront treatment intensity, achieve PET-negative disease status after systemic therapy in a 
vast majority of patients to potentially enable omission of radiation therapy, and achieve a 
PFS superior to that with conventional chemotherapy. Newer trials are designed to exploit 
the tumor biology with the use of anti-PD-1 agents in both early-stage and late-stage cHL, 
and attempts are underway to eliminate radiotherapy while maximizing the cure rate.
2.2.3
Role of 2-Fluorodeoxyglucose-positron Emission Tomography
FDG-PET has become a standard imaging modality complementing CT scans in the 
management of HL [Friedberg, J. W., et al 2004] [Jerusalem, G., et al 2003] [Jerusalem, G., 
et al 2001] [Stumpe, K. D. M., et al 1998]. Efforts over the last decade have focused on 
tailoring therapy according to risk using an interim PET scan. A major objective of these 
studies has been to assess if radiotherapy can be omitted in patients with interim PET-
negative results and whether intensifying therapy will improve outcomes for patients who are 
PET-positive.
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The data on response-adapted therapy have led to it becoming increasingly accepted as the 
standard of care, as it supports both de-escalation of therapy for patients with a good early 
response and intensification of treatment for those with persistent FDG-avid disease early in 
the course. The findings in early stage disease highlight the utility of interim PET in 
providing information to patients about the option of omitting consolidation radiotherapy or 
the advisability of escalating chemotherapy. In advanced-stage disease, a risk-adapted 
approach combined with a response-adapted approach may be optimal in using more 
intensive initial therapy for those with the worst disease, but performing interim PET scans to 
assess the response in all and adjusting subsequent therapy accordingly. The data so far 
suggest that modulating treatment of advanced-stage HL both upward and downward after 
interim PET is an effective approach, which may improve the results and reduce morbidity 
and mortality in the long-term, although longer follow-up is needed to confirm this.
Several large-scale studies with strikingly similar results have now reported the results of 
treating patients with a positive PET scan with escBEACOPP after 2 cycles of ABVD. In the 
response-adapted therapy for advanced HL study, which included unfavorable risk Stage II 
disease as well as Stages III to IV, 16% of patients had a positive interim PET scan, and 
among 182 patients who went on to receive either 4 cycles of escBEACOPP or 6 dose-dense 
cycles of BEACOPP-14, there was a subsequent complete metabolic response in 74% of 
cases, with a 3-year PFS of 68% and OS of 88% [Johnson, P., et al 2016]. Similar results 
were seen in the Gruppo Italiano Terapie Innovative nei Linfomi/Fondazione Italiana 
Linfomi (GITIL/FIL) 0607 study, in which treatment was increased to 4 cycles of 
escBEACOPP followed by 4 cycles of standard BEACOPP with or without rituximab; the 3-
year PFS and OS were 57% and 89% in 76 participants treated with escBEACOPP, and 63% 
and 90% in 72 participants treated with rituximab-supplemented escBEACOPP [Gallamini, 
A., et al 2018]. In the Southwest Oncology Group S0816 study, in which patients received 6 
cycles of escBEACOPP, the 2-year PFS in 60 patients was 64% [Press, O. W., et al 2016].
2.2.4
Incorporating Anti-PD-1 in Frontline Hodgkin Lymphoma
Although PET-guided approaches might help to individualize chemotherapy and radiation 
therapy exposure, implementation of novel agents such as the anti–programmed death 1 
antibodies nivolumab or pembrolizumab, approved for the treatment of relapsed or refractory 
HL, might further optimize therapy [Chen, R., et al 2017]. By exploiting potential synergies 
(eg, in combination with chemotherapy, radiation therapy, or other targeted agents) and the 
distinct HL biology with its dependence on a protective immunosuppressive 
microenvironment [Hude, I., et al 2017], these strategies might also improve outcomes for 
elderly patients or those with relevant comorbidities. Fueled by the data in relapsed or 
refractory HL, several Phase 1/2 studies of first-line therapy for HL are planned or actively 
enrolling patients to investigate combinations of ABVD variants with nivolumab 
(NCT03004833, NCT03033914), or pembrolizumab (NCT03226249). In addition, studies in 
elderly patients are studying the combination of brentuximab vedotin, and nivolumab 
(NCT01716806, NCT02758717) as well as AVD chemotherapy combined with brentuximab 
vedotin, and nivolumab (NCT03233347).
The results of 2 studies with anti-PD-1 in combination with chemotherapy in frontline cHL 
has recently been reported: Cohort D of Checkmate 205 in advanced-stage cHL, and the 
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GHSG Phase 2 NIVAHL study in early unfavorable cHL [Ramchandren, R., et al 2019] 
[Brockelmann, P. J., et al 2020]. In Checkmate 205, Cohort D, nivolumab was administered 
as monotherapy for 4 doses followed by 6 cycles of concurrent nivolumab and AVD. The 
response rate to single-agent nivolumab in this study was identical to that reported previously 
in the relapsed setting (18% CR). With the addition of AVD chemotherapy, CR rate 
increased to 51% and 67% at interim and EOT time points [Ramchandren, R., et al 2019].
While these response rates are lower than the CR rate of >80% reported with ABVD alone, 
the PFS of 83% at 21 months in Cohort D is similar to the historical controls [Domingo-
Domenech, E., et al 2019].
The GHSG randomized Phase 2 NIVAHL study for early unfavorable disease compared 
concurrent nivolumab and AVD to a sequential strategy. All patients were consolidated with 
radiotherapy. The investigators found no significant differences in outcomes with the 
concurrent or sequential approaches. Notably, this study showed a CR rate of 51% to 
frontline single agent nivolumab [Brockelmann, P. J., et al 2020].
2.2.5
Information on Other Study-related Therapy
For additional information on doxorubicin, vinblastine, dacarbazine, bleomycin, etoposide, 
cyclophosphamide, vincristine, procarbazine, and prednisone refer to the respective approved 
product labels.
2.3
Benefit/Risk Assessment
It cannot be guaranteed that participants in clinical studies will directly benefit from 
treatment during participation, as clinical studies are designed to provide information about 
the safety and effectiveness of an investigational medicine.
The investigational agent pembrolizumab is a potent inhibitor of PD-1 signaling that 
enhances tumor-cell specific T-cell activation and has shown activity in adult patients with 
rrcHL. Pembrolizumab has been approved in the United States for the treatment of both adult 
and pediatric patients with rrcHL. Based on current evidence, no difference in mechanism of 
action and activity are expected in cHL between the frontline and relapsed/refractory 
settings. Thus, pembrolizumab has the potential to provide therapeutic benefit to patients 
with newly diagnosed cHL. Pembrolizumab monotherapy has a positive benefit-risk profile 
and is well tolerated in the approved indications. Most AEOSIs are mild to moderate in 
severity, and are generally readily manageable with appropriate care in the clinical setting. In 
combination with chemotherapy, the safety profiles were generally consistent with the known 
safety profiles of pembrolizumab monotherapy and the chemotherapy regimens administered 
(refer to the pembrolizumab IB). Preliminary data to support the efficacy and safety of 
pembrolizumab in combination with chemotherapy in frontline cHL is also available 
(Section 2.2.4). Thus, pembrolizumab has the potential to offer patients with newly 
diagnosed cHL a therapy that is expected to be efficacious with a generally tolerable safety 
profile. Moreover, addition of pembrolizumab to the chemotherapy backbone in cHL may 
improve disease control and reduce cumulative drug toxicities.
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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
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In males and females with newly diagnosed early unfavorable or advanced-stage classical 
Hodgkin Lymphoma:
Primary Objective
Primary Endpoint
To evaluate complete response (CR) rate at 
the end of study intervention in participants 
with newly diagnosed classical Hodgkin 
Lymphoma (cHL) assessed by independent 
central review according to Lugano 2014 
response criteria
CR
Secondary Objectives
Secondary Endpoints
To evaluate the CR rate at the end of study 
intervention in participants with newly 
diagnosed cHL by investigator assessment 
according to Lugano 2014 response criteria
CR
To evaluate the rate of Positron Emission 
Tomography (PET) negativity at PET2 
following 3 cycles of pembrolizumab 
monotherapy by independent central review 
according to the 2-fluorodeoxyglucose 
(FDG)-PET 5-point scale
PET negativity: a score of 1, 2, or 3 on the 
FDG-PET 5-point scale after 3 cycles of 
pembrolizumab monotherapy
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To evaluate the rate of PET negativity at 
PET3 after completion of 3 cycles of 
pembrolizumab monotherapy followed by 
2 cycles of doxorubicin in combination with 
vinblastine and dacarbazine (AVD) by 
independent central review according to the
FDG-PET 5-point scale
PET negativity: a score of 1, 2, or 3 on the 
FDG-PET 5-point scale after 3 cycles of 
pembrolizumab monotherapy followed by 2 
cycles of AVD
To evaluate the safety and tolerability of 
initial pembrolizumab monotherapy 
followed by chemotherapy and 
pembrolizumab consolidation in 
participants with newly diagnosed cHL
-Adverse Events (AEs)
-Discontinuation of study intervention due 
to an AE
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2, uncontrolled, open-label, multicenter study of sequential pembrolizumab 
monotherapy followed by chemotherapy and pembrolizumab consolidation in adults 
≥18 years of age with newly diagnosed, early unfavorable or advanced-stage cHL.
The study design is depicted in Figure 1 (Section 1.2) and study intervention regimens are 
described in Table 2 (Section 6.1).
This study will examine the safety and efficacy of 200 mg Q3W pembrolizumab 
monotherapy, followed by either AVD or escBEACOPP chemotherapy, followed by 
pembrolizumab consolidation of 400 mg Q6W.
Participants must have newly diagnosed, histologically confirmed, untreated, early 
unfavorable or advanced-stage cHL. For the purposes of this protocol “early unfavorable” is 
defined as Stage I or II disease with at least 1 unfavorable NCCN risk factor (Appendix 11) 
and “advanced” is defined as Stage III or IV disease.
Approximately 140 participants will be enrolled.
Study intervention will be administered as follows:
•
Pembrolizumab Monotherapy: all participants will receive 200 mg pembrolizumab 
monotherapy Q3W for 3 cycles.
-
PET scan (PET2) will be performed after pembrolizumab monotherapy to determine 
PET response to pembrolizumab alone.
•
Chemotherapy Phase 1: all participants will receive AVD on Days 1 and 15 Q4W for 
2 cycles.
-
PET scan (PET3) will be performed after 2 cycles of AVD therapy. Investigators will 
assess PET3 response to determine if participants are PET-negative (a score of 1, 2, 
or 3 on the FDG-PET 5-point scale) or PET-positive (a score of 4 or 5 on the 
FDG-PET 5-point scale) (Appendix 9). Participants will receive additional 
chemotherapy (during Chemotherapy Phase 2) according to their PET3 response and 
age at screening.
•
Chemotherapy Phase 2:
-
If a participant is PET3-negative, they will receive 4 cycles of AVD on Days 1 and 15 
Q4W.
-
If a participant is PET3-positive and ≥60 years of age, they will receive 4 cycles of 
AVD on Days 1 and 15 Q4W.
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-
If a participant is PET3-positive and <60 years of age, they will receive 4 cycles of 
escBEACOPP Q3W.
-
Participants with early unfavorable, nonbulky disease will receive 2 cycles of AVD 
OR 2 cycles of escBEACOPP according to the PET3 and age criteria above.
•
Pembrolizumab Consolidation: all participants will receive 4 cycles of 400 mg 
pembrolizumab monotherapy Q6W. Before starting pembrolizumab consolidation, any 
toxicity from chemotherapy must have resolved to ≤Grade 1 or baseline. Non-clinically 
significant toxicities (such as: alopecia, low lymphocyte count) may not need dose 
delays.
-
PET scan (PET EOT) and CT EOT scan will be performed at the end of 
pembrolizumab consolidation (end of study intervention; 6 weeks [±7 days] after 
pembrolizumab consolidation Cycle 4 Day 1 dose).
Participants will continue to receive study intervention as defined above until unacceptable 
AE(s), intercurrent illness that prevents further administration of treatment, investigator’s 
decision to discontinue the participant, administrative reasons requiring cessation of 
treatment, or until the participant has received the maximum duration of treatment specified 
by the protocol. Additional study intervention discontinuation criteria are outlined in Section 
7.1.
Participants with CR at the end of study intervention, or participants who discontinue for 
reasons other than disease progression, will progress into Efficacy Follow-up. During 
Efficacy Follow-up, participants will be monitored for disease status every 24 weeks for 
2 years after EOT imaging, then at investigator’s discretion until the end of the study, or until 
disease progression, the start of a new anticancer treatment, withdrawal of consent, 
pregnancy, death, or loss to follow-up, whichever occurs first. When one of these criteria are 
met, the participant will progress to Survival Follow-up. Participants without CR at the end 
of study intervention, or participants who discontinue study intervention due to disease 
progression, will progress immediately to Survival Follow-up. All participants will be 
followed for OS until death, withdrawal of consent, or the end of the study, whichever occurs 
first.
Participants with PET-positive residual mass at EOT should not receive radiotherapy as part 
of study intervention but should be transitioned to Survival Follow-up (see Section 8.11.4.3) 
before receiving non-study anticancer treatment for residual disease. If at EOT, either 
anatomic or metabolic imaging shows findings suspicious for residual disease, a biopsy may 
be obtained, which will contribute to the assessment of disease per Lugano 2014 response 
criteria (Appendix 9).
AE monitoring will be ongoing throughout the study and graded according to the guidelines 
outlined in the NCI CTCAE version v5.0. All AEs will be reported through 30 days after the 
last dose of study intervention. All SAEs will be reported through 90 days after the last dose 
of study intervention, or 30 days after the last dose if participant initiates a new anticancer 
treatment, whichever is earlier. For participants who undergo allogeneic stem cell transplant
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within 2 years after the last pembrolizumab dose, ECIs will be recorded as detailed in 
Section 8.4.7. Safety data will be reviewed on a monthly basis by the Sponsor, with 
additional review of cumulative Grade 3-5 TEAE data for each treatment performed by the 
Sponsor’s study team every 4 months. If the criteria outlined in Section 6.6.3 are met, 
enrollment will be paused and an internal DMC will review all available safety data.
The primary efficacy endpoint is CR at the end of study intervention, assessed by 
independent central review according to Lugano 2014 response criteria (Appendix 9).
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
A Phase 2, uncontrolled, open-label, multicenter study design is considered appropriate for 
examining the efficacy of sequential pembrolizumab monotherapy followed by 
chemotherapy and pembrolizumab consolidation in adults ≥18 years of age with newly 
diagnosed, early unfavorable or advanced-stage cHL.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
Complete Response
The primary efficacy endpoint is CR at the end of study intervention assessed by independent 
central review according to Lugano 2014 response criteria (Appendix 9).
One secondary efficacy endpoint is CR at the end of study intervention assessed by 
investigators according to Lugano 2014 response criteria (Appendix 9).
Assessment of CR at the end of study intervention as per the Lugano 2014 response criteria 
(Appendix 9) will include both PET and CT. As described in Lugano, the PET response, 
when available, will be the main determinant of the overall visit response.
Treatment effect measured by CR rate can represent direct clinical benefit based on the 
specific disease, context of use, magnitude of the effect, number of participants with CRs, 
durability of response, disease setting, location of the tumors, available therapy, and 
risk-benefit relationship. Treatment effect measured by CR rate can be a surrogate endpoint 
to support accelerated approval according to FDA guidance [Food and Drug Administration 
2018].
Duration of Complete Response
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Rate of PET Negativity
Additional secondary efficacy endpoints include the rate of PET negativity at PET2 after
3 cycles of pembrolizumab monotherapy by independent central review according to the 
FDG-PET 5-point scale (Appendix 9), and the rate of PET negativity at PET3 after 3 cycles 
of pembrolizumab monotherapy followed by 2 cycles of AVD (see Section 2.2.3).
Progression-free Survival and Overall Survival
4.2.1.2
Safety Endpoints
Safety parameters frequently 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.
4.2.1.3
4.2.1.3.1
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4.2.1.3.2
4.2.1.4
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4.2.1.5
4.3
Justification for Dose
4.3.1
Pembrolizumab
The planned dose of pembrolizumab for this study is 200 mg Q3W followed by 400 mg 
Q6W. The current approved dosing regimens of pembrolizumab for IV administration are 
200 mg Q3W and 400 mg Q6W for adults.
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 flat dose- and exposure-efficacy relationships from 2 mg/kg Q3W to 
10 mg/kg Q2W representing an approximate 5- to 7.5-fold exposure range (refer to IB, 
Section 5.2.2)
•
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
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400 mg Q6W
A 400 mg Q6W dosing regimen of pembrolizumab is expected to have a similar benefit-risk 
profile as 200 mg Q3W, in all treatment settings in which 200 mg Q3W pembrolizumab is 
currently appropriate [Lala, M., et al 2020]. Specifically, the dosing regimen of 400 mg Q6W 
for pembrolizumab is considered adequate based on M&S analyses, given the following 
rationale:
PK simulations demonstrating that in terms of pembrolizumab exposures:
•
Cavg (or AUC) at 400 mg Q6W is similar to the approved 200 mg Q3W dose, thus 
bridging efficacy between dosing regimens.
