A Phase 2 Study of Pembrolizumab (MK-3475) Every 6 Weeks (Q6W) in Participants With Relapsed or Refractory Classical Hodgkin's Lymphoma (rrcHL) or Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)
Phase: PHASE2
Conditions: Hodgkin's Lymphoma, Primary Mediastinal Large B-cell Lymphoma (PMBCL)
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase 2 Study of Pembrolizumab (MK-3475) every 6 
weeks (Q6W) in Participants with Relapsed or 
Refractory Classical Hodgkin’s Lymphoma (rrcHL) or 
Relapsed or Refractory Primary Mediastinal Large B-
cell Lymphoma (rrPMBCL)
NCT04875195
06-June-2023

PRODUCT: MK-3475
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TITLE PAGE
THIS PROTOCOL AND ALL OF THE INFORMATION RELATING TO IT ARE 
CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & 
DOHME LLC, RAHWAY, NJ, USA (MSD).
Protocol Title: A Phase 2 Study of Pembrolizumab (MK-3475) every 6 weeks (Q6W) in 
Participants with Relapsed or Refractory Classical Hodgkin’s Lymphoma (rrcHL) or 
Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)
Protocol Number: B68-04
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
NCT04875195
EU CT
Not applicable
EudraCT
2020-005609-20
JRCT
Not applicable
WHO
Not applicable
UTN
Not applicable
IND
118604
Approval Date: 06 June 2023
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Sponsor Signatory
Typed Name:
Title:
Date
Protocol-specific Sponsor contact information can be found in the Investigator Study 
File Binder (or equivalent).
Investigator Signatory
I agree to conduct this clinical study in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol.
Typed Name:
Title:
Date
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TABLE OF CONTENTS
DOCUMENT HISTORY ........................................................................................................3
PROTOCOL AMENDMENT SUMMARY OF CHANGES...............................................4
1
PROTOCOL SUMMARY ............................................................................................14
1.1
Synopsis.................................................................................................................14
1.2
Schema ..................................................................................................................18
1.3
Schedule of Activities...........................................................................................19
2
INTRODUCTION..........................................................................................................28
2.1
Study Rationale....................................................................................................28
2.2
Background ..........................................................................................................28
2.2.1
Pharmaceutical and Therapeutic Background .............................................28
2.2.2
Preclinical and Clinical Studies ...................................................................29
2.2.3
Ongoing Clinical Studies.............................................................................29
2.2.4
Information on Other Study-related Therapy ..............................................29
2.3
Benefit/Risk Assessment......................................................................................29
3
HYPOTHESES, OBJECTIVES, AND ENDPOINTS................................................31
4
STUDY DESIGN............................................................................................................33
4.1
Overall Design......................................................................................................33
4.2
Scientific Rationale for Study Design.................................................................34
4.2.1
Rationale for Endpoints ...............................................................................34
4.2.1.1
Efficacy Endpoints.............................................................................34
4.2.1.2
Safety Endpoints................................................................................34
4.2.1.3
Pharmacokinetic Endpoints ...............................................................35
4.2.1.4
Antidrug Antibodies (ADA) ..............................................................35
4.2.1.5
Pharmacodynamic Endpoints.............................................................35
4.2.1.6
.........................................35
4.2.1.7
..............................................................37
4.2.2
Rationale for the Use of Comparator/Placebo .............................................37
4.3
Justification for Dose...........................................................................................37
4.3.1
Starting Dose for This Study........................................................................38
4.3.2
Maximum Dose Exposure for This Study ...................................................38
4.4
Beginning and End-of-Study Definition ............................................................38
4.4.1
Clinical Criteria for Early Study Termination .............................................38
5
STUDY POPULATION ................................................................................................39
5.1
Inclusion Criteria.................................................................................................39
5.2
Exclusion Criteria................................................................................................43
5.3
Lifestyle Considerations......................................................................................44
5.3.1
Meals and Dietary Restrictions....................................................................45
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5.3.2
Caffeine, Alcohol, and Tobacco Restrictions ..............................................45
5.3.3
Activity Restrictions ....................................................................................45
5.4
Screen Failures.....................................................................................................45
5.5
Participant Replacement Strategy......................................................................45
6
STUDY INTERVENTION............................................................................................46
6.1
Study Intervention(s) Administered...................................................................46
6.1.1
Treatment .....................................................................................................48
6.2
Preparation/Handling/Storage/Accountability .................................................48
6.2.1
Dose Preparation..........................................................................................48
6.2.2
Handling, Storage, and Accountability........................................................48
6.3
Measures to Minimize Bias: Randomization and Blinding..............................49
6.3.1
Intervention Assignment..............................................................................49
6.3.2
Stratification.................................................................................................49
6.3.3
Blinding........................................................................................................49
6.4
Study Intervention Compliance..........................................................................49
6.5
Concomitant Therapy..........................................................................................49
6.5.1
Rescue Medications and Supportive Care ...................................................51
6.6
Dose Modification (Escalation/Titration/Other)...............................................51
6.6.1
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue).................................................................................................52
6.7
Intervention After the End of the Study............................................................58
6.8
Clinical Supplies Disclosure................................................................................58
6.9
Standard Policies..................................................................................................59
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
WITHDRAWAL............................................................................................................60
7.1
Discontinuation of Study Intervention...............................................................60
7.2
Participant Withdrawal From the Study...........................................................61
7.3
Lost to Follow-up .................................................................................................61
8
STUDY ASSESSMENTS AND PROCEDURES........................................................62
8.1
Administrative and General Procedures ...........................................................62
8.1.1
Informed Consent.........................................................................................62
8.1.1.1
General Informed Consent.................................................................63
8.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................63
8.1.2
Inclusion/Exclusion Criteria ........................................................................63
8.1.3
Participant Identification Card.....................................................................63
8.1.4
Medical History ...........................................................................................64
8.1.5
Prior and Concomitant Medications Review...............................................64
8.1.5.1
Prior Medications...............................................................................64
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8.1.5.2
Disease Details...................................................................................64
8.1.5.3
Prior Treatment Details......................................................................64
8.1.5.4
Concomitant Medications..................................................................65
8.1.5.5
Subsequent Antineoplastic Therapy Status........................................65
8.1.6
Assignment of Screening Number...............................................................65
8.1.7
Assignment of Treatment/Randomization Number.....................................65
8.1.8
Study Intervention Administration ..............................................................65
8.1.8.1
Timing of Dose Administration.........................................................66
