A Phase Ib Multi-Cohort Trial of MK-3475 (Pembrolizumab) in Subjects With Hematologic Malignancies
Phase: PHASE1
Conditions: Myelodysplastic Syndrome, Multiple Myeloma, Hodgkin Lymphoma, Non-Hodgkin Lymphoma, Diffuse Large B-Cell Lymphoma, Follicular Lymphoma, Primary Mediastinal B-Cell Lymphoma
Sponsor: Merck Sharp & Dohme LLC

Official Protocol Title: 
NCT number: 
Document Date: 
A Phase Ib Multi-Cohort Trial of MK-3475 (pembrolizumab) in 
Subjects with Hematologic Malignancies
16-Apr-2020
NCT01953692

Product:  MK-3475 (SCH 900475)
1
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING 
TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK 
SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., 
WHITEHOUSE STATION, NJ, U.S.A.
SPONSOR:
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. 
(hereafter referred to as the Sponsor or Merck)
One Merck Drive
P.O. Box 100
Whitehouse Station, NJ 08889-0100, U.S.A.
Protocol-specific Sponsor Contact information can be found in the Investigator Trial File
Binder.
TITLE:
A Phase Ib Multi-Cohort Trial of MK-3475 (pembrolizumab) in Subjects with Hematologic 
Malignancies
IND NUMBER:  118604
EudraCT NUMBER:  2013-001603-37
NCT NUMBER:  NCT01953692
 
 
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TABLE OF CONTENTS
DOCUMENT HISTORY ..................................................................................................... 13
SUMMARY OF CHANGES................................................................................................ 17
1.0
TRIAL SUMMARY.................................................................................................. 19
2.0
TRIAL DESIGN........................................................................................................ 20
2.1
Trial Design ........................................................................................................... 20
2.2
Trial Diagram........................................................................................................ 22
3.0
OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 25
3.1
Primary Objective(s) & Hypothesis(es).............................................................. 25
3.2
Secondary Objective(s) & Hypothesis(es)........................................................... 26
3.3
Exploratory Objectives......................................................................................... 28
4.0
BACKGROUND & RATIONALE.......................................................................... 29
4.1
Background ........................................................................................................... 29
Pharmaceutical and Therapeutic Background .................................................... 29
Pre-clinical and Clinical Trials ........................................................................... 30
Ongoing Pembrolizumab Clinical Trials ............................................................ 31
4.2
Rationale................................................................................................................ 36
Rationale for the Trial and Selected Subject Population .................................... 36
Rationale 
for 
Evaluating 
anti-PD-1 
Therapy 
in 
Hematologic 
Malignancies................................................................................................ 36
Myelodysplastic Syndrome.......................................................................... 36
Hodgkin and non-Hodgkin Lymphoma....................................................... 37
4.2.1.3.1
Lenalidomide + Pembrolizumab Combination in Diffuse Large B-
Cell Lymphoma .................................................................................... 38
Multiple Myeloma ....................................................................................... 40
Rationale for Dose Selection/Regimen/Modification......................................... 41
Rationale for Dose Selection/Regimen for Pembrolizumab (Cohort 1, 2, 
3, 4A, 4B)..................................................................................................... 41
Rationale for 200 mg Q3W Fixed Dose of Pembrolizumab (Cohort 2, 4A, 
4C, 4D, and 5).............................................................................................. 41
Rationale for Selection of Lenalidomide Dose............................................ 42
Rationale for Endpoints ...................................................................................... 43
 
 
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Safety Endpoints.......................................................................................... 43
Efficacy Endpoints....................................................................................... 43
Biomarker Research..................................................................................... 44
Future Biomedical Research........................................................................ 45
4.3
Benefit/Risk ........................................................................................................... 45
5.0
METHODOLOGY ................................................................................................... 46
5.1
Entry Criteria........................................................................................................ 46
Diagnosis/Condition for Entry into the Trial...................................................... 46
Subject Inclusion Criteria.................................................................................... 46
Subject Exclusion Criteria .................................................................................. 52
5.2
Trial Treatments................................................................................................... 56
Dose Selection/Modification .............................................................................. 57
Dose Selection ............................................................................................. 57
Dose Modification for Pembrolizumab ....................................................... 58
Cohort 5 (DLBCL) Lenalidomide + Pembrolizumab Combination 
Therapy: Safety Run-in and Expansion....................................................... 62
5.2.1.3.1
Part 1: Safety Run-In ............................................................................ 62
5.2.1.3.2
Part 2: Expansion.................................................................................. 64
5.2.1.3.3
Definition of Dose-Limiting Toxicities ................................................ 64
5.2.1.3.4
Dose Modification for Lenalidomide ................................................... 65
5.2.1.3.5
Replacement of Subjects During Safety Run-in................................... 67
Timing of Dose Administration.......................................................................... 67
Extent of Treatment ............................................................................................ 69
Trial Blinding/Masking....................................................................................... 70
5.3
Randomization or Treatment Allocation............................................................ 70
5.4
Stratification.......................................................................................................... 70
5.5
Concomitant Medications/Vaccinations (allowed & prohibited)..................... 70
Acceptable Concomitant Medications ................................................................ 70
Prohibited Concomitant Medications.................................................................. 71
5.6
Rescue Medications & Supportive Care............................................................. 71
Supportive Care Guidelines for Pembrolizumab ................................................ 71
Supportive Care Guidelines for Lenalidomide ................................................... 74
 
 
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5.7
Diet/Activity/Other Considerations..................................................................... 74
Diet...................................................................................................................... 74
Contraception...................................................................................................... 75
Subjects Enrolled in Cohorts 1, 2, 3, and 4.................................................. 75
Subjects Enrolled in Cohort 5 (DLBCL) ..................................................... 76
5.7.2.2.1
Risk Minimization Program.................................................................. 77
5.7.2.2.2
Additional Precautions.......................................................................... 78
Pregnancy............................................................................................................ 78
Use in Nursing Women....................................................................................... 79
5.8
Subject Withdrawal/Discontinuation Criteria................................................... 79
Discontinuation of Study Therapy After CR ...................................................... 80
5.9
Subject Replacement Strategy............................................................................. 80
5.10
Beginning and End of the Trial ........................................................................... 81
5.11
Clinical Criteria for Early Trial Termination ................................................... 81
6.0
TRIAL FLOW CHART ........................................................................................... 82
6.1
Study Flow Chart A:  Cohort 1-MDS ................................................................. 82
6.2
Study Flow Chart B:  Cohort 2-Multiple Myeloma (Subjects allocated to 
10mg/kg Q2W) ...................................................................................................... 88
6.3
Study Flow Chart C:  Cohort 3, 4A, & 4B-Hodgkin Lymphoma, 
Mediastinal Large B-Cell Lymphoma, & any-other PD-L1 Positive Non-
Hodgkin Lymphoma (Subjects allocated to 10mg/kg Q2W). ........................... 94
6.4
Study Flow Chart D:  Cohort 2 Multiple Myeloma (Subjects allocated to 
200 mg Q3W)......................................................................................................... 99
6.5
Study Flow Chart E:  Cohort 4A, 4C, 4D Mediastinal Large B-Cell 
Lymphoma, Follicular Lymphoma (FL), and Diffuse Large B-Cell 
Lymphoma (DLBCL) (Subjects allocated to 200 mg Q3W)........................... 105
6.6
Study Flow Chart F:  Cohort 5 Diffuse Large B-Cell Lymphoma (DLBCL) 
(Subjects allocated to pembrolizumab 200 mg administered intravenously 
once every 21 days in combination with lenalidomide taken orally once 
daily for 21 days + 7 days off.  The cycle length is 28 days.)........................... 110
Study Dose Chart F2:  Cohort 5 Diffuse Large B-Cell Lymphoma (DLBCL) 
(Subjects allocated to pembrolizumab 200 mg administered intravenously 
once every 21 days in combination with lenalidomide taken orally once daily 
for 21 days + 7 days off.  The cycle length is 28 days.) ................................... 116
6.7
Study Flow Chart G:  Cohort 1-MDS Second Course Phase (Retreatment 
for Post-Complete Response Relapse Only)..................................................... 117
 
 
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6.8
Study Flow Chart H:  Cohort 2-Multiple Myeloma Second Course Phase 
(Retreatment for Post-Stringent Complete Response (sCR) Relapse Only) 
(Subjects allocated to 10mg/kg Q2W)............................................................... 122
6.9
Study Flow Chart I:  Cohort 3, 4A, 4B Hodgkin Lymphoma, Mediastinal 
Large B-Cell Lymphoma, & any-other PD-L1 Positive Non-Hodgkin 
Lymphoma Second Course Phase (Retreatment for Post-Complete 
Response Relapse Only) (Subjects allocated to 10 mg/kg Q2W).................... 128
6.10
Study Flow Chart J:  Multiple Myeloma (Cohort 2) Second Course Phase 
(Retreatment for Post-Stringent Complete Response (sCR) Relapse Only) 
(For subjects allocated to 200 mg Q3W)........................................................... 134
6.11
Study Flow Chart K:  Cohort 4A, 4C, 4D Mediastinal Large B-Cell 
Lymphoma, Follicular Lymphoma (FL), and Diffuse Large B-Cell 
Lymphoma (DLBCL) Second Course Phase (Retreatment for Post-
Complete Response Relapse Only) (Subjects allocated to 200 mg Q3W)...... 139
6.12
Study Flow Chart L:  Cohort 5 Diffuse Large B-Cell Lymphoma (DLBCL) 
Second Course Phase (Retreatment for Post-Complete Response Relapse 
Only) (Subjects allocated to pembrolizumab 200 mg administered 
intravenously once every 21 days in combination with lenalidomide taken 
orally once daily for 21 days + 7 days off.  The cycle length is 28 days.)....... 144
Study Dose Chart L2:  Cohort 5 Diffuse Large B-Cell Lymphoma (DLBCL) 
(Retreatment for Post-Complete Response Relapse Only) (Subjects allocated 
to pembrolizumab 200 mg administered intravenously once every 21 days in 
combination with lenalidomide taken orally once daily for 21 days + 7 days 
off.  The cycle length is 28 days.)..................................................................... 150
7.0
TRIAL PROCEDURES ......................................................................................... 151
7.1
Trial Procedures ................................................................................................. 151
Administrative Procedures................................................................................ 151
Informed Consent....................................................................................... 151
7.1.1.1.1
General Informed Consent.................................................................. 151
7.1.1.1.2
Consent and Collection of Specimens for Future Biomedical 
Research.............................................................................................. 152
Inclusion/Exclusion Criteria ...................................................................... 152
Subject Identification Card ........................................................................ 152
Medical History ......................................................................................... 152
Prior and Concomitant Medications Review............................................. 152
7.1.1.5.1
Prior Medications................................................................................ 152
7.1.1.5.2
Concomitant Medications................................................................... 152
Disease Details and Treatments................................................................. 153
 
 
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7.1.1.6.1
Disease Details.................................................................................... 153
7.1.1.6.2
Prior Treatment Details....................................................................... 153
7.1.1.6.3
Subsequent Antineoplastic Therapy Status......................................... 153
Assignment of Screening Number............................................................. 153
Assignment of Randomization Number..................................................... 153
Trial Compliance (Medication/Diet/Activity/Other)................................. 153
Clinical Procedures/Assessments...................................................................... 154
Adverse Event (AE) Monitoring................................................................ 154
Physical Exam............................................................................................ 154
7.1.2.2.1
Full Physical Exam ............................................................................. 154
7.1.2.2.2
Directed Physical Exam...................................................................... 154
Vital Signs.................................................................................................. 154
Electrocardiogram...................................................................................... 155
Pulmonary Function Testing...................................................................... 155
Eastern Cooperative Oncology Group (ECOG) Performance Scale ......... 155
Assessment of Disease and Tumor Imaging.............................................. 155
7.1.2.7.1
Criteria for Assessment of Disease..................................................... 155
7.1.2.7.2
Hodgkin and Non-Hodgkin Lymphoma Disease Response 
Assessment.......................................................................................... 155
7.1.2.7.3
Disease Assessment of Immunotherapeutic Agents ........................... 156
7.1.2.7.4
Timing of Disease Assessments ......................................................... 156
7.1.2.7.5
Initial Disease Assessment.................................................................. 157
7.1.2.7.6
Disease Assessment During Trial....................................................... 157
7.1.2.7.7
Confirmation Assessments ................................................................. 158
7.1.2.7.8
Biopsy Collection and Correlative Studies Blood Collection ............ 159
Laboratory Procedures/Assessments ................................................................ 161
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
................................................................................................................... 161
Pharmacokinetic/Pharmacodynamic Evaluation ....................................... 163
7.1.3.2.1
Blood Collection for Serum MK-3475 ............................................... 163
7.1.3.2.2
Blood Collection for Anti-pembrolizumab Antibodies ...................... 163
Future Biomedical Research...................................................................... 163
Other Procedures............................................................................................... 163
 
 
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Withdrawal/Discontinuation...................................................................... 163
7.1.4.1.1
Withdrawal From Future Biomedical Research ................................. 164
Blinding/Unblinding .................................................................................. 164
Visit Requirements............................................................................................ 164
Screening Period ........................................................................................ 164
7.1.5.1.1
Prospective Enrollment of PD-L1 Positive Subjects (Cohort 4B:  
Any-other NHL Only) ........................................................................ 165
Treatment Period........................................................................................ 165
7.1.5.2.1
Second Course Phase (Retreatment Period for Post-Complete 
Remission Relapse ONLY) ................................................................ 166
Post-Treatment Visits................................................................................. 167
7.1.5.3.1
Safety Follow-Up Visit....................................................................... 167
7.1.5.3.2
Efficacy Follow-up Visits................................................................... 167
7.1.5.3.3
Survival Follow-up ............................................................................. 168
Survival Status ........................................................................................... 168
7.2
Assessing and Recording Adverse Events ........................................................ 169
Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor ............................................................................................................. 170
Reporting of Pregnancy and Lactation to the Sponsor ..................................... 170
Immediate Reporting of Adverse Events to the Sponsor.................................. 172
Serious Adverse Events ............................................................................. 172
Events of Clinical Interest.......................................................................... 173
Protocol-Specific Exceptions to Serious Adverse Event Reporting.......... 174
Evaluating Adverse Events............................................................................... 174
Sponsor Responsibility for Reporting Adverse Events .................................... 177
8.0
STATISTICAL ANALYSIS PLAN ...................................................................... 177
8.1
Statistical Analysis Plan Summary ................................................................... 177
Efficacy Analyses ............................................................................................. 178
Safety Analyses................................................................................................. 180
Power and Sample Size..................................................................................... 180
Interim Analysis................................................................................................ 182
8.2
Statistical Analysis Plan ..................................................................................... 183
Responsibility for Analyses/In-House Blinding ............................................... 183
 
 
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Hypotheses/Estimation ..................................................................................... 183
Analysis Endpoints ........................................................................................... 183
Efficacy/Immunogenicity/Pharmacokinetics Endpoints............................ 184
Safety Endpoints........................................................................................ 186
Analysis Populations......................................................................................... 186
Efficacy Analysis Populations................................................................... 186
Safety Analysis Populations ...................................................................... 187
Statistical Methods............................................................................................ 187
Statistical Methods for Efficacy Analyses................................................. 187
Statistical Methods for Safety Analyses .................................................... 190
Summaries of Baseline Characteristics, Demographics, and Other 
Analyses..................................................................................................... 190
8.2.5.3.1
Demographic and Baseline Characteristics ........................................ 190
Multiplicity ....................................................................................................... 190
Sample Size and Power Calculations................................................................ 190
Subgroup Analyses and Effect of Baseline Factors.......................................... 192
Interim Analyses ............................................................................................... 192
Compliance (Medication Adherence)............................................................... 194
Extent of Exposure............................................................................................ 194
9.0
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ............................................................................................................... 195
9.1
Investigational Product ...................................................................................... 195
9.2
Packaging and Labeling Information ............................................................... 195
9.3
Clinical Supplies Disclosure............................................................................... 195
9.4
Storage and Handling Requirements................................................................ 196
9.5
Discard/Destruction/Returns and Reconciliation ............................................ 196
10.0
ADMINISTRATIVE AND REGULATORY DETAILS..................................... 196
10.1
Confidentiality..................................................................................................... 196
Confidentiality of Data ..................................................................................... 196
Confidentiality of Subject Records................................................................... 196
Confidentiality of Investigator Information...................................................... 197
Confidentiality of IRB/IEC Information........................................................... 197
10.2
Compliance with Financial Disclosure Requirements..................................... 197
 
 
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10.3
Compliance with Law, Audit and Debarment ................................................. 198
10.4
Compliance with Trial Registration and Results Posting Requirements ...... 199
10.5
Quality Management System............................................................................. 200
10.6
Data Management............................................................................................... 200
10.7
Publications ......................................................................................................... 200
11.0
LIST OF REFERENCES....................................................................................... 202
12.0
APPENDICES......................................................................................................... 211
12.1
Merck Code of Conduct for Clinical Trials...................................................... 211
12.2
Collection and Management of Specimens for Future Biomedical Research
.............................................................................................................................. 213
12.3
Understanding the Intent, Scope and Public Health Benefits of Exploratory 
Biomarker Research: A Guide for IRBs/IECs and Investigational Site Staff
.............................................................................................................................. 219
12.4
ECOG Performance Status................................................................................ 230
12.5
Common Terminology Criteria for Adverse Events V4.0 (CTCAE)............. 231
12.6
Multiple Myeloma Diagnostic Criteria............................................................. 232
12.7
Disease Response Criteria.................................................................................. 233
MDS Disease Response Criteria....................................................................... 233
.................................................. 235
Lymphoma Disease Response Criteria ............................................................. 237
12.8
Interim Analysis Decision Rules........................................................................ 238
12.9
Dose Timing Table for Lenalidomide + Pembrolizumab Combination 
Treatment ............................................................................................................ 239
12.10 Lenalidomide Pregnancy Prevention Plan for Subjects in Clinical Trials.... 242
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines 
and Acceptable Birth Control Methods ............................................................ 242
Risks Associated with Pregnancy.............................................................. 242
Definition of Females of Childbearing Potential....................................... 242
Definition of Females Not of Childbearing Potential................................ 243
Counseling ................................................................................................. 243
Females of Childbearing Potential............................................................. 243
Females Not of Childbearing Potential...................................................... 243
Males.......................................................................................................... 244
Contraception............................................................................................. 244
 