•
Trough concentrations (Cmin) at 400 mg Q6W are generally within the range of those 
achieved with 2 mg/kg or 200 mg Q3W in the majority (>99%) of patients.
•
Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the highest 
clinically tested dose of 10 mg/kg Q2W, supporting that the safety profile for 400 mg 
Q6W should be comparable to the established safety profile of pembrolizumab.
•
E-R for pembrolizumab has been shown to be flat across indications, and OS predictions 
in melanoma and NSCLC show that efficacy at 400 mg Q6W is expected to be similar to 
200 mg or 2 mg/kg Q3W, given the similar exposures; thus, 400 mg Q6W is expected to 
be efficacious across indications.
4.3.2
AVD and escBEACOPP
ABVD and escBEACOPP are recommended for newly diagnosed early unfavorable or 
advanced cHL per NCCN guidelines [National Comprehensive Cancer Network 2019]. 
However, the omission of bleomycin has been associated with decreased risk of toxicity 
[Allen, P. B., et al 2020], therefore AVD will be used in this study after pembrolizumab 
monotherapy in participants who are PET-negative at PET3, and in participants who are 
PET-positive at PET3 and 60 years of age. escBEACOPP will be used in participants who 
are PET-positive at PET3 and <60 years of age, which is expected to represent a small 
minority of participants in whom PET3 is performed.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). Upon study completion, participants are to be discontinued and may be enrolled in an 
extension study using pembrolizumab monotherapy, if available. For purposes of analysis 
and reporting, the overall study ends when the Sponsor receives the last laboratory test result 
or at the time of final contact with the last participant, whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
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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.
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5
STUDY POPULATION
Male/female participants with newly diagnosed early unfavorable or advanced-stage cHL, 
who are at least 18 years old will be enrolled in this study.
As stated in the Code of Conduct for Clinical Trials (Appendix 1.1), this study includes 
participants of varying age (as applicable), race, ethnicity, and sex (as applicable). The 
collection and use of these demographic data will follow all local laws and participant 
confidentiality guidelines while supporting the study of the disease, its related factors, and 
the IMP under investigation.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
An individual is eligible for inclusion in the study if the individual meets all of the following 
criteria:
Type of Participant and Disease Characteristics
1. Has a histologically confirmed diagnosis of Ann Arbor Stage III or IV cHL. Stage I and 
II patients may be enrolled but must have at least one NCCN unfavorable risk factor (see 
Appendix 11).
Note: Participants with bulky disease are eligible.
2. Has measurable FDG-avid disease based on investigator assessment according to Lugano 
2014 response criteria (Appendix 9).
3. Has not received prior radiation therapy, chemotherapy, immunotherapy, or other 
systemic therapy (including investigational agents) for the treatment of cHL before the 
first dose of study intervention.
Demographics
4. Is male or female, at least 18 years of age, at the time of providing the informed consent.
Male Participants
5. Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least the time needed to eliminate each study intervention 
after the last dose of study intervention. The length of time required to continue 
contraception for each study intervention is as follows:
-
Pembrolizumab: no contraception requirement
-
Chemotherapy: 90 days
•
Refrain from donating sperm
PLUS either:
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•
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.
•
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the contraception 
requirements in the local label for any of the study interventions is more stringent than 
the requirements above, the local label requirements are to be followed.
Refer to Appendix 7 for country-specific requirements.
Female Participants
6. 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), with low user dependency, 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 the time 
needed to eliminate each study intervention after the last dose of study intervention and 
agrees not to donate eggs (ova, oocytes) to others or freeze/store for her own use for the 
purpose of reproduction during this period. The length of time required to continue 
contraception for each study intervention is as follows:
-
Chemotherapy: 180 days
-
Pembrolizumab: 120 days
The investigator should evaluate the potential for contraceptive method failure (ie, 
noncompliance, recently initiated) in relationship to the first dose of study intervention
-
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as 
required by local regulations) within 72 hours 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.
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-
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.7.
-
The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
-
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. If the 
contraception requirements in the local label for any of the study interventions is 
more stringent than the requirements above, the local label requirements are to be 
followed.
Refer to Appendix 7 for country-specific requirements.
Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed
consent for the study. The participant may also provide consent for FBR. However, the 
participant may participate in the study without participating in FBR.
Additional Categories
8. Has an ECOG Performance Status of 0 to 1 assessed within 7 days before the start of 
study intervention.
9. Has adequate organ function as defined in the following table (Table 1). Specimens must 
be collected within 7 days before the start of study intervention. Refer to Appendix 7 for 
country-specific requirements.
Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1500/µL
Platelets
≥50 000/µL
Hemoglobin
≥8.0 g/dLa
Renal
Measured or calculatedb creatinine clearance
(GFR can also be used in place of CrCl)
≥30 mL/min
Hepatic
Total bilirubin
≤1.5 ×ULN OR direct bilirubin ≤ULN for participants 
with total bilirubin levels >1.5 × ULN
AST (SGOT) and ALT (SGPT)
≤2.5 × ULN (≤5 × ULN for participants with liver 
metastases)
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System
Laboratory Value
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.
aCriteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks.
bCreatinine clearance (CrCl) should be calculated using Cockcroft-Gault.
(140-age [years] × weight (kg) (×F)*
Serum creatinine (mg/dL) × 72
*where F = 0.85 for females and F = 1 for males
Note: This table includes eligibility-defining laboratory value requirements for treatment; laboratory value 
requirements should be adapted according to local regulations and guidelines for the administration of 
specific chemotherapies.
5.2
Exclusion Criteria
An individual must be excluded from the study if the individual meets any of the following 
criteria:
Medical Conditions
1. Has confirmed nodular lymphocyte-predominant HL.
2. Has an uncontrolled intercurrent cardiovascular illness including, but not limited to the 
following:
•
Symptomatic congestive heart failure (ejection fraction lower than institutional LLN)
•
Unstable angina pectoris
•
Cardiac arrythmia
Prior/Concomitant Therapy
3. 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 coinhibitory T-cell receptor (eg, CTLA-4, 
OX-40, CD137).
4. Has received or is expected to receive a live or live-attenuated vaccine within 30 days 
before the first dose of study intervention. Administration of killed vaccines are allowed.
Prior/Concurrent Clinical Study Experience
5. Is currently participating in or has participated in a study of an investigational agent or 
has used an investigational device within 4 weeks before the first dose of study 
intervention.
Note: Participants who have entered the follow-up phase of an investigational study will 
be eligible to participate as long as ≥4 weeks has elapsed since the last dose of an 
investigational agent administered for a disease/condition other than cHL.
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Diagnostic Assessments
6. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior the first dose of study medication. The 
use of physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor.
7. Has a known additional malignancy that is progressing or has required active treatment 
within the past 5 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.
8. Has radiographically detectable (even if asymptomatic and/or previously treated) central 
nervous system metastases and/or carcinomatous meningitis as assessed by investigator at 
the time of diagnosis.
9. Has severe hypersensitivity (≥Grade 3) to any of the study interventions or their
excipients.
10. 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.
11. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
12. Has a history or current evidence of pulmonary fibrosis.
13. Has an active infection requiring systemic therapy.
14. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority.
15. 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.
16. 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.
17. 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
18. Has any contraindication to the use of any of the chemotherapeutic agents used in the 
study.
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19. Has not recovered adequately from surgery and/or any complications from the surgery.
20. Has had an allogenic tissue/solid organ transplant.
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.
Participants who fail screening may be rescreened for eligibility after consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
5.5
Participant Replacement Strategy
A participant who discontinues from study intervention OR withdraws from the study will 
not be replaced.
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6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
Clinical supplies will be packaged to support enrollment. Clinical supplies will be affixed 
with a clinical label in accordance with regulatory requirements.
6.1
Study Intervention(s) Administered
The study interventions to be used in this study are outlined in Table 2.
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Table 2
Study Interventions
Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulatio
n
Unit Dose 
Strength(s
)
Dosage 
Level(s
)
Route of 
Administratio
n
Regimen/
Treatment 
Period/
Vaccinatio
n Regimen
Use
IMP 
or 
NIMP
/
AxMP
Sourcin
g
All 
participant
s
Experimenta
l
Pembrolizumab
Biological/Vaccin
e
Injection, 
Solution
25 mg/mL
200 mg IV Infusion
Day 1 of 
each cycle, 
Q3W, 
3 cycles
Test 
Produc
t
IMP
Central
All 
participant
s
Experimenta
l
Doxorubicin
Drug
Injection, 
Solution
Variable
25 
mg/m2
Per Local 
Guidelines
Days 1 and 
15 of each 
cycle, 
Q4W, 
2 cycles
Test 
Produc
t
IMP
Local or 
Central
All 
participant
s
Experimenta
l
Vinblastine
Drug
Injection, 
Solution
Variable
6 
mg/m2
Per Local 
Guidelines
Days 1 and 
15 of each 
cycle, 
Q4W, 
2 cycles
Test 
Produc
t
IMP
Local or 
Central
All 
participant
s
Experimenta
l
Dacarbazine
Drug
Injection, 
Solution
Variable
375 
mg/m2
Per Local 
Guidelines
Days 1 and 
15 of each 
cycle, 
Q4W, 2 
cycles
Test 
Produc
t
IMP
Local or 
Central
PET3 
negative, 
or PET3 
positive 
and ≥60 
years of 
age
Experimenta
l
Doxorubicin
Drug
Injection, 
Solution
Variable
25 
mg/m2
Per Local 
Guidelines
Days 1 and 
15 of each 
cycle, 
Q4W, 
4 cycles
Test 
Produc
t
IMP
Local or 
Central
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Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulatio
n
Unit Dose 
Strength(s
)
Dosage 
Level(s
)
Route of 
Administratio
n
Regimen/
Treatment 
Period/
Vaccinatio
n Regimen
Use
IMP 
or 
NIMP
/
AxMP
Sourcin
g
PET3 
negative, 
or PET3 
positive 
and ≥60 
years of 
age
Experimenta
l
Vinblastine
Drug
Injection, 
Solution
Variable
6 
mg/m2
Per Local 
Guidelines
Days 1 and 
15 of each 
cycle, 
Q4W, 
4 cycles
Test 
Produc
t
IMP
Local or 
Central
PET3 
negative, 
or PET3 
positive 
and ≥60 
years of 
age
Experimenta
l
Dacarbazine
Drug
Injection, 
Solution
Variable
375 
mg/m2
Per Local 
Guidelines
Days 1 and 
15 of each 
cycle, 
Q4W, 
4 cycles
Test 
Produc
t
IMP
Local or 
Central
PET3 
positive 
and <60 
years of 
age
Experimenta
l
Bleomycin
Drug
Injection, 
Solution
Variable
10 
units/m
2
Per Local 
Guidelines
Day 8 of 
each cycle, 
Q3W, 
4 cycles
Test 
Produc
t
IMP
Local or 
Central
PET3 
positive 
and <60 
years of 
age
Experimenta
l
Etoposide
Drug
Injection, 
Solution
Variable
200 
mg/m2
Per Local 
Guidelines
Days 1 to 3 
of each 
cycle, 
Q3W, 
4 cycles
Test 
Produc
t
IMP
Local or 
Central
PET3 
positive 
and <60 
years of 
age
Experimenta
l
Doxorubicin
Drug
Injection, 
Solution
Variable
35 
mg/m2
Per Local 
Guidelines
Day 1 of 
each cycle, 
Q3W, 
4 cycles
Test 
Produc
t
IMP
Local or 
Central
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Arm 
Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulatio
n
Unit Dose 
Strength(s
)
Dosage 
Level(s
)
Route of 
Administratio
n
Regimen/
Treatment 
Period/
Vaccinatio
n Regimen
Use
IMP 
or 
NIMP
/
AxMP
Sourcin
g
PET3 
positive 
and <60 
years of 
age
Experimenta
l
Cyclophosphamid
e
Drug
Injection, 
Solution
Variable
1250 
mg/m2
Per Local 
Guidelines
Day 1 of 
each cycle, 
Q3W, 
4 cycles
Test 
Produc
t
IMP
Local or 
Central
PET3 
positive 
and <60 
years of 
age
Experimenta
l
Vincristine
Drug
Injection, 
Solution
Variable
1.4 
mg/m2
Per Local 
Guidelines
Day 8 of 
each cycle, 
Q3W, 
4 cycles
Test 
Produc
t
IMP
Local or 
Central
PET3 
positive 
and <60 
years of 
age
Experimenta
l
Procarbazine
Drug
Tablet
Variable
100 
mg/m2
Oral
Days 1 to 7 
of each 
cycle, 
Q3W, 
4 cycles
Test 
Produc
t
IMP
Local or 
Central
PET3 
positive 
and <60 
years of 
age
Experimenta
l
Prednisone
Drug
Tablet
Variable
40 
mg/m2
Oral
Days 1 to 
14 of each 
cycle, 
Q3W, 
4 cycles
Test 
Produc
t
IMP
Local or 
Central
All 
participant
s
Experimenta
l
Pembrolizumab
Biological/Vaccin
e
Injection, 
Solution
25 mg/mL
400 mg IV Infusion
Day 1 of 
each cycle, 
Q6W, 
4 cycles
Test 
Produc
t
IMP
Central
AVD=doxorubicin in combination with vinblastine and dacarbazine; EEA=European Economic Area; escBEACOPP=escalated bleomycin in combination with etoposide, doxorubicin, 
cyclophosphamide, vincristine, procarbazine, and prednisone; IMP=investigational medicinal product; IV=intravenous; NIMP/AxMP=noninvestigational/auxiliary medicinal product; PET=positron emission tomography; 
Q3W=every 3 weeks; Q4W=every 4 weeks; Q6W=every 6 weeks.
The classification of IMP and NIMP/AxMP in this table is based on guidance issued by the European Commission and applies to countries in the EEA. Country differences with respect to the definition/classification of IMP and 
NIMP/AxMP may exist. In these circumstances, local legislation is followed.
Note: Age is based on age at screening. Participants ≥60 years of age will continue to receive AVD in Chemotherapy Phase 2 regardless of their PET3 response, and will not receive escBEACOPP.
For vincristine, maximum dose=2 mg.
For participants with early unfavorable, nonbulky disease will receive 2 cycles of AVD if PET3-negative, or if PET3-positive and ≥60 years of age, or 2 cycles of escBEACOPP if PET3-positive and <60 years of age.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 2 will be provided centrally by the Sponsor or locally by the 
study site, subsidiary, or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the study site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number. 
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product as per local guidelines unless otherwise instructed by the 
Sponsor.
Refer to Section 8.1.8 for details regarding administration of the study intervention.
6.1.1
Treatment
The treatment consists of 7 cycles of pembrolizumab and 4 or 6 cycles of chemotherapy 
(AVD or escBEACOPP). Note: The number of treatments is calculated starting with the first 
dose.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
Details on preparation and administration of pembrolizumab are provided in the Pharmacy 
Manual. Doxorubicin, vinblastine, dacarbazine, bleomycin, etoposide, cyclophosphamide, 
vincristine, procarbazine, and prednisone will be prepared and administered as per the 
approved product label(s) or institutional guidelines.
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 
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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. Intervention allocation
will occur centrally using an IWRS system.
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. A delay of more than 7 days in pembrolizumab 
administration is to be discussed with the Sponsor.
Refer to Section 6.6.2 for dose modification of AVD and escBEACOPP.
When participants are dosed at the site, they will receive study intervention directly from the 
investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents and recorded in the CRF. 
The dose of study intervention and study participant ID will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention.
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6.4.1
Procarbazine and Prednisone Compliance
When participants receiving escBEACOPP self-administer procarbazine and prednisone at 
home, compliance with study intervention will be assessed at applicable visits. Compliance 
will be assessed by direct questioning, counting returned tablets/capsules, etc, during the site 
visits and documented in the source documents and CRF. Deviation(s) from the prescribed 
dosage regimen should be recorded in the CRF.
A record of the number of procarbazine and prednisone tablets/capsules dispensed to and 
taken by each participant must be maintained and reconciled with study intervention and 
compliance records. Intervention start and stop dates, including dates for intervention delays 
and/or dose reductions will also be recorded in the CRF.
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 medications or vaccinations 
prohibited, the investigator must discuss any questions regarding this with the Sponsor’s 
Clinical Director. The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant’s primary physician. However, the decision to continue the 
participant on study intervention requires the mutual agreement of the investigator and the 
Sponsor.
6.5.1
Prohibited Concomitant Medications
Participants are prohibited from receiving the following therapies during the screening and 
intervention phases of this study (unless otherwise noted):
•
Antineoplastic systemic chemotherapy or biological therapy not specified in this protocol
•
Immunotherapy not specified in this protocol
•
Chemotherapy not specified in this protocol
•
Investigational agents other than pembrolizumab, AVD, or escBEACOPP
•
Radiation therapy
•
Live or live-attenuated vaccines within 30 days before the first dose of study intervention 
and while participating in the study. Note: Killed vaccines are allowed. Any licensed 
COVID-19 vaccine (including for Emergency Use) in a particular country is allowed in 
the study as long as they are mRNA vaccines, replication-incompetent adenoviral 
vaccines, or inactivated vaccines. These vaccines will be treated just as any other 
concomitant therapy.