8.1.9
Discontinuation and Withdrawal .................................................................66
8.1.9.1
................................66
8.1.10
Participant Blinding/Unblinding..................................................................67
8.1.11
Domiciling ...................................................................................................67
8.1.12
Calibration of Equipment.............................................................................67
8.1.13
.............................................................67
8.2
Efficacy/Immunogenicity Assessments ..............................................................67
8.2.1
Lymphoma Disease Response Assessment Criteria ....................................67
8.2.1.1
Disease Assessment of Immunotherapeutic Agents ..........................68
8.2.1.2
Lymphoma B Symptoms ...................................................................68
8.2.2
Tumor Imaging and Assessment of Disease................................................69
8.2.2.1
Initial Tumor Scans............................................................................69
8.2.2.2
Lymphoma Disease Response Assessment/Scan During the Study..69
8.2.2.3
Disease Progression Assessment and Treatment ...............................70
8.2.2.4
End-of-Treatment and Follow-up Tumor Scans................................71
8.2.2.5
Lymph Node Biopsy..........................................................................71
8.2.3
Quality-of-Life Assessments .......................................................................72
8.2.4
Patient-reported Outcomes...........................................................................72
8.3
Safety Assessments...............................................................................................72
8.3.1
Physical Examinations.................................................................................73
8.3.1.1
Full Physical Examination.................................................................73
8.3.1.2
Directed Physical Examination..........................................................73
8.3.2
Vital Signs....................................................................................................73
8.3.3
Electrocardiograms ......................................................................................73
8.3.4
Clinical Safety Laboratory Assessments .....................................................74
8.3.4.1
Laboratory Safety Evaluations (Hematology, Chemistry and 
Urinalysis)..........................................................................................74
8.3.5
Pregnancy Testing........................................................................................75
8.3.6
Performance Assessments............................................................................75
8.3.6.1
Eastern Cooperative Oncology Group Performance Status...............75
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8.4
Adverse Events, Serious Adverse Events, and Other Reportable Safety 
Events....................................................................................................................75
8.4.1
Time Period and Frequency for Collecting AE, SAE, and Other 
Reportable Safety Event Information ..........................................................76
8.4.2
Method of Detecting AEs, SAEs, and Other Reportable Safety Events......78
8.4.3
Follow-up of AE, SAE, and Other Reportable Safety Event Information...78
8.4.4
Regulatory Reporting Requirements for SAE .............................................78
8.4.5
Pregnancy and Exposure During Breastfeeding ..........................................79
8.4.6
Disease-related Events and/or Disease-related Outcomes Not Qualifying 
as AEs or SAEs............................................................................................79
8.4.7
Events of Clinical Interest............................................................................79
8.5
Treatment of Overdose........................................................................................80
8.6
Pharmacokinetics.................................................................................................80
8.6.1
Blood Collection for Plasma MK-3475 PK and Immunogenicity...............80
8.6.1.1
Blood Collection for PK ....................................................................81
8.6.1.2
Blood Collection for Antipembrolizumab Antibodies.......................81
8.7
Pharmacodynamics..............................................................................................81
8.8
Biomarkers ...........................................................................................................81
8.8.1
.............................................81
8.9
..............................................82
8.10
Medical Resource Utilization and Health Economics.......................................82
8.11
Visit Requirements...............................................................................................82
8.11.1
Screening......................................................................................................82
8.11.2
Treatment Period/Vaccination Visit ............................................................83
8.11.3
Participants Discontinued From Study Intervention but Continuing to be 
Monitored in the Study ................................................................................83
8.11.4
Posttreatment Visit.......................................................................................83
8.11.4.1
Safety Follow-up Visit.......................................................................83
8.11.4.2
Efficacy Follow-up Visits..................................................................83
8.11.4.3
Survival Follow-up Contacts .............................................................83
8.11.5
Vital Status...................................................................................................84
9
STATISTICAL ANALYSIS PLAN .............................................................................85
9.1
Statistical Analysis Plan Summary.....................................................................85
9.2
Responsibility for Analyses/In-house Blinding .................................................86
9.3
Hypotheses/Estimation ........................................................................................86
9.4
Analysis Endpoints...............................................................................................86
9.4.1
Efficacy Endpoints.......................................................................................86
9.4.2
Safety Endpoints..........................................................................................87
9.4.3
Pharmacokinetic Endpoints .........................................................................87
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9.5
Analysis Populations............................................................................................87
9.5.1
Efficacy Analysis Population.......................................................................87
9.5.2
Safety Analysis Population..........................................................................87
9.6
Statistical Methods...............................................................................................87
9.6.1
Statistical Methods for Efficacy Analysis....................................................88
9.6.1.1
Objective Response Rate ...................................................................88
9.6.1.2
Duration of Response.........................................................................88
9.6.1.3
...................................................................89
9.6.1.4
.................................................................................89
9.6.1.5
Analysis Strategy for Key Efficacy Variables...................................89
9.6.2
Statistical Methods for Safety Analyses ......................................................90
9.6.3
Demographic and Baseline Characteristics .................................................91
9.7
Interim Analyses ..................................................................................................91
9.8
Multiplicity ...........................................................................................................91
9.9
Sample Size and Power Calculations .................................................................91
9.10
Subgroup Analyses...............................................................................................92
9.11
Compliance (Medication Adherence).................................................................92
9.12
Extent of Exposure...............................................................................................92
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS.....................................................................................................93
10.1
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations........93
10.1.1
Code of Conduct for Clinical Trials.............................................................93
10.1.2
Financial Disclosure.....................................................................................96
10.1.3
Data Protection.............................................................................................97
10.1.3.1
Confidentiality of Data ......................................................................97
10.1.3.2
Confidentiality of Participant Records...............................................97
10.1.3.3
Confidentiality of IRB/IEC Information............................................97
10.1.4
Publication Policy........................................................................................98
10.1.5
Compliance with Study Registration and Results Posting Requirements ...98
10.1.6
Compliance with Law, Audit, and Debarment ............................................98
10.1.7
Data Quality Assurance ...............................................................................99
10.1.8
Source Documents .....................................................................................100
10.1.9
Study and Site Closure...............................................................................100
10.2
Appendix 2: Clinical Laboratory Tests............................................................101
10.3
