A Phase II Clinical Trial of MK-3475 (Pembrolizumab) in Subjects With Relapsed or Refractory (R/R) Classical Hodgkin Lymphoma (cHL)
Phase: PHASE2
Conditions: Hodgkin Lymphoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title:
NCT number:
Document Date:
A Phase II Clinical Trial of MK-3475
(Pembrolizumab) in Subjects with Relapsed or
Refractory (R/R) Classical Hodgkin Lymphoma
(cHL)
NCT02453594
07-December-2022

Product:  MK-3475 
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THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME LLC, RAHWAY, NJ, USA (MSD).
This protocol amendment is applicable only to Sweden
SPONSOR:
Merck Sharp & Dohme LLC
(hereafter referred to as the Sponsor or MSD)
126 East Lincoln Avenue
P.O. Box 2000
Rahway, NJ 07065 USA
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder (or equivalent).
TITLE:
A Phase II Clinical Trial of MK-3475 (Pembrolizumab) in Subjects with Relapsed or 
Refractory (R/R) Classical Hodgkin Lymphoma (cHL)
IND NUMBER:  118604
EudraCT NUMBER:  2014-004482-24 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 11
SUMMARY OF CHANGES................................................................................................ 13
1.0
TRIAL SUMMARY.................................................................................................. 14
2.0
TRIAL DESIGN........................................................................................................ 15
Trial Design ........................................................................................................... 15
Trial Diagram........................................................................................................ 16
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 17
Primary Objective(s) & Hypothesis(es).............................................................. 17
Secondary Objective(s) & Hypothesis(es)........................................................... 17
Exploratory Objectives......................................................................................... 17
4.0
BACKGROUND & RATIONALE.......................................................................... 18
Background ........................................................................................................... 18
Pharmaceutical and Therapeutic Background .................................................... 18
Pre-clinical and Clinical Trials ........................................................................... 19
Ongoing Clinical Trials....................................................................................... 20
Rationale................................................................................................................ 20
Rationale for the Trial and Selected Subject Population .................................... 20
Hodgkin Lymphoma.................................................................................... 20
Rationale for Evaluating anti-PD-1 Therapy in Hodgkin Lymphoma......... 20
Rationale for Dose Selection/Regimen/Modification......................................... 21
Rationale for Fixed Dose pembrolizumab ................................................... 21
Rationale for Endpoints ...................................................................................... 22
Safety Endpoints.......................................................................................... 22
Efficacy Endpoints....................................................................................... 23
4.2.3.2.1
Exploratory ........................................................................................... 23
PD-L1 Expression .......................................................................... 23
Patient Reported Outcomes............................................................ 23
Pharmacokinetic Endpoints ......................................................................... 24
Planned Exploratory Biomarker Research................................................... 24
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Future Biomedical Research........................................................................ 26
Benefit/Risk ........................................................................................................... 26
5.0
METHODOLOGY ................................................................................................... 27
Entry Criteria........................................................................................................ 27
Diagnosis/Condition for Entry into the Trial...................................................... 27
Subject Inclusion Criteria.................................................................................... 27
Subject Exclusion Criteria .................................................................................. 30
Trial Treatment(s) ................................................................................................ 31
Dose Selection/Modification .............................................................................. 32
Dose Selection (Preparation) ....................................................................... 32
Immune-Related Events and Dose Modification (Withhold, Treat, 
Discontinue)................................................................................................. 32
Timing of Dose Administration.......................................................................... 36
Extent of Trial Treatment.................................................................................... 36
Trial Blinding/Masking....................................................................................... 36
Randomization or Treatment Allocation............................................................ 36
Stratification.......................................................................................................... 36
Concomitant Medications/Vaccinations (Allowed & Prohibited).................... 37
Acceptable Concomitant Medications ................................................................ 37
Prohibited Concomitant Medications.................................................................. 37
Rescue Medications & Supportive Care............................................................. 38
Supportive Care Guidelines ................................................................................ 38
Diet/Activity/Other Considerations..................................................................... 42
Diet...................................................................................................................... 42
5.7.2
Contraception...................................................................................................... 42
5.7.3
Use in Pregnancy ................................................................................................ 43
5.7.4
Use in Nursing Women....................................................................................... 44
Subject Withdrawal/Discontinuation Criteria................................................... 44
Discontinuation of Study Therapy after CR ....................................................... 45
Subject Replacement Strategy............................................................................. 45
Beginning and End of the Trial ........................................................................... 45
Clinical Criteria for Early Trial Termination ................................................... 45
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6.0
TRIAL FLOW CHART ........................................................................................... 46
Study Flow Chart: Cohorts 1, 2, and 3 ............................................................... 46
Study Flow Chart: Cohorts 1, 2, and 3: Second Course Phase 
(Retreatment for Post-Complete Response Relapse Only) ............................... 51
7.0
TRIAL PROCEDURES ........................................................................................... 54
Trial Procedures ................................................................................................... 54
Administrative Procedures.................................................................................. 54
Informed Consent......................................................................................... 54
7.1.1.1.1
General Informed Consent.................................................................... 54
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research................................................................................................ 55
Inclusion/Exclusion Criteria ........................................................................ 55
Subject Identification Card .......................................................................... 55
Medical History ........................................................................................... 55
Prior and Concomitant Medications Review............................................... 55
7.1.1.5.1
Prior Medications.................................................................................. 55
7.1.1.5.2
Concomitant Medications..................................................................... 55
Disease Details and Treatments................................................................... 56
7.1.1.6.1
Disease Details...................................................................................... 56
7.1.1.6.2
Prior Treatment Details......................................................................... 56
7.1.1.6.3
Subsequent Antineoplastic Therapy Status........................................... 56
Assignment of Screening Number............................................................... 56
Assignment of Randomization Number....................................................... 56
Trial Compliance (Medication/Diet/Activity/Other)................................... 57
Clinical Procedures/Assessments........................................................................ 57
Adverse Event (AE) Monitoring.................................................................. 57
Physical Exam.............................................................................................. 57
7.1.2.2.1
Full Physical Exam ............................................................................... 57
7.1.2.2.2
Directed Physical Exam........................................................................ 57
Vital Signs.................................................................................................... 58
Electrocardiogram........................................................................................ 58
Eastern Cooperative Oncology Group (ECOG) Performance Status .......... 58
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Assessment of Disease and Tumor Imaging................................................ 58
7.1.2.6.1
Criteria for Assessment of Disease....................................................... 58
7.1.2.6.2
Lymphoma Disease Response Assessment .......................................... 58
7.1.2.6.3
Disease Assessment of Immunotherapeutic Agents ............................. 59
7.1.2.6.4
Timing of Disease Assessments ........................................................... 59
7.1.2.6.5
Initial Disease Assessment.................................................................... 59
7.1.2.6.6
Disease Assessments During the Trial.................................................. 60
7.1.2.6.7
Disease Progression Assessments......................................................... 60
7.1.2.6.8
Biopsy Collection and Correlative Studies Blood Collection .............. 60
Patient Reported Outcomes (PROs)............................................................. 62
Laboratory Procedures/Assessments .................................................................. 62
Laboratory 
Safety 
Evaluations 
(Hematology, 
Chemistry, 
and 
Urinalysis).................................................................................................... 62
Pharmacokinetic/Pharmacodynamic Evaluations........................................ 64
7.1.3.2.1
Pharmacokinetic Evaluations................................................................ 64
7.1.3.2.2
Blood Collection for Anti-pembrolizumab Antibodies MK-3475 ....... 64
Future Biomedical Research........................................................................ 64
Other Procedures................................................................................................. 65
Withdrawal/Discontinuation........................................................................ 65
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................... 65
Blinding/Unblinding .................................................................................... 65
Calibration of Critical Equipment................................................................ 65
Visit Requirements.............................................................................................. 66
Screening...................................................................................................... 66
Treatment Period.......................................................................................... 67
7.1.5.2.1
Subjects Who Continue Treatment Beyond Disease Progression ........ 67
7.1.5.2.2
Second Course Phase (Retreatment Period for Post-complete 
Remission Relapse ONLY) .................................................................. 67
Post-treatment Visits.................................................................................... 68
7.1.5.3.1
Safety Follow-up Visit.......................................................................... 68
Follow-up Visits........................................................................................... 68
7.1.5.4.1
Follow-up Post-allogeneic Stem Cell Transplantation......................... 69
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7.1.5.4.2
Survival Follow-up ............................................................................... 69
Assessing and Recording Adverse Events .......................................................... 70
Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor.......................................................................................................... 71
Reporting of Pregnancy and Lactation to the Sponsor ....................................... 71
Immediate Reporting of Adverse Events to the Sponsor.................................... 72
Serious Adverse Events ............................................................................... 72
Events of Clinical Interest............................................................................ 73
Protocol-Specific Exceptions to Serious Adverse Event Reporting............ 74
Evaluating Adverse Events................................................................................. 74
Sponsor Responsibility for Reporting Adverse Events ...................................... 77
8.0
STATISTICAL ANALYSIS PLAN ........................................................................ 77
Statistical Analysis Plan Summary ..................................................................... 77
Responsibility for Analyses/In-House Blinding ................................................. 78
Hypotheses/Estimation......................................................................................... 78
Analysis Endpoints ............................................................................................... 79
Efficacy Endpoints.............................................................................................. 79
Safety Endpoints ................................................................................................. 79
Analysis Population .............................................................................................. 79
Efficacy Analysis Population.............................................................................. 79
Safety Analysis Population................................................................................. 80
Statistical Methods................................................................................................ 80
Statistical Methods for Efficacy Analyses.......................................................... 80
Overall Response Rate (ORR)..................................................................... 80
Complete Remission Rate (CRR)................................................................ 81
Progression-Free Survival (PFS) ................................................................. 81
Duration of Response (DOR)....................................................................... 82
Overall Survival (OS) .................................................................................. 83
Statistical Methods for Safety Analyses ............................................................. 84
Summaries of Baseline Characteristics, Demographics, and Other Analyses.... 84
Baseline Characteristics and Demographics................................................ 84
CCI
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Patient-reported Outcomes (PRO)............................................................... 84
Population PK Analyses .............................................................................. 85
Other Analyses............................................................................................. 85
Interim Analysis.................................................................................................... 85
Sample Size and Power Calculation.................................................................... 86
Multiplicity ............................................................................................................ 86
Subgroup Analyses and Effect of Baseline Factors ........................................... 87
Compliance (Medication Adherence).................................................................. 87
Extent of Exposure................................................................................................ 87
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 87
Investigational Product ........................................................................................ 87
Packaging and Labeling Information ................................................................. 88
Clinical Supplies Disclosure................................................................................. 88
Storage and Handling Requirements.................................................................. 88
Discard/Destruction/Returns and Reconciliation .............................................. 88
Standard Policies................................................................................................... 89
10.0
ADMINISTRATIVE AND REGULATORY DETAILS....................................... 89
Confidentiality....................................................................................................... 89
Confidentiality of Data ....................................................................................... 89
Confidentiality of Subject Records..................................................................... 89
Confidentiality of Investigator Information........................................................ 89
Confidentiality of IRB/IEC Information............................................................. 90
Compliance with Financial Disclosure Requirements....................................... 90
Compliance with Law, Audit and Debarment ................................................... 90
Compliance with Trial Registration and Results Posting Requirements........ 92
Quality Management System............................................................................... 93
Data Management................................................................................................. 93
Publications ........................................................................................................... 93
11.0
LIST OF REFERENCES......................................................................................... 94
12.0
APPENDICES........................................................................................................... 99
Code of Conduct for Clinical Trials.................................................................... 99
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Collection and Management of Specimens for Future Biomedical 