 
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Female Subjects of Childbearing Potential................................................ 244
Male Subjects............................................................................................. 245
Pregnancy Testing...................................................................................... 245
Pregnancy Precautions for Lenalidomide Use........................................... 246
Before Starting Lenalidomide.................................................................... 246
12.10.5.1.1 Female Subjects of Childbearing Potential....................................... 246
12.10.5.1.2 Male Subjects.................................................................................... 246
During and After Study Participation........................................................ 246
12.10.5.2.1 Female Subjects ................................................................................ 246
12.10.5.2.2 Male Subjects.................................................................................... 247
Lenalidomide Education and Counseling Guidance Document for 
Female Subjects ................................................................................................ 248
Female of Childbearing Potential:............................................................. 248
Female Not of Childbearing Potential (Natural Menopause for at Least 
24   Consecutive Months, a Hysterectomy, or Bilateral Oophorectomy):. 250
Lenalidomide Education and Counseling Guidance Document for Male 
Subjects............................................................................................................. 252
Lenalidomide Information Sheet ............................................................... 254
12.11 List of Abbreviations .......................................................................................... 256
13.0
SIGNATURES......................................................................................................... 259
13.1
Sponsor's Representative ................................................................................... 259
13.2
Investigator.......................................................................................................... 259
 
 
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LIST OF TABLES
Table 1
MDS Adequate Organ Function Laboratory Values.............................................. 47
Table 2
Multiple Myeloma Adequate Organ Function Laboratory Values ........................ 49
Table 3
Lymphoma Adequate Organ Function Laboratory Values .................................... 51
Table 4
Trial Treatment....................................................................................................... 57
Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab.................................................................... 59
Table 6
Dose Modification Guidelines for Hematological Pembrolizumab-Related 
Adverse Events....................................................................................................... 62
Table 7
Monitoring Guidance in Dose Evaluation (Target DLT Rate of 30%).................. 64
Table 8
Dose Modification Guidelines for Hematologic Lenalidomide-Related Adverse 
Events ..................................................................................................................... 66
Table 9
Infusion Reaction Treatment Guidelines................................................................ 73
Table 10 Disease Response Assessments............................................................................ 157
Table 11 Bone Marrow and Lymph Node Biopsy Assessments......................................... 160
Table 12 Blood Collection for Correlative Biomarkers Studies ......................................... 161
Table 13 Laboratory Tests................................................................................................... 162
Table 14 Evaluating Adverse Events .................................................................................. 175
Table 15 Primary Analysis Strategy for Efficacy Endpoints .............................................. 179
Table 16 Summary of Interim Analysis Strategy................................................................ 183
Table 17 Analysis Strategy for Key Efficacy Variables ..................................................... 188
Table 18 Historic Response Rates for Hematologic Malignancies..................................... 191
Table 19 Precision (90% Confidence
Intervals) for range of observed ORR 
(33% - 83%) ......................................................................................................... 192
Table 20 Operating Characteristics of Interim Analysis Rule for MDS and HL –  Pause 
Enrollment if ≤1/10 Subjects Achieve an Overall Response (MDS) or a 
Complete Response (HL); Final Analysis with 25 Subjects ................................ 193
Table 21 Operating Characteristics of Interim Analysis Rule for MLBCL and PD-L1 
Positive NHL subjects (Cohorts 4A and 4B) and MM (Cohort 1)– Pause 
Enrollment if ≤3/10 Subjects Achieve an Overall Response (PR or better); Final 
Analysis with 28 Subjects .................................................................................... 194
Table 22 Product Descriptions ............................................................................................ 195
 
 
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LIST OF FIGURES
Figure 1 Trial Design Prior to Amendment 013-04.............................................................. 23
Figure 2 Trial Design Amendment 013-04 (Cohorts 4C and 4D) ........................................ 24
Figure 3 Trial Design Amendment 013-05 (Cohort 5)......................................................... 24
Figure 4 Kaplan-Meier Graph of Overall Survival (Intent to Treat Population).................. 32
Figure 5 Kaplan-Meier Graph of Time to Progression Per IMWG 2011 Based on 
Confirmed Investigator Review (Primary Censoring Rule, Intent to Treat 
Population) ............................................................................................................. 33
Figure 6 Kaplan-Meier Graph of Overall Survival (Intent to Treat Population).................. 34
Figure 7 Kaplan-Meier Graph of Time to Progression Per IMWG 2011 Based on 
Confirmed Investigator Review (Primary Censoring Rule, Intent to Treat
Population) ............................................................................................................. 35
 
 
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DOCUMENT HISTORY
Document
Date of Issue
Overall Rationale
MK-3475-013-09
16-APR-2020
To add a 12-month limit to follow-up after discontinuation to allow for closure of the 
study.
MK-3475-013-08
21-NOV-2017
This amendment was to discontinue treatment of subjects with combination therapy 
lenalidomide and pembrolizumab in Cohort 5. On 03-JUL-2017, the United States (US) 
Food and Drug Administration (FDA) placed on clinical hold KEYNOTE-183 
(pembrolizumab/ pomalidomide/dexamethasone for refractory or relapsed and refractory 
multiple myeloma [MM]), KEYNOTE-185 (pembrolizumab/ lenalidomide/ 
dexamethasone for treatment naïve MM), and Cohort 1 of KEYNOTE-023
(pembrolizumab/ lenalidomide/ dexamethasone for refractory or relapsed and refractory 
MM). The FDA determined that the risks of pembrolizumab plus pomalidomide or 
lenalidomide outweighed any potential benefit for subjects with MM. Based on the 
summary of data from KEYNOTE-183 and KEYNOTE-185, subjects enrolled in Cohort 
5 of KEYNOTE-013 have to discontinue combination therapy with lenalidomide and 
pembrolizumab. If subjects are experiencing clinical benefit at time of discontinuation, 
subjects have the option of entering a 90 day transition period where they receive 
monotherapy pembrolizumab or lenalidomide and then must enter long term safety and 
survival follow-up. There will be no further enrollment of subjects in this cohort. 
Additionally, enrollment in Cohort 2 has been completed; all subjects have previously 
discontinued study treatment and must transition into long-term safety and survival 
follow-up. There will be no further enrollment of subjects in this cohort. 
 
 
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Document
Date of Issue
Overall Rationale
MK-3475-013-07
25-SEP-2017
This amendment was finalized, but not submitted. The primary rationale was to remove 
the requirement for reporting immune-related adverse events (AEs) as Events of Clinical 
Interest (ECTs). Additional updates to align the protocol with current pembrolizumab 
standard language and to provide clarifications to protocol procedures and timing of 
assessments and/or procedures were also made.
MK-3475-013-06
13-JUL-2016
This amendment was to clarify the exclusion criteria related to pneumonitis to insure 
patients who may have a history of pneumonitis are excluded from the study (when 
applicable).
MK-3475-013-05
20-MAR-2016
This amendment added Cohort 5 to the study to enroll approximately 30-66 additional 
subjects with relapsed/refractory Diffuse Large B Cell Lymphoma (DLBCL) that have 
failed, are ineligible for, or refused a stem cell transplant. These subjects will be 
allocated to receive pembrolizumab 200 mg administered intravenously once every 21 
days in combination with lenalidomide taken orally once daily for 21 days + 7 days off.  
The cycle length is 28 days.  This increases the total number of subjects targeted for 
enrollment in the trial from approximately 156 to approximately 222. Updates were 
made throughout the protocol to provide entry criteria, study intervention directions, 
response assessment, dose modification and monitoring guidelines, and statistical 
analysis plans for this new cohort.
 
 
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Document
Date of Issue
Overall Rationale
MK-3475-013-04
14-APR-2015
This amendment expanded Cohort 4 to enroll approximately 50 additional subjects with 
relapsed/refractory Follicular Lymphoma (FL) (Cohort 4C) or Diffuse Large B-Cell 
Lymphoma (DLBCL) (Cohort 4D) (approximately 25 each) that have failed, are 
ineligible for, or refused a stem cell transplant. These subjects are not required to have 
PD-L1 testing to determine eligibility.  These subjects will be allocated to receive 200 
mg Q3W.  This increases the total number of subjects targeted for enrollment in the trial 
from 106 to approximately 156.  Remaining open slots in Cohort 4 will be allocated to 
MLBCL subjects (Cohort 4A) that will receive 200 mg Q3W instead of 10mg/kg Q2W.  
The total number of subjects in Cohort 4A and 4B combined will be 28.
Subjects enrolled under this amendment in Cohort 2, 4A, 4C and 4D will now receive 
200 mg Q3W because the pembrolizumab program has moved to a 200 mg fixed dose 
regimen given every 3 weeks.  Enrollment in Cohort 1 and 3 have been completed. 
Subjects enrolled prior to this amendment will continue on their current regimen of 
10 mg/kg Q2W.  
The objectives for subjects with relapsed/refractory NHL (Cohort 4) were updated to 
indicate that in addition to the overall Cohort, the objectives also pertain to disease
subtype within the cohort (MLBCL, FL, DLBCL, Other) because it was thought that an 
adequate number of subjects would be enrolled to obtain preliminary efficacy 
assessments for these disease subtypes. Objectives and hypothesis testing in NHL 
subjects (Cohort 4) was also updated to be done regardless of PD-L1 status; where 
adequate numbers permit, descriptive statistics and/or subject listings will be provided 
by PD-L1 status.
The amendment also added conditions under which an investigator, after consultation 
with the Sponsor, might continue treatment after confirmed progression in subjects who 
are clinically stable or clinically improved.
Additional updates to provide clarification and correct errors were made.
 
 
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Document
Date of Issue
Overall Rationale
MK-3475-013-03
30-JAN-2014
This amendment was to add a cohort for relapsed refractory multiple myeloma to the 
protocol.
MK-3475-013-02
18-DEC-2013
This amendment was primarily made to remove the smoldering multiple myeloma 
cohort per request of the FDA. Changes were made throughout the protocol to 
accommodate this update.
Additional clarifications and corrections
MK-3475-013-01
21-AUG-2013
The primary reason for this amendment was to address requests made by the US Food 
and Drug Administration to clarify inclusion and exclusion criteria, revise the dose 
modification and supportive care guidelines, and clarify the duration of treatment for all 
cohorts. A criterion for ending the trial due to adverse events reported in this trial or 
other trials was removed.
Additionally, revisions were made to assessment of the efficacy endpoint and to 
inclusion criterion #16; clarifications were made to subject replacement strategy, to 
efficacy assessments timing, to timing of imaging procedures, and to the study flow 
chart.
MK-3475-013-00
14-JUN-2013
Original protocol
 
 
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SUMMARY OF CHANGES
PRIMARY REASON(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
1.0
2.1
Trial Summary
Trial Design
Updated follow-up after 
treatment discontinuation to 
add a 12-month duration to 
follow-up.
To allow for closing of the trial 
after 12 months of follow-up.
7.2.3.2
Events of Clinical Interest
Updated follow-up after 
allogeneic stem cell transplant 
(SCT) to provide for 
completion of follow-up at the 
end of the trial. 
Follow-up post allogeneic-
SCT will end when the trial 
closes.
 
 
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ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:
Section Number (s)
Section Title(s)
Description of Change (s)
Rationale
4.2.3.4
7.1.1.1.2
12.2
Future Biomedical Research
Consent and Collection of 
Specimens for Future 
Biomedical Research
Collection and Management of 
Specimens for Future 
Biomedical Research
Revised text to omit references 
to a “sub-trial” for future 
biomedical research.
Template updates for 
clarification that future 
biomedical research is not a 
sub-trial of this protocol.
6.0
7.1.5.3.2
Trial Flow Chart
Efficacy Follow-up Visits
Updated heading/column 
heading text for Follow-up 
Visits to include “efficacy.”
Template update for 
clarification.
6.0
Trial Flow Chart
Updated column heading for 
Post Treatment Safety Follow-
up to add “Visit”
Template update for 
clarification
 
 
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1.0 TRIAL SUMMARY
Abbreviated Title
A Phase Ib Multi-cohort Trial of MK-3475 (pembrolizumab) in Subjects 
with Hematological Malignancies
Trial Phase
Ib
Clinical Indication
Cohort 1: The treatment of subjects with intermediate-1, intermediate-2, 
or high risk myelodysplastic syndrome (MDS) who have failed to respond 
to at least 4 cycles of prior treatment with a hypomethylating agent.
Cohort 2: The treatment of subjects with relapsed refractory or refractory 
multiple myeloma (MM).
Cohort 3: The treatment of subjects with relapsed / refractory nodular 
sclerosing or mixed cellularity Hodgkin lymphoma (HL) 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.
Cohort 4: The treatment of subjects with relapsed / refractory non-
Hodgkin Lymphoma (NHL)
1.
Cohort 4A: The treatment of subjects with relapsed / refractory 
mediastinal large B-cell lymphoma (MLBCL) that have failed, 
are ineligible for, or refused a stem cell transplant.
2.
Cohort 4B: Subjects with any other relapsed / refractory 
programmed cell death ligand 1 (PD-L1) positive NHL that have 
failed, are ineligible for, or refused a stem cell transplant.
3.
Cohort 4C: Irrespective of PD-L1 status, NHL subjects with
relapsed / refractory Follicular Lymphoma (FL) that have failed, 
are ineligible for, or refused a stem cell transplant.
4.
Cohort 4D: Irrespective of PD-L1 status, NHL subjects with
relapsed / refractory Diffuse Large B-Cell Lymphoma (DLBCL)
that have failed, are ineligible for, or refused a stem cell 
transplant.
Cohort 5: Irrespective of PD-L1 status, NHL subjects with relapsed /
refractory DLBCL that have failed, are ineligible for, or refused a stem 
cell transplant.
Trial Type
Interventional
Type of control
No treatment control
Route of administration
Intravenous
Trial Blinding
Unblinded Open-label
Treatment Groups 
Subjects enrolled prior to Amendment 013-04 in Cohorts 1, 2, 3, 4A, and 
4B received pembrolizumab 10 mg/kg every 2 weeks. Subjects enrolled 
under Amendment 013-04 or Amendment 013-05 in Cohort 2, 4A, 4C, 
and 4D will receive pembrolizumab 200 mg every 3 weeks. Subjects 
enrolled in Cohort 5 (DLBCL) will receive pembrolizumab 200 mg 
intravenously once every 21 days in combination with lenalidomide taken 
orally once daily for 21 days + 7 days off. The cycle length is 28 days.
 
 
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Number of trial subjects
Approximately 222 subjects will be enrolled.
Estimated duration of trial
The sponsor estimates that the trial will require approximately 55 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 Cycle 1 Day 1. Treatment with pembrolizumab or lenalidomide + 
pembrolizumab will continue 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 requiring cessation of treatment. Subjects who 
attain a complete response (CR) or stringent CR (sCR) (MM) 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 the occurrence of adverse 
events and spontaneously reported pregnancy as described under Section 
7.2 of the protocol. Subjects who discontinue for reasons other than 
disease progression will have post-treatment follow-up for at least 12 
months for disease status until disease progression, initiating a non-study 
cancer treatment, withdrawing consent, or becoming lost to follow-up. 
All subjects will be followed by telephone for at least 12 months after 
their discontinuation visit for overall survival until death, withdrawal of 
consent, or the end of the study.
Due to the unfavorable results (risks outweighed benefits) of KEYNOTE-
183 and KEYNOTE-185 in subjects with MM treated with 
pembrolizumab plus pomalidomide or lenalidomide, subjects enrolled in 
Cohort 5 who are still receiving combination treatment are to stop 
combination treatment immediately, complete the discontinuation visit, 
and move into the long-term safety and survival follow-up per protocol. 
If clinically benefitting at time of stopping combination therapy, subjects 
may enter a transition period remaining on single agent lenalidomide or 
pembrolizumab for up to 90 days from 15-SEP-2017 and then enter long-
term survival and safety follow-up. For Cohort 2, enrollment has been 
completed and all subjects have previously discontinued study treatment
and must transition into long-term and survival follow-up. There will be 
no further enrollment of subjects in this cohort.
A list of abbreviations used in this document can be found in Section 12.11.
2.0 TRIAL DESIGN
2.1
Trial Design
This is a multicenter, nonrandomized trial of MK-3475 (pembrolizumab) in subjects with 
intermediate-1, intermediate-2, or high risk myelodysplastic syndrome (MDS) who have failed 
 
 
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to respond to at least 4 cycles of prior treatment with a hypomethylating agent (HMA) (Cohort 
1); subjects with relapse refractory or refractory multiple myeloma (MM, Cohort 2); subjects 
with relapsed / refractory nodular sclerosing or mixed cellularity Hodgkin lymphoma (HL) 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 (Cohort 3); subjects with relapsed / refractory 
mediastinal large B-cell lymphoma (MLBCL) that have failed, are ineligible for, or refused a 
stem cell transplant (Cohort 4A); subjects with other relapsed / refractory programmed cell 
death ligand 1 (PD-L1) positive non-Hodgkin lymphoma (NHL) that have failed, are ineligible
for, or refused a stem cell transplant (Cohort 4B); irrespective of PD-L1 status, subjects with 
relapsed / refractory Follicular Lymphoma (FL, Cohort 4C) or Diffuse Large B-Cell 
Lymphoma (DLBCL, Cohort 4D) that have failed, are ineligible for, or refused a stem cell 
transplant.
This multicenter, nonrandomized trial under Amendment 013-05 will also evaluate MK-3475 
(pembrolizumab) given in combination with lenalidomide in subjects with relapsed / refractory 
DLBCL (Cohort 5) who have failed, are ineligible for, or refused a stem cell transplant.  
Approximately 222 subjects will be enrolled in this trial to examine the safety and efficacy of 
pembrolizumab or lenalidomide + pembrolizumab combination.   Adverse events (AEs) will 
be monitored throughout the trial and graded in severity according to the guidelines outlined 
in the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0.  
Treatment with pembrolizumab or lenalidomide + pembrolizumab combination will continue 
until documented disease progression, unacceptable AEs, 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 requiring cessation of treatment. Per the investigator’s 
discretion subjects who attain an investigator-determined confirmed complete response (CR) 
or stringent complete response (sCR) (MM) may consider stopping trial treatment after 
receiving at least 24 weeks of therapy. At least two doses of pembrolizumab must be received 
after CR or sCR (MM) is documented for subjects receiving pembrolizumab monotherapy. An 
additional 21 consecutive daily doses of lenalidomide + 2 doses of pembrolizumab must be 
received after CR is documented in subjects in Cohort 5 (DLBCL). 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 trial treatment, the 
subject still meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial 
remains open (refer to Section 7.1.5.2.1 for further details). After the end of treatment, each 
subject will be followed for the occurrence of AEs and spontaneously reported pregnancy as 
described under Section 7.2 of the protocol. Subjects who discontinue treatment for reasons 
other than disease progression will have post-treatment follow-up for at least 12 months for 
disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent, or becoming lost to follow-up. All subjects will be followed by telephone contact for 
at least 12 months after their discontinuation visit for overall survival (OS) until death, 
withdrawal of consent or the end of the study, whichever comes first.
 