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting.............................................................103
10.3.1
Definitions of Medication Error, Misuse, and Abuse................................103
10.3.2
Definition of AE ........................................................................................103
10.3.3
Definition of SAE ......................................................................................104
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10.3.4
Additional Events Reported in the Same Manner as SAE.........................105
10.3.5
Recording AE and SAE .............................................................................106
10.3.6
Reporting of AEs, SAEs, and Other Reportable Safety Events to the 
Sponsor ......................................................................................................109
10.4
Appendix 4: Medical Device and Drug–Device Combination Products: 
Product Quality Complaints/Malfunctions: Definitions, Recording, and 
Follow-up ............................................................................................................111
10.5
Appendix 5: Contraceptive Guidance..............................................................112
10.5.1
Definitions..................................................................................................112
10.5.2
Contraceptive Requirements......................................................................113
10.6
Appendix 6: Collection and Management of Specimens for Future 
Biomedical Research..........................................................................................114
10.7
Appendix 7: Country-specific Requirements..................................................118
10.7.1
Czech Republic-specific Requirements .....................................................118
10.7.2
France-specific Requirements....................................................................119
10.7.3
Italy-specific Requirements .......................................................................119
10.7.4
Turkey-specific Requirements...................................................................119
10.8
Appendix 8: Lymphoma Disease Criteria .......................................................120
10.9
Appendix 9: Abbreviations ...............................................................................123
11
REFERENCES.............................................................................................................127
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LIST OF TABLES
Table 1
Study Schedule of Activities........................................................................19
Table 2
Adequate Organ Function Laboratory Values .............................................42
Table 3
Study Interventions......................................................................................47
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations ...........................................................................53
Table 5
Pembrolizumab Monotherapy, Coformulations or IO Combinations 
Infusion Reaction Dose Modification and Treatment Guidelines ...............................57
Table 6
Reporting Periods and Time Frames for Adverse Events and Other 
Reportable Safety Events.............................................................................................77
Table 7
.................................................88
Table 8
..............................................................................89
Table 9
Analysis Strategy for Key Efficacy Variables.............................................90
Table 10
.............................91
Table 11
.............................92
Table 12
Protocol-required Clinical Laboratory Assessments .................................101
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LIST OF FIGURES
Figure 1
Study Diagram .............................................................................................18
Figure 2
Criteria for Response Assessment .............................................................121
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2 Study of Pembrolizumab (MK-3475) every 6 weeks (Q6W) in 
Participants with Relapsed or Refractory Classical Hodgkin’s Lymphoma (rrcHL) or 
Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL)
Short Title: Phase 2 study of MK 3475 Q6W in rrcHL or rrPMBCL
Acronym: None
Hypotheses, Objectives, and Endpoints:
Hypotheses are aligned with objectives in the Objectives and Endpoints table.
In male and female, programmed cell death 1 protein (PD-1) naïve, participants ≥18 years of 
age with either
•
rrcHL who have failed to respond or relapsed after ≥1 line of multiagent therapy (can 
include brentuximab vedotin), or who have failed to achieve a complete response (CR) or 
relapsed after auto-stem cell transplantation (SCT), or are ineligible for auto-SCT, 
OR
•
rrPMBCL who have failed to respond or relapsed after ≥2 lines of therapy (at least 1 of 
the prior lines of therapy must contain a rituximab-based regimen), or who have failed to 
achieve a CR or relapsed after auto-SCT, or are ineligible for auto-SCT: 
Primary Objective
Primary Endpoint
To evaluate objective response rate (ORR), 
by cohort, rrcHL and rrPMBCL, as assessed 
by the investigator according to Lugano 
classification criteria [Cheson, B. D., et al 
2014] in individuals treated with 
pembrolizumab Q6W.
Participants with complete response (CR) or 
partial response (PR).
Secondary Objectives
Secondary Endpoints
To evaluate objective response rate (ORR), 
by cohort, rrcHL and rrPMBCL, as assessed 
by blinded independent central review 
(BICR) according to Lugano classification 
criteria [Cheson, B. D., et al 2014] in 
individuals treated with pembrolizumab 
Q6W.
Participants with complete response CR or
PR.
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To evaluate duration of response (DOR), by 
cohort, rrcHL and rrPMBCL, as assessed by 
the investigator according to Lugano 
classification criteria [Cheson, B. D., et al 
2014] in individuals treated with 
pembrolizumab Q6W.
The time from first documented evidence of 
CR or PR until disease progression or death 
due to any cause, whichever occurs first.
To evaluate duration of response (DOR), by 
cohort, rrcHL and rrPMBCL, as assessed by 
BICR according to Lugano classification 
criteria [Cheson, B. D., et al 2014] in 
individuals treated with pembrolizumab 
Q6W.
The time from first documented evidence of 
CR or PR until disease progression or death 
due to any cause, whichever occurs first.
To evaluate the pharmacokinetic (PK) 
profile, immunogenicity of pembrolizumab 
400 mg Q6W.
-PK parameters of pembrolizumab 
including AUC, Cmax and Cmin.
-Antidrug antibody levels.
To evaluate the safety and tolerability of 
pembrolizumab Q6W.
-Adverse Events (AEs).
-Discontinuations due to AEs.
Overall Design:
Study Phase
Phase 2
Primary Purpose
Treatment
Indication
Relapsed and/or Refractory Primary 
mediastinal large B-cell lymphoma, 
Hodgkin's lymphoma
Population
PD-1 naïve adult participants with rrcHL, 
who have failed to respond or relapsed after 
≥1 line of multiagent therapy (with or 
without brentuximab vedotin), or who have 
failed to achieve a CR or relapsed after 
auto-SCT, or are ineligible for auto-SCT
OR
PD-1 naïve adult participants with 
rrPMBCL who have failed to respond or 
relapsed after ≥2 lines of therapy, or failed 
to achieve a CR or relapsed after auto-SCT, 
or are ineligible for auto-SCT
Study Type
Interventional
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Intervention Model
Single Group
This is a single group, multi site study.
Type of Control
No Treatment Control
Study Blinding
Unblinded open-label
Blinding Roles
No blinding
Estimated Duration of Study
The Sponsor estimates that the study will 
require approximately 4 years from the time 
the first participant (or their legally 
acceptable representative) provides 
documented informed consent until the last 
participant’s last study-related contact.
Number of Participants:
Approximately 60 participants will be allocated into 2 cohorts based on baseline disease as 
described in Section 6.3.1.
Intervention Groups and Duration:
Arm Name
Intervention 
Name
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
Arm 1
Cohort 1 
:rrcHL
Cohort 2
rrPMBCL
Pembrolizumab 
(MK-3475)
25 mg/mL
400 mg
IV Infusion
Day 1, then Q6W 
up to 18 doses 
(approximately 
2 years)
Test 
Product
Other current or former name(s) or alias(es) for study intervention(s) are as follows: 
MK-3475.
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Total Number of Intervention Groups/Arms
1 arm, 2 cohorts
Duration of Participation
Each participant will participate in the study 
from the time that the participant provides 
documented informed consent through the 
final protocol-specified contact
After a screening phase of 28 days, each 
participant will be assigned to receive study 
intervention until one of the conditions for 
discontinuation of study intervention is met.
After the end of treatment, each participant 
will be followed for the occurrence of 
adverse events and spontaneously reported 
pregnancy.
Participants who discontinue for reasons 
other than radiographic disease progression 
will have posttreatment follow-up imaging 
for disease status until any of the conditions 
for discontinuation of imaging are met.
All participants will be followed for overall 
survival until death, withdrawal of consent, 
or the end of the study.
Study Governance Committees:
Executive Oversight Committee
No
Data Monitoring Committee
No
Clinical Adjudication Committee
No
There are no governance committees in this study. Regulatory, ethical, and study oversight 
considerations are outlined in Appendix 1.
Study Accepts Healthy Participants: No
A list of abbreviations is in Appendix 9.
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1.2
Schema
The study design is depicted in Figure 1.
Figure 1
Study Diagram
BICR=Blinded Independent Central Review; Q6W=every 6 weeks; Q12W=every 12 weeks; rrcHL=relapsed and refractory 
classical Hodgkin’s lymphoma; rrPMBCL=relapsed and refractory primary mediastinal B-cell lymphoma
a
Imaging Q12W by investigator and BICR assessment according to Lugano classification.
rrcHL
rrPMBCL
Pembrolizumab 
400 mg Q6W
Response 
Assessmenta
Discontinue Treatment
•
not disease 
progression
•
no new treatment
Follow-up with 
response assessment
Disease progression
Survival Follow-up
Discontinue Treatment
•
disease progression
Survival Follow-up
Screening
Treatment
Follow-up