•
Systemic glucocorticosteroids, except for the purposes listed in Section 6.5.1.1
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All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the eCRF including all 
prescription, OTC products, herbal supplements, and IV medications, and fluids. If changes 
occur during the study period, documentation of drug dosage, frequency, route, and date 
should also be included on the eCRF.
All concomitant medications received within 28 days prior to the first dose of study 
intervention and up to 30 days after the last dose of study intervention should be recorded. 
All concomitant medications administered during SAEs or ECIs are to be recorded. SAEs 
and ECIs are defined in Section 8.4.
6.5.1.1
Systemic Corticosteroid Use
Systemic corticosteroids are permitted in the following situations:
•
Prednisone when administered as part of the escBEACOPP regimen
•
To modulate symptoms of an AE that is suspected to have an immunologic etiology
•
As needed for the prevention of emesis
•
Premedication for IV contrast allergies
•
Short-term oral or IV use in doses >10 mg/day prednisone equivalent for chronic 
obstructive pulmonary disease exacerbations
•
For chronic systemic replacement not to exceed 10 mg/day prednisone equivalent
In addition, the following glucocorticoid use is allowed:
•
For topical use or ocular use
•
Intraarticular joint use
•
For inhalation in the management of asthma or chronic obstructive pulmonary disease
6.5.1.2
Cautions for Use of Chemotherapy
Caution should be exercised when AVD/escBEACOPP is concomitantly administered with 
sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index.
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Note: a current list of sensitive CYP3A substrates and CYP3A substrates with a narrow 
therapeutic index can be found at the following website: https://www.fda.gov/drugs/drug-
interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-
and-inducers
6.5.2
Rescue Medications and Supportive Care
Participants receiving escBEACOPP in Chemotherapy Phase 2 should be started on growth 
factor support on Day 8 of each escBEACOPP cycle and continue during the cycle until 
ANC returns to normal.
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.
Suggested supportive care measures for the management of AEs with potential immunologic
etiology are outlined along with the dose modification guidelines in Section 6.6.
6.6
Dose Modification (Escalation/Titration/Other)
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)
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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T1DM or 
Hyperglycemia
New onset 
T1DM or 
Grade 3 or 4 
hyperglycemia 
associated 
with evidence 
of -cell 
failure
Withholdd
Initiate insulin 
replacement 
therapy for 
participants with 
T1DM
Administer 
antihyperglycemic 
in participants 
with 
hyperglycemia
Monitor participants for 
hyperglycemia or other 
signs and symptoms of 
diabetes
Hypophysitis
Grade 2
Withhold
Administer 
corticosteroids 
and initiate 
hormonal 
replacements as 
clinically 
indicated
Monitor for signs and 
symptoms of 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinued
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 
discontinued
Hypothyroidism
Grade 2
Continue
Initiate thyroid 
replacement 
hormones (eg, 
levothyroxine or 
liothyronine) per 
standard of care
Monitor for signs and 
symptoms of thyroid 
disorders
Grade 3 or 4
Withhold or 
permanently 
discontinued
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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
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
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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.
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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 h
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (eg, from 
100 mL/hr to 50 mL/hr). Otherwise dosing will 
be held until symptoms resolve and the 
participant should be premedicated for the next 
scheduled dose.
Participants who develop Grade 2 toxicity 
despite adequate premedication should be 
permanently discontinued from further study 
drug treatment.
Participant may be 
premedicated 1.5 h 
(± 30 minutes) prior to 
infusion of pembrolizumab 
with:
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic).
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms following 
initial improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs as medically 
indicated until the participant is deemed 
medically stable in the opinion of the 
investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, epinephrine should be 
used immediately.
Participant is permanently discontinued from 
further study drug treatment.
No subsequent dosing
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NCI CTCAE Grade
Treatment
Premedication at 
Subsequent Dosing
CTCAE = Common Terminology Criteria for Adverse Event; IV = intravenous; NCI = National Cancer Institute; 
NSAID = nonsteroidal anti-inflammatory drug; po = orally.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab
Pembrolizumab Monotherapy
Pembrolizumab C2D1 and C3D1 must occur within +3 days of the scheduled dosing day 
except in case of AEs as described in Table 3 and Table 4.
Pembrolizumab Consolidation
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical or surgical events and/or unforeseen circumstances not related to study intervention. 
However, study intervention is to be restarted within 6 weeks (42 days) of the originally 
scheduled dose and within 84 days of the previously administered dose, unless otherwise 
discussed with the Sponsor. The reason for study intervention interruption is to be 
documented in the participant's study record.
6.6.2
AVD and escBEACOPP Dose Modification
Dose modifications must follow approved product labeling and institutional guidelines. No 
dose reduction or modification of AVD should be done for uncomplicated cytopenias.
6.6.3
Additional Safety Data Monitoring
Routine medical monitoring of safety data will be performed by the Sponsor on a monthly 
basis during the study. In addition, every 4 months the Sponsor’s study team will review 
cumulative Grade 3-5 TEAE data for each treatment (pembrolizumab, AVD, or 
escBEACOPP) for participants who have completed at least 1 cycle of pembrolizumab, 
1 cycle of AVD, and 1 cycle of escBEACOPP, respectively. For pembrolizumab, the 
Grade 3-5 TEAEs occurring during the monotherapy and consolidation phases will be 
pooled, and for AVD, the Grade 3-5 TEAEs occurring during Chemotherapy Phase 1 and 2 
will be pooled. The cumulative Grade 3-5 TEAE data for each treatment will be compared 
with historical control frequencies of 50% for pembrolizumab (based on the pembrolizumab 
monotherapy cumulative RSD referenced in the pembrolizumab IB), 70% for AVD (based 
on the RATHL study [Johnson, P., et al 2016]), and 85% for escBEACOPP (based on the 
RATHL study [Johnson, P., et al 2016]). If a ≥10% increase is observed in the frequency of 
Grade 3-5 TEAEs, compared with the specified historical control frequencies, enrollment 
will be paused and an internal DMC will review all available safety data.
The internal DMC is composed of members of Sponsor staff, none of whom otherwise are 
directly associated with the conduct of this study. Following internal DMC review, the study 
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may be discontinued if the totality of the data does not support a favorable risk-benefit trade-
off for this study. If the study is discontinued, participants will continue in Survival Follow-
up.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
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 8.11.3 unless the participant has 
withdrawn from the study Section 7.2.
Participants may discontinue study intervention at any time for any reason or be discontinued 
from the study intervention at the discretion of the investigator should any untoward effect 
occur. In addition, a participant may be discontinued from study intervention by the 
investigator or the Sponsor if study intervention is inappropriate, the study plan is violated, or 
for administrative and/or other safety reasons.
A participant must be discontinued from study intervention, but continue to be monitored in 
the study for any of the following reasons:
•
The participant or participant’s legally acceptable representative requests to discontinue 
study intervention.
•
Any prolonged interruption of study intervention beyond the permitted periods, for irAE 
management or other allowed dose interruptions, as noted in Section 6.6.1, require 
Sponsor consultation prior to restarting treatment. If treatment will not be restarted, the 
participant will continue to be monitored in the study and the reason for discontinuation 
of study intervention will be recorded in the medical record.
•
The participant has a medical condition or personal circumstance which, in the opinion of 
the investigator and/or Sponsor, placed the participant at unnecessary risk from continued 
administration of study intervention.
•
The participant has a confirmed positive serum pregnancy test.
•
Any progression or recurrence of malignancy, or any occurrence of another malignancy 
that requires active treatment.
•
Any study intervention-related toxicity specified as a reason for permanent 
discontinuation as defined in the guidelines for dose modification due to AEs in 
Section 6.6.
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.
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Discontinuation from study intervention is “permanent.” Once a participant is discontinued 
from study intervention, they shall not be allowed to restart study intervention.
Note: All participants will continue on through the study and into pembrolizumab 
consolidation regardless of PET2 or PET3 (prior to chemotherapy Phase 1 and Phase 2, 
respectively) findings.
7.2
Participant Withdrawal From the Study
A participant must be withdrawn from the study if the participant or participant’s legally 
acceptable representative withdraws consent from the study.
If a participant withdraws from the study, they will no longer receive study intervention or be 
followed at scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the 
study, as well as specific details regarding withdrawal from FBR, are outlined in 
Section 8.1.9. The procedures to be performed should a participant repeatedly fail to return 
for scheduled visits and/or if the study site is unable to contact the participant are outlined in
Section 7.3.
7.3
Lost to Follow-up
If a participant fails to return to the clinic for a required study visit and/or if the site is unable 
to contact the participant, the following procedures are to be performed:
•
The site must attempt to contact the participant and reschedule the missed visit. If the 
participant is contacted, the participant should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
•
The investigator or designee must make every effort to regain contact with the participant 
at each missed visit (eg, telephone calls and/or a certified letter to the participant’s last 
known mailing address or locally equivalent methods). These contact attempts should be 
documented in the participant’s medical record.
•
Note: A participant is not considered lost to follow-up until the last scheduled visit for the 
individual participant. The missing data for the participant will be managed via the 
prespecified statistical data handling and analysis guidelines.
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8
STUDY ASSESSMENTS AND PROCEDURES
•
Study procedures and their timing are summarized in the SoA.
•
Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.
•
The investigator is responsible for ensuring that procedures are conducted by 
appropriately qualified (by education, training, and experience) staff. Delegation of 
study-site personnel responsibilities will be documented in the Investigator Trial File 
Binder (or equivalent).
•
All study-related medical decisions must be made by an investigator who is a qualified 
physician.
•
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
•
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before providing documented informed consent may be used for 
screening or baseline purposes provided the procedures meet the protocol-specified 
criteria and were performed within the time frame defined in the SoA.
•
Additional evaluations/testing may be deemed necessary by the investigator and or the 
Sponsor for reasons related to participant safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (eg, HIV, hepatitis C), and thus local regulations 
may require that additional informed consent be obtained from the participant. In these 
cases, such evaluations/testing will be performed in accordance with those regulations.
•
The maximum amount of blood collected from each participant over the duration of the 
study will not exceed the amount specified in the Laboratory Manual.
•
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples.
8.1
Administrative and General Procedures
8.1.1
Informed Consent
The investigator or medically qualified designee (consistent with local requirements) must 
obtain documented informed consent from each potential participant (or their legally 
acceptable representative) prior to participating in this clinical study or FBR. If there are 
changes to the participant’s status during the study (eg, health or age of majority 
requirements), the investigator or medically qualified designee must ensure the appropriate 
documented informed consent is in place.
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8.1.1.1
General Informed Consent
Informed consent given by the participant or their legally acceptable representative must be 
documented on a consent form. The form must include the study protocol number, study 
protocol title, dated signature, and agreement of the participant (or his/her legally acceptable 
representative) and of the person conducting the consent discussion.
A copy of the signed and dated informed consent form should be given to the participant (or 
their legally acceptable representative) before participation in the study.
The initial ICF, any subsequent revised ICF, and any written information provided to the 
participant must receive the IRB/IEC’s approval/favorable opinion in advance of use. The 
participant or his/her legally acceptable representative should be informed in a timely manner 
if new information becomes available that may be relevant to the participant’s willingness to 
continue participation in the study. The communication of this information will be provided 
and documented via a revised consent form or addendum to the original consent form that 
captures the participant’s or the participant’s legally acceptable representative’s dated 
signature.
Specifics about the study and the study population are to be included in the study informed 
consent form.
Informed consent will adhere to IRB/IEC requirements, applicable laws and regulations, and 
Sponsor requirements.
8.1.1.2
Consent and Collection of Specimens for Future Biomedical Research
The investigator or medically qualified designee will explain the FBR consent to the 
participant, or the participant’s legally acceptable representative, answer all of his/her 
questions, and obtain documented informed consent before performing any procedure related 
to FBR. A copy of the informed consent will be given to the participant before performing 
any procedure related to FBR.
8.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator, who is a qualified 
physician, to ensure that the participant qualifies for the study.
8.1.3
Participant Identification Card
All participants will be given a participant identification card identifying them as participants 
in a research study. The card will contain study-site contact information (including direct 
telephone numbers) to be used in the event of an emergency. The investigator or qualified 
designee will provide the participant with a participant identification card immediately after 
the participant provides documented informed consent. At the time of intervention allocation,
site personnel will add the treatment/randomization number to the participant identification 
card.
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The participant ID card also contains contact information for the emergency unblinding call 
center so that a health care provider can obtain information about study intervention in 
emergency situations where the investigator is not available.
8.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. 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.
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).
8.1.4.1
Classical Hodgkin Lymphoma Disease History
The investigator or qualified designee will obtain current details regarding cHL disease 
status.
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 starting the study. Treatment for cancer other than the disease under 
study will be recorded as prior medication even if taken by the participant more than 28 days 
before starting the study.
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.
8.1.5.3
Subsequent Antineoplastic Therapy Status
The investigator or qualified designee will record all new antineoplastic therapy initiated 
after the last dose of study intervention, including, but not limited to radiation therapy, 
systemic therapy, surgery, and stem cell transplant. Stem cell transplant details including date 
and type of transplant and conditioning regimen will be collected.
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 
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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 
participant will be assigned only 1 screening number. Screening numbers must not be reused 
for different participants.
Any individual who is screened multiple times will retain the original screening number 
assigned at the initial Screening Visit. Specific details on the screening/rescreening visit 
requirements are in Section 8.11.1.
8.1.7
Assignment of Treatment/Randomization Number
All eligible participants will be allocated, by nonrandom assignment, and will receive a 
treatment/allocation number. The treatment/allocation number identifies the participant for 
all procedures occurring after treatment allocation. Once a treatment/allocation number is 
assigned to a participant, it can never be reassigned to another participant.
A single participant cannot be assigned more than 1 treatment/allocation number.
8.1.8
Study Intervention Administration
Pembrolizumab will be administered by the investigator and/or study staff according to the 
specifications within the Pharmacy Manual. AVD and escBEACOPP will be administered 
per the approved product label(s) or institutional guidelines; participants will self-administer 
procarbazine and prednisone according to instructions provided by study staff. Refer to 
Appendix 7 for country-specific requirements.
After ensuring participants meet study-related inclusion/exclusion criteria, study staff will 
access IWRS to obtain treatment number.
Study intervention should begin within 3 days of intervention allocation.
Participants will be administered pembrolizumab using a 30-minute IV infusion. Sites should 
make every effort to target infusion timing to be as close to the planned infusion time 
possible. However, given the variability of infusion pumps from site to site, a window 
between -5 minutes and +10 minutes is permitted.
Note that participants with PET-positive residual mass at EOT should not receive 
radiotherapy as part of study intervention but should be transitioned to Survival Follow-up 
(see Section 8.11.4.3) before receiving nonstudy anticancer treatment for residual disease.
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8.1.8.1
Timing of Dose Administration
Study interventions will be administered after all predose procedures and assessments have 
been completed according to the SoAs (Section 1.3).
Pembrolizumab Monotherapy
Pembrolizumab will be administered on Day 1 of each 3-week (21-day) cycle for 3 cycles. 
Each cycle may be administered up to 3 days after the scheduled Day 1 of each cycle due to 
administrative reasons per the investigator’s judgment.
Chemotherapy
Following PET2, AVD will be administered on Day 1 and Day 15 of each 4-week (28-day) 
cycle for 2 cycles. Each cycle may be administered up to 3 days after the scheduled Day 1 of 
each cycle.
Participants will receive additional chemotherapy according to their PET3 response and age 
at screening.
If the participant is PET-negative at PET3, or PET-positive at PET3 and 60 years of age at 
the time of Screening, AVD will be administered on Day 1 and Day 15 of each 4-week (28-
day) cycle for 4 cycles. However, participants with early unfavorable, nonbulky disease will 
receive 2 cycles of AVD. Each cycle may be administered up to 3 days after the scheduled 
Day 1 of each cycle.
If the participant is PET-positive at PET3 and <60 years of age at the time of Screening, 
escBEACOPP will be administered as follows: doxorubicin (Day 1), cyclophosphamide 
(Day 1), etoposide (Days 1 to 3), procarbazine (Days 1 to 7), prednisone (Days 1 to 14), 
bleomycin (Day 8), and vincristine (Day 8) of each 3-week (21-day) cycle for 4 cycles. 
However, participants with early unfavorable, nonbulky disease will receive 2 cycles of 
escBEACOPP. Each cycle may be administered up to 7 days after the scheduled Day 1 of 
each cycle. The maximum dose of vincristine is 2 mg.
Pembrolizumab Consolidation
During pembrolizumab consolidation, pembrolizumab will be administered on Day 1 of each 
6-week (42-day) cycle for 4 cycles. Before starting pembrolizumab consolidation, any 
chemotherapy associated toxicity that is deemed clinically significant by the investigator 
must have resolved to ≤Grade 1 or baseline. Non-clinically significant toxicities (such as: 
alopecia, low lymphocyte count) may not need dose delays. Cycle 1 may be administered up 
to 3 days after the scheduled Day 1 and subsequent cycles may be administered up to 3 days 
before or 3 days after the scheduled Day 1.