 
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The primary objectives of the trial are to determine safety, tolerability, and efficacy of 
pembrolizumab or lenalidomide + pembrolizumab combination in subjects with hematologic 
malignancies. Secondary objectives include further analysis of various efficacy parameters 
(time to progression [TTP]/progression-free survival [PFS]/ OS for each respective cohort, as 
well as an analysis of PD-L1 expression and corresponding efficacy. The pharmacokinetic 
(PK) properties of pembrolizumab and pembrolizumab when given in combination with 
lenalidomide, and the relationship of candidate efficacy/resistance biomarkers and anti-tumor 
activity of pembrolizumab will be investigated as exploratory objectives.  
With the initiation of Amendment 013-04, the protocol will be enrolling subjects in the 
following Cohorts: Cohort 2 (MM), 4A (MLBCL), 4C (FL), and 4D (DLBCL).
With the initiation of Amendment 013-05, subjects will be enrolled in Cohort 5 (DLBCL) to 
receive lenalidomide + pembrolizumab combination treatment.
This study will be conducted in conformance with Good Clinical Practices.
Due to the unfavorable results (risks outweighed benefits) of KEYNOTE-183 and 
KEYNOTE-185 in subjects with MM treated with pembrolizumab plus pomalidomide or 
lenalidomide, subjects enrolled in Cohort 5 who are still receiving combination are to stop 
combination treatment immediately, complete the discontinuation visit, and move into the 
long-term safety and survival follow-up per protocol. If clinically benefitting at time of 
stopping combination therapy, subjects may enter a transition period remaining on single 
agent lenalidomide or pembrolizumab for up to 90 days from 15-SEP-2017 and then enter 
long-term survival and safety follow-up.
For Cohort 2, enrollment has been completed and all subjects have previously discontinued 
study treatment and must transition into long-term safety and survival follow-up. There will 
be no further enrollment of subjects in this cohort
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.
An interim analysis will be performed if fewer than 10 subjects are enrolled in a cohort after 
being open for 6 months from the time that the first subject is treated in the respective cohort.  
Results will be reviewed by the study team.
The safety run-in will be conducted on at least the first 12 subjects enrolled in Cohort 5
(DLBCL) to determine the recommended phase II dose (RP2D) for lenalidomide when given 
in combination with pembrolizumab. The Sponsor will review dose limiting toxicities (DLTs) 
reported by the investigator during the safety run-in and will determine the appropriate 
adjustment to the dose of lenalidomide, if necessary.
2.2
Trial Diagram
The trial design for Cohorts 1, 2, 3, and 4 is depicted in Figure 1 and Figure 2.
 
 
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Figure 1
Trial Design Prior to Amendment 013-04
 
 
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Figure 2
Trial Design Amendment 013-04 (Cohorts 4C and 4D)
The trial design for Cohort 5 (DLBCL) is depicted in Figure 3.
Figure 3
Trial Design Amendment 013-05 (Cohort 5)
 
 
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3.0 OBJECTIVE(S) & HYPOTHESIS(ES)
3.1
Primary Objective(s) & Hypothesis(es)
MDS (Cohort 1)
1) Objective: To determine the safety and tolerability of pembrolizumab in subjects with 
intermediate-1, intermediate-2, or high risk MDS whose disease has failed to respond 
to at least 4 cycles of a HMA.
2) Objective: To evaluate the objective response rate (ORR) of pembrolizumab based on
International Working Group (IWG) criteria for MDS in subjects with intermediate-1, 
intermediate-2, or high risk MDS whose disease has failed to respond to at least 4 cycles 
of a HMA.
Hypotheses: Intravenous (IV) administration of single agent pembrolizumab to subjects 
with intermediate-1, intermediate-2, or high risk MDS whose disease has failed to respond 
to at least 4 cycles of a HMA will result in an ORR greater than 10% based on IWG criteria 
for MDS.
Multiple Myeloma (Cohort 2)
1) Objective: To determine the safety and tolerability of pembrolizumab in subjects with 
relapse refractory or refractory MM.
2) Objective: To evaluate ORR of pembrolizumab based on International Myeloma 
Working Group (IMWG) 2006 Criteria in subjects with relapse refractory or refractory 
MM.
Hypotheses: IV administration of single agent pembrolizumab to subjects with relapse
refractory or refractory MM will result in an ORR greater than 25% based on IMWG 2006
Criteria.
Hodgkin Lymphoma and Non-Hodgkin Lymphoma Monotherapy (Cohort 3 and 4) 
1) Objective: To determine the safety and tolerability of pembrolizumab in subjects with 
relapsed / refractory nodular sclerosing or mixed cellularity HL, relapsed / refractory 
MLBCL, and relapsed / refractory NHL, that have failed, are ineligible for, or refused 
a stem cell transplant.
2) Objective: To evaluate complete remission rate (CRR) of pembrolizumab based on the 
Revised Response Criteria for Malignant Lymphoma in subjects with relapsed /
refractory nodular sclerosing or mixed cellularity HL (Cohort 3).
Hypotheses: IV administration of single agent pembrolizumab to subjects with relapsed /
refractory nodular sclerosing or mixed cellularity HL will result in a CRR greater than 10%
(Cohort 3) based on the Revised Response Criteria for Malignant Lymphoma.
 
 
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3) Objective: To evaluate ORR of pembrolizumab based on the Revised Response 
Criteria for Malignant Lymphoma in subjects with relapsed / refractory NHL 
(Cohort 4).
Hypotheses: IV administration of single agent pembrolizumab to subjects with relapsed /
refractory NHL will result in an ORR greater than 25% (Cohort 4) based on the Revised 
Response Criteria for Malignant Lymphoma.
4) Objective: To evaluate ORR of pembrolizumab based on the Revised Response 
Criteria for Malignant Lymphoma in subjects with relapsed / refractory NHL by disease 
subtype within Cohort 4 (MLBCL, FL, DLBCL, Other).
Non-Hodgkin Lymphoma (DLBCL) Combination Therapy (Cohort 5)
1) Objective: To determine the safety and tolerability of combination lenalidomide + 
pembrolizumab in subjects with relapsed / refractory DLBCL (Cohort 5) that have 
failed, are ineligible for, or refused a stem cell transplant.
2) Objective: To evaluate the ORR of combination lenalidomide + pembrolizumab based 
on the Revised Response Criteria for Malignant Lymphoma in subjects with relapsed /
refractory DLBCL (Cohort 5).
3.2
Secondary Objective(s) & Hypothesis(es)
MDS (Cohort 1)
1) Objective: To evaluate the OS in subjects with intermediate-1, intermediate-2, or high 
risk MDS whose disease has failed to respond to at least 4 cycles of a HMA.
2) Objective: To evaluate Bone Marrow Response in subjects with intermediate-1, 
intermediate-2, or high risk MDS whose disease has failed to respond to at least 4 cycles 
of a HMA.
3) Objective: To evaluate Hematologic Improvement based on IWG criteria for MDS in 
subjects with intermediate-1, intermediate-2, or high risk MDS whose disease has
failed to respond to at least 4 cycles of a HMA.
4) Objective: To evaluate Cytogenetic Response based on IWG criteria for MDS in 
subjects with intermediate-1, intermediate-2, or high risk MDS whose disease has
failed to respond to at least 4 cycles of a HMA.
5) Objective: To evaluate Duration of Response (DOR) in subjects with intermediate-1, 
intermediate-2, or high risk MDS whose disease has failed to respond to at least 4 cycles 
of a HMA.
6) Objective: To compare in bone marrow biopsies the extent of pre- pembrolizumab PD-
L1 expression and change in PD-L1 expression after treatment with a HMA for 
pembrolizumab responders versus non-responders in subjects with intermediate-1, 
intermediate-2, or high risk MDS whose disease has failed to respond to at least 4 cycles 
of a HMA.
 
 
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Multiple Myeloma (Cohort 2)
1) Objective: To evaluate complete response and stringent response rate (CR + sCR)
based on IMWG 2006 Criteria in subjects with relapse refractory or refractory MM.
2) Objective: To evaluate TTP in subjects with relapse refractory or refractory MM.
3) Objective: To evaluate DOR in subjects with relapse refractory or refractory MM.
4) Objective: To evaluate PFS in subjects with relapse refractory or refractory MM.
5) Objective: To evaluate OS in subjects with relapse refractory or refractory MM.
6) Objective: To compare in bone marrow biopsies, the extent of pre- pembrolizumab
PD-L1 expression for pembrolizumab responders versus non-responders in subjects 
with relapse refractory or refractory MM.
Hodgkin Lymphoma and Non-Hodgkin Lymphoma Monotherapy (Cohort 3 and 4) 
1) Objective: To evaluate PFS in subjects with relapsed / refractory nodular sclerosing or 
mixed cellularity HL (Cohort 3), relapsed / refractory NHL (Cohort 4) and by disease 
subtype within Cohort 4 (MLBCL, FL, DLBCL, Other).
2) Objective: To evaluate the OS in subjects with relapsed / refractory nodular sclerosing 
or mixed cellularity HL (Cohort 3), relapsed / refractory NHL (Cohort 4), and by 
disease subtype within Cohort 4 (MLBCL, FL, DLBCL, Other).
3) Objective: To evaluate ORR of pembrolizumab based on the Revised Response 
Criteria for Malignant Lymphoma in subjects with relapsed / refractory nodular 
sclerosing or mixed cellularity HL (Cohort 3).
4) Objective: To evaluate DOR in subjects with relapsed / refractory nodular sclerosing 
or mixed cellularity HL (Cohort 3), relapsed / refractory NHL (Cohort 4), and by 
disease subtype within Cohort 4 (MLBCL, FL, DLBCL, Other).
5) Objective: To compare the extent of pre- pembrolizumab PD-L1 expression in tumor 
biopsies for pembrolizumab responders versus non-responders in subjects with 
relapsed / refractory nodular sclerosing or mixed cellularity HL (Cohort 3), relapsed /
refractory NHL (Cohort 4), and by disease subtype within Cohort 4 (MLBCL, FL, 
DLBCL, Other).
Non-Hodgkin Lymphoma (DLBCL) Combination Therapy (Cohort 5)
1) Objective: To evaluate PFS of combination lenalidomide + pembrolizumab based on 
the Revised Response Criteria for Malignant Lymphoma in subjects with relapsed /
refractory DLBCL (Cohort 5).
 
 
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2) Objective: To evaluate the OS of combination lenalidomide + pembrolizumab based 
on the Revised Response Criteria for Malignant Lymphoma in subjects with relapsed /
refractory DLBCL (Cohort 5).
3) Objective: To evaluate the DOR of combination lenalidomide + pembrolizumab based 
on the Revised Response Criteria for Malignant Lymphoma in subjects with relapsed /
refractory DLBCL (Cohort 5).
4) Objective: To compare the extent of pre-pembrolizumab PD-L1 expression in tumor 
biopsies for combination lenalidomide + pembrolizumab responders versus non-
responders in subjects with relapsed / refractory DLBCL (Cohort 5).
3.3
Exploratory Objectives 
MDS (Cohort 1)
1) Objective: To explore the PK profile of pembrolizumab in this subject population.
2) Objective: To investigate the relationship between candidate efficacy biomarkers and 
anti-tumor activity of pembrolizumab utilizing pre and post-treatment bone marrow 
biopsies/aspirates and blood sampling using flow cytometric technology. Gene 
sequencing will be evaluated in baseline bone marrow biopsy samples. Utilizing both 
pre and post treatment bone marrow biopsy samples acquired for purposes of disease 
assessment change in baseline of candidate biomarkers will also be assessed using 
multi-parametric immunohistochemistry (IHC) and Nanostring for gene expression.
3) Objective: To compare programmed cell death 1 (PD-1) expression on circulating 
lymphocytes in responders versus non-responders to pembrolizumab utilizing blood 
sampling pre and post-treatment.
4) Objective: To evaluate responses based on International Prognostic Scoring System
(IPSS) and Revised International Prognostic Scoring System classifications in this 
patient population.
Multiple Myeloma (Cohort 2)
1) Objective: To explore the PK profile of pembrolizumab in this patient population.
2) Objective: To investigate the relationship between candidate efficacy biomarkers and 
anti-tumor activity of pembrolizumab utilizing pre and post-treatment bone marrow 
biopsies/aspirates and blood sampling using flow cytometric technology. Gene 
sequencing will be evaluated in baseline bone marrow biopsy samples. Utilizing both 
pre and post treatment bone marrow biopsy samples acquired for purposes of disease 
assessment change in baseline of candidate biomarkers will also be assessed using 
multi-parametric IHC and Nanostring for gene expression.
 
 
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3) Objective: To compare PD-1 expression on circulating lymphocytes in responders 
versus non-responders to pembrolizumab utilizing blood sampling pre and post-
treatment.
Hodgkin Lymphoma and Non-Hodgkin Lymphoma (Cohort 3, 4, and 5) 
1) Objective: To explore the PK profile of pembrolizumab, or pembrolizumab when 
given in combination with lenalidomide, in subjects with relapsed / refractory nodular 
sclerosing or mixed cellularity HL (Cohort 3), relapsed / refractory NHL (Cohort 4), 
and by disease subtype within Cohort 4 and Cohort 5 (MLBCL, FL, DLBCL, Other).
2) Objective: To investigate the relationship between candidate efficacy biomarkers and 
anti-tumor activity of pembrolizumab, or pembrolizumab when given in combination 
with lenalidomide, utilizing pre and post-treatment lymph node biopsies and blood 
sampling in subjects with relapsed / refractory nodular sclerosing or mixed cellularity 
HL (Cohort 3), relapsed / refractory NHL (Cohort 4), and by disease subtype within 
Cohort 4 and Cohort 5 (MLBCL, FL, DLBCL, Other). Gene sequencing will be 
evaluated in baseline tumor biopsies. Utilizing both pre and post treatment tumor 
biopsies, change in baseline of candidate biomarkers will also be assessed using multi-
parametric IHC and Nanostring for gene expression.
3) Objective: To compare PD-1 expression on circulating lymphocytes in responders 
versus non-responders to pembrolizumab, or pembrolizumab when given in 
combination with lenalidomide, utilizing blood sampling pre and post-treatment in 
subjects with relapsed / refractory nodular sclerosing or mixed cellularity HL (Cohort 
3), relapsed / refractory NHL (Cohort 4), and by disease subtype within Cohort 4 and 
Cohort 5 (MLBCL, FL, DLBCL, Other).
4.0 BACKGROUND & RATIONALE
4.1
Background
Refer to the Investigator’s Brochure (IB) for detailed background information on 
pembrolizumab (MK-3475).  Refer to the current version of the local prescribing information 
for detailed information on lenalidomide.
Pharmaceutical and Therapeutic Background
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 in cancer tissue and favorable prognosis in various 
malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector T-
cells / FoxP3+ regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors [2] [3].
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-
 
 
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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 immunoglobulin 
(Ig) superfamily member related to CD28 and cytotoxic T-lymphocyte-associated antigen-4 
(CTLA-4) which has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or programmed cell death ligand 2 (PD-L2) [4] [5]. The 
structure of murine PD-1 has been resolved [6]. PD-1 and family members are type I 
transmembrane glycoproteins containing an Ig Variable-type (V-type) domain responsible for 
ligand binding and a cytoplasmic tail which is responsible for the binding of signaling 
molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an 
immunoreceptor tyrosine-based inhibition motif and an immunoreceptor tyrosine-based switch 
motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 
and SHP-2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell 
signaling cascade [5] [7] [8] [9]. 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 [10] [11].  PD-1 was shown to be expressed on activated 
lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer
(NK) cells [12] [13]. Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic cells [14]. 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 [15] [16] [17]
[18]. 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 [15]. 
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 [19]. 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.
Pembrolizumab is a potent and highly selective humanized monoclonal antibody of the 
IgG4/kappa isotype designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2 without antibody-dependent cellular cytotoxicity (ADCC) or complement 
dependent cytotoxicity activity.
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, 
 
 
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melanoma, and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted 
CD8+ T-cell infiltration into the tumor and the presence of interferon (IFN)-, granzyme B,
and perforin, indicating that the mechanism of action involved local infiltration and activation 
of effector T-cell function in vivo [20] [2] [3] [21] [5] [4]. 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 (see the IB).
Recent data of nivolumab (MDX-1106, BMS-936558), an IgG4 antibody against PD-1, have 
validated PD-1 as an attractive target for clinical therapeutic intervention [22]. Nivolumab was 
tested in multiple solid tumors and promising clinical activity was noted in melanoma, renal 
cell carcinoma, and non-small cell lung cancer (NSCLC) at multiple doses. The most common 
AEs occurring in 25% or more of subjects included fatigue, decreased appetite, diarrhea, 
nausea, and cough. The most commonly observed immune-related AEs (irAEs) were pruritus, 
skin rash, and diarrhea. Other irAEs reported include increase of thyroid stimulating hormone, 
increase of alanine transaminase (ALT)/aspartate transaminase (AST), pneumonitis, infusion 
reaction, and vitiligo.
Ongoing Pembrolizumab Clinical Trials
Ongoing clinical trials are being conducted in advanced melanoma, NSCLC, head and neck 
cancer, urothelial tract cancer, gastric cancer, and triple negative breast cancer. For study 
details please refer to the IB.
On 03-JUL-2017, the United States (US) Food and Drug Administration (FDA) placed on 
clinical hold KEYNOTE-183 (pembrolizumab/pomalidomide/dexamethasone for refractory 
or relapsed and refractory MM), KEYNOTE-185 (pembrolizumab/
lenalidomide/
dexamethasone 
for 
treatment 
naïve 
MM), 
and 
Cohort 
1 
of 
KEYNOTE-023 
(pembrolizumab/lenalidomide/dexamethasone for refractory or relapsed and refractory MM). 
The FDA determined that the risks of pembrolizumab plus pomalidomide or lenalidomide 
outweighed any potential benefit for subjects with MM. Based on the summary of data shown 
below from KEYNOTE-183 and KEYNOTE-185, subjects enrolled in Cohort 5 of 
KEYNOTE-013 have to discontinue
combination therapy with lenalidomide and 
pembrolizumab. If subjects are experiencing clinical benefit at time of discontinuation, 
subjects have the option of entering a 90 day transition period where they receive monotherapy 
pembrolizumab or lenalidomide and then must enter long-term safety and survival follow-up. 
There will be no further enrollment of subjects in this cohort. Additionally, enrollment in 
Cohort 2 has been completed; all subjects have previously discontinued study treatment and 
must transition into long-term safety and survival follow-up. There will be no further 
enrollment of subjects in this cohort. A full safety and efficacy analysis based on a 02-JUN-
2017 data cutoff date was conducted for studies KEYNOTE-183 and KEYNOTE-185. A 
summary of these results is presented below.
 