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1.3
Schedule of Activities
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2
INTRODUCTION
2.1
Study Rationale
On 28-APR-2020, the FDA granted accelerated approval to the additional dosing regimen of 
400 mg every Q6W for pembrolizumab across all currently approved adult indications, in 
addition to 200 mg Q3W dosing regimen. This study is being conducted upon the request of 
the FDA as a post-marketing requirement to provide additional data on the efficacy and 
safety of pembrolizumab 400 mg Q6W dosing regimen in participants with rrcHL and 
rrPMBCL. The results of this study will contribute to an understanding of the safety and 
efficacy of pembrolizumab administered IV, in a Q6W dosing regimen in the indications 
rrcHL and rrPMBCL.
2.2
Background
Pembrolizumab is a potent humanized IgG4 mAb with high specificity of binding to the 
PD-1 receptor, thus inhibiting its interaction with PD-L1 and PD-L2. Based on preclinical in 
vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. 
Pembrolizumab has an acceptable preclinical safety profile and is in clinical development as 
an IV immunotherapy for advanced malignancies. Keytruda® (pembrolizumab) is indicated 
for the treatment of patients across several indications. For more details on specific 
indications refer to the IB.
2.2.1
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 
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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, 
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 rrcHL and rrPMBCL.
2.2.2
Preclinical and Clinical Studies
Please refer to the pembrolizumab IB for descriptions of the respective preclinical and 
clinical evaluations.
2.2.3
Ongoing Clinical Studies
Additionally, there is an expansive ongoing research program of clinical studies evaluating 
pembrolizumab in participants with a number of hematological and solid malignancies, 
including rrcHL and rrPMBCL. For further study details, please refer to the pembrolizumab 
IB.
2.2.4
Information on Other Study-related Therapy
Not applicable.
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.
However, reassurance of the benefit/risk profile for the proposed study is provided by the 
fact that pembrolizumab has marketing approval in the US and other countries for the 
following:
•
Treatment of adult participants with rrcHL.
•
Treatment of adult participants with refractory PMBCL, or who have relapsed after 2 or 
more prior lines of therapy. 
•
Note, KEYTRUDA® is not recommended for treatment of participants with PMBCL 
who require urgent cytoreductive therapy.
•
Dosage of 400 mg Q6W across all adult indications.
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In addition, interim results (based on data cutoff date 16-JAN-2020) from KEYNOTE-204, 
an ongoing, randomized, open-label, Phase 3 study of IV pembrolizumab 200 mg Q3W 
compared with IV brentuximab vedotin 1.8 mg/kg Q3W in participants with rrcHL who have 
failed to respond or relapsed on at least 1 prior multiagent chemotherapy regimen, 
demonstrate that pembrolizumab provides a clinically meaningful and statistically significant 
benefit in PFS compared with brentuximab vedotin (HR = 0.65 [95% CI: 0.48, 0.88], 
p=0.00271). ORR and DOR findings support the PFS results.
The efficacy of a pembrolizumab 400 mg Q6W dosing regimen is expected to be similar to 
the initially approved 200 mg Q3W regimen in the rrcHL and rrPMBCL indications (see 
Section 4.3).
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 male and female, programmed cell death 1 protein (PD-1) naïve, participants ≥18 years of 
age with either
•
rrcHL who have failed to respond or relapsed after ≥1 line of multiagent therapy (can 
include brentuximab vedotin), or who have failed to achieve a complete response (CR) or 
relapsed after auto-stem cell transplantation (SCT), or are ineligible for auto-SCT, 
OR
•
rrPMBCL who have failed to respond or relapsed after ≥2 lines of therapy (at least 1 of 
the prior lines of therapy must contain a rituximab-based regimen), or who have failed to 
achieve a CR or relapsed after auto-SCT, or are ineligible for auto-SCT: 
Primary Objective
Primary Endpoint
To evaluate objective response rate (ORR), 
by cohort, rrcHL and rrPMBCL, as assessed 
by the investigator according to Lugano 
classification criteria [Cheson, B. D., et al 
2014] in individuals treated with 
pembrolizumab Q6W.
Participants with complete response (CR) or 
partial response (PR).
Secondary Objectives
Secondary Endpoints
To evaluate objective response rate (ORR), 
by cohort, rrcHL and rrPMBCL, as assessed 
by blinded independent central review 
(BICR) according to Lugano classification 
criteria [Cheson, B. D., et al 2014] in 
individuals treated with pembrolizumab 
Q6W.
Participants with complete response CR or
PR.
To evaluate duration of response (DOR), by 
cohort, rrcHL and rrPMBCL, as assessed by 
the investigator according to Lugano 
classification criteria [Cheson, B. D., et al 
2014] in individuals treated with 
pembrolizumab Q6W.
The time from first documented evidence of 
CR or PR until disease progression or death 
due to any cause, whichever occurs first.
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To evaluate duration of response (DOR), by 
cohort, rrcHL and rrPMBCL, as assessed by 
BICR according to Lugano classification 
criteria [Cheson, B. D., et al 2014] in 
individuals treated with pembrolizumab 
Q6W.
The time from first documented evidence of 
CR or PR until disease progression or death 
due to any cause, whichever occurs first.
To evaluate the pharmacokinetic (PK) 
profile, immunogenicity of pembrolizumab 
400 mg Q6W.
-PK parameters of pembrolizumab 
including AUC, Cmax and Cmin.
-Antidrug antibody levels.
To evaluate the safety and tolerability of 
pembrolizumab Q6W.
-Adverse Events (AEs).
-Discontinuations due to AEs.
Tertiary/Exploratory Objectives
Tertiary/Exploratory Endpoints
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4
STUDY DESIGN
4.1
Overall Design
This is a Phase 2, nonrandomized, multisite, open-label study of the efficacy and safety of IV 
pembrolizumab 400 mg Q6W in adult participants with rrcHL or rrPMBCL. Participants 
should be PD-1 naïve.
Participants with rrcHL (Cohort 1) must have failed to respond or relapsed after at least 1 line 
of multiagent therapy (chemotherapy with or without brentuximab vedotin), or have failed to 
achieve CR or relapsed after an auto-SCT, or are ineligible for auto-SCT.
Participants with rrPMBCL (Cohort 2) must have failed to respond or relapsed after ≥2 lines 
of prior therapy, or failed to achieve a CR or relapsed after auto-SCT or are ineligible for 
auto-SCT. At least 1 of the prior lines of therapy must contain a rituximab-based regimen. 
Participants with rrPMBCL must not require urgent cytoreductive therapy.
The study design is summarized in Figure 1. The planned objectives and endpoints are 
detailed in Section 3.
After Screening, approximately 60 participants will receive pembrolizumab 400 mg fixed 
dose administered Q6W for up to 18 cycles (approximately 2 years) until documented 
disease progression per investigator assessment according to Lugano classification or the 
participant meets 1 of the discontinuation criteria (Section 7.1). 
Disease will be assessed every 12 weeks using the Lugano response criteria [Cheson, B. D., 
et al 2014] per investigator assessment. 
Participants who discontinue treatment for reasons other than disease progression will have 
posttreatment follow-up for disease status until disease progression, initiating a non-study 
cancer treatment, withdrawing consent, death, or becoming lost to follow-up. All participants 
will be followed for OS until death, withdrawal of consent, the end of the study, or becoming 
lost to follow-up, whichever comes first.
AEs will be monitored throughout the study and graded in severity according to the 
guidelines outlined in the NCI CTCAE 5.0. After the end-of-treatment, each participant will 
be followed for AE monitoring (see Section 8.4). Participants who undergo allogeneic SCT 
within 2 years after their last dose of study treatment will be followed for ECIs for up to 18 
months post-transplant. This additional follow-up for participants undergoing an allogeneic 
SCT within 2 years after their last treatment is necessary to provide data for a post-marketing 
requirement from the FDA.
Specific procedures to be performed during the study, including prescribed times and 
associated visit windows, are outlined in Section 1.3 of the SoA. Details of each procedure 
are provided in Section 8.
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4.2
Scientific Rationale for Study Design
This is a Phase 2, nonrandomized, multisite, open-label study of the efficacy and safety of IV 
pembrolizumab 400 mg Q6W in adult, PD-1 naïve, participants with rrcHL or rrPMBCL.
The rationale for selected dose and dosing schedule are summarized in Section 2.1 and 
Section 4.3. The study includes 2 cohorts (rrcHL or rrPMBCL); enrollment into each cohort 
will not be controlled as the number of rrPMBCL participants could vary since this is a rare 
form of DLBCL. 
The study is open-label as pembrolizumab is already approved for use in the rrcHL and 
rrPMBCL, making blinding unnecessary. 
The results of this study will contribute to an understanding of the PK characteristics of 
pembrolizumab administered in a Q6W dosing regimen in rrcHL and rrPMBCL.
4.2.1
Rationale for Endpoints
4.2.1.1
Efficacy Endpoints
The primary endpoint for this study will be the achievement of objective response, meaning a 
best overall response of PR or CR, defined according to the Lugano classification [Cheson, 
B. D., et al 2014], as assessed by the investigator. Response assessment per Lugano includes 
anatomic imaging (CT), metabolic imaging (FDG-PET), and clinical information. The 
proportion of participants in a treatment group who achieve an objective response is called 
the ORR. ORR is an acceptable measure of clinical benefit for a late-stage study that 
demonstrates superiority of a new antineoplastic therapy, especially if the magnitude of the 
effect is large and the therapy has an acceptable benefit/risk profile. The Lugano 
classification, published in 2014, is the revised response criteria for assessing ORR in HL 
and NHL and recommended by the current NCCN guidelines for B-cell lymphoma [National 
Comprehensive Cancer Network 2019]. All images and clinical data will be assessed by the 
investigator. 
 