The reason for any variability in administration outside the protocol-specified window should 
be documented in the participant’s chart and recorded on the eCRF.
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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 8.11.3.
Participants who withdraw from the study should be encouraged to complete all applicable 
activities scheduled for the EOT visit at the time of withdrawal. Any AEs that are present at 
the time of withdrawal should be followed in accordance with the safety requirements 
outlined in Section 8.4.
8.1.9.1
8.1.10
Participant Blinding/Unblinding
This is an open-label study; there is no blinding for this study. The emergency unblinding 
call center will be available so that a health care provider can obtain information about study 
intervention in emergency situations where the investigator is not available.
8.1.11
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.
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8.1.12
8.2
Efficacy Assessments
8.2.1
Tumor Imaging and Assessment of Disease
Throughout this section, the term ‘scan’ refers to any medical imaging data used to assess 
tumor burden and may include cross-sectional imaging (such as CT or MRI), medical 
photography, or other methods as specified in this protocol.
In addition to survival, efficacy will be assessed based on imaging evaluation of changes in 
tumor burden over time, until the participant is discontinued from the study or goes into 
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Survival Follow-up. Disease response assessments may use CT/MRI and/or PET imaging, 
laboratory studies, physical examination, and biopsy results when a biopsy is performed. The 
Site Imaging Manual details the scan schedule, anatomic requirements, and imaging methods 
to be used, as well as the process for scan collection and transmission to the iCRO.
The scheduled imaging time points, and the type of imaging to be performed at each 
scheduled time point, are specified in the SoA (Section 1.3). All participants require imaging 
of the neck, chest, abdomen, and pelvis at baseline and all later time points (the neck may be 
omitted after Screening if no disease is seen in the neck at that time). Anatomic imaging (for 
this protocol, this term refers to CT or MRI, although CT is preferred) should be of 
diagnostic quality and acquired with IV contrast. Metabolic imaging (whole body FDG-PET) 
should be performed with correlative anatomic imaging for attenuation correction. The Site 
Imaging Manual will provide detailed scan acquisition guidelines, and alternative methods 
for imaging if the preferred methods cannot be done due to medical contraindication or local 
practice. The same scan technique should be used in a participant throughout the study.
Other types of medical imaging (such as ultrasound) will not be included in response 
assessment.
Local assessment (investigator assessment with site radiology reading) will be used to 
determine participant eligibility and for participant management. Note: For the purposes of 
assessing tumor scans, the term “investigator” refers to the local investigator at the site 
and/or the radiological reviewer at the site or at an offsite facility. All scheduled scans for 
participants will be submitted to the iCRO. In addition, a scan that is obtained at an 
unscheduled time point, for any reason (including suspicion of progression or other clinical 
reason), should also be submitted to the iCRO if it shows disease progression, or if it is used 
to support a response assessment. All scans acquired within the protocol-specified window of 
time around a scheduled scan visit are to be classified as pertaining to that visit.
Assessment of scans (including classification of lesions before treatment and response 
determination during treatment) will be performed according to the Lugano Classification 
[Cheson, B. D., et al 2014], as detailed in Appendix 9.
8.2.1.1
Initial Tumor Scans
Anatomic and metabolic imaging (PET1) must be performed during Screening, within 
28 days before the date of the first dose of study intervention. Any imaging obtained after 
Cycle 1 Day 1 of treatment cannot be included in the screening assessment. The site study 
team must review screening images to confirm the participant has measurable FDG-avid 
disease as defined by the Lugano Classification (Appendix 9).
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 before the first dose of study intervention.
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8.2.1.2
Tumor Scans During the Study
Following Screening, disease response assessments will be performed based on the schedules 
described below. However, imaging should occur at any time when there is clinical suspicion 
of progression.
During Pembrolizumab Monotherapy: FDG-PET scan (PET2) must be performed 3 weeks 
(±3 days) after pembrolizumab Cycle 3 Day 1 and before AVD Cycle 1 Day 1. CT scans are 
not required during this phase.
During Chemotherapy: PET3 must be performed between AVD Cycle 2 Day 26 and 
Cycle 2 Day 29 and before starting additional AVD or escBEACOPP chemotherapy 
(Sections 1.3.2 and 1.3.3). CT scans are not required during this phase.
During Pembrolizumab Consolidation: Imaging should occur at any time when there is 
clinical suspicion of progression.
8.2.1.3
End-of-treatment and Follow-up Tumor Scans
End-of-Treatment: For participants who complete study intervention, EOT FDG-PET (EOT 
PET) and CT (EOT CT) scans must be performed 6 weeks (±7 days) after the 
pembrolizumab consolidation Cycle 4 Day 1 dose. For participants who discontinue before 
completing study intervention, the EOT PET and EOT CT should be performed within 
6 weeks (±7 days) after the last dose of study intervention.
If at EOT, either anatomic or metabolic imaging shows findings suspicious for residual 
disease, a biopsy may be obtained, which will contribute to the assessment of disease per 
Lugano 2014 response criteria (Appendix 9).
Efficacy Follow-up: Participants with CR at the end of study intervention, or participants 
who discontinue for reasons other than investigator discontinuation due to disease 
progression, will enter Efficacy Follow-up. The first scheduled imaging during Efficacy 
Follow-up will be performed 24 weeks (±7 days) after EOT imaging. CT scans will then be 
performed every 24 weeks (±7 days) for 2 years after EOT CT, then at investigator’s 
discretion until one of the following conditions are met:

Disease progression

Start of a new anticancer treatment

Pregnancy

Death

Withdrawal of consent

End of the study
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During Efficacy Follow-up, MRI can be considered in place of CT if MRI was performed at 
EOT for comparison. FDG-PET is only required if CT scan suggests progression or there is 
clinical suspicion of progression.
Participants without CR at the end of study intervention will progress immediately to 
Survival Follow-up, and no additional imaging will be performed after EOT imaging.
8.2.1.4
Scan Evaluation
The Lugano Classification [Cheson, B. D., et al 2014] will be used to assess response to 
treatment including best overall response and date of disease progression, and as a basis for 
all protocol guidelines related to disease status. Rules for Lugano assessment of response 
using CT and PET are outlined in Appendix 9.
8.2.1.5
Bone Marrow Biopsy/Aspirate
Bone marrow biopsy and/or aspirate should be obtained as clinically indicated during the 
study. If bone marrow biopsy is inconclusive, bone marrow aspirate may be substituted. If 
bone marrow assessment is performed at Screening, subsequent bone marrow assessments 
will be performed only in subjects who have bone marrow involvement at Screening.
Bone marrow assessments will be performed by the local laboratory according to institutional 
practice and results will be recorded in the eCRF.
8.2.2
8.3
Safety Assessments
Details regarding specific safety procedures/assessments to be performed in this study are 
provided. The total amount of blood to be drawn/collected over the course of the study, 
including approximate blood volumes drawn/collected by visit and by sample type per 
participant, can be found in the Laboratory Manual.
Planned time points for all safety assessments are provided in the SoA.
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8.3.1
Physical Examinations
8.3.1.1
Full Physical Examination
The investigator or qualified designee will perform a full physical examination during the 
Screening period (consistent with local requirements) as per institutional standard. Clinically 
significant abnormal findings during Screening should be recorded as medical history. A full 
physical examination also will be performed at the EOT visit. After the first dose of study 
intervention, new clinically significant abnormal findings should be recorded as AEs if they
fall within the safety reporting period.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.2
Directed Physical Examination
For visits that do not require a full physical examination as defined in Section 1.3, the 
investigator or qualified designee will perform a directed physical examination. During the 
treatment period, a directed physical examination will be performed within 3 days before 
dosing on Day 1 of each cycle and as clinically indicated. During Efficacy Follow-up, a 
directed physical examination will be performed every 12 weeks for 2 years after EOT 
imaging, and then at investigator’s discretion for the remainder of Efficacy Follow-up. New 
clinically significant abnormal findings should be recorded as AEs if they fall within the 
safety reporting period.
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.3.1.3
Assessment of Lymphoma B Symptoms
Lymphoma B symptoms are a set of clinical criteria assessed during diagnosis and treatment 
of cHL. Assessment of Lymphoma B symptoms should occur at Screening and as specified 
in the SoA (Section 1.3). These symptoms include the following:
•
Unintentional weight loss ≥10% within the previous 6 months.
•
Fevers of 100.5°F or 38.0°C for ≥2 weeks without evidence of infection.
•
Night sweats without evidence of infection.
8.3.2
Vital Signs
The investigator or qualified designee will assess vital signs at Screening and as specified in 
the SoA (Section 1.3). Vital signs will include height (at Screening only), weight, 
temperature, systolic and diastolic blood pressure, pulse rate, and respiratory rate.
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8.3.3
Electrocardiograms
•
Single 12-lead ECG will be obtained and reviewed by an investigator or medically 
qualified designee (consistent with local requirements) at Screening and as clinically 
indicated using an ECG machine that automatically calculates the HR and measures PR, 
QRS, QT, and QTc intervals.
•
Clinically significant abnormal findings at Screening should be recorded as medical 
history. Additional ECG(s) should be performed when clinically indicated. Clinically 
significant abnormal findings on postscreening ECGs should be recorded as AEs.
8.3.4
Echocardiography or Multigated Acquisition Scan
An ECHO or MUGA scan will be required at Screening, at the end of AVD Cycle 2 (before 
starting AVD Cycle 3 or escBEACOPP Cycle 1), and at the end of the last cycle of 
chemotherapy (before starting pembrolizumab consolidation).
The assessment method will be at the investigator’s discretion and per the local standard of 
care. Additional assessments may be performed as clinically indicated.
8.3.5
Pulmonary Function Testing
Pulmonary function testing will be performed according to institutional guidelines within 
7 days before escBEACOPP dosing on Day 1 Cycle 1 and at the end of the last cycle of 
chemotherapy (before starting pembrolizumab consolidation). Additional tests may be 
performed as clinically indicated.
Pulmonary function testing should include an assessment of FVC, forced expiratory flow 
between 25 and 75 percent of FVC (FEF25-75), forced expiratory volume in one second, and 
peak expiratory flow.
8.3.6
Clinical Safety Laboratory Assessments
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency.
•
The investigator or medically qualified designee (consistent with local requirements) 
must review the laboratory report, document this review, and record any clinically 
relevant changes occurring during the study in the AE section of the CRF. The laboratory 
reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition.
•
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
•
If laboratory values from nonprotocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in study participant management or are 
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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.
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood to be drawn/collected over the course of the 
study, including approximate blood volumes drawn/collected by visit and by sample type per 
participant can be found in the Laboratory Manual. Refer to the SoA (Section 1.3) for the 
timing of laboratory assessments.
8.3.6.1
Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis)
Details regarding specific laboratory procedures/assessments to be performed in this study 
are provided below. The total amount of blood/tissue to be drawn/collected over the course 
of the study (from prestudy to poststudy visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per participant can be found in the Laboratory 
Manual. Refer to the Study Flow Chart (Section 1.3) for the timing of laboratory 
assessments.
Laboratory tests for hematology, chemistry, and urinalysis are specified in Appendix 2.
The laboratory criteria in Table 1 must be met before dosing on Day 1 of every cycle (the 
requirement for ANC is ≥1000/µL from pembrolizumab Cycle 2 onwards), with the 
exception of hematological parameters for AVD cycles.
8.3.7
Pregnancy Testing
• Pregnancy testing:
- Pregnancy testing requirements for study inclusion are described in Section 5.1.
- Pregnancy testing (urine or serum) should be conducted at every protocol treatment 
cycle as per SoA.
- Pregnancy testing (urine or serum) should be conducted for the time required to 
eliminate systemic exposure after the last dose of each study intervention and should 
correspond with the time frame for the participant’s contraception, as noted in Section 
5.1. The length of time required to continue pregnancy testing for each study 
intervention is:
◦
Pembrolizumab: 120 days
◦
Chemotherapy: 180 days
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- 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.
- In case of suspected false positive pregnancy test in participants with fertility 
preservation, consult Sponsor.
8.3.8
International Prognostic Score
The investigator or qualified designee will assess IPS (see Appendix 10) at Screening as 
specified in the SoA (Section 1.3).
8.3.9
Unfavorable Risk Factors
For participants with early stage disease (Ann Arbor Stage I or II), the investigator or 
qualified designee will assess unfavorable risk factors according to NCCN guidelines (see 
Appendix 11) at Screening as specified in the SoA (Section 1.3).
8.3.10
Performance Assessments: 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 status (see Appendix 12) at 
Screening (within 7 days before the Cycle 1 Day 1 dose of pembrolizumab), before dosing on 
Day 1 of each subsequent cycle, and at EOT as specified in the SoA (Section 1.3).
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 participant provides 
documented informed consent, but before intervention allocation, must be reported by the 
investigator if the participant is receiving placebo run-in or other run-in treatment, if the 
event cause the participant to be excluded from the study, or is the result of a protocol-
specified intervention, including, but not limited to washout or discontinuation of usual 
therapy, diet, or a procedure.
•
All AEs from the time of intervention allocation through 30 days after cessation of study 
intervention must be reported by the investigator.
•
All AEs meeting serious criteria, from the time of intervention allocation through 90 days 
after cessation of study intervention or 30 days after cessation of study intervention if the 
participant initiates new anticancer therapy, whichever is earlier, must be reported by the 
investigator.
•
All pregnancies and exposure during breastfeeding, from the time of intervention 
allocation through the time required to eliminate systemic exposure after cessation of 
study intervention as described in Sections 5.1 and 8.3.7, or 30 days after cessation of 
study intervention if the participant initiates new anticancer therapy must be reported by 
the investigator.
•
Additionally, any SAE brought to the attention of an investigator at any time outside the 
time specified above must be reported immediately to the Sponsor if the event is 
considered related to study intervention.
Investigators are not obligated to actively seek AEs or SAEs or other reportable safety events 
in former study participants. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
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.
Exception: A positive pregnancy test at the time of initial screening is not a reportable event 
unless the participant has received study intervention.
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Table 5
Reporting Periods and Time Frames for Adverse Events and Other Reportable 
Safety Events
Type of Event
Reporting Time 
Period:
Consent to 
Randomization/ 
Allocation
Reporting Time 
Period:
Randomization/ 
Allocation 
through Protocol-
specified Follow-
up Period
Reporting Time Period:
After the Protocol-
specified Follow-up 
Period
Time Frame to 
Report Event 
and Follow-up 
Information to 
Sponsor:
NSAE
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Not required
Per data entry 
guidelines
SAE including Cancer 
and Overdose
Report if:
- due to protocol-
specified 
intervention
- causes exclusion
- participant is 
receiving placebo 
run-in or other run-
in treatment
Report all
Report if:
- drug/vaccine related.
(Follow ongoing to 
outcome)
Within 24 hours 
of learning of 
event
Pregnancy/
Lactation Exposure
Report if:
- participant has 
been exposed to 
any protocol-
specified 
intervention (eg, 
procedure, washout 
or run-in treatment 
including placebo 
run-in)
Exception: A 
positive pregnancy 
test at the time of 
initial screening is 
not a reportable 
event.
Report all
Previously reported –
Follow to 
completion/termination; 
report outcome
Within 24 hours 
of learning of 
event
ECI (require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- potential DILI
- require regulatory 
reporting
Not required
Within 24 hours 
of learning of 
event
ECI (do not require 
regulatory reporting)
Report if:
- due to 
intervention
- causes exclusion
Report
- non-DILI ECIs 
and those not 
requiring 
regulatory 
reporting
Not required
Within 5 calendar 
days of learning 
of event
DILI=drug-induced liver injury; ECI=event of clinical interest; NSAE=nonserious adverse event; SAE=serious adverse 
event.
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8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs and other 
reportable safety events. Open-ended and nonleading verbal questioning of the participant is 
the preferred method to inquire about AE occurrence.
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts. All AEs, SAEs, and other reportable safety events, 
including pregnancy and exposure during breastfeeding, ECIs, cancer, and overdose will be 
followed until resolution, stabilization, until the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). In addition, the investigator will 
make every attempt to follow all nonserious AEs that occur in 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), or a pregnancy that occurs during the study in a 
nonparticipant whose sexual partner is a participant capable of producing ejaculate is 
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 that the fetus will be 
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born with severe abnormalities/congenital anomalies that leads to an elective termination of a 
pregnancy will be reported as an SAE for the fetus.
Pregnancy outcomes of ectopic pregnancy, spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage, and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying as 
AEs or SAEs
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 8.4.1.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will ensure that unblinded aggregated efficacy endpoint events and safety data 
are monitored to safeguard the participants in the study.
8.4.7
Events of Clinical Interest
Selected serious and nonserious AEs are also known as ECIs and must be reported to the 
Sponsor.