Research............................................................................................................... 102
Understanding the Intent, Scope and Public Health Benefits of 
Exploratory Biomarker Research: A Guide for IRBs/IECs and 
Investigational Site Staff .................................................................................... 108
Abbreviations ...................................................................................................... 119
ECOG Performance Status................................................................................ 122
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 123
Lymphoma Disease Response Criteria ............................................................. 124
Lugano Classification ....................................................................................... 125
13.0
SIGNATURES......................................................................................................... 127
Sponsor's Representative ................................................................................... 127
Investigator.......................................................................................................... 127
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LIST OF TABLES
Table 1
Lymphoma Adequate Organ Function Laboratory Values............................. 29
Table 2
Trial Treatment ............................................................................................... 31
Table 3
Dose Modification Guidelines for Hematological Drug-Related Adverse 
Events.............................................................................................................. 32
Table 4
Dose Modification and Toxicity Management Guidelines for Immune-
related Adverse Events Associated with Pembrolizumab Monotherapy, 
Coformulations or IO Combinations .............................................................. 33
Table 5
Infusion Reaction Treatment Guidelines ........................................................ 41
Table 6
Disease Response Assessments ...................................................................... 59
Table 7
Bone Marrow and Lymph Node Biopsy Assessments ................................... 61
Table 8
Blood for Correlative Studies ......................................................................... 61
Table 9
Laboratory Tests ............................................................................................. 63
Table 10
Evaluating Adverse Events............................................................................. 75
Table 11
Statistical Analysis Plan Summary................................................................. 77
Table 12
Censoring rules for Primary and Sensitivity Analyses of PFS ....................... 82
Table 13
Efficacy Analysis Methods for Primary and Secondary Efficacy 
Endpoints ........................................................................................................ 83
Table 14
Operating Characteristics of Interim Analysis Rule....................................... 86
Table 15
Product Descriptions....................................................................................... 88
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LIST OF FIGURES
Figure 1
Trial Diagram.................................................................................................. 16
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
Amendment 17
07-Dec-2022
To add language allowing eligible participants to enroll in an extension study, if 
available, following the end of MK-3475-087. To clarify that specific events will 
be collected as ECIs for 18 months from the date of the allogeneic transplant 
unless the trial closes earlier (Sweden-specific).
Amendment 16
05-Dec-2022
To add language allowing eligible participants to enroll in an extension study, if 
available, following the end of MK-3475-087. To clarify that specific events will 
be collected as ECIs for 18 months from the date of the allogeneic transplant 
unless the trial closes earlier. 
Amendment 15
23-Aug-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only 
in an entity name change and update to the address (Sweden-specific).
Amendment 14
23-Aug-2022
Merck Sharp & Dohme Corp. underwent an entity name and address change to 
Merck Sharp & Dohme LLC, Rahway, NJ, USA. This conversion resulted only 
in an entity name change and update to the address.
Amendment 13
17-May-2021
To update the dose modification and toxicity management guidelines for irAEs
(Sweden-specific).
Amendment 12
19-Apr-2021
To update the dose modification and toxicity management guidelines for irAEs.
Amendment 11
24-Oct-2017
Added additional safety data collection (Sweden-specific).
Amendment 10
29-Sep-2017
Added clarification on allostem cell transplant data collection.
Amendment 9
01-Feb-2017
Added clarification on OS interim and posttreatment analyses (Sweden-specific).
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Document
Date of Issue
Overall Rationale
Amendment 8
27-Jan 2017
Added clarification on efficacy interim and posttreatment analyses.
Amendment 7
15-Oct-2016
Clarified timing of efficacy analyses.
Amendment 6
13-Oct-2016
Clarified timing of efficacy analyses.
Amendment 5
25-Feb-2016
Revised statistical section and added safety updates (Sweden-specific).
Amendment 4
Not done
N/A
Amendment 3
21-Dec-2015
Revised statistical section and added safety updates.
Amendment 2
26-May-2015
Ensure language alignment with other protocols and CHMB recommendations.
Amendment 1
Not done
N/A
Original protocol
27-Feb-2015
N/A
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
5.10
Beginning and End of Trial 
Definition
Added 
language 
regarding 
extension study.
Revision to allow eligible participants 
to enroll in an extension study, if 
available, 
following 
the 
end 
of 
MK-3475-087.
7.1.5.4.1
Follow-up Post-allogenic Stem 
Cell Transplantation
Added parenthetical statement 
regarding the study closing 
early.
Revision to clarify that specific events 
will be collected as ECIs for 18 months 
from the date of the allogeneic 
transplant unless the trial closes earlier.
ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Minor administrative, formatting, grammatical, and typographical changes were made throughout the document to ensure clarity and 
accurate interpretation of the intent of the protocol.
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1.0 TRIAL SUMMARY
Abbreviated 
Title
A Phase II Clinical Trial of MK-3475 (Pembrolizumab) in Subjects with Relapsed or 
Refractory (R/R) Classical Hodgkin Lymphoma (cHL)
Trial Phase
Phase II
Clinical 
Indication
Cohort 1: Subjects with relapsed/refractory classical Hodgkin lymphoma (cHL) who
have failed to achieve a response or progressed after autologous stem cell transplant
(auto-SCT) and have relapsed after treatment with or failed to respond to brentuximab 
vedotin post auto-SCT.
Cohort 2: Subjects with relapsed/refractory classical Hodgkin lymphoma (cHL) who 
were unable to achieve a CR or PR to salvage chemotherapy and did not receive auto-
SCT, but have relapsed after treatment with or failed to respond to brentuximab vedotin.
Cohort 3: Subjects with relapsed/refractory classical Hodgkin lymphoma (cHL) who 
have failed to achieve a response to or progressed after auto-SCT and have not received 
brentuximab vedotin post auto-SCT. These subjects may or may not have received 
brentuximab vedotin as part of primary treatment, or salvage treatment.
Trial Type
Interventional
Type of control
No treatment control
Route of 
administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment 
Groups
Cohorts 1, 2 and 3: pembrolizumab 200mg IV every three weeks 
Number of trial 
subjects
Approximately 180 subjects will be enrolled.
Estimated 
duration of trial
The sponsor estimates that the trial will require approximately 35 months from the time 
the first subject signs the informed consent until the last subject’s last visit.
Duration of 
Participation
Each subject will participate in the trial from the time the subject signs the Informed 
Consent Form (ICF) 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 up to 35 cycles (approximately 24 
months) per subject or until documented confirmed disease progression, unacceptable 
adverse event(s), intercurrent illness that prevents further administration of treatment, 
investigator’s decision to withdraw the subject, subject withdraws consent, pregnancy of 
the subject, noncompliance with trial treatment or procedure requirements, or 
administrative reasons.  Subjects who attain a complete response (CR) 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 adverse event 
monitoring (serious adverse events 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 for overall survival 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 a multicenter, single arm, multi-cohort, nonrandomized trial of pembrolizumab (MK-
3475) in subjects with relapsed or refractory classical Hodgkin lymphoma: who have failed
to achieve a response or progressed after auto-SCT and have relapsed after treatment with or 
failed to respond to brentuximab vedotin
post auto-SCT (Cohort 1); who were unable to 
achieve a CR or PR to salvage chemotherapy and did not receive auto-SCT, but have 
relapsed after treatment with or failed to respond to brentuximab vedotin (Cohort 2); and 
subjects who have failed to respond to or progressed after auto-SCT and have not received 
brentuximab vedotin post auto-SCT. These patients may or may not have received 
brentuximab vedotin as part of primary or salvage treatment (Cohort 3).   
Approximately 180 subjects will be enrolled in this trial to examine the safety and efficacy of 
pembrolizumab 200 mg fixed dose administered every 3 weeks (Q3W). Approximately 60
subjects will be enrolled in each of the cohorts. Adverse events will be monitored every 
three weeks throughout the trial and graded in severity according to the guidelines outlined in 
the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  
Treatment with pembrolizumab will continue up to 35 cycles (approximately 24 months) per 
subject or until documented disease progression, unacceptable adverse event(s), intercurrent 
illness that prevents further administration of treatment, investigator’s decision to withdraw 
the subject, 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 an investigator-determined confirmed complete response (CR)
may consider stopping trial treatment after receiving at least 24 weeks (8 cycles) of therapy. 
At least two doses must be received after CR is documented. These subjects will be eligible 
for retreatment 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 (refer to Section 7.1.5.2.2 for further details).  
After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events 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 for overall survival until death, withdrawal of 
consent or the end of the study, whichever comes first.
The primary objectives of the trial are to determine safety, tolerability, and overall response 
rate (ORR) by independent central review (utilizing the IWG response assessment criteria per 
Cheson 2007) of pembrolizumab in subjects with relapsed and/or refractory classical 
Hodgkin Lymphoma.  Secondary objectives include further analysis of various efficacy 
parameters (complete remission rate [CRR], progression free survival [PFS], overall survival
[OS] and duration of response [DOR]). Response assessments, by independent central 
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review, utilizing the 5-point scale according to the Lugano Classification; analysis of PD-L1 
expression and corresponding efficacy; changes in health related quality of life assessments, 
along with the relationship of candidate efficacy/resistance biomarkers and anti-tumor 
activity of pembrolizumab will be investigated as exploratory objectives.  
Unless specified otherwise, the statistical analyses will be conducted separately by cohort.  In 
addition, a separate clinical study report may be issued for a single cohort if the actual 
enrollment rate among cohorts is markedly different.
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
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
Primary Objective(s) & Hypothesis(es)
Within each of, and pooled over, the 3 specified cohorts defined in Section 5.1.2. for subjects 
with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL):
(1) Objective:  To determine the safety and tolerability of pembrolizumab.
Within each of the 3 cohorts of subjects with R/R cHL:
(2) Objective: To evaluate the Overall Response Rate (ORR) of pembrolizumab by 
independent central review according to the International Working Group (IWG) 
response criteria (Cheson, 2007).
Hypothesis: Intravenous administration of single agent pembrolizumab will result in an
ORR of greater than 20% in each of the three cohorts using IWG response criteria 
(Cheson, 2007) by independent central review.
Secondary Objective(s) & Hypothesis(es)
Within each of the 3 cohorts of subjects with R/R cHL:
(1) Objective:  Evaluate ORR of pembrolizumab by investigator assessment according to the 
IWG response criteria; and additionally by independent central review using the 5-point 
scale according to the Lugano Classification.
(2) Objective:  Evaluate Complete Remission Rate (CRR) of pembrolizumab by independent 
central review and by investigator assessment according to the IWG response criteria;
and additionally by independent central review using the 5-point scale according to the 
Lugano Classification.
(3) Objective:  Evaluate Progression Free Survival (PFS) and Duration of Response (DOR) 
of pembrolizumab by independent central review and by investigator assessment 
according to the IWG response criteria.
(4) Objective:  Evaluate the Overall Survival (OS) of pembrolizumab.
Exploratory Objectives 
Within each of, and potentially pooled over, the 3 cohorts of subjects with R/R cHL:
(1) Objective: To evaluate ORR, CRR, PFS and DOR for subjects who continue treatment
with pembrolizumab beyond documented progression (see Section 8.6.1).
(2) Objective: To explore the PK profile of pembrolizumab (see Section 7.1.3.2.1)
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(3) Objective: To evaluate changes in health-related quality-of-life assessments from 
baseline using the EORTC QLQ-C30 and EuroQol EQ-5D (see Section 4.2.3.2.1.2)
(4) Objective: To further evaluate pembrolizumab immunogenicity and exposure of the 
proposed dose and dosing regimen (see Section 4.2.3.3).
(5) Objective:  To compare the extent of pre-pembrolizumab PD-L1 expression in tumor 
biopsies for pembrolizumab responders versus non-responders (see Section 4.2.3.2.1.1)
(6) 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 4.2.3.4).  
(7) 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 4.2.3.4).
4.0 BACKGROUND & RATIONALE
Background
Refer to the Investigator’s Brochure (IB)/approved labeling 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 (mAb) of the IgG4/kappa isotype designed to 
directly block the interaction between PD-1 and its ligands, PD-L1 and PD-L2 without 
ADCC or CDC activity.
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades [1].  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis in 
various malignancies [2; 3; 4; 5; 6].  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 CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) [7; 
8]. The structure of murine PD-1 has been resolved [9].  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 
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molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif (ITIM) 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; 10; 11; 12].  The mechanism by which PD-1 
down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both 
molecules regulate an overlapping set of signaling proteins [13; 14]. 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 [15; 16].  Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells [17].  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 [13; 18; 19; 20].  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 (MEL) 
[21].  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 mono-therapy or in combination with other 
treatment modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated 
anti-tumor responses as a mono-therapy in models of squamous cell carcinoma, pancreatic 
carcinoma, MEL and colorectal carcinoma.  Blockade of the PD-1 pathway effectively 
promoted CD8+ T-cell infiltration into the tumor and the presence of IFN-, granzyme B,
and perforin, indicating that the mechanism of action involved local infiltration and 
activation of effector T-cell function in vivo [22; 23; 24; 25; 26; 27].  Experiments have 
confirmed the in vivo efficacy of PD-1 blockade as a mono-therapy as well as in combination 
with chemotherapy in syngeneic mouse tumor models (refer to the IB).
In a phase 1/2 study of 135 patients with advanced melanoma treatment with pembrolizumab 
produced an ORR of 38% (95% 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 
[49].
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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, and triple negative 
breast cancer and in a number of hematologic malignancies.  For study details please refer to 
the IB.
Rationale
Rationale for the Trial and Selected Subject Population
Hodgkin Lymphoma
Hodgkin lymphoma (HL) accounts for approximately 10 percent of all lymphomas and 
approximately 0.6 percent of all cancers diagnosed in the developed world annually [30]. In 
the United States, HL newly presents in over 8,400 individuals per year accounting for 
approximately 8.7% of all lymphomas in the US [31; 32]. Classical HL (CHL) is divided into 
four histologic subtypes: Nodular Sclerosis CHL, Mixed cellularity CHL, Lymphocyte rich 
CHL and Lymphocyte depleted CHL [33]. Although, HL is curable in 80% of patients 
diagnosed, new therapies are needed, especially for patients who present with advanced 
disease. The standard of care for patients with relapsed or refractory HL is salvage 
chemotherapy followed by autologous stem-cell transplantation (auto-SCT), which can 
induce long-term remissions in approximately 50% of patients [34; 35].  For patients who 
experience relapse or progressive HL within 1 year after auto-SCT, especially those who 
have received newer agents such as brentuximab vedotin (anti-CD-30), the prognosis is 
exceedingly poor with a median survival time of approximately 1.2 years [36]. Varied classes 
of novel agents have demonstrated activity in patients with relapsed/refractory HL who have 
failed auto-SCT.  However, the median PFS is still remains less than 6 months [42;43;44;45]. 
Although brentuximab vedotin has demonstrated an ORR of 75%, median PFS is only 5.6 
months requiring the development of additional therapies that will improve PFS in this 
patient population [35].  Patients with progressive disease after brentuximab vedotin have no 
available standard of care and represent an urgent unmet medical need. 
Rationale for Evaluating anti-PD-1 Therapy in Hodgkin Lymphoma
Hematologic (Heme) malignancies are known to be responsive to a variety of 
immunotherapies. Allogeneic cellular therapy (bone marrow transplant and donor 
lymphocyte infusions) is effective in chronic myeloid leukemia (CML), acute myeloid 
leukemia (AML), chronic lymphocytic leukemia (CLL), and many lymphomas. 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 Heme malignancies.
High frequency of expression of PD-L1 by IHC and flow cytometry has been demonstrated 
in classic HL, and NHL tumor cells including primary mediastinal large B cell lymphoma 
(PMLBCL) [29]. A recent integrative analysis reveals selective 9p24.1 amplification, which 
includes the PD-L1 and PD-L2 loci, increased PD-L1 expression, and further induction via 
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JAK2 in nodular sclerosing HL and PMLBCL [38]. Furthermore, Epstein–Barr virus (EBV) 
infection of malignant Reed Sternberg cells, which is implicated in approximately 40% of 
cases of HL, contributes to overexpression of PD-L1 even in the absence of 9p24.1 
amplification.  The EBV latent membrane protein 1 exerts direct and indirect effects on PD-
L1 promoter and enhancer elements leading to increased PD-L1 protein expression (Green et 
al, 2012, Clin Cancer Res).
A phase 1 clinical trial conducted in advanced hematologic malignancies using CT-011, 
showed clinical responses in 6 of 17 patients including HL and NHL patients [39].
Preliminary results from our ongoing Phase 1b study evaluating MK-3475 10 mg/kg every 
