A Phase II Study of Pembrolizumab (MK-3475) in Subjects With Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) or Relapsed or Refractory Richter Syndrome (rrRS)
Phase: PHASE2
Conditions: Mediastinal Large B-cell Lymphoma, Richter Syndrome
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
A Phase II Study of Pembrolizumab (MK-3475) in Subjects 
with Relapsed or Refractory Primary Mediastinal Large B-
cell Lymphoma (rrPMBCL) or Relapsed or Refractory 
Richter Syndrome (rrRS)
08-Jul-2020
NCT02576990

Product:  MK-3475 
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Protocol/Amendment No.: 170-06 
MK-3475-170-06 Final Protocol
08-Jul-2020
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, New Jersey, 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File 
Binder (or equivalent).
TITLE:
A Phase II Study of Pembrolizumab (MK-3475) in Subjects with Relapsed or Refractory 
Primary Mediastinal Large B-cell Lymphoma (rrPMBCL) or Relapsed or Refractory Richter 
Syndrome (rrRS)
IND NUMBER:  118604
EudraCT NUMBER:  2015-002406-37
NTC NUMBER:  NCT02576990
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 14
1.0
TRIAL SUMMARY.................................................................................................. 15
2.0
TRIAL DESIGN........................................................................................................ 16
Trial Design ........................................................................................................... 16
Trial Diagram........................................................................................................ 17
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 18
Primary Objective(s) & Hypothesis(es).............................................................. 18
Secondary Objective(s) & Hypothesis(es)........................................................... 18
Exploratory Objectives......................................................................................... 18
4.0
BACKGROUND & RATIONALE.......................................................................... 19
Background ........................................................................................................... 19
Pharmaceutical and Therapeutic Background .................................................... 19
Pre-clinical and Clinical Trials ........................................................................... 20
Ongoing Clinical Trials....................................................................................... 20
Rationale................................................................................................................ 21
Rationale for the Trial and Selected Subject Population .................................... 21
4.2.1.1
Primary Mediastinal Large B-Cell Lymphoma ........................................... 21
4.2.1.2
Richter Syndrome ........................................................................................ 22
4.2.1.3
Rationale for Evaluating anti-PD-1 Therapy in Primary Mediastinal 
Large B-Cell Lymphoma and Richter syndrome......................................... 23
Rationale for Dose Selection/Regimen/Modification......................................... 24
4.2.2.1
Rationale for Fixed Dose Pembrolizumab................................................... 24
Rationale for Endpoints ...................................................................................... 25
4.2.3.1
Efficacy Endpoints....................................................................................... 25
4.2.3.2
Safety Endpoints.......................................................................................... 25
4.2.3.3
Patient Reported Outcomes.......................................................................... 26
4.2.3.4
Planned Exploratory Biomarker Research................................................... 26
 
 
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4.2.3.5
Future Biomedical Research........................................................................ 27
Benefit/Risk ........................................................................................................... 28
5.0
METHODOLOGY ................................................................................................... 28
Entry Criteria........................................................................................................ 28
Diagnosis/Condition for Entry into the Trial...................................................... 28
Subject Inclusion Criteria.................................................................................... 28
Subject Exclusion Criteria .................................................................................. 31
Trial Treatment(s) ................................................................................................ 33
Dose Selection/Modification .............................................................................. 33
5.2.1.1
Dose Selection (Preparation) ....................................................................... 33
5.2.1.2
Dose Modification ....................................................................................... 33
Timing of Dose Administration.......................................................................... 37
Extent of Trial Treatment.................................................................................... 37
Trial Blinding/Masking....................................................................................... 37
Randomization or Treatment Allocation............................................................ 37
Stratification.......................................................................................................... 37
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 38
Acceptable Concomitant Medications ................................................................ 38
Prohibited Concomitant Medications.................................................................. 38
Rescue Medications & Supportive Care............................................................. 39
Supportive Care Guidelines ................................................................................ 39
Diet/Activity/Other Considerations..................................................................... 40
Diet...................................................................................................................... 40
Contraception...................................................................................................... 40
5.7.3
Use in Pregnancy ................................................................................................ 41
5.7.4
Use in Nursing Women....................................................................................... 42
Subject Withdrawal/Discontinuation Criteria................................................... 42
Discontinuation of Treatment ............................................................................. 42
Withdrawal from the Trial .................................................................................. 43
Subject Replacement Strategy............................................................................. 43
Beginning and End of the Trial ........................................................................... 43
Clinical Criteria for Early Trial Termination ................................................... 43
 
 
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6.0
TRIAL FLOW CHART ........................................................................................... 44
Trial Flow Chart................................................................................................... 44
Trial Flow Chart:  Second Course Phase (Retreatment for Post-Complete 
Response Relapse Only) ....................................................................................... 48
7.0
TRIAL PROCEDURES ........................................................................................... 51
Trial Procedures ................................................................................................... 51
Administrative Procedures.................................................................................. 51
7.1.1.1
Informed Consent......................................................................................... 51
7.1.1.1.1
General Informed Consent.................................................................... 51
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 52
7.1.1.2
Inclusion/Exclusion Criteria ........................................................................ 52
7.1.1.3
Subject Identification Card .......................................................................... 52
7.1.1.4
Medical History ........................................................................................... 52
7.1.1.5
Prior and Concomitant Medications Review............................................... 52
7.1.1.5.1
Prior Medications.................................................................................. 52
7.1.1.5.2
Concomitant Medications..................................................................... 52
7.1.1.5.3
Prior Cancer Treatment Details ............................................................ 53
7.1.1.5.4
Subsequent Antineoplastic Therapy ..................................................... 53
7.1.1.6
Assignment of Screening Number............................................................... 53
7.1.1.7
Assignment of Treatment/Randomization Number..................................... 53
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)................................... 53
Clinical Procedures/Assessments........................................................................ 54
7.1.2.1
Oncologic Disease Details........................................................................... 54
7.1.2.2
Adverse Event Monitoring........................................................................... 54
7.1.2.3
Electrocardiogram........................................................................................ 54
7.1.2.4
Physical Exam.............................................................................................. 54
7.1.2.4.1
Full Physical Exam ............................................................................... 54
7.1.2.4.2
Directed Physical Exam........................................................................ 54
7.1.2.5
Vital Signs.................................................................................................... 55
7.1.2.6
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 55
7.1.2.7
Assessment of Disease and Tumor Imaging................................................ 55
 
 
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7.1.2.7.1
Tumor Imaging and Criteria for Assessment of Disease...................... 55
7.1.2.7.2
Disease Assessment of Immunotherapeutic Agents ............................. 56
7.1.2.7.3
Initial Disease Assessment.................................................................... 56
7.1.2.7.4
Disease Response Assessments/Imaging During the Trial................... 56
7.1.2.7.5
Disease Progression Assessments......................................................... 57
7.1.2.7.6
Biopsy Collection and Correlative Studies Blood Collection .............. 58
7.1.2.8
Patient Reported Outcomes (PROs)............................................................. 60
Laboratory Procedures/Assessments .................................................................. 60
7.1.3.1
Laboratory 
Safety 
Evaluations 
(Hematology, 
Chemistry, 
and 
Urinalysis).................................................................................................... 60
7.1.3.2
Pregnancy Test............................................................................................. 62
7.1.3.3
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 62
7.1.3.4
Planned Genetic Analysis Sample Collection.............................................. 62
7.1.3.5
Future Biomedical Research Sample Collection ......................................... 62
Other Procedures................................................................................................. 63
7.1.4.1
Withdrawal/Discontinuation........................................................................ 63
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 63
7.1.4.1.2
Lost to Follow-up.................................................................................. 63
7.1.4.2
Blinding/Unblinding .................................................................................... 64
7.1.4.3
Calibration of Critical Equipment................................................................ 64
Visit Requirements.............................................................................................. 64
7.1.5.1
Screening...................................................................................................... 64
7.1.5.2
Treatment Period.......................................................................................... 65
7.1.5.2.1
Second Course Phase (Retreatment Period for Post-Complete 
Remission Relapse ONLY) .................................................................. 65
7.1.5.3
Post-Treatment Visits................................................................................... 66
7.1.5.3.1
Safety Follow-Up Visit......................................................................... 66
7.1.5.4
Follow-up Visits........................................................................................... 67
7.1.5.4.1
Follow-Up Post-Allogeneic Stem Cell Transplantation....................... 67
7.1.5.4.2
Survival Follow-up ............................................................................... 67
7.1.5.5
Survival Status ............................................................................................. 67
Assessing and Recording Adverse Events .......................................................... 68
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 69
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 69
Immediate Reporting of Adverse Events to the Sponsor.................................... 70
7.2.3.1
Serious Adverse Events ............................................................................... 70
7.2.3.2
Events of Clinical Interest............................................................................ 71
7.2.3.2.1
Follow-Up Post-Allogeneic Stem Cell Transplantation ....................... 71
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 72
Evaluating Adverse Events................................................................................. 72
Sponsor Responsibility for Reporting Adverse Events ...................................... 75
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 75
Statistical Analysis Plan Summary ..................................................................... 75
Responsibility for Analyses/In-House Blinding ................................................. 76
Hypotheses/Estimation ......................................................................................... 76
Analysis Endpoints ............................................................................................... 76
Efficacy Endpoints.............................................................................................. 76
Safety Endpoints ................................................................................................. 77
Analysis Population .............................................................................................. 77
Efficacy Analysis Population.............................................................................. 77
Safety Analysis Population................................................................................. 77
Statistical Methods................................................................................................ 77
Statistical Methods for Efficacy Analyses.......................................................... 77
8.6.1.1
Objective Response Rate ............................................................................. 77
8.6.1.2
Disease Control Rate.................................................................................... 78
8.6.1.3
Progression-Free Survival............................................................................ 78
8.6.1.4
Duration of Response................................................................................... 79
8.6.1.5
Overall Survival........................................................................................... 79
Statistical Methods for Safety Analyses ............................................................. 80
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 81
8.6.3.1
Baseline Characteristics and Demographics................................................ 81
8.6.3.2
Other Analyses............................................................................................. 81
Interim Analysis.................................................................................................... 81
 
 
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Sample Size and Power Calculation.................................................................... 82
Multiplicity ............................................................................................................ 83
Subgroup Analyses and Effect of Baseline Factors ........................................... 83
Compliance (Medication Adherence).................................................................. 83
Extent of Exposure................................................................................................ 83
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 84
Investigational Product ........................................................................................ 84
Packaging and Labeling Information ................................................................. 84
Clinical Supplies Disclosure................................................................................. 84
Storage and Handling Requirements.................................................................. 84
Discard/Destruction/Returns and Reconciliation .............................................. 85
Standard Policies................................................................................................... 85
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 85
Confidentiality....................................................................................................... 85
Confidentiality of Data ....................................................................................... 85
Confidentiality of Subject Records..................................................................... 85
Confidentiality of Investigator Information........................................................ 86
Confidentiality of IRB/IEC Information............................................................. 86
Compliance with Financial Disclosure Requirements....................................... 86
Compliance with Law, Audit and Debarment ................................................... 87
Compliance with Trial Registration and Results Posting Requirements ........ 88
Quality Management System............................................................................... 89
Data Management................................................................................................. 89
Publications ........................................................................................................... 89
11.0
LIST OF REFERENCES......................................................................................... 90
12.0
APPENDICES........................................................................................................... 95
Merck Code of Conduct for Clinical Trials........................................................ 95
Collection and Management of Specimens for Future Biomedical 
Research................................................................................................................. 97
 
 
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Understanding the
Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 101
Abbreviations ...................................................................................................... 112
ECOG Performance Status................................................................................ 115
Common Terminology Criteria for Adverse Events V4.0 .............................. 116
Lymphoma Disease Response Criteria ............................................................. 117
Lugano Classification ......................................................................................... 118
13.0
SIGNATURES......................................................................................................... 121
Sponsor's Representative ................................................................................... 121
Investigator.......................................................................................................... 121
 
 
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LIST OF TABLES
Table 1
Adequate Organ Function Laboratory Values..................................................... 30
Table 2
Trial Treatment.................................................................................................... 33
Table 3
Dose Modification and Toxicity Management Guidelines for Immune-
Related Adverse Events Associated With Pembrolizumab................................. 34
Table 4
Bone Marrow and Lymph Node Biopsy Assessments........................................ 59
Table 5
Blood for Correlative Studies.............................................................................. 59
Table 6
Laboratory Tests.................................................................................................. 61
Table 7
Evaluating Adverse Events ................................................................................. 73
Table 8
Statistical Analysis Plan Summary...................................................................... 75
Table 9
Censoring rules for Primary and Sensitivity Analyses of Progression-Free 
Survival ............................................................................................................... 79
Table 10
Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints ..... 80
Table 11
Decision Guidance at Each Efficacy rrPMBCL Analysis................................... 82
Table 12
Precision (90% Confidence Intervals) for range of observed ORR (30%-
70%) .................................................................................................................... 83
Table 13
Product Descriptions ........................................................................................... 84
 
 
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LIST OF FIGURES
Figure 1
Trial Diagram ...................................................................................................... 17
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-3475-170-06
08-JUL-2020
To provide conditions for ending the study.
MK-3475-170-05
06-FEB-2018
The efficacy update for subjects with rrPMBCL was updated to be conducted 
at 9 months after the last subject initiated treatment and 12 months after the 
last subject initiated treatment.  This change was implemented because 
PMBCL is an aggressive disease, and the expectation for response rate is low 
and the overall survival (OS) is less than 1 year, so the statistical analysis plan 
was revised to further characterize the efficacy at an earlier time point.
MK-3475-170-04
20-NOV-2017
This amendment was to expand the Dose Modification and Toxicity 
Management Guidelines table to cover supportive care, monitoring, and follow 
up. Myocarditis row was also added.  Clarification was also added to provide 
flexibility for collection of survival follow-up information.
Additionally, the collection of samples for PK analyses was ended and 
associated language in the protocol was updated or omitted, enrollment of the 
Richter Syndrome cohort was ended, requirement for immediate notification of 
site personnel if a male subject impregnates a partner was removed, and 
clarification of the post-allogeneic stem cell follow-up was added.  The 
statistical analysis plan was updated in response to the end of the RS cohort 
enrollment.
 
 
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Document
Date of Issue
Overall Rationale
MK-3475-170-03
23-AUG-2017
This amendment implemented recommendations from the FDA to perform an 
interim analysis for the rrPMBCL group when at least 50% of these subjects 
are evaluable for a response. Also recommended by FDA was formal 
hypothesis testing of the primary objective, ORR, which was added, and 
additional long-term follow-up of subjects who underwent allogeneic stem cell 
transplant. In response to changes in the analysis of the primary objective, 
updates to the statistical analysis plan were also made to the sample size and 
power calculations and to add an O-Brien-Fleming Type I error spending 
function for the final analysis of the rrPMBCL hypothesis.
MK-3475-170-02
18-JAN-2017
This major amendment included updates to clarify the inclusion criteria with 
regard to consent/assent to the use of samples for future biomedical research 
and to require that subjects with Richter syndrome (RS) must have at least 1 
lesion attributable to malignancy and with appropriate correlation to anatomic 
imaging, with uptake greater than that of normal liver tissue. Adequate organ 
function laboratory criteria were also updated to clarify requirements for the 
studied population, to include those with RS.  Exclusion criteria were also 
updated/clarified to provide for the RS cohort.
Tumor imaging and assessment for RS subjects was clarified and additional 
clarification was made to the timing of follow-up and confirmatory imaging.
Additional updates were made in the dose modification guidelines, guidelines 
for discontinuation due to pregnancy, and other updates to pembrolizumab 
standard protocol template text. New sections were added to provide guidance 
on pregnancy testing, post-allogeneic stem-cell transplantation follow-up. 
Clarifications and corrections were made to increase accuracy and avoid 
confusion.
 
 
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Document
Date of Issue
Overall Rationale
MK-3475-170-01
13-JUN-2016
This amendment added a cohort of subjects with Richter syndrome to the study 
to be treated with pembrolizumab in order to confirm the safety and efficacy of 
pembrolizumab in subjects with Richter syndrome based on preliminary data 
from another pembrolizumab trial. Modifications to the response criteria 
specific for Richter syndrome were also made.
In addition, the futility analysis was removed from the protocol because data 
from other trials supported the continuation of enrollment.
MK-3475-170-00
14-JUL-2015
Original Protocol
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.2.3
Extent of Trial Treatment
Added the condition “and the 
trial is still ongoing” to the 
option for restarting treatment if 
a subject who had a complete 
response subsequently 
progresses.
To allow for ending the trial.
5.10
Beginning and End of the 
Trial
Added that the trial may be 
ended by the Sponsor.
To allow for ending the trial.
5.11
Clinical Criteria for Early 
Trial Termination
Added that the trial may be 
ended by the Sponsor.
To allow for ending the trial.
7.1.5.4.1
7.2.3.2.1
Follow-Up Post-Allogeneic 
Stem Cell Transplantation 
Follow-Up Post-Allogeneic 
Stem Cell Transplantation
Added that follow-up for ECI 
post allogeneic stem cell 
transplant would continue for 18 
months “unless the trial closes 
earlier.”
To allow for ending data collection on 
post-treatment allogeneic stem cell 
transplants when the trial is closed.
9.1
Investigational Product
Added the liquid formulation of 
pembrolizumab to Table 13.
To update and add pertinent details to the 
formulation information.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
No additional changes.
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
A phase II study of pembrolizumab in subjects with relapsed or 
refractory primary mediastinal B-cell lymphoma (rrPMBCL) or 
relapsed or refractory Richter Syndrome (rrRS)
Trial Phase
Phase II
Clinical Indication
Treatment of subjects with relapsed or refractory PMBCL or RS.
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous (IV)
Trial Blinding
Unblinded Open-label
Treatment Groups
Pembrolizumab (MK-3475) 200 mg every 3 weeks (Q3W).
Number of trial subjects
Approximately 106 subjects will be enrolled.
Estimated duration of trial
The Sponsor estimates that the trial will require approximately 
45 months from the time the first subject signs the informed consent 
until the last subject’s last study-related phone call or visit.
Duration of Participation
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form through the final protocol-specified 
contact.  After a screening phase of 28 days, eligible subjects will 
receive treatment on Day 1 of each 3-week dosing cycle.  Treatment 
with pembrolizumab
will continue for a maximum of 35 
administrations (approximately 2 years)
per subject or until 
documented 
disease 
progression
by 
investigator 
assessment, 
unacceptable adverse event(s) (AEs), intercurrent illness that prevents 
further administration of treatment, subject withdraws consent, 
pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, or administrative reasons.  The total duration 
of participation is up to approximately 2 years.  Subjects who attain a 
complete response (CR) as determined by independent central review
may consider stopping trial treatment if they meet criteria for holding 
therapy.  At the discretion of the investigator, these subjects will be 
eligible for retreatment if they experience disease progression, as long 
as they meet the criteria for retreatment and the trial is ongoing.  After 
the end of treatment, each subject will be followed for 30 days for AE
monitoring (serious adverse events (SAEs) and events of clinical 
interest (ECIs) will be collected for 90 days after the end of 
treatment).  Subjects who discontinue for reasons other than disease 
progression will have post-treatment follow-up for disease status until 
disease progression, initiating a non-study cancer treatment, 
withdrawing consent, or becoming lost to follow-up.  All subjects will 
be followed by telephone for OS until death, withdrawal of consent, or 
the end of the study.
A list of abbreviations used in this document can be found in Section 12.4.
 
 
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2.0 TRIAL DESIGN
Trial Design
This is an open label, multicenter, single-arm trial of pembrolizumab (MK-3475) in subjects 
with relapsed or refractory Primary Mediastinal Large B-Cell Lymphoma (rrPMBCL) or 
relapsed or refractory Richter syndrome (rrRS).  
Subjects with rrPMBCL must have failed to achieve a complete response (CR) or relapsed 
after autologous stem cell transplant (auto-SCT) or are ineligible for auto-SCT and have 
failed to respond or relapsed after ≥2 lines of prior treatment. Subjects with rrRS must have
transformed from underlying chronic lymphocytic leukemia (CLL), and have been treated 
with at least 1 previous therapy for RS, and must be either refractory or have progressive 
disease (PD).  
Subjects with PMBCL and rrRS are required to submit screening positron emission 
tomography (PET)/computed tomography (CT) scans for confirmation of measurable disease 
before enrolling in the study.  
Pathologic diagnosis of rrPMBCL and rrRS via local institutional review is acceptable to 
enable study enrollment.  Tissue is to be submitted for central review (Section 7.1.2.7.6).
Approximately 106 subjects will be enrolled in this trial to examine the safety and efficacy of 
pembrolizumab 200 mg fixed dose administered every 3 weeks (Q3W).
This will give a 
sample size of approximately 50 subjects in the analysis population of PMBCL, and
approximately 50 subjects with RS, for safety and efficacy, assuming that approximately 6% 
of the total of 106 enrolled subjects will not be treated.  RS cohort is closed early after
enrollment of 24 subjects.  In the rrPMBCL cohort, a single interim analysis will be 
conducted (Section 8.7).  Adverse events (AEs) will be monitored throughout the trial and 
graded in severity according to the guidelines outlined in the National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  Treatment will 
continue up to a maximum of 35 administrations of pembrolizumab (approximately 2 years)
per subject or until documented disease progression by investigator assessment, unacceptable 
AE(s), intercurrent illness that prevents further administration of treatment, subject 
withdraws consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, or administrative reasons.  
Per the investigator’s discretion subjects who attain a confirmed CR by independent central 
review may consider stopping trial treatment after receiving at least 8 administrations of 
pembrolizumab. At least two administrations of pembrolizumab must be received after CR is 
documented. These subjects will be eligible for retreatment for up to 17 administrations of 
pembrolizumab (approximately 1 year) after they have experienced disease progression at the 
discretion of the investigator if no cancer treatment was administered since the last dose of 
pembrolizumab, the subject still meets the safety parameters listed in the Inclusion/Exclusion 
criteria, and the trial remains open (see Section 7.1.5.2.1).
In subjects with rrRS, additional therapies to treat the underlying CLL (according to 
treatment guidelines) may be added (Section 5.5.1) at the physician’s discretion if medically 
necessary and with Sponsor approval. 
 