Events of clinical interest for this study include:
1. An overdose of Sponsor's product, as defined in Section 8.5.
2. Potential DILI events defined as an elevated AST or ALT laboratory value that is greater 
than or equal to 3× the ULN and an elevated total bilirubin laboratory value that is greater 
than or equal to 2× the ULN and, at the same time, an alkaline phosphatase laboratory 
value that is less than 2× the ULN, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note: These criteria are based on available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an 
additional evaluation for an underlying etiology. The study-site guidance for assessment 
and follow up of these criteria can be found in the Investigator Study File Binder (or 
equivalent).
In the event a participant receives an allogeneic SCT within 24 months of the last dose of 
pembrolizumab, the following events will be collected as ECIs through 18 months from the 
date of allogeneic SCT: GVHD, febrile syndrome treated with steroids, pulmonary 
complications, hepatic veno-occlusive disease and/or sinusoidal syndrome, immune-
mediated AEs, critical illness, and transplant-related mortality. Additional medically 
important AEs may be submitted at the investigator’s discretion.
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Details to be collected and suggested events to be reported will be provided in the Collection 
of Stem Cell Transplant (SCT) Details and Post-Allogeneic SCT Events of Clinical Interest 
(ECI) Guidance Document. Post allogenic SCT ECIs that occur after the normal Safety 
Follow-up period must be assessed for seriousness and causality and be reported to the 
Sponsor as follows: within 24 hours if serious regardless of causality or if nonserious and 
considered to be drug-related; and within 5 calendar days if nonserious and not considered to 
be drug-related.
If available and relevant to an event post allogeneic SCT, concomitant medications and/or 
laboratory results may be reported.
8.5
Treatment of Overdose
8.5.1
Pembrolizumab
For this study, an overdose of pembrolizumab will be defined as any dose of 1000 mg or 
greater.
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.
8.5.2
AVD and escBEACOPP
AVD contains the following medications: doxorubicin, vinblastine, and dacarbazine.
escBEACOPP contains the following medications: doxorubicin, cyclophosphamide, 
etoposide, procarbazine, prednisone, bleomycin, and vincristine.
In this study, an overdose of any of these agents is any dose exceeding the prescribed dose.
In the event of overdose, the administration of the agent should be discontinued, and the
participant should be observed closely for signs of toxicity. Appropriate supportive treatment 
should be provided if clinically indicated.
8.6
Pharmacokinetics
PK parameters will not be evaluated in this study.
8.7
Pharmacodynamics
Pharmacodynamic parameters will not be evaluated in this study.
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8.8
8.10
Medical Resource Utilization and Health Economics
All-cause hospitalizations and emergency room visits must be reported in the eCRF, from the 
time of treatment allocation through 90 days after cessation of study intervention, or 30 days 
after cessation of study intervention, if the participant initiates new anticancer therapy, 
whichever is earlier.
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8.11
Visit Requirements
Visit requirements are outlined in Section 1.3. Specific procedure-related details are provided 
in Section 8.
8.11.1
Screening
Documented informed consent must be provided before performing any protocol-specific 
procedure. Results of a test performed before the participant signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the 
specified time frame.
Screening procedures are to be completed within 28 days before the first dose of study 
intervention.
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.
8.11.2
Treatment Period
Visit requirements are outlined in the SoA (Section 1.3). Specific procedure-related details 
are provided in Section 8.
8.11.3
Discontinued Participants Continuing to be Monitored in the Study
Discontinuation of treatment does not represent withdrawal from the study.
Participants who discontinue study intervention for reasons other than investigator 
discontinuation due to disease progression will have a Safety Follow-up Visit by phone and 
an in-clinic EOT Visit and then proceed to Efficacy Follow-up as described in Section 
8.11.4.2.
Participants who discontinue study intervention due to unacceptable AE(s), intercurrent 
illness that prevents further administration of treatment, investigator’s decision to discontinue 
the participant, administrative reasons requiring cessation of treatment, or after the 
participant has received the maximum duration of treatment specified by the protocol will 
have a Safety Follow-up Visit by phone and an in-clinic EOT Visit and then proceed to 
Survival Follow-up as described in Section 8.11.4.3. The Safety Follow-up Visit and the 
EOT Visit should occur before the start of new anticancer therapy.
For participants who discontinue study intervention early, the EOT Visit should occur within 
6 weeks (±7 days) after the last dose of study intervention. If the EOT Visit occurs 30 days 
from the last dose of study intervention, at the time of the mandatory Safety Follow-up Visit, 
the EOT Visit procedures and assessments should be performed. Additional details regarding 
participants treatment discontinuation can be found in Section 7.1.
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8.11.4
Posttreatment Visit
8.11.4.1
Safety Follow-up Visit
The mandatory Safety Follow-up Visit should be conducted 30 days (+7 days) after the last 
dose of study intervention or before the initiation of a new anticancer treatment, whichever 
comes first. This visit will be conducted by telephone call.
8.11.4.2
Efficacy Follow-up Visits
Participants who complete the protocol-required cycles of study intervention with CR or who 
discontinue study intervention for a reason other than investigator discontinuation due to 
disease progression will begin Efficacy Follow-up. Visits will occur every 12 weeks 
(±7 days) with imaging assessments for efficacy to be performed every 24 weeks (±7 days)
for 2 years after EOT imaging, then at investigator’s discretion until end of study, or until the 
start of new anticancer therapy, disease progression, pregnancy, withdrawal of consent,
death, or loss to follow-up, whichever occurs first (imaging as specified in the SoA 
Section 1.3.4). Information regarding poststudy anticancer treatment will be collected if new 
treatment is initiated. Participants who will not have further efficacy assessments must enter 
Survival Follow-up.
8.11.4.3
Survival Follow-up Contacts
Participant survival follow-up status will be assessed approximately every 12 weeks to assess 
for survival status until death, withdrawal of consent, or the end of the study, whichever 
occurs first.
The first survival follow-up assessment should be scheduled as described below:
1. For participants without CR at the end of study intervention, or who discontinue study 
intervention due to disease progression, and will not enter Efficacy Follow-up, the first 
survival follow-up contact will be scheduled 12 weeks after the EOT Visit and/or Safety 
Follow up Visit (whichever is last).
2. For participants who completed assessments in Efficacy Follow-up, the first survival 
follow-up contact will be scheduled 12 weeks after the last Efficacy Follow-up Visit has 
been performed.
8.11.5
Vital Status
To ensure current and complete vital status for survival data is available at the time of 
database locks, updated vital status for survival data may be requested during the study by 
the Sponsor. For example, updated vital status for survival data may be requested before but 
not limited to, an eDMC review, interim and/or final analysis. Upon Sponsor notification, all 
participants who do not/will not have a scheduled study visit or study contact during the 
Sponsor-defined time period will be contacted for their vital status for survival data 
(excluding participants that have a previously recorded death event in the collection tool).
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. If, after the
study has begun, but prior to any final database lock, changes are made to primary and/or key 
secondary hypotheses, or the statistical methods related to those hypotheses, then the 
protocol will be amended (consistent with ICH Guideline E9). 
 
9.1
Statistical Analysis Plan Summary
Study Design 
Overview
Phase 2 study of sequential pembrolizumab followed by chemotherapy in 
patients with newly diagnosed cHL (KEYNOTE-C11)
Treatment 
Assignment
This is an open-label study.
Analysis 
Populations
Efficacy: All Participants as Treated (APaT)
Safety: All Participants as Treated (APaT) 
Primary 
Endpoint(s)
CR 
Key Secondary 
Endpoint(s)
PET Negativity
 
Statistical 
Methods for 
Key Efficacy 
Analyses
The primary hypothesis will be evaluated by comparing CR rate at the 
end of study intervention to a fixed historical control rate of 
 using a 
binomial exact test. The point estimate of the CR rate will be provided, 
together with 95% CI using exact binomial method proposed by Clopper 
and Pearson (1934) [Clopper, C. J. and Pearson, E. S. 1934].
Statistical 
Methods for 
Key Safety 
Analyses
Counts and percentages of participants with AEs will be provided.
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Sample Size 
and Power 
The planned sample size is 140 participants for the primary analysis. 
9.2
Responsibility for Analyses/In-house Blinding
The statistical analysis of the data obtained from this study will be the responsibility of the 
Clinical Biostatistics department of the Sponsor.
This study is being conducted as a nonrandomized, open-label study, ie, participants, 
investigators, and Sponsor personnel will be aware of participant treatment assignments after 
each participant is enrolled and treatment is assigned.
9.3
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.
9.4
Analysis Endpoints
9.4.1
Efficacy Endpoints
Primary
•
CR: having a complete response, assessed by independent central review according to 
Lugano 2014 response criteria (Appendix 9).
Secondary
•
CR: having a complete response, assessed by investigators according to Lugano 2014 
response criteria (Appendix 9).
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•
PET negativity: a score of 1, 2, or 3 assessed by independent central review according to 
FDG-PET 5-point scale (Appendix 9).
9.4.2
Safety Endpoints
Safety and tolerability will be assessed by clinical review of all relevant parameters, 
including AEs, laboratory values, and vital signs.
9.5
9.5.1
9.5.2
9.6
Statistical Methods
9.6.1
Statistical Methods for Efficacy Analyses
This section describes the statistical methods that address the primary and secondary 
objectives. 
.
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9.6.1.1
Complete Response
The CR rate is defined as the proportion of participants who have CR at the end of study 
intervention, after the completion of pembrolizumab consolidation. An exact binomial test 
will be conducted to test the hypothesis that the CR rate is greater than the fixed control rate 
of 
 
 The point estimate of CR rate and its 95% CI will be 
provided using exact binomial method proposed by Clopper and Pearson (1934) [Clopper, C. 
J. and Pearson, E. S. 1934]. Response for the primary analysis will be determined by 
independent central review according to Lugano 2014 response criteria (Appendix 9).  
9.6.1.2
PET Negativity
The rate of PET negativity is defined as a score of 1, 2, or 3, assessed by independent central 
review according to the FDG-PET 5-point scale (Appendix 9). Descriptive statistics will be 
performed for the rate of PET negativity, (i) after 3 cycles of pembrolizumab monotherapy 
(PET2); and (ii) after 3 cycles of pembrolizumab monotherapy followed by 2 cycles of AVD 
(PET3).
9.6.1.3
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9.6.1.4
Analysis Strategy for Key Efficacy Variables
A summary of the primary analysis strategy for the key efficacy endpoints is provided in 
Table 7.
Table 7
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
CR rate per Lugano 
2014 response criteria 
by independent 
central review
Testing and estimation: 
Exact method based on 
binomial distribution
APaT
Participants with missing 
data are considered 
nonresponders
APaT=All Participants as Treated; CR=complete response; DurCR=duration of complete response.
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9.6.2
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs and laboratory parameters. The broad AE categories consisting of the percentage of 
participants with any AE, a drug-related AE, a serious AE, an AE which is both drug-related 
and serious, a Grade 3 to 5 AE, a drug-related Grade 3 to 5 AE, and who discontinued due to 
an AE will be summarized. The number and percentage of participants with increased 
laboratory toxicity grade shift from baseline will also be provided.
The safety analyses will include data after the initial PD at PET2 or PET3 timepoints if 
participants continued on to the next treatment phase as per Section 7.1 (Note).
9.6.3
Demographic and Baseline Characteristics
Each relevant demographic and baseline characteristic will be assessed by the use of tables 
and/or graphs. No statistical hypothesis tests will be performed on these characteristics. The 
number and percentage of participants screened and enrolled and the primary reasons for 
screening failure and discontinuation will be displayed. Demographic variables, baseline 
characteristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized either by descriptive statistics or categorical tables.
9.7
9.7.1
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9.7.2
9.8
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9.9
Sample Size and Power Calculations
Approximately 140 participants will be enrolled in the study. With 140 participants in the 
primary analysis population, there is 
 (1-sided nominal 2.5% 
alpha) to detect a 
or higher CR rate, compared to a fixed control rate of 
 
9.10
Subgroup Analyses
To determine whether the CR rate is consistent across various subgroups, the point estimate 
of the CR rate (with an exact 95% CI) will be provided within each category of the following 
classification variables:
If the observed numbers are too small to make a meaningful clinical interpretation, then that 
subgroup analysis will not be conducted.
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.
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9.12
Extent of Exposure
Extent of exposure for a participant is defined as the number of cycles in which the 
participant receives the study intervention. Summary statistics will be provided on the extent 
of exposure for the APaT population.
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10
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
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. Participants must meet protocol entry criteria to be enrolled in the trial.
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2. Site Selection
MSD selects investigative sites based on medical expertise, access to appropriate 
participants, adequacy of facilities and staff, previous performance in clinical 
trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess 
the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol 
and Good Clinical Practice (GCP). MSD reviews clinical data for accuracy, 
completeness, and consistency. Data are verified versus source documentation 
according to standard operating procedures. Per MSD policies and procedures, if 
potential fraud, scientific/research misconduct, privacy incidents/breaches or 
Clinical Trial-related Significant Quality Issues are reported, such matters are 
investigated. When necessary, appropriate corrective and/or preventative actions 
are defined and regulatory authorities and/or ethics review committees are 
notified.
B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary 
results of its registered trials of marketed products in which treatment is assigned, 
according to the pre-specified plans for data analysis. To the extent scientifically 
appropriate, MSD seeks to publish the results of other analyses it conducts that are 
important to patients, physicians, and payers. Some early phase or pilot trials are 
intended to be hypothesis-generating rather than hypothesis testing; in such cases, 
publication of results may not be appropriate since the trial may be underpowered and 
the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the 
International Committee of Medical Journal Editors (ICMJE). In summary, 
authorship should reflect significant contribution to the design and conduct of the 
trial, performance or interpretation of the analysis, and/or writing of the manuscript. 
All named authors must be able to defend the trial results and conclusions. MSD 
funding of a trial will be acknowledged in publications.
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 
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national regulations. Changes to the protocol that are required urgently to eliminate 
an immediate hazard and to protect participant safety may be enacted in anticipation 
of ethics committee approval. MSD will inform regulatory authorities of such new 
measures to protect participant safety, in compliance with local and/or national 
regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is 
of primary importance. Potential participants will be informed of the risks and 
benefits of, as well as alternatives to, trial participation. At a minimum, trial designs 
will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only 
after informed consent is obtained. Participants may withdraw from an MSD trial at 
any time, without any influence on their access to, or receipt of, medical care that 
may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent 
possible, as well as all applicable data protection rights. Unless required by law, only 
the investigator, Sponsor (or individuals acting on behalf of MSD), ethics committee, 
and/or regulatory authorities will have access to confidential medical records that 
might identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed 
consent authorized by an ethics committee.
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 
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noted above, all publications resulting from MSD trials will indicate MSD as a source 
of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, 
investigator meetings, etc.) will be consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the 
trial protocol, and in signing the protocol, agree to support these ethical and scientific 
standards.
10.1.2
Financial Disclosure
Financial disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the 
Sponsor’s responsibility to determine, based on these regulations, whether a request for 
financial disclosure information is required. It is the investigator’s/subinvestigator’s 
responsibility to comply with any such request.
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements. 
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, frequently known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes. This may involve the 
transmission of information to countries that do not have laws protecting personal data.
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.
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10.1.3.1
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the IRB, IEC, or similar or expert committee, affiliated institution, and 
employees, only under an appropriate understanding of confidentiality with such board or 
committee, affiliated institution, and employees. Data generated by this study will be 
considered confidential by the investigator, except to the extent that it is included in a 
publication as provided in the Publications section of this protocol.
10.1.3.2
Confidentiality of Participant Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/IEC, or regulatory authority representatives may consult and/or copy study documents to 
verify worksheet/CRF data. By signing the consent form, the participant agrees to this 
process. If study documents will be photocopied during the process of verifying 
worksheet/CRF information, the participant will be identified by unique code only; full 
names/initials will be masked before transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all participant data used and 
disclosed in connection with this study in accordance with all applicable privacy laws, rules,
and regulations.
10.1.3.3
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC that reviews and 
approves this study. The Sponsor is also required to document that each IRB/IEC meets 
regulatory and ICH GCP requirements by requesting and maintaining records of the names 
and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
10.1.4
Committees Structure
10.1.4.1
Internal Data Monitoring Committee
To supplement the routine monitoring outlined in this protocol, a separate internal DMC will 
monitor the interim data from this study. The internal DMC is comprised of members of 
Sponsor Senior Management, none of whom are directly associated with the conduct of this 
study. The internal DMC will monitor the study progress for evidence of any adverse effects 
of study intervention. The internal DMC will also make recommendations to the Sponsor 
study team regarding steps to ensure both participant safety and the continued ethical 
integrity of the study in the internal DMC charter.
10.1.5
Publication Policy
The results of this study may be published or presented at scientific meetings. The Sponsor 
will comply with the requirements for publication of study results. In accordance with 
standard editorial and ethical practice, the Sponsor will generally support publication of 
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multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement.
If publication activity is not directed by the Sponsor, the investigator agrees to submit all 
manuscripts or abstracts to the Sponsor before submission. This allows the Sponsor to protect
proprietary information and to provide comments.
Authorship will be determined by mutual agreement and in line with ICMJE authorship 
requirements.