4.2.1.2
Safety Endpoints
A secondary objective of this study is to characterize the safety and tolerability of 400 mg 
pembrolizumab when administered IV Q6W.
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.
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4.2.1.3
Pharmacokinetic Endpoints
An objective of this study is to characterize the PK profile of pembrolizumab after 
administration as an IV infusion Q6W. PK data will be analyzed after all participants 
complete Cycle 5. PK parameters will include AUC, Cmax, and Cmin. Results of PK 
analysis will be provided in a separate report added to the CSR as an appendix.
4.2.1.4
Antidrug Antibodies (ADA)
Formation of ADAs can potentially confound drug exposures at therapeutic doses and prime 
for subsequent infusion-related toxicity. ADA response to pembrolizumab at the beginning of 
each of the first 5 cycles will be determined. Any impact of presence of ADAs on exposure 
of pembrolizumab will be explored. Results of ADA analysis will be provided in a separate 
report added to the CSR as an appendix.
4.2.1.5
Pharmacodynamic Endpoints
There are no pharmacodynamic endpoints in this study.
4.2.1.6
 
 
 
 
 
 
 
 
 
 
 
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4.2.1.7
 
 
 
 
 
 
 
 
 
4.2.2
Rationale for the Use of Comparator/Placebo
Not applicable.
4.3
Justification for Dose
The current approved dosing regimen of pembrolizumab for an IV administration are 200 mg 
Q3W or 400 mg Q6W for adults.
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 modeling and simulation analyses, given 
the following rationale:
•
PK simulations demonstrating that in terms of pembrolizumab exposures:
◦
Average concentration over the dosing interval 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 
participants.
◦
Peak concentrations (Cmax) at 400 mg Q6W are well below the Cmax for the 
highest clinically tested dose of 10 mg/kg every 2 weeks, supporting that the 
safety profile for 400 mg Q6W should be comparable to the established safety 
profile of pembrolizumab.
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•
Exposure-response 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.
4.3.1
Starting Dose for This Study
The study will use pembrolizumab at a fixed dose of 400 mg Q6W.
4.3.2
Maximum Dose Exposure for This Study
All participants may receive up to 18 infusions of pembrolizumab (approximately 2 years) or 
until confirmed PD, whichever comes first.
4.4
Beginning and End-of-Study Definition
The overall study begins when the first participant (or their legally acceptable representative) 
provides documented informed consent. The overall study ends when the last participant 
completes the last study-related contact, withdraws consent, or is lost to follow-up (Section 
7.3). For purposes of analysis and reporting, the overall study ends when the Sponsor 
receives the last laboratory test result or at the time of final contact with the last participant, 
whichever comes last.
If the study includes countries in the European Economic Area (EEA), the local start of the 
study in the EEA is defined as First Site Ready (FSR) in any Member State.
4.4.1
Clinical Criteria for Early Study Termination
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
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. Male/female participants who are at least 18 years of age on the day of documented 
informed consent.
2. Have a histologically confirmed diagnosis of cHL or PMBCL, according to the WHO 
classification of neoplasms of the hematopoietic and lymphoid tissues [Swerdlow, S. H., 
et al 2008]. 
3. Have radiographically measurable cHL or PMBCL disease as per Lugano classification 
with at least 1 nodal lesion (which has not been previously radiated) that is >15 mm in 
long axis, regardless of the length of the short axis, and/or extranodal lesion of >10 mm 
in long and short axis.
PMBCL-Specific Disease Characteristics:
4. Have relapseda or refractoryb PMBCL and:
•
Have relapsed after auto-SCT or have failed to achieve a CR or PR within 60 days of 
auto-SCT. Participants may have received intervening therapy after auto-SCT for 
relapsed or refractory disease, in which case they must have relapsed after or be 
refractory to their last treatment.
OR
•
For participants who are ineligible for auto-SCT, have received at least ≥2 lines of 
prior therapy and have failed to respond to or relapsed after their last line of 
treatment. At least 1 of the prior lines of therapy must contain a rituximab-based 
regimen. For participants who received consolidative local radiotherapy after 
systemic therapy, local radiotherapy will not be considered as a separate line of 
treatment.
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Note: Participants should not need urgent cytoreductive therapy.
a
Relapsed Disease: disease progression after achieving an overall response of PR or 
CR in response to the most recent therapy
b
Refractory Disease: failure to achieve CR or PR to the most recent therapy.
cHL-Specific Disease Characteristics:
5. Have relapseda or refractoryb cHL and:
•
Have relapsed during their last cHL regimen after receiving at least 2 cycles of 
therapy or within 12 months after completing the last regimen for cHL.
OR
•
Have received at least ≥1 line of prior multiagent therapy with/without brentuximab 
vedotin (excluding radiation) or auto-SCT for cHL and have failed to respond to or 
relapsed after their last line of treatment (for country-specific requirements see 
Appendix 7). 
*a Relapsed Disease: disease progression after achieving an overall response of PR or 
CR to the most recent therapy
*b Refractory Disease: failure to achieve CR or PR to the most recent therapy.
Demographics
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) or be abstinent from heterosexual intercourse as their preferred 
and usual lifestyle (abstinent on a long-term and persistent basis), as described in 
Appendix 5 during the intervention period and for at least 120 days after the last dose 
of study intervention. The investigator should evaluate the potential for contraceptive 
method failure (ie, noncompliance, recently initiated) in relationship to the first dose 
of study intervention.
• A WOCBP must have a negative highly sensitive pregnancy test (urine or serum, as 
required by local regulations) within 24 hours for urine or within 72 hours for serum 
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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• Abstains from breastfeeding during the study intervention period and for at least 120 
days after study intervention.
• Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.3.5.
• The investigator is responsible for review of medical history, menstrual history, and 
recent sexual activity to decrease the risk for inclusion of a woman with an early 
undetected pregnancy.
• Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
Informed Consent
7. The participant (or legally acceptable representative) has provided documented informed 
consent/assent for the study. The participant may also provide consent/assent for FBR. 
However, the participant may participate in the study without participating in FBR.
Additional Categories
8. Submit an evaluable core lymph node biopsy for biomarker analysis from an archival 
(>60 days) or newly obtained core or incisional (within 30 days) biopsy, which was not 
previously irradiated at Screening (Visit 1).
Note: If no archival tissue is available, 2 new fresh core needle samples are required.
9. Have an ECOG Performance Status of 0 to 1 assessed within 7 days before allocation. 
10. Life expectancy >3 months.
11. Have blood oxygen saturation >92%.
12. Have adequate organ function as defined in the following table (Table 2). Specimens 
must be collected within 7 days before the start of study intervention.
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Table 2
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1000/µL (unless marrow involvement)
Plateletsa
≥75 000/µL (unless marrow involvement)
Hemoglobina
≥8.0 g/dL or ≥5.6 mmol/La
(unless marrow involvement)
Renal
Creatinine 
OR
Measured or calculated creatinine clearance (GFR can also 
be used in place of creatinine or CrCl)
≤1.5 × ULN 
OR
≥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)
Coagulation
International normalized ratio (INR) or prothrombin time 
(PT)
Activated partial thromboplastin time (aPTT)
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT 
is within therapeutic range of intended use of 
anticoagulants
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or PTT 
is within therapeutic range of intended use of 
anticoagulants
ALT (SGPT)=alanine aminotransferase (serum glutamic pyruvic transaminase); AST (SGOT)=aspartate 
aminotransferase (serum glutamic oxaloacetic transaminase); GFR=glomerular filtration rate; ULN=upper limit of 
normal.
a Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within 
last 2 weeks prior to first dose of study intervention.
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5.2
Exclusion Criteria
The participant must be excluded from the study if the participant meets any of the following 
criteria:
Medical Conditions
1. Has undergone solid organ transplant at any time, or prior allogeneic hematopoietic SCT 
within the last 5 years. 
 