 
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KEYNOTE-183
KEYNOTE-183 is a phase 3, randomized, controlled trial of pomalidomide and low-dose
dexamethasone with or without pembrolizumab in subjects with relapsed and refractory MM
who had received at least two prior lines of therapy.
Using a data cutoff date of 02-JUN-2017, a complete evaluation of safety and efficacy was
performed. There were 249 randomized subjects included in the analysis (Figure 4). The 
median follow-up was 8.1 months. For OS, there were 29 deaths on the pembrolizumab-
containing investigational arm and 21 deaths on the control arm. The hazard ratio (HR) of
the pembrolizumab-containing investigational arm compared to the control arm was 1.61 (95%
confidence interval [CI], 0.91-2.85), increasing the relative risk of death by more than 50%
compared to the control arm.
Figure 4
Kaplan-Meier Graph of Overall Survival (Intent to Treat Population)
 
 
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The ORR was 34% in the investigational arm compared to 40% in the control arm. In an 
exploratory TTP analysis, an HR of 1.14 (95% CI, 0.75-1.74) was observed (Figure 5).
Figure 5
Kaplan-Meier Graph of Time to Progression Per IMWG 2011 Based on 
Confirmed Investigator Review (Primary Censoring Rule, Intent to Treat Population)
There was an 18% increase of severe, Grade 3 to 5 toxicity (83% vs. 65%, investigational vs.
control arm). The incidence of serious adverse events (SAE) was 63% compared to 46% in
the control arm. The following non-disease progression causes of death were identified in the
pembrolizumab
arm: myocarditis, Stevens-Johnson
syndrome,
myocardial infarction,
pericardial hemorrhage, cardiac failure, respiratory tract infection, neutropenic sepsis, sepsis, 
multiple organ dysfunction, respiratory failure, and unknown.
KEYNOTE-185
KEYNOTE-185 is a phase 3, randomized, controlled trial of lenalidomide and low-dose
dexamethasone with or without pembrolizumab in subjects with newly diagnosed MM who are
ineligible for autologous stem cell transplant.
The data cutoff date of 02-JUN-2017 was used for these analyses. There were 301 randomized
subjects included in the analysis. The median follow-up was 6.6 months. For OS, there
 
 
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were 19 deaths on the pembrolizumab-containing investigational arm, and 9 deaths on the
control arm. The HR of the pembrolizumab-containing investigational arm compared to the
control arm was 2.06 (95% CI, 0.93-4.55), more than doubling the relative risk of death 
compared to the control arm (Figure 6).
Figure 6
Kaplan-Meier Graph of Overall Survival (Intent to Treat Population)
There was an ORR of 64% in the investigational arm compared to 62% in the control arm. An
exploratory TTP analysis (Figure 7) demonstrated an HR of 0.55 (95% CI, 0.20-1.50).
 
 
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Figure 7
Kaplan-Meier Graph of Time to Progression Per IMWG 2011 Based on 
Confirmed Investigator Review (Primary Censoring Rule, Intent to Treat Population)
There was a 22% increase of severe, Grade 3 to 5 toxicity (72% vs. 50%, investigational vs.
control arm). The incidence of SAEs was 54% compared to 39% in the control arm. There 
were 19 deaths in the investigational arm and 9 deaths in the control arm. The following non-
disease progression causes of death were identified in the pembrolizumab arm: intestinal
ischemia, cardio-respiratory arrest, suicide, pulmonary embolism, cardiac arrest, pneumonia,
sudden death, myocarditis, large intestine perforation, and cardiac failure.
There is no benefit in efficacy and the risk of death is increased with the investigational
regimen when compared to the standard of care in both trials. As noted above, the imbalance 
in deaths in the investigational treatment arm was driven primarily by a diverse set of AEs.
In conclusion, the benefit-risk profile is unfavorable for:
1. the combination of pembrolizumab, pomalidomide, and dexamethasone in relapsed
refractory MM, and
2. the combination of pembrolizumab, lenalidomide, and dexamethasone in newly
diagnosed treatment naive MM.
 
 
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4.2
Rationale
Rationale for the Trial and Selected Subject Population
Rationale for Evaluating anti-PD-1 Therapy in Hematologic Malignancies
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, acute myeloid leukemia (AML), chronic 
lymphocytic leukemia (CLL), and many lymphomas. Some Heme malignancies are also 
responsive to systemic immunotherapies, such as lenalidomide in multiple myeloma and IFN
in chronic myeloid leukemia. 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 PD-L1 expression has been reported in literature for MM, AML, CLL, 
NHL, and HL [23]. Additionally, PD-1 expression on infiltrating or circulating T cells can be 
associated with Heme malignancies and may contribute to immune escape, as in the cases of 
MDS, FL, and CLL [24] [25] [26]. Likewise, functional T-cell impairment after bone marrow 
transplant for AML can be associated with PD-1/PD-L1 expression[27]. The rationale for 
evaluating MDS, HL, and NHL are detailed below.
Myelodysplastic Syndrome
MDS comprises a heterogeneous group of malignant hematopoietic stem cell disorders 
characterized by dysplastic and ineffective blood cell production and a variable risk of 
transformation to acute leukemia. Patients often die of complications that arise from cytopenias 
or from subsequent AML. MDS occurs primarily in the elderly, with a median age of 72 years 
and male predominance. There are approximately 10,000 cases diagnosed annually in the 
United States [28]. However, a recent study indicates that the incidence may be as high as 
45,000 cases per year, and potentially increasing with an aging population, which would make 
it the most common type of Heme malignancies [29]. MDS is classified using the World Health 
Organization (WHO) system based on morphology, immunophenotype, genetics and clinical 
feature into six entities: refractory cytopenia with unilineage dysplasia, refractory anemia with 
ringed sideroblasts, refractory anemia with multilineage dysplasia, refractory anemia with 
excess blasts, MDS with isolated del 5 and MDS, and unclassified [30]. Patients with untreated 
MDS are categorized into 4 IPSS prognostic risk groups: low, intermediate 1, intermediate 2 
and high, which are associated with median survival times of 5.7, 3.1, 1.2, and 0.5 years, 
respectively [31]. Allogeneic stem cell transplantation (allo-SCT) from a human leukocyte 
antigen-matched sibling donor is a preferred approach for treating a selected group of patients 
with MDS, particularly those otherwise healthy patients with high-risk disease [32]. 5-
azacytidine (5-Aza), and decitabine have been recently approved by the FDA for treating 
higher risk MDS patients. Despite these advances, the overall ORR with monotherapy of 
demethylating agents remains relatively low and the median survival reaches only about 2 
years. Outcome after 5-Aza failure in high risk MDS is poor with a median OS of 5.6 months 
[33].
Aberrant up-regulation of PD-1, PD-L1, PD-L2, and CTLA4 expression has been 
demonstrated in peripheral blood mononuclear cells from MDS patients. This up-regulation is 
 
 
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further enhanced by therapeutic epigenetic modifiers, such as 5-Aza, and has been associated 
with poor survival outcome in this patient population [24]. This provides an especially strong 
rationale for anti-PD-1 therapy after first line 5-Aza failure. Patients with high-risk MDS with 
excess myeloid blasts (defined as 5%-20%) represent a relatively stable pre-leukemia 
population in whom an anti-PD-1 therapy would have sufficient time for evaluation before 
disease progression and death.
Hodgkin and non-Hodgkin Lymphoma
HL accounts for approximately 10% of all lymphomas and approximately 0.6% of all cancers 
diagnosed in the developed world annually [34]. 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 [35] [36]. Classical HL (CHL) is divided into 4 histologic subtypes: Nodular Sclerosis 
CHL, Mixed cellularity CHL, Lymphocyte rich CHL, and Lymphocyte depleted CHL [37]. 
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 and anti-CD-30 therapy followed by autologous 
stem-cell transplantation (auto-SCT), which can induce long-term remissions in approximately 
50% of patients [38] [39]. 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 [40]. Although varied classes of novel agents have demonstrated activity in patients 
with relapsed / refractory HL who have failed auto-SCT, this patient population has no 
currently available standard of care and represents an urgent unmet medical need. 
The incidence of NHL has increased over the last three decades to represent about 55,000 new 
cases a year in the United States [41]. At 5 years, the expected OS rate is 60%, and the event-
free survival rate is 50% [42] [43]. NHL encompasses multiple entities with distinct clinical 
features and outcomes. Although the majority of patients with NHL respond to initial therapy, 
a large number eventually relapse, experience disease progression and death from disease after 
initial therapy [42] [44]. Auto-SCT has improved survival in patients with aggressive NHL, 
the treatment of patients who fail to respond to second-line chemotherapy regimens, or who 
relapse after auto-SCT is generally palliative. 
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) [27]. 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 
JAK2 in nodular sclerosing HL and PMLBCL [45]. This affords a significant opportunity to 
define a targeted approach based on a novel biologically defined treatment mechanism such as 
the PD1/PD-L1 axis, with the goal of improving tolerability and efficacy in this patient 
population. 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 [46]. 
Because the current data related to 9p24.1 amplification provide the strongest rationale for HL 
and the PMLBCL, other NHL subtypes will be enrolled regardless of PD-L1 positivity by IHC.
 
 
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4.2.1.3.1 Lenalidomide + Pembrolizumab Combination in Diffuse Large B-Cell 
Lymphoma
Lenalidomide
Lenalidomide, an analogue of thalidomide, has known immunomodulatory and anti-
angiogenic properties. It is currently approved for use in the United States for multiple 
myeloma, 5q MDS-induced anemia, and mantle cell lymphoma [47], and in the European 
Union (EU) for MM and 5q deletion MDS-induced anemia [48]. Nonclinical in vitro and in 
vivo studies have clarified how lenalidomide acts on various hematopoietic tumor types [49] 
[50] [51] [52] [53]. Recent clinical studies have demonstrated the efficacy of both single-agent 
[54] [55] [56] and combination lenalidomide therapies [57] [58] [59] [60] [61] in relapsed or 
refractory DLBCL.  
Lenalidomide in vitro inhibits proliferation and induces apoptosis of certain hematopoietic 
tumor cells, including multiple myeloma, del (5q) MDSs, and mantle cell lymphoma [47].
Enhancement of NK T cells, known to play a role in immune protection from tumors, is also 
activated by lenalidomide [49]. Although, the exact mechanism of action of lenalidomide is 
still unknown, early in vitro studies suggest immunomodulatory effects by inhibited Akt and 
Gab1 phosphorylation and inhibited Gab1 association with tyrosine kinase [50]. Additional 
immunomodulatory properties, suggested by nonclinical in vivo hematopoietic tumor models, 
include a delay in tumor growth by activation of T cells and NK cells, increased numbers of 
NK T cells, and inhibition of proinflammatory cytokines (e.g., tumor necrosis factor-α and 
interleukin-6 by monocytes [47]. Lenalidomide enhanced NK cell- and monocyte-mediated 
ADCC CD20+ tumor cells treated with rituximab [51]. More recent investigations of the gene 
expression changes in specifically activated B-cell-like (ABC) DLBCL suggest that 
lenalidomide kills ABC DLBCL cells by increasing IFNproduction. This increase, associated 
with the downregulation of IFN regulatory factor (IRF)-4 and SPIB, prevents IFNproduction 
by repressing IRF7 and amplifying nuclear factor -B [52] [53].
Two early phase clinical studies of the efficacy of lenalidomide monotherapy in subjects with 
relapsed or refractory DLBCL who were not eligible for auto-SCT demonstrated ORRs (CR + 
unconfirmed CR+ partial response [PR]) of 19% (n=5/26) and 28% (n=30/108) [54] [55]. The 
most common Grade 3/4 AEs in these single-agent trials were neutropenia, thrombocytopenia,
and leukopenia. In a comparison of single-agent lenalidomide in subjects with non-germinal 
center B-cell-like (GCB) DLBCL (also termed ABC DLBCL) versus GCB DLBCL, the ORR 
(CR + PR) was significantly higher in the non-GCB group (52.9% [n=9/17]) than in the GCB 
group (8.7% [n=2/23]), p=0.006; CR in the non-GCB group was 29.4% (n=5/17) compared to 
4.3% (n=1/23) in the GCB group [56]. The most common AEs (Medical Dictionary for 
Regulatory Activities 16.0) reported in 2 or more subjects who received lenalidomide (n=54) 
were anemia, febrile neutropenia, DLBCL, pyrexia, pneumonia, urinary tract infection, 
dyspnea, and pulmonary embolism [NCT01197560]. Lenalidomide 25 mg was given orally 
for the first 21 consecutive days within 28-day cycles. Median ages of the subjects ranged from 
65 to 66 years.
Combination treatment with lenalidomide in the DLBCL population has also demonstrated 
efficacy in 5 clinical studies. Three of these studies, which combined lenalidomide with 
 
 
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rituximab, achieved ORRs (CR + PR) of 35% (n=8/23), 28% (n=9/32), and 41.2% (n=7/17), 
and [57] [58] [59]. The most common Grade 3/4 hematologic AEs were neutropenia, 
thrombocytopenia, leukopenia, lymphopenia, and anemia. Subjects were either not eligible to 
receive autoSCT or were censored from the analysis from the time of transplant. 
Lenalidomide 25 mg was given orally for the first 21 consecutive days within 28-day cycles. 
When lenalidomide was combined with rituximab in elderly subjects with DLBCL, the 
lenalidomide dose was reduced to 20 mg. Median ages of subjects in these studies ranged from 
62 to 69 years.
Lenalidomide combined with R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin 
hydrochloride, vincristine sulfate, and prednisone every 3 weeks [Q3W]) in 2 frontline studies 
achieved ORRs (CR + PR) of 98% (95% CI, 91-100) (n=59/60) and 92% (95% CI, 81–97)
(n=45/49) [60] [61]. The most common Grade 3/4 hematologic AEs were neutropenia, 
leukopenia, thrombocytopenia, anemia, and febrile neutropenia. Subjects did not receive auto-
SCT during either study. Lenalidomide 25 mg was given orally for the first 10 consecutive 
days within a 21-day cycle in newly diagnosed subjects, and was reduced to 15 mg given over 
14 days in an elderly population.
R-CHOP-21 comprised rituximab 375 mg/m2, 
cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 (capped at 2.0 
mg), all on day 1; and prednisone 100 mg/m2 per day on days 1 through 5. Median ages of 
subjects ranged from 65 to 75 years.
The most common AEs in the single-agent and combination treatment studies with 
lenalidomide were myelosuppression, with most events reversible with dose modifications.  
Pembrolizumab
Pembrolizumab is a humanized monoclonal antibody that blocks the interaction between PD1 
and its ligands, PD-L1 and PD-L2, and is currently approved for use in the United States for 
unresectable or metastatic melanoma and metastatic NSCLC in tumors that express PD-L1 and 
in the EU for unresectable or metastatic melanoma [62] [63].
The in vitro and in vivo effects of upregulation of PD-1 in various tumor types and in NHL 
have already been described (see Section 4.1 and Section 4.2.1.3). DLBCL is a known 
clinically aggressive type of NHL. Recent studies in the tumor tissue of subjects with DLBCL 
showed variable expression of PD-L1, which was also found in infiltrating macrophages and 
in the tumor environment. Overexpression of PD-L1 in DLBCL has been associated with a 
poor prognosis [64] [65]. Tissue microarray immunostaining showed overexpression of PD-1, 
PD-L1, PD-L2, and lymphocyte-activation gene 3 in FL and DLBCL tumor tissues, with 
DLBCL tumor cells co-expressing PD-1, PDL1 and PDL2. The ABC DLBCL subtype 
comprised more PD-L1 and PD-L2 expressing lymphoma cells than did the GCB subtype [66].
Pembrolizumab has a known AE profile, with most events Grade 3 or lower; the exception in 
clinical studies were rare Grade 4 events of hyperglycemia, increased AST, and anemia. AEs
were primarily managed with dose interruptions and, if immunerelated, treated with 
corticosteroids until resolution.
 