10.1.6
Compliance with Study Registration and Results Posting Requirements
Under the terms of the FDAAA of 2007 and the EMA clinical trial Directive 2001/20/EC, the 
Sponsor of the study is solely responsible for determining whether the study and its results 
are subject to the requirements for submission to http://www.clinicaltrials.gov, 
www.clinicaltrialsregister.eu, or other local registries. MSD, as Sponsor of this study, will 
review this protocol and submit the information necessary to fulfill these requirements. MSD 
entries are not limited to FDAAA or the EMA clinical trials directive mandated trials. 
Information posted will allow participants to identify potentially appropriate studies for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate study locations and study-site contact information.
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive, or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this study or its results to those 
registries.
10.1.7
Compliance with Law, Audit, and Debarment
By signing this protocol, the investigator agrees to conduct the study in an efficient and 
diligent manner and in conformance with this protocol, generally accepted standards of GCP 
(eg, ICH GCP: Consolidated Guideline and other generally accepted standards of GCP), and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by MSD, is provided in this appendix 
under the Code of Conduct for Clinical Trials.
The investigator agrees not to seek reimbursement from participants, their insurance 
providers, or from government programs for procedures included as part of the study 
reimbursed to the investigator by the Sponsor.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this study.
The investigator agrees to provide the Sponsor with relevant information from inspection 
observations/findings to allow the Sponsor to assist in responding to any citations resulting 
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from regulatory authority inspection and will provide the Sponsor with a copy of the 
proposed response for consultation before submission to the regulatory authority.
Persons debarred from conducting or working on clinical studies by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s studies. The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the study is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
10.1.8
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The investigator 
or qualified designee is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
Study documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the study site upon request for inspection, 
copying, review, and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities. The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor or any regulatory authorities as a result of an audit or inspection to 
cure deficiencies in the study documentation and worksheets/CRFs.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
Study monitors will perform ongoing source data review and verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that the 
study is being conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including participants’ documented informed consent, pertaining to 
the conduct of this study must be retained by the investigator for 15 years after study 
completion unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
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10.1.9
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. The investigator/institution should maintain adequate and 
accurate source documents and study records that include all pertinent observations on each 
of the site’s participants. Source documents and data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Changes to source data should be 
traceable, should not obscure the original entry, and should be explained if necessary (eg, via 
an audit trail). Source documents are filed at the investigator’s site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator/institution may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available.
10.1.10
Study and Site Closure
The Sponsor or its designee may stop the study or study-site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP.
In the event the Sponsor prematurely terminates a particular study site, the Sponsor or 
designee will promptly notify that study site’s IRB/IEC as specified by applicable regulatory 
requirement(s).
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10.2
Appendix 2: Clinical Laboratory Tests
•
The tests detailed in Table 9 will be performed by the local laboratory.
•
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol.
•
The laboratory criteria in Table 1 must be met before dosing on Day 1 of every cycle (the 
requirement for ANC is ≥1000/µL from pembrolizumab Cycle 2 onwards), with the 
exception of hematological parameters for AVD cycles.
•
Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. Refer to Appendix 7 for country 
specific requirements.
Table 9
Protocol-required Safety Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count 
WBC count with Differentiala:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
RBC Count
Hemoglobin
Hematocrit
Chemistry
BUNb
Potassium
AST/SGOT
Total bilirubin 
(and direct 
bilirubin, if total 
bilirubin is above 
the ULN)
Albumin
Bicarbonate or CO2c
Chloride
Phosphorous
Creatinine
Sodium
ALT/SGPT
Total Protein
Glucose (fasting or 
nonfasting per 
institutional standard)
Calcium
Alkaline phosphatase
Magnesiumc
Uric Acidc
LDH
CrCld
Routine Urinalysis
•
Specific gravity
•
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick]
•
Microscopic examination (if blood or protein is abnormal)
Pregnancy Testing
•
hCG pregnancy test (as needed for WOCBP)
Other Screening 
Tests
•
Coagulation: PT/INR and aPTT/PTTe
•
ESR
•
FSH (as needed to confirm postmenopausal state)
•
Serology (HIV antibody, HBsAg, and HCV antibody) is not required unless mandated by 
local health authority. 
Note: If required, testing will be conducted per local regulations and institutional standards.
Other Required Tests 
During Study
•
Thyroid function tests: total or free T3, total or free T4, and TSH
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Laboratory 
Assessments
Parameters
ALT=alanine aminotransferase; aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase; BUN=blood urea 
nitrogen; CO2=carbon dioxide; CrCl=creatinine clearance; ESR=erythrocyte sedimentation rate; FSH=follicle-stimulating hormone; 
GFR=glomerular filtration rate; HBsAg=hepatitis B surface antigen; hCG=human chorionic gonadotropin; HCV=hepatitis C virus; 
HIV=human immunodeficiency virus; INR=international normalized ratio; LDH=lactate dehydrogenase; PT=prothrombin time; 
PTT=partial thromboplastin time; RBC=red blood cell; SGOT=serum glutamic oxaloacetic transaminase; SGPT=serum glutamic 
pyruvic transaminase; T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; ULN=upper limit of normal; 
WBC=white blood cell; WOCBP=women of childbearing potential.
a
Absolute or % acceptable per institutional standard.
b
BUN is preferred, but if not available then urea may be tested. Record either BUN or urea result, but not both.
c
Only required if part of standard of care.
d
Measured or calculated CrCl (GFR can also be used in place of CrCl). Creatinine clearance should be calculated per the Cockcroft-
Gault equation (see Table 1).
e
Coagulation tests must include PT or INR plus aPTT or PTT.
Notes: For laboratory assessments with different testing options, the same test should be performed throughout the duration of the study.
The investigator (or medically qualified designee) must document their review of each 
laboratory safety report.
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10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1
Definitions of Medication Error, Misuse, and Abuse
Medication error
This is an unintended failure in the drug treatment process that leads to or has the potential to 
lead to harm to the patient.
Misuse
This refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the terms of the product information.
Abuse
This corresponds to the persistent or sporadic intentional, excessive use of a medicinal 
product for a perceived psychological or physiological reward or desired nontherapeutic 
effect.
10.3.2
Definition of AE
AE definition
•
An AE is any untoward medical occurrence in a clinical study participant, temporally 
associated with the use of study intervention, whether or not considered related to the 
study intervention.
•
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a study intervention.
•
Note: For purposes of AE definition, study intervention includes any pharmaceutical 
product, biological product, vaccine, diagnostic agent, medical device, combination 
product, or protocol-specified procedure whether investigational or marketed (including 
placebo, active comparator product, or run-in intervention), manufactured by, licensed 
by, provided by, or distributed by the Sponsor for human use in this study.
Events meeting the AE definition
•
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the investigator.
•
Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.
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•
New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.
•
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
•
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
•
For all reports of overdose (whether accidental or intentional) with an associated AE, the 
AE term should reflect the clinical symptoms or abnormal test result. An overdose 
without any associated clinical symptoms or abnormal laboratory results is reported using 
the terminology “accidental or intentional overdose without adverse effect.”
•
Any new cancer (that is not a condition of the study). Progression of the cancer under 
study is not considered a reportable event unless it results in hospitalization or death.
Events NOT meeting the AE definition
•
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
•
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
•
Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
•
Surgical procedure(s) planned prior to informed consent to treat a preexisting condition 
that has not worsened.
•
Refer to Section 8.4.6 for protocol-specific exceptions.
10.3.3
Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met.
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b. Is life-threatening
-
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
-
Hospitalization is defined as an inpatient admission, regardless of length of stay, even 
if the hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a preexisting condition that has not 
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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
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 the cancer under study) as noted in Section 8.4.1.
•
Is associated with an overdose.
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.
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•
The investigator will record all relevant AE/SAE information on the AE 
CRFs/worksheets at each examination.
•
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to the Sponsor in lieu of completion of the AE CRF page.
•
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor. In this case, all participant identifiers, with the exception of the participant 
number, will be blinded on the copies of the medical records before submission to the 
Sponsor.
•
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
Assessment of intensity/toxicity
•
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, not when it is rated as severe.
•
The investigator will make an assessment of intensity for each AE and SAE (and other 
reportable safety event) according to the NCI CTCAE, version 5.0. Any AE that changes 
CTCAE grade over the course of a given episode will have each change of grade 
recorded on the AE CRFs/worksheets.
-
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated.
-
Grade 2: Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADL.
-
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-
care ADL.
-
Grade 4: Life-threatening consequences; urgent intervention indicated.
-
Grade 5: Death related to AE.
Assessment of causality
•
Did the 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.
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•
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 IMP)?
-
Likely Cause: Is the AE not reasonably explained by another etiology such as 
underlying disease, other drug(s)/vaccine(s), or other host or environmental factors.
-
Dechallenge: Was the 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.)
-
Rechallenge: Was the participant reexposed 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; (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 REEXPOSURE 
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 
IRB/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.
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•
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.)
•
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.
•
For studies in which multiple agents are administered as part of a combination regimen, 
the investigator may attribute each AE causality to the combination regimen or to a single 
agent of the combination. In general, causality attribution should be assigned to the 
combination regimen (ie, to all agents in the regimen). However, causality attribution 
may be assigned to a single agent if in the investigator’s opinion, there is sufficient data 
to support full attribution of the AE to the single agent.
Follow-up of AE and SAE
•
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
•
New or updated information will be recorded in the CRF.
•
The investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information.
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10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the Sponsor
AE, SAE, and other reportable safety event reporting to Sponsor via electronic data 
collection tool
•
The primary mechanism for reporting to the Sponsor will be the EDC tool.
-
Electronic reporting procedures can be found in the EDC data entry guidelines (or 
equivalent).
-
If the electronic system is unavailable for more than 24 hours, then the site will use 
the paper AE Reporting form.
-
Reference Section 8.4.1 for reporting time requirements.
•
The site will enter the SAE data into the electronic system as soon as it becomes 
available.
•
After the study is completed at a given site, the EDC tool will be taken off-line to prevent 
the entry of new data or changes to existing data.
•
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the EDC tool has been taken off-line, then the site can 
report this information on a paper SAE form or by telephone (see next section).
•
Contacts for SAE reporting can be found in the Investigator Study File Binder (or 
equivalent).
SAE reporting to the Sponsor via paper CRF
•
If the EDC tool is not operational, facsimile transmission or secure email of the SAE 
paper CRF is the preferred method to transmit this information to the Sponsor.
•
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by overnight 
mail or courier service.
•
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.
•
Contacts and instructions for SAE reporting and paper reporting procedures can be found 
in the Investigator Study File Binder (or equivalent).
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10.4
Appendix 4: Medical Device and Drug–Device Combination Products: Product 
Quality Complaints/Malfunctions: Definitions, Recording, and Follow-up
Not applicable.
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10.5
Appendix 5: Contraceptive Guidance
10.5.1
Definitions
Women of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below):
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
•
Premenarchal
•
Premenopausal female with 1 of the following:
- Documented hysterectomy
- Documented bilateral salpingectomy
- Documented bilateral oophorectomy
For individuals with permanent infertility due to an alternate medical cause other than the 
above (eg, Mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determining study entry.
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview.
•
Postmenopausal female
- A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
◦
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with two FSH 
measurements in the postmenopausal range is required.
- Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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10.5.2
Contraceptive Requirements
Contraceptives allowed during the study includea:
Highly Effective Contraceptive Methods That Have Low User Dependency
Failure rate of <1% per year when used consistently and correctly.
•
Progestogen-only subdermal contraceptive implantb,c
•
IUSc,d
•
Non-hormonal IUD
•
Bilateral tubal occlusion
•
Azoospermic partner (vasectomized or secondary to medical cause)
This is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used. A spermatogenesis cycle is approximately 90 days.
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of 
the participant’s medical records, medical examination, or medical history interview.
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    If locally required, in accordance with CTFG guidelines, acceptable contraceptive implants are limited to 
those which inhibit ovulation.
c    Male condoms must be used in addition to female participant hormonal contraception.
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
1. Definitions
a.
Biomarker: A biological molecule found in blood, other body fluids, or tissues that is 
a sign of a normal or abnormal process or of a condition or disease. A biomarker may 
be used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics 
as related to drug/vaccine response.2
c.
Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence 
of variations in DNA sequence on drug/vaccine response.2
d. DNA: Deoxyribonucleic acid.
e.
RNA: Ribonucleic acid.
2. Scope of Future Biomedical Research3, 4
The specimens consented and/or collected in this study as outlined in Section 8.8 will be 
used in various experiments to understand:
-
The biology of how drugs/vaccines work
-
Biomarkers responsible for how a drug/vaccine enters and is removed by the body
-
Other pathways with which drugs/vaccines may interact
-
The biology of disease
The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease, and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need. All specimens will be used by the Sponsor or those working for or 
with the Sponsor.
3. Summary of Procedures for Future Biomedical Research3, 4
a.
Participants for Enrollment
All participants enrolled in the clinical study will be considered for enrollment in 
future biomedical research.
b. Informed Consent
Informed consent for specimens (ie, DNA, RNA, protein, etc) will be obtained during 
screening for protocol enrollment from all participants or legal guardians, at a study 
visit by the investigator or his or her designate. Informed consent for future 
biomedical research should be presented to the participants on the visit designated in 
the SoA. If delayed, present consent at next possible Participant Visit. Consent forms 
signed by the participant will be kept at the clinical study site under secure storage for 
regulatory reasons.
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A template of each study site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of participant consent for future biomedical research will be captured 
in the eCRFs. Any specimens for which such an informed consent cannot be verified 
will be destroyed.
d. Future Biomedical Research Specimen(s)
Collection of specimens for future biomedical research will be performed as outlined 
in the SoA. In general, if additional blood specimens are being collected for future 
biomedical research, these will usually be obtained at a time when the participant is 
having blood drawn for other study purposes.
4. Confidential Participant Information for Future Biomedical Research3, 4
In order to optimize the research that can be conducted with future biomedical research 
specimens, it is critical to link participants’ clinical information with future test results. In 
fact, little or no research can be conducted without connecting the clinical study data to 
the specimen. The clinical data allow specific analyses to be conducted. Knowing 
participant characteristics like sex, age, medical history, and intervention outcomes is
critical to understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for future 
biomedical research, the Sponsor has developed secure policies and procedures. All 
specimens will be single coded per ICH E15 guidelines as described below.
At the clinical study site, unique codes will be placed on the future biomedical research 
specimens. This code is a random number that does not contain any personally 
identifying information embedded within it. The link (or key) between participant 
identifiers and this unique code will be held at the study site. No personal identifiers will 
appear on the specimen tube.
5. Biorepository Specimen Usage3, 4
Specimens obtained for the Sponsor will be used for analyses using good scientific 
practices. Analyses using the future biomedical research specimens may be performed by 
the Sponsor, or an additional third party (eg, a university investigator) designated by the 
Sponsor. The investigator conducting the analysis will follow the Sponsor’s privacy and 
confidentiality requirements. Any contracted third-party analyses will conform to the 
specific scope of analysis outlined in future biomedical research protocol and consent. 
Future biomedical research specimens remaining with the third party after specific 
analysis is performed will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research3, 4
Participants may withdraw their consent for FBR and ask that their biospecimens not be 
used for FBR. Participants may withdraw consent at any time by contacting the study 
investigator. If medical records for the study are still available, the investigator will 
contact the Sponsor using the designated mailbox 
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(clinical.specimen.management@MSD.com). Subsequently, the participant's specimens 
will be flagged in the biorepository and restricted to study use only. If specimens were 
collected from study participants specifically for FBR, these specimens will be removed 
from the biorepository and destroyed. Documentation will be sent to the investigator 
confirming withdrawal and/or destruction, if applicable. It is the responsibility of the 
investigator to inform the participant of completion of the withdrawal and/or destruction, 
if applicable. Any analyses in progress at the time of request for withdrawal/destruction 
or already performed before the request being received by the Sponsor will continue to be 
used as part of the overall research study data and results. No new analyses would be 
generated after the request is received.
If the medical records for the study are no longer available (eg, if the investigator is no 
longer required by regulatory authorities to retain the study records) or the specimens 
have been completely anonymized, there will no longer be a link between the 
participant’s personal information and their specimens. In this situation, the request for 
withdrawal of consent and/or destruction cannot be processed.
7. Retention of Specimens3, 4
Future biomedical research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the study. Specimens may be stored for longer 
if a regulatory or governmental authority has active questions that are being answered. In 
this special circumstance, specimens will be stored until these questions have been 
adequately addressed.
Specimens from the study site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not used in a particular 
study, the study site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility, which 
operates to assure the integrity of the specimens. Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security3, 4
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated study administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Participants3, 4
No information obtained from exploratory laboratory studies will be reported to the 
participant, family, or physicians. Principle reasons not to inform or return results to the 
participant include lack of relevance to participant health, limitations of predictive 
capability, and concerns regarding misinterpretation.
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If important research findings are discovered, the Sponsor may publish results, present 
results in national meetings, and make results accessible on a public website in order to 
rapidly report this information to doctors and participants. Participants will not be 
identified by name in any published reports about this study or in any other scientific 
publication or presentation.