 
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After the end of treatment, each subject will be followed for 30 days for AE monitoring 
(serious adverse events [SAEs] and events of clinical interest [ECIs] will be collected for 
90 days after the end of treatment).  Subjects who discontinue treatment for reasons other 
than disease progression will have post-treatment follow-up for disease status until disease 
progression, initiating a non-study cancer treatment, withdrawing consent, or becoming lost 
to follow-up.  All subjects will be followed by telephone contact for OS until death, 
withdrawal of consent or the end of the study, whichever comes first.
The primary objective of the trial is to determine the objective response rate (ORR) as 
assessed by independent central review (utilizing the International Working Group [IWG]
response assessment criteria per Cheson 2007 [1]) of pembrolizumab in subjects with 
relapsed or refractory PMBCL.  For subjects with rrRS, IWG criteria with special 
considerations for RS will be used (Section 12.7).
Secondary objectives for each cohort include other efficacy parameters as progression free 
survival (PFS), OS, disease control rate (DCR), duration of response (DOR) and safety and 
tolerability.
Analysis of programmed cell death ligand 1 (PD-L1) expression and 
corresponding efficacy; along with the relationship of candidate efficacy/resistance 
biomarkers and anti-tumor activity of pembrolizumab, and ORR utilizing the 5-point scale 
Lugano Classification (Section 12.8) will be investigated as exploratory objectives for each 
cohort.
This trial will be conducted in conformance with Good Clinical Practices.
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures.
Trial Diagram
The trial design is depicted in Figure 1.
Figure 1
Trial Diagram
Abbreviations not defined above:  mg – milligram(s), Q3W – every three weeks, rrPMBCL - relapsed or 
refractory primary mediastinal large B-cell lymphoma; rrRS:  relapsed or refractory Richter syndrome.
rrPMBCL
rrRS
Pembrolizumab
200 mg Q3W
Survival
Follow-Up
Progressive
Disease or 
35 cycles
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
In subjects with rrPMBCL or rrRS:
1. Objective:  rrPMBCL: Estimate the ORR of pembrolizumab by independent central 
review according to the IWG response criteria (Cheson, 2007 [1]).  
Hypothesis:  Intravenous (IV) administration of single agent pembrolizumab will 
result in an ORR of greater than 15% using IWG response criteria by independent 
central review.
2. Objective:  rrRS: Estimate the ORR of pembrolizumab by independent central 
review according to the IWG response criteria (Cheson, 2007 [1]) with special 
considerations for RS (Section 12.7).
Secondary Objective(s) & Hypothesis(es)
In subjects with rrPMBCL or rrRS:
1. Objective:  To estimate the ORR of pembrolizumab by investigator assessment 
according to the IWG response criteria (Cheson, 2007 [1]) or IWG with special 
considerations for RS.
2. Objective: To evaluate PFS, DOR, and DCR of pembrolizumab by independent 
central review and investigator assessment according to the IWG response criteria 
(Cheson, 2007 [1]) or IWG with special considerations for RS.
3. Objective:  To evaluate the OS of pembrolizumab.
4. Objective:  To determine the safety and tolerability of pembrolizumab.
Exploratory Objectives
In subjects with rrPMBCL or rrRS:
1. Objective:  To evaluate efficacy (ORR, PFS, DOR, and DCR) by independent central 
review according to the IWG response criteria (Cheson, 2007 [1]) or IWG with 
special consideration for RS, incorporating response assessments for subjects 
continuing pembrolizumab treatment after initial progression.
2. Objective:  To evaluate the ORR of pembrolizumab by independent central review,
using the 5-point scale according to the Lugano Classification (Cheson, 2014 [2]).
3. Objective:  To compare the extent of pre-pembrolizumab PD-L1 expression in tumor 
biopsies for pembrolizumab responders versus non-responders (see Section 4.2.3.5).
4. Objective:  To investigate the relationship between candidate efficacy biomarkers 
and anti-tumor activity of pembrolizumab utilizing pre- and post-treatment lymph 
node biopsies and blood sampling (see Section 4.2.3.5).
 
 
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5. Objective: To explore the relationship between genetic variation and response to the 
treatment(s) administered.  Variation across the human genome will be analyzed for 
association with clinical data collected in this study (see Section 4.2.3.5).
6. Objective: To evaluate changes in health-related quality-of-life assessments from 
baseline using the European Organization for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire (QLQ)-Core 30 items (C30) and European 
Quality of Life 5-Dimension (EuroQoL, EQ-5D [see Section 4.2.3.4]).
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on MK-3475.
Pharmaceutical and Therapeutic Background
Pembrolizumab (previously known as MK-3475 and SCH 9000475) is a potent and highly 
selective humanized monoclonal antibody of the immunoglobulin (Ig)G4/kappa isotype 
designed to directly block the interaction between the programmed cell death-1 receptor (PD-
1) and its ligands, PD-L1 and programmed cell death ligand 2 (PD-L2) without antibody-
dependent cell-mediated cytotoxicity or complement dependent cytotoxicity activity.
Keytruda™ (pembrolizumab) is indicated for the treatment of patients across a number of 
indications.  For more details on specific indications refer to the IB.
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [3].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies [4, 5].  In particular, the presence of CD8+ T-cells and the ratio of CD8+ 
effector T-cells/FoxP3+ regulatory T-cells seems to correlate with improved prognosis and 
long-term survival in many solid tumors.
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control.  The normal function of PD-1, expressed on the cell surface of activated 
T-cells under healthy conditions, is to down-modulate unwanted or excessive immune 
responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) is an Ig 
superfamily member related to CD28 and cytotoxic T-lymphocyte-associated antigen-4
(CTLA-4) which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) [6, 7].  The structure of murine PD-1 has 
been resolved [8].  PD-1 and family members are type I transmembrane glycoproteins 
containing an Ig Variable-type (V-type) domain responsible for ligand binding and a 
cytoplasmic tail which is responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor 
tyrosine-based inhibition motif and an immunoreceptor tyrosine based switch motif (ITSM).  
Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-2 to 
the ITSM 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 [7, 9, 10, 11].  The mechanism by which PD-1 down modulates T-cell responses is 
similar to, but distinct from that of CTLA-4 as both molecules regulate an overlapping set of 
 
 
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signaling proteins [12, 13].  PD -1 was shown to be expressed on activated lymphocytes 
including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells [14, 
15].  Expression has also been shown during thymic development on CD4-CD8- (double 
negative) T-cells as well as subsets of macrophages and dendritic cells [16].  The ligands for 
PD-1 (PD-L1 and PD-L2) are constitutively expressed or can be induced in a variety of cell 
types, including non-hematopoietic tissues as well as in various tumors [3, 13, 17, 18, 19].  
Both ligands are type I transmembrane receptors containing both IgV- and IgC-like domains 
in the extracellular region and contain short cytoplasmic regions with no known signaling 
motifs.  Binding of either PD-1 ligand to PD-1 inhibits T-cell activation triggered through the 
T-cell receptor.  PD-L1 is expressed at low levels on various non-hematopoietic tissues, most 
notably on vascular endothelium, whereas PD-L2 protein is only detectably expressed on 
antigen-presenting cells found in lymphoid tissue or chronic inflammatory environments. 
PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 
serves to dampen unwarranted T-cell function in peripheral tissues [13].  Although healthy 
organs express little (if any) PD -L1, a variety of cancers were demonstrated to express 
abundant levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific 
T-cell expansion in subjects with melanoma [20].  This suggests that the PD-1/PD-L1 
pathway plays a critical role in tumor immune evasion and should be considered as an 
attractive target for therapeutic intervention.
Pre-clinical and Clinical Trials
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities.  Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor 
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
melanoma and colorectal carcinoma.  Blockade of the PD-1 pathway effectively promoted 
CD8+ T-cell infiltration into the tumor and the presence of interferon gamma , granzyme B, 
and perforin, indicating that the mechanism of action involved local infiltration and 
activation of effector T-cell function in vivo [21, 22, 23, 24, 25, 26].  Experiments have 
confirmed the in vivo efficacy of PD-1 blockade as a monotherapy as well as in combination 
with chemotherapy in syngeneic mouse tumor models (refer to the IB).
In a Phase 1/2 study of 135 subjects with advanced melanoma treatment with pembrolizumab 
produced an ORR of 38% (95% confidence interval [CI], 25% to 44%).  Many of the 
responses were durable, with a median duration that had not been reached after a median 
follow-up time of 11 months [27].
Ongoing Clinical Trials
Ongoing clinical trials are being conducted in advanced melanoma, non-small cell lung 
cancer, head and neck cancer, urothelial tract cancer, gastric cancer, triple negative breast 
cancer and in a number of hematologic malignancies.  For study details please refer to the IB.
 
 
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Rationale
Rationale for the Trial and Selected Subject Population
4.2.1.1
Primary Mediastinal Large B-Cell Lymphoma
Non Hodgkin lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders 
originated in B-lymphocytes, T-lymphocytes or natural killer cells. In the United States,
(US) B-cell lymphomas comprise 80 to 85% of NHL subjects.  It is estimated that in 2015 
around 71,850 new NHL cases will be diagnosed in United States, with approximately 
19,790 deaths due to the disease [28]. Diffuse Large B-Cell lymphoma (DLBCL) is the most 
common type of adult NHL in both North America and Europe, making up 30% to 40% of 
NHL.  PMBCL is a distinct subtype of NHL that histologically can be indistinguishable from 
DLBCL and account only for 2% to 3% of all cases. This subtype tends to occur in young 
adults with a median age of 35 years with a slight female predominance [29, 30, 31].
Interestingly, gene expression profiling has revealed that the pattern of gene expression in 
PMBCL is more similar to classical Hodgkin lymphoma (CHL) than DLBCL [32, 33].
The optimal therapeutic approach to PMBCL is controversial due to the limited availability
of prospective studies resulted from the rarity of the disease. For the most part, therapeutic 
approaches for PMBCL have been the same as the ones used for other subtypes of DLBCL, 
with regimens like R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, 
vincristine sulfate, and prednisone) widely used in front line.  However, the recently reported
high efficacy of increased dose intensity regimens as MACOP-B (methotrexate, leucovorin, 
doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin) followed by 
mediastinal radiation therapy in this disease suggests it may require a unique therapeutic 
approach [34, 35, 36]. Two retrospective studies have reported data regarding comparison 
between CHOP-like regimens and MACOP-B–like regimens as induction chemotherapy for
subjects with PMBCL [36, 37]. In these studies CR rates were between 49% and 53% with 
projected 10-year overall survival rates between 44% and 77% and projected 10-year 
progression free survival rates between 35% and 78%, respectively.
Overall, in the absence of randomized PMBCL clinical trials recommendations for optimal 
front line treatment for PMBCL subjects is more controversial than for other subtypes of 
DLBCL, with the consensus in US that R-CHOP followed by +/- radiotherapy or dose 
adjusted R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate 
[Oncovin], cyclophosphamide, doxorubicin hydrochloride [Hydroxydaunorubicin]) followed 
by +/- radiotherapy for persistent local disease are the preferred options for front line 
treatment.
There is currently very limited data available regarding the optimal treatment for relapsed or 
refractory PMBCL. The current approach is to extrapolate from modalities commonly used 
in the relapsed and refractory setting for other DLBCL subtypes like auto-SCT following 
front line or salvage chemotherapy regimens for auto-SCT ineligible subjects.
In the case of auto-SCT results from the Grupo Espanol de Linfomas y Transplante Autologo 
de Medula Osea (GEL-TAMO) group suggested that auto-SCT should be considered for 
subjects who do not achieve CR to front line treatment but who are still judged to be 
sensitive to chemotherapy, although in the absence of randomized clinical trials these results
 
 
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continue to be controversial [38]. The GEL-TAMO group registry included 71 subjects with 
PMBCL who received induction chemotherapy, followed by auto-SCT as frontline therapy. 
At transplant, 49% of subjects were in CR, 32% in partial response/remission (PR) and 18% 
failed induction therapy; 53% received radiotherapy. After the transplant, 75% of subjects
achieved CR. With a median follow-up of 52.5 months, the OS, PFS and disease-free 
survival at 4 years from diagnosis were, respectively, 84%, 81% and 81% for the first CR 
subjects and 49%, 42% and 82% for the induction failure (PR and refractory) subjects. 
Disease progression was the main cause of death (79%). Based on these results, the GEL-
TAMO group concluded that subjects with PMBCL presenting at diagnosis with high-risk 
features or PR response to induction therapy had an encouraging survival with frontline auto-
SCT. However, subjects who received the transplant after failing the induction regimen have
a very poor prognosis and should be tested with other innovative approaches.
In US, the recommendation from the National Comprehensive Cancer Network for subjects
who are not eligible for auto-SCT is to be treated in the context of clinical trials or 
alternatively with individualized salvage chemotherapy regimens with or without rituximab 
depending on whether the patient was deemed to be refractory to previous rituximab 
regimens. In a pilot study of 46 subjects with relapsed or refractory B-cell lymphoma, the 
majority of whom had DLBCL (72%), rituximab, gemcitabine, and oxaliplatin resulted in an 
ORR of 83% and half of the subjects achieved a CR [39]. The 2-year event-free survival and 
OS rates in this study were 43% and 66% respectively. The lack of clinical trials focusing on 
rrPMBCL make difficult the ability to select a specific chemotherapy regimen for this patient 
population, with no defined standard of care in the relapsed and refractory setting.
Preliminary results from our ongoing Phase 1b study evaluating pembrolizumab 10 mg/kg 
every 2 weeks (Q2W) in subjects with hematologic malignancies including myelodysplastic 
syndromes, Hodgkin lymphoma (HL), PD-L1-positive NHL, rrPMBCL and multiple 
myeloma indicate a response rate of 53.3%, including a CR rate of 20.0% in heavily 
pretreated HL subjects who had progressed after all lines of prior therapy including stem cell 
transplant [40]. Preliminary results for the rrPMBCL cohort in this study indicate a response 
rate of 33.3%, including a CR rate of 11.1% for this patient population.
Overall, treatments for recurrence and progression of disease for PMBCL subjects are of 
limited efficacy and their prognosis is exceedingly poor [34, 36]. Subjects with PD after 
salvage treatment are unlikely to derive clinical benefit from current treatment modalities. 
Therefore, in the absence of standard of care, relapsed or refractory PMBCL represents an 
urgent unmet medical need.
4.2.1.2
Richter Syndrome
The 2008 World Health Classification of hematopoietic tumors defines RS as the 
transformation of CLL into a more aggressive lymphoma [41].  Approximately 2% to 10% of 
CLL patients will experience transformation to a more aggressive lymphoma during the 
course of their disease, with a transformation rate of 0.5% to 1% per year [42].  The vast 
majority of these transformations are DLBCL; transformation to HL is reported rarely.  
Diagnosis of RS follows an investigation of apparently rapidly progressing underlying 
disease per signs and symptoms, and assessed by PET/CT.  A standardized uptake value > 5 
 
 
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is suggestive of RS, which may be confirmed by lymph node biopsy demonstrating DLBCL 
(or HL). 
The treatment for patients with RS is challenging due to the lack of randomized clinical trials 
to establish strategies.  Standard treatment approaches for RS have been suboptimal, as 
evident by the overall survival duration.  Induction therapy with R-CHOP can be used, but if 
the patient has previously received anthracyclines for their underlying disease, platinum-
based inductions regimens may be considered. (Induction with ABVD [doxorubicin
{Adriamycin}, bleomycin, vinblastine, dacarbazine] should be considered for RS to HL.)  If 
eligible for SCT, allogeneic transplant is preferred (to also target the underlying disease) if 
there is a donor; otherwise auto-SCT may be considered for treatment of the DLBCL (not the 
underlying disease).  For patients who do not respond to induction with anthracycline or 
platinum therapy, clinical trials of novel agents and/or supportive care should be considered
[42].
In a report of patients with CLL treated with ibrutinib, approximately half of the patients with 
disease progression on ibrutinib had RS transformation.  In these n=18 RS patients the 
median survival was 3.5 months (10 days to 6 months) following transformation despite 
treatment with commonly used regimen for DLBCL including R-EPOCH, R-CHOP, R-ICE
(rituximab, ifosfamide, carboplatin, etoposide), or others [43].  In another report, in n=46 
newly transformed RS patients treated with R-EPOCH the median PFS was 3.5 months and 
median OS was 5.9 months [44].
Patients with RS have a generally poor prognosis after transformation, and represent an 
unmet medical need.
4.2.1.3
Rationale for Evaluating anti-PD-1 Therapy in Primary Mediastinal Large 
B-Cell Lymphoma and Richter syndrome
Lymphoid malignancies are known to be responsive to a variety of immunotherapies, 
including allogeneic stem cell transplantation. While data are currently limited, there is some 
indication that PD-L1/PD-1 biology may be an important mechanism of tumor immune 
escape in hematologic malignancies.
High frequency of expression of PD-L1 by immunohistochemistry and flow cytometry has 
been demonstrated in classic HL and NHL tumor cells including PMBCL [45]. A recent 
integrative genetic analysis revealed frequent selective 9p24.1 amplification in PMBCL, 
which includes the PD-L1 and PD-L2 loci, resulting in increased PD-L1 expression and 
further induction via JAK2 [45].
Amplification on chromosome 9p24 is observed in 
approximately 70% of PMBCL cases [46].  The 9p24 amplicon contains several key targets, 
such as CD274 (encoding PD-L1), PDCD1LG2 (encoding PD-L2) and JAK2 [45, 47].  The 
frequent over-expression of PD-L1 and PD-L2 on PMBCL tumor cells suggests that this is an 
important mechanism for tumor evasion [48, 49].  Recurrent unbalanced rearrangements 
involving the major histocompatibility complex class II transactivator (CIITA), with multiple 
fusion partners, were reported in 38% of cases of PMBCL and these CIITA gene fusions were 
found to result in overexpression of PD-1 ligands [50].  These results further implicate the 
PD-1 pathway as a potential target in PMBCL.
 
 
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A Phase I clinical trial conducted in advanced hematologic malignancies using CT-011, a 
humanized antibody anti PD-1, showed clinical responses in 6 of 17 subjects including HL 
and NHL subjects [51]. Preliminary results from our ongoing Phase Ib study [Keynote-013] 
evaluating pembrolizumab
10 mg/kg every 2 weeks in subjects
with hematologic 
malignancies including myelodysplastic syndromes, HL, PD-L1-positive NHL, and multiple 
myeloma indicate a response rate of 53.3%, including a CR rate of 20.0% in heavily 
pretreated HL subjects who had progressed after all lines of prior therapy including stem cell 
transplant [40]. This is particularly important since PMBCL and HL share many common 
biological features, including the frequent 9p24 amplification mentioned above.  Indeed, 
preliminary results for the rrPMBCL cohort in this study indicate a response rate of 33.3%, 
including a CR rate of 11.1% for this patient population.
From the preliminary results of a phase 2 trial [52] of pembrolizumab monotherapy for the 
treatment of rrCLL including RS, among 7 RS patients enrolled, there was 1 CR, 2 PR 
(possible CR for RS without nodal biopsy confirmation but residual underlying CLL, 
resulting in overall PR), 3 stable disease (SD), and 1 PD.  Among these, 5 RS patients 
experienced previous PD on ibrutinib; all 5 had either CR/PR or SD with nodal or skin 
lymphoma responses [Data on file; Merck].  
Two subjects with newly transformed RS without any prior treatment for RS have been 
treated with pembrolizumab monotherapy, and achieved PR [Data on file; Merck].
Rationale for Dose Selection/Regimen/Modification
4.2.2.1
Rationale for Fixed Dose Pembrolizumab
The planned dose of pembrolizumab for this trial is 200 mg Q3W. Based on the totality of 
data generated in the Keytruda development program, 200 mg Q3W is the appropriate dose 
of pembrolizumab across all indications and regardless of tumor type. As outlined below, 
this dose is justified by:
•
Clinical data from 8 randomized studies demonstrating flat dose- and exposure-
efficacy relationships from 2 mg/kg Q3W to 10 mg/kg Q2W;
•
Clinical data showing meaningful improvement in benefit-risk including OS at 200 
mg Q3W across multiple indications; and
•
Pharmacology data showing full target saturation in both systemic circulation 
(inferred from pharmacokinetic [PK] data) and tumor (inferred from physiologically 
based pharmacokinetic [PBPK] analysis) at 200 mg Q3W.
Among the 8 randomized dose-comparison studies, a total of 2262 subjects were enrolled 
with melanoma and non-small cell lung cancer, covering different disease settings (treatment 
naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy). Five studies compared 2 mg/kg 
Q3W vs. 10 mg/kg Q3W (Keynote-001 B2, Keynote-001 D, Keynote-002, Keynote-010, and 
Keynote-021), and 3 studies compared 10 mg/kg Q3W vs. 10 mg/kg Q2W (Keynote-001 B3, 
Keynote-001 F2, and Keynote-006). 
All of these studies demonstrated flat dose- and 
 
 
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exposure-response relationships across the doses studied representing an approximate 5- to 
7.5-fold difference in exposure. The 2 mg/kg (or 200 mg fixed-dose) Q3W provided similar 
responses to the highest doses studied. 
Subsequently, flat dose-/exposure-response 
relationships were also observed in other tumor types including head and neck cancer, 
bladder cancer, gastric cancer, and CHL, confirming 200 mg Q3W as the appropriate dose 
independent of the tumor type. These findings are consistent with the mechanism of action 
of pembrolizumab, which acts by interaction with immune cells, and not via direct binding to 
cancer cells.
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W. First, PK 
data in Keynote-001 evaluating target-mediated drug disposition conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W. 
Secondly, a PBPK analysis was conducted to predict tumor PD-1 saturation over a wide 
range of tumor penetration and PD-1 expression.
This evaluation concluded that 
pembrolizumab at 200 mg Q3W achieves full PD-1 saturation in both blood and tumor.
Finally, population PK analysis of pembrolizumab, which characterized the influence of 
body weight and other subject covariates on exposure, has shown that the fixed-dosing 
provides similar control of PK variability as weight-based dosing, with considerable overlap 
in the distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.
Supported by these PK characteristics, and given that fixed-dose has advantages of reduced 
dosing complexity and reduced potential of dosing errors, the 200 mg Q3W fixed dose was 
selected for evaluation across all pembrolizumab protocols.
Rationale for Endpoints
4.2.3.1
Efficacy Endpoints
The primary efficacy objective of this study is to evaluate the anti-tumor activity of 
pembrolizumab in subjects with rrPMBCL or rrRS. The primary efficacy endpoint will be 
ORR as assessed by independent central review, according to the IWG response criteria
(Cheson, 2007 [1]) for PMBCL, and for RS, the IWG criteria with special considerations for 
RS (Section 12.7).
Other secondary efficacy endpoints will include PFS, DOR, DCR, OS and as exploratory 
endpoints, efficacy (ORR, PFS, DOR, and DCR) incorporating response assessments for 
subjects continuing pembrolizumab treatment after initial progression and ORR using the 
5-point scale per the Lugano Classification.
4.2.3.2
Safety Endpoints
The safety and tolerability of pembrolizumab in subjects with rrPMBCL or rrRS will be 
characterized in this study.  The safety analysis will be based on subjects who experienced 
toxicities as defined by CTCAE criteria.  Safety will be assessed by quantifying the toxicities 
and grades experienced by subjects who have received pembrolizumab, including SAEs and 
ECIs.
 