2. Has clinically significant (ie, active) cardiovascular disease: cerebral vascular 
accident/stroke (<6 months prior to enrollment), myocardial infarction (<6 months prior 
to enrollment), unstable angina, congestive heart failure (New York Heart Association 
Classification Class ≥II), or serious cardiac arrhythmia requiring medication.
3. Has pericardial effusion or clinically significant pleural effusion.
4. Has a history of a second malignancy, unless potentially curative treatment has been 
completed with no evidence of malignancy for 2 years.
Note: The time requirement does not apply to participants who underwent successful 
definitive resection of basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, superficial bladder cancer, in situ cervical cancer, or other in situ cancers.
Prior/Concomitant Therapy
5. Is receiving systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone 
equivalent) <3 days prior to the first dose of study intervention. 
Note: Participants who receive daily steroid replacement therapy are an exception. Daily 
prednisone at doses of 5 to 7.5 mg is an example of replacement therapy.
Note: Equivalent hydrocortisone doses are permitted if administered as replacement 
therapy.
6. Has received prior monoclonal antibody within 4 weeks prior to first dose of study 
intervention or has not recovered (ie, ≤Grade 1 or at baseline) from AEs due to agents 
administered more than 4 weeks earlier.
7. 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).
8. Has received prior CAR-T therapy (for country-specific requirements see Appendix 7).
9. Has received prior systemic anticancer therapy, or radiotherapy, including investigational 
agents within 4 weeks prior to the first dose of study intervention.
10. Has received prior radiotherapy within 2 weeks of start of study intervention or has 
radiation-related toxicities, requiring corticosteroids.
Note: Two weeks or fewer of palliative radiotherapy for non-CNS disease, with a 1-week 
washout, is permitted.
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11. Has received a live or live-attenuated vaccine within 30 days before the first dose of 
study drug. 
Note: Killed vaccines are allowed (for country-specific requirements see Appendix 7). 
Refer to Section 6.5 for information on COVID-19 vaccines.
Prior/Concurrent Clinical Study Experience
12. Has received an investigational agent or has used an investigational device 4 weeks prior 
to study intervention administration.
Diagnostic Assessments
13. 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.
14. Has known active CNS lymphoma involvement or active CNS involvement by 
lymphoma. Participants with prior CNS involvement are eligible if their CNS disease is 
in radiographic, cytological (for cerebrospinal fluid disease) and clinical remission.
15. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
16. Has an active autoimmune disease that has required systemic treatment in past 2 years 
except replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid).
17. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required 
steroids or has current pneumonitis/interstitial lung disease.
18. Has an active infection requiring systemic therapy.
19. Has a known history of HIV infection. No HIV testing is required unless mandated by 
local health authority (see Appendix 7).
20. 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 (see Appendix 7).
21. 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.
22. Has a known psychiatric or substance abuse disorder that would interfere with the 
participant’s ability to cooperate with the requirements of the study.
5.3
Lifestyle Considerations
No lifestyle restrictions are required.
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5.3.1
Meals and Dietary Restrictions
Participants should maintain a normal diet unless modifications are required to manage an 
AE such as diarrhea, nausea, or vomiting.
5.3.2
Caffeine, Alcohol, and Tobacco Restrictions
No restrictions are required.
5.3.3
Activity Restrictions
No restrictions are necessary.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study, but 
are not subsequently entered in the study. A minimal set of screen-failure information is 
required to ensure transparent reporting of screen-failure participants to meet the CONSORT 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen-failure details, eligibility criteria, and any AEs or 
SAEs meeting reporting requirements as outlined in the data entry guidelines.
Participants who fail Screening may be rescreened for eligibility after consultation between 
the investigator and the Sponsor and written documentation of the collaborative decision on 
participant management.
5.5
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 (study intervention(s) provided by the Sponsor) 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 intervention to be used in this study is outlined in Table 3.
Country-specific requirements are noted in Appendix 7.
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Table 3
Study Interventions
Arm Name
Arm Type
Intervention 
Name
Intervention 
Type
Dose 
Formulation
Unit Dose 
Strength(s)
Dosage 
Level(s)
Route of 
Administration
Regimen/
Treatment 
Period/
Vaccination 
Regimen
Use
IMP or 
NIMP/
AxMP
Sourcing
Arm 1
Cohort 1 
:rrcHL
Cohort 2
rrPMBCL
Experimental Pembrolizum
ab (MK-
3475)
Biological/Va
ccine
Solution
25 mg/mL
400 mg
IV Infusion
Day 1, then 
Q6W up to 
18 doses 
(approximately 
2 years)
Test Product IMP
Central by 
Sponsor
EEA=European Economic Area; IMP=investigational medicinal product; NIMP/AxMP=noninvestigational/auxiliary medicinal product.
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.
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All study interventions will be administered on an outpatient basis.
All products indicated in Table 3 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 of pembrolizumab monotherapy consists of 18 treatments.
Note: The number of treatments is calculated starting with the first dose.
6.2
Preparation/Handling/Storage/Accountability
6.2.1
Dose Preparation
All participants will receive 400 mg pembrolizumab by IV infusion Q6W. Details on 
preparation and administration of pembrolizumab  are provided in the Pharmacy Manual.
There are no specific calculations or evaluations required to be performed to administer the 
proper dose to each participant. The rationale for selection of doses to be used in this study is 
in Section 4.3.
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).
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For all study sites, the local country Sponsor personnel or designee will provide appropriate 
documentation that must be completed for drug accountability and return, or local discard 
and destruction if appropriate. Where local discard and destruction is appropriate, the 
investigator is responsible for ensuring that a local discard/destruction procedure is 
documented.
The study site is responsible for recording the lot number, manufacturer, and expiry date for 
any locally purchased product (if applicable) as per local guidelines unless otherwise 
instructed by the Sponsor.
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution, and usage of study 
interventions in accordance with the protocol and any applicable laws and regulations.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Intervention Assignment
Enrollment into Cohorts 1 and 2 are of equal priority. All participants will receive 400 mg IV 
pembrolizumab Q6W. 
Intervention allocation will occur centrally using an IRT system. There are 2 cohorts of 
participants and 1 study intervention arm.
Participants in this study will be allocated by nonrandom assignment.
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.
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Table 4
 
General instructions:
1.
Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should begin if 
the irAEs are not controlled by corticosteroids.
2.
Pembrolizumab monotherapy, coformulations or IO combinations must be permanently discontinued if the irAE does not resolve or the corticosteroid 
dose is not ≤10 mg/day within 12 weeks of the last treatment. 
3.
The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks.
4.
If pembrolizumab monotherapy, coformulations or IO combinations have been withheld, treatment may resume after the irAE decreased to ≤ Grade 1 
after corticosteroid taper.
irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
 
Grade 2
Withhold 
•
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
•
Add prophylactic antibiotics 
for opportunistic infections
•
Monitor participants for signs and symptoms 
of pneumonitis
•
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment
Recurrent Grade 2, 
Grade 3 or 4 
Permanently 
discontinue
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
 
Grade 2 or 3
Withhold
•
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus)
•
Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis
•
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion
Recurrent Grade 3 
or Grade 4
Permanently 
discontinue
 