10. Future Biomedical Research Study Population3, 4
Every effort will be made to recruit all participants diagnosed and treated on Sponsor 
clinical studies for future biomedical research.
11. Risks Versus Benefits of Future Biomedical Research3, 4
For future biomedical research, risks to the participant have been minimized and are 
described in the future biomedical research informed consent.
The Sponsor has developed strict security, policies, and procedures to address participant 
data privacy concerns. Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality. In this highly unlikely situation, there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be emailed directly to 
clinical.specimen.management@MSD.com.
13. References
1. National Cancer Institute [Internet]: Available from 
https://www.cancer.gov/publications/dictionaries/cancer-terms?cdrid=45618
2. International Council on Harmonisation [Internet]: E15: Definitions for Genomic 
Biomarkers, Pharmacogenomics, Pharmacogenetics, Genomic Data and Sample 
Coding Categories. Available from 
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/definitions-
for-genomic-biomarkers-pharmacogenomics-pharmacogenetics-genomic-data-and-
sample-cod.html
3. Industry Pharmacogenomics Working Group [Internet]: Understanding the Intent, 
Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff. Available at http://i-pwg.org/
4. Industry Pharmacogenomics Working Group [Internet]: Pharmacogenomics 
Informational Brochure for IRBs/IECs and Investigational Site Staff. Available at 
http://i-pwg.org/
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10.7
Appendix 7: Country-specific Requirements
10.7.1
France-specific Requirements
Section 5.1 Inclusion Criteria
Criterion #5
Male Participants
The length of time required to continue contraception after the last dose of each study 
intervention is as follows:
•
Pembrolizumab: no contraception requirement
•
Cyclophosphamide: 9 months
•
Other chemotherapy: 90 days
Criterion #6
Female Participants
The length of time required to continue contraception after the last dose of each study 
intervention is as follows:
•
Pembrolizumab: 120 days
•
Cyclophosphamide: 12 months
•
Other chemotherapy: 180 days
Criterion #9
Participants will be included according to the renal function requirement below:
Renal
Creatinine AND
Measured or calculatedb creatinine clearance (GFR can 
also be used in place of creatinine or CrCl)
≤1.5 × ULN AND
≥30 mL/min for participant with creatinine levels 
>1.5 × institutional ULN
b
Creatinine clearance (CrCl) should be calculated per institutional standard.
Section 8.1.8 Study Intervention Administration
Investigators should refer to http://base-donnees-publique.medicaments.gouv.fr for updated
Summary of Product Characteristics of the marketing authorization of commercially
available products used during the study for participant management, particularly regarding
safety monitoring, product contraindications, and precautions.
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Section 10.5.2 Contraception Requirements
List of countries that follow CTFG guidelines (including France): 
https://www.hma.eu/nationalcontacts_hum.html
Refer to Appendix 7 for country-specific requirements
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10.8
Appendix 8: Description of the iRECIST Process for Assessment of Disease 
Progression
Not applicable.
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10.9
Appendix 9: Application of the Lugano Classification for Treatment Response 
Assessment
10.9.1
Overview
NOTE: This Lugano appendix defines general rules for the Lugano criteria. Not all 
requirements will apply to this study. Refer to relevant protocol sections for trial specifics.
This appendix describes the process for assessing treatment response according to the 
Lugano Classification [Cheson, B. D., et al 2014] (“Lugano” from now on) for malignant 
lymphoma. This assessment includes anatomic imaging with CT or MRI (size assessments of 
lymph nodes, extranodal lesions, spleen, and liver), metabolic imaging (whole body 
assessment with FDG-PET), and clinical findings (physical examination and biopsy results), 
when these are available and appropriate.
Anatomic imaging may include CT, MRI or some combination of the two, with details 
specified in the Site Imaging Manual. CT is the most common modality used, and for the 
purposes of this document the term “CT” will be used to represent all anatomic imaging, no 
matter which imaging modality is used.
Before treatment (“baseline”), on CT all focal lesions (nodal and extranodal) will be 
classified as “target” (selected for quantitative assessment) and “non-target” (selected for 
qualitative assessment). The spleen will be assessed quantitatively (by measuring the vertical 
length), and the liver will be assessed qualitatively. The FDG-PET will be assessed using the 
5-point scale (5PS, a method similar to the older Deauville criteria [Barrington, S. F., et al 
2014]). If biopsy is performed, or if there are any physical examination findings that cannot 
be evaluated by imaging, these should be documented.
After therapy has begun, response assessment will include anatomic response based on CT 
(when a CT is available), which includes target, non-target, and new focal lesions, as well as 
spleen and liver size assessment. Metabolic response, when an FDG-PET is available, will be 
based on the 5PS along with qualitative assessment of changes in FDG uptake from 
preceding timepoints. Anatomic response, metabolic response, and clinical information will 
be combined to produce the overall response for each timepoint. The criteria are summarized 
in the tables below, and detailed in the following sections.
10.9.2
Lugano Summary Table
The following tables summarize the assessments based on both CT and PET, as described in 
the summary table in the original publication [Cheson, B. D., et al 2014]. For details about 
implementation, please see the sections following the tables.
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Complete Response (CR)
CR
PET-Based Response –
CMR
CT/MRI-Based Response –
CR
Target lesions
Score 1, 2, or 3 with or 
without a residual mass 
Target nodes/nodal masses 
regress to <1.5 cm in LDi; no 
extranodal sites of disease
remain
Non-target lesions
Not applicable
Absent
Organ enlargement
Not applicable
Regress to normal
New lesions
None
None
Bone marrow
No evidence of FDG-avid 
disease in marrow
Normal by morphology; if 
indeterminate, negative by 
immunohistochemistry
CMR=complete metabolic response; CR=complete response; CT=computed tomography; 
FDG=2-fluorodeoxyglucose; LDi=longest diameter; MRI=magnetic resonance imaging; PET=positron 
emission tomography. 
Partial Response (PR)
PR
PET-Based Response – PMR
CT/MRI-Based Response –
PR
Target lesions
Score 4 or 5 without new lesions
Reduced uptake compared to 
baseline 
≥50% decrease from 
baseline in SPD of target 
lymph nodes and extranodal 
sites (up to 6)
Non-target lesions
Not applicable
Anything other than 
progression 
Organ enlargement
Not applicable
Spleen must have regressed 
by ≥50% in excess length 
New lesions
None
None
Bone marrow
Residual uptake higher than uptake 
in normal marrow but reduced 
compared to baseline.
If there are persistent focal changes 
in the marrow in the context of a 
nodal response and without recent 
growth factor use, perform biopsy, or 
consider MRI, or an interval scan.
Not applicable 
CT=computed tomography; MRI=magnetic resonance imaging; PET=positron emission tomography
PMR=partial metabolic response; PR=partial response; SPD=sum of products of diameters.
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Stable Disease (SD)
SD
PET- Based Response – SMD
CT/MRI-Based Response 
– SD
Target lesions
Score 4 or 5 (without new lesions)
No significant change in FDG 
uptake from baseline or nadir 
<50% decrease from 
baseline in SPD of target 
lesions.
No lesion shows progression
Non-target lesions
Not applicable
No increase consistent with 
progression 
Organ enlargement
Not applicable
No increase consistent with 
progression 
New lesions
None
None
Bone marrow
No change from baseline 
Not applicable 
CT=computed tomography; FDG=2-fluorodeoxyglucose; MRI=magnetic resonance imaging; PET=positron 
emission tomography; SD=stable disease; SMD=stable metabolic disease; SPD=sum of products of 
diameters.
Progressive Disease (PD)
PD
PET-Based Response – PMD
CT/MRI-Based Response –
PD
Target lesions
Score 4 or 5 with an increase in 
intensity of uptake compared to 
nadir
Growth of any target lesion:
Increase ≥50% from nadir 
PPD and
Increase in LDi or SDi from 
nadir of:
≥0.5 cm for lesions <2 cm
≥1.0 cm for lesions ≥2 cm
and
Current LDi >1.5 cm
Non-target lesions 
Not applicable
Clear progression of pre-
existing non-target lesions 
New lesions
New FDG-avid foci consistent 
with lymphoma rather than 
another cause (eg, infection, 
inflammation).
If uncertain regarding cause of 
new lesions, biopsy or interval 
scan may be considered.
Regrowth of previously 
resolved lesions
A new node >1.5 cm in LDi
A new extranodal site of any 
size, as long as its presence is 
unequivocal and attributable to 
lymphoma 
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PD
PET-Based Response – PMD
CT/MRI-Based Response –
PD
Organ enlargement
Not applicable
When splenomegaly was 
already present, the excess 
length must increase by ≥50% 
(≥1 cm absolute increase) 
from baseline.
If no prior splenomegaly, or 
prior splenomegaly had 
resolved, spleen length must 
increase by ≥2 cm to >13 cm.
Bone marrow
New or recurrent FDG-avid foci, 
confirmed by biopsy 
New or recurrent involvement 
CT=computed tomography; FDG=2-fluorodeoxyglucose; LDi=longest diameter; MRI=magnetic resonance 
imaging; PET=positron emission tomography; PD=progressive disease; PMD=progressive metabolic
disease; PPD=product of perpendicular diameters; SDi=short axis diameter.
10.9.3
Anatomic Disease Assessment
Anatomic assessment specifically refers to the size of focal lesions or organs, assessed using 
computed tomography or magnetic resonance imaging. As stated previously, for simplicity 
the term “CT” will be used to represent all anatomic imaging.
10.9.3.1
Screening (Baseline) Assessment
Documentation of focal lesions
All focal lesions caused by lymphoma are identified at screening and classified as 
measurable or non-measurable. Up to 6 of the measurable lesions are selected to serve as 
“target” lesions, which are then followed quantitatively throughout the trial. All other focal 
lesions are documented as “non-target” lesions and evaluated qualitatively thereafter.
Measurable and non-measurable lesions
Malignant lymph nodes (nodal lesions) are considered measurable if they are consistent with 
lymphoma, clearly and reproducibly measurable in 2 dimensions on an axial slice, and 
measure >1.5 cm in LDi when assessed by CT/MRI scan, irrespective of scanner type and 
slice thickness/interval. Extranodal lesions are considered measurable if they are consistent 
with lymphoma, clearly and reproducibly measurable in 2 dimensions on an axial slice and 
are ≥1.0 cm in both LDi and SDi when assessed by CT/MRI scan, regardless of slice 
thickness.
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Lesions considered non-measurable include:
•
Lymph nodes and nodal masses that are PET-positive and considered consistent with 
lymphoma, but that do not meet the size and reproducibility requirements to be 
considered measurable, and lesions visible on PET but not CT
•
PET-negative lesions which meet the size criteria for measurability, and are considered 
consistent with lymphoma
•
Uni-dimensionally measurable lesions (clearly measurable in only one dimension)
•
Extranodal lesions which do not meet the requirements for measurability, but are 
considered to be clearly due to lymphoma
•
Truly non-measurable/assessable sites of disease, including:
-
Effusions and ascites
-
Bone lesions
-
Brain lesions, central nervous system (CNS) lesions, leptomeningeal disease
-
Mucosal lesions in the gastrointestinal tract
-
Pleural, peritoneal or bowel wall thickening
Target and Non-target Lesions
Up to 6 target lesions will be selected from among the measurable lesions and documented as 
target nodal and target extranodal lesions. Target lesions should be selected based on their 
size (largest lesions preferred) and suitability for reproducible measurements. Measurements 
of the LDi and SDi should be made in the axial plane on the slice of the tumor with the 
longest in-plane diameter. Calculate the PPD for each target lesion and the SPD for all target 
lesions.
Non-target lesions will be all focal (nodal and extranodal) lesions that are consistent with 
lymphoma, but not chosen as target lesions, whether they were measurable or not.
Once lesions are designated as target or non-target, those designations may not change during 
later assessments.
Spleen Assessment at Baseline
Splenic involvement will be assessed quantitatively, as a separate category from the 
assessment of measurable or non-measurable focal lesions. The spleen length will be 
measured from cranial to caudal. All spleen measurements referred to hereafter will refer to 
this cranio-caudal measurement. The spleen is considered normal if it is less than 13 cm, or if 
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the spleen has been removed surgically. It is considered enlarged if it is greater than 13 cm in 
length. The portion of the measurement that exceeds 13 cm will be considered the abnormal 
portion.
Liver Assessment at Baseline
Hepatic enlargement will be assessed qualitatively, separately from the assessment of 
measurable or non-measurable disease. At baseline, the liver will be assessed qualitatively as 
either normal or enlarged (qualitatively enlarged based on expert judgment on CT scans, 
without an explanation of the enlargement from benign causes).
10.9.3.2
Post-baseline Assessment
Target lesions
At every timepoint after screening, each target lesion is measured. Calculate the PPD for 
each target lesion and the SPD for all target lesions together. Response categories are as 
defined below:
•
Complete Response (CR): All target lymph nodes must have regressed to normal size 
defined as ≤1.5 cm in LDi. Target extranodal sites must be absent (0 by 0 cm).
•
Partial Response (PR): ≥50% decrease in SPD of target lesions from baseline, and no 
individual lesion meets the criteria for progression.
•
Progressive Disease (PD): Target lesion progression is based on the progression of any 
single lesion (not a change in the SPD), which meets all of the following requirements:
o
The lesion must have increased by ≥50% from its nadir in PPD.
o
For a lymph node, it must be >1.5 cm in LDi, and for an extranodal lesion it must be 
≥1.0 cm in LDi.
o
And one of the following:
◦
For lesions <2 cm at nadir, the lesion’s LDi or SDi must have increased by 
≥0.5 cm at the current timepoint from its nadir.
◦
For lesions ≥2 cm at nadir, the lesion’s LDi or SDi must have increased by 
≥1 cm at the current timepoint from its nadir.
•
Stable Disease (SD): A target lesion assessment of SD requires all of the following:
o
Target lesions do not meet the criteria for CR or PR
o
No individual lesion meets the criteria for progression
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•
Not Evaluable (NE): When a target lesion identified at baseline cannot be evaluated at a 
post-baseline timepoint due to missing imaging, poor image quality, changes in the lesion 
or background that precludes assessment, or focal therapy or other procedures that 
change the lesion size, the target lesion assessment will be NE, unless progression is 
assessed in another target lesion.
Non-target lesions
Non-target lesions will be assessed at each post-baseline timepoint individually and as a 
group. Response categories are as defined below:
•
Absent/Normalized (CR): All individual non-target nodal lesions must have returned to 
normal size. All extranodal lesions must have disappeared.
•
Unequivocal Progression (PD): Any individual non-target lesion must unequivocally 
progress in the context of the overall disease burden to be assessed as PD. For increased 
thickening of the wall of a hollow viscus, the reviewer will use their cautious judgment to 
determine whether the increase is most likely caused by disease progression.
PD should not be called based on enlarging pleural effusions or ascites, or enlarging lytic 
bone lesions, and rather, the overall assessment should be based on the rest of the disease 
burden.
•
Stable Disease (SD): At least one non-target lesion is still present, or a node enlarged, 
without any individual lesions showing unequivocal progression.
•
Not Evaluable (NE): When an individual non-target lesion lymph node, extranodal 
lesion, or non-measurable disease cannot be assessed at a post-baseline timepoint due to 
missing imaging, poor image quality, changes in the lesion or background that precludes 
assessment, or focal therapy to a lesion, the individual non-target lesion will be assessed 
as NE. The assessment of the non-target lesions as a whole will be NE if any of the non-
target lesions are NE and none are PD.
New lesions
Lesions will be considered new if they were not present at the baseline timepoint, but are 
visible at the current timepoint.
A node consistent with lymphoma will be recorded as a new lesion if it was previously 
normal in size and is now >1.5 cm in LDi. An unequivocal, new extranodal lesion consistent 
with lymphoma of any size is considered a new lesion. If multiple new extranodal lesions are 
noted, at least one should be recorded as a new lesion.
New lesions must be consistent with lymphoma rather than another etiology (eg, infection, 
inflammation) and must be PET-positive, if PET is available. New lesions will be treated as 
PET-positive when PET is not available to confirm avidity.
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Some types of truly non-measurable lesions generally require further verification that they 
are attributable to lymphoma through biopsy or cytology. These include ascites, pleural or 
pericardial effusions, and lytic bone lesions. They may be recorded as new lesions only when 
there is other evidence of progression.
Other truly non-measurable lesions will not require verification to be considered a new 
lesion, as long as their appearance is unequivocal in the judgment of the reviewer:
•
Non-measurable lesions such as brain and CNS lesions including leptomeningeal disease 
attributable to lymphoma
•
Non-measurable nodal masses such as infiltrative mesenteric masses or retroperitoneal 
masses
Extranodal lesions which disappeared and then reappeared at a later timepoint will have the 
same effect as a new lesion but are not designated “new.”
Spleen response
The spleen will be measured in the craniocaudal length as at baseline, and the enlarged 
portion calculated by subtracting 13 cm. Response categories for the spleen are as defined 
below:
•
Normal (CR): Spleen was enlarged at baseline and has regressed to ≤13 cm at the current 
timepoint, or the spleen was assessed as normal at baseline and is still normal, or there is 
radiological evidence of splenectomy at baseline, or the spleen was normal at baseline, 
and there has been a splenectomy since then.