 
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Safety will be assessed by reported AEs using CTCAE, Version 4.0.  The attribution to drug, 
time-of-onset, duration of the event, its resolution, and any concomitant medications 
administered will be recorded.  AEs will be analyzed including but not limited to all AEs, 
SAEs, fatal AEs, and laboratory changes.  Furthermore, the occurrence of a Grade 2 or 
higher immune-related adverse events (irAEs) will be collected and designated as irAEs.
4.2.3.3
Patient Reported Outcomes
EORTC QLQ-C30, EQ-5D are not pure efficacy or safety endpoints because they are 
affected by both disease progression and treatment tolerability.
EORTC QLQ-C30
EORTC QLQ-C30 was developed to assess the quality of life of cancer subjects. It has been 
translated and validated into 81 languages and used in more than 3,000 studies worldwide.  It 
contains 5 functioning scales (physical, role, cognitive, emotional, and social), 3 symptom 
scales (fatigue, nausea, pain) and additional single symptom items. It is scored on a 4 point 
scale (1=not at all, 2=a little, 3=quite a bit, 4=very much). The EORTC QLQ-C30 instrument 
also contains 2 global scales that use 7 point scale scoring with anchors (1=very poor and 
7=excellent).
eEuroQoL-5D
The electronic (e) EQ-5D is a standardized instrument for use as a measure of health 
outcome.  The eEQ-5D will provide data for use in economic models and analyses including 
developing health utilities or quality-adjusted life years.  The five health state dimensions in 
this instrument include the following: mobility, self-care, usual activities, pain/discomfort, 
and anxiety/depression.  Each dimension is rated on a three point scale from 1 (extreme 
problem) to 3 (no problem).  The eEQ-5D also includes a graded (0 to 100) vertical visual 
analog scale on which the subject rates his or her general state of health at the time of the 
assessment.  The eEQ-5D will always be completed by subjects first before completing the 
EORTC QLQ-C30.
4.2.3.4
Planned Exploratory Biomarker Research
Planned Genetic Analysis
Understanding genetic determinants of drug response is an important endeavor during 
medical research. This research will evaluate whether genetic variation within a clinical trial 
population correlates with response to the treatment(s) under evaluation. If genetic variation 
is found to predict efficacy or adverse events, the data might inform optimal use of therapies 
in the patient population. This research contributes to understanding genetic determinants of 
efficacy and safety associated with the treatments in this study.
Biomarker research to identify factors important for pembrolizumab therapy may be pursued.  
For example, pre- and post-dose bone marrow biopsies/aspirates, lymph node biopsies and 
blood samples from this study may undergo flow cytometric, proteomic, genomic, and 
transcriptional analyses at a central laboratory.  Lymph node biopsies and blood samples will 
be evaluated using deoxyribonucleic acid (DNA) sequencing.  Utilizing both pre- and post-
treatment tumor biopsies and/or blood samples (serum or plasma), change in baseline of 
candidate biomarkers will also be assessed.
 
 
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Additional research may evaluate factors important for predicting responsiveness or 
resistance to pembrolizumab therapy and other immunologic targets.  In addition, biomarker 
assay characterization may be performed to evaluate factors important for the identification 
of biomarkers.
Assays may include but are not be limited to:
Multiplex Flow Cytometric Analysis
Emerging data suggest that blockade of the PD-1/PD-L1 pathway results in enhanced T-cell 
mediated immune response.  To test the hypothesis that T-cell activation mediated by 
pembrolizumab treatment correlates with clinical response, total T-cell count and T-cell 
subsets in peripheral blood, e.g., Naïve, activated, memory and regulatory T cells, will be 
assessed pre- and post-dose and in both responders and non-responders.  Natural killer cells 
enumeration will also be performed pre- and post-dose in both responders and non-
responders.
Transcriptional Analyses
Messenger ribonucleic acid (RNA) expression profiling in archival material, lymph node 
samples, and blood samples will be completed to assess gene expression and to attempt to 
define a gene set critical for clinical response to pembrolizumab.  The hypothesis to be tested 
is that pembrolizumab responders will exhibit a “stalled Cytotoxic T Lymphocyte” response 
within the tumor reflected in the physical proximity between PD-1 and PD-L1 expression 
and the presence of an aborted (e.g., weak but discernible) interferon-gamma transcriptional 
program will be detectable by profiling analyses.  Global profiling will also be pursued.
Expression of individual genes related to the immune system may also be evaluated such as 
immune signatures and critical cytokines (e.g., interleukin-10).
Gene Sequencing
New data are emerging that suggest we can define certain tumor types as having high 
mutational burden.  There is a potential that this hypermutated state may correlate with 
response to pembrolizumab therapy, and/or that the converse, ‘hypomutated’ state may 
correlate with non-response.
Genome-wide whole exome sequencing may be performed from archival material, lymph 
node samples, and blood samples to assess genomic events such as but not limited to 
mutational burden as well as to evaluate fusion and amplification events such as 9p24.1 
amplification.
4.2.3.5
Future Biomedical Research
The Sponsor will conduct Future Biomedical Research on specimens collected for future 
biomedical research during this clinical trial.  This research may include genetic analyses 
(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or 
the measurement of other analytes.
 
 
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Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from treatment
during participation, as clinical trials are designed to provide information about the safety 
and effectiveness of an investigational medicine.
Additional details regarding specific benefits and risks for subjects participating in this 
clinical trial may be found in the IB and Informed Consent documents.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with rrPMBCL or rrRS, of at least 18 years of age will be enrolled in 
this trial.
Subject Inclusion Criteria
In order to be eligible for participation in this trial, the subject must:
1. Be willing and able to provide written informed consent/assent for the trial.  The 
subject may also provide consent/assent for Future Biomedical Research (FBR).  
However, the subject may participate in the main trial without participating in 
FBR.
2. Be ≥18 years of age on day of signing informed consent.
PMBCL:
3. Diagnosis of PMBCL, according to the World Health Organization (WHO)
classification of neoplasms of the hematopoietic and lymphoid tissues (WHO 
Criteria, 2008 [48]).  Subject must be able to provide an evaluable core or 
excisional lymph node biopsy for evaluation of PMBCL diagnosis from an 
archival or newly obtained lymph node biopsy at Screening.  (Central review is 
not required before enrollment.  Enrollment can be done on local pathologic 
review for diagnosis.)
4. Have relapsed*a or refractory*b PMBCL and:

Have relapsed after auto-SCT or have failed to achieve a CR or PR within 60 
days of auto-SCT. Subjects may have received intervening therapy after auto-
SCT for relapsed or refractory disease, in which case they must have relapsed 
after or be refractory to their last treatment.
OR
 
 
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
For subjects who are ineligible for auto-SCT, have received at least ≥ 2 lines 
of prior therapy and have failed to respond to or relapsed after their last line of 
treatment. For subjects who received consolidative local radiotherapy after 
systemic therapy, local radiotherapy will not be considered as a separate line 
of treatment.
*a Relapsed Disease: progression of disease after achieving a remission to the most recent 
therapy
*b Refractory Disease: failure to achieve CR or PR to the most recent therapy
5. Must have been previously exposed to rituximab as part of prior lines of 
treatment.
Richter syndrome:
6. Pathologic diagnosis per local institutional review of Richter syndrome that 
transformed from CLL.
7. Have relapsed or refractory RS and has received at least 1 previous treatment for 
RS.
All Subjects:
8. Have radiographically measureable disease by independent central review,
defined as at least one lesion that can be accurately measured in at least two 
dimensions with appropriate anatomic imaging (CT scan or magnetic resonance 
imaging [MRI]).  Minimum measurement must be > 15 mm in the longest 
diameter.
a.
RS subjects must also be (PET positive at screening, defined as having at least 
one lesion, attributable to malignancy and with appropriate correlation to 
anatomic imaging, with uptake greater than that of normal liver tissue.  
9. Must have a performance status of 0 or 1 on the Eastern Cooperative Oncology 
Group (ECOG) Performance Scale.
10. Life expectancy > 3 months
11. Must demonstrate adequate organ function as defined in Table 1; all screening 
labs should be performed within 7 days of treatment initiation.  (Subjects may be 
enrolled based on local laboratory results pending central laboratory results.)
 
 
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Table 1
Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count
PMBCL):>1,000.0/mcL/ RS:>500/mcL  (unless 
marrow involvement)
Granulocyte colony stimulating factor
allowed 
during screening for RS only
Platelets
PMBCL ≥75,000.0/mcL  (RS: ≥ 25,000/mcL)
(unless marrow involvement)
Hemoglobin
≥8.0 g/dL (unless marrow involvement)
Renal
Creatinine OR
Measured or calculateda creatinine clearance
(Glomerular filtration rate can also be used in 
place of creatinine or creatinine clearance) 
≤1.5 X upper limit of normal (ULN) OR
≥60.0 mL/min for subject with creatinine levels > 1.5 
X institutional ULN
Hepatic
Total bilirubin
≤ 1.5 X ULN OR
Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN
Aspartate aminotransferase (SGOT)and alanine 
aminotransferase (SGPT)
≤ 2.5 X ULN OR
≤ 5 X ULN for subjects with liver metastasis
Albumin
≥3.0 g/100 mL
Coagulation
International Normalized Ratio or
Prothrombin Time (PT)
Activated Partial Thromboplastin Time (aPTT)
≤1.5 
X 
ULN 
unless 
subject 
is 
receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
≤1.5 
X 
ULN 
unless 
subject 
is 
receiving 
anticoagulant therapy as long as PT or PTT is within 
therapeutic range of intended use of anticoagulants
Abbreviations: PMBCL – primary mediastinal B-cell lymphoma; RS – Richter Syndrome; SGOT – serum glutamate 
oxaloacetic transaminase; SGPT – serum glutamate pyruvic transaminase.
a Creatinine clearance should be calculated per institutional standard.
12. Female subjects of childbearing potential must have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study 
medication.  If the urine test is positive or cannot be confirmed as negative, a 
serum pregnancy test will be required.
13. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception, as outlined in Section 5.7.2 Contraception, 
for the course of the study through 120 days after the last dose of study 
medication.
Note: 
Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
 
 
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14. Male subjects of childbearing potential (Section 5.7.2) must agree to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception, 
starting with the first dose of study therapy through 120 days after the last dose of 
study therapy.
Note: 
Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment.
2. Is receiving systemic steroid therapy < 3 days before the first dose of trial treatment 
or receiving any other form of immunosuppressive medication.
Note:
a.  Corticosteroid use on study after Cycle 1 for management of AEs, SAEs, and 
ECIs, as a premedication for IV contrast allergies/reactions, or if considered 
necessary for a subject’s welfare is allowed.
b.  Subjects 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. 
c.  Equivalent hydrocortisone doses are also permitted if administered as replacement 
therapy.
3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 (2 weeks
for RS subjects) or who has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs 
due to agents administered more than 4 weeks earlier (2 weeks for RS subjects).
4. Has had prior chemotherapy or targeted small molecule therapy within 2 weeks prior 
to study Day 1 or has had prior radiation therapy within 4 weeks prior to study Day 1 
or who has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to a previously 
administered agent.
Exception:  Subjects with RS with CLL may receive ibrutinib (or similar for CLL) up 
to 24 hours before first dose. 
Note: If subject received major surgery, they must have recovered adequately from 
the toxicity and/or complications from the intervention prior to starting therapy.
Note: Toxicity that has not recovered to ≤ Grade 1 is allowed if it meets the inclusion 
requirements for laboratory parameters defined in Table 1.
 
 
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5. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 
5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as 
long as there are no symptoms of Graft versus Host Disease (GVHD).
6. Has a known additional malignancy (except underlying CLL for RS) that is 
progressing or requires active treatment.  Exceptions include basal cell carcinoma of 
the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has 
undergone potentially curative therapy.
7. Has known active central nervous system (CNS) involvement. Subjects with prior 
CNS involvement are eligible if their CNS disease is in radiographic, cytological (for 
cerebrospinal fluid disease) and clinical remission.
8. Has active autoimmune disease that has required systemic treatment in past 2 years 
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs).  Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a 
form of systemic treatment.
9. Has a history of (non-infectious) pneumonitis that required steroids, or current
pneumonitis.
10. Has an active infection requiring intravenous systemic therapy.
11. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial.
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit 
through 120 days after the last dose of trial treatment.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, 
or anti-CTLA-4 antibody (including ipilimumab or any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathways).
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1 and 2
antibodies).
15. Has known active Hepatitis B (e.g., Hepatitis B surface antigen reactive) or Hepatitis 
C (e.g., Hepatitis C virus RNA [qualitative] is detected).
16. Has received a live vaccine within 30 days prior to first dose.
 
 
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Trial Treatment(s)
The treatment to be used in this trial is outlined below in Table 2.  
Table 2
Trial Treatment
Study Drug
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
pembrolizumab
200 mg
Q3W
IV infusion
Day 
1 
of 
each 
treatment cycle up 
to 
35 administrations 
(approximately 
2 years)
Experimental
Abbreviations: IV – intravenous; Q3W – every 3 weeks
Trial treatment should begin on the day of treatment allocation or as close as possible to the 
date on which the subject is allocated/assigned to treatment on the study.
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 trial 
treatments in accordance with the protocol and any applicable laws and regulations.
Dose Selection/Modification
5.2.1.1
Dose Selection (Preparation)
The rationale for selection of doses to be used in this trial is provided in Section 4.0 –
Background and Rationale.
All subjects will receive 200 mg pembrolizumab by IV infusion within a 30 minute period,
Q3W.  Details on the preparation and administration of study drug are provided in the 
Pharmacy Manual.
5.2.1.2
Dose Modification
Adverse events (both nonserious and serious) associated with pembrolizumab exposure may 
have an immunologic etiology.  These AEs may occur shortly after the first dose or several 
months after the last dose of treatment.  Pembrolizumab must be withheld for drug related 
toxicities and severe or life-threatening AEs as per Table 3.
In addition, subjects should receive appropriate supportive care measures as deemed 
necessary by the treating investigator.  Suggested supportive care measures, as described in 
Section 5.6.1, are also included in Table 3. 
Dosing interruptions are permitted in the case of medical/surgical events or logistical reasons 
not related to trial therapy (e.g., elective surgery, unrelated medical events, subject vacation, 
and/or holidays).  Subjects should be placed back on trial therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor.  The reason for 
interruption should be documented in the subject's trial record.
 
 
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Table 3
Dose Modification and Toxicity Management Guidelines for Immune-Related Adverse Events Associated With 
Pembrolizumab
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid has 
been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 
Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs and 
symptoms of pneumonitis

Evaluate participants with suspected 
pneumonitis with radiographic imaging 
and initiate corticosteroid treatment

Add 
prophylactic 
antibiotics 
for 
opportunistic infections
Grade 3 or 4, or 
recurrent Grade 2
Permanently discontinue
Diarrhea / colitis 
Grade 2 or 3
Withhold

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper

Monitor participants for signs and 
symptoms of enterocolitis (i.e., diarrhea, 
abdominal pain, blood or mucus in stool 
with or without fever) and of bowel 
perforation (i.e., 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.
Grade 4
Permanently discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
AST 
/ 
ALT 
elevation 
or 
increased bilirubin
Grade 2
Withhold

Administer corticosteroids 
(initial dose of 0.5-
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 or 4 
Permanently discontinue

Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisone or equivalent) 
followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
Newly onset T1DM or 
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence 
of 
-cell 
failure
Withhold

Initiate insulin replacement 
therapy 
for 
participants 
with T1DM 

Administer 
anti-
hyperglycemic 
in 
participants 
with 
hyperglycemia 

Monitor participants for hyperglycemia 
or other signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer corticosteroids 
and 
initiate 
hormonal 
replacements as clinically 
indicated.  

Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism 
and adrenal insufficiency)
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat with non-selective 
beta-blockers 
(e.g.,
propranolol) or thioamides
as appropriate 

Monitor for signs and symptoms of 
thyroid disorders. 
Grade 3 or 4 
Withhold or 
Permanently discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate 
thyroid 
replacement 
hormones 
(e.g.,
levothyroxine 
or 
liothyronine) per standard 
of care

Monitor for signs and symptoms of 
thyroid disorders. 
Nephritis 
and 
renal dysfunction
Grade 2
Withhold 

Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by 
taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action taken to 
pembrolizumab
irAE management with 
corticosteroid and/or other 
therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 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
All 
Other 
immune-related 
AEs
Intolerable/ persistent 
Grade 2
Withhold

Based on type and severity 
of 
AE 
administer 
corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold or discontinue based 
on the type of event.  Events that 
require discontinuation include 
and not limited to:  Guillain-
Barre Syndrome, encephalitis
Grade 4 or recurrent 
Grade 3 
Permanently discontinue
Abbreviations: AE  – adverse event; ALT  – alanine transaminase’ AST  – aspartate transaminase; CTCAE – Common Terminology Criteria for Adverse Events; 
GI  – gastrointestinal; irAE  – immune-related adverse event; IV  – intravenous; T1DM  – type 2 diabetes mellitus.
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when AE 
resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).
 
 
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Timing of Dose Administration
Trial treatment should be administered on Day 1 of each cycle after all 
procedures/assessments have been completed as detailed on the Trial Flow Chart 
(Section 6.0).  Cycle 1 may not be administered until after completion of all screening 
assessments and randomization.  Beginning with Cycle 2 trial treatment may be administered 
up to 3 days before or after the scheduled Day 1 of each cycle due to administrative reasons.  
Interruptions from the treatment plan for greater than 3 days and up to 3 weeks may be 
allowed, but require consultation between the investigator and Sponsor, and written 
documentation of the collaborative decision on subject management.
Trial treatments will be administered on an outpatient basis.
Inpatient study drug 
administration may be allowed with sponsor consultation.
Pembrolizumab will be administered as a 30 minute IV infusion every 3 weeks. Sites should 
make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes 
and +10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for pembrolizumab reconstitution, 
preparation of the infusion fluid, and administration.
Extent of Trial Treatment

All subjects may remain on treatment for up to 35 administrations of pembrolizumab 
(approximately 2 years) or until confirmed PD.

Per the investigator’s discretion subjects who achieve a CR may stop treatment and 
are eligible to restart treatment upon documented progression as long as they meet 
eligibility criteria specified in the protocol (see Section 7.1.5.2.1) and the trial is still 
ongoing. These subjects will be eligible for retreatment for up to 17 administrations 
of pembrolizumab (approximately 1 year).
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
Treatment allocation/randomization will occur centrally using an interactive voice response 
system / integrated web response system (IVRS/IWRS). There is one treatment arm. 
Subjects participating in this trial will be allocated by non-random assignment.
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
 
 
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Concomitant Medications/Vaccinations (Allowed & Prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the trial, discontinuation from trial therapy or vaccination may 
be required.  The investigator should discuss any questions regarding this with the Sponsor 
Clinical Director.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the subject's primary physician.  However, the decision to continue the 
subject on trial therapy or vaccination schedule requires the mutual agreement of the 
investigator, the Sponsor and the subject.
Acceptable Concomitant Medications
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care.  All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over-the-counter (OTC), herbal supplements, and IV medications 
and fluids.  If changes occur during the trial period, documentation of drug dosage, 
frequency, route, and date may also be included on the CRF.  Subject may remain on anti-
coagulation therapy as long as the prothrombin time or partial thromboplastin time is within 
therapeutic range of the intended use of anticoagulants
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2.
In subjects with rrRS, additional therapies to treat the underlying CLL (according to 
treatment guidelines) may be added at the physician’s discretion if medically necessary and
with Sponsor approval.  These therapies must be approved by regulatory authorities for CLL 
and commercially available.
Corticosteroid use on study for management of AEs, SAEs, and ECIs, as a premedication for 
IV contrasts, allergies/reactions, or if considered necessary for a subject’s welfare is allowed.
Prohibited Concomitant Medications
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial:

Antineoplastic systemic chemotherapy or biological therapy

Granulocyte Macrophage - Colony Stimulating Factor

Immunotherapy not specified in this protocol, however Immunoglobulin Therapy
(IVIG) is allowed

Chemotherapy not specified in this protocol
 
 
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
Investigational agents other than pembrolizumab

Radiation therapy
Note:  Radiation therapy to a symptomatic soft tissue lesion, bone lesions, or to the brain 
may be allowed after consultation with Sponsor.
Note: Radiation may be administered ONLY to subjects that have CR, PR, or SD who in 
the opinion of the investigator may have a tumor flare reaction in an isolated area. 
Subjects that are progressing with no suspicion of tumor flare and require radiation
therapy must be discontinued from study treatment.

Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, chickenpox, yellow fever, rabies, Bacillus 
Calmette-Guerin, and oral typhoid vaccine.  Seasonal influenza vaccines for injection 
are generally killed virus vaccines and are allowed; however intranasal influenza 
vaccines (e.g., FluMist®) are live attenuated vaccines, and are not allowed.
Subjects who, in the assessment by the investigator and after consultation with the Sponsor, 
require the use of any of the aforementioned treatments for clinical management should be 
removed from the trial.  Subjects may receive other medications that the investigator deems 
to be medically necessary.
The Exclusion Criteria describes other medications which are prohibited in this trial.
There are no prohibited therapies during the Post-Treatment Follow-up Phase. Subjects must 
be discontinued from the active follow-up phase if they begin a non-trial treatment for their 
underlying disease.
Rescue Medications & Supportive Care
Supportive Care Guidelines
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.1.2 (Table 3).  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the Investigator determines the events to be 
related to pembrolizumab. 
Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the Investigator does not need to follow the treatment guidance.  Refer to Table 3 in Section
5.2.1.2 for guidelines regarding dose modification and supportive care. 
 