2 weeks in patients with hematologic malignancies including myelodysplastic syndromes, 
HL, PD-L1-positive non-Hodgkin lymphoma, and multiple myeloma indicate a response rate 
of 53.3%, including a complete response rate of 20.0 % in heavily pretreated HL patients 
who had progressed after all lines of prior therapy including stem cell transplant [46].
Rationale for Dose Selection/Regimen/Modification
Rationale for Fixed Dose pembrolizumab 
An open-label Phase I trial (KEYNOTE 001) is being conducted to evaluate the safety and 
clinical activity of single agent pembrolizumab (MK-3475).  The dose escalation portion of 
this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors. All three dose levels were well 
tolerated and no dose-limiting toxicities were observed. This first in human study of 
pembrolizumab (MK-3475) showed evidence of target engagement and objective evidence of 
tumor size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). The 
maximum tolerated dose (MTD) was not reached.
In KEYNOTE 001, two randomized cohort evaluations of melanoma subjects receiving 
pembrolizumab (MK-3475) at a dose of 2 mg/kg versus 10 mg/kg Q3W have been 
completed, and one randomized cohort evaluation of 10 mg/kg Q3W versus 10 mg/kg Q2W 
has also been completed. The clinical efficacy and safety data demonstrate a lack of 
clinically important differences in efficacy response or safety profile at these doses. For 
example, in Cohort B2, advanced melanoma subjects who had received prior ipilimumab 
therapy were randomized to receive pembrolizumab (MK-3475) at 2 mg/kg versus 10 mg/kg 
Q3W. The ORR was 26% (21/81) in the 2mg/kg group and 26% (20/76) in the 10 mg/kg 
group (FAS). The proportion of subjects with drug-related AE, grade 3-5 drug-related AE, 
serious drug-related AE, death or discontinuation due to an AE was comparable between 
groups or lower in the 10 mg/kg group. In Cohort B3, advanced melanoma subjects 
(irrespective of prior ipilimumab therapy) were randomized to receive pembrolizumab (MK-
3475) at 10 mg/kg Q2W versus 10 mg/kg Q3W. The ORR was 30.9% (38/123) in the 
10mg/kg Q2W group and 24.8% (30/121) in the 10 mg/kg Q3W group (APaT). The 
proportion of subjects with drug-related AE, grade 3-5 drug-related AE, serious drug-related 
AE, death or discontinuation due to an AE was comparable between groups.
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PK data analysis of pembrolizumab (MK-3475) administered Q2W and Q3W showed slow 
systemic clearance, limited volume of distribution, and a long half-life (refer to IB).  
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement is 
durable (>21 days).  This early PK and pharmacodynamic data provides scientific rationale 
for testing a Q3W dosing schedule.  Because Q3W dosing is more convenient for patients, 
Q3W dosing will be further studied.
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
(MK-3475) in relapsed/refractory classical Hodgkin lymphoma is based on data in melanoma 
patients: 1) similar efficacy and safety of pembrolizumab (MK-3475) when dosed at either 2 
mg/kg or 10 mg/kg Q3W, 2) the flat exposure-response relationships of pembrolizumab 
(MK-3475) for both efficacy and safety in the dose ranges of 2 mg/kg Q3W to 10 mg/kg 
Q3W, 3) the lack of effect of tumor burden or indication on distribution behavior of 
pembrolizumab (MK-3475) (as assessed by the population PK model).
These observations in melanoma patients may be extended to HL because MK-3475 is 
expected to drive anti-tumor effect through immune system activation, and HL and 
melanoma patients show similar pembrolizumab (MK-3475) driven activation of immune 
system as measured by ex-vivo cytokine release assay. Additionally, exposures of 
pembrolizumab (MK-3475) in HL patients (at 10 mg/kg Q2W) are comparable to those in 
melanoma patients. Based on these data, the dynamics of pembrolizumab (MK-3475) target 
engagement is not expected to vary meaningfully between HL and melanoma patients.
The choice of 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on 
simulations performed using the population PK model of pembrolizumab (MK-3475) 
showing that the fixed dose of 200 mg Q3W will provide exposures that: 1) are optimally 
consistent with those obtained with 2 mg/kg dose Q3W, 2) will maintain individual patient 
exposures in the exposure range established in melanoma as associated with maximal 
efficacy response and 3) will maintain individual patients exposure in the exposure range 
established in melanoma that are well tolerated and safe. 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians 
and to reduce potential for dosing errors.  A fixed dosing scheme will also reduce complexity 
in the logistical chain at treatment facilities and reduce wastage. While the existing data 
suggest 200 mg Q3W as the optimal dose, dose modification may be considered if efficacy or 
toxicity with 200 mg Q3W is found to be unfavorable.
Rationale for Endpoints
Safety Endpoints
The primary safety objective of this study is to characterize the safety and tolerability of 
pembrolizumab in subjects with relapsed or refractory Hodgkin Lymphoma.  The primary 
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 
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subjects who have received pembrolizumab, including serious adverse events (SAEs) and 
events of clinical interest (ECIs).  
Safety will be assessed by reported adverse events 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.  
Efficacy Endpoints
The primary efficacy objective of this study is to evaluate the anti-tumor activity of 
pembrolizumab in subjects with relapsed or refractory classical Hodgkin lymphoma. The 
primary efficacy endpoint for Hodgkin lymphoma will be overall response rate (ORR) as 
assessed by independent central review per Cheson 2007 International Working Group
(IWG) response criteria for malignant lymphoma [40]. ORR will also be assessed using the 
5-point scale per the Lugano Classification [41] by independent central review as a
secondary endpoint.
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. 
4.2.3.2.1 Exploratory
PD-L1 Expression
PD-L1 expression in tumor tissue will be characterized by immunohistochemistry to explore 
the relationship between tumor PD-L1 expression and response to treatment with 
pembrolizumab (MK-3475).
Patient Reported Outcomes
EORTC QLQ-C30 and eEQ-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).
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eEuroQoL-5D
The eEuroQol-5D (eEQ-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 QALYs. The five health state dimensions in this instrument 
include the following: mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression [37]. Each dimension is rated on a 3-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. 
Pharmacokinetic Endpoints
Blood samples will be obtained to measure pharmacokinetics of serum pembrolizumab
monotherapy. The pembrolizumab serum maximum concentration (Cmax) and minimum 
concentration (Ctrough) at planned visits and times will be summarized.
Pharmacokinetic data will also be analyzed using nonlinear mixed effects modeling.  Based 
on PK data obtained in this study as well as PK data obtained from other studies (if 
available), a population PK analysis will be performed to characterize PK parameters 
(Clearance [CL], Volume of distribution [V]) and evaluate the effect of extrinsic and intrinsic 
factors to support proposed dosing regimen. Pharmacokinetic data will also be used to 
explore the exposure-response relationships for pembrolizumab antitumor activity/efficacy as 
well as safety in the proposed patient population, if feasible. The results of these analyses, if 
performed, will be reported separately.  
Planned Exploratory Biomarker Research
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 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 using Nanostring/RNAseq for gene expression as well as Nanostring for 
miRNA profiling.
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.
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Assays may include but are not limited to:  
Multiplex Flow Cytometric Analysis
Emerging data suggest that blockade of the PD-1/PDL-1 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, eg, Naïve, activated, memory and regulatory T cells, will be 
assessed pre- and post-dose and in both responders and non-responders. NK cells 
enumeration will also be performed pre- and post-dose in both responders and non-
responders.
Transcriptional Analyses
mRNA 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 (CTL)” response within the tumor 
reflected in the physical proximity between PD-1 and PD-L1 expression and the presence of 
an aborted  (eg, 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 (eg, IL-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 (WES) 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.
Planned Genetic Analysis
In addition, 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.
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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.
Such research is for biomarker testing to address emergent questions not described elsewhere 
in the protocol (as part of the main trial) and will only be conducted on specimens from 
appropriately consented subjects. The objective of collecting specimens for Future 
Biomedical Research is to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments. For instance, exploratory 
pharmacogenetic 
(PGt) 
studies 
may 
be 
performed 
if 
significant 
Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adverse events 
are identified.  Genomic markers of disease may also be investigated.  Such retrospective 
pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis 
and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to 
outcome would require validation in future clinical trials. The overarching goal is to use such 
information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects 
receive the correct dose of the correct drug/vaccine at the correct time.  The details of Future 
Biomedical Research are presented in Section 12.2 - Collection and Management of 
Specimens for Future Biomedical Research.  Additional informational material for 
institutional review boards/ethics committees (IRBs/ERCs) and investigational site staff is 
provided in Section 12.3.
Benefit/Risk
Subjects in clinical trials generally cannot expect to receive direct benefit from 
treatment/vaccination 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 accompanying IB and Informed Consent documents.  Based on results from 
the ongoing clinical studies, there is no contraindication to the continued clinical 
investigation of pembrolizumab.
In addition, beneficial effects of pembrolizumab have been seen in several trials to date.  
Publications of a significantly positive benefit/risk ratio have been reported for melanoma 
both in a single arm study encompassing nearly 1000 patients (KEYNOTE 001), which led to 
USFDA approval in September 2014, and in a randomized comparison to chemotherapy 
(KEYNOTE-002 – detailed in the IB).  Additional potential benefits for Hodgkin Lymphoma 
are addressed in section 4.2.1.2 which details responses observed in KEYNOTE-013 trial; a 
multi-cohort Phase Ib study of which one cohort enrolled subjects with relapsed or refractory 
classical Hodgkin lymphoma (n = 31) that have failed, are ineligible for, or refused a stem 
cell transplant and have relapsed after treatment with or failed to respond to Brentuximab 
vedotin. Published results from this study indicate an overall response rate (ORR) of 65%,
including a complete response rate (CRR) of 16%.  In terms of safety, most adverse events 
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observed were Grade 1 and 2, which resolved with appropriate clinical management. No 
Grade 4-5 drug related adverse events (DRAEs) were reported, but two patients discontinued 
therapy due to a DRAE: Grade 2 pneumonitis, and Grade 3 nephrotic syndrome [47]. The 
present study, KEYNOTE-087 (ClinicalTrials.gov, NCT02453594), is a multicenter, single-
arm, multicohort phase 2 study of pembrolizumab in 3 cohorts of patients. Among 210 
treated patients in cohorts 1 (n = 69), 2 (n = 81), and 3 (n = 60), all patients had refractory 
disease or relapsed HL.   Per blinded independent central review, the ORR was 69.0% (95% 
CI, 62.3% to 75.2%), and the CRR was 22.4% (95% CI, 16.9% to 28.6%). By cohort, ORRs 
were 73.9% for cohort 1, 64.2% for cohort 2, and 70.0% for cohort 3. Thirty-one patients had 
a response ≥6 months. With a median of 13 treatment cycles, the most common treatment-
related AEs (TRAEs) were hypothyroidism (12.4%) and pyrexia (10.5%). The most common 
grade 3/4 TRAEs were neutropenia (2.4%), dyspnea (1%), and diarrhea (1%). Immune-
mediated AEs (events with potentially drug-related immunologic causes regardless of 
treatment attribution) and infusion-related reactions were reported in 60 patients (28.6%), 
most commonly hypothyroidism (13.8%). Nine patients (4.3%) discontinued because of 
TRAEs (myocarditis, myelitis, myositis, pneumonitis, infusion-related reactions, cytokine 
release syndrome), and 26 patients (12.4%) experienced TRAEs resulting in treatment
interruptions. Two patients died during follow-up as a result of septic shock and acute graft-
versus-host disease, respectively; neither of these deaths were considered to be treatment 
related [48].  Taken together, the observed efficacy and safety data indicate that MK-3475 
has the potential to alter the disease course in these RRHL patients and potentially prolong 
patient survival.
In conclusion, pembrolizumab demonstrates a very promising anti-cancer activity in relapsed 
or refractory Hodgkin Lymphoma patients with an acceptable safety profile compared to 
those of existing therapeutic options. On-going and planned studies will allow for a more 
comprehensive analysis of benefit/risk balance of pembrolizumab.
5.0 METHODOLOGY
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with relapsed or refractory de novo classical Hodgkin lymphoma 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. However, the subject 
may participate in the main trial without participating in Future Biomedical Research.
2. Be 18 years of age on day of signing informed consent.
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3. Have relapsed* or refractory* de novo classical Hodgkin lymphoma and meet one of the 
following cohort inclusions:
*Relapsed: disease progression after most recent therapy
*Refractory: failure to achieve CR or PR to most recent therapy
a.
Cohort 1: Have failed to achieve a response or progressed after auto-SCT.  Subjects 
must have relapsed after treatment with or failed to respond to brentuximab vedotin
post auto-SCT.
b. Cohort 2: Were unable to achieve a complete or a partial response to salvage 
chemotherapy and did not receive auto-SCT. Subjects must have relapsed after 
treatment with or failed to respond to brentuximab vedotin.
c.
Cohort 3: Have failed to achieve a response or progressed after auto-SCT and have 
not have received brentuximab vedotin post auto-SCT. Note: These subjects may or 
may not have received brentuximab vedotin as part of primary treatment, or 
salvage treatment.
4. Have measurable disease defined as at least one lesion that can be accurately measured in 
at least two dimensions with spiral CT scan.  Minimum measurement must be > 15 mm 
in the longest diameter or > 10 mm in the short axis.
5. Be able to provide an evaluable core or excisional lymph node biopsy for biomarker 
analysis from an archival or newly obtained biopsy at Screening. In addition subjects 
may provide additional biopsy at Week 12 and at the time of discontinuation due to 
progression. If submitting unstained cut slides, freshly cut slides should be submitted to 
the testing laboratory within 14 days from when the slides are cut. See Section 7.1.2.6.8
for an explanation.
6. Must have a performance status of 0 or 1 on the ECOG Performance Scale.
7. Must demonstrate adequate organ function as defined in Table 1; all screening labs 
should be performed within 7 days of treatment initiation.
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Table 1
Lymphoma Adequate Organ Function Laboratory Values 
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1000 / mcL
Plateletsb
≥75,000 / mcL
Hemoglobinb
≥8 g/dL 
Renal
Creatinine OR
Measured or calculateda creatinine clearance
(GFR can also be used in place of creatinine or 
CrCl)
≤1.5 X upper limit of normal (ULN) OR
≥60 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
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN OR
≤ 5 X ULN for subjects with liver metastases
Coagulation
International Normalized Ratio (INR) 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
a Creatinine clearance should be calculated per institutional standard.
b Hemoglobin and platelet requirements cannot be met by use of recent transfusion or growth factor support (G-CSF or 
erythropoietin) within 2 weeks prior to treatment initiation unless bone marrow infiltration by disease is documented, in 
which case red blood cell transfusion is allowed.
8. Female subject of childbearing potential should have a negative urine or serum pregnancy 
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.
9. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of birth control 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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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 investigation device within 4 
weeks of the first dose of treatment.
2. Has a diagnosis of immunosuppression or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment.  The use of physiologic doses of corticosteroids may be approved after 
consultation with the Sponsor.
3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not 
recovered (ie, ≤ Grade 1 or at baseline) from adverse events due to agents administered 
more than 4 weeks earlier. 
-Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study.
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (ie, ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent.
-Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may 
qualify for the study.
-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.
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 GVHD.)
6. Has a known additional malignancy 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 clinically active CNS involvement.  
8. Has active autoimmune disease that has required systemic treatment in past 2 years (ie,
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement 
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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-Cytotoxic T-lymphocyte-associated antigen-4 (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 1/2 antibodies).
15. Has known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA 
[qualitative] is detected).
16. Has received a live vaccine within 30 days prior to first dose.
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
200mg
Q3W
IV Infusion
Day 1 of each 
treatment cycle
experimental
Trial treatment should begin on the day of randomization or as close as possible to the date 
on which the subject is allocated/assigned.
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.
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Dose Selection/Modification
Dose Selection (Preparation)
All subjects will receive 200 mg via IV infusion Q3W.  Details on the preparation and 
administration are provided in the Pharmacy Manual.
Immune-Related Events and Dose Modification (Withhold, Treat, Discontinue)
Dose Modification and Toxicity Management for Immune-related AEs Associated with 
Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immune-related response. 
These irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than one body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of pembrolizumab, administration of corticosteroids and/or other supportive 
care. For suspected irAEs, ensure adequate evaluation to confirm etiology or exclude other 
causes. Additional procedures or tests such as bronchoscopy, endoscopy, skin biopsy may be 
included as part of the evaluation. Based on the severity of irAEs, withhold or permanently 
discontinue pembrolizumab and administer corticosteroids. 
Hematological Toxicity Management Guidelines for Pembrolizumab are provided in Table 3. 
Dose Modification and Toxicity Management Guidelines for irAEs associated with 
pembrolizumab monotherapy, coformulations, or IO combinations are provided in Table 4.
 