 
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Lenalidomide + Pembrolizumab Combination
In KEYNOTE-023, 33 subjects with relapsed or refractory MM who had failed at least 2 lines 
of prior therapy, including a proteasome inhibitor (e.g., bortezomib or carfilzomib) and an 
immunomodulatory imide drug (IMiD [thalidomide, pomalidomide, lenalidomide), received 
lenalidomide 25 mg daily for 21 days and 7 days off + dexamethasone 40 mg weekly + 
pembrolizumab 200 mg every 2 weeks (Q2W). Determination and confirmation of maximum 
tolerated dose in 17 subjects allowed for a total of 50 subjects to receive the combination. An 
interim efficacy analysis showed an overall response rate for the 17 subjects of 76% (n=13/17)
(CR + Very Good PR + PR), a disease control rate of 88% (n=15/17) (CR + Very Good PR + 
PR + Stable Disease [SD]), and a SD rate of 18% (n=3/17). The most common AEs seen in ≥4 
subjects were neutropenia, thrombocytopenia, diarrhea, fatigue, anemia, pruritis, 
hyperglycemia, muscle spasms, myalgia, constipation, and asthenia; with 46% (n=23/50) 
experiencing hematologic Grade 3/4 toxicities (neutropenia, thrombocytopenia, anemia) with 
6% (n=3/50) experiencing hyperglycemia. No dose modifications or treatment 
discontinuations were required for the management of reported immune-related events. These 
preliminary data suggest that a lenalidomide + dexamethasone + pembrolizumab treatment 
combination has an acceptable safety and tolerability profile [67].
On 
03-JUL-2017, 
the 
US 
FDA 
placed 
on 
clinical
hold 
KEYNOTE-183 
(pembrolizumab/pomalidomide/dexamethasone for refractory or relapsed and refractory MM), 
KEYNOTE-185 (pembrolizumab/lenalidomide/dexamethasone for treatment naïve MM), and 
Cohort 1 of KEYNOTE-023 (pembrolizumab/lenalidomide/dexamethasone for refractory or 
relapsed and refractory MM). The FDA determined that the risks of pembrolizumab plus 
pomalidomide or lenalidomide outweighed any potential benefit for subjects with MM. As of 
Amendment 04 of KEYNOTE-013, use of pembrolizumab as a single agent at a fixed dose of 
200 mg Q3W is ongoing. In Amendment 05, combining lenalidomide with pembrolizumab in 
subjects with DLBCL will explore leveraging the combined known immunomodulatory effects 
of lenalidomide with the effects of pembrolizumab on PD-L1 within a manageable risk profile.
Note: At least 25 subjects will be enrolled in Cohort 4D before Cohort 5 (DLBCL) is opened
for enrollment.
Multiple Myeloma
MM is a malignant neoplasm of plasma cells that accumulate in the bone marrow leading to 
bone destruction and marrow failure. It accounts for 10% of all hematological malignancies, 
with an incidence of 5 cases per 100,000/year and a median age at onset of 65 to 70 years [68] 
[69] [70] [71]. The American Cancer Society has estimated 21,700 new cases of MM in the 
United States in 2012, with an estimated 10,710 deaths [72]. It is diagnosed by the presence of 
monoclonal plasma cell proliferation with more than 10% plasma cells in the bone marrow, 
presence of monoclonal proteins in serum, and/or in urine with one or more of end organ effects 
such as CRAB (hypercalcemia, renal failure, anemia, or bone destruction) [73] [74]. MM is 
responsive to systemic immunotherapy, lenalidomide. Although, improvements in OS have 
been achieved with newer therapies such as proteasome inhibitors and IMiDs, myeloma 
remains an incurable disease. Relapse refractory MM patients have an OS of 9 months, but 
 
 
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only 3 months if they receive no therapy following relapse, thus reflecting the poor outcome 
among these patients [75] [76] [77].
PD-L1 is expressed on most MM plasma cells [78], and PD-L1 overexpression enhanced MM 
invasiveness and rendered tumor cells less susceptible to cytotoxic T lymphocytes (CTLs). 
This effect was alleviated by anti–PD-L1 antibody treatment, demonstrating the importance of 
the PD-1/PD-L1 pathway in this process [79]. In addition, a recent report demonstrated 
increased levels of PD-L1 on MM cells together with enhanced PD-1 expression on T cells 
with an “exhausted” phenotype. The immunosuppressive effects of myeloma are overcome by 
PD-L1 blockade [80]. A Phase 1 clinical trial conducted in advanced hematologic malignancies 
using CT-011, showed clinical responses in 6 of 17 patients including SD in MM patients [46].
Rationale for Dose Selection/Regimen/Modification
Rationale for Dose Selection/Regimen for Pembrolizumab (Cohort 1, 2, 3, 4A, 
4B) 
In the dose escalation phase (1, 3, and 10 mg/kg Q2W) of the first in human study 
(pembrolizumab KEYNOTE-001), target engagement and objective evidence of tumor size 
reduction was noted at all dose levels and a maximum tolerated dose was not reached. PK data 
analysis of pembrolizumab administered Q2W showed slow systemic clearance, limited 
volume distribution, and a long half-life suggesting that peripheral target engagement is 
durable (> 21 days); therefore, the Q3W schedule was initially selected for the program. 
Although, the optimal dose and schedule for pembrolizumab has not been fully defined for 
melanoma or NSCLC, the highest dose evaluated (10 mg/kg Q2W) has been generally well 
tolerated.
Data from Bristol-Myers Squibb suggest that some indications, such as NSCLC, may require 
higher doses than melanoma. Because the optimal dose for new indications in this study cannot 
be fully informed by clinical data, POC will be evaluated using the maximum administered 
dose of 10 mg/kg Q2W. This dose was chosen to generate safety data at the highest possible 
dose and schedule currently in clinical development and may alleviate any doubt about sub-
optimal dose compromising clinical efficacy. 
Rationale for 200 mg Q3W Fixed Dose of Pembrolizumab (Cohort 2, 4A, 4C, 
4D, and 5)
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 evaluating 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 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 (full analysis set [FAS]). The proportion of 
subjects with drug-related AEs, Grade 3 to 5 drug-related AEs, serious drug-related AEs, death 
or discontinuation due to an AE was comparable between groups or lower in the 10 mg/kg 
 
 
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group. In Cohort B3, advanced melanoma subjects (irrespective of prior ipilimumab therapy) 
were randomized to receive MK-3475 at 10 mg/kg Q2W versus 10 mg/kg Q3W. Preliminary 
results demonstrate that the ORR was 32.8% (38/116) in the 10 mg/kg Q2W group and 27.8% 
(30/108) in the 10 mg/kg Q3W group (FAS Population by immune-related response criteria; 
data through 28-FEB-2014). The proportion of subjects with drug-related AEs, Grade 3 to 5 
drug-related AEs, serious drug-related AEs, death or discontinuation due to an AE was 
comparable between groups. Available PK results in subjects with melanoma, NSCLC, and 
other solid tumor types support a lack of meaningful difference in PK exposures obtained at a 
given dose among tumor types. Moreover, population PK analysis has been performed and has 
confirmed the expectation that intrinsic factors do not affect exposure to pembrolizumab (MK-
3475) to a clinically meaningful extent. Importantly, the analysis revealed no significant impact 
of tumor burden on exposure. Taken together, these data support the use of lower doses (with 
similar exposure to 2 mg/kg Q3W) in all solid tumor indications. Selection of 200 mg as the 
appropriate dose for a switch to fixed dosing is based on simulation results indicating that 200 
mg will provide exposures that are reasonably consistent with those obtained with 2 mg/kg 
dose and importantly will maintain individual patient exposures within the exposure range 
established in melanoma as associated with maximal clinical response. A population PK model 
which characterized the influence of body weight and other patient covariates on exposure has 
been developed using available data from 476 subjects from KEYNOTE-001. The distribution 
of exposures from the 200 mg fixed dose are predicted to considerably overlap those obtained 
with the 2 mg/kg dose, with some tendency for individual values to range slightly higher with 
the 200 mg fixed dose. The slight increase in PK variability predicted for the fixed dose relative 
to weight-based dosing is not expected to be clinically important given that the range of 
individual exposures is well contained within the range of exposures shown in the melanoma 
studies of 2 and 10 mg/kg to provide similar efficacy and safety. The population PK evaluation 
revealed that there was no significant impact of tumor burden on exposure. In addition, 
exposure was similar between the NSCLC and melanoma indications. Therefore, there are no 
anticipated changes in exposure between different indication settings. Thus, with the newly 
available rationale for a fixed dose, Cohort 2, 4A, 4C and 4D will explore a fixed dose of 
pembrolizumab 200 mg Q3W in subjects enrolled under Amendment 013-04.
Rationale for Selection of Lenalidomide Dose 
Lenalidomide is currently approved in the United States for the treatment of MM and mantle 
cell lymphoma at a dose of 25 mg orally for 21 consecutive days within a 28-day cycle. 
Lenalidomide at this same dose level was administered as a single agent in subjects with 
DLBCL in recent clinical studies (see Section 4.2.1.3.1). Given the established efficacy of 
lenalidomide at the 25-mg level and the preliminary safety data available for the proposed 
lenalidomide + dexamethasone + pembrolizumab combination seen in KEYNOTE-023, the 
Amendment 013-05 portion of this study will include a safety run-in as described in Section 
5.2.1.3 to confirm the safety and tolerability for lenalidomide daily for 21 days + 7 days off 
when given in combination with pembrolizumab once Q3W without dexamethasone.
 
 
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Rationale for Endpoints
Safety Endpoints
The primary safety objective of this study is to characterize the safety and tolerability of 
pembrolizumab or lenalidomide + pembrolizumab in subjects with hematologic malignancies. 
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 subjects who have received pembrolizumab, or lenalidomide + pembrolizumab, including 
SAEs and events of clinical interest (ECIs).  
Safety will be assessed by reported adverse experiences 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 hematologic malignancies (MDS, MM, HL, and NHL) or 
lenalidomide + pembrolizumab combination in Cohort 5 (DLBCL). 

The primary efficacy endpoint for MDS will be ORR as assessed by the investigator
per the IWG response criteria in MDS [81].  

The primary efficacy endpoint for MM will be ORR as assessed by the investigator per 
IMWG uniform response criteria [82].

The primary efficacy endpoint for HL will be CRR as assessed by the investigator 
Revised Response Criteria for Malignant Lymphoma [83].

The primary efficacy endpoint for NHL will be ORR as assessed by the investigator 
Revised Response Criteria for Malignant Lymphoma [83].  
For lymphoma subjects, radiographic images will also be transferred to an imaging vendor for 
retrospective central review and assessment of response by Revised Response Criteria for 
Malignant Lymphoma if the minimum number of responses required for success for the 
primary hypothesis is observed. For MDS subjects, if the study meets its primary endpoints of 
safety and tolerability and efficacy, sites may be asked to submit/provide slides and 
hematopathology reports for a central review and confirmation.
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 lymphoma 
disease response assessment criteria may not provide a comprehensive response assessment of 
 
 
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immunotherapeutic agents such as pembrolizumab. Therefore, in the setting where a subject’s 
lymphoma disease response assessment shows progressive disease (PD), trial treatment may 
be continued at the discretion of the principal investigator in a subject whose clinical condition 
is stable until repeat imaging performed 4 to 6 weeks later confirms progression. However, 
imaging should occur at any time where there is clinical suspicion of progression. See Section 
7.1.2.7.7 for additional information about the timing of the disease response assessment after 
PD.
Biomarker Research
Bone marrow and lymph node biopsy specimens that are collected will be evaluated at a central 
laboratory for expression status of PD-L1 by IHC. When available, hematopathology reports 
should be submitted to the central laboratory performing the IHC analysis. Additional 
biomarker research to identify factors important for pembrolizumab therapy may also be 
pursued. For example, pre- and post-dose bone marrow biopsies/aspirates, lymph node 
biopsies (lymphoma cohorts only), and blood samples from this study may undergo flow 
cytometric, proteomic, genomic, and transcriptional analyses at a central laboratory. 
Additional research may evaluate factors important for predicting responsiveness or resistance 
to pembrolizumab therapy and other immunologic targets. In addition, biomarker assay 
characterization may be performed to evaluate factors important for the identification of
biomarkers.
Assays may include but are not be limited to:  
Multiplex Flow Cytometric Analysis
Emerging data suggest that blockade of the PD-1/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, T cell subsets in peripheral blood, 
e.g., PD-1+ T cells, effector, memory and regulatory T cells, will be assessed pre- and post-
dose and in both responders and non-responders. In addition, PD-L1 expression on bone 
marrow mononuclear cells of MDS will be tested.  
Multiparametric (Two-Color) IHC
Spatial association of PD-1+ tumor-infiltrating lymphocytes and PD-L1+ cells (tumor and 
myeloid cells) suggests “induction” of PD-L1. Interferon-gamma production by antigen-
specific PD-1+ CD8+ T cells is hypothesized to drive local intratumoral upregulation of PD-
L1 on adjacent tumor and myeloid cells, leading to a “stalled CTL” response which may be 
predictive of response to pembrolizumab therapy. By assessing both of the required elements, 
i.e., PD-L1 positive cells and PD-1+ T cells, a two-color IHC assay may be a better predictor 
of response than PD-L1 positivity alone.
Transcriptional Analyses
Messenger ribonucleic acid (RNA) expression profiling in archival material will be completed
to assess gene expression and to attempt to define a gene set critical for clinical response to 
 
 
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pembrolizumab. The hypothesis to be tested is that pembrolizumab responders will exhibit a 
“stalled CTL” response within the tumor reflected in the physical proximity between PD-1 and 
PD-L1 expression and the presence of an aborted (e.g., weak but discernible) IFN-gamma 
transcriptional program will be detectable by profiling analyses. Global profiling will also be 
pursued. 
Expression of individual genes related to the immune system may also be evaluated such as 
immune signatures and critical cytokines (e.g., interleukin-10).
Gene Sequencing
New data are emerging that suggest we can define certain tumor types as being ‘hypermutated’. 
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.
Future Biomedical Research
Merck will conduct Future Biomedical Research (FBR) on blood, lymph node and bone 
marrow specimens collected during this clinical trial. This research may include genetic 
analyses (deoxyribonucleic acid [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 FBR 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 AEs are identified. Genomic markers of disease may also be investigated. Such 
retrospective PGt 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, and/or to ensure that subjects receive the 
correct dose of the correct drug at the correct time. The details of FBR are presented in Section 
12.2 - Collection and Management of Specimens for FBR. Additional informational material 
for institutional review boards/ethics review committees (IRBs/ERCs) and investigational site 
staff is provided in Section 12.3.
4.3
Benefit/Risk
It cannot be guaranteed that subjects in clinical trials will directly benefit from treatment during 
participation, as clinical trials are designed to provide information about the safety and 
effectiveness of an investigational medicine.
Efficacy and safety information in regard to pembrolizumab are provided in the current version 
of the IB and in regard to lenalidomide are provided in Section 4.2.1.3.1 and per the most 
current local prescribing information.
 
 
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5.0 METHODOLOGY
5.1
Entry Criteria
Diagnosis/Condition for Entry into the Trial
Male/Female subjects with intermediate-1, intermediate-2, or high risk MDS who have failed 
at least 4 cycles of HMA treatment (Cohort 1); relapse refractory or refractory MM (Cohort 
2); relapsed / refractory HL (Cohort 3); relapsed / refractory MLBCL (Cohort 4A); PD-L1 
positive relapsed / refractory NHL (Cohort 4B); irrespective of PD-L1 status, relapsed /
refractory FL (Cohort 4C) or DLBCL (Cohort 4D) or (Cohort 5) 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:
MDS (Cohort 1)
1. Be willing and able to provide written informed consent/assent for the trial. The subject 
may also provide consent/assent for FBR. However, the subject may participate in the main 
trial without participating in FBR.
2. Be 18 years of age on day of signing informed consent.
3. Have primary or secondary MDS with IPSS score of Intermediate-1, Intermediate-2, or 
High and has failed (defined as worsening of cytopenias, increase in percentage of bone 
marrow blasts, or progression to more advanced MDS FAB subtype than pretreatment) to 
respond to at least 4 cycles of prior treatment with a HMA (azacitidine and decitabine).
Per IWG criteria, progression is defined as: 

Less than 5% blasts: 50% increase in blasts to > 5% blasts

5%-10% blasts:   50% increase to > 10% blasts

10%-20% blasts:   50% increase to >20% blasts

20%-30% blasts:   50% increase to > 30% blasts
Or any of the following:

At least 50% decrement from maximum remission/response in granulocytes or platelets

Reduction in Hgb by 2 g/dL

Transfusion dependence
4. Be expected to survive long enough to assess for response or benefit from treatment at 
investigator’s discretion.
5. Have a performance status of 0 or 1 on the ECOG Performance Scale.
 
 
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6. Be able to provide bone marrow biopsy/aspirate material for biomarker analysis or is 
willing to provide a newly obtained bone marrow biopsy/aspirate.  
7. Demonstrate adequate organ function as defined in Table 1, all screening laboratory tests 
should be performed within 7 days of treatment initiation.
Table 1
MDS Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Bone marrow blasts
Blast percentage ≤30% a
White blood cell count
< 30,000 mcL
(Subjects with a rapid increase in WBC indicative of progressive disease 
per investigator’s assessment should be excluded.)
Renal
Creatinine OR
Measured or calculated creatinine 
clearance b
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5X 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  
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 The protocol follows FAB classification which allows inclusion of subjects with blasts percentages up to 30%.  Please 
note that per the 2008 WHO classification, subjects with blast counts of 20-30% are considered AML.
b Creatinine clearance should be calculated per institutional standard.
8. Female subjects of childbearing potential should have a negative urine or serum pregnancy
test within 72 hours prior to receiving the first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
9. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate 
method of contraception as outlined in Section 5.7.2 – Contraception for the course of the 
study through 120 days after the last dose of study medication.
-Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
 
 
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10. Male subjects of childbearing potential (Section 5.7.2) must agree to use an adequate 
method of contraception as outlined in Section 5.7.2 Contraception starting with the first 
dose of study therapy through 120 days after the last dose of study therapy.
-Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
Multiple Myeloma (Cohort 2, enrollment has been completed and no further enrollment 
will be allowed)
11. 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.
12. Be 18 years of age on day of signing informed consent.
13. Has a confirmed diagnosis of multiple myeloma based on standard criteria (see Durie 1986 
for criteria [84]). See Appendix 12.6 for MM Diagnostic Criteria. 
14. Currently has MM with measurable disease, defined as:

a monoclonal immunoglobulin spike on serum electrophoresis of at least 0.5 g/dL 
and/or 

urine monoclonal protein levels of at least 200 mg/24 hours 

for subjects without measurable serum and urine M-protein levels, an abnormal free 
light chain ratio (normal value: 0.26 - 1.65) with involved FLC level ≥10 mg/dL (≥100 
mg/L).
15. Has relapse refractory or refractory MM who has failed at least two lines of prior therapy, 
including a proteasome inhibitor (bortezomib, carfilzomib) and an IMiD (thalidomide, 
pomalidomide, lenalidomide).
a.
Relapse Refractory MM defined as achieving at least a partial response to previous 
treatment with a proteasome inhibitor or an IMiD, or both, but progressed within 6 
months (and had developed progressive disease on or within 60 days after completing 
their last treatment)
b. Refractory MM defined as progressed on or within 60 days of treatment with a 
proteasome inhibitor or an IMiD, or both (and had developed progressive disease on or 
within 60 days after completing their last treatment)
16. Be able to provide archival (if available) and newly obtained bone marrow aspirate/biopsy 
material for biomarker analysis and disease assessment.
17. Must have a performance status of 0 or 1 on the ECOG Performance Scale.
 