 
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It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.
Diet/Activity/Other Considerations
Diet
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea, or vomiting.
Contraception
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.  
For this trial, male subjects will be considered to be of non-reproductive potential if they 
have azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).
Female subjects will be considered of non-reproductive potential if they are either:
1. postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) 
level in the postmenopausal range may be used to confirm a post-menopausal state in 
women not using hormonal contraception or hormonal replacement therapy. In the 
absence of 12 months of amenorrhea, a single FSH measurement is insufficient.);
OR
2. have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or 
bilateral tubal ligation/occlusion, at least 6 weeks prior to screening;
OR
3. has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant 
or impregnating a partner, respectively, while receiving study drug and for 120 days after the 
last dose of study drug by complying with one of the following:
1. practice abstinence† from heterosexual activity;
OR
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):

intrauterine device

vasectomy of a female subject’s male partner 

contraceptive rod implanted into the skin
 
 
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Combination method (requires use of two of the following):

diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

cervical cap with spermicide (nulliparous women only)  

contraceptive sponge (nulliparous women only) 

male condom or female condom (cannot be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and Ethic Review 
Committees (ERCs)/Institutional Review Boards (IRBs).  Periodic abstinence (e.g., 
calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal 
are not acceptable methods of contraception.
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate 
in the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the 
initiation of study medication for oral contraception) throughout the study period up to 120 
days after the last dose of trial therapy.  If there is any question that a subject of childbearing 
potential will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study.
5.7.3
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab the 
subject will be immediately discontinued from trial treatment.  The site will contact the 
subject at least monthly and document the subject’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to the Sponsor 
without delay and within 24 hours if the outcome is a serious adverse experience (e.g., death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).  The trial Investigator will make every effort to obtain permission to 
follow the outcome of the pregnancy and report the condition of the fetus or newborn to the 
Sponsor.
 
 
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5.7.4
Use in Nursing Women
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment.
Subject Withdrawal/Discontinuation Criteria
Discontinuation of Treatment
Discontinuation of treatment does not represent withdrawal from the trial.
As certain data on clinical events beyond treatment discontinuation are important to the 
study, they must be collected through the subject’s last scheduled follow-up, even if the 
subject has discontinued treatment.  Therefore, all subjects who discontinue trial treatment
prior to completion of the treatment period will still continue to participate in the trial as 
specified in Section 6.0 - Trial Flow Chart and Section 7.1.5.3 – Post Treatment Visits.
Subjects may discontinue treatment at any time for any reason or be dropped from treatment 
at the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be discontinued from treatment by the investigator or the Sponsor if treatment is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
Specific details regarding procedures to be performed at treatment discontinuation are 
provided in Section 7.1.4 – Other Procedures.
A subject must be discontinued from treatment but continue to be monitored in the trial for 
any of the following reasons:

The subject or subject’s legally acceptable representative requests to discontinue 
treatment.
o
Confirmed radiographic disease progression outlined in Section 7.1.2.7.5 (exception 
if the Sponsor approves treatment continuation).
o
Unacceptable adverse experiences as described in Section 7.2
o
Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment
o
Intercurrent illness other than another malignancy as noted above that prevents 
further administration of treatment 
o
Recurrent Grade 2 pneumonitis
o
A confirmed positive serum pregnancy test
o
Noncompliance with trial treatment or procedure requirements
o
Investigator's decision to withdraw the subject
For subjects who are discontinued from treatment but continue to be monitored in the trial, 
all visits and procedures, as outlined in the trial flowchart, should be completed.
 
 
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Withdrawal from the Trial
A subject must be withdrawn from the trial if the subject or subject’s legally acceptable 
representative withdraws consent from the trial.
If a subject withdraws from the trial, they will no longer receive treatment or be followed at 
scheduled protocol visits.
Specific details regarding procedures to be performed at the time of withdrawal from the trial 
including the procedures to be performed should a subject repeatedly fail to return for 
scheduled visits and/or if the study site is unable to contact the subject, as well as specific 
details regarding withdrawal from Future Biomedical Research are outlined in Section 7.1.4 
– Other Procedures.
Subject Replacement Strategy
A subject who discontinues from the trial will not be replaced.
Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, 
discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by 
the investigator) or the Sponsor ends the trial, whichever occurs first.
Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete,
2. Poor adherence to protocol and regulatory requirements,
3. Plans to modify or discontinue the development of the study drug.
4. Sponsor’s decision to terminate the study.
In the event of Sponsor decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
 
 
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6.0 TRIAL FLOW CHART
Trial Flow Chart
Trial Period
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
To be repeated beyond 9 cycles
Treatment Cycle/Title
Screening
(Visit 1)
1
2
3
4
5
6
7
8
9
Discon
Post-
Treatment 
Safety 
Follow-up
Follow-up 
Visits a
Survival 
Follow-up b
Scheduling Window (Day 1 of 
each cycle + 3 days)
-28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
last dose
(±3 days)
Every 12 
weeks post 
Discon
(±14 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Administrative Procedures
Informed Consent
X
Informed Consent for Future 
Biomedical Research
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical 
History
X
Prior and Concomitant 
Medication Review
X
X
X
X
X
X
X
X
X
X
X
X
Obtain randomization number 
and study drug assignment using 
IVRS/IWRS
X
Pembrolizumab Administration
X
X
X
X
X
X
X
X
X
Post-study anticancer therapy 
status
X
X
X
Survival Status b
X b
Clinical 
Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X h
Full Physical Examination
X
X
X
X
X h
Directed Physical Examination
X
X
X
 
 
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Trial Period
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
To be repeated beyond 9 cycles
Treatment Cycle/Title
Screening
(Visit 1)
1
2
3
4
5
6
7
8
9
Discon
Post-
Treatment 
Safety 
Follow-up
Follow-up 
Visits a
Survival 
Follow-up b
Scheduling Window (Day 1 of 
each cycle + 3 days)
-28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
last dose
(±3 days)
Every 12 
weeks post 
Discon
(±14 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
X
X h
12-Lead Electrocardiogram
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
X
X h
Neck, Chest, Abdominal, Pelvic 
PET, CT
X
X c, d
X c, d
X d
X a
Disease Response Assessment by 
IWG criteria
X
X
X
X a
Assessment of Lymphoma B 
Symptoms
X
X
X
X
X a
Laboratory 
Procedures/Assessments:  
analysis performed by local 
laboratory
Pregnancy Test – Urine or Serum 
-HCG e
(≤ 72 hrs) 
X
X
X
X
X
X
X
X
X
X
Bone Marrow Biopsy and
Aspirate f
X
PRN f
PRN f
Bone marrow morphology, 
Cytogenetics
X
  
 
 
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Trial Period
Screening 
Phase
Treatment Cycles
End of 
Treatment
Post-treatment
To be repeated beyond 9 cycles
Treatment Cycle/Title
Screening
(Visit 1)
1
2
3
4
5
6
7
8
9
Discon
Post-
Treatment 
Safety 
Follow-up
Follow-up 
Visits a
Survival 
Follow-up b
Scheduling Window (Day 1 of 
each cycle + 3 days)
-28 to -1
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
last dose
(±3 days)
Every 12 
weeks post 
Discon
(±14 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Laboratory 
Procedures/Assessments: 
analysis performed by central 
laboratory
Lymph Node Biopsy (archival or 
newly obtained sample)
X fg
X h
X fh
Whole Blood for Correlative 
Studies (RNA/DNA)
X
X
X
X
Blood for Biomarker Studies 
(plasma and serum)
X
X
X
X
Blood for Genetics
X
PT/INR and aPTT
X
CBC with Differential
X
(-7 days)
X
X
X
X
X
X
X
X
X
X
X
X i
Comprehensive Chemistry  Panel
X
(-7 days)
X
X
X
X
X
X
X
X
X
X
X
X i
LDH
X
X
Urinalysis
X
X
X
X
X
X
T3 (or FT3 per local standard), 
FT4 and TSH
X
X
X
X
X
X
Patient Reported Outcomes
EuroQoL EQ-5D k
X j
X j
X j
X j
X j
X j
X j
X j
EORTC QLQ-C30 k
X j
X j
X j
X j
X j
X j
X j
X j
 
 
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Abbreviations: aPTT – activated partial thromboplastin time; β-hCG  – beta human chorionic gonadotropin; CBC– complete blood count; CLL – chronic lymphocytic leukemia; 
CR – complete response/remission; CT – computed tomography; DNA – deoxyribonucleic acid; ECOG – Eastern Cooperative Oncology Group; EORTC QLQ C30 – European 
Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items; ePRO – electronic patient reported outcome; EQ-5D – European Quality of Life 
5-Dimension; FT3 – free triiodothyronine; FT4 – free thyroxine; INR – International Normalized Ratio; IVRS – Integrated Voice Response System; IWG – International Working 
Group; IWRS  – Integrated Web Response System; LDH – lactate dehydrogenase; PET – positron emission tomography; PD – progressive disease; PRO – patient reported 
outcome; PT – prothrombin time; RNA – ribonucleic acid; RS – Richter Syndrome; T3 – triiodothyronine; TSH – thyroid stimulating hormone.
a.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging every 12 weeks (± 7 days) until (1) the start of new anti-cancer treatment, (2) documented disease progression by investigator assessment, (3) death, or (4) the end of 
the study, whichever occurs first.
b. After the start of new anti-cancer treatment or documented disease progression by investigator assessment, the subject will transition to the Survival Follow-up and should be 
contacted by telephone (or in person if recent contact for other purposes during window) approximately every 12 weeks to assess survival status.  Updated survival status may 
be requested by the Sponsor at any time during the course of the study.  Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study 
contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death event previously recorded).
c.
If subjects have stable disease, partial remission, or complete response they should continue on every 12 week (± 7 days) assessment schedule as described in section 7.1.2.7.4. 
Imaging should occur at any time where there is clinical suspicion of progression.
d. In subjects with an unconfirmed PD assessment who continued study therapy, a radiological assessment should be performed 12 weeks (± 7 days) later or at the time of 
treatment discontinuation. If previous scan was obtained within 4 weeks prior to the date of discontinuation, then a repeat scan at treatment discontinuation isn’t mandatory. 
However, imaging should occur at any time where there is clinical suspicion of progression.
e.
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to each cycle of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test performed by the local study site laboratory will be required.  Pregnancy tests (serum and/or urine tests) should be repeated if 
required by local guidelines.
f.
For all subjects, collect bone marrow biopsy and aspirate at baseline.  Repeat bone marrow biopsy and aspirate as needed to confirm CR. Local results of bone marrow biopsy 
and aspirate will be used for baseline and to confirm CR (or other reason).  Residual bone marrow biopsy sample (all subjects for any sample obtained) should be sent to the 
central lab for potential future central analysis per sponsor discretion.  For RS it is necessary to confirm marrow clearance of RS or lymphoma clone to confirm CR.  If 
indeterminate by morphology, immunohistochemistry should be negative.  Residual underlying CLL may persist in node and/or marrow and still qualify as CR. 
g. At screening subjects are required to submit an archival or newly obtained sample of lymph node biopsy. An archival sample is acceptable for subjects in which tumors are 
inaccessible or contraindicated due to subject safety concerns. 
h. Newly obtained sample of lymph node biopsies at Week 12 (± 7 days) and at the time of discontinuation due to disease progression are optional but highly recommended. 
Newly obtained samples of lymph node biopsies for subjects in which tumors are inaccessible or contraindicated due to subject safety concerns are exempt from this 
requirement.  Detailed instructions for tissue collection, processing, and shipment are provided in the Procedures Manual
i.
To be performed only up to 90 days of the end of treatment or before initiation of a new antineoplastic treatment.
j.
Patient reported outcomes (PROs) are assessed every cycle for the first five cycles and every 4 cycles thereafter until PD or up to 1 year while the subject is receiving study 
treatment. PROs will also be obtained at the Treatment Discontinuation Visit and 30-day Safety Follow-up Visit. If the Treatment Discontinuation Visit occurs 30 days from 
the last dose of study treatment, at the time of the mandatory Safety Follow up Visit, PROs do not need to be repeated. PROs are to be administered by trained site personnel
and completed electronically by subjects. It is strongly recommended that all electronic PROs (ePROs) are administered prior to drug administration, adverse event evaluation 
and disease status notification.  The PROs should be administered in the following order: EQ-5D followed by EORTC QLQ-C30. If the subject does not complete the ePROs,
the MISS_MODE form must be completed to capture the reason the assessment was not performed.  Subjects who are on-study (signed informed consent) before approval of 
Amendment 01 (which instituted PROs) do not need to complete PROs.
 
 
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Trial Flow Chart: Second Course Phase (Retreatment for Post-Complete Response Relapse Only)
Trial Period
Treatment Cycles
End of 
Treatment
Post-treatment
To be repeated beyond 9 cycles
Treatment Cycle/Title
1
2
3
4
5
6
7
8
9
Discon
Post-
Treatment 
Safety 
Follow-up
Follow-up 
Visits a
Survival 
Follow-up b
Scheduling Window (Day 1 of each cycle 
+ 3 days)
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
last dose
(±3 days)
Every 12
weeks post 
Discon
(±14 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Administrative Procedures
Eligibility Criteriac
X
Prior and Concomitant Medication 
Review
X
X
X
X
X
X
X
X
X
X
X
Pembrolizumab Administration
X
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
X
Survival Statusb
Xb
Clinical Procedures/Assessments
Review Adverse Events
X
X
X
X
X
X
X
X
X
X
X
Xf
Full Physical Examination
X
X
X
Directed Physical Examination
X
X
X
Vital Signs and Weight
X
X
X
X
X
X
X
X
X
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Neck, Chest, Abdominal, Pelvic PET/CT
Xd,e
X
Xe
X a
Disease Response Assessment by IWG
criteria
X
X
X
X a
Assessment of Lymphoma B Symptoms
X
X
X
X a
 
 
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Trial Period
Treatment Cycles
End of 
Treatment
Post-treatment
To be repeated beyond 9 cycles
Treatment Cycle/Title
1
2
3
4
5 
6
7
8
9
Discon
Post-
Treatment 
Safety 
Follow-up
Follow-up 
Visitsa
Survival 
Follow-upb
Scheduling Window (Day 1 of each 
cycle + 3 days)
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
last dose
(±3 days)
Every 12
weeks post 
Discon
(±14 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Laboratory Procedures/Assessments:  
analysis performed by local 
laboratory
Pregnancy Test – Urine or Serum -
HCG
X
X
X
X
X
X
X
X
X
X
Bone Marrow Biopsy and Aspirate
X
Laboratory Procedures/Assessments: 
analysis performed by central 
laboratory
Blood for Correlative Studies
(DNA/RNA)
X
X
CBC with Differential
X
X
X
X
X
X
X
X
X
X
Comprehensive Chemistry Panel
X
X
X
X
X
X
X
X
X
X
LDH
X
X
X
X
Urinalysis
X
X
X
X
X
T3 (or FT3 per local standard), FT4 and 
TSH
X
X
X
X
X
X
 
 
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Abbreviations: aPTT – activated partial thromboplastin time; β-hCG  – beta human chorionic gonadotropin; CBC– complete blood count; CLL – chronic lymphocytic 
leukemia; CR – complete response/remission; CT – computed tomography; DNA – deoxyribonucleic acid; ECOG – Eastern Cooperative Oncology Group; FT3 – free 
triiodothyronine; FT4 – free thyroxine; INR – International Normalized Ratio; IVRS – Integrated Voice Response System; IWG – International Working Group; IWRS  –
Integrated Web Response System; LDH – lactate dehydrogenase; PET – positron emission tomography; PD – progressive disease; PT – prothrombin time; RNA – ribonucleic 
acid; T3 – triiodothyronine; TSH – thyroid stimulating hormone.
a.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status by radiologic 
imaging every 12 weeks (± 7 days) until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or (4) the end of the study, whichever 
occurs first.
b.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone (or in person if recent contact for other 
purposes during window) approximately every 12 weeks to assess for survival status.  Updated survival status may be requested by the Sponsor at any time during the 
course of the study.  Upon Sponsor notification, all subjects who do not/will not have a scheduled study visit or study contact during the Sponsor-defined time period 
will be contacted for their survival status (excluding subjects who have a death event previously recorded).
c.
Subjects who attain a CR by independent central review and discontinue treatment may restart trial treatment if they meet the criteria specified in Section 7.1.5.2.1.
d.
If subjects have stable disease, partial remission, or complete response they should continue on every 12 week assessment schedule. Imaging should occur at any time 
where there is clinical suspicion of progression.
e.
Imaging should occur as described in Section 7.1.2.7.4 In subjects with an unconfirmed PD assessment who continued study therapy, a radiological assessment should 
be performed 4-6 weeks later or at the time of treatment discontinuation. If previous scan was obtained within 4 weeks prior to the date of discontinuation, then a repeat 
scan at treatment discontinuation isn’t mandatory. However, imaging should occur at any time where there is clinical suspicion of progression.
f.
To be performed only up to 90 days of the end of treatment or before initiation of a new antineoplastic treatment.
 
 
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7.0 TRIAL PROCEDURES
Trial Procedures
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator.
Furthermore, additional evaluations/testing may be deemed necessary by the investigator and 
or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing 
may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations 
may require that additional informed consent be obtained from the subject.  In these cases, 
such evaluations/testing will be performed in accordance with those regulations.
Administrative Procedures
7.1.1.1
Informed Consent
The investigator or qualified designee must obtain documented consent from each potential 
subject or each subject’s legally acceptable representative prior to participating in a clinical 
trial or Future Biomedical Research.
7.1.1.1.1 General Informed Consent
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion. 
A copy of the signed and dated consent form should be given to the subject before 
participation in the trial.
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature.
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.  
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements.
 
 
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7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research
The investigator or qualified designee will explain the Future Biomedical Research consent 
to the subject, answer all of his/her questions, and obtain written informed consent before 
performing any procedure related to the Future Biomedical Research sub-trial.  A copy of the 
informed consent will be given to the subject.
7.1.1.2
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.
7.1.1.3
Subject Identification Card
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial.  The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency.  The investigator or qualified designee 
will provide the subject with a Subject Identification Card immediately after the subject 
provides written informed consent.
The subject identification card also contains contact information for the emergency 
unblinding call center so that a health care provider can obtain information about trial 
medication/vaccination in emergency situations where the investigator is not available.
7.1.1.4
Medical History
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the investigator. Details regarding the disease 
for which the subject has enrolled in this trial will be recorded separately and not listed as 
medical history.
Prior acute or chronic GVHD, maximum grade, and dates will be collected.
7.1.1.5
Prior and Concomitant Medications Review
7.1.1.5.1 Prior Medications
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in the study will be recorded separately and not listed as a prior medication.
7.1.1.5.2 Concomitant Medications
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial through the Safety Follow-up visit.  Record all medications taken for SAEs 
and ECIs as defined in Section 7.2.
 
 
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7.1.1.5.3 Prior Cancer Treatment Details
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, prior transplantation, radiation, and surgeries and record in the trial 
database.
7.1.1.5.4 Subsequent Antineoplastic Therapy 
The investigator or qualified designee will review all new antineoplastic therapy initiated 
after the last dose of trial treatment.  If a subject initiates a new antineoplastic therapy within 
30 days after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur 
before the first dose of the new therapy.  Once new antineoplastic therapy has been initiated 
the subject will move into survival follow-up.
Collect transplant parameters after study treatment to include the conditioning regimen, date,
and type of transplant.
7.1.1.6
Assignment of Screening Number
All consented subjects will be given a unique screening number that will be used to identify 
the subject for all procedures that occur prior to randomization or treatment allocation.  Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.
Any subject who is screened multiple times will retain the original screening number 
assigned at the initial screening visit.
Specific details on the screening visit requirements (screening/rescreening) are provided in 
Section 7.1.5.1.
7.1.1.7
Assignment of Treatment/Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
treatment/randomization number.  The treatment/randomization number identifies the subject 
for all procedures occurring after treatment allocation/randomization.   Once a 
treatment/randomization number is assigned to a subject, it can never be re-assigned to 
another subject.
A single subject cannot be assigned more than 1 treatment/randomization number.
7.1.1.8
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment (for 12 weeks between pembrolizumab 
doses due to toxicity) require consultation between the investigator and the Sponsor and 
written documentation of the collaborative decision on subject management.
Administration of trial medication will be witnessed by the investigator and/or trial staff.  
The total volume of trial treatment infused will be compared to the total volume prepared to 
determine compliance with each dose administered.
The instructions for preparing and administering pembrolizumab will be provided in the 
Pharmacy Manual.
 
 
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Clinical Procedures/Assessments
7.1.2.1
Oncologic Disease Details
The investigator or qualified designee will obtain prior and current details regarding 
oncologic disease status.
7.1.2.2
Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for potential new 
or worsening AEs as specified in the Trial Flow Chart and more frequently if clinically 
indicated.  Adverse experiences will be graded and recorded throughout the study and during 
the follow-up period according to NCI CTCAE Version 4.0 (see Section 12.6).  Toxicities 
will be characterized in terms regarding seriousness, causality, toxicity grading, and action 
taken with regard to trial treatment.
All AEs of unknown etiology associated with pembrolizumab exposure should be evaluated 
to determine if it is possibly an event of a potentially immunologic etiology (irAE).  See 
Section 7.2 regarding the identification, evaluation, and management of AEs of a potential 
immunological etiology.
Please refer to Section 7.2 for detailed information regarding the assessment and recording of 
AEs.
7.1.2.3
Electrocardiogram
A standard 12-lead electrocardiogram (ECG) will be performed using local standard 
procedures at screening.  Clinically significant abnormal findings should be recorded as 
medical history.
7.1.2.4
Physical Exam
7.1.2.4.1 Full Physical Exam
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening (height need be taken at 
screening only) and repeated as per the frequency defined in the Study Flow Chart.  After the 
first dose of trial treatment new clinically significant abnormal findings should be recorded 
as AEs.
7.1.2.4.2 Directed Physical Exam
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.  New clinically significant abnormal findings should be 
recorded as AEs.
 