Toxicity
Grade
Hold 
Treatment 
(Y/N)
Timing for 
restarting 
treatment
Treatment Discontinuation 
(after consultation with 
Sponsor)
N/A
4
Yes
Toxicity resolves 
to Grade 0-1 or 
baseline
Toxicity does not resolve 
within 12 weeks of last infusion
Permanent discontinuation 
should be considered for any 
life-threatening event
CCI
CCI
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CCI
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CCI
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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).  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.
All trial treatments will be administered on an outpatient basis.
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 (ie, 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 who experience a partial response or have stable disease may remain on 
treatment for up to 35 cycles (approximately two years) or until progression.  Per the 
investigator’s discretion subjects who achieve a CR are eligible to restart treatment 
upon documented progression as long as they meet eligibility criteria specified in the 
protocol (See Section 7.1.5.2.2).  

Subjects who achieve a CR and choose not to stop therapy may continue treatment for 
a total duration of 35 cycles (approximately two years).
Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
Randomization or Treatment Allocation
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 PT or PTT 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 30 days after the last dose of trial treatment should be recorded for 
SAEs and ECIs as defined in Section 7.2.
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 

Immunotherapy not specified in this protocol

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab

Radiation therapy 
o
Any need for radiotherapy should be considered progressive disease and result in 
discontinuation of study therapy.

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, chicken pox, yellow fever, rabies, BCG, and oral 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
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vaccines and are allowed; however intranasal influenza vaccines (eg, Flu-Mist®) are 
live attenuated vaccines, and are not allowed.

Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology. The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor.
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 adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous 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 the event is determined not to be related, the investigator is 
instructed to refer to Section 5.2.1.2 for dose modification guidelines. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.

Pneumonitis: 
o
For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over no 
less than 4 weeks.
o
For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed.
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o
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.

Diarrhea/Colitis:
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).  
o
All subjects who experience 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.  For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis.
o
For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids.  
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.

Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA)
o
For T1DM or Grade 3-4 Hyperglycemia

Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria. 

Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 

Hypophysitis:
o
For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 
1 or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered.
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by 
oral corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement of 
appropriate hormones may be required as the steroid dose is tapered.
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
Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders.
o
Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism):

In hyperthyroidism, non-selective beta-blockers (eg,
propranolol) are
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with levothyroxine 
or liothyronine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroid followed by oral corticosteroids. 
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned to 
baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours. 
o
When symptoms improve to Grade 1 or less, a steroid taper should be started and 
continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids.
o
When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 

Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
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Table 5 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475).
Table 5
Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
None
Grade 2
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (eg, antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated for 
≤24 hrs
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
If symptoms resolve within one hour of 
stopping drug infusion, the infusion may 
be restarted at 50% of the original 
infusion rate (eg, from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held 
until symptoms resolve and the subject 
should be premedicated for the next 
scheduled dose.
Subjects who develop Grade 2 toxicity 
despite adequate premedication should 
be permanently discontinued from 
further trial treatment administration.
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
(MK-3475) with:
Diphenhydramine 50 mg po (or 
equivalent dose of 
antihistamine).
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
antipyretic).
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; hospitalization 
indicated for other clinical 
sequelae (eg, renal 
impairment, pulmonary 
infiltrates)
Stop Infusion.
Additional appropriate medical therapy 
may include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
No subsequent dosing
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NCI CTCAE Grade
Treatment
Premedication at subsequent 
dosing
Grade 4:
Life-threatening; pressor or 
ventilatory support indicated
Epinephrine
Increase monitoring of vital signs as 
medically indicated until the subject is 
deemed medically stable in the opinion of 
the investigator.
Hospitalization may be indicated.
Subject is permanently discontinued 
from further trial treatment 
administration.
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration.
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.
5.7.2
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.  Therefore, non-
pregnant, non-breastfeeding women may only be enrolled if they are willing to follow the
Clinical Trial Facilitation Group (CTFG) Guidance (Final Version 2014-09-15, Sections 4.1
and 4.2) for highly effective birth control as outlined below, or are considered to be highly
unlikely to conceive.  Highly unlikely to conceive is defined as:
1. surgically sterilized, or 
2. 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
3. not heterosexually active for the duration of the study. Subjects should use birth control 
methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly and are considered as highly effective birth control methods.
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Such methods include:
o
Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation:

Oral

Intravaginal

Transdermal
o
Progestogen-only hormonal contraception associated with inhibition of ovulation:

Oral

Injectable

Implantable
o
IUD
o
Intrauterine hormone-releasing system (IUS)
o
Bilateral tubal occlusion
o
Vasectomized partner
o
Sexual abstinence
Subjects should be informed that taking the trial medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the trial.  In order to participate in 
the trial, subjects of childbearing or reproductive potential must adhere to the contraception 
requirement (described above) from the day of trial medication initiation (or 14 days prior to 
the initiation of trial medication for oral contraception) throughout the trial period up to 
120 days after the last dose of trial medication.  If there is any question that a subject of 
childbearing or reproductive potential will not reliably comply with the requirements for 
contraception, that subject should not be entered into the trial.
5.7.3
Use in Pregnancy
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will be immediately  discontinued from the 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 (eg, death, 
abortion, congenital anomaly, or other disabling or life-threatening complication to the 
mother or newborn).  The study 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 
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Sponsor.  If a male participant impregnates his female partner, the study personnel at the site 
must be informed immediately and the pregnancy must be reported to the Sponsor and 
followed as described in Section 7.2.2.
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
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal procedures; including specific details regarding 
withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other 
Procedures.
A subject must be discontinued from the trial for any of the following reasons:
●
The subject or legal representative (such as a parent or legal guardian) withdraws 
consent.
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons:

The subject or legal representative (such as a parent or legal guardian) withdraws 
consent for treatment

Documented disease progression Note: Subjects may continue to receive trial 
treatment beyond progression if the subject meets the criteria outlined in Section
7.1.2.6.7.

Unacceptable adverse experiences as described in Section 5.2.1.2, 5.6.1, and 7.2

Intercurrent illness that prevents further administration of treatment

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements

The subject is lost to follow-up

Administrative reasons
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The End of Treatment and Follow-up visit procedures are listed in Section 6 (Flow Chart) 
and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will be 
followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 7.2.3.1). Subjects who 
discontinue for reasons other than progressive disease 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.  After documented disease progression or the start of 
new antineoplastic therapy each subject will be followed for overall survival until death, 
withdrawal of consent, or the end of the study, whichever occurs first.
Discontinuation of Study Therapy after CR
Per investigator discretion subjects who attain a CR may consider stopping pembrolizumab
after receiving a minimum of 8 cycles (approximately six months) of treatment with at least
two doses since CR has been confirmed. Subjects who later experience disease progression 
will be eligible for retreatment with pembrolizumab at the discretion of the investigator if no 
cancer treatment was administered since the last dose of pembrolizumab, the subject meets 
the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is open.  Subjects 
will resume therapy at the same dose and schedule at the time of initial discontinuation.  
Additional details are provided in Section 7.1.5.2.2.
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).
Upon study completion, subjects are to be discontinued and may be enrolled in an extension 
study using pembrolizumab monotherapy, if available.
Clinical Criteria for Early Trial Termination
The clinical trial may be terminated early if the extent (incidence and/or severity) of 
emerging effects/clinical endpoints is such that the risk/benefit ratio to the trial population as 
a whole is unacceptable.  In addition, further recruitment in the trial or at (a) particular trial 
site(s) may be stopped due to insufficient compliance with the protocol, GCP, and/or other 
applicable regulatory requirements, procedure-related problems, or the number of 
discontinuations for administrative reasons is too high.
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e.
Written consent 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 (e.g., within 28 days prior to the first dose of trial treatment).  
Screening number will be assigned when the study informed consent is signed.  
f.
Signing the informed consent for future biomedical research (FBR) samples is optional.  Detailed instructions for the management of specimens for FBR are provided in the 
Procedures Manual and Section 12.2.
g.
Prior medications – Record all medications taken within 28 days of screening visit.  Concomitant medications – Enter new medications started during the trial through the 
Safety Follow-up visit.  Record all medications taken for SAEs as defined in Section 7.2.
h.
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.
i.
Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment), and ECIs occurring up until 90 days 
after the last dose of trial treatment or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  Afterwards, report only 
SAEs and ECIs that are related to trial treatment, or that occur within 18 months after allogeneic transplant.
j.
Full physical exam to be performed at screening Cycle 5 Day1, Cycle 9 Day1, every 12 weeks after the Week 24 assessment (eg, Cycle 13, Cycle 17, Cycle 21, etc.), and at 
the time of discontinuation. Directed physical exam to be performed at Cycle1 Day 1, Cycle 3 Day1, and Cycle 7 Day 1only.  
k.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at Visit 1 only.  
l.
Pulmonary function tests should include an assessment of forced vital capacity, forced expiratory flow between 25 and 75 percent of FVC (FEF25-75), forced expiratory 
volume in one second and peak expiratory flow (PEF) and diffusion capacity.  Additionally, oxygen saturation as assessed by pulse oximetry is required. These tests should 
be performed at baseline and subsequently at the discretion of the investigator. Hemoglobin must be obtained within 3 days of pulmonary function testing.
m.
Treatment response assessment is based upon the IWG response criteria (Cheson 2007). “Diagnostic quality” CT and PET scans should be performed at Screening (within 
28 days prior to first dose of trial treatment). If PET or CT scan at Screening is positive for disease of the neck, subsequent CT scans must include the neck. If CT and PET 
scans at Screening are negative for disease in the neck, subsequent CT scans may omit the neck. Following screening, CT scans should be repeated every 12 weeks for 
subsequent assessments. PET should be repeated at Week 12, Week 24, to confirm CR, and as clinically indicated. PET may provide additional information when 
progression is suspected, and can be obtained at the investigator’s discretion. Response assessments should occur at Wk. 12, and every 12 weeks ( +/- 7 days) following the 
Wk. 12 assessment. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts or extension of pembrolizumab cycle frequencies. For 
subjects who discontinue for reasons other than PD, assessments should continue until the subject has documented PD. The first assessment may be performed earlier than 
12 weeks if in the opinion of the investigator the patient is clinically progressing. During the follow up period, the imaging schedule should proceed every 12 weeks from 
the day of the last imaging performed before subject enters the follow up period.  Assessment of lymphoma B symptoms should occur with each disease response 
assessment. Bone marrow assessment is required to document CR, if the bone marrow was involved at screening.
n.
If subjects have stable disease, partial response, or complete response a repeat CT scan is not required for confirmation, they should continue on the every 12 week 
assessment schedule. In the setting where a subject assessment shows PD at the Week 12 disease response assessment study drug may be continued, at the discretion of the 
PI, until the next disease response assessment provided that the subjects’ clinical condition is stable. However, imaging should occur at any time where there is clinical 
suspicion of progression 
o.
In subjects with PD at Wk. 12, who continued study therapy beyond week 12 a radiological assessment should be performed 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.  
p.
For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose 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.
q.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  
r.
Laboratory tests for screening are to be performed within 7 days prior to the first dose of trial treatment.  See Section 7.1.3 for details regarding laboratory tests.  
s.
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests.  
t.
Unresolved abnormal labs that are drug related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal 
range.
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u.
CBC with Differential, Comprehensive Chemistry Panel should be performed every 2 cycles after Cycle 8 (eg, Cycle 10, Cycle 12, Cycle 14, etc.).
v.
LDH to be performed every 4th cycle after the Wk. 12 assessment (eg, Cycle 9, Cycle 13, Cycle 17, etc.).
w.
Thyroid function tests (T3, FT4, and TSH) and urinalysis should be repeated every 2 cycles after Cycle 8 until treatment discontinuation (eg, Cycle 10, Cycle 12, etc.). 
x.
All subjects will have bone marrow biopsy/aspirate performed at baseline.  Bone marrow aspirate will be performed if considered part of local standard of care.  If this test is 
not done as part of local standard of care, then this test does not need to be performed. Subsequent bone marrow assessments will only be performed in subjects who have 
bone marrow involvement.  A bone marrow assessment should be performed to confirm CR (if subject had bone marrow involvement) and as clinically indicated. 
y.
If the subject signs the Future Biomedical Research (FBR) consent, any leftover tissue that would ordinarily be discarded at the end of the main study will be retained for 
FBR.
z.
Bone marrow morphology and cytogenetics should be performed at baseline.  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.
aa.
Tumor biopsies are required for subjects at Screening. At Screening an archival biopsy may be used, if an archival biopsy is not available a new biopsy must be obtained.  
Tumor biopsies may be obtained at Wk. 12 (± 7 days).  A biopsy is also highly recommended at time of discontinuation due to progression, but is not required. Biopsy of 
lesions on study should be limited to non-target lesions or new lesions if their pathologic etiology is ambiguous and the tissue sample should have proper size to enable 
multiple planned biomarker analyses, but not artificially decrease the longest diameter of the lesion. If a tumor biopsy was of a target lesion during eligibility assessment, it 
is preferred to obtain a new baseline scan.  
bb. Whole blood for Correlative Study samples (RNA/DNA) should be collected at Screening, pre-dose on Cycle 2 Day 1, at the time of the Wk. 12 disease response 
assessment, and upon progression. See Procedures Manual. Any leftover samples from the correlative blood studies will be stored for future biomedical research if the 
subject signs the FBR Consent.
cc.
Whole Blood for Correlative Study samples (Immunophenotyping) should be collected pre-dose on Cycle 1, Cycle 2, Cycle 3 and pre-dose at the time of the Wk. 12 disease 
response assessment. Cycle 5.  See Procedures Manual. Any leftover samples from the correlative blood studies will be stored for future biomedical research if the subject 
signs the FBR Consent.
dd. Plasma and Serum biomarker samples should only be collected at Screening.
ee.
Plasma for Correlative Studies (Nanostring) should be collected at Screening and post-dose on Wk. 12. See Procedures Manual. Any leftover samples from the correlative 
blood studies will be stored for future biomedical research if the subject signs the FBR Consent.
ff.
For Both PK and anti-pembrolizumab antibody; Pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, 6, 8 and every 4 cycles 
thereafter (eg, Cycle 12, Cycle 16, Cycle 20, etc.), 30 days after discontinuation of study drug and 3 months after discontinuation of study drug (or until the subject starts 
new anti-cancer therapy). All pre-dose trough samples should be drawn within 24 hours before infusion of pembrolizumab (-24 to 0 hrs. window at Cycle 1; -48 to 0 hrs. 
window at subsequent visits is allowed).
gg. For PK sample collection only; Additional post-dose peak PK samples will be drawn within 30 minutes (0 – 45 minutes) after end of pembrolizumab infusion at Cycles 1 
and 8. An additional single PK sample should be drawn at 24 hours (20 – 28 hours) (Day 2), between 72 and 168 hours (48 – 192 hours) (Day 4-8), and 336 hours (288 –
384 hours) (Day 15) after Cycle 1 dosing.
hh. This sample should be drawn for planned genetic analysis of DNA and drug response unless there is either a documented law or regulation prohibiting collection, or unless
the IRB/IEC does not approve of the collection of the sample for these purposes. If the sample is collected, any leftover extracted DNA will be stored for future biomedical 
research if the subject signs the FBR consent.
ii.
Patient reported outcomes (PROs) are assessed every cycle for the first five cycles and every 12 weeks thereafter until PD 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.
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Trial Period:
Treatment Cycles a
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 b
Survival 
Follow-up c
Scheduling Window (Days)d
+ 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post Last 
Infusion
(±3 days)
Every 12 weeks 
(±7 days)
Every 12 
weeks
(±14 days)
Bone Marrow Biopsy & Aspiratet, u
X
Lymphoma adequate organ function 
laboratory tests v
X
a.
IV pembrolizumab at 200mg flat dose over 30 minutes will be administered once every 3 weeks. In general, assessments/procedures are to be performed on Day 1 and prior 
to the first dose of treatment for each cycle unless otherwise specified.  
b. 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. The imaging schedule should proceed every 12 weeks from the day of the last imaging performed before subject enters the follow up period.
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted approximately every 12 weeks to assess for survival status.
Upon Sponsor notification, all participants who do not/will not have a scheduled study visit or study contact during the Sponsor defined time period will be contacted for 
their survival status (excluding participants that have a death event previously recorded).
d. In general, the window for each visit is ± 3 days unless otherwise noted. 
e.
Any procedures to confirm eligibility should be conducted prior to dosing. Subjects who in the first course of treatment attained a CR and discontinued or finished treatment,
may restart trial treatment if they meet the criteria specified in Section 7.1.5.2.2 and if eligibility has been confirmed by completing all Cycle 1 assessments prior to dosing.  
f.
Prior medications – Record all medications taken within 28 days of Cycle 1 visit.  Concomitant medications – Enter new medications started during the trial through the 
Safety Follow-up visit.  Record all medications taken for SAEs as defined in Section 7.2.
g. AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0.  All AEs, whether gradable by CTCAE or not, will also be evaluated for seriousness.
h. Record all AEs occurring within 30 days after the last dose of trial treatment.  Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days 
after the last dose of trial treatment or 30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier.  Afterwards, report only 
SAEs and ECIs that are related to trial treatment or that occur within 18 months after allogeneic transplant.
i.
Full physical exam to be performed at Cycle 1, Cycle 5 Day 1, Cycle 9 Day 1, repeated every 4 cycles after the Week 24 assessment (eg, Cycle 13, Cycle 17, Cycle 21, etc.),
and at the time of discontinuation. Directed physical exam to be performed on Cycle 1 Day 1, Cycle 3 Day 1 and Cycle 7 Day 1 only. 
j.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at visit 1 only.  
k. Treatment response assessment is based upon the IWG response criteria (Cheson 2007).  “Diagnostic quality” CT and PET scans should be performed prior to Cycle 1 
dosing (within approximately 6 weeks prior to first dose of trial treatment) and subject must meet criteria described in Section 7.1.5.2.2.  If PET or CT scan at Cycle 1 is 
positive for disease of the neck, subsequent CT scans must include the neck. If CT and PET scans at Cycle 1 are negative for disease in the neck, subsequent CT scans may
omit the neck. Following Cycle 1, CT scans should be repeated every 12 weeks for subsequent assessments.  PET should be repeated at Week 12, Week 24, to confirm CR, 
and as clinically indicated. PET may provide additional information when progression is suspected, and can be obtained at the investigator’s discretion. Response 
assessments should occur at Wk. 12, and every 12 weeks (± 7 days) following the Wk. 12 assessment.  Imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts or extension of pembrolizumab cycle frequencies.  For subjects who discontinue for reasons other than PD, assessments should continue 
until the subject has documented PD.  The first assessment may be performed earlier than 12 weeks if in the opinion of the investigator the patient is clinically progressing.  
During the follow up period, the imaging schedule should proceed every 12 weeks from the day of the last imaging performed before subject enters the follow up period.  
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Assessment of lymphoma B symptoms should occur with each disease response assessment. Bone marrow assessment is required to document CR if the bone marrow was 
involved at screening
l.
If subjects have stable disease, partial response, or complete response a CT scan confirmation assessment is not required, they should continue on the every 12 week 
assessment schedule. Therefore in the setting where a subject assessment shows PD at the Week 12 disease response assessment, study drug may be continued until next 
disease response assessment provided that the subjects’ clinical condition is stable. However, imaging should occur at any time where there is clinical suspicion of 
progression.
m. Subjects with PD at week 12, who continued study therapy beyond week 12 a radiological assessment should be performed 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.  
n. For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose 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.
o. At Cycle 1, lab tests should be within 7 days prior to dosing. After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 
for details regarding laboratory tests.  
p. Unresolved abnormal labs that are drug related AEs should be followed until resolution.  Labs do not need to be repeated after the end of treatment if labs are within normal 
range.
q. CBC with Differential, Comprehensive Chemistry Panel may be performed every 2 cycles after Cycle 8 (eg, Cycle 10, Cycle 12, Cycle 14, etc.).
r.
LDH may be performed every 4th cycle after the week 12 assessment (eg, Cycle 9, Cycle 13, Cycle 17, etc.).
s.
Thyroid function tests (T3, FT4 and TSH) and urinalysis should be repeated every 2 cycles after Cycle 8 until treatment discontinuation (eg, Cycle 10, Cycle 12, etc.).
t.
Bone marrow assessments will only be performed in subjects who have bone marrow involvement.  A bone marrow assessment should be performed to confirm CR (if 
subject had bone marrow involvement) and as clinically indicated. 
u. If the subject signs the Future Biomedical Research (FBR) consent, any leftover tissue that would ordinarily be discarded at the end of the main study will be retained for 
FBR.
v. Conduct tests to evaluate organ function as per Table 1.  
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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
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 Future Biomedical Research.  A copy of the informed 
consent will be given to the subject.
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.
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.
Medical History
A medical history will be obtained by the investigator or qualified designee. Prior history of 
acute and chronic GVHD, maximum grade, and dates will be collected.
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. In addition, new medications started 
within 28 days prior to and during the Second Course Phase through the Second Course 
Safety Follow-up visit should be recorded.
All medications related to reportable SAEs and ECIs should be recorded as defined in 
Section 7.2.
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Disease Details and Treatments
7.1.1.6.1 Disease Details
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.6.2 Prior 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.
7.1.1.6.3 Subsequent Antineoplastic Therapy Status
The investigator or qualified designee will collect transplant parameters (ie. date and type of 
transplant, conditioning regimen), and 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.
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 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.  
Assignment of Randomization Number
All eligible subjects will be allocated, by non-random assignment, and will receive a 
randomization number.  The randomization number identifies the subject for all procedures 
occurring after treatment allocation.   Once a 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 randomization number.
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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
Clinical Procedures/Assessments
Adverse Event (AE) 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 clinical interest (ECI) of a potentially immunologic 
etiology (irAE). See Section 5.6.1 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.
Physical Exam
7.1.2.2.1 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 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.
7.1.2.2.2 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 
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trial treatment administration.  New clinically significant abnormal findings should be 
recorded as AEs.  
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.
Electrocardiogram
A standard 12-lead ECG will be performed using local standard procedures at screening.  
Clinically significant abnormal findings should be recorded as medical history.  
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.
Assessment of Disease and Tumor Imaging
7.1.2.6.1 Criteria for Assessment of Disease
1. Anti-tumor activity of pembrolizumab will be evaluated using the following criteria