 
Grade 2 a
Withhold
•
Administer corticosteroids 
(initial dose of 0.5 to 1 mg/kg 
prednisone or equivalent) 
followed by taper
•
Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable)
Grade 3 b or 4 c
Permanently 
discontinue
•
Administer corticosteroids 
(initial dose of 1 to 2 mg/kg 
prednisone or equivalent) 
followed by taper
 
New onset T1DM 
or 
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of b-cell 
failure
Withhold d
•
Initiate insulin replacement 
therapy for participants with 
T1DM
•
Administer 
antihyperglycemic in 
participants with 
hyperglycemia
•
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes
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irAEs
Toxicity Grade 
(CTCAE v5.0)
Action With 
Pembrolizumab 
Monotherapy, 
Coformulations or 
IO Combinations
Corticosteroid and/or Other 
Therapies
Monitoring and Follow-up
Grade 2
Withhold
•
Administer corticosteroids 
and initiate hormonal 
replacements as clinically 
indicated
•
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4
Withhold or 
permanently 
discontinue d
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 
 
Grade 2, 3 or 4
Continue
•
Initiate thyroid replacement 
hormones (eg, levothyroxine 
or liothyronine) per standard 
of care
•
Monitor for signs and symptoms of thyroid 
disorders
 
 
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
 
Grade 2
Withhold
•
Based on severity of AE 
administer corticosteroids
•
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
Grade 1
Withhold
•
Based on severity of AE 
administer corticosteroids
•
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 2, 3 or 4
Permanently 
discontinue
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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
 
 
 
 
 
 
 
 
Grade 3
Withhold or 
discontinue based on 
the event e 
 
 
 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug Rash 
with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; T1DM=type 1 
diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal.
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations.
a     AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal; 
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal
b     AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if 
baseline abnormal
c     AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal; 
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal
d   The decision to withhold or permanently discontinue pembrolizumab monotherapy, coformulations or IO combinations is at the discretion of the investigator or treating 
physician. If control achieved or ≤Grade 2, pembrolizumab monotherapy, coformulations or IO combinations may be resumed.
e    Events that require discontinuation include but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis).
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Dose Modification and Toxicity Management of Infusion Reactions Related to 
Pembrolizumab Monotherapy, Coformulations or IO Combinations
Pembrolizumab monotherapy, coformulations or IO combinations may cause severe or life-
threatening infusion reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve 
completely within 24 hours of completion of infusion. Dose modification and toxicity 
management guidelines on pembrolizumab monotherapy, coformulations or IO combinations 
associated infusion reaction are provided in Table 5.
Table 5
Pembrolizumab Monotherapy, Coformulations or IO Combinations Infusion 
Reaction Dose Modification and Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grade 1
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator
None
Grade 2
Requires therapy or 
infusion interruption 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs
Stop Infusion
Additional appropriate medical 
therapy may include but is not 
limited to:
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
If symptoms resolve within 1 hour 
of stopping drug infusion, the 
infusion may be restarted at 50% 
of the original infusion rate (eg, 
from 100 mL/h to 50 mL/h). 
Otherwise dosing will be held 
until symptoms resolve and the 
participant should be 
premedicated for the next 
scheduled dose.
Participants who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further study drug intervention.
Participant may be premedicated 1.5 h (±30 
min) prior to infusion of study intervention 
with:
Diphenhydramine 50 mg PO (or equivalent 
dose of antihistamine).
Acetaminophen 500 to 1000 mg PO (or 
equivalent dose of analgesic).
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NCI CTCAE Grade
Treatment
Premedication at Subsequent Dosing
Grades 3 or 4
Grade 3:
Prolonged (ie, not 
rapidly responsive to 
symptomatic 
medication and/or brief 
interruption of 
infusion); recurrence of 
symptoms after initial 
improvement; 
hospitalization 
indicated for other 
clinical sequelae (eg, 
renal impairment, 
pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor or ventilatory 
support indicated
Stop Infusion.
Additional appropriate medical 
therapy may include but is not 
limited to:
Epinephrine**
IV fluids
Antihistamines
NSAIDs
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
Increase monitoring of vital signs 
as medically indicated until the 
participant is deemed medically 
stable in the opinion of the 
investigator.
Hospitalization may be indicated.
**In cases of anaphylaxis, 
epinephrine should be used 
immediately.
Participant is permanently 
discontinued from further study 
drug intervention.
No subsequent dosing
IV=Intravenous; NSAIDS=Non-steroidal anti-inflammatory drugs; PO=by mouth.
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the 
period of drug administration.
For further information, please refer to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) at 
http://ctep.cancer.gov
Other Allowed Dose Interruption for Pembrolizumab Monotherapy, Coformulations, 
or IO Combinations
Pembrolizumab monotherapy, coformulations, or IO combinations may be interrupted for 
situations other than treatment-related AEs such as medical or surgical events and/or 
unforeseen circumstances not related to study intervention. However, study intervention is to 
be restarted within 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.
6.7
Intervention After the End of the Study
There is no study-specified intervention after the end of the study.
6.8
Clinical Supplies Disclosure
This study is open-label; therefore, the participant, the study-site personnel, the Sponsor, 
and/or designee are not blinded. Study intervention (name, strength, or potency) is included 
in the label text; random code/disclosure envelopes or lists are not provided.
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6.9
Standard Policies
Not applicable.
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8.2.2
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 evaluation of scan changes in 
tumor burden over time, until the participant is discontinued from the study or enters the 
Survival Follow-up. Disease response assessments may use CT/MRI and/or PET scans, 
laboratory studies, and physical examination. The process for scan collection (including 
anatomical coverage, preferred modalities, and specifics of scanning technique) can be found 
in the Site Imaging Manual. Tumor scans should include CT (in this protocol, the term CT is 
used to mean anatomic imaging that could be CT or MRI) that is of diagnostic quality and 
acquired with IV contrast, and metabolic imaging by PET. All participants require contrast 
enhanced CT or PET-CT scans of the neck, chest, abdomen, and pelvis. The Site Imaging 
Manual will provide alternative methods for scanning if PET-CT cannot be performed due to 
medical contraindication or local practice. The same type of scan should be used in a 
participant throughout the study to optimize the reproducibility of the assessment and 
improve the accuracy of the response assessment. 
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. 
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.
8.2.2.1
Initial Tumor Scans
Diagnostic quality anatomic scans (typically contrast enhanced CT scan) and metabolic scans 
via FDG-PET must be performed during Screening. 
Initial tumor scans at Screening must be performed within 28 days prior to the date of the 
first dose of study intervention. Any scans obtained after Cycle 1 Day 1 cannot be included 
in the screening assessment. The site must review screening scans to confirm the participant 
has measurable disease as defined in the inclusion criteria.
Disease assessments or scans performed as part of routine clinical management are 
acceptable for use as the screening scan if they are of diagnostic quality and performed 
within 28 days prior to the first dose of study intervention.
8.2.2.2
Lymphoma Disease Response Assessment/Scan During the Study
After Screening, disease response assessments will occur at Week 12 (±7 days) and every 
12 weeks (±7 days) thereafter as detailed in the SoA (Section 1.3, Table 1). The first 
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9
STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study. Changes to 
analyses made after the protocol has been finalized will be documented in a sSAP and 
referenced in the CSR for the study. Post hoc exploratory analyses will be clearly identified 
in the CSR.
9.1
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized below; the comprehensive plan 
is provided in Sections 9.2 through 9.12.
Study Design Overview
This is a Phase 2 Study of Pembrolizumab (MK-3475) 
400 mg Q6W in Participants with rrcHL or rrPMBCL.
Treatment Assignment
Participants meeting inclusion/exclusion criteria will be 
allocated to one of the 2 cohorts, rrcHL or rrPMBCL, and 
receive 400 mg of pembrolizumab Q6W. The population 
of each cohort, rrcHL and rrPMBCL, is defined in 
Section 3.
Analysis Populations
Efficacy: APaT
Safety: APaT
Primary Endpoints
Objective Response per Lugano classification as assessed 
by Investigator.
Secondary Endpoints
Objective Response per Lugano classification as assessed 
by BICR.
DOR per Lugano classification as assessed by 
Investigator.
DOR per Lugano classification as assessed by BICR.
AEs and study intervention discontinuations due to AEs.
Statistical Methods for Key 
Efficacy Analyses
The point estimate of ORR 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
Summary statistics (counts, percentage, mean, standard 
deviation, etc.) will be provided for the safety endpoints 
as appropriate.
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Interim Analyses
There are no planned interim analyses for this study.
Multiplicity
No multiplicity adjustment is planned as there is no 
hypothesis testing.
Sample Size and Power 
The sample size is expected to be approximately 60 
participants with no required minimum in either cohort.
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 non-randomized, 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 of the study are stated in Section 3.
9.4
Analysis Endpoints
Efficacy, safety, and PK endpoints that will be evaluated are listed below, followed by the 
descriptions of the derivations of selected endpoints.
9.4.1
Efficacy Endpoints
Primary
•
Objective Response Rate
The ORR is defined as the proportion of participants who achieve a CR or PR per Lugano 
classification as assessed by investigator.
Secondary
•
Objective Response Rate
The ORR is defined as the proportion of participants who achieve a CR or PR per Lugano 
classification as assessed by BICR.
•
Duration of Response
For participants who demonstrate CR or PR, DOR is defined as the time from the first 
documented evidence of CR or PR until disease progression or death due to any cause, 
whichever occurs first. DOR will be created, separately, for investigator and BICR 
assessments.
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9.4.2
Safety Endpoints
The safety endpoints include AEs, SAEs, and study treatment discontinuation due to AEs. In 
addition, safety and tolerability will be assessed by clinical review of all relevant parameters 
including AEs, laboratory tests, vital signs, and ECGs. A description of safety measures is 
provided in Section 8.3 and 8.4.
9.4.3
Pharmacokinetic Endpoints
PK and ADA analyses will be reported in separate memos that will be attached to the CSR as 
an appendix. PK and ADA data will be analyzed after all participants complete Cycle 5. PK 
parameters, such as AUC, Cmax, and Cmin as well as incidence of ADA, will be summarized 
(see Sections 4.2.1.3, 4.2.1.4, and 8.6 for additional details).
9.5
Analysis Populations
9.5.1
Efficacy Analysis Population
The APaT population will be used for the primary analysis of efficacy data in this study. The 
APaT population consists of all allocated participants who received at least 1 dose of study 
treatment.
9.5.2
Safety Analysis Population
The APaT population will be used for the analysis of safety data in this study. The APaT 
population consists of all allocated subjects who received at least 1 dose of study treatment.
At least 1 laboratory, vital sign, or ECG measurement obtained after at least 1 dose of study 
treatment is required for inclusion in the analysis of each specific parameter. To assess 
change from baseline, a baseline measurement is also required.
9.6
Statistical Methods
This section describes the statistical methods that address the primary and secondary 
objectives. Methods related to the exploratory endpoints will be described in the sSAP. No 
formal hypothesis tests will be conducted for this study.
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9.6.1
Statistical Methods for Efficacy Analysis
Efficacy (ORR, DOR, PFS and OS) will be evaluated separately in each cohort, rrcHL and 
rrPMBCL.
9.6.1.1
Objective Response Rate
The primary efficacy endpoint for this study is the ORR, defined as the proportion of 
participants who have response (CR or PR) according to Lugano classification as assessed by 
the investigator. Participants without response data will be considered as nonresponders. The 
ORR based on BICR will also be provided as supportive.
The point estimate along with 95% exact CI using exact binomial method proposed by 
[Clopper. J. and Pearson, E. S. 1934] will be calculated.
9.6.1.2
Duration of Response
If sample size permits, DOR will be summarized descriptively using Kaplan-Meier medians 
and quartiles. Only the subset of participants who show a CR or PR will be included in this 
analysis. Censoring rules for DOR are summarized in Table 7. DOR analysis will be 
conducted, separately, for investigator and BICR assessments.
For each DOR analysis, a corresponding summary of the reasons responding participants are 
censored will also be provided. Responding participants who are alive, have not progressed, 
 