 
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7.1.2.5
Vital Signs
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only.
7.1.2.6
Eastern Cooperative Oncology Group (ECOG) Performance Status
The investigator or qualified designee will assess ECOG status (see Section 12.5) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart.
7.1.2.7
Assessment of Disease and Tumor Imaging
7.1.2.7.1 Tumor Imaging and Criteria for Assessment of Disease
The process for image collection and transmission to the independent central imaging vendor 
can be found in the Site Imaging Manual. Independent central review based on IWG 
response criteria (Cheson, 2007 [1]) will be used to determine subject eligibility. 
The central imaging vendor will receive all CT/PET images from the sites including baseline 
images and will confirm eligibility. Eligibility will be based on the independent central 
review assessment, rather than site assessment.  Expedited confirmation of measurable 
disease as determined by central review will be communicated to the site.
Anti-tumor activity of pembrolizumab by CT/PET will be evaluated using the following 
criteria:

PMBCL:  IWG response criteria (Cheson, 2007 [1]) See Section 12.7.  

RS:  IWG response criteria (Cheson, 2007 [1]) with special considerations for RS 
(Section 12.7). In subjects with rrRS, assessment of disease in the bone marrow
will be limited to RS lymphoma.
The IWG will be applied by the independent central imaging vendor as the primary measure 
for eligibility, assessment of tumor response, and date of disease progression. CT/PET 
imaging showing subject’s eligibility should be submitted to the central imaging vendor 
immediately. The site will be notified if the independent central review confirms eligibility. 
Additionally, the investigator will apply the IWG response criteria for assessment of disease 
response and disease progression. In addition, assessment of lymphoma B symptoms should 
occur with each lymphoma disease response assessment.
In subjects with RS, assessment of disease in the bone marrow will distinguish changes due 
to RS or transformed lymphoma from changes due to the pre-existing CLL.  RS subjects may 
be assessed as showing radiographic CR if all lesions resolve on anatomic imaging, or if all 
remaining lesions show PET avidity lower than normal liver tissue, consistent with complete 
disappearance of fluorodeoxyglucose (FDG)-avid disease.  If radiographic CR is observed 
(no evidence of active disease on imaging), a final response determination of CR requires 
marrow clearance of RS (as determined by marrow biopsy and aspirate), as well as 
 
 
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disappearance of other clinical evidence of disease (such as physical exam findings). If the 
bone marrow is indeterminate by morphology, immunohistochemistry should be negative for 
RS. Residual underlying CLL may persist in node and/or marrow and still qualify as CR, 
denoting complete response of RS to pembrolizumab. Additional node biopsies for RS 
should be considered in the presence of enlarging lymph nodes to determine if due to 
underlying CLL or RS.
Anti-tumor activity of pembrolizumab will also be evaluated by independent central review
as part of the exploratory analyses using the Lugano Classification (Cheson, 2014 [2]), see 
Section 12.8.
7.1.2.7.2 Disease Assessment of Immunotherapeutic Agents
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses, which may be functionally 
anergic.  The response patterns seen with such an approach may extend beyond the typical 
time course of responses seen with cytotoxic agents, and can manifest a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions.  Standard 
response assessment criteria may not provide a comprehensive response assessment of 
immunotherapeutic agents such as pembrolizumab.  Therefore in the setting where a subject
assessment shows unconfirmed PD by investigator assessment, study drug may be continued 
upon Sponsor consultation, if the investigator considers the subject is deriving clinical 
benefit and providing subsequent radiographic imaging shows evidence of reduction or 
stabilization in tumor burden from the prior time point where initial unconfirmed PD was 
observed. If repeat imaging shows a reduction or stabilization in the tumor burden compared 
to the initial scan demonstrating PD, treatment may be continued/resumed. If repeat imaging 
confirms PD by investigator assessment, subjects will be discontinued from study therapy.
Imaging should occur at any time where there is clinical suspicion of progression.
7.1.2.7.3 Initial Disease Assessment
Initial disease assessment or tumor imaging must be performed within 28 days prior to the 
first dose of trial treatment.  The site study team must review pre-trial images to assess if the 
subject has measurable disease as defined in the inclusion criteria and submit CT/PET 
imaging showing subject’s eligibility to the central imaging vendor immediately for 
confirmation.  The site will be notified if the independent central review confirms eligibility 
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 trial treatment.  CT and PET should be used 
throughout the study as stated in section 7.1.2.7.4 below.  For lymphomas that are not FDG-
avid at screening, PET does not need to be repeated in follow-up assessments.
7.1.2.7.4 Disease Response Assessments/Imaging During the Trial
Following screening, disease response assessments will occur at Week 12 (±7 days) and 
every 12 weeks (±7 days) as detailed in the Trial Flow Chart in Section 6.0. The first 
 
 
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assessment may be performed earlier than 12 weeks if, in the opinion of the investigator, the 
subject is clinically progressing. 
Imaging assessments should be performed (every 12 weeks from the first dose of study 
medication).  There is a ± 7 day window for assessments performed after entry in the study.  
If PET and CT scan at Screening are negative for disease involvement in the neck, 
subsequent CT scans may not include neck. If PET or CT scans at Screening are positive for 
disease involvement of the neck, subsequent CT scans must include neck. 
Following 
screening, CT scans should be repeated every 12 weeks for subsequent assessments.  PET 
should be repeated at Week 12, Week 24, or to confirm CR and as clinically indicated. PET 
to confirm PD is strongly encouraged, but not required, if CT clearly demonstrates PD.  
Disease assessments and imaging should not be delayed for delays in cycle starts.
Disease assessments and imaging should continue to be performed until documented disease 
progression by investigator assessment, the start of new anti-cancer treatment, withdrawal of 
consent, death, or the end of the study, whichever occurs first.
During Second Course, imaging should continue to occur every 12 weeks (+/- 7 days) 
following the same parameters listed above.
7.1.2.7.5 Disease Progression Assessments
After the first documentation of progression it is at the discretion of the investigator to keep a 
clinically stable subject on trial treatment or to stop trial treatment until repeat imaging 
performed 4-6 weeks later confirms progression. Clinical Stability may be defined as:

Absence of signs and symptoms (including worsening of laboratory values) 
indicating disease progression

No decline in ECOG performance status

Absence of rapid progression of disease or progressive tumor at critical 
anatomical sites (e.g., cord compression) requiring urgent alternative medical 
intervention.
Subjects that are deemed clinically unstable are not required to have repeat imaging for 
confirmation. 
If progression is confirmed, then the subject will be discontinued from trial treatment. If 
progression is not confirmed, then the subject should resume/continue trial treatment 
provided:

The sponsor is consulted and provides approval to continue treatment

No other anti-tumor therapy (e.g.,
chemotherapy, radiation, etc.) has been 
administered
Patients should have their next scan according to the every 12-week schedule from first dose 
of study treatment, which would be approximately 12 weeks from the date of the scan that 
first showed progression. When feasible, subjects should not be discontinued until 
progression is confirmed.
 
 
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For subjects who have stable disease, partial remission, or complete response following the 
first disease response assessment (at Week 12), disease assessments and imaging should 
continue per the regular frequency every 12 weeks as outlined in the Section 7.1.2.7.4.
7.1.2.7.6 Biopsy Collection and Correlative Studies Blood Collection
All PMBCL subjects should submit an archived lymph node formalin-fixed paraffin 
embedded (FFPE) biopsy sample or when feasible, a newly obtained core or excisional
biopsy (fine needle aspirate [FNA] not adequate) for confirmation of rrPBMCL and 
characterization of PD-L1 expression at a central lab. Central review for diagnosis is not 
required prior to enrollment.
Similar lymph node tissue from subjects with rrRS should be submitted, although central 
review will be determined by the Sponsor.  Central review for diagnosis is not required prior 
to enrollment.
Submission of formalin-fixed paraffin embedded tumor tissue sample blocks are preferred; if 
submitting unstained slides, the slides should be freshly cut and submitted to the testing 
laboratory within 14 days from site slide sectioning date otherwise a new specimen will be 
requested.
For newly obtained lymph node biopsy, when feasible, sites should be selected so that 
subsequent biopsies can be performed at the same location.  Tumors that are inaccessible or 
contraindicated due to subject safety concerns are exempt from this requirement. Detailed 
instructions for tissue collection, processing, and shipment are provided in the Procedures 
Manual.
Baseline tumor tissue for biomarker analysis from a newly obtained core or excisional lymph 
node biopsy (FNA) not adequate] should be provided if feasible to the central vendor prior to 
randomization or (if newly obtained biopsy not available) an archival tissue sample could 
alternatively be collected.  Adequacy of the fresh biopsy specimen for PD-L1 biomarker 
analysis will be confirmed by the central laboratory.  Detailed instructions for tissue 
collection, processing and shipment of the newly obtained sample tissue or archival tumor 
tissue are provided in the Procedures Manual.  If the subject signs the FBR consent, any 
leftover tissue that would ordinarily be discarded at the end of the study will be retained for 
FBR (see Section 12.3).
•
Newly Obtained Tumor Tissue
This sample should be sent to the vendor in formalin (strongly preferred) or as a FFPE block.
If slides are submitted they must be sent to designated laboratory within 14 days of being 
sectioned.
•
Archival Tumor Tissue (if available)
Archival tissue sample should be provided in the form of FFPE tissue block (preferred).  
Unstained/freshly cut slides cut from FFPE tissue block may be accepted.  If slides are 
submitted they must be sent to designated laboratory within 14 days of being sectioned.  
Refer to the Procedures Manual for number of slides and instructions.
 
 
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
Bone Marrow
For all subjects, collect bone marrow biopsy and aspirate at baseline.  Repeat bone marrow 
biopsy and aspirate as needed to confirm CR. Local results of bone marrow biopsy and 
aspirate will be used for baseline and to confirm CR (or other reason).  Residual bone 
marrow biopsy sample (all subjects for any sample obtained) should be sent to the central lab 
for potential future central analysis per sponsor discretion.  
For RS it is necessary to confirm marrow clearance of RS or lymphoma clone to confirm CR.  
If indeterminate by morphology, immunohistochemistry should be negative.  Residual 
underlying CLL may persist in node and/or marrow and still qualify as CR
Bone marrow and lymph node biopsies will be collected as per Table 4.
Table 4
Bone Marrow and Lymph Node Biopsy Assessments
Indication
Timing of Biopsy
Lymph Node Biopsy
Screening biopsy (archival or newly obtained sample) 
is required. Biopsy at Week 12 (± 7 days) and at the 
time of discontinuation due to progression are optional 
but highly recommended.  
Additional node biopsies for RS should be considered 
in the presence of enlarging lymph nodes to determine 
if due to underlying CLL or RS.
Bone marrow biopsy and aspirate
(All subjects will have bone marrow biopsy and 
aspirate performed at Screening.  Subsequent bone 
marrow assessments will only be performed in 
subjects who have bone marrow involvement.)
Screening, to confirm CR (if subject has baseline bone 
marrow involvement), and as clinically indicated.
For RS, CR can be confirmed by clearance of the RS 
or lymphoma clone on marrow biopsy and aspirate.  
Residual underlying CLL may persist in node and/or 
marrow and still qualify as CR.  Bone marrow 
morphology and cytogenetics should be performed at 
Screening. Cytogenetics will be performed only if 
considered standard of care in your country.  If this 
test is not done as part of local standard of care, then 
this test does not need to be performed.
Abbreviations: CLL – chronic lymphocytic leukemia; CR – complete response; RS – Richter syndrome.
Blood for correlative biomarker studies should be collected as per Table 5.
Table 5
Blood for Correlative Studies
Indication
Timing of Correlative Blood Collection
Whole Blood for RNA/DNA:
Screening, pre-dose on Cycle 2 Day 1, Week 12 
assessment, and upon progression.
Abbreviations: DNA – deoxyribonucleic acid; RNA – ribonucleic acid.
 
 
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7.1.2.8
Patient Reported Outcomes (PROs)
The EuroQol EQ-5D and EORTC QLQ-C30 questionnaires will be administered by trained 
site personnel and completed electronically by the subjects themselves.  It is strongly 
recommended that all electronic PROs are administered prior to drug administration, AE
evaluation and disease status notification.   The PROs are completed in the following order: 
EuroQol EQ-5D first, then EORTC QLQ-C30 at the time points specified in the Trial Flow 
Chart.  Subjects who are on-study (signed informed consent) before approval of Amendment 
1 (which instituted PROs) do not need to complete PROs.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.
7.1.3.1
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Applicable laboratory tests are specified in Table 6.
 
 
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Table 6
Laboratory Tests
Hematologyf
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)a
Hemoglobin
Alkaline phosphatase
Glucose
Prothrombin 
time 
(PT)
International 
Normalized 
Ratio INR)d
Platelet count
Alanine aminotransferase (ALT)
Protein
Activated 
partial 
thromboplastin time (aPTT)d
White blood cell 
count (total and 
differential)
Aspartate 
aminotransferase 
(AST)
Specific gravity
Total Triiodothyronine (T3)e
Red 
Blood 
Cell 
Count
Calcium
Microscopic 
exam, 
if 
abnormal 
results 
are 
noted
Free thyroxine (free T4)
Absolute 
Neutrophil Count
Bicarbonate/Carbon dioxideb
Urine pregnancy testa
Thyroid 
stimulating 
hormone (TSH)
Absolute 
Lymphocyte Count
Blood 
for 
Future 
Biomedical Research (FBR)
Chloride
Blood for Proteomics
Creatinine
Blood for Genetics
Glucose
Blood for Transcriptional 
Analysis
Phosphorus
Potassium
Sodium
Total Bilirubin
Direct Bilirubin, if total bilirubin 
is elevated above upper limit of 
normal (ULN)
Total protein
Blood Urea Nitrogen
Uric acid
Ureac
a.
Perform on women of childbearing potential only.  Urine pregnancy test is preferred.  If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required.  Pregnancy test is to be done within 72 
hours of each cycle of trial treatment and 30 days post-treatment.
b.
Test only if part of Standard of Care locally.
c.
Blood Urea Nitrogen is preferred; if not available urea may be tested.
d.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Any 
subject receiving anticoagulant therapy should have coagulation factors monitored closely throughout the trial.
e.
Total T3 is preferred, if not available free T3 may be tested.
f.
Absolute values or percentage.
All laboratory tests will be performed by a central laboratory. Prior to pembrolizumab 
infusion, specific laboratory tests could be performed locally as clinically indicated per 
investigator assessment, in parallel to central laboratory testing, if necessary to ensure 
subject’s safety prior to treatment. Subjects may be enrolled based on local laboratory results 
with central laboratory results pending.  Treatment decisions may be made on local 
laboratory tests.
 
 
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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 7 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.
7.1.3.2
Pregnancy Test
All women who are being considered for participation in the trial, and who are not surgically 
sterilized or postmenopausal, must be tested for pregnancy within 72 hours of each cycle of 
trial treatment and 30 days post-treatment.  If a urine test is positive or not evaluable, a serum 
test will be required.  Subjects must be excluded/discontinued from the trial in the event of a 
positive or borderline-positive test result.
7.1.3.3
Pharmacokinetic/Pharmacodynamic Evaluations
The accumulation of robust PK and anti-drug antibody (ADA) data has allowed for the 
adequate characterization of the clinical pharmacology of pembrolizumab across indications.
Therefore, upon approval of Amendment 04 each site is to stop the collection of PK and 
ADA samples for all subjects. 
Blood samples for PK and ADA collected prior to 
Amendment 04 may only be stored. Analysis will be performed only if required.
7.1.3.4
Planned Genetic Analysis Sample Collection
This sample should be drawn for planned analysis of the association between genetic variants 
in DNA and drug response. If there is either a documented law or regulation prohibiting 
collection, or if the IRB/IEC does not approve the collection of the sample for these 
purposes, then this sample will not be collected at that site. If the sample is collected, leftover 
extracted DNA will be stored for future biomedical research if the subject signs the FBR 
consent. If the planned genetic analysis is not approved, but FBR is approved and consent is 
given, this sample will be collected for the purpose of FBR.  Sample collection, storage and 
shipment instructions for Planned Genetic Analysis samples will be provided in the 
procedure manual.
7.1.3.5
Future Biomedical Research Sample Collection
The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future use

Leftover bone marrow biopsy/aspirate samples

Leftover tissue samples

Leftover lymph node biopsies
 
 
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Other Procedures
7.1.4.1
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from study treatment prior to completion of the treatment
regimen should be encouraged to continue to be followed for all remaining study visits.
When a subject discontinues/withdraws from participation in the trial, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 7.2 - Assessing and 
Recording Adverse Events.
Subjects who attain a CR confirmed by independent central 
review may discontinue treatment with the option of restarting treatment if they meet the 
criteria specified in Section 7.1.5.2.1.  After discontinuing treatment following assessment of 
CR, these subjects should return to the site for a Safety Follow-up Visit (Section 7.1.5.3.1) 
and then proceed to the Follow-Up Period of the study (Section 7.1.5.4).
7.1.4.1.1 Withdrawal From Future Biomedical Research
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact the Sponsor using the designated mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter will 
be sent from the Sponsor to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to the 
request being received by the Sponsor will continue to be used as part of the overall research 
trial data and results.   No new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for 
specimen destruction cannot be processed.
7.1.4.1.2 Lost to Follow-up
If a subject fails to return to the clinic for a required study visit and/or if the site is unable to 
contact the subject, the following procedures are to be performed:

The site must attempt to contact the subject and reschedule the missed visit.  If the 
subject is contacted, the subject should be counseled on the importance of 
maintaining the protocol-specified visit schedule.
 
 
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
The investigator or designee must make every effort to regain contact with the 
subject at each missed visit (e.g., phone calls and/or a certified letter to the 
subject’s last known mailing address or locally equivalent methods). These 
contact attempts should be documented in the subject’s medical record.

Note:  A subject is not considered lost to follow up until the last scheduled visit 
for the individual subject.  The amount of missing data for the subject will be 
managed via the pre-specified data handling and analysis guidelines.
7.1.4.2
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
7.1.4.3
Calibration of Critical Equipment
The investigator or qualified designee has the responsibility to ensure that any critical device
or instrument used for a clinical evaluation/test during a clinical trial that provides important 
information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be 
suitably calibrated and maintained to ensure that the data obtained is reliable and/or 
reproducible.  Documentation of equipment calibration must be retained as source 
documentation at the trial site.
Critical Equipment for this trial includes:
•
Laboratory equipment- as required for inclusion labs and trial assessments
•
Imaging equipment- as required for trial objectives
•
Infusion equipment- as required for administering drug product.
See protocol-specified guidance in the Administrative Binder, Procedures Manual, Pharmacy 
Manual and Site Imaging Manual.
Visit Requirements
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures.
7.1.5.1
Screening
Approximately 28 days prior to treatment allocation, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1.  Screening 
procedures may be repeated after consultation with the Sponsor.  Visit Requirements are 
outlined in Section 6.0.
 
 
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Written consent for the main study must be obtained prior to performing any protocol 
specific procedure.  Results of a test performed prior to the subject signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the
specified time frame.  Screening procedures are to be completed within 28 days prior to the 
first dose of trial treatment except for the following:

Laboratory tests are to be performed within 7 days prior to the first dose of trial 
treatment.

For women of reproductive potential, a urine pregnancy test will be performed within 
72 hours prior to the first dose of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test will be required (performed by the 
local study site laboratory).

When an archival biopsy is being used for confirmation of diagnosis, it is not required 
to be obtained within 28 days prior to the first dose of trial treatment.
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments performed during the initial screening period are acceptable in lieu 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met.
7.1.5.2
Treatment Period
Visit requirements are outlined in Section 6.0 – Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 7.1 – Trial Procedures.
7.1.5.2.1 Second Course Phase (Retreatment Period for Post-Complete Remission 
Relapse ONLY)
Subjects who achieved a CR confirmed by independent central review and decided to stop 
initial treatment, at the time of recurrence may be eligible to receive pembrolizumab in the 
Retreatment Period of this study if the study remains open and the subject meets all of the 
following conditions:

Stopped initial treatment with pembrolizumab after attaining a confirmed CR by 
independent central review according to IWG response criteria.

Received at least 8 administrations of pembrolizumab before discontinuing therapy.

Received at least two treatments with pembrolizumab beyond the date when the 
initial CR was declared.

Experienced an investigator-determined confirmed disease progression after stopping 
their initial treatment with pembrolizumab.

Did not receive any anti-cancer treatment since the last dose of pembrolizumab.
 
 
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
Have a performance status of 0 or 1 on the ECOG Performance Scale.

Demonstrate adequate organ function as detailed in Section 5.1.2.

Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving retreatment at each cycle with study 
medication.

Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference 
Section 5.7.2).  Subjects of child bearing potential are those who have not been 
surgically sterilized or have not been free from menses for > 1 year.
Note: 
Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.

Male subjects should agree to use an adequate method of contraception starting with 
the first dose of study therapy through 120 days after the last dose of study therapy.
Note: 
Abstinence is acceptable if this is the usual lifestyle and preferred 
contraception for the subject.

Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration 
of the trial or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator.
Subjects who restart treatment will be retreated at the same dose frequency as when they last 
received pembrolizumab for a treatment duration of a maximum of 17 additional
administrations (approximately 1 year). Visit requirements are outlined in Section 6.0 – Trial 
Flow Chart.
7.1.5.3
Post-Treatment Visits
7.1.5.3.1 Safety Follow-Up Visit
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new antineoplastic treatment, 
whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded.  Subjects with an AE of Grade > 1 will be followed until the resolution of the AE 
to Grade 0-1 or until the beginning of a new antineoplastic therapy, whichever occurs first.  
SAEs that occur within 90 days of the end of treatment or before initiation of a new 
antineoplastic treatment should also be followed and recorded.
Subjects who are eligible for retreatment with pembrolizumab
(as described in 
Section 7.1.5.2.1) may have up to two safety follow-up visits, one after the Treatment Period 
and one after the Second Course Phase.
 