Revised Response Criteria for Malignant Lymphoma.  (Cheson et al, J Clin 
Oncol, 2007) [40] See Section 12.7
The International Working Group criteria will be applied by the site as the primary 
measure for assessment of disease response and as a basis for all protocol guidelines 
related to disease status (eg, discontinuation of study therapy).  
2. Anti-tumor activity of pembrolizumab will also be evaluated by independent central 
review as part of the exploratory analyses using the following criteria:
5-Point-Scale per the Lugano Classification (Cheson et al, J Clin Oncol, 2014) [41] See 
Section 12.7.1
7.1.2.6.2 Lymphoma Disease Response Assessment
Lymphoma response assessment by CT/PET is based on the International Working Group 
response criteria for malignant lymphoma (Cheson et al, J Clin Oncol, 2007) [41]. Local 
reading (investigator assessment with site radiology reading) will be used to determine 
subject eligibility and for subject management.  The Sponsor will also receive radiologic 
images for a retrospective analysis of subject eligibility and treatment response to be 
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performed by a central vendor.  Assessment of lymphoma B symptoms should occur with 
each lymphoma disease response assessment.
7.1.2.6.3 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 complete response assessment of 
immunotherapeutic agents such as pembrolizumab. Therefore in the setting where a subject 
assessment shows PD, study drug may be continued, at the discretion of the PI, until the next 
disease response assessment provided that the subjects’ clinical condition is stable. However, 
imaging should occur at any time where there is clinical suspicion of progression.
NOTE:  With next response assessment if the disease is clinically stable or clinically 
improved, an exception may be considered to continue treatment upon consultation with the 
Sponsor.  
7.1.2.6.4 Timing of Disease Assessments
Uniform disease response assessments will occur every 12 weeks following the first 
assessment at Week 12 (see Table 6 below).  
Table 6
Disease Response Assessments
Indication
Assessment Frequency
HL (Cohorts 1, 2, and 3)
Every 12 weeks following first assessment 
at Week 12
7.1.2.6.5 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 confirm the 
subject has measurable disease as defined in the inclusion criteria. 
Disease assessments or scans performed as part of routine clinical management are 
acceptable for use as the screening scan if they are of diagnostic quality and performed 
within 28 days prior to the first dose of trial treatment.  CT and PET should be used 
throughout the study at time-points designated in Section 6.0-Flowchart.  For lymphomas 
that are not FDG-avid at screening, PET does not need to be repeated in follow-up 
assessments.   
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7.1.2.6.6 Disease Assessments During the Trial
Disease assessments should be performed per the frequency defined above.  There is a ± 7 
day window for assessments performed after Day 1.  If PET and CT scan at Screening are
negative for disease involvement in the neck, subsequent CT scans may not include neck. If 
PET and 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, to confirm 
CR or PD and as clinically indicated. 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, the start of new anti-cancer treatment, withdrawal of consent, death, or the end 
of the study, whichever occurs first.  
7.1.2.6.7 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:
1) Absence of symptoms and signs indicating clinical significant progression of disease 
(including worsening of laboratory values) indicating disease progression.
2) No decline in ECOG performance status.
3) Absence of rapid progression of disease or progressive tumor at critical anatomical 
sites (eg, 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 (eg, 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.
7.1.2.6.8 Biopsy Collection and Correlative Studies Blood Collection
All subjects enrolled into this study must be able to provide an archived FFPE biopsy sample 
or newly obtained core or excisional biopsy (FNA not adequate) to be submitted for 
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characterization at a central lab.  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.
Biopsy 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. 
Bone marrow and lymph node biopsies will be collected as per Table 7 below.
Table 7
Bone Marrow and Lymph Node Biopsy Assessments
Indication
Timing of Biopsy
Cohorts 1, 2 and 3: Lymph Node Biopsy
(Lymph node biopsy)
Screening biopsy (archival or new) is required. 
Biopsy at Wk. 12 (± 7 days) and at the time of 
discontinuation due to progression is optional
but highly recommended.  
Cohorts 1, 2 and 3: Bone marrow biopsy/aspirate 
(All 
subjects 
will 
have 
bone 
marrow 
biopsy/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 bone 
marrow 
involvement), 
and 
as 
clinically 
indicated.
Blood for correlative biomarker studies should be collected as per Table 8 below.
Table 8
Blood for Correlative Studies
Cohorts
Timing of Correlative Blood Collection
Cohorts 1, 2, and 3
Whole Blood for RNA/DNA: Screening, pre-
dose on Cycle 2 Day 1, Wk. 12 assessment, 
and upon progression. 
Cohorts 1, 2, and 3
Whole Blood for Immunophenotyping: pre-
dose on Cycles 1, 2, 3 and pre-dose on Wk. 12 
assessment.
Cohorts 1, 2, and 3
Plasma for Nanostring: Screening and Wk. 12 
assessment
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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 (ePROs) are administered prior to drug 
administration, adverse event evaluation and disease status notification. The ePROs are 
completed in the following order: EuroQol EQ-5D first, then EORTC QLQ-C30 at the time 
points specified in the Trial Flow Charts. 
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 9.
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Table 9
Laboratory Tests
Hematology
Chemistry
Urinalysis
Other
Hematocrit
Albumin
Blood
Serum β-human chorionic 
gonadotropin (β-hCG)
Hemoglobin
Alkaline phosphatase
Glucose
PT (INR)
CBC with 
differential 
Alanine aminotransferase (ALT)
Protein
aPTT
Platelet count
Aspartate aminotransferase 
(AST)
Specific gravity 
Total Triiodothyronine (T3) 
(or FT3)
WBC (total and 
differential)
Lactate dehydrogenase (LDH)
Microscopic exam, if
abnormal results are 
noted
Free thyroxine (T4)
Red Blood Cell 
Count
Carbon Dioxide (CO2 or 
bicarbonate) a
Urine pregnancy test 
Thyroid stimulating 
hormone (TSH)
Absolute 
Neutrophil Count
Creatinine
Anti-pembrolizumab 
Antibodies
Absolute 
Lymphocyte Count
Uric Acid
PK
Calcium
Blood for FBR
Chloride
Blood for correlative studies
Glucose
Phosphorus
Potassium
Sodium
Magnesium  
Total Bilirubin  
Direct and Indirect Bilirubin, if 
total bilirubin is elevated above 
the upper limit of normal
Total protein
Blood Urea Nitrogen b
a If considered standard of care in your region.  If these tests are not done as part of standard of care in your region then 
these tests do not need to be performed
b Blood Urea Nitrogen is preferred; if not available Urea may be tested.
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.
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Pharmacokinetic/Pharmacodynamic Evaluations
7.1.3.2.1 Pharmacokinetic Evaluations
To further evaluate pembrolizumab immunogenicity and pembrolizumab exposure in this 
indication, and also to evaluate exposure of the proposed dosing regimen, sample collections 
for analysis of anti-drug antibodies (ADA) and PK are currently planned as shown in the 
Trial Flowchart (Sections 6.1. and 6.2).  Blood samples will be obtained to measure 
pharmacokinetics of serum pembrolizumab monotherapy.  The pembrolizumab serum 
maximum concentration (Cmax) and minimum concentration (Ctrough) at planned visits and 
times will be summarized.  If ongoing ADA and/or PK results continue to be consistent with 
existing ADA and/or PK data from other pembrolizumab clinical trials, it may be decided to 
discontinue or reduce further sample collection in this study.  
Pharmacokinetic data will also be analyzed using nonlinear mixed effects modeling.  Based 
on pharmacokinetic (PK) data obtained in this study as well as PK data obtained from other 
studies (if available), a population PK analysis will be performed to characterize 
pharmacokinetic parameters (Clearance (CL), Volume of distribution (V) and evaluate the 
effect of extrinsic and intrinsic factors to support proposed dosing regimen. Pharmacokinetic 
data will also be used to explore the exposure-response relationships for pembrolizumab 
antitumor activity/efficacy as well as safety in the proposed patient population, if 
feasible. The results of these analyses, if performed, will be reported separately.  
Blood Collection for Serum MK-3475 Sample collection, storage and shipment instructions 
for serum samples will be provided in the procedure manual.  PK samples should be drawn 
according to the PK collection schedule for subjects who receive pembrolizumab (MK-
3475).  Every effort should be taken to collect samples at 30 days (+/- 3 days) and 3 months
(+/- 3 days) after end of pembrolizumab treatment.  
7.1.3.2.2 Blood Collection for Anti-pembrolizumab Antibodies MK-3475
Sample collection, storage and shipment instructions for serum samples will be provided in 
the procedure manual. Anti- pembrolizumab antibody samples should be drawn according to 
the ADA collection schedule for subjects who receive pembrolizumab (MK-3475). Every 
effort should be taken to collect samples at 30 days and 3 months after end of pembrolizumab 
treatment for ADA.  Simultaneous PK sampling is required for interpretation of ADA 
analysis.
Future Biomedical Research
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 Lymph node biopsies