 
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18. Must demonstrate adequate organ function as defined by the following table (Table 2). All 
screening laboratory tests should be performed within 7 days of treatment initiation.
Table 2
Multiple Myeloma Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,000 /mcL
Platelets
≥75,000 / mcL 
Hemoglobin
≥8 g/dL 
Renal
Creatinine OR
Measured 
or 
calculated1
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 > 1.5X 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  
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
1 Creatinine clearance should be calculated per institutional standard.
19. Female subjects of childbearing potential should have a negative urine or serum pregnancy
test within 72 hours prior to receiving the first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required.
20. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate 
method of contraception as outlined in Section 5.7.2 – Contraception for the course of the 
study through 120 days after the last dose of study medication.
-Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
21. Male subjects of childbearing potential (Section 5.7.2) must agree to use an adequate 
method of contraception as outlined in Section 5.7.2 – Contraception starting with the first 
dose of study therapy through 120 days after the last dose of study therapy.
-Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
 
 
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Hodgkin Lymphoma (Cohort 3); Mediastinal Large B-Cell Lymphoma (Cohort 4A); any 
other PD-L1 positive Non-Hodgkin Lymphoma (Cohort 4B); Follicular Lymphoma 
(Cohort 4C); or Diffuse Large B-Cell Lymphoma (Cohort 4D) and (Cohort 5, enrollment 
has been discontinued and no further enrollment will be allowed).
22. 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.
23. Be 18 years of age on day of signing informed consent.
24. Have relapsed / refractory nodular sclerosing or mixed cellularity Hodgkin lymphoma, 
relapsed / refractory mediastinal large B cell lymphoma, relapsed / refractory PD-L1 
positive non-Hodgkin lymphoma, or irrespective of PD-L1 status, non-Hodgkin lymphoma 
subjects with relapsed / refractory Follicular Lymphoma (FL) or Diffuse Large B-Cell 
Lymphoma (DLBCL). Subjects must have failed, are ineligible for, or refused a stem cell 
transplant (where stem cell transplant is standard of care). Hodgkin lymphoma subjects 
must have relapsed after treatment with or failed to respond to Brentuximab vedotin.
-Note:  Amendment 013-04 will exclusively enroll subjects with relapsed / refractory 
MLBCL, FL or DLBCL NHL subtypes. 
25. 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 by > 10 mm in the short axis.
26. Cohort 3, 4A, 4C, 4D, and 5:  Be able to provide a core or excisional lymph node biopsy 
for biomarker analysis from an archival or newly obtained biopsy at Screening. In addition,
be able to provide additional biopsy at Week 12. 
27. For Cohort 4B (PD-L1 positive relapsed / refractory NHL) only: PD-L1 positivity must be 
confirmed by IHC from an archival sample (if available) or from a newly obtained lymph 
node biopsy (excision or core needle biopsy) prior to study entry. In addition these subjects 
must be able to provide additional biopsy material at Screening and the completion of 
Cycle 7.  
28. Must have a performance status of 0 or 1 on the ECOG Performance Scale.
29. Must demonstrate adequate organ function as defined in Table 3, all screening laboratory 
tests should be performed within 7 days of treatment initiation.  
 
 
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Table 3
Lymphoma Adequate Organ Function Laboratory Values
System
Laboratory Value
Hematological
Absolute neutrophil count (ANC)
≥1,000 /mcL
Platelets
≥75,000 / mcL
Hemoglobin
≥8 g/dL 
Renal
Creatinine OR
Measured or calculated a 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
Serum albumin
> 3.0 g/dL
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.
30. Have a life expectancy > 3 months
31. Female subjects of childbearing potential should have a negative urine or serum pregnancy
test within 72 hours prior to receiving the first dose of study medication or per local 
requirements as described in the current version of the lenalidomide prescribing 
information. If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required.
32. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate 
method of contraception as outlined in Section 5.7.2 – Contraception for the course of the 
study through 120 days after the last dose of study medication.
-Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
 
 
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33. Male subjects of childbearing potential (Section 5.7.2) must agree to use an adequate 
method of contraception as outlined in Section 5.7.2 – Contraception starting with the first 
dose of study therapy through 120 days after the last dose of study therapy.
-Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject.
Non-Hodgkin Lymphoma Diffuse Large B Cell Lymphoma (Cohort 5, enrollment has 
been discontinued and no further enrollment will be allowed)
34. Must demonstrate adequate renal function as confirmed by both a creatinine ≤1.5 times 
the upper limit of normal (ULN) and a creatinine clearance ≥60 mL/min obtained per 
institutional standards.
35. Must be willing to use thromboprophylaxis as selected by the investigator.
36. All subjects must agree to follow the regional requirements for lenalidomide counseling, 
pregnancy testing, and birth control; and be willing and able to comply with the regional 
requirements (for example, periodic pregnancy tests, safety laboratory tests, etc.).
Subject Exclusion Criteria
The subject must be excluded from participating in the trial if the subject:
MDS (Cohort 1)
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 
weeks of the first dose of treatment.
2. Is currently receiving treatment with any colony stimulating factors including G-CSF, GM-
CSF, erythropoietin, and other hematopoietic cytokines within 2 weeks of enrollment into 
trial.
3. Has active autoimmune disease that has required systemic treatment in past 2 years (i.e.,
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.
4. Has received a monoclonal antibody within 4 weeks prior to study Day 1 or has not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered 
more than 4 weeks earlier. 
5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 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.
 
 
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-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.
6. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 
years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as
there are no symptoms of graft-versus-host-disease [GVHD]).
7. 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.
8. Has known clinically active CNS involvement.
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 Human Immunodeficiency Virus (HIV), Hepatitis B (HBV) (e.g., HBsAg 
reactive), or Hepatitis C (HCV) (e.g., HCV RNA [qualitative] is detected) infection.
15. Has known symptomatic congestive heart failure, unstable angina pectoris, or cardiac 
arrhythmia.
16. Has received a live vaccine within 30 days prior to first dose.
Multiple Myeloma (Cohort 2)
17. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 
weeks of the first dose of treatment.
18. Has myeloma and a history of repeated infections, primary amyloidosis, hyperviscosity, 
plasma cell leukemia, POEMS syndrome, Waldenström's macroglobulinemia, or IgM 
myeloma. 
 
 
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19. Has active autoimmune disease that has required systemic treatment in past 2 years (i.e.,
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).  
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.
20. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered 
more than 4 weeks earlier. 
21. Has had prior chemotherapy (including dexamethasone), targeted small molecule therapy, 
or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 
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 trial.
-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 2.
22. 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.
23. Has known clinically active CNS involvement.
24. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis. 
25. Has an active infection requiring intravenous systemic therapy.
26. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
27. 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.
28. 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).
29. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV) (e.g., HBsAg 
reactive), or Hepatitis C (HCV) (e.g., HCV RNA [qualitative] is detected) infection.
30. Has a clinically significant coagulopathy per investigator’s assessment.
 
 
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31. Has known symptomatic congestive heart failure, unstable angina pectoris, or cardiac 
arrhythmia.
32. Has received an allogeneic stem cell transplant 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.)
33. Has received autologous stem cell transplant within 12 weeks before the first infusion. 
34. Is planning for or is eligible for allogeneic hematopoietic stem cell transplant.
35. Has received a live vaccine within 30 days prior to first dose.
Hodgkin Lymphoma (Cohort 3); Mediastinal Large B-Cell Lymphoma (Cohort 4A); any 
other PD-L1 positive Non-Hodgkin Lymphoma (Cohort 4B); Follicular Lymphoma
(Cohort 4C); or Diffuse Large B-Cell Lymphoma (Cohort 4D) and (Cohort 5).
36. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 
weeks of the first dose of treatment.
37. Has active autoimmune disease that has required systemic treatment in past 2 years (i.e.,
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.
38. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not 
recovered (i.e. ≤ Grade 1 or at baseline) from adverse events due to agents administered 
more than 4 weeks earlier. 
39. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 
2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ 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 3.
40. 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.)
 
 
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41. 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.  
42. Has known clinically active CNS involvement.  
43. Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis.
44. Has an active infection requiring intravenous systemic therapy.
45. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial.
46. 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.
47. 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).
48. Has a known Human Immunodeficiency Virus (HIV), Hepatitis B (HBV) (e.g., HBsAg 
reactive), or Hepatitis C (HCV) (e.g., HCV RNA [qualitative] is detected) infection.
49. Has known symptomatic congestive heart failure, unstable angina pectoris, or cardiac 
arrhythmia.
50. Has received a live vaccine within 30 days prior to first dose.  
5.2
Trial Treatments
The treatment to be used in this trial is outlined below in Table 4.
 
 
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Table 4
Trial Treatment
Drug & Cohort 
Dose/Potency
Dose 
Frequency
Route of 
Administration
Regimen/Treatment 
Period
Use
Pembrolizumab
Cohort 1, 2, 3, 4A, 
and 4B
10 mg/kg
Q2W
IV infusion
Day 1 of each cycle
Experimental
Pembrolizumab
Cohort 2, 4A, 4C, 
4D 
200 mg*
Q3W
IV infusion
Day 1 of each cycle
Experimental 
Lenalidomide
+
Pembrolizumab
Cohort 5
(DLBCL)**
25 mg
or
RP2D
200 mg
Daily 
Q3W
Oral
IV infusion
First 21 consecutive 
days + 7 days off 
Every 21 days 
The cycle length = 
28 days
Experimental
Abbreviations: DLBCL=diffuse large B-cell lymphoma; IV=intravenous; Q2W=every 2 weeks; 
Q3W=every 3 weeks; RP2D=recommended Phase II dose.
See Section 5.2.3 for the expected duration of treatment.
*Applicable after amendment 013-04.
**Applicable after amendment 013-05.
All trial treatments will be administered on an out-patient basis.
All products indicated in Table 4 will be provided centrally by the Sponsor or locally by the 
trial site, subsidiary or designee, depending on local country operational or regulatory 
requirements.
For any commercially available product that is provided by the trial site, subsidiary, or 
designee, every attempt will be made to source these supplies from a single lot/batch number.  
The trial site is responsible for recording the lot number, manufacturer, and expiry date for any 
locally purchased product as per local guidelines unless otherwise instructed by the Sponsor.
Dose Selection/Modification
Dose Selection
The rationale for selection of doses to be used in this trial is provided in Section 4.2.2 Rationale 
for Dose Selection/Regimen/Modification.  
The dose amount required to prepare the pembrolizumab infusion solution will be based on the 
subject’s weight in kilograms (kg) for all subjects receiving 10 mg/kg Q2W in Cohort 1, 2, 3, 
4A and 4B enrolled prior to approval of Amendment 013-04. Subjects enrolled in Cohort 2, 
4A, 4C and 4D under Amendment 013-04 or 013-05 will receive 200 mg Q3W.  Subjects 
enrolled in Cohort 5 (DLBCL) will be allocated to receive pembrolizumab 200 mg 
administered intravenously once every 21 days in combination with lenalidomide taken orally 
once daily for 21 days + 7 days off.  The cycle length is 28 days.  Details on the dose 
calculation, preparation, and administration of pembrolizumab are provided in the Pharmacy 
 
 
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Manual.  For additional information regarding lenalidomide, please refer to the current version 
of the local prescribing information.
Dose Modification for Pembrolizumab
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
irAEs may occur shortly after the first dose or several months after the last dose of 
pembrolizumab treatment and may affect more than on body system simultaneously. 
Therefore, early recognition and initiation of treatment is critical to reduce complications. 
Based on existing clinical trial 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. Dose modification and toxicity management 
guidelines for irAEs associated with pembrolizumab are provided in Table 5.
 
 
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Table 5
Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab 
General instructions:
1.
Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks.
2.
For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤ 10 mg prednisone or equivalent per day within 12 weeks. 
3.
For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should 
be initiated if irAEs cannot be controlled by corticosteroids.
Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action 
taken 
to 
pembrolizumab
irAE 
management 
with 
corticosteroid and/or other therapies 
Monitor and follow-up 
Pneumonitis 
Grade 2
Withhold 

Administer corticosteroids (initial 
dose of 1-2mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of pneumonitis

Evaluate 
participants 
with 
suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment

Add prophylactic antibiotics for opportunistic 
infections
Grade 3 or 4, or 
recurrent grade 2
Permanently 
discontinue
Diarrhea / colitis 
Grade 2 or 3
Withhold

Administer corticosteroids (initial 
dose of 1-2mg/kg prednisone or 
equivalent) followed by taper

Monitor participants for signs and symptoms 
of enterocolitis (i.e., diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (i.e., peritoneal signs 
and ileus).

Participants 
with 
≥ 
Grade 
2 
diarrhea 
suspecting 
colitis 
should 
consider 
GI 
consultation and performing endoscopy to rule 
out colitis. 

Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion.
Grade 4
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action 
taken 
to 
pembrolizumab
irAE 
management 
with 
corticosteroid and/or other therapies 
Monitor and follow-up 
AST 
/ 
ALT 
elevation 
or 
Increased 
Bilirubin
Grade 2
Withhold

Administer corticosteroids (initial 
dose of 0.5- 1mg/kg prednisone or 
equivalent) followed by taper

Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable
Grade 3 or 4 
Permanently 
discontinue

Administer corticosteroids (initial 
dose of 1-2mg/kg prednisone or 
equivalent) followed by taper
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia
Newly 
onset 
T1DM or 
Grade 
3 
or 
4 
hyperglycemia 
associated 
with 
evidence of -cell 
failure
Withhold

Initiate insulin replacement therapy 
for participants with T1DM 

Administer anti-hyperglycemic in 
participants with hyperglycemia 

Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes.
Hypophysitis
Grade 2
Withhold

Administer 
corticosteroids 
and 
initiate hormonal replacements as 
clinically indicated.  

Monitor 
for 
signs 
and 
symptoms 
of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue1
Hyperthyroidism 
Grade 2
Continue 

Treat 
with 
non-selective 
beta-
blockers 
(e.g.,
propranolol) 
or 
thionamides as appropriate 

Monitor for signs and symptoms of thyroid 
disorders. 
Grade 3 or 4 
Withhold or 
Permanently 
discontinue1
Hypothyroidism
Grade 2-4
Continue 

Initiate 
thyroid 
replacement 
hormones (e.g., levothyroxine or 
liothyronine) per standard of care

Monitor for signs and symptoms of thyroid 
disorders. 
Nephritis 
and 
renal dysfunction
Grade 2
Withhold 

Administer 
corticosteroids 
(prednisone 
1-2mg/kg 
or 
equivalent) followed by taper.

Monitor changes of renal function
Grade 3 or 4 
Permanently 
discontinue
 
 
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Immune-related 
AEs
Toxicity grade or 
conditions 
(CTCAEv4.0)
Action 
taken 
to 
pembrolizumab
irAE 
management 
with 
corticosteroid and/or other therapies 
Monitor and follow-up 
Myocarditis
Grade 1 or 2
Withhold

Based on severity of AE administer 
corticosteroids

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3 or 4
Permanently 
discontinue
All 
Other 
immune-related 
AEs
Intolerable/ 
persistent Grade 2
Withhold

Based on type and severity of AE 
administer corticosteroids 

Ensure adequate evaluation to confirm 
etiology and/or exclude other causes
Grade 3
Withhold 
or 
discontinue 
based 
on the type of event.  
Events that require 
discontinuation 
include 
and 
not 
limited to:  Guillain-
Barre 
Syndrome, 
encephalitis
Grade 
4 
or 
recurrent Grade 3 
Permanently 
discontinue
Abbreviations: AE=adverse event; ALT=alanine transaminase; AST=aspartate transaminase; CTCAE=Common Terminology Criteria for Adverse Events; GI=gastrointestinal; 
irAE=immune-related adverse event; IV=intravenous; T1DM=type 2 diabetes mellitus.
1.
Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.  
NOTE: 
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed when 
AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).  
Pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities (exception MDS) as per Table 6 below.  
 
 
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Table 6
Dose Modification Guidelines for Hematological Pembrolizumab-Related 
Adverse Events
Toxicity
Grade
Hold 
Treatment 
(Y/N)
Timing for 
restarting 
treatment
Discontinue Subject (after 
consultation with Sponsor)
Hematological Toxicity
1, 2, 3
No
N/A
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
Abbreviations: N=no; N/A=not applicable; Y=yes
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, subject vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the subject’s study record.
Cohort 5 (DLBCL) Lenalidomide + Pembrolizumab Combination Therapy:
Safety Run-in and Expansion
The safety evaluation for subjects enrolled in Cohort 5 (DLBCL) will include Part 1 (safety 
run-in) for a maximum of 12 subjects per dose level of lenalidomide. Once RP2D is established 
at the end of Part 1, Part 2 (expansion) will enroll up to approximately 30 subjects treated at 
the RP2D. With 4 potential doses of lenalidomide to be evaluated, the sample size can range 
from approximately 30 to 66 subjects for this cohort. 
5.2.1.3.1 Part 1: Safety Run-In
Amendment 013-05 is using a design based on the toxicity probability intervals method [85].
DLTs will be used to determine the dose level of lenalidomide used in the safety run-in. 
Pembrolizumab 200 mg is to be administered intravenously once every 21 days in combination 
with lenalidomide taken orally once daily for 21 days + 7 days off. The cycle length is 28 days.
Only the lenalidomide dose level will be reduced by 5-mg increments to a dose no lower than 
10 mg; i.e., the dose of pembrolizumab is fixed at 200 mg. 
The safety run-in will begin with an enrollment of 6 subjects treated at an initial level of 25 mg 
lenalidomide. The number of subjects who are evaluable for DLT (columns) versus the number 
of subjects who developed a DLT during Cycle 1 (rows) will be continuously assessed as 
shown in Table 7 below as follows:
1) If 2 or fewer of the 6 subjects at the initial level develop a DLT, then enrollment would 
continue at this level following the rules of the table. There is no elevation beyond 25 
mg lenalidomide, so that an “E” (escalate) is considered an “S” (stay) at that dose level. 
 