 
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7.1.5.4
Follow-up Visits
Subjects who discontinue trial treatment for a reason other than confirmed disease 
progression will move into the Follow-Up Phase and should be assessed every 12 weeks 
(± 14 days) to monitor disease status.  Subjects should receive a full physical examination 
and ECOG status, vital signs and labs should be repeated with each assessment until disease 
progression or up to 90 days of the end of treatment or before initiation of a new 
antineoplastic treatment. Every effort should be made to collect information regarding 
disease response status until the start of new antineoplastic therapy, documented disease 
progression by investigator assessment, death, end of the study, or if the subject begins 
retreatment with pembrolizumab as detailed in Section 7.1.5.2.1.  Information regarding post-
study antineoplastic treatment will be collected if new treatment is initiated.
For subjects who achieve CR determined by independent central review and are in the 
Follow-Up Phase, when they experience disease progression determined by investigator 
assessment are eligible to receive retreatment with pembrolizumab according to the criteria in 
Section 7.1.5.2.1 will move from the follow-up phase to the Second Course Phase. Details 
are provided in Section 6.2 – Trial Flow Chart for Retreatment.
7.1.5.4.1 Follow-Up Post-Allogeneic Stem Cell Transplantation
For subjects who receive allogeneic SCT within 24 months of last dose of pembrolizumab, 
the following events will be collected as ECIs through 18 months from the date of the 
allogeneic transplant, unless the trial closes earlier: graft-versus-host-disease, febrile 
syndrome treated with steroids, pulmonary complications, hepatic veno-occlusive disease
and/or sinusoidal syndrome, immune-mediated adverse events, critical illness, and transplant-
related mortality.
Additional medically important AEs post-allogeneic SCT may be 
submitted at the investigator’s discretion (Section 7.2.3.2).  If available and relevant to an 
event post-allogeneic SCT, concomitant medications and/or laboratory results may also be 
reported.
Guidance on details to be collected and suggested events to be reported can be found in the 
Procedure Manual.
7.1.5.4.2 Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new antineoplastic 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone (or in person if recent contact for other purposes during window) approximately
every 12 weeks (± 7 days) to assess for survival status until death, withdrawal of consent, or 
the end of the study, whichever occurs first.
7.1.5.5
Survival Status
To ensure current and complete survival data is available at the time of database locks, 
updated survival status may be requested during the course of the study by the Sponsor.  For 
example, updated survival status may be requested prior to, but not limited to, an interim 
and/or final analysis.  Upon Sponsor notification, all subjects who do not/will not have a 
scheduled study visit or study contact during the Sponsor-defined time period will be 
 
 
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contacted for their survival status (excluding subjects who have a previously recorded death 
event in the collection tool).
Assessing and Recording Adverse Events
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 
symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the 
use of the Sponsor’s product, is also an adverse event.
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  
Examples of this may include, but are not limited to, teething, typical crying in infants and 
children and onset of menses or menopause occurring at a physiologically appropriate time.
Sponsor's product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including placebo 
or active comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by the Sponsor for human use.
Adverse events may occur during clinical trials, or as prescribed in clinical practice, from 
overdose (whether accidental or intentional), from abuse and from withdrawal.
Progression of the cancer under study is not considered an adverse event.
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. From the time of treatment allocation/randomization through 30 days following 
cessation of treatment, all adverse events must be reported by the investigator. Such events 
will be recorded at each examination on the Adverse Event case report forms/worksheets.  
The reporting timeframe for adverse events meeting any serious criteria is described in 
Section 7.2.3.1. The investigator will make every attempt to follow all subjects with non-
serious adverse events for outcome.
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting.
 
 
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Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab defined as any dose of 1000 mg or greater. No specific information 
is available on the treatment of overdose of pembrolizumab. In the event of overdose, 
pembrolizumab should be discontinued and the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated.
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or 
vaccine, the adverse event(s) is reported as a serious adverse event, even if no other 
seriousness criteria are met.
If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken 
without any associated clinical symptoms or abnormal laboratory results, the overdose is 
reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental 
or intentional overdose without adverse effect.”
All reports of overdose with and without an adverse event must be reported by the 
investigator within 24 hours to the Sponsor either by electronic media or paper. Electronic 
reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Reporting of Pregnancy and Lactation to the Sponsor
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial.
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be
excluded from the trial, or are the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. Pregnancies and lactations that occur from the time of treatment 
allocation/randomization through 120 days following cessation of Sponsor’s product, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, 
whichever is earlier, must be reported by the investigator. All reported pregnancies  must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes of 
spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal 
death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of 
infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Immediate Reporting of Adverse Events to the Sponsor
7.2.3.1
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event.
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or follow up 
to a serious adverse event, including death due to any cause other than progression of the 
cancer under study (reference Section 7.2.3.3 for additional details), whether or not related to 
the Sponsor's product, must be reported within 24 hours to the Sponsor either by electronic 
media or paper. Electronic reporting procedures can be found in the EDC data entry 
guidelines. Paper reporting procedures can be found in the Investigator Trial File Binder (or 
equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
All subjects with serious adverse events must be followed up for outcome.
 
 
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7.2.3.2
Events of Clinical Interest
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported to the Sponsor.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days 
following cessation of treatment, or 30 days following cessation of treatment if the subject 
initiates new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, 
whether or not related to the Sponsor’s product, must be reported within 24 hours to the 
Sponsor, either by electronic media or paper.  Electronic reporting procedures can be found 
in the EDC data entry guidelines.  Paper reporting procedures can be found in the 
Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with 
clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is less 
than 2X the upper limit of normal, as determined by way of protocol-specified laboratory 
testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology. The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder (or 
equivalent).
7.2.3.2.1 Follow-Up Post-Allogeneic Stem Cell Transplantation
For subjects who receive allogeneic SCT within 24 months of last dose of pembrolizumab, 
the following events will be collected as ECIs through 18 months from the date of the 
allogeneic transplant, unless the trial closes earlier: graft-versus-host-disease, febrile 
syndrome treated with steroids, pulmonary complications, hepatic veno-occlusive disease
and/or sinusoidal syndrome, immune-mediated adverse events, critical illness, and transplant-
related mortality. 
Additional medically important AEs post-allogeneic SCT may be 
submitted at the investigator’s discretion (Section 7.2.3.2).  If available and relevant to an 
event post-allogeneic SCT, concomitant medications and/or laboratory results may also be 
reported.
 
 
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Guidance on details to be collected and suggested events to be reported can be found in the 
Procedure Manual.
Post-allogeneic-SCT ECIs that occur after the normal safety follow-up period must be 
assessed for seriousness and causality and reported to the Sponsor as follows: within 24 
hours if serious regardless of causality, or if non-serious and considered to be drug-related; 
and 5 calendar days if non-serious and not considered to be drug-related.
7.2.3.3
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints as outlined in this section will not be reported to the Sponsor as described 
in Section 7.2.3. Immediate Reporting of Adverse Events to the Sponsor.
Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study.
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial.  Any suspected endpoint which upon review is 
not progression of the cancer under study will be forwarded to global safety as a SAE within 
24 hours of determination that the event is not progression of the cancer under study.
Evaluating Adverse Events
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets.
All adverse events regardless of CTCAE grade must also be evaluated for seriousness.
 
 
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Table 7
Evaluating Adverse Events
An investigator who is a qualified physician, will evaluate all adverse events as to:
V4.0 CTCAE 
Grading
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated.
Grade 2
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL.
Grade 3
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; 
disabling; limiting self-care ADL.
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE
Seriousness
A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor’s product that:
†Results in death; or
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in 
the patient’s medical history.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE 
form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The 
criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event 
based upon the available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
the 
Sponsor’s 
product? 
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 
CLINICAL DIRECTOR AS PER DOSE MODIFICATION GUIDELINES IN THE PROTOCOL.
Consistency 
with Trial 
Treatment 
Profile
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor’s product or drug class pharmacology 
or toxicology?
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements.
Record one of the following
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor’s product relationship).
Yes, there is a reasonable 
possibility of Sponsor's product 
relationship.
There is evidence of exposure to the Sponsor's product.  The temporal sequence of the AE onset relative to the administration of the Sponsor's 
product is reasonable.  The AE is more likely explained by the Sponsor's product than by another cause.
No, there is not a reasonable 
possibility of Sponsor's product 
relationship
Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not 
reasonable OR the AE is more likely explained by another cause than the Sponsor’s product.  (Also entered for a subject with overdose without an 
associated AE.)
 
 
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Sponsor Responsibility for Reporting Adverse Events
All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in 
accordance with all applicable global laws and regulations, i.e., per ICH Topic E6 (R1) 
Guidelines for Good Clinical Practice.
8.0 STATISTICAL ANALYSIS PLAN
This section outlines the statistical analysis strategy and procedures for the study.  If changes 
are made to the primary and/or key secondary hypotheses, or the statistical methods related 
to those hypotheses post study initiation and prior to final database lock, the protocol will be 
amended (consistent with International Council for Harmonisation [ICH] Guideline E-9).  
After the protocol has been finalized and prior to the final database lock any changes to 
exploratory or other non-confirmatory analyses, will be documented in a supplemental 
Statistical Analysis Plan (sSAP) and referenced in the Clinical Study Report (CSR) for the 
study.  Post hoc exploratory analyses will also be identified in the CSR.  Due to the RS 
cohort being closed early, statistical analyses may be modified and changes will be reported 
in the CSR.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized in Table 8; the comprehensive 
plan is provided in Sections 8.2 to 8.12.
Table 8
Statistical Analysis Plan Summary
Study Design Overview
This study, entitled “A Study of Pembrolizumab (MK 3475) in Subjects with 
Relapsed or Refractory Primary Mediastinal Large B-cell Lymphoma 
(rrPMBCL) or relapsed or refractory Richter syndrome (rrRS)” is a 
multicenter, single arm, nonrandomized trial of pembrolizumab (MK-3475) in 
subjects with rrPMBCL or rrRS.
Treatment Assignment
Subjects meeting inclusion/exclusion criteria will be assigned to each cohort
and receive 200 mg of pembrolizumab every 3 weeks (Q3W).
Analysis Populations
The primary analysis population for both efficacy and safety assessments is
the “All Subjects as Treated” (ASaT) population, defined as all subjects who 
receive at least one dose of study medication (pembrolizumab).
Primary Endpoint(s)
The primary efficacy endpoint is the Objective Response Rate (ORR), defined 
as the proportion of subjects in the analysis population who have complete 
remission (CR) or partial remission (PR) using International Working Group 
(IWG) criteria, Cheson 2007 at any time during the study.  Response for the 
primary analysis will be determined by central review.
Key Secondary 
Endpoints
1.
Progression-Free Survival (PFS)
2.
Duration of Response (DOR)
3.
Disease Control Rate (DCR)
4.
Overall Survival (OS)
Statistical Methods for 
Key Efficacy Analyses
rrPMBCL:  The primary hypothesis will be evaluated by comparing ORR for 
pembrolizumab to a fixed historical control rate using a binomial exact test.  
The ORR will be estimated as well as a 95% 2-sided exact confidence interval 
using the Clopper-Pearson method.
rrRS: The ORR will be estimated, along with the 90% 2-sided confidence 
interval using the Clopper-Pearson method.
 
 
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Statistical Methods for 
Key Safety Analyses
Summary statistics (counts, percentage, mean, standard deviation, etc.) will be 
provided for the safety endpoints as appropriate.
Interim Analyses
rrPMBCL:  An interim analysis will be conducted when between 50%-60% of 
the ASaT population is evaluable for response; see Section 8.7 for details.
rrRS:  Interim analyses may be conducted as needed to monitor study efficacy 
and safety, e.g., when 40% of subjects are evaluable for response; see Section 
8.7 for details.
Multiplicity
No multiplicity adjustment is planned.
Sample Size and Power The planned sample size is 50 subjects for the primary analysis in each 
cohort. Assuming ~6% of those enrolled will not be treated, approximately 53 
subjects for each cohort will be enrolled into the study to obtain 50 subjects in 
the primary analysis population (ASaT). With 50 subjects in the primary 
analysis population for the rrPMBCL cohort, there is at least 88% statistical 
power (1-sided nominal 2.5% alpha) to detect a 35% or higher ORR for the 
pembrolizumab arm compared to a fixed control rate of 15% using the exact 
binomial test; see Section 8.8 for details.
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 trial is being conducted as a single arm, open-label study, i.e., subjects, investigators, 
and Sponsor personnel will be aware of subject treatment assignments after each subject is 
enrolled and treatment is assigned.
Hypotheses/Estimation
Objectives, hypothesis, and associated estimations of the study are stated in Section 3.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated are listed below.
Efficacy Endpoints
Efficacy endpoints that will be evaluated are listed below, followed by the descriptions of the 
derivations of selected endpoints.
The primary efficacy endpoint is the ORR for each cohort, defined as the proportion of 
subjects in the analysis population who have CR or PR at any time during the study, prior to 
disease progression.
For rrPMBCL, response assessment will be based on IWG criteria 
(Cheson, 2007 [1]) using independent central review.  For subjects with rrRS, IWG criteria 
with special considerations for RS will be used (Section 12.7).  A secondary efficacy 
endpoint is ORR based on investigator assessment.
Other secondary efficacy endpoints include: (1) PFS, defined as the time from first dose of 
pembrolizumab to the first documented disease progression or death due to any cause, 
whichever occurs first; (2) DOR, defined as time from first response (CR, PR) to disease 
progression in subjects who achieve a PR or better, (3) DCR, defined as the proportion of 
subjects in the analysis population who have CR, PR, or SD at any time during the study 
prior to disease progression and (4) OS, defined as time from first dose to date of death.  
 
 
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PFS, DOR, and DCR will be based both on central review (primary) and investigator 
assessment (secondary).
Exploratory efficacy endpoints include ORR, PFS, DOR, and DCR, incorporating response 
assessments for subjects continuing pembrolizumab treatment after initial progression.  An 
additional exploratory endpoint is the ORR based on the Lugano classification [2] using 
independent central review.
Safety Endpoints
Safety measurements are described in Section 7.
Analysis Population
Efficacy Analysis Population
The analysis of primary efficacy endpoints are based on the All Subjects as Treated (ASaT) 
population, i.e., subjects will be included if they receive at least one dose of study medication
(pembrolizumab).
Supportive analyses will be conducted in the Full Analysis Set (FAS) population, which 
consists of all subjects who 1) receive at least one dose of study medication; 2) have a 
baseline disease assessment, and 3) have a post baseline disease assessment or discontinue 
the trial due to PD/drug related AE.
Safety Analysis Population
The ASaT population will be used for the analysis of safety data in this study. The ASaT 
population consists of all enrolled subjects who received at least 1 dose of study treatment
(pembrolizumab). At least one laboratory or vital sign measurement obtained subsequent to 
at least one dose of trial treatment is required for inclusion in the analysis of each specific 
parameter. To assess change from baseline, a baseline measurement is also required.
Statistical Methods
Statistical Methods for Efficacy Analyses
A summary of the primary analysis strategy for the primary and secondary efficacy endpoints 
is provided in Table 10 below.  The primary evaluation will be by central review for ORR, 
DCR, PFS, and DOR.
8.6.1.1
Objective Response Rate
The primary efficacy endpoint for this study is the ORR for each cohort, defined as the 
proportion of subjects who have response (CR or PR) prior to disease progression.  In the 
rrPMBCL cohort, an exact binomial test will be conducted versus a fixed control rate.  In 
both cohorts, the final analysis for the primary endpoint will be conducted when the last 
subject has reached the Week 12 response assessment or has discontinued study therapy.
The analysis will consist of the point estimate and 95% (90% for rrRS cohort) 2-sided exact 
CI using the Clopper-Pearson method which will have at least 95% (90% for rrRS cohort) 
coverage of the true rate.  
 
 
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Since an investigator may still continue to treat subjects with pembrolizumab who have 
progressed according to IWG criteria, exploratory analyses (point estimate and 90% 2-sided 
exact confidence interval) will be conducted for ORR to consider these subjects who later 
achieve PR or CR post-progression as responders.  An additional exploratory analysis for 
ORR will be conducted based on the Lugano classification (Cheson, 2014 [2]).
8.6.1.2
Disease Control Rate
The DCR, defined as the proportion of subjects in the analysis population who have achieved 
a CR, PR or SD response prior to disease progression.  The analysis will consist of the point 
estimate and 90% 2-sided exact CI; analogous to ORR, an exploratory analysis of DCR will 
be performed to consider subjects who continue to receive pembrolizumab and later achieve 
PR, CR or SD following initial progression.
8.6.1.3
Progression-Free Survival
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve.
Since disease progression is assessed periodically, PD can occur any time in the time interval 
between the last assessment where PD was not documented and the assessment when PD is 
documented. For the primary analysis, for the subjects who have PD, the true date of disease 
progression will be approximated by the date of the first assessment at which PD is 
objectively documented per IWG criteria, regardless of discontinuation of study drug. Death 
is always considered as a confirmed PD event.
In order to evaluate the robustness of the PFS endpoint, we will perform two sensitivity 
analyses with a different set of censoring rules. The first sensitivity analysis is the same as 
the primary analysis except that it censors at the last disease assessment without PD when PD 
or death is documented after more than one missed disease assessment. 
The second 
sensitivity analysis is the same as the primary analysis except that it considers 
discontinuation of treatment or initiation of new anticancer treatment, whichever occurs later, 
to be a PD event for subjects without documented PD or death.  The censoring rules for 
primary and sensitivity analyses are summarized in Table 9.
 
 
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Table 9
Censoring rules for Primary and Sensitivity Analyses of Progression-Free 
Survival
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No progressive disease 
(PD) and no death; new 
anticancer treatment is 
not initiated
Censored at last 
disease assessment 
Censored 
at 
last 
disease assessment 
Censored at last disease 
assessment 
No PD and no death; new 
anticancer treatment is 
initiated
Censored at last 
disease assessment 
before 
new 
anticancer 
treatment
Censored 
at 
last 
disease 
assessment 
before new anticancer 
treatment
Progressed at date of new 
anticancer treatment
PD or death documented 
after ≤ 1 missed disease 
assessment
Progressed at date 
of documented PD 
or death
Progressed at date of 
documented 
PD 
or 
death
Progressed 
at 
date 
of 
documented PD or death
PD or death documented 
after ≥ 2 missed disease 
assessments
Progressed at date 
of documented PD 
or death
Censored 
at 
last 
disease 
assessment 
prior to the ≥ 2 missed 
disease assessment
Progressed 
at 
date 
of 
documented PD or death
No PD and no death and 
lost to follow-up after ≥2 
missed 
disease 
assessments
Censored at last 
disease assessment 
Censored 
at 
last 
disease assessment 
Progressed at date of lost 
to follow-up
Analogous to other efficacy endpoints, an exploratory analysis will be performed on PFS
incorporating additional response assessments
where subjects 
are treated with 
pembrolizumab following initial progression; details on this analysis will appear in the sSAP.
8.6.1.4
Duration of Response
DOR is defined, only for the subgroup of subjects who achieve CR or PR, as the time from 
start of the first documentation of objective tumor response (CR or PR) to the first 
documentation of tumor progression or to death due to any cause, whichever comes first. 
The analysis will consist of Kaplan-Meier estimates.  Duration of response data will be 
censored on the date of the last disease assessment documenting absence of PD for subjects 
who do not have tumor progression and are still on study at the time of an analysis, are given 
antitumor treatment other than the study treatment, or are removed from study prior to 
documentation of tumor progression.
An exploratory analysis will be performed including response duration for those subjects 
who continue to receive pembrolizumab following progression and later achieve CR or PR.
8.6.1.5
Overall Survival
The median OS, if reached, will be estimated in the given analysis population.  In addition, 
the Kaplan-Meier method will be used to estimate the survival curve.
 
 
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Table 10
Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data Approach
Primary:
Objective Response Rate (ORR)

Central review 
rrPMBCL: Exact test of 
binomial parameter; Point 
Estimate and 2-sided 95% 
exact 
CI
rrRS: Point estimate and
2-sided 90% exact CI
ASaT/FAS
Subjects with missing 
data 
are 
considered 
non-responders
Secondary:
Objective Response Rate (ORR)

Investigator Assessment
Point estimate; 2-sided 
90% exact CI
ASaT/FAS
Subjects with missing 
data 
are 
considered 
non-responders
Progression-free survival (PFS)

Central review

Investigator assessment
Summary statistics using 
Kaplan-Meier method
ASaT/FAS
Censored 
at 
last 
assessment (see Table 9
for sensitivity analyses 
based 
on 
alternative 
censoring)
Duration of Response (DOR)

Central review

Investigator assessment
Summary statistics using 
Kaplan-Meier method
All 
responders
Non-responders 
are 
excluded in analysis
Disease Control Rate (DCR)

Central review

Investigator assessment
Point Estimate; 2-sided 
90% exact CI
ASaT/FAS
Subjects with missing 
data 
are 
considered 
non-responders
Overall survival (OS)
Summary statistics using 
Kaplan-Meier method
ASaT/FAS
Censored 
at 
last 
assessment
Abbreviations: ASaT  − All Subjects as Treated; CI  − confidence interval;  FAS  − Full Analysis Set; rrPMBCL  − 
relapsed or refractory primary mediastinal B-cell lymphoma; rrRS  − relapsed or refractory Richter Syndrome; 
For the rrPMBCL cohort, efficacy updates for the parameters in the above table will be 
conducted using a data cut-off based on when the last subject remaining on study has 
completed approximately 9 months and 12 months of efficacy assessments and then at 2 
years after the last subject initiated treatment, which corresponds to the end of the protocol-
specified treatment period. No formal statistical testing is planned. Subsequent yearly 
analyses will be conducted (i.e., 3 years after the last subject initiated treatment, etc.) until 
the trial is complete, including follow-up information on subjects who enter the re-treatment 
period.
Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, ECIs, laboratorytests, vital signs, and ECG measurements.
Summary statistics (counts, percentage, mean, standard deviation, etc.) will be provided for 
the safety endpoints as appropriate.
 