Leftover Correlative blood samples
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Other Procedures
Withdrawal/Discontinuation
Subjects who discontinue/withdraw from 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 may discontinue treatment with the 
option of restarting treatment if they meet the criteria specified in Section 7.1.5.2.2.  After 
discontinuing treatment following assessment of CR, these subjects should return to the site 
for a Safety Follow-up Visit (described in Section 7.1.5.3.1) and then proceed to the Follow-
Up Period of the study (described in 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 
 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.
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
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 
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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, 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.
Screening
Approximately 28 days prior to randomization, 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.
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 PD-L1 characterization, 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 
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of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met.
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. Subjects who have not 
progressed may receive up to 35 cycles (approximately 2 years) of pembrolizumab during 
treatment period.
7.1.5.2.1 Subjects Who Continue Treatment Beyond Disease Progression
Subjects that continue treatment with pembrolizumab after documented disease progression
(Section 7.1.5.2.2), must follow the same visit requirements as outlined in Section 6.2 Study
Flow Chart.
7.1.5.2.2
Second Course Phase (Retreatment Period for Post-complete Remission 
Relapse ONLY) 
Subjects may be eligible to receive up to an additional 17 cycles (approximately 1 year) of 
pembrolizumab in the Retreatment Period of this study if the study remains open and the 
subject meets all of the following conditions:

Stopped (or completed) initial treatment with pembrolizumab after attaining an 
confirmed CR by investigator assessment according to respective response criteria

Was treated for at least 24 weeks (8 cycles) with 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

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 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 
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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 achieved CR and received up to 35 doses (approximately 2 years) of treatment 
with pembrolizumab may be eligible for up to 17 doses (approximately 1 year) of 
retreatment. Subjects who restart treatment will be retreated at the same dose frequency as 
when they last received pembrolizumab.
Confirm subjects are eligible for retreatment as described above. The Second Course 
Eligibility Visit may be conducted on the day of the first dose, but eligibility must be 
confirmed prior to dosing. See Section 6.2 – Second Course Trial Flow Chart.
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 
7.1.5.2.2) may have up to two safety follow-up visits, one after the Treatment Period and one 
after the Second Course Phase.
Follow-up Visits
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 12 weeks (± 7 days) to monitor 
disease status.  Subjects should receive a full physical examination and ECOG status, vital 
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signs and labs should be repeated with each assessment. Every effort should be made to 
collect information regarding disease status until the start of new antineoplastic therapy, 
disease progression, death, end of the study, or if the subject begins retreatment with 
pembrolizumab as detailed in Section 7.1.5.2.2.  Information regarding post-study 
antineoplastic treatment will be collected if new treatment is initiated.
For subjects who achieve CR determined by the investigator 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 7.1.5.2.2 will 
move from the follow-up phase to the Second Course Phase. Details are provided in Section 
6.2 – Trial Flow Chart for Retreatment.   
7.1.5.4.2 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 
approximately every 12 weeks to assess for survival status until death, withdrawal of 
consent, or the end of the study, whichever occurs first.
7.1.5.4.3 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 external Data 
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Monitoring Committee (eDMC) review, interim and/or final analysis.
Upon Sponsor 
notification, all participants who do not/will not have a scheduled study visit or study contact 
during the sponsor defined time period will be contacted for their survival status (excluding 
participants that have previously recorded a 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 
unfavourable 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 
randomization/treatment allocation 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 randomization/treatment allocation 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).
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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.
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 of 1000mg 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 
randomization/treatment allocation 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 
randomization/treatment allocation 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 
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(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).
Immediate Reporting of Adverse Events to the Sponsor
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 cancer;
●
Is associated with an overdose.
Refer to Table 10 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until randomization/treatment 
allocation, 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 randomization/treatment allocation 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 
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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 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.
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 randomization/treatment 
allocation, 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 randomization/treatment allocation 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:

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. 

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 
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assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent).

Post-transplant complications (see Sec 7.1.5.4.1) that occurred within 18 months from 
the date of the allogeneic transplant, for subjects who were previously exposed to 
pembrolizumab.

Additional Adverse Events:
Events of Clinical Interest identified from the date of first dose through 90 days 
following cessation of treatment, or 30 days after the initiation of a new anticancer 
therapy, whichever is earlier need to be reported to the Sponsor within 24 hours of the 
event consistent with standard SAE reporting guidelines and either by electronic 
media or paper.  Sponsor Contact information can be found in the administrative 
binder.
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should 
be evaluated and subjects should be asked for signs and symptoms suggestive of an 
immune-related event.  Subjects who develop an ECI thought to be immune-related 
should have additional testing to rule out other etiologic causes.  If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be 
performed to rule out other etiologic causes.  If no other cause is found, then it is 
assumed to be immune-related.
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 4.0. 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 10
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 an MSD 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 cancer (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local requirements); or
Is associated with 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 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 SAP (sSAP) and referenced in the Clinical
Study Report (CSR) for the study.  Post hoc exploratory analyses will also be identified in 
the CSR. 
Unless specified otherwise, the statistical analyses will be conducted separately by cohort.  In 
addition, a separate CSR may be issued for a single cohort if the actual enrollment rate 
among cohorts is markedly different.
Statistical Analysis Plan Summary
Key elements of the statistical analysis plan are summarized in Table 11 below; the 
comprehensive plan is provided in Sections 8.2-8.12.
Table 11
Statistical Analysis Plan Summary
Study Design Overview
This study, “A Phase II clinical trial of MK-3475 (pembrolizumab) in 
subjects with relapsed or refractory (R/R) classical Hodgkin Lymphoma 
(cHL)” is a multicenter, single arm, multi-cohort, nonrandomized trial of 
pembrolizumab (MK-3475) in subjects with relapsed or refractory classical 
Hodgkin lymphoma.
Treatment Assignment
Subjects meeting inclusion/exclusion criteria will be allocated to one of three 
cohorts, depending on their prior disease history and therapy:
Cohort 1:  failed to achieve a response or progressed after auto-SCT and 
have relapsed after treatment with or failed to respond to brentuximab 
vedotin post auto-SCT.
Cohort 2: unable to achieve a CR or PR to salvage chemotherapy for an 
auto-SCT and did not receive auto-SCT, but have relapsed after treatment 
with or failed to respond to brentuximab vedotin.
Cohort 3:  failed to respond to or progressed after auto-SCT and have not 
received brentuximab vedotin post auto-SCT. These subjects may or 
may not have received brentuximab vedotin as part of primary 
treatment or salvage therapy.
Analysis Populations
Efficacy: All Subjects as Treated (ASaT)
Safety: All Subjects as Treated (ASaT)
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Primary Endpoint(s)
The primary efficacy endpoint is the Overall Response Rate (ORR), defined 
as the proportion of subjects in the analysis population who have complete 
remission (CR) or partial remission (PR) using 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. Complete Remission Rate
2. Progression-free Survival
3. Duration of Response
4. Overall Survival
Statistical Methods for 
Key Efficacy/
Immunogenicity/ 
Pharmacokinetic Analyses
The primary hypothesis will be evaluated, for each Cohort separately, by 
comparing ORR for MK-3475 to a fixed control rate using a binomial exact 
test.  The point estimate of the ORR will be calculated for each Cohort as 
well as a 95% 2-sided exact confidence interval. 
Statistical Methods for 
Key Safety Analyses
Within each Cohort, summary statistics (counts, percentage, mean, standard 
deviation, etc.) will be provided for the safety endpoints as appropriate.  A 
pooled analysis over Cohorts may be performed as well to obtain a larger 
safety database.
Interim Analyses
An interim analysis will be performed by the sponsor in this study for futility 
alone and the results will be reviewed internally.  The interim analysis would 
be conducted when 50% of the subjects within a cohort have been evaluated 
for response. Details are provided in Section 8.7. 
Multiplicity
No multiplicity adjustment is planned as there is a single comparison of 
MK-3475 using 1 endpoint in the primary hypothesis within each Cohort. 
Other efficacy analyses will be considered supportive and/or explanatory.
Sample Size and Power 
The planned sample size is 60 subjects for each Cohort for the primary 
analysis. For the three cohorts, there is at least 93% power (one-sided 2.5% 
alpha level) within each Cohort to demonstrate that MK-3475 is superior to a 
fixed control rate of 20% assuming the underlying MK-3475 ORR is at least 
40%.  
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 non-randomized open-label study, ie, subjects, 
investigators, and sponsor personnel will be aware of subject treatment assignments after 
each subject is enrolled and treatment is assigned.
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3. 
Unless stated otherwise, objectives will be evaluated within each Cohort.  There is one 
hypothesis, within each Cohort, to be formally tested in this study, ie, whether the ORR is 
greater than a fixed control rate using the IWG criteria based on independent central review; 
details on how this will be tested appear below in Section 8.6.1.1.  Secondary objectives, 
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again within each Cohort, will not involve hypothesis testing, and will assess the efficacy of 
pembrolizumab on secondary efficacy endpoints (CRR, PFS, DOR, and OS) and will 
include, where appropriate, assessments based on investigator and Lugano classification; 
details appear below in the corresponding sections of Section 8.6.1.
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 Overall Response Rate (ORR), defined as the proportion 
of subjects in the analysis population who have complete remission (CR) or partial remission
(PR) using IWG criteria (Cheson 2007) at any time during the study.  Response for the 
primary analysis will be determined by central review.
Secondary efficacy endpoints include: (1) ORR according to investigator (site) assessment
using IWG criteria; (2) ORR according to central review using Lugano 5-point classification; 
(3) complete remission rate (CRR), defined as the proportion of subjects in the analysis 
population who have complete remission (CR) by IWG criteria; (4) progression-free survival 
(PFS), defined as the time from first dose to the first documented disease progression 
according to IWG criteria or death due to any cause, whichever occurs first; (5) duration of 
response (DOR), defined as time from first IWG response to disease progression in subjects 
who achieve a PR or better, and (6) overall survival (OS), defined as time from first dose to 
date of death.
Exploratory efficacy endpoints include: (1) eligibility for SCT post-study therapy (yes/no); 
(2) receiving SCT following post-study therapy (yes/no); (3) ORR, (4) DOR, (5) CRR, and 
(6) PFS, incorporating response assessments for subjects continuing pembrolizumab 
treatment after initial progression.
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, ie, subjects will be included if they receive at least one dose of study medication. 
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 
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baseline disease assessment, and 3) have a post baseline disease assessment OR discontinue 
the trial due to progressive disease/drug related AE.
Safety Analysis Population
The All Subjects as Treated (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. 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
Unless specified otherwise, analyses will be conducted separately by Cohort.
Safety analyses are described in Section 8.6.2; efficacy results that will be considered to be 
statistically significant after consideration of the strategy for controlling the Type I error are 
described in Section 8.9, Multiplicity. Nominal p-values may be computed for other efficacy 
analyses as a measure of strength of association between the endpoint and the treatment 
effect rather than formal tests of hypotheses.
Statistical Methods for Efficacy Analyses
A summary of the primary analysis strategy for the primary and secondary efficacy endpoints 
is provided in Table 13 below.
Overall Response Rate (ORR)
The primary efficacy endpoint for this study is the Overall Response Rate (ORR), defined as 
the proportion of subjects who have response (CR or PR) according to the IWG criteria, and 
will be analyzed separately by cohort.  The primary analysis will be conducted for that cohort 
when the last subject in that cohort has reached the Week 12 response assessment or has 
discontinued study therapy.
The analysis will consist of the point estimate and 95% 2-sided exact confidence interval (CI)
using the Clopper-Pearson method which will have at least 95% coverage of the true rate.  
An exact binomial test will be conducted for each cohort versus a fixed control rate for each 
cohort.
Secondary analyses for ORR will be performed based on investigator's (ie, study site)
assessment and by central review based on the Lugano Classification (JCO, 2014).
Since an investigator may still continue to treat subjects with MK-3475 who have progressed 
according to central review or by site assessment, exploratory analyses (point estimate and 
95% 2-sided exact confidence interval) will be conducted for ORR to consider these subjects 
who later achieve PR or CR post-progression as responders.
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Complete Remission Rate (CRR)
The complete remission rate (CRR), defined as the proportion of subjects who have a CR 
response according to the IWG criteria using central review. The analysis will consist of the 
point estimate and 95% 2-sided exact CI, separately by Cohort. Additional analyses will be 
based on site assessment and by central review using the Lugano (2014) criteria.
Progression-Free Survival (PFS)
The non-parametric Kaplan-Meier method will be used to estimate the PFS curve.  
Since disease progression is assessed periodically, progressive disease (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. 
A secondary analysis will be performed for PFS based on investigator's assessment.
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 initiation of 
new anticancer treatment to be a PD event for subjects without documented PD or death and 
lost to follow-up to be a PD event for subjects without documented PD or death and lost to 
follow-up after ≥ 2 missed disease assessments. The censoring rules for primary and 
sensitivity analyses are summarized in Table 12. 
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Table 12
Censoring rules for Primary and Sensitivity Analyses of PFS
Situation
Primary Analysis
Sensitivity
Analysis 1
Sensitivity
Analysis 2
No 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; 
subject receives SCT 
following response to 
pembrolizumab
Censored at last disease 
assessment before SCT
Censored at last 
disease assessment 
before SCT
Censored at date of SCT
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 
assessments
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 prior to the  
≥ 2 missed disease 
assessments 
Censored at last 
disease assessment 
prior to the  ≥ 2 
missed disease 
assessments
Progressed at date of lost to 
follow-up.
Similar to the exploratory analysis for ORR above where subjects are treated with MK-3475 
by the site following progression, an exploratory analysis will be performed on PFS
incorporating additional response assessments; details on this analysis will appear in the 
sSAP.
Duration of Response (DOR)
Duration of response 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 progressive 
disease for subjects who do not have tumor progression and are still on study at the time of 
an analysis, are given antitumor treatment (including stem cell transplant) other than the 
study treatment, or are removed from study prior to documentation of tumor progression.
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Duration of Response will be based upon central review according to the IWG criteria; a 
secondary analysis of DOR will be conducted using investigator assessment.  In addition, 
since stem cell transplant post-initiation of MK-3475 is considered to be an indicator of 
positive efficacy rather than failure of the current treatment, an exploratory analysis of DOR 
may be conducted where date of SCT is not considered censored for those subjects; details 
will appear in the sSAP.
Overall Survival (OS)
The median overall survival, if reached, will be estimated in the given analysis population, 
separately by cohort.  In addition, the Kaplan-Meier method will be used to estimate the 
survival curve, separately by Cohort.
Table 13
Efficacy Analysis Methods for Primary and Secondary Efficacy Endpoints
Endpoint/Variable
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary:
Overall Response Rate