 
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If a “D” (de-escalate) is reached, then lenalidomide will be reduced to 20 mg and a new 
cohort of 6 subjects will be enrolled at that level.  
2) If 3 of the 6 subjects at the initial level develop a DLT, then a new cohort of 6 subjects 
would be assessed at the 20 mg lenalidomide level, again following the rules of the 
table starting at the column for 6 subjects, where an “E” would trigger an increase back 
to the 25 mg lenalidomide level and evaluation would resume at the number of subjects 
where it previously left off. If “D” is reached in the table, then a new cohort of 6 
subjects would be assessed at the 15 mg lenalidomide level analogously, with further 
de-escalation to 10 mg lenalidomide if indicated (based on a “D” reached for the 15 mg 
lenalidomide table).
3) If 4 or more of the 6 (or fewer) subjects at the initial level develop a DLT, then that 
level is considered unacceptable (“DU”) and a new cohort of 6 subjects would be 
assessed at the 20 mg lenalidomide level as described above. There is no re-escalation 
allowed to a dose level that was found unacceptable (“DU”) according to the table.
Once a DLT is observed, the number of subjects who are enrolled at that dose but are not yet 
fully evaluable for DLT assessment may not exceed the number of remaining subjects who are 
at risk of developing a DLT before the dose would be considered unacceptably toxic (denoted 
as DU in Table 7). For example, if 2/6 subjects have experienced a DLT at a given dose level, 
no more than an additional 4 subjects should be enrolled at this dose level until additional DLT 
data are available. This is because this dose level would be considered unacceptably toxic if 
all 4 of the additional subjects experience a DLT (i.e., 6/10 subjects with DLT in Table 7). To 
find out how many more subjects can be enrolled, one can count steps in diagonal direction 
(down and to the right) from the cell to the first cell marked DU.
Enrollment would continue until 12 subjects have been evaluated in at least one dose level. 
When ≤5 of the 12 subjects at a given dose level develop a DLT, then that dose level is taken 
as the lenalidomide RP2D with pembrolizumab 200 mg. Thus, the RP2D for lenalidomide 
could be 25, 20, 15, or 10 mg depending on the guidance below.  
All decisions regarding dose levels for subject enrollment and dosing will be made by the 
Sponsor and communicated to the investigators. Note that while 30% has been the target 
toxicity rate used to generate the guidelines in Table 7, the observed rate of subjects with DLT 
at the RP2D may be slightly above or below 30%.
 
 
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Table 7
Monitoring Guidance in Dose Evaluation (Target DLT Rate of 30%)
Number of Toxicities
Number of subjects treated at current dose level
6
7
8
9
10
11
12
0
E
E
E
E
E
E
E
1
E
E
E
E
E
E
E
2
S
S
E
E
E
E
E
3
D
S
S
S
S
S
E
4
DU
D
D
S
S
S
S
5
DU
DU
DU
D
D
D
S
6
DU
DU
DU
DU
DU
DU
D
7
DU
DU
DU
DU
DU
DU
8
DU
DU
DU
DU
DU
9
DU
DU
DU
DU
10
DU
DU
DU
E = Escalate to the next higher dose level
S = Stay at the current dose level
D = De-escalate to the next lower dose level
DU = Current dose level is unacceptably toxic
Target DLT rate = 30%; a=.005, b=.005, k1=1.1; k2=0.5; pow=1
Source:  [86]
After reaching the RP2D according to the design above, enrollment in the expansion portion 
will be started, with additional patients treated at the RP2D to achieve 30 subjects treated at 
that dose (inclusive of those treated at that dose during the safety run-in).
5.2.1.3.2 Part 2: Expansion
During the expansion portion of Cohort 5 (DLBCL), the RP2D level of lenalidomide taken
once daily for 21 consecutive days + 7 days off will be administered in combination with
pembrolizumab 200 mg once every 21 days. The maximum number of subjects to be enrolled 
in the expansion portion will be 30 subjects, including those treated at the RP2D during 
Part 1.
Safety will be evaluated as described in Section 7.2.  
Subjects enrolled in the safety-run-in who do not experience DLTs will remain on their initial 
dose regardless of the RP2D established for the trial.
5.2.1.3.3 Definition of Dose-Limiting Toxicities 
All toxicities will be graded using NCI CTCAE, version 4.0 (Section 12.5).
All subjects enrolled during safety run-in will complete all doses of study drug for Cycle 1 
before the additional subjects are enrolled.
 
 
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The occurrence of any of the following toxicities during the safety run-in for subjects enrolled 
in Cohort 5 (DLBCL) will be considered a DLT if judged by the investigator as related to 
lenalidomide or pembrolizumab. 

Grade 4 non-hematologic toxicity (not laboratory).

Grade 4 hematologic toxicity lasting ≥7 days, except thrombocytopenia
o
Grade 4 thrombocytopenia of any duration
o
Grade 3 thrombocytopenia if associated with bleeding

Febrile neutropenia Grade 3 or Grade 4.

The use of colony stimulating factor G-CSF for neutropenia.

Grade 3 non-hematologic toxicity (not laboratory) will be considered a DLT, with the 
exception of Grade 3 nausea, vomiting, or diarrhea, which will not be considered a 
DLT unless lasting more than 3 days despite optimal supportive care.

Any Grade 3 non-hematologic laboratory value if: 
o
medical intervention is required to treat the subject, or
o
the abnormality leads to hospitalization, or
o
the abnormality persists for >1 week.

Any drug-related AE that causes a subject to discontinue treatment during Cycle 1.

Grade 5 toxicity.

Any treatment-related toxicity that causes a greater than 1 week delay in initiating 
Cycle 2.

Unable to complete at least 80% of either of the 2 treatments during the first course of 
therapy due to treatment-related toxicity (even if not meeting above DLT criteria).
5.2.1.3.4 Dose Modification for Lenalidomide 
Lenalidomide must be withheld for drug-related toxicities and severe or life-threatening AEs 
as per Table 8.
 
 
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Table 8
Dose Modification Guidelines for Hematologic Lenalidomide-Related 
Adverse Events
Toxicity
Grade
Hold Treatment (Y/N)
Timing for restarting 
treatment
Thrombocytopenia
1 or 2
N
Continue to monitor CBC as 
per protocol.
3 or 4
Y
Follow CBC weekly
until 
platelet 
count 
returns 
to 
≥50,000 mcL.
Resume lenalidomide at 5 mg 
less than the previous dose. 
If 
the 
reduced 
dose 
of 
lenalidomide falls below 10
mg, Sponsor consultation is 
required 
to 
continue 
the 
subject 
on 
lenalidomide 
treatment.
Neutropenia
1 or 2
N
Continue to monitor CBC as 
per protocol.
3 for at least 7 
days
OR
4
Y
Follow CBC weekly
until 
neutrophil count returns to 
≥1,000 mcL.
Resume lenalidomide at 5 mg 
less than the previous dose. 
If 
the
reduced
dose 
of 
lenalidomide falls below 10
mg, Sponsor consultation is 
required 
to 
continue 
the 
subject 
on 
lenalidomide 
treatment.
Febrile neutropenia
3
Y
Follow CBC weekly
until 
neutrophil count returns to 
≥1,000 mcL.
Resume lenalidomide at 5 mg 
less than the previous dose. 
If 
the 
reduced 
dose 
of 
lenalidomide falls below 10
mg, Sponsor Consultation is 
required 
to 
continue 
the 
subject 
on 
lenalidomide 
treatment.
4
Y
Discontinue 
lenalidomide 
permanently.
Abbreviations: CBC=complete blood cell count; N=no; Y=yes.
 
 
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Dose Modification Guidelines for Non-Hematologic Lenalidomide-Related Adverse 
Events
Hold treatment for non-hematologic Grade 3/4 toxicities judged to be related to lenalidomide. 
When the toxicity has resolved to ≤Grade 2, restart lenalidomide at 5 mg less than the previous 
dose. If the reduced dose of lenalidomide falls below 10 mg, Sponsor Consultation is required 
to continue the subject on lenalidomide treatment.    
In subjects in Cohort 5 (DLBCL) who experience a decrease in renal function, the most current
version of the local prescribing information should be followed.
5.2.1.3.5 Replacement of Subjects During Safety Run-in
In order to determine safety, all subjects selected must meet the criteria for evaluability in 
Cycle 1. Subjects are considered non-evaluable for DLT assessment and will be replaced if:

they are allocated but not treated,

they discontinue from the trial prior to completing Cycle 1 for reasons other than 
treatment-related AEs (if a subject experiences a DLT and does not complete Cycle 1 
for any reason this subject will be considered evaluable for DLT assessment), they 
received <90% of the total pembrolizumab infusion in Cycle 1 (e.g., because the 
infusion had to be discontinued due to an infusion reaction) and did not experience a 
DLT, 

they received <80% of lenalidomide doses in Cycle 1 for reasons other than treatment-
related AEs.
Non-evaluable subjects will not be counted toward the cohort total for DLT evaluation.
If a subject experiences a DLT in Cycle 1, the dose of lenalidomide may be reduced or 
lenalidomide can be discontinued only after discussion and agreement between the Sponsor 
and investigator. However, if the subject is deriving clinical benefit from pembrolizumab, the 
subject may be allowed to continue on pembrolizumab as described in Section 7.1.2.7.7.
Timing of Dose Administration
Pembrolizumab should be administered on Day 1 of each cycle for subjects receiving 
pembrolizumab monotherapy after all procedures/assessments have been completed as 
detailed on the Trial Flow Chart (Section 6.0). Pembrolizumab may be administered up to 3 
days before or after the scheduled Day 1 of each cycle due to administrative reasons.
All trial treatments will be administered on an outpatient basis. Administration during in-
patient hospitalization requires Sponsor consultation.
Pembrolizumab will be administered as a 30 minute IV infusion. Sites should make every effort 
to target infusion timing to be as close to 30 minutes as possible. However, given the variability 
 
 
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of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted (i.e., 
infusion time is 30 minutes: -5 min/+10 min).
The Pharmacy Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration.
Subjects in Cohort 5 (DLBCL) will receive pembrolizumab 200 mg administered 
intravenously once every 21 days in combination with lenalidomide taken orally once daily for 
21 days + 7 days off.  The cycle length is 28 days. After RP2D is established for Cohort 5
(DLBCL), treatment should continue for 26 cycles or until confirmed disease progression or 
unacceptable toxicity. 
Because a subject treated with PD-1 inhibitors may have pseudoprogression of disease (there 
is progression per imaging, but the subject is clinically stable or improving), confirmation of 
progression should be conducted as follows:
After the first documentation of progression at Week 12, it is at the discretion of the 
investigator to keep a clinically stable subject on trial treatment or to stop trial treatment until 
a disease response assessment performed 4 to 6 weeks later confirms progression. 
Clinical stability may be defined as:
1) Absence of symptoms and signs indicating clinically significant progression of 
disease (including worsening of laboratory values) with the exception of M-protein 
elevation for the multiple myeloma cohort.
2) No decline in ECOG performance status.
3) Absence of rapid progression of disease or progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent medical intervention.
Subjects that are deemed clinically unstable are not required to have a confirmation 
assessment.  
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
no other anti-tumor therapy (e.g., chemotherapy, radiation, etc.) has been administered.
Subjects should have their next disease response assessment as detailed in the Trial Flow Chart 
(see Section 6.0). When feasible, subjects should not be discontinued until progression is 
confirmed.
For subjects who have SD, partial response, or CR following the disease response assessment 
at Week 12, a confirmation assessment is not required.  Disease assessments and imaging 
should continue per the regular frequency.  
 
 
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Extent of Treatment

Subjects receiving pembrolizumab monotherapy who experience a partial response or 
have SD may remain on treatment until unacceptable toxicity or progression. Subjects 
receiving pembrolizumab monotherapy Q3W may receive up to 35 doses; subjects 
receiving pembrolizumab monotherapy Q2W may receive up to 52 doses.

Per the investigator’s discretion, subjects receiving pembrolizumab monotherapy who 
achieve a CR or sCR (MDS subjects must meet both bone marrow and peripheral blood 
criteria for CR; MM subjects must achieve a sCR) may stop treatment after 24 weeks
provided that there are two doses received after the CR was documented. These 
subjects, with the exception of subjects in Cohort 2 (MM) who are not allowed, are 
eligible to restart treatment upon documented progression as long as they meet 
eligibility criteria specified in the protocol (See Section 7.1.5.2.1).  

Subjects receiving pembrolizumab monotherapy who achieve a CR or sCR and choose 
not to stop therapy may continue treatment until progression. Subjects receiving 
pembrolizumab monotherapy Q3W may receive up to 35 doses; subjects receiving 
pembrolizumab monotherapy Q2W may receive up to 52 doses.

Subjects in Cohort 5 (DLBCL) who receive lenalidomide + pembrolizumab and 
achieve a PR or SD response may remain on treatment for up to 26 cycles or until 
unacceptable toxicity or progression. Note: Cohorts 5 has been discontinued and all 
subjects must stop combination treatment immediately, complete the discontinuation 
visit, and move into the long-term safety and survival follow-up per protocol. If 
clinically benefitting at time of stopping combination therapy, subjects may enter a 
transition period remaining on single agent lenalidomide or pembrolizumab for up to 
90 days from 15-SEP-2017 and then must transition into long-term survival and safety 
follow-up.

Per the investigator’s discretion, subjects who achieve a CR in Cohort 5 (DLBCL) may 
stop treatment after 24 weeks provided they receive an additional 21 consecutive daily 
doses of lenalidomide + 2 doses of pembrolizumab after CR was documented.  These 
subjects are eligible to restart treatment upon documented progression as long as they 
meet eligibility criteria specified in the protocol (See Section 7.1.5.2.1). Note: Cohorts 
5 has been discontinued and all subjects must stop combination treatment immediately, 
complete the discontinuation visit, and move into the long-term safety and survival 
follow-up per protocol. If clinically benefitting at time of stopping combination 
therapy, subjects may enter a transition period remaining on single agent lenalidomide 
or pembrolizumab for up to 90 days from 15-SEP-2017 and then must transition into 
long-term survival and safety follow-up. Subjects who achieve a CR in Cohort 5 will 
not be eligible any longer to restart treatment.
 
 
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Trial Blinding/Masking
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered.
5.3
Randomization or Treatment Allocation
Subjects participating in this trial will be allocated to trial treatment by non-random 
assignment. 
5.4
Stratification
No stratification based on age, sex or other characteristics will be used in this trial.
5.5
Concomitant Medications/Vaccinations (allowed & prohibited)
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  Listed below are some specific restrictions for concomitant therapy 
or vaccination during the course of the trial.  If there is a clinical indication for one of these or 
other medications or vaccinations specifically prohibited during the trial, discontinuation from 
trial therapy or vaccination may be required.  The investigator should discuss any questions 
regarding this with the local Clinical Monitor.  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 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 case report form.  Subject may remain on anti-coagulation 
therapy as long as the prothrombin time or partial thromboplastin time is within therapeutic 
range of the intended use of anticoagulants.
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2.
For subjects enrolled in Cohort 5 (DLBCL), digoxin should be administered with caution. 
Please refer to the current version of the local prescribing information for lenalidomide for 
additional information.  
 
 
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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 

GM-CSF

Immunotherapy not specified in this protocol (IV Ig therapy is permissible)

Chemotherapy not specified in this protocol

Investigational agents other than pembrolizumab or lenalidomide

Radiation therapy 
o
Note: Radiation therapy to a symptomatic solitary lesion, plasmacytoma, bone 
lesions, or to the brain may be allowed after consultation with Sponsor.  

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, Bacille 
Calmette-Guerin, and oral typhoid vaccine. Seasonal influenza vaccines for injection 
are generally killed virus vaccines and are allowed; however intranasal influenza 
vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

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.
o
Note: Steroid premedications for contrast CTs are permissible.
Subjects who, in the assessment by the investigator, 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.
5.6
Rescue Medications & Supportive Care
Supportive Care Guidelines for Pembrolizumab
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of AEs with 
 
 
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potential immunologic etiology are outlined in Section 5.2.1.2. Where appropriate, these 
guidelines include the use of oral or IV treatment with corticosteroids as well as additional 
anti-inflammatory agents if symptoms do not improve with administration of corticosteroids. 
Note that several courses of steroid tapering may be necessary as symptoms may worsen when 
the steroid dose is decreased. For each disorder, attempts should be made to rule out other 
causes such as metastatic disease or bacterial or viral infection, which might require additional 
supportive care. The treatment guidelines are intended to be applied when the investigator
determines the events to be related to pembrolizumab. 
-Note: if after the evaluation the event it is determined not to be related to pembrolizumab, the 
investigator does not need to follow the treatment guidance. Refer to Table 5 in Section 5.2.1 
for guidelines regarding dose modification and supportive care. 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab
Pembrolizumab may cause severe or life threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. 
Dose modification and toxicity management guidelines on pembrolizumab associated infusion 
reaction are provided in Table 9. 
 
 
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Table 9
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 (e.g., 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 
(e.g., 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 
(i.e., 
not 
rapidly 
responsive 
to 
symptomatic 
medication 
and/or 
brief 
interruption 
of 
infusion); 
recurrence of symptoms following 
initial 
improvement; 
hospitalization indicated for other 
clinical 
sequelae 
(e.g., 
renal 
impairment, pulmonary infiltrates)
Grade 4:
Life-threatening; 
pressor 
or 
ventilatory support indicated
Stop Infusion.
Additional appropriate medical therapy may 
include but is not limited to:
IV fluids
Antihistamines
NSAIDS
Acetaminophen
Narcotics
Oxygen
Pressors
Corticosteroids
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.
No subsequent dosing
Abbreviations: CTCAE=Common Terminology Criteria for Adverse Events; IV=intravenous; NCI=National Cancer 
Institute; NSAIDs=non-steroidal anti-inflammatory drugs.
Appropriate resuscitation equipment should be available in the room and a physician readily available during the 
period of drug administration.
 