 
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Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.6.3.1
Baseline Characteristics and Demographics
Baseline characteristics will be assessed by the use of tables and/or graphs.  No statistical 
hypothesis tests will be performed on these characteristics. The number and percentage of 
subjects screened, allocated, the primary reasons for screening failure, and the primary 
reason for discontinuation will be displayed. Demographic variables (e.g., age, gender), 
baseline characteristics, primary and secondary diagnoses, and prior and concomitant 
therapies will be summarized by descriptive statistics or categorical tables.
8.6.3.2
Other Analyses
Descriptive statistics, including cross-tabulations, will be performed for those subjects with 
evaluable samples, to assess PD-L1 expression using immunohistochemistry will be analyzed 
in the context of response (CR, PR, SD, PD).
Additional exploratory analyses will be described in the sSAP.
Interim Analysis
rrPMBCL:
An interim analysis will be conducted after all subjects (approximately 50) have enrolled into 
the rrPMBCL cohort and will consist of between 50% to 60% of the treated population who 
are evaluable for response, i.e., up to and including that subject at the cut-off who have 
reached the Week 12 assessment or have discontinued study therapy prior to Week 12.  The 
selection of at least half of the treated population as the minimum is intended to minimize 
statistical bias and corresponds to a rejection boundary greater than twice that of the 
historical control (15%), which would be clinically meaningful.  The actual boundaries used 
for the interim and final analyses will be based on the actual number of response evaluable 
subjects in the interim analysis as well as the total known treated subjects using the 
corresponding alpha-spending function.
Table 11 below summarizes the timing and decision guidance for the interim and final 
analysis for ORR.  
 
 
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Table 11
Decision Guidance at Each Efficacy rrPMBCL Analysis
Analysis
Criteria for Conduct of Analysis
Value
Efficacy §
Interim ORR 
50-60% 
of 
treated 
subjects 
are evaluable* for response
P-value**
at bound 
ORR at bound
Number of responders
0.0029
36.7%
11
Final ORR
All treated subjects are evaluable*
for response
P-value** at bound
ORR at bound
Number of responders
0.0132
28.0%
14
Abbreviations: ORR − objective response rate; rrPMBCL − relapsed or refractory primary mediastinal B-cell 
lymphoma.
Note: O’Brien-Fleming Type I error spending function used to construct boundaries (see Section 8.9)
§ Assumes 30 response evaluable subjects in interim analysis and a total of 50 treated subjects in rrPMBCL
* Treated subjects who have reached Week 12 assessment or have discontinued study therapy prior to Week 12
** One-sided
There is no planned stopping early for futility or superiority; the study will continue to 
enroll the rrPMBCL cohort completely.
Sample Size and Power Calculation
Efficacy for each cohort will be analyzed separately; the proposed sample size in each cohort 
is 50 subjects in the primary analysis population (ASaT). To obtain 50 subjects in each 
cohort, approximately 53 subjects will need to be enrolled in the study assuming that 
approximately 6% of enrolled subjects are not treated.
rrPMBCL:
With 50 subjects in the primary analysis population, there is at least 88% statistical power (1-
sided nominal 2.5% alpha) to detect a 35% or higher ORR for the pembrolizumab arm 
compared to a fixed control rate of 15% using the exact binomial test.
The selection of 15% as a fixed control rate is based on historical data in previously 
conducted studies in rrPMBCL where response rates ranged between 13% to 17% [53, 54]
for subjects who received brentuximab vedotin after at least 2 prior lines of therapy and were 
ineligible or had failed autologous stem cell transplant.
rrRS:
The primary objective for this cohort is the estimation of ORR.  With a sample size of 50, the 
maximum half-width of the two-sided 90% exact confidence interval for ORR is 12%.  
Table 12 describes examples of 90% CIs per cohort across a possible range of ORRs. 
 
 
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Table 12
Precision (90% Confidence Intervals) for range of observed ORR (30%- 70%)
Number of responses/
Number of treated subjects (ORR) 
90% 2-sided Confidence Interval*
15/50 (30%)
25/50 (50%)
35/50 (70%)
(19%, 42%)
(38%, 62%)
(58%, 81%)
Abbreviation: ORR − objective response rate
*Exact (Clopper-Pearson) confidence limit for the binomial proportion
Multiplicity
Given the single hypothesis for the rrPMBCL cohort, no adjustment for multiplicity (i.e.,
Type I error) is required for multiple hypotheses.  An O’Brien-Fleming Type I error spending 
function will be used to construct group sequential boundaries to control the Type I error rate 
for the interim and final analyses of the single rrPMBCL hypothesis.
Subgroup Analyses and Effect of Baseline Factors
To determine whether ORR is consistent across various subgroups, the point estimate of the 
ORR (with an exact 90% CI) will be provided and plotted within each category of the 
following classification variables:

Age category (≤65 vs. >65 years)

Sex (female vs. male)

Race (white vs. non-white)

Region (US, ex-US)

Prior auto-SCT (failed, ineligible/refused)
If the observed numbers for a particular subgroup are too small to make a meaningful clinical 
interpretation, then that subgroup analysis will not be conducted.
Compliance (Medication Adherence)
Drug accountability data for trial treatment will be collected during the study. Compliance 
with trial treatment administration will be measured by subjects: 1) receiving unscheduled 
study agent infusions/injections; 2) missing an infusion/injection. Numbers and percentages 
of subjects and infusion/injection visits with any deviation in these measures will be reported.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles. Dose intensity 
will also be summarized as appropriate.
 
 
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9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
Investigational Product
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 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 13.
Clinical supplies will be packaged to support enrollment and replacement subjects as 
required.  When a replacement subject is required, the Sponsor or designee needs to be 
contacted prior to dosing the replacement supplies.
Table 13
Product Descriptions
Product Name & Potency
Dosage Form
Source/Additional 
Information
pembrolizumab (MK-3475)
50 mg/vial (25 mg/mL 
reconstituted)
Lyophilized Powder for IV 
Injection / Infusion
Provided centrally by the 
Sponsor
pembrolizumab (MK-3475)
100 mg/4 mL vial
(25 mg/mL)
Liquid for IV Injection / 
Infusion
Provided centrally by the 
Sponsor
Abbreviation: IV – intravenous.
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Subjects will receive open label pembrolizumab (MK-3475) vials.
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Treatment (name, strength or potency) is included in the label text; 
random code/disclosure envelopes or lists are not provided.
Storage and Handling Requirements
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site.
Clinical supplies may not be used for any purpose other than that stated in the protocol.
 
 
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Discard/Destruction/Returns and Reconciliation
The investigator is responsible for keeping accurate records of the clinical supplies received 
from the Sponsor or designee, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. For all trial 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.
Standard Policies
Trial 
site 
personnel 
will 
have 
access 
to 
a 
central 
electronic 
treatment 
allocation/randomization system (IVRS/IWRS system) to allocate subjects, to assign 
treatment to subjects and to manage the distribution of clinical supplies. Each person 
accessing the IVRS system must be assigned an individual unique PIN.  They must use only 
their assigned PIN to access the system, and they must not share their assigned PIN with 
anyone.
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will 
be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar 
or expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and 
regulations.
 
 
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Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory 
submissions, and as required by law.  This information may include:
1. name, address, telephone number and e-mail address;
2. hospital or clinic address and telephone number;
3. curriculum vitae or other summary of qualifications and credentials; and
4. other professional documentation.
Consistent with the purposes described above, this information may be transmitted to the 
Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other 
countries, including countries that do not have laws protecting such information.  
Additionally, the investigator’s name and business contact information may be included 
when reporting certain serious adverse events to regulatory authorities or to other 
investigators.  By signing this protocol, the investigator expressly consents to these uses and 
disclosures.
If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor 
may share an investigator’s name and contact information with other participating 
investigators upon request.
Confidentiality of IRB/IEC Information
The Sponsor is required to record the name and address of each IRB/IEC member that 
reviews and approves this trial.  The Sponsor is also required to document that each IRB/IEC 
meets regulatory and ICH GCP requirements by requesting and maintaining records of the 
names and qualifications of the IRB/IEC members and to make these records available for 
regulatory agency review upon request by those agencies.
Compliance with Financial Disclosure Requirements
Financial Disclosure requirements are outlined in the US Food and Drug Administration 
Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54).  It is the 
Sponsor's responsibility to determine, based on these regulations, whether a request for 
Financial Disclosure information is required.  It is the investigator's/subinvestigator's 
responsibility to comply with any such request.  
The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  
The investigator/subinvestigator(s) further agree to provide this information on a 
Certification/Disclosure Form, commonly known as a financial disclosure form, provided by 
the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this 
information to the Sponsor in the United States for these purposes.  This may involve the 
transmission of information to countries that do not have laws protecting personal data.
 
 
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Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and 
diligent manner and in conformance with this protocol; generally accepted standards of Good 
Clinical Practice (e.g., International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: 
Consolidated Guideline and other generally accepted standards of good clinical practice); and 
all applicable federal, state and local laws, rules and regulations relating to the conduct of the 
clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access 
to all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local 
laws, rules and regulations; and, for each subject participating in the trial, provide all data, 
and, upon completion or termination of the clinical trial, submit any other reports to the 
Sponsor as required by this protocol or as otherwise required pursuant to any agreement with 
the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the 
conduct of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, 
correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s 
curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or 
quality control procedures and laboratory director curriculum vitae.  By signing this protocol, 
the investigator agrees that documentation shall be retained until at least 2 years after the last 
approval of a marketing application in an ICH region or until there are no pending or 
contemplated marketing applications in an ICH region or until at least 2 years have elapsed 
since the formal discontinuation of clinical development of the investigational product.  
Because the clinical development and marketing application process is variable, it is 
anticipated that the retention period can be up to 15 years or longer after protocol database 
lock. The Sponsor will determine the minimum retention period and notify the investigator 
 
 
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when documents may be destroyed.  The Sponsor will determine the minimum retention 
period and upon request, will provide guidance to the investigator when documents no longer 
need to be retained.  The sponsor also recognizes that documents may need to be retained for 
a longer period if required by local regulatory requirements. All trial documents shall be 
made available if required by relevant regulatory authorities. The investigator must consult 
with and obtain written approval by the Sponsor prior to destroying trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator 
will immediately disclose in writing to the Sponsor if any person who is involved in 
conducting the trial is debarred or if any proceeding for debarment is pending or, to the best 
of the investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site 
is open in an EU country, Merck, as the Sponsor, will designate, per country, a national 
principal coordinator (Protocol CI), responsible for coordinating the work of the principal 
investigators at the different trial sites in that Member State, according to national 
regulations.  For a single-center trial, the Protocol CI is the principal investigator.  In 
addition, the Sponsor must designate a principal or coordinating investigator to review the 
trial report that summarizes the trial results and confirm that, to the best of his/her 
knowledge, the report accurately describes the conduct and results of the trial [Clinical Study 
Report (CSR) CI].  The Sponsor may consider one or more factors in the selection of the 
individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the 
anticipated review process, thorough understanding of clinical trial methods, appropriate 
enrollment of subject cohort, timely achievement of trial milestones).  The Protocol CI must 
be a participating trial investigator.
Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements 
for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Merck, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  Merck entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
 
 
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By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this 
trial or its results to the Clinical Trials Data Bank.
Quality Management System
By signing this protocol, the Sponsor agrees to be responsible for implementing and 
maintaining a quality management system with written development procedures and 
functional area standard operating procedures (SOPs) to ensure that trials are conducted and 
data are generated, documented, and reported in compliance with the protocol, accepted 
standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and 
regulations relating to the conduct of the clinical trial.
Data Management
The investigator or qualified designee is responsible for recording and verifying the accuracy 
of subject data.  By signing this protocol, the investigator acknowledges that his/her 
electronic signature is the legally binding equivalent of a written signature.  By entering 
his/her electronic signature, the investigator confirms that all recorded data have been 
verified as accurate.
Detailed information regarding Data Management procedures for this protocol will be 
provided separately.
Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided 
the complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also 
include the protocol and statistical analysis plan to facilitate the peer and editorial review of 
the manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will 
allow the journal, if it so desires, to post on its website the key sections of the protocol that 
are relevant to evaluating the trial, specifically those sections describing the trial objectives 
and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 
 
 
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the efficacy and safety measures, the statistical analysis plan, and any amendments relating to 
those sections.  The Sponsor reserves the right to redact proprietary information.
For multicenter trials, subsequent to the multicenter publication (or after public disclosure of 
the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an 
investigator and his/her colleagues may publish their data independently.  In most cases, 
publication of individual trial site data does not add value to complete multicenter results, 
due to statistical concerns.  In rare cases, publication of single trial site data prior to the main 
paper may be of value.  Limitations of single trial site observations in a multicenter trial 
should always be described in such a manuscript.
Authorship credit should be based on 1) substantial contributions to conception and design, 
or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising 
it critically for important intellectual content; and 3) final approval of the version to be 
published. Authors must meet conditions 1, 2 and 3.  Significant contributions to trial 
execution may also be taken into account to determine authorship, provided that 
contributions have also been made to all three of the preceding authorship criteria.  Although 
publication planning may begin before conducting the trial, final decisions on authorship and 
the order of authors’ names will be made based on participation and actual contributions to 
the trial and writing, as discussed above. The first author is responsible for defending the 
integrity of the data, method(s) of data analysis and the scientific content of the manuscript.
The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or 
presentations regarding this trial 45 days prior to submission for publication/presentation. 
Any information identified by the Sponsor as confidential must be deleted prior to 
submission; this confidentiality does not include efficacy and safety results. Sponsor review 
can be expedited to meet publication timelines.
11.0 LIST OF REFERENCES
1.
Cheson BD, Pfistner B, Juweid ME, et al. Revised Response Criteria for Malignant 
Lymphoma. J Clin Oncol.  2007; 25:579-586.
2.
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification, J Clin Oncol. 2014; Sep 20;32(27):3059-68.
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Disis ML.  Immune regulation of cancer. J Clin Oncol. 2010; 28(29):4531-8.
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Dudley ME, Wunderlich JR, Yang JC, et al. Adoptive cell transfer therapy following 
non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with 
refractory metastatic melanoma. J Clin Oncol. 2005;23(10):2346-2357.
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Hunder NN, Wallen H, Cao J, et al. Treatment of metastatic melanoma with autologous 
CD4+ T cells against NY-ESO-1. N Engl J Med. 2008;358(25):2698-2703.
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Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 
2005;23:515-548.
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Okazaki T, Maeda A, Nishimura H, et al. PD-1 immunoreceptor inhibits B cell receptor-
mediated signaling by recruiting src homology 2-domain-containing tyrosine 
phosphatase 2 to phosphotyrosine. PNAS. 2001;98(24):13866-13871.
 
 
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8.
Zhang X, Schwartz JC, Guo X, et al.  Structural and functional analysis of the 
costimulatory receptor programmed death-1.  Immunity. 2004;20:337-347.
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Chemnitz JM, Parry RV, Nichols KE, et al.  SHP-1 and SHP-2 associate with 
immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary 
human T-cell stimulation, but only receptor ligation prevents T-cell activation.  J 
Immunol.  2004;173:945-954.
10. Sheppard KA, Fitz LJ, Lee JM, et al.  PD-1 inhibits T-cell receptor induced 
phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to 
PKCtheta.  FEBS Lett.  2004;574:37-41.
11. Riley JL.  PD-1 signaling in primary T-cells.  Immunol Rev.  2009;229:114-125.
12. Parry RV, Chemnitz JM, Frauwirth KA, et al.  CTLA-4 and PD-1 receptors inhibit T-
cell activation by distinct mechanism.  Mol Cell Biol. 2005;25:9543-9553.
13. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev. 2010;236:219-42.
14. Agata Y, Katasaki A, Nishimura H, et al.  Expression of the PD-1 antigen on the surface 
of stimulated mouse T and B lymphocytes.  Int Immunol.  1996;8(5):765-772.
15. Vibhakar R, Juan G, Traganos F, et al.  Activation induced expression of human 
programmed death-1 gene in T-lymphocytes.  Exp Cell Res.  1997;232:25-28.
16. Nishimura H, Honjo T, Minato N.  Facilitation of beta selection and modification of 
positive selection in the thymus of PD-1-deficient mice.  J Exp Med.  2000;191:891-898.
17. Brown JA, Dorfman DM, Ma F-R, et al. Blockade of programmed death-1 ligands on 
dendritic cells enhances T cell activation and cytokine production. J Immunol. 
2003;170:1257-66.
18. Dong H, Strome SE, Salomao DR, et al.  Tumor-associated B7-H1 promotes T-cell 
apoptosis: a potential mechanism of immune evasion.  Nat Med.  2002;8:790-800.
19. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature. 2002;2:116-26.
20. Fourcade J, Kudela P, Sun Z, et al.  PD-1 is a regulator of NY-ESO-1-specific CD8+ T-
cell expansion in melanoma patients.  J Immunol.  2009;182:5240-5249.
21. Nomi T, Sho M, Akahori T, et al.  Clinical significance and therapeutic potential of the 
programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer.  
Clin Cancer Res.  2007;13:2151-2157.
22. Cai G, Karni A, Oliveira EM, et al. PD-1 ligands, negative regulators for activations of 
naïve, memory, and recently activated human CD4+ T-cells.  Cell Immunol.  
2004;20:98-89.
23. Blank C, Mackensen A.  Contribution of the PD-L1/PD-1 pathway to T-cell exhaustion: 
an update on implications for chronic infections and tumor evasion.  Cancer Immunol 
Immunother.  2007;56:739-745.
 
 
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24. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PDL1 on tumor cells in the escape 
from host immune system and tumor immunotherapy by PD-L1 blockade.  Proc Natl 
Acad Sci USA.  2002;99:12293-12297.
25. Tsushima F, Tanaka K, Otsuki N, et al.  Predominant expression of B7-H1 and its 
immunoregulatory roles in oral squamous cell carcinoma.  Oral Oncol.  2006;42:268-
274.
26. Korman A, Chen B, Wang C, Wu L, Cardarelli J, Selby M.  Activity of Anti-PD-1 in 
murine tumor models: role of “Host” PD-L1 and synergistic effect of anti-PD-1 and anti-
CTLA-4.  J Immunol.  2007;`78:abstr.48.37.
27. Hamid O, Robert C, Daud A, et. al. Safety and tumor responses with lambrolizumab 
(anti-PD 1) in melanoma. N Engl J Med. 2013 Jul 11;369(2):134-44.
28. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015; 65:5-
29.
29. Aisenberg AC. Primary large cell lymphoma of the mediastinum. Semin Oncol 1999; 
26:251-258.
30. Faris JE, LaCasce AS. Primary Mediastinal Large B-Cell lymphoma. Clin Adv Hematol 
Oncol 2009;7:125-133.
31. Cazals-Hatem D, Lepage E, Brice P, et al. Primary Mediastinal Large B-Cell 
Lymphoma. A clinicophatologic study of 141 cases compared with 916 nonmediastinal 
large B-Cell lymphoma, a GELA study. Am J Surg Pathol 1996; 20:877-878.
32. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of Primary Mediastinal B-
Cell lymphoma identifies a clinically favorable subgroup of diffuse large B-cell 
lymphoma related to Hodgkin lymphoma. J Exp Med 2003;198:851-862.
33. Savage KJ, Monti S, Kutok JL, et al. The molecular signature of mediastinal large B-cell 
lymphoma differs from that of other diffuse large B-cell lymphomas and share features 
with classical Hodgkin lymphoma. Blood 2003; 102:3871-3879.
34. Dunleavy K, Wilson W. Primary Mediastinal B-Cell lymphoma and mediastinal grey 
zone lymphoma: do they require a unique therapeutic approach? Blood 2015; 125(1).
35. Rieger M, Osterborg A, Pettengell R, et al. MabThera International Trial (MInT) Group. 
Primary mediastinal B-cell lymphoma treated with CHOP-like chemotherapy with or 
without rituximab: results of the Mabthera International Trial Group study. Ann Oncol. 
2011;22(3):664-670.
36. Zinzani PL, Martelli M, Bertini M, et al. International Extranodal Lymphoma Study 
Group (IELSG). Induction chemotherapy strategies for primary mediastinal large B-cell 
lymphoma with sclerosis: a retrospective multinational study on 426 previously 
untreated patients. Haematologica. 2002;87(12):1258-1264.
37. Todeschini G, Secchi S, Morra E, et al. Primary mediastinal large B-cell lymphoma 
(PMLBCL): long-term results from a retrospective multicentre Italian experience in 138 
patients treated with CHOP or MACOP-B/VACOP-B. Br J Cancer. 2004;90(2):372 6.
 
 
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38. Rodríguez J, Conde E, Gutiérrez A, et al. Primary mediastinal large cell lymphoma 
(PMBL): frontline treatment with autologous stem cell transplantation (ASCT). The 
GEL-TAMO experience. Hematol Oncol. 2008 Sep;26(3):171-8. doi: 10.1002/hon.858.
39. López A, Gutiérrez A, Palacios A, et al. GEMOX-R regimen is a highly effective 
salvage regimen in patients with refractory/relapsing diffuse large-cell lymphoma: a 
phase II study. Eur J Haematol. 2008 Feb;80(2):127-32. Epub 2007 Nov 20.
40. Moskowitz A, Ribrag V, Michot JM, et al. PD-1 Blockade with the Monoclonal 
Antibody Pembrolizumab (MK-3475) in Patients with Classical Hodgkin Lymphoma 
after Brentuximab Vedotin Failure: Preliminary Results from a Phase 1b Study 
(Keynote-013) Blood Dec 2014,124 (21)290.
41. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of 
Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press; 2008.
42. Parikh S, Kay N, and Shanafelt T.  How we treat Richter syndrome.  Blood. 
2014;123(11):1647-1657.
43. Maddocks K, Ruppert A, Lozanski G, et al.  Etiology of ibrutinib therapy 
discontinuation and outcomes in patients with chronic lymphocytic leukemia.  JAMA 
Oncol.  2015;1(1):80-87.
44. Rogers K, Salem G, Stephens D, et al.  A single-institution retrospective cohort study of 
patients treated with R-EPOCH for Richter’s transformation of chronic lymphocytic 
leukemia.  ASH 2015; Abstract 2951.
45. Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 
amplification, increased PD-1 ligand expression, and further induction via JAK2 in 
nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. 
Blood. 2010;116:3268-3277.
46. Joos S, Otano-Joos MI, Ziegler S, et al. Primary mediastinal (thymic) B cell lymphoma 
is characterized by gains of chromosomal material including 9p and amplification of the 
REL gene. Blood 87, 1571–1578 (1996).
47. Rui L, Emre NC, Kruhlak MJ, et al. Cooperative epigenetic modulation by cancer 
amplicon genes. Cancer Cell 18, 590–605 (2010).
48. Iwai Y, Ishida M, Tanaka Y, et al. Involvement of PD L1 on tumor cells in the escape 
from host immune system and tumor immunotherapy by PD L1 blockade. Proc. Natl 
Acad. Sci. USA 99, 12293–12297 (2002).
49. Chen BJ, Chapuy B, Ouyang J, et al. PD L1 expression is characteristic of a subset of 
aggressive B cell lymphomas and virus-associated malignancies. Clin. Cancer Res. 19, 
3462–3473 (2013).
50. Steidl C, Shah SP, Woolcock BW, et al. MHC class II transactivator CIITA is a 
recurrent gene fusion partner in lymphoid cancers. Nature 471, 377–381 (2011).
51. Berger R, Rotem-Yehudar R, Slama G, et al. Phase I Safety and Pharmacokinetic Study 
of CT-011, a Humanized Antibody Interacting with PD-1, in Patients with Advanced 
Hematologic Malignancies. Clin Cancer Res. 2008;14:3044-3051.
 