IWG criteria (2007)
o
Central review 
Exact test of binomial 
parameter; 2-sided 95% 
exact CI
ASaT/FAS
Subjects with missing 
data are considered 
non-responders
Secondary:
    Overall Response Rate 

IWG criteria (2007) 
o
Study site

Lugano criteria (2014)
o
Central review
Point estimate; 2-sided 
95% exact CI
ASaT/FAS
Subjects with missing 
data are considered 
non-responders
    Complete Remission Rate 

IWG criteria (2007) 
o
Central review
o
Study site

Lugano criteria (2014)
o
Central review
Point estimate; 2-sided 
95% exact CI
ASaT/FAS
Subjects with missing 
data are considered 
non-responders
Progression-free survival

IWG criteria (2007)
o
Central review
o
Study site
Summary statistics 
using Kaplan-Meier 
method
ASaT/FAS
Censored at last 
assessment
(see Table 12 for 
sensitivity analyses 
based on alternative 
censoring)
Duration of Response 

IWG criteria (2007) 
o
Central review
o
Study site
Summary statistics 
using Kaplan-Meier 
method
All 
responders
Non-responders are 
excluded in analysis
Overall survival
Summary statistics 
using Kaplan-Meier 
method
ASaT/FAS
Censored at last 
assessment
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As indicated in Section 8.6.1.1, the primary analysis of ORR will be conducted when the last 
treated subject has reached the Week 12 response assessment or has discontinued study 
therapy.  At that time point, analyses of other efficacy endpoints in the table above (eg, DOR, 
CRR, PFS and OS) will also be conducted.  An efficacy update for all endpoints in the table 
above will be conducted when the last treated subject has reached at least the Week 24 
response assessment or has discontinued study therapy.  An efficacy update will be 
conducted at one year after the last subject initiated treatment and then at 2 years after the 
last subject initiated treatment, which corresponds to the end of the protocol-specified 
treatment period.  Subsequent yearly analyses will be conducted (ie, 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
adverse experiences (AEs), laboratory tests, vital signs, and ECG measurements.
Summary statistics (counts, percentage, mean, standard deviation, etc.) will be provided for 
the safety endpoints as appropriate.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
Baseline Characteristics and Demographics
Baseline characteristics will be assessed by the use of tables and/or graphs for each Cohort.  
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 (eg, age, 
gender), baseline characteristics, primary and secondary diagnoses, and prior and 
concomitant therapies will be summarized by cohort either by descriptive statistics or 
categorical tables.
Patient-reported Outcomes (PRO)
EORTC QLQ-C30 and EuroQoL EQ-5D data will be summarized as part of the pre-specified 
exploratory analysis. Patient-reported treatment effects will be evaluated for each cohort 
separately at pre-specified time points while on treatment and 30 days following treatment 
discontinuation as measured by change from baseline in the QLQ-C30 QoL domain and all 
sub-scales/single items. In addition to the estimated mean effects, cumulative distribution and 
the number and proportion of patients who “improved,” “worsened,” or “remained stable” 
from baseline to a pre-defined visit will also be estimated. For EQ-5D, pre-specified 
exploratory analyses will be performed to describe the distribution of responses. Additional 
details will be included in the sSAP.
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Population PK Analyses
Based on pharmacokinetic data obtained within this study, a separate population 
Pharmacokinetics (PK) analysis will be performed.  The prospective details of this analysis 
will be specified in a separate population PK analysis plan.
Other Analyses
Subjects that respond to study therapy (CR/PR) in this study may now be considered for SCT 
(autologous for prior ineligible subjects, allogenic for previous transplant failure subjects).  
The number of subjects that become eligible for SCT post study therapy and the number of 
subjects that actually receive SCT post study therapy will be estimated using descriptive 
statistics, separately by cohort. 
Descriptive statistics, including cross-tabulations, will be performed for those patients with 
evaluable samples, to assess PD-L1 expression using immunohistochemistry will be analyzed 
in the context of response determined by central review (CR, PR, SD, PD).
Additional exploratory analyses will be described in the sSAP.
Interim Analysis
An interim analysis will be performed within each cohort for the purpose of futility alone.  
The analysis will be performed and reviewed by the study team. In each cohort separately, 
the analysis will be performed based on response assessed by the investigators for 30 
subjects.  The analysis will be conducted when the 30th subject who starts study treatment for 
that cohort has reached the Week 12 response assessment or has discontinued study therapy 
prior to Week 12,  ie, all 30 subjects will have been evaluated for response with at least the 
Week 12 response assessment or have discontinued prior to Week 12.  
Enrollment into each cohort will not be paused pending the results of the analysis.  
For Cohorts 1 2 and 3, if 6 or fewer responses (CR or PR at any assessment) out of 30 
subjects are observed (20%), the cohort may be stopped for further enrollment. The operating 
characteristics of the futility stopping rule are given in Table 14 below, ie, the probability of 
potentially stopping a cohort under the rule for a range of true ORR for MK-3475.
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Table 14
Operating Characteristics of Interim Analysis Rule
True ORR
Probability of Stopping Enrollment 
Cohorts 1, 2 and 3
(if observe ≤6/30 [20%])
5%
>0.99
10%
0.97
15%
0.85
20%
0.61
25%
0.35
30%
0.16
35%
0.06
40%
0.02
45%
<0.01
Sample Size and Power Calculation
Efficacy for each cohort will be analyzed separately.
The proposed sample size for each of the three cohorts is 60 subjects in the primary analysis 
population (ASaT), i.e. 180 subjects in all.  To obtain 180 total subjects in the ASaT 
population, 190 will need to be enrolled in the study assuming that approximately 5% of 
enrolled subjects are not treated.  
With 60 subjects per cohort in the primary analysis population, there is at least 93% 
statistical power (1-sided nominal 2.5% alpha) to detect a 40% or higher overall response 
rate (ORR) for the MK-3475 arm compared to a fixed control rate of 20% using the exact 
binomial test (nQuery version 2.0 software).  Success for this hypothesis requires at least 
16/60 responses.  If an interim analysis is performed within a cohort (see Section 8.7), the 
power will be approximately 92%. 
The selection of 20% as a fixed control rate is based partly on historical data in previously 
conducted studies in R/R HL prior to the approval of brentuximab vedotin, where response 
rates ranged between 18%-53% (Johnston et al, 2010, Feninger et al, 2011, Younes et al, 
2012, and Moscowitz et al, 2012).  However, since this study is being conducted in 
brentuximab vedotin failures and to date, there is no published data on the ORR in this 
particular patient population.  Thus, a 20% ORR may be taken as a conservative control rate 
considering that all subjects to be enrolled in this study have failed an additional line of 
therapy (brentuximab vedotin) than seen previously.  
Multiplicity
The false positive rate for testing the primary efficacy endpoint is controlled at 0.025 (1-
sided) within each cohort.  No additional multiplicity adjustment is required because each
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cohort will be evaluated independently and only once, i.e. at the time of the primary analysis 
when all subjects in the cohort have reached the week 12 assessment or have discontinued study 
therapy.
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 95% CI) will be provided and plotted within each category of the 
following classification variables within each Cohort:

Age category (≤65 vs. >65 years)

Sex (female vs. male)

Race (white vs. non-white)

Region (US, ex-US)

Number of prior therapies (˂4 vs ≥4)
For Cohorts 1 and 3 only:

Time elapsed since transplant failure (˂12 months vs. ≥12)
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,
separately by Cohort.
Extent of Exposure
The extent of exposure will be summarized as duration of treatment in cycles. Dose intensity 
will also be summarized as appropriate, separately by Cohort.
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 
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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 15.  
Table 15
Product Descriptions
Product Name & Potency
Dosage Form
pembrolizumab (MK-3475) 100 mg/ 4 mL 
Solution for Infusion
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.
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.
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Standard Policies
Trial site personnel will have access to a central electronic 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.
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;
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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 or through a secure password-protected electronic portal 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.
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 
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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 MSD, is provided in Section 12.1 -
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 
when documents may be destroyed.  The Sponsor will determine the minimum retention 
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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, MSD, 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.  MSD, as 
Sponsor of this trial, will review this protocol and submit the information necessary to fulfill 
these requirements.  MSD entries are not limited to FDAMA/FDAAA mandated trials. 
Information posted will allow subjects to identify potentially appropriate trials for their 
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disease conditions and pursue participation by calling a central contact number for further 
information on appropriate trial locations and trial site contact information.    
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. MSD 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. 
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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, 
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.
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26. Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor 
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28. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. 
Safety, activity, and immune correlates of Anti-PD-1 antibody in cancer. N Engl J Med. 
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29. Wilcox RA, Feldman AL, Wada DA, Yang ZZ, Comfeere NI, Dong H, et al. B7-H1 
(PD-L1, CD274) suppresses host immunity in T-cell lymphoproliferative disorders. 
Blood. 2009;114:2149-2158.
30. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009; 
59(4):225-249.
31. Jemal A, Siegel R, Xu J, and Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010; 
60:277-300.
32. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide 
burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010; 127: 2893–2917. 
33. Scott DW, Chan FC, Hong F, Rogic S, Tan KL, Meissner B, et al. Gene Expression-
Based Model using Formalin-Fixed Paraffin-Embedded Biopsies Predicts Overall 
Survival in Advanced-Stage Classical Hodgkin Lymphoma. J Clin Onc. 2013;31(6):692-
700. 
34. Sureda A, Constans M, Iriondo A, Arranz R, Caballero MD, Vidal MJ, et al. Prognostic 
factors affecting long-term outcome after stem cell transplantation in Hodgkin’s 
lymphoma autografted after a first relapse. Ann Oncol. 2005;16:625–633.
35. Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt,JD, Savage KJ, et al. Results of 
a Pivotal Phase II Study of Brentuximab Vedotin for Patients with Relapsed or 
Refractory
36. Horning S, Fanale M, deVos S, et al. Defining a population of Hodgkin lymphoma 
patients for novel therapeutics: An international effort. Ann Oncol. 2008;19(Suppl 
4)120. Abstract #118
37. Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Ferme C, et al. 
Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse 
large B-cell lymphoma: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J 
Clin Oncol. 2005;23:4117-4126.
38. Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O’Donnell E, 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.
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39. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, 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.
40. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al.  Revised 
Response Criteria for Malignant Lymphoma.  J Clin Oncol.  2007;25:579-586.
41. Cheson BD, Cavalli F, Schwartz L, Zucca E, Lister A et al. Recommendations for Initial 
Evaluation, Staging and Response Assessment of Hodgkin and Non-Hodgkin 
Lymphoma: Lugano Classification.  J Clin Oncol. 2014;32; 3064-3065.
42. Younes A, Sureda A, Ben-Yehuda D, Per Luigi Z, Tee Chaun O, et al. Panobistat in
Patients with Relapsed/Refractory Hodgkin’s Lymphoma after Autologous Stem Cell 
Transplantation: Results of a Phase II Study. J Clin Oncol. 2012;30:2197-2203.
43. Johnston PB, Inwards DJ, Colgan JP, Laplant BR, et al. A Phase II trial of oral mTOR 
inhibitor everolimus in relapsed Hodgkin lymphoma. Am. J. Hematol. 2010;85;320-325
44. Fehniger TA, Larson S, Trinkaus K, Seigel MS, et al. A phase 2 multicenter study of 
lenalidomide in relapsed or refractory classical Hodgkin lymphoma. Blood. 
2011;19;5119-5126.
45. Moskowitz A, Hamlin Jr PA, Miguel-Angel P, et al. Phase II Study of Bendamustine in 
Relapsed and Refractory Hodgkin lymphoma. J Clin Oncol. 2012;31:456-460.
46. 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.
47. Armand P, Shipp MA, Ribrag V, Michot JM, Zinzani PL, Kuruvilla J, et al. 
Programmed death-1 blockade with pembrolizumab in patients with classical hodgkin 
lymphoma after brentuximab vedotin failure. J Clin Oncol. 2016 Jun 27. [Epub ahead of 
print].
48. Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, et al. Phase II Study 
of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin 
Lymphoma. J Clin Oncol. 2017 Jul 1;35(19):2125-2132.
49. Hamid O, Robert C, Daud A, et al. Safety and Tumor Responses with Lambrolizumab 
(Anti–PD-1) in Melanoma. N Engl J Med. 2013;369:134-44.
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12.0 APPENDICES
Code of Conduct for Clinical Trials
Merck Sharp & Dohme LLC, Rahway, NJ, USA (MSD)
Code of Conduct for Interventional Clinical Trials
I.
Introduction
A. Purpose
MSD, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing, and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of participants in clinical trials is the 
overriding concern in the design and conduct of clinical trials. In all cases, MSD clinical trials will be conducted in 
compliance with local and/or national regulations (including all applicable data protection laws and regulations), and 
International Council for Harmonisation Good Clinical Practice (ICH-GCP), and also in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki.
B. Scope
Highest ethical and scientific standards shall be endorsed for all clinical interventional investigations sponsored by 
MSD irrespective of the party (parties) employed for their execution (e.g., contract research organizations, 
collaborative research efforts). This Code is not intended to apply to trials that are observational in nature, or which 
are retrospective. Further, this Code does not apply to investigator-initiated trials, which are not under the full control 
of MSD.
II. Scientific Issues
A. Trial Conduct
1. Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy 
and/or pharmacokinetic or pharmacodynamic indices of MSD or comparator products. Alternatively, MSD may 
conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine 
patient preferences, etc.
The design (i.e., participant population, duration, statistical power) must be adequate to address the specific 
purpose of the trial and shall respect the data protection rights of all participants, trial site staff and, where 
applicable, third parties. All trial protocols are and will be assessed for the need and capability to enroll 
underrepresented groups. Participants must meet protocol entry criteria to be enrolled in the trial.
2. Site Selection
MSD’s clinical trials are conducted globally in many different countries and in diverse populations, including 
people of varying age, race, ethnicity, gender, and accounting for other potential disease related factors. MSD 
selects investigative sites based on medical expertise, access to appropriate participants, adequacy of facilities and 
staff, previous performance in clinical trials, as well as budgetary considerations. Prior to trial initiation, sites are 
evaluated by MSD personnel (or individuals acting on behalf of MSD) to assess the ability to successfully conduct 
the trial.
Where appropriate, and in accordance with regulatory authority guidance, MSD will make concerted efforts to 
raise awareness of clinical trial opportunities in various communities. MSD will seek to engage underrepresented 
groups and those disproportionately impacted by the disease under study. MSD will support clinical trial 
investigators to enroll underrepresented groups and expand access to those who will ultimately use the products 
under investigation.
3. Site Monitoring/Scientific Integrity
Investigative trial sites are monitored to assess compliance with the trial protocol and Good Clinical Practice 
(GCP). MSD reviews clinical data for accuracy, completeness, and consistency. Data are verified versus source 
documentation according to standard operating procedures. Per MSD policies and procedures, if potential fraud, 
scientific/research misconduct, privacy incidents/breaches or Clinical Trial-related Significant Quality Issues are 
reported, such matters are investigated. When necessary, appropriate corrective and/or preventative actions are 
defined and regulatory authorities and/or ethics review committees are notified.
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B. Publication and Authorship
Regardless of trial outcome, MSD commits to publish the primary and secondary results of its registered trials of 
marketed products in which treatment is assigned, according to the pre-specified plans for data analysis. To the extent 
scientifically appropriate, MSD seeks to publish the results of other analyses it conducts that are important to patients, 
physicians, and payers. Some early phase or pilot trials are intended to be hypothesis-generating rather than 
hypothesis testing; in such cases, publication of results may not be appropriate since the trial may be underpowered 
and the analyses complicated by statistical issues such as multiplicity.
MSD’s policy on authorship is consistent with the recommendations published by the International Committee of 
Medical Journal Editors (ICMJE). In summary, authorship should reflect significant contribution to the design and 
conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named authors 
must be able to defend the trial results and conclusions. MSD funding of a trial will be acknowledged in publications.
III. Participant Protection
A. Regulatory Authority and Ethics Committee Review (Institutional Review Board [IRB]/Independent Ethics 
Committee [IEC])
All protocols and protocol amendments will be submitted by MSD for regulatory authority acceptance/authorization 
prior to implementation of the trial or amendment, in compliance with local and/or national regulations.
The protocol, protocol amendment(s), informed consent form, investigator’s brochure, and other relevant trial 
documents must be reviewed and approved by an IRB/IEC before being implemented at each site, in compliance with 
local and/or national regulations. Changes to the protocol that are required urgently to eliminate an immediate hazard 
and to protect participant safety may be enacted in anticipation of ethics committee approval. MSD will inform 
regulatory authorities of such new measures to protect participant safety, in compliance with local and/or national 
regulations.
B. Safety
The guiding principle in decision-making in clinical trials is that participant welfare is of primary importance. 
Potential participants will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a 
minimum, trial designs will take into account the local standard of care.
All participation in MSD clinical trials is voluntary. Participants enter the trial only after informed consent is obtained. 
Participants may withdraw from an MSD trial at any time, without any influence on their access to, or receipt of, 
medical care that may otherwise be available to them.
C. Confidentiality
MSD is committed to safeguarding participant confidentiality, to the greatest extent possible, as well as all applicable 
data protection rights. Unless required by law, only the investigator, Sponsor (or individuals acting on behalf of 
MSD), ethics committee, and/or regulatory authorities will have access to confidential medical records that might 
identify the participant by name.
D. Genomic Research
Genomic research will only be conducted in accordance with a protocol and informed consent authorized by an ethics 
committee.
IV. Financial Considerations
A. Payments to Investigators
Clinical trials are time- and labor-intensive. It is MSD’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of MSD trials. MSD does not pay incentives to enroll 
participants in its trials. However, when enrollment is particularly challenging, additional payments may be made to 
compensate for the time spent in extra recruiting efforts.
MSD does not pay for participant referrals. However, MSD may compensate referring physicians for time spent on 
chart review and medical evaluation to identify potentially eligible participants.
B. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by MSD, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial. However, the local ethics committee may wish 
to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted 
above, all publications resulting from MSD trials will indicate MSD as a source of funding.
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C. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices.
V. Investigator Commitment
Investigators will be expected to review MSD’s Code of Conduct as an appendix to the trial protocol, and in signing the 
protocol, agree to support these ethical and scientific standards.
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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 7.1.3.3 – Future Biomedical 
Research 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 MSD 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 MSD or designees and research 
will be monitored and reviewed by a committee of our scientists and clinicians.
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 Future 
Biomedical Research.
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.  Information contained on the consent form alone cannot be traced 
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to any specimens, test results, or medical information once the specimens have been 
rendered de-identified
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.  
Each informed consent approved by an ethics committee is assigned a unique tracking 
number.  The tracking number on this document will be used to assign specimen 
permissions for each specimen into the Entrusted Keyholder’s Specimen Database.
c.
eCRF Documentation for Future Biomedical Research Specimens
Documentation of both consent and acquisition of Future Biomedical Research 
specimens will be captured in the electronic Case Report Forms (eCRFs).  
Reconciliation of both forms will be performed to assure that only appropriately-
consented specimens are used for research purposes. Any specimens for which such 
an informed consent cannot be verified will be destroyed.
d. Future Biomedical Research Specimen Collections
Blood specimens for DNA or RNA isolation will usually be obtained at a time when 
the subject is having blood drawn for other trial purposes. Specimens like tissue and 
bone marrow will usually be obtained at a time when the subject is having such a 
procedure for clinical purposes.
Specimens will be collected and sent to the laboratory designated for the trial where 
they will be processed (e.g., DNA or RNA extraction, etc) following the MSD
approved policies and procedures for specimen handling and preparation.
If specimens are collected for a specific genotype or expression analysis as an 
objective to the main trial, this analysis is detailed in the main body of this protocol 
(Section 8.0 – Statistical Analysis Plan).  These specimens will be processed, 
analyzed, and the remainder of the specimen will be destroyed.  The results of these 
analyses will be reported along with the other trial results.  A separate specimen will 
be obtained from properly-consented subjects in this protocol for storage in the 
biorepository for Future Biomedical Research.
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, MSD has developed secure policies and procedures.  All 
specimens will be de-identified as described below. 
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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.  
This first code will be replaced with a second code at a MSD designated storage/lab 
facility.  The second code is linked to the first code via a second key. The specimen is 
now double coded.  Specimens with the second code are sometimes referred to as de-
identified specimens. The use of the second code provides additional confidentiality and 
privacy protection for subjects over the use of a single code.  Access to both keys would 
be needed to link any data or specimens back to the subject's identification.
The second code is stored separately from the first code and all associated personal 
specimen identifiers.  A secure link, the second key, will be utilized to match the second 
code to the first code to allow clinical information collected during the course of the trial 
to be associated with the specimen.  This second key will be transferred under secure 
procedures by the MSD designated facility to an Entrusted Keyholder at MSD.  The 
second code will be logged into the primary biorepository database at MSD and, in this 
database, this identifier will not have identifying demographic data or identifying clinical 
information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen 
will be stored in a designated biorepository site with secure policies and procedures for 
specimen storage and usage.
The second key can be utilized to reconstruct the link between the results of future 
biomedical research and the clinical information, at the time of analysis.  This linkage 
would not be possible for the scientist conducting the analysis, but can only be done by 
the MSD Entrusted Keyholder under strict security policies and procedures.  The MSD
Entrusted Keyholder will link the information and then issue a de-identified data set for 
analysis.  The only other circumstance by which future biomedical research data would 
be directly linked to the full clinical data set would be those situations mandated by 
regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly 
transferred to the regulatory authority.
5. Biorepository Specimen Usage
Specimens obtained for the MSD Biorepository will be used for analyses using good 
scientific practices.  However, exploratory analyses will not be conducted under the 
highly validated conditions usually associated with regulatory approval of diagnostics.  
The scope of research performed on these specimens is limited to the investigation of the 
variability in biomarkers that may correlate with a clinical phenotype in subjects.
Analyses utilizing the Future Biomedical Research specimens may be performed by 
MSD, or an additional third party (e.g., a university investigator) designated by MSD.  
The investigator conducting the analysis will be provided with double coded specimens.  
Re-association of analysis results with corresponding clinical data will only be conducted 
by the MSD Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in Future Biomedical Research protocol and 
consent.  Future Biomedical Research specimens remaining with the third party after the 
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specific analysis is performed will be returned to the sponsor or destroyed and 
documentation of destruction will be reported to MSD.
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 MSD using the designated mailbox 
and a form will be provided by MSD to 
specimen withdrawal.  Subsequently, the 
subject's specimens will be removed from the biorepository and be destroyed. A letter 
will be sent from MSD 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 acquisition.  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 MSD 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 MSD policies and procedures and this 
destruction will be documented in the biorepository database.
8. Data Security
Separate databases for specimen information and for results from Future Biomedical 
Research will be maintained by MSD.  This is done to separate the future exploratory test 
results (which include genetic data) from the clinical trial database thereby maintaining a 
separation of subject number and these results.  The separate databases are accessible 
only to the authorized Sponsor 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 in international standards (e.g., 
ISO17799) to protect against unauthorized access.  The MSD Entrusted Keyholder 
CCI
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maintains control over access to all specimen data.  These data are collected for future 
biomedical research purposes only and will not be used for any other purpose.
9. Reporting of Future Biomedical Research Data to Subjects
There is no definitive requirement in either authoritative ethical guidelines or in relevant 
laws/regulations globally that research results have to be, in all circumstances, returned to 
the trial participant.  Some guidelines advocate a proactive return of data in certain 
instances.  No information obtained from exploratory laboratory studies will be reported 
to the subject or family, and this information will not be entered into the clinical database 
maintained by MSD on subjects.  Principle reasons not to inform or return results to the 
subject include: lack of relevance to subject health, limitations of predictive capability, 
concerns of misinterpretation and absence of good clinical practice standards in 
exploratory research typically used for diagnostic testing.
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 as 
to how to offer clinical diagnostic  testing (paid for by MSD) to subjects enrolled and will 
be advised that counseling should be made available for all who choose to participate in 
this diagnostic testing. 
If any exploratory results are definitively associated with clinical significance after 
completion of a clinical trial, MSD will publish the results without revealing specific 
subject information, inform all trial sites who participated in the MSD clinical trial and 
post anonymized results on our website or other accredited website(s) that allow for 
public access (e.g., disease societies who have primary interest in the results) in order that 
physicians and patients may pursue clinical diagnostic testing if they wish to do so.
10. Gender, Ethnicity and Minorities
Although many diagnoses differ in terms of frequency by ethnic population and gender, 
every effort will be made to recruit all subjects diagnosed and treated on MSD clinical 
trials for future biomedical research.  When trials with specimens are conducted and 
subjects identified to serve as controls, every effort will be made to group specimens 
from subjects and controls to represent the ethnic and gender population representative of 
the disease under current investigation.
11. Risks Versus Benefits of Future Biomedical Research 
For future biomedical research, risks to the subject have been minimized. [insert: Risks 
include those associated with venipuncture to obtain the whole blood specimen.  This 
specimen will be obtained at the time of routine blood specimens drawn in the main trial. 
OR Buccal swab specimens will be collected inside the cheek with no associated 
venipuncture to obtain the specimen. Therefore, there will not be an additional risk for 
the subject.]
MSD 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.
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It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, 
age, toxicities, etc.) to be re-associated to double coded specimens at the time of data 
analysis.  These subject data will be kept in a separate, secure MSD database, and all 
specimens will be stripped of subject identifiers.  No information concerning results 
obtained from future biomedical research will be entered into clinical records, nor will it 
be released to outside persons or agencies, in any way that could be tied to an individual 
subject.
12. Self-Reported Ethnicity
Subjects who participate in future biomedical research will be asked to provide self-
reported ethnicity.  Subjects who do not wish to provide this data may still participate in 
future biomedical research.
13. Questions
Any questions related to the future biomedical research should be e-mailed directly to 
14. 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
CCI
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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
1L
First Line
AE
Adverse Event
ADA
Anti-Drug Antibodies
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
AP
Alkaline Phosphatase
APaT
All Patients as Treated
aPTT
Activated Partial Thromboplastin Time
ASCO
American Society of Clinical Oncology
AST
Aspartate Aminotransferase
ß-HCG
Beta Human Chorionic Gonadotropin
CBC
Complete Blood Count
CI
Confidence Interval
CNS
Central Nervous System
CR
Complete Response
CrCl
Calculated Creatinine Clearance
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Toxicity Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Antigen-4
DAP
Data Analysis Plan
DNA
Deoxyribonucleic acid
DR
Drug Related
ECI
Events of Clinical Interest
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EORTC
European Organization for Research and Treatment of Cancer
ePRO
Electronic Patient Reported Outcomes
ERC
Ethics Review Committee
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
FFPE
Formalin Fixed Paraffin Embedded
FNA
Fine Needle Aspirate
GC
Gemcitabine/Carboplatin
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HBsAg
Hepatitis B surface Antigen
HCV
Hepatitis C Virus
HEA
Health Economic Assessment
HIV
Human Immunodeficiency Virus
HL
Hodgkin Lymphoma
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IHC
Immunohistochemistry
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Abbreviation/Term
Definition
INR
International Normalized Ratio
irAEs
Immune-related Adverse Events
IRB
Institutional Review Board
ITIM
Immunoreceptor Tyrosine-based Inhibition Motif
ITSM
Immunoreceptor Tyrosine-based Switch Motif
ITT
Intention To Treat
IV
Intravenous
IVRS
Interactive Voice Response System
IWG
International Working Group
IWRS
Integrated Web Response System
Kg
Kilogram
KM
Kaplan-Meier
mAb
Monoclonal Antibody
mcL
Microliters
MEL
Melanoma 
Mg
Milligram
Mg/kg
Milligram per Kilogram
mL
Milliliter
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NA or N/A
Not Applicable
NCI
National Cancer Institute
NSAID
Non-Steroidal Anti-inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
ORR
Overall Response Rate
OS
Overall Survival
OTC
Over-the-counter
PD
Progressive Disease
PET
Positron emission tomography
PFS
Progression Free Survival
PGt
Pharmacogenetic
PIN
Personal Identification Number
PK
Pharmacokinetic
PK-PD
Pharmacokinetic-Pharmacodynamic
PO
Oral Administration
PR
Partial Response
PT
Prothrombin Time
PS
Performance Status
QoL
Quality of Life
R/M
Recurrent or Metastatic
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic Acid
RR
Response Rate
Q2W
Every 2 Weeks
Q3W
Every 3 Weeks
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
Stable Disease
SFU
Survival Follow-Up
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
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Abbreviation/Term
Definition
SOC
Standard of Care
SOP
Standard Operating Procedures
T3
Total triiodothyronine
T4
Free thyroxine 
TIL
Tumor Infiltrating Lymphocytes
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
V-type
Ig Variable-type
WBC
White Blood Cell
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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 
(eg, light housework, office work).
2
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% of 
waking hours.
3
In bed >50% of the time. Capable of only limited self-care, confined to 
bed or chair more than 50% of waking hours.
4
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair.
5
Dead.
* 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 (CTCAE)
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (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 et al.  Revised Response Criteria for Malignant Lymphoma.  J Clin Oncol.  2007; 
25:579-586.
Criteria for lymphoma disease assessment:
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Lugano Classification
Cheson et al. Recommendations for Initial Evaluation, Staging and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: Lugano Classification.  J Clin Oncol.  2014; 
32:3064-3065.
Revised Response Assessment
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Product:  MK-3475 
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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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