 
Table 7
 
 
 
 
 
 
 
 
 
 
 
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9.6.1.3
 
 
 
 
 
 
 
 
 
 
 
Table 8
 
 
 
 
 
 
 
 
 
9.6.1.4
 
9.6.1.5
Analysis Strategy for Key Efficacy Variables
A summary of the primary analysis strategy for the key efficacy variables is provided in 
Table 9.
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Table 9
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary Analyses
ORR per Lugano 
classification by 
investigator assessment
Summary statistics with 95% CI 
using exact method based on 
binomial distribution
APaT
 
 
Secondary Analyses
ORR per Lugano 
classification by BICR
assessment
Summary statistics with 95% CI 
using exact method based on 
binomial distribution
APaT
 
 
DOR per Lugano 
classification by 
investigator assessment
Summary statistics using Kaplan-
Meier method
APaT
 
DOR per Lugano 
classification by BICR 
assessment
Summary statistics using Kaplan-
Meier method
APaT
 
Exploratory Analyses
PFS per Lugano 
classification by 
investigator assessment
Summary statistics using Kaplan-
Meier method
APaT
 
PFS per Lugano 
classification by BICR
assessment
Summary statistics using Kaplan-
Meier method
APaT
 
OS
Summary statistics using Kaplan-
Meier method
APaT
 
 
Abbreviations: APaT=all participants as treated; DOR=duration of response; ORR=objective response rate; OS=overall 
survival; PFS=progression-free survival.
No formal statistical testing is planned.
9.6.2
Statistical Methods for Safety Analyses
Both cohorts, rrcHL and rrPMBCL, will be pooled for safety evaluations. Safety and 
tolerability will be assessed by clinical review of all relevant parameters including AEs, 
laboratory parameters, vital signs, and ECG measurements. 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.
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9.6.3
Demographic and Baseline Characteristics
The number and percentage of participants screened and allocated 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 by descriptive statistics or categorical tables.
9.7
Interim Analyses
No interim analyses are planned for this study.
9.8
Multiplicity
No multiplicity adjustment is required because there is no hypothesis testing.
9.9
Sample Size and Power Calculations
A total of 60 participants with rrPMBCL or rrcHL are expected to be enrolled. There is no 
required minimum enrollment for either cohort. There are no formal hypotheses to be tested. 
Based on the objectives and the estimated enrollment rates, along with a range of anticipated 
effect sizes and associated 95% CIs (refer to Table 10 and Table 11) a sample size of 60 was 
chosen.
rrPMBCL: Due to rarity of the disease, low enrollment is anticipated for rrPMBCL. Table 10
provides the two-sided 95% exact CIs for ORR for a range of observed response rates (20%, 
40% and 60%) for different sample sizes.
Table 10
rrcHL: Table 11 shows the two-sided 95% exact CIs for ORR for a range of observed 
response rates (20%, 40% and 60%) for different sample sizes.
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Table 11
9.10
 
 
9.11
Compliance (Medication Adherence)
Drug accountability data for study treatment will be collected during the study. Any 
deviation from protocol-directed administration will be reported.
9.12
Extent of Exposure
Extent of exposure for a participant is defined as the number of cycles and number of days 
for which the participant receives the study treatment. Summary statistics will be provided on 
the extent of exposure for the overall study treatment, by cohort, for the APaT population.
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11
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