 
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52. Ding W, Dong H, Call T, et al.  PD-1 blockade with pembrolizumab (MK-3475) in 
relapsed/refractory CLL including Richter transformation: an early efficacy report from 
a phase 2 trial (MC1485).  ASH 2015; Abstract 834.
53. Zinzani PL, Pellegrini C, Chiappella A, et al. Brentuximab vedotin in relapsed primary 
mediastinal large B-cell lymphoma: results from a phase 2 clinical trial. Blood. 2017 Apr 
20;129(16):2328-2330.
54. Jacobsen ED, Sharman JP, Oki Y, et al. Brentuximab vedotin demonstrates objective 
responses in a phase 2 study of relapsed/refractory DLBCL with variable CD30 
expression. Blood. 2015;125(9):1394-1402.
 
 
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12.0 APPENDICES
Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in 
the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or 
national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
subject preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose 
of the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
2. Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
3. Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, 
misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, 
the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified and 
data disclosed accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of 
results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues 
of multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice 
guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, 
performance or interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to 
defend the trial results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
A. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC 
approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
B. Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial 
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or 
receipt of, medical care that may otherwise be available to them.
C. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
D. Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by 
an Ethics Committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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Collection and Management of Specimens for Future Biomedical Research
1. Definitions
a.
Biomarker:  A biological molecule found in blood, other body fluids, or tissues that is a 
sign of a normal or abnormal process or of a condition or disease.  A biomarker may be 
used to see how well the body responds to a treatment for a disease or condition.1
b. Pharmacogenomics:  The investigation of variations of DNA and RNA characteristics as 
related to drug/vaccine response.2
c.
Pharmacogenetics:  A subset of pharmacogenomics, pharmacogenetics is the influence of 
variations in DNA sequence on drug/vaccine response.2
d. DNA:  Deoxyribonucleic acid.
e.
RNA:  Ribonucleic acid.
2. Scope of Future Biomedical Research
The specimens collected in this trial as outlined in Section 7.1.3.5 – Future Biomedical 
Research Sample Collection will be used to study various causes for how subjects may 
respond to a drug/vaccine.  Future biomedical research specimen(s) will be stored to 
provide a resource for future trials conducted by the Sponsor focused on the study of 
biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a 
drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of 
disease. The specimen(s) may be used for future assay development and/or drug/vaccine 
development.
It is now well recognized that information obtained from studying and testing clinical 
specimens offers unique opportunities to enhance our understanding of how individuals 
respond to drugs/vaccines, enhance our understanding of human disease and ultimately 
improve public health through development of novel treatments targeted to populations 
with the greatest need.  All specimens will be used by the Sponsor or those working for 
or with the Sponsor.
3. Summary of Procedures for Future Biomedical Research
a.
Subjects for Enrollment
All subjects enrolled in the clinical trial will be considered for enrollment in the 
Future Biomedical Research sub-trial.
b. Informed Consent
Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained 
during screening for protocol enrollment from all subjects or legal guardians, at a trial 
visit by the investigator or his or her designate.  Informed consent for Future 
Biomedical Research should be presented to the subjects on Visit 1.  If delayed, 
present consent at next possible Subject Visit. Informed consent must be obtained 
prior to collection of all Future Biomedical Research specimens.  Consent forms 
signed by the subject will be kept at the clinical trial site under secure storage for 
regulatory reasons.  
 
 
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A template of each trial site’s approved informed consent will be stored in the 
Sponsor’s clinical document repository. Each consent will be assessed for appropriate 
specimen permissions.  
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of patient consent for Future Biomedical Research will be captured in 
the electronic Case Report Forms (eCRFs). Any specimens for which such an 
informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Collection of specimens for Future Biomedical Research will be performed as 
outlined in the trial flow chart. In general, if additional blood specimens are being 
collected for Future Biomedical Research, these will usually be obtained at a time 
when the subject is having blood drawn for other trial purposes.
4. Confidential Subject Information for Future Biomedical Research 
In order to optimize the research that can be conducted with Future Biomedical Research 
specimens, it is critical to link subject' clinical information with future test results. In fact 
little or no research can be conducted without connecting the clinical trial data to the 
specimen. The clinical data allow specific analyses to be conducted. Knowing subject 
characteristics like gender, age, medical history and treatment outcomes are critical to
understanding clinical context of analytical results.
To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, the Sponsor has developed secure policies and procedures. All 
specimens will be single-coded per ICH E15 guidelines as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
5. Biorepository Specimen Usage
Specimens obtained for the Merck Biorepository will be used for analyses using good 
scientific practices.  Analyses utilizing the Future Biomedical Research specimens may 
be performed by the Sponsor, or an additional third party (e.g., a university investigator) 
designated by the Sponsor. The investigator conducting the analysis will follow the 
Sponsor’s privacy and confidentiality requirements. Any contracted third party analyses 
will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical 
Research specimens remaining with the third party after specific analysis is performed 
will be reported to the Sponsor.
6. Withdrawal From Future Biomedical Research 
Subjects may withdraw their consent for Future Biomedical Research and have their 
specimens and all derivatives destroyed.   Subjects may withdraw consent at any time by 
contacting the principal investigator for the main trial. If medical records for the main 
trial are still available, the investigator will contact the Sponsor using the designated 
 
 
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mailbox (clinical.specimen.management@merck.com) and a form will be provided to 
obtain appropriate information to complete specimen withdrawal. Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. 
Documentation will be sent to the investigator confirming the destruction. It is the 
responsibility of the investigator to inform the subject of completion of destruction.  Any 
analyses in progress at the time of request for destruction or already performed prior to 
the request being received by the Sponsor will continue to be used as part of the overall 
research trial data and results. No new analyses would be generated after the request is 
received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial 
records) or the specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens. In this situation, the 
request for specimen destruction can not be processed. 
7. Retention of Specimens 
Future Biomedical Research specimens will be stored in the biorepository for potential 
analysis for up to 20 years from the end of the main study. Specimens may be stored for 
longer if a regulatory or governmental authority has active questions that are being 
answered. In this special circumstance, specimens will be stored until these questions 
have been adequately addressed.
Specimens from the trial site will be shipped to a central laboratory and then shipped to 
the Sponsor-designated biorepository. If a central laboratory is not utilized in a particular 
trial, the trial site will ship directly to the Sponsor-designated biorepository. The 
specimens will be stored under strict supervision in a limited access facility which 
operates to assure the integrity of the specimens.  Specimens will be destroyed according 
to Sponsor policies and procedures and this destruction will be documented in the 
biorepository database.
8. Data Security
Databases containing specimen information and test results are accessible only to the 
authorized Sponsor representatives and the designated trial administrator research 
personnel and/or collaborators. Database user authentication is highly secure, and is 
accomplished using network security policies and practices based on international 
standards (e.g., ISO17799) to protect against unauthorized access.
9. Reporting of Future Biomedical Research Data to Subjects
No information obtained from exploratory laboratory studies will be reported to the 
subject, family, or physicians. Principle reasons not to inform or return results to the 
subject include: Lack of relevance to subject health, limitations of predictive capability, 
and concerns regarding misinterpretation.
If any exploratory results are definitively associated with clinical significance for subjects 
while the clinical trial is still ongoing, investigators will be contacted with information. 
After the clinical trial has completed, if any exploratory results are definitively associated 
with clinical significance, the Sponsor will endeavor to make such results available 
 
 
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through appropriate mechanisms (e.g., scientific publications and/or presentations). 
Subjects will not be identified by name in any published reports about this study or in any 
other scientific publication or presentation.
10. Future Biomedical Research Study Population
Every effort will be made to recruit all subjects diagnosed and treated on Sponsor clinical 
trials for Future Biomedical Research.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. No additional 
risks to the subject have been identified as no additional specimens are being collected 
for Future Biomedical Research (i.e., only leftover samples are being retained).
The Sponsor has developed strict security, policies and procedures to address subject data 
privacy concerns.  Data privacy risks are largely limited to rare situations involving 
possible breach of confidentiality.  In this highly unlikely situation there is risk that the 
information, like all medical information, may be misused.
12. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
clinical.specimen.management@merck.com.
13. References
1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker
2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC 
BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC 
DATA 
AND 
SAMPLE 
CODING 
CATEGORIES 
-
E15; 
http://www.ich.org/LOB/media/MEDIA3383.pdf
 
 
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Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 
IRBs/IECs and Investigational Site Staff
 
 
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Abbreviations
Abbreviation/Term
Definition
AE
Adverse Event
ADA
Anti-Drug Antibodies
ALT
Alanine Aminotransferase
aPTT
Activated Partial Thromboplastin Time
ASaT
All Subjects as Treated
AST
Aspartate Aminotransferase
auto-SCT
autologous-Stem Cell Transplant
ABVD
Doxorubicin, Bleomycin, Vinblastine, Dacarbazine
ß-HCG
Beta Human Chorionic Gonadotropin
CIITA
Class II Transactivator
CBC
Complete Blood Count
CFR
Code of Federal Regulations
CHL
Classical Hodgkin Lymphoma
CI
Confidence Interval
CLL
Chronic Lymphocytic Leukemia
CNS
Central Nervous System
CR
Complete Response/Remission
CRF
Case Report Form
CSR
Clinical Study Report
CSR CI
Clinical Study Report Coordinating Investigator
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
DCR
Disease Control Rate
DLBCL
Diffuse Large B-Cell Lymphoma
DNA
Deoxyribonucleic Acid
DOR
Duration of Response
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EORTC QLQ-C30
European Organization for Research and Treatment of Cancer Quality of Life 
Questionnaire Core 30 items
EQ-5D
European Quality of Life 5-Dimension
ERC
Ethics Review Committee
EU
European Union
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Amendments Act
FDAMA
Food and Drug Administration Modernization Act
FDG
Fluorodeoxyglucose
FFPE
Formalin-fixed paraffin embedded
FNA
Fine needle aspirate
FSH
Follicle stimulating hormone
GCP
Good Clinical Practice
GEL-TAMO
Grupo Espanol de Linfomas y Transplante Autologo de Medula Osea
GI
Gastrointestinal
GVHD
Graft Versus Host Disease
 
 
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Abbreviation/Term
Definition
HIV
Human Immunodeficiency Virus
HL
Hodgkin Lymphoma
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
Ig
Immunoglobulin
INR
International Normalized Ratio
irAE
Immune-Related Adverse Event
IRB
Institutional Review Board
ITSM
Immunoreceptor Tyrosine-based Switch Motif
IV
Intravenous
IVRS
Integrated Voice Response System
IWRS
Integrated Web Response System
IWG
International Working Group
MACOP-B
Methotrexate, leucovorin, doxorubicin, cyclophosphamide, vincristine, 
prednisone, and bleomycin
MRI
Magnetic Resonance Imaging
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
NCI
National Cancer Institute
NHL
Non-Hodgkin Lymphoma
ORR
Objective Response Rate
OS
Overall Survival
OTC
Over-The-Counter
PBPK
Physiologically based pharmacokinetic
PD
Progressive Disease
PD-1
Programmed cell death 1 receptor
PD-L1
Programmed cell death ligand 1 receptor
PD-L2
Programmed cell death ligand 2 receptor
PET
Positron Emission Tomography
PFS
Progression Free Survival
PIN
Personal Identification Number
PK
Pharmacokinetic
PMBCL
Primary Mediastinal B-Cell Lymphoma
PR
Partial Remission/Response
PRO
Patient Reported Outcome
Protocol CI
Protocol Coordinating Investigator
PT
Prothrombin Time
R-CHOP
Rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine 
sulfate, and prednisone
R-EPOCH
rituximab, etoposide phosphate, prednisone, vincristine sulfate (Oncovin), 
cyclophosphamide, doxorubicin hydrochloride (Hydroxydaunorubicin)
R-ICE
rituximab, ifosfamide, carboplatin, etoposide
RNA
Ribonucleic Acid
rr
Relapsed or Refractory
RS
Richter Syndrome
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
SAE
Serious Adverse Events
sSAP
Supplemental Statistical Analysis Plan
SD
Stable Disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SOP
Standard Operating Procedures
 
 
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Abbreviation/Term
Definition
sSAP
supplemental Statistical Analysis Plan
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
US
United States
WHO
World Health Organization
 
 
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ECOG Performance Status
Grade
Description
0
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction.
1
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, 
but unable to carry out any work activities. Up and about more than 
50% of waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-
care. Totally confined to bed or chair.
5
Dead.
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative 
Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, 
Robert Comis M.D., Group Chair.
 
 
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Common Terminology Criteria for Adverse Events V4.0
The descriptions and grading scales found in the revised NCI CTCAE version 4.0 will be 
utilized for adverse event reporting. (http://ctep.cancer.gov/reporting/ctc.html).
 
 
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Lymphoma Disease Response Criteria
Cheson BD, Pfistner B, Juweid ME, et al. Revised Response Criteria for Malignant 
Lymphoma. J Clin Oncol.  2007; 25:579-586.  
Additional information is located in the Site Imaging Charter.
Criteria for lymphoma disease assessment:
Special considerations for RS:  
In subjects with RS, assessment of disease in the bone marrow will distinguish changes due 
to RS or transformed lymphoma from changes due to the pre-existing CLL.
For RS, CR requires clearance of the RS on marrow biopsy and aspirate. If radiographic CR 
is observed (no evidence of active disease on imaging), a final response determination of CR 
requires marrow clearance of RS, as well as disappearance of other clinical evidence of 
disease (such as physical exam findings). If the bone marrow is indeterminate by 
morphology, immunohistochemistry should be negative for RS. Residual underlying CLL 
may persist in node and/or marrow and still qualify as CR, denoting complete response of RS 
to pembrolizumab.
For RS, PET positive is defined as a lesion with uptake greater than that of the normal liver 
uptake.  PET must be positive at baseline and must be negative (no lesions with uptake 
greater than that of the normal liver) to be CR.
 
 
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Lugano Classification
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, 
and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification, 
J Clin Oncol. 2014; Sep 20;32(27):3059-68.
Additional information is located in the Site Imaging Charter.
Revised Criteria for Response Assessment
Response and Site
PET-CT Based Response
CT-Based Response
Complete
Complete metabolic response
Complete radiologic response (all 
of the following)
     Lymph nodes and 
extralymphatic sites
Score 1, 2, or 3* with or without a 
residual mass on 5PS†
Target nodes/nodal masses must 
regress to ≤ 1.5 cm in LDi
It is recognized that in Waldeyer's 
ring or extranodal sites with high 
physiologic 
uptake 
or 
with 
activation within spleen or marrow 
(eg, with chemotherapy or myeloid 
colony-stimulating factors), uptake 
may 
be 
greater 
than 
normal 
mediastinum and/or liver. In this 
circumstance, complete metabolic 
response may be inferred if uptake 
at sites of initial involvement is no 
greater than surrounding normal 
tissue even if the tissue has high 
physiologic uptake.
No extralymphatic sites of disease
    Nonmeasured lesion
Not applicable
Absent
    Organ enlargement
Not applicable
Regress to normal
    New lesions
None
None
     Bone marrow
No evidence of FDG-avid disease 
in marrow
Normal 
by 
morphology; 
if 
indeterminate, IHC negative
Partial
Partial metabolic response
Partial 
remission 
(all 
of 
the 
following)
     Lymph nodes and 
extralymphatic sites
Score 4 or 5† with reduced uptake 
compared 
with 
baseline 
and 
residual mass(es) of any size
≥ 50% decrease in SPD of up to 6 
target 
measurable 
nodes 
and 
extranodal sites
At interim, these findings suggest 
responding disease
When a lesion is too small to 
measure on CT, assign 5 mm × 5 
mm as the default value
At end of treatment, these findings 
indicate residual disease
When no longer visible, 0 × 0 mm
For a node > 5 mm × 5 mm, but 
smaller than normal, use actual 
measurement for calculation
     Nonmeasured lesions
Not applicable
Absent/normal, regressed, but no 
increase
     Organ enlargement
Not applicable
Spleen must have regressed by 
> 50% in length beyond normal
    New lesions
None
None
 
 
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Response and Site
PET-CT Based Response
CT-Based Response
     Bone marrow
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline (diffuse 
uptake compatible with reactive 
changes 
from 
chemotherapy 
allowed). If there are persistent 
focal changes in the marrow in the 
context of a nodal response, 
consideration should be given to 
further evaluation with MRI or 
biopsy or an interval scan
Not applicable
No response or stable disease
No metabolic response
Stable disease
     Target nodes/nodal masses, 
extranodal lesions
Score 4 or 5 with no significant 
change in FDG uptake from 
baseline at interim or end of 
treatment
< 50% decrease from baseline in 
SPD 
of 
up 
to 
6 
dominant, 
measurable nodes and extranodal 
sites; no criteria for progressive 
disease are met
     Nonmeasured lesions
Not applicable
No 
increase 
consistent 
with 
progression
     Organ enlargement
Not applicable
No 
increase 
consistent 
with 
progression
    New lesions
None
None
    Bone marrow
No change from baseline
Not applicable
Progressive disease
Progressive metabolic disease
Progressive disease requires at 
least 1 of the following
     Individual target nodes/nodal 
masses
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or
PPD progression
     Extranodal lesions
New FDG-avid foci consistent 
with lymphoma at interim or end-
of-treatment assessment
An individual node/lesion must be 
abnormal with:
LDi > 1.5 cm and
Increase by ≥ 50% from PPD nadir 
and
An increase in LDi or SDi from 
nadir
0.5 cm for lesions ≤ 2 cm
1.0 cm for lesions > 2 cm
In the setting of splenomegaly, the 
splenic length must increase by 
> 50% of the extent of its prior 
increase beyond baseline (eg, a 
15-cm spleen must increase to 
> 16 cm). If no prior splenomegaly, 
must increase by at least 2 cm from 
baseline.
New or recurrent splenomegaly.
Nonmeasured lesions
None
New or clear progression of 
preexisting nonmeasured lesions
 
 
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Response and Site
PET-CT Based Response
CT-Based Response
     New lesions
New FDG-avid foci consistent 
with lymphoma rather than another 
etiology 
(eg, 
infection, 
inflammation). 
If 
uncertain 
regarding etiology of new lesions, 
biopsy or interval scan may be 
considered.
Regrowth of previously resolved 
lesions
A new node > 1.5 cm in any axis
A new extranodal site > 1.0 cm in 
any axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and 
must be attributable to lymphoma
Assessable disease of any size 
unequivocally 
attributable 
to 
lymphoma
    Bone marrow
New or recurrent FDG-avid foci
New or recurrent involvement
•Abbreviations: 5PS - 5-point scale; CT - computed tomography; FDG - fluorodeoxyglucose; IHC - immunohistochemistry; 
LDi - longest transverse diameter of a lesion; MRI - magnetic resonance imaging; PET - positron emission tomography; 
PPD - cross product of the LDi and perpendicular diameter; SDi - shortest axis perpendicular to the LDi; SPD - sum of the 
product of the perpendicular diameters for multiple lesions.
• * A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the time of an interim 
scan. However, in trials involving PET where de-escalation is investigated, it may be preferable to consider a score of 3 as 
inadequate response (to avoid undertreatment). Measured dominant lesions: Up to six of the largest dominant nodes, nodal 
masses, and extranodal lesions selected to be clearly measurable in two diameters. Nodes should preferably be from 
disparate regions of the body and should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions 
include those in solid organs (eg, liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or those noted on 
palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly assessable disease 
should be considered not measured. These sites include any nodes, nodal masses, and extranodal sites not selected as 
dominant or measurable or that do not meet the requirements for measurability but are still considered abnormal, as well as 
truly assessable disease, which is any site of suspected disease that would be difficult to follow quantitatively with 
measurement, including pleural effusions, ascites, bone lesions, leptomeningeal disease, abdominal masses, and other 
lesions that cannot be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone 
marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but should be no higher 
than surrounding normal physiologic uptake (eg, with marrow activation as a result of chemotherapy or myeloid growth 
factors).
• † PET 5PS: 1, no uptake above background; 2, uptake ≤ mediastinum; 3, uptake > mediastinum but ≤ liver; 4, uptake 
moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X, new areas of uptake unlikely to be related to 
lymphoma
 
 
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13.0 SIGNATURES
Sponsor's Representative
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
Investigator
I agree to conduct this clinical trial in accordance with the design outlined in this protocol 
and to abide by all provisions of this protocol (including other manuals and documents 
referenced from this protocol).  I agree to conduct the trial in accordance with generally 
accepted standards of Good Clinical Practice.  I also agree to report all information or data in 
accordance with the protocol and, in particular, I agree to report any serious adverse events 
as defined in Section 7.0 – Assessing and Recording Adverse Events.  I also agree to handle 
all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in 
accordance with the protocol.  I understand that information that identifies me will be used 
and disclosed as described in the protocol, and that such information may be transferred to 
countries that do not have laws protecting such information.  Since the information in this 
protocol and the referenced Investigator’s Brochure is confidential, I understand that its 
disclosure to any third parties, other than those involved in approval, supervision, or conduct 
of the trial is prohibited.  I will ensure that the necessary precautions are taken to protect such 
information from loss, inadvertent disclosure or access by third parties.
TYPED NAME
TITLE
SIGNATURE
DATE SIGNED
 
 
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