•
Partial Resolution (PR): Spleen was assessed as enlarged at baseline, and its excess 
length has decreased by ≥50%.
•
Stable Splenomegaly (SD): No decrease consistent with PR and no increase consistent 
with progression.
•
Unequivocal increase (PD): The spleen is assessed as PD if any of the following are true:
o
Recurrent splenomegaly: A spleen which was abnormal at baseline (>13 cm) first 
returned to normal, but at the current timepoint the spleen increases by >2 cm from its 
nadir and the length is >13 cm.
o
New splenomegaly: No prior splenomegaly and spleen increases by >2 cm from 
baseline and the length is >13 cm.
o
Progression of existing splenomegaly: A spleen which is abnormal at baseline has the 
enlarged portion increase by ≥50% at the current timepoint from its nadir value.
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Liver response
The liver will be assessed qualitatively. Response categories are as defined below:
•
Normal (CR): Liver was assessed as enlarged at baseline and has regressed to a normal 
size, OR liver was assessed as normal at baseline and continues to be normal in size.
•
Stable Disease (SD): Liver is considered stable when it is qualitatively enlarged, without 
unequivocal increase, on the basis of CT and/or MRI scans.
•
Unequivocal increase (PD): New hepatomegaly, recurrent hepatomegaly, or clear 
progression of existing hepatomegaly.
Anatomic Response
The anatomic response should be assessed at each post-baseline timepoint based on the 
criteria below.
Complete Response (CR)
An anatomic response of complete response (CR) requires one of the following 
combinations:
Target Lesion 
Non-Target Lesion 
Spleen 
Liver 
New Lesions
CR
CR or NA
CR
CR
No
CR or NA
CR
CR
CR
No
CR or NA
CR or NA
CR and 
Enlarged at 
baseline
Normal (CR)
No
CR=complete response; NA=none identified at baseline.
Partial Response (PR)
An anatomic response of partial response (PR) requires one of the following combinations:
Target Lesion 
Non-Target Lesion 
Spleen 
Liver 
New Lesions
PR
CR or SD or NA
PR or CR
CR or SD 
No
CR or PR
SD
PR or CR
CR or SD
No
CR or PR
SD or CR or NA
PR
CR or SD
No
CR, PR
CR, SD, NA
CR or PR 
SD
No
CR=complete response; NA=none identified at baseline; PR=partial response; SD=stable disease.
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Stable Disease (SD)
An anatomic response of SD requires one of the following combinations:
Target Lesion 
Non-Target Lesion 
Spleen 
Liver 
New Lesions
SD
CR or SD or NE or NA
CR or PR or 
SD 
CR or SD 
No
CR or PR or SD 
or NA
CR or SD or NE or NA
SD
CR or SD 
No
NA
CR or SD or NE or NA
PR
CR or SD 
No
CR=complete response; NA=none identified at baseline; NE=not evaluable; PR=partial response; 
SD=stable disease.
Progressive Disease (PD)
An anatomic response of PD requires ANY of the following criteria:
Target Lesion 
PD
Non-Target Lesion 
PD
Spleen 
PD
Liver 
PD
New Lesions
Any new lesions except the following:

New lesions meeting the size requirements for new 
lesions but PET-negative, when PET is available* and

New ascites, effusion or lytic bone lesions
*When PET is not available, any unequivocal new lesions will be assumed to be PET-positive and will trigger 
PD.
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Not Evaluable (NE)
An anatomic response of NE during radiology review requires that the criteria for PD are 
NOT met and any of following criteria are met:
Target Lesion Assessment
NE
Non-Target Lesion Assessment NE
Note: If the NE is caused solely by lesions that are not 
evaluated because scans of the neck and pelvis did not 
completely cover the anatomic space, the reviewer may base 
their overall assessment on the remaining lesions. 
Spleen 
Enlarged 
Liver 
Enlarged 
General
The radiologist determines at any timepoint that a valid 
timepoint response cannot be made and there is no evidence of 
progression. As an example, if the radiologist suspects that a 
lesion was resected, NE may be reported for the anatomic
response unless progression was seen in another parameter.
10.9.4
Metabolic Response
In addition to anatomic imaging, metabolic imaging using FDG-PET can contribute to the 
assessment, if it is available, or may form the sole basis for response if no anatomic imaging 
is performed at a time point. An FDG-PET is required at screening. Subsequent time points 
that require PET are shown in the schedule of assessments. If lesions are not FDG-avid at 
baseline, PET is not required at follow-up timepoints unless clinically indicated.
PET Assessment [Barrington, S. F., et al 2014]
For every FDG-PET scan, a 5PS score is obtained by comparing the maximum standardized 
uptake value (SUVmax) of the lesion that shows the greatest tracer uptake (the “hottest” 
lesion) to surrounding normal tissue, to a region of interest (ROI) placed over blood in the 
heart or major vessels of the mediastinum (the “mediastinal blood pool”) and to an ROI 
placed over normal liver.
Depending on the uptake, a score between 1-5 will be assigned as follows:
Score
Definition
1
No uptake above background
2
Uptake above background, but below mediastinal blood pool
3
Uptake > mediastinal blood pool, but ≤ uptake in liver
4
Uptake moderately higher than liver
5
Uptake markedly higher than liver (SUVmax >2 × normal liver)
OR (after treatment has started)
New FDG-positive lymphoma lesions
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After screening, in addition to the 5PS score the assessment of the FDG-PET also involves an 
assessment of the overall uptake (a combination of extent and intensity) by tissue consistent 
with lymphoma, and comparison of this uptake to the baseline and to the scan on which the 
overall uptake was lowest (nadir).
Metabolic response determination
Metabolic response categories are defined as follows:
Metabolic Response
Definition
Complete metabolic response 
(CMR)
A score of 1, 2, or 3.
Partial metabolic response 
(PMR)
A score of 4 or 5 (without new lesions), AND
Overall uptake decreased compared to baseline
Stable metabolic disease
(SMD)
A score of 4 or 5 (without new lesions), AND
Overall uptake unchanged compared to baseline and 
nadir
Progressive metabolic disease
(PMD)
A score of 4 or 5 with overall uptake increased 
compared to nadir, OR with new FDG-positive lesions 
consistent with lymphoma
In Waldeyer’s ring or extranodal sites with high physiologic uptake or with activation within 
spleen or marrow (eg, with chemotherapy or myeloid colony-stimulating factors), uptake 
may be greater than normal mediastinum and/or liver. In this circumstance, CMR may be 
inferred if uptake at sites of initial involvement is no greater than surrounding normal tissue,
even if the tissue has high physiologic uptake.
10.9.5
Clinical Data
Bone marrow assessment
To allow an overall response of CR, the bone marrow must be clear of lymphoma (negative 
for lymphoma).
Lugano allows assessment of bone marrow based on FDG-PET, if the lymphoma type is 
FDG-avid. Bone marrow on FDG-PET may be normal, may show diffuse uptake (compatible 
with reactive changes due to chemotherapy or colony-stimulating factors), or may show focal 
increased uptake that is consistent with lymphoma.
A negative PET allows the bone marrow to be declared negative, even without biopsy, and 
would support a CR overall (diffuse uptake compatible with reactive changes from 
chemotherapy or growth factor use can fall into this category). A PR may occur with residual 
uptake higher than uptake in normal marrow but reduced compared with baseline. If there are 
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persistent focal changes in the marrow in the context of a nodal response, consideration 
should be given to further evaluation with MRI or biopsy or an interval scan.
Bone marrow aspirate or biopsy is required only as clinically indicated, or if FDG-PET 
evaluation of bone marrow is judged inconclusive. If bone marrow biopsy is performed and 
shows lymphoma, the bone marrow is considered positive, regardless of the results of the 
PET.
Physical examination findings
On rare occasions, lesions may be present on physical examination that are not seen on 
imaging at all. An example might be lymphadenopathy in the popliteal fossa, when the 
“whole body” imaging includes only anatomy to the mid-femur. Such lesions should be 
documented as non-target lesions in study forms. They can contribute to progression if new 
lesions appear this way, and if any were present at baseline, they must disappear for an 
overall response of CR.
Other clinical data
Information on the use of hematopoietic growth factors and other medications can affect the 
response assessment as described above.
At certain protocol-specified time points, additional tissue biopsies may be collected and 
incorporated into the response assessment.
10.9.6
Overall Response
Overall response at each timepoint is determined by combining the anatomic response, 
metabolic response, and clinical data.
When both CT and FDG-PET are available, the overall response is driven primarily by the 
metabolic response. When only one imaging modality is available at a given timepoint, that 
modality is the main determinant of overall response.
Metabolic 
Response
Anatomic 
Response
Bone 
Marrow
Physical Exam
Overall 
Response
CMR
CR, PR, or SD
Negative
No lesions
CR
PMR
CR, PR, or SD
Any
No new lesions
PR
SMD
CR, PR, or SD
Any
No new lesions
SD
PMD
Any
Any
Any
PD
Any
PD
Any
Any
PD
CMR=complete metabolic response; CR=complete response; PD=progressive disease; PMD=progressive 
metabolic disease; PMR=partial metabolic response; PR=partial response; SD=stable disease; SMD=stable 
metabolic disease.
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During determination of overall response, if no FDG-PET was performed at the timepoint in 
question, the results of a preceding PET may be “carried forward,” unless there has been 
worsening of disease on the CT. For example, if a post-baseline assessment shows a CMR on 
the PET, and PR on the CT, the overall response is CR. If the next timepoint shows 
continued PR on the CT, but there is no PET available, the overall response for that visit is 
still CR.
If there is PR based on either anatomic or metabolic imaging, but a biopsy demonstrates that 
the tissue in question is not malignant, the response can be upgraded to a CR.
Lugano Classification 2014 [Cheson, B. D., et al 2014].
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10.10 Appendix 10: International Prognostic Score
IPS 1 Point per Factor
Albumin <4 g/dL
Hemoglobin <10.5 g/dL
Male
Age ≥45 years
Stage IV disease (according to the Ann Arbor classification) 
Leukocytosis (white blood cell count at least 15,000/mm3)
Lymphocytopenia (lymphocyte count less than 8% of white blood cell count, and/or 
lymphocyte count less than 600/mm3)
Source: [Hasenclever, D. 1998]
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10.11 Appendix 11: Unfavorable Risk Factors – NCCN Guidelines
Unfavorable Risk Factors for Stage I-II Classical Hodgkin Lymphoma
Risk factor
NCCN
Age
-
Histology
-
ESR and B symptoms
≥50 or any B symptoms
Mediastinal mass
MMR >0.33
Number of nodal sites
>3
E lesion
-
Bulky
>10 cm
ESR=erythrocyte sedimentation rate; MMR=mediastinal mass ratio, maximum width of mass/maximum 
intrathoracic diameter; NCCN=National Comprehensive Cancer Network.
Source: [National Comprehensive Cancer Network 2020]
Under NCCN criteria, lymph node regions are defined using Ann Arbor definitions listed 
below.
Ann Arbor Definitions of Lymph Node Regions
Ann Arbor
Supradiaphragmatic Nodal 
Regions
R Cervical/SCL
R ICL/Subpectoral
R Axilla
L Cervical/SCL
L ICL/Subpectoral
L Axilla
Mediastinum
R Hilum
L Hilum
Infradiaphragmatic Nodal 
Regions
Celiac/Spleen hilar
Paraortic
Mesenteric
R Iliac
L Iliac
R Inguinal/Femoral
L Inguinal/Femoral
Source: [National Comprehensive Cancer Network 2020]
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10.12 Appendix 12: Eastern Cooperative Performance Status
Grade
Performance Status
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 (eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any 
work activities. Up and about more than 50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to bed or chair more than 
50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead.
[ECOG ACRIN Cancer Research Group 2016]
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10.13 Appendix 13: Abbreviations
Abbreviation
Expanded Term
5PS
5-point scale
ABVD
doxorubicin in combination with bleomycin, vinblastine, and 
dacarbazine
AE
adverse event 
AEOSI
adverse events of special interest
ALT
alanine aminotransferase
ANC
absolute neutrophil count
APaT
All Participants as Treated
AST
aspartate aminotransferase
AUC
area under the curve
AVD
doxorubicin in combination with vinblastine and dacarbazine
BEACOPP
bleomycin in combination with etoposide, doxorubicin, 
cyclophosphamide, vincristine, procarbazine, and prednisone
Cavg
average plasma concentration
CD28
cluster of differentiation 28
CD3ζ
CD3 zeta
CFR
Code of Federal Regulations
cHL
classical Hodgkin Lymphoma
CI
confidence interval
Cmax
peak plasma concentration
Cmin
trough plasma concentration
CMR
complete metabolic response
CNS
central nervous system 
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
CR
complete response
CRF
Case Report Form 
CSR
Clinical Study Report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
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Abbreviation
Expanded Term
CTCAE 5.0
Common Terminology Criteria for Adverse Events, Version 5.0
ctDNA
circulating tumor deoxyribonucleic acid
CTFG
Clinical Trial Facilitation Group 
CTLA-4
cytotoxic T-lymphocyte-associated protein 4
CYP
cytochrome P450
DMC
Data Monitoring Committee 
DNA
deoxyribonucleic acid 
DurCR
duration of complete response
ECG
electrocardiogram 
ECHO
echocardiogram
ECI
event of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EDC
electronic data collection 
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EORTC QLQ-
C30
European Organisation for Research and Treatment of Cancer quality of 
life questionnaire C30
EOT
end-of-treatment
ePROs
electronic patient-reported outcomes
escBEACOPP
escalated bleomycin in combination with etoposide, doxorubicin, 
cyclophosphamide, vincristine, procarbazine, and prednisone
ESR
erythrocyte sedimentation rate
EU CT
European Union Clinical Trial 
EU CTR
European Union Clinical Trial Regulations
EudraCT
European Union Drug Regulating Authorities Clinical Trials
EuroQoL EQ-
5D-5L
5-level EQ-5D questionnaire
FBR
future biomedical research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
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Abbreviation
Expanded Term
FDG
2-fluorodeoxyglucose
FFPE
formalin-fixed paraffin-embedded
FSH
follicle-stimulating hormone 
FVC
forced vital capacity
GCP
Good Clinical Practice 
GHSG
German Hodgkin Study Group
HA
Health Authority
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
HL
Hodgkin Lymphoma
HRQoL
health-related quality of life
HRT
hormone replacement therapy
IB
Investigator’s Brochure 
ICF
Informed Consent Form
ICH
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use
ICMJE
International Committee of Medical Journal Editors
iCRO
imaging CRO
ID
identification
IEC
Independent Ethics Committee
Ig
immunoglobulin
IgG4
immunoglobulin G4
IgV
immunoglobulin-variable
IHC
immunohistochemistry
IMP
investigational medicinal product
IND
Investigational New Drug 
IO
immuno-oncology
IPS
International Prognostic Score
irAEs
immune-related AEs
IRB
Institutional Review Board
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Abbreviation
Expanded Term
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IV
intravenous
IVD
in vitro diagnostic
IWRS
integrated web response system
LAM
lactational amenorrhea method
LDi
longest diameter
LLN
lower limit of normal
MHRA
Medicines and Healthcare products Regulatory Agency
MRI
magnetic resonance imaging
mRNA
messenger RNA
MSI
microsatellite instability
MUGA
multigated acquisition
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NE
not evaluable
NIVAHL
nivolumab and doxorubicin, vinblastine, and dacarbazine for early stage 
unfavorable Hodgkin Lymphoma
NSCLC
non–small cell lung cancer
OS
overall survival
OTC
over-the-counter
PBMC
peripheral blood mononuclear cell
PBPK
physiological based pharmacokinetic modeling and simulation
PD
progressive disease
PD-1
programmed cell death 1 protein
PD-L1
programmed cell death ligand 1
PD-L2
programmed cell death ligand 2
PET
positron emission tomography 
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetic
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Abbreviation
Expanded Term
PKCθ
protein kinase C-theta
PMD
progressive metabolic disease
PMR
partial metabolic responses
po
by mouth
PPD
product of perpendicular diameters
PR
partial response
PRO
patient-reported outcome
Q3W
every 3 weeks
Q4W
every 4 weeks
Q6W
every 6 weeks
QoL
quality of life
RNA
ribonucleic acid
rrcHL
relapsed or refractory classical Hodgkin Lymphoma
RSD
Reference Safety Dataset
SAE
serious adverse event 
SCT
stem cell transplantation
SD
stable disease
SDi
short axis diameter
SLAB
Supplemental laboratory test(s)
SMD
stable metabolic disease
SoA
schedule of activities
SPD
sum of products of diameters
sSAP
supplemental Statistical Analysis Plan
SUSAR
suspected unexpected serious adverse reaction
SUVmax
maximum standardized uptake value
TCR
T-cell receptor
TEAE
treatment-emergent adverse event
UK
United Kingdom
US
United States
WOCBP
woman/women of childbearing potential
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Abbreviation
Expanded Term
ZAP70
zeta-chain-associated protein kinase
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11
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