 
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Supportive Care Guidelines for Lenalidomide
Supportive care for lenalidomide toxicities is summarized below. Follow the guidance 
provided in the current version of the lenalidomide local prescribing information for updated 
information related to supportive care for Grade 3 or Grade 4 AEs related to lenalidomide.  

Hematologic: Subjects may require dose interruption and/or dose reduction. In the 
mantle cell lymphoma trial, Grade 3 or 4 neutropenia was reported in 43% of the 
subjects. Grade 3 or 4 thrombocytopenia was reported in 28% of the subjects.
o
Neutropenia: Monitor subjects with neutropenia for signs of infection, and treat 
appropriately.
o
Thrombocytopenia: Advise subjects to observe for bleeding or bruising, 
especially with use of concomitant medications that may increase risk of 
bleeding.  

Venous and arterial thromboembolism: Deep vein thrombosis, pulmonary embolism, 
and arterial thrombosis events are increased in subjects treated with lenalidomide. 
However, subjects with mantle cell lymphoma experienced lower rates of 
thromboembolic events than did subjects with multiple myeloma [47].
o
Thromboprophylaxis is recommended. The regimen of thromboprophylaxis 
should be based on an assessment of the subject’s underlying risks by the 
investigator. 
o
Instruct subjects to report immediately any signs and symptoms suggestive of 
thrombotic events. 
o
Selection of treatment for thromboembolic AEs is at the discretion of the 
investigator.
o
Erythropoietin-stimulating agents and estrogens may further increase the risk 
of thrombosis, and their use should be based on a benefit-risk decision in 
subjects receiving lenalidomide.
5.7
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.
 
 
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Contraception
Subjects Enrolled in Cohorts 1, 2, 3, and 4
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).  
Female subjects will be considered of non-reproductive potential if they are either: 
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone 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 follicle stimulating hormone measurement is insufficient.); 
OR 
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening; 
OR 
(3) has a congenital or acquired condition that prevents childbearing.
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:  
(1) practice abstinence† from heterosexual activity; 
OR 
(2) use (or have their partner use) acceptable contraception during heterosexual activity.  
Acceptable methods of contraception are‡:
Single method (one of the following is acceptable):

intrauterine device (IUD)

vasectomy of a female subject’s male partner 

contraceptive rod implanted into the skin
 
 
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Combination method (requires use of two of the following):

diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide)

cervical cap with spermicide (nulliparous women only)  

contraceptive sponge (nulliparous women only) 

male condom or female condom (cannot be used together)

hormonal contraceptive: oral contraceptive pill (estrogen/progestin pill or progestin-
only pill), contraceptive skin patch, vaginal contraceptive ring, or subcutaneous 
contraceptive injection
†Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subject’s preferred and usual 
lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs.  
Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation 
methods, etc.) and withdrawal are not acceptable methods of contraception. 
‡If a contraceptive method listed above is restricted by local regulations/guidelines, 
then it does not qualify as an acceptable method of contraception for subjects 
participating at sites in this country/region.
Subjects should be informed that taking the study medication may involve unknown risks to 
the fetus (unborn baby) if pregnancy were to occur during the study.  In order to participate in 
the study subjects of childbearing potential must adhere to the contraception requirement 
(described above) from the day of study medication initiation (or 14 days prior to the initiation 
of study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy. If there is any question that a subject of childbearing potential 
will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study.
Monthly pregnancy testing should be conducted as per local regulations where applicable.
Subjects Enrolled in Cohort 5 (DLBCL) 
Subjects enrolled in Cohort 5 (DLBCL) receive lenalidomide + pembrolizumab in 
combination. When both treatments are administered, the contraception, counseling, and 
dispensing requirements for lenalidomide will apply. If lenalidomide treatment is temporarily 
withheld, as described in Section 5.2.1.3.4, the contraception requirements for lenalidomide 
will continue to be followed. If lenalidomide is restarted, the contraception, counseling, and 
dispensing requirements will apply. If lenalidomide is permanently discontinued, but 
pembrolizumab is continued, the contraception requirements for lenalidomide will apply for at 
least 4 weeks after the last dose of lenalidomide. Subsequent to this 4-week period, the 
 
 
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contraception requirements in Section 5.7.2.1 will apply until the subject discontinues from or 
completes the trial.
Lenalidomide is a thalidomide analogue and is contraindicated for use during pregnancy.
Thalidomide is a known human teratogen that causes life-threatening human birth defects or 
embryo-fetal death. An embryo-fetal development study in monkeys indicates that 
lenalidomide produced malformations in the offspring of female monkeys who received the 
drug during pregnancy, similar to birth defects observed in humans following exposure to 
thalidomide during pregnancy. Lenalidomide is only available through the REVLIMID Risk 
Evaluation and Mitigation Strategy (REMS)program or as provided by the Sponsor after the 
Lenalidomide Education and Counseling Guidance Document is completed and signed by a 
trained counselor prior to each dispensing of lenalidomide (see Section 12.10). A copy of this 
document must be maintained in the subject’s records for each dispense.  
Subjects should be informed that taking study medication may involve unknown risks to the 
fetus (unborn baby) if pregnancy were to occur during the study. Subjects enrolled in Cohort 5
(DLBCL) must follow the contraception requirements detailed in Celgene’s REVLIMID 
REMS program for the duration of the study and during the follow-up period defined in Section 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor. If there is any question that a 
subject will not reliably comply with the requirements for contraception, that subject should 
not be entered into the study. Please refer to the current versions of the local prescribing 
information, the Prescriber Guide, the Pharmacy Guide, and the Global Pregnancy Prevention 
Plan (see Section 12.10) for the REVLIMID REMS program for any updated information.  
5.7.2.2.1 Risk Minimization Program
Because of the embryo-fetal risk, lenalidomide is available only through a restricted program 
under a REMS, the REVLIMID REMSprogram in the United States and for trial sites not 
participating in REVLIMID REMS  lenalidomide will be provided by the Sponsor.
Compliance with the REVLIMID REMSTM program in the United States or any protocol-
specified requirements is mandatory for all subjects enrolled in this study.
Required components of the REVLIMID REMS program include the following:

Prescribers must be certified with the REVLIMID REMS program by enrolling and 
complying with the REMS requirements. 

Study investigators must follow the Global Pregnancy Prevention Plan as detailed in 
the REVLIMID REMS program (see Section 12.10 for the Global Pregnancy 
Prevention Plan).

Subjects must sign a Patient-Physician agreement form and comply with the 
REVLIMID REMS requirements.  In particular, female subjects of reproductive 
potential who are not pregnant must comply with the pregnancy testing and 
contraception requirements and males must comply with contraception requirements.  
Refer to the current version of the local prescribing information.
 
 
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
Pharmacies must be certified with the REVLIMID REMS program and must dispense 
only to subjects who are authorized to receive lenalidomide and comply with 
REVLIMID REMS requirements.
Further information about the REVLIMID REMS program in the United States is available at 
 or by telephone at 
5.7.2.2.2 Additional Precautions

Subjects should be instructed to never give lenalidomide to another person.

Subjects should be instructed to return any unused capsules to the study doctor.

Subjects should not donate blood while receiving lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide.

No more than a 28-day lenalidomide supply may be dispensed with each cycle of 
lenalidomide. 
Pregnancy
If, while on treatment with lenalidomide + pembrolizumab (Cohort 5), a female subject misses 
a menstrual period or if there is any abnormality in menstrual bleeding, lenalidomide should 
be discontinued immediately. The investigator will obtain a pregnancy test and counsel the 
subject. 
If, while on treatment with pembrolizumab (Cohorts 1, 2, 3, and 4) or lenalidomide + 
pembrolizumab (Cohort 5), a female subject inadvertently becomes pregnant, the subject will 
be immediately discontinued from trial treatment. The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to the Sponsor without delay and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn). The 
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 Sponsor.   
If a female partner of a male subject enrolled in Cohort 5 (DLBCL) inadvertently becomes 
pregnant while the male subject is on treatment with lenalidomide + pembrolizumab, the male 
subject will continue in the trial and will receive additional counseling from the investigator. 
Refer to section 7.2.2 for additional information regarding reporting pregnancy in a female 
partner of a male study subject to the Sponsor.
Additionally, for sites in the United States, any suspected embryo-fetal exposure to 
lenalidomide must be reported immediately to the Sponsor, Celgene Corporation at
and the FDA via the MedWatch number at 
. For sites outside the United 
 
 
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States, any suspected embryo-fetal exposure to lenalidomide must be reported immediately to 
the Sponsor. 
Use in Nursing Women
It is unknown whether pembrolizumab or lenalidomide 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.
5.8
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 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.

Confirmed disease progression per respective response assessment criteria
Note: A subject may be granted an exception to continue on treatment with 
confirmed progression if clinically stable or clinically improved, please see 
Section 7.1.2.7.7.

Unacceptable adverse experiences as described in Section 7.2.

Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy requires active treatment

Intercurrent illness other than another malignancy as noted above that prevents further 
administration of treatment.

Recurrent Grade 2 pneumonitis

Investigator’s decision to withdraw the subject

The subject has a confirmed positive serum pregnancy test

Noncompliance with trial treatment or procedure requirements
 
 
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
The subject is lost to follow-up

Administrative reasons
The End of Treatment and Follow-up visit procedures are listed in Section 6.0 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements). After the end of treatment, each subject will be 
followed for 30 days for AE monitoring (SAEs 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 PD
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 by 
telephone for OS 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 an investigator-determined CR or sCR (MM) 
per respective response criteria may consider stopping pembrolizumab monotherapy after 
receiving a minimum of 24 weeks of treatment with at least two doses since CR or sCR has 
been confirmed. Subjects who later experience disease progression, with the exception of 
subjects in Cohort 2 (MM) who are not allowed, 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 7.1.5.2.1.
Per investigator discretion, subjects who achieve a CR in Cohort 5 (DLBCL) may stop 
treatment after 24 weeks provided they receive an additional 21 consecutive daily doses of 
lenalidomide + 2 doses of pembrolizumab after CR was achieved. Cohort 5 has been 
discontinued and all subjects must stop combination treatment immediately, complete the 
discontinuation visit, and move into the long-term safety and survival follow-up per protocol. 
If clinically benefitting at time of stopping combination therapy, subjects may enter a transition 
period remaining on single agent lenalidomide or pembrolizumab for up to 90 days from 15-
SEP-2017 and then must transition into long-term survival and safety follow-up. Subjects who 
achieve a CR in Cohort 5 will not be eligible any longer to restart treatment.
5.9
Subject Replacement Strategy
Subjects will not be replaced in the trial, with the exception of subjects enrolled in the safety 
run-in for Cohort 5 (DLBCL) as detailed in Section 5.2.1.3.5. However, additional subjects 
may be enrolled in a given cohort to ensure that the required number of evaluable subjects in 
each cohort is achieved in the applicable analysis population. Further details are provided in 
Section 8.1.3 (Power and Sample Size), Section 8.2.4 (Analysis Populations), and Section 8.2.7 
(Sample Size and Power Calculations).
 
 
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5.10 Beginning and End of the Trial
The overall trial begins when the first subject signs the informed consent form.  The overall 
trial ends when the last subject completes the last study-related phone-call or visit, discontinues 
from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the 
investigator) or the Sponsor ends the trial, whichever occurs first.
5.11 Clinical Criteria for Early Trial Termination
Early trial termination will be the result of the criteria specified below:
1. Quality or quantity of data recording is inaccurate or incomplete
2. Poor adherence to protocol and regulatory requirements
3. Plans to modify or discontinue the development of the study drug
4. Sponsor’s decision to terminate the study 
In the event of Sponsor decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made.
 
 
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6.0 TRIAL FLOW CHART
6.1
Study Flow Chart A:  Cohort 1-MDS 
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety Follow-
up Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 6 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
Administrative Procedures
Informed Consent
Xe
Informed 
Consent 
for 
Future 
Biomedical Research
Xf
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication 
Review
Xg
X
X
X
X
X
X
X
X
X
X
Review Transfusion History h
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events i
X
X
X
X
X
X
X
X
X
X
X j
X j
Full Physical Examination
X
X
Xk
X
Directed Physical Examination
X
X
X
X
X
X
Vital Signs and Weight l
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety Follow-
up Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 6 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Determine FAB classification, WHO 
Classification, IPSS Score, and IPSS-R 
Score
X
X
X
International Working Group criteria 
for MDS m
X
Xn
Xo
Xb
Laboratory Procedures/Assessments:  
analysis 
performed 
by 
local 
laboratory
Pregnancy Test – Urine or Serum -
HCG p
X
PT/INR and aPTT q
Xr
CBC with Differential s
Xr
X
X
X
X
X
X
X
X
Xt
Comprehensive Chemistry Panel s
Xr
X
X
X
X
Xt
Reticulocyte Count s
Xr
X
X
X
X
X
X
X
X
Xt
LDH s
Xr
X
X
X
X
Xt
Urinalysis s
Xr
X u
Xt
T3 (or FT3 per local standard), FT4 and 
TSH s
Xr
X
X v
Xt
Bone Marrow Biopsy & Aspirate w,x
X
X
X
Bone marrow morphology, Iron stain (at 
screening only), Blast percentage, 
Cytogenetics y
X
X
X
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety Follow-
up Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 6 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
Laboratory Procedures/Assessments: 
analysis 
performed 
by 
central 
laboratory
Archival 
Bone 
Marrow 
Biopsy 
Collection x,z
X
Correlative 
Studies 
Blood/Bone 
Marrow Collection x,aa
X aa
X aa
X aa
Anti-pembrolizumab antibodies bb
Xbb
Xb
b
Xbb
Xbb
Xbb
Pharmacokinetics bb
Xbb, cc
Xb
b
Xbb
Xbb
Xbb
Blood for Future Biomedical Research
dd
X
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; -HCG=beta human chorionic gonadotropin; CBC=complete blood cell count; 
CTCAE=Common Terminology Criteria for Adverse Events; DNA=deoxyribonucleic acid; Discon=discontinuation; ECOG=Eastern Cooperative Oncology Group; 
ECI=events of clinical interest; FAB=French-American-British; FT3=free triiodothyronine; FT4=free thyroxine; HMA=hypomethylating agent; INR=International 
Normalized Ratio; IPSS= International Prognostic Scoring System; IPSS-R=Revised International Prognostic Scoring System; LDH=lactate dehydrogenase; 
MDS=myelodysplastic syndrome; NCI=National Cancer Institute; PD=progressive disease; PK=pharmacokinetic; PT=prothrombin time; SAE=serious adverse event; 
T3=triiodothyronine; TSH=thyroid stimulating hormone; WHO=World Health Organization.
a.
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.  Treatment cycles are 2 
weeks.
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status every 6 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.
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for 
survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will 
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety Follow-
up Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 6 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death event 
previously recorded).
d.
In general, the window for each visit is ± 3 days unless otherwise noted. 
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 collection and 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.
Transfusion history should be documented for 3 months prior to start of study and every 6 weeks during response assessment.  Transfusion history should be obtained from 
subject medical records and/or blood bank records.  
i.
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.
j.
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.
k.
To be repeated every 6 weeks after cycle 6.
l.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at visit 1 only.  
m. Disease response assessment is made based upon the MDS response criteria and includes CBC and documentation of transfusions. Response assessments should occur at 
screening, Wk 6, Wk 12, and every 6 weeks (± 7 days).  For subjects who discontinue for reasons other than PD, assessments should continue until the subject has documented 
PD.  Bone marrow assessments should be performed at Screening, Wk 6 (± 7 days), Wk 12 (± 7 days), and then every 12 weeks or as clinically indicated.  
n.
Subjects who have progressive disease at the Wk 12 assessment should have a confirmation assessment performed at least 28 days later (after Wk 16). See Section 7.1.2.7.7 
for additional details regarding confirmation assessments.
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety Follow-
up Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 6 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
o.
In subjects who discontinue study therapy without confirmed disease progression, a response assessment should be performed at the time of treatment discontinuation (i.e. 
date of discontinuation ± 4 week window).  If previous assessment was performed within 4 weeks prior to the date of discontinuation, then a repeat assessment at treatment 
discontinuation is not 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.  Any subject receiving anticoagulant therapy should have 
coagulation factors monitored closely throughout the trial.  
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, laboratory 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 laboratory tests that are drug related AEs should be followed until resolution.  Laboratory tests do not need to be repeated after the end of treatment if 
laboratory tests are within normal range.
u.
To be repeated every 4 cycles after Cycle 5.
v.
To be repeated every 3 cycles after cycle 7.
w. Detailed instructions for bone marrow collection, processing and shipment are provided in the Procedures Manual.  Bone marrow biopsy and aspirate should be collected at 
screening, Wk 6 (± 7 days), Wk 12 (± 7 days), and every 12 weeks while on study treatment or as clinically indicated.  If a subject has disease progression at Wk 12 and a 
confirmatory assessment is performed at Wk 16, a biopsy and aspirate should be performed as part of the confirmation assessment.  A confirmation biopsy does not need to 
be performed for subjects who have stable disease, partial response, or complete response at Wk 12.
x.
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.
y.
Bone marrow morphology, Blast percentage, and Cytogenetics should be performed with each bone marrow biopsy/aspirate procedure. Iron stain is performed at screening 
only.  Cytogenetics is done to evaluate whether genetic variation within a clinical trial population correlates with response to the treatment(s) under evaluation.  If it is not a 
standard procedure in your region, this test does not need to be performed.
z.
If available, bone marrow biopsies will be collected from pre and post HMA treatment.
aa. Correlative study samples should be collected at Screening, at the time of the Wk 6/Wk 12 disease response assessments, and upon progression.
 
 
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Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety Follow-
up Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 6 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
bb. Pre-dose trough and post-dose peak PK samples will be collected at Cycles 1 and 2.  Pre-dose trough samples only will be collected at Cycle 4, Cycle 7, every 6 cycles 
thereafter, 30 days after discontinuation of study drug, and 3 months and 6 months after discontinuation of study drug (or until the subject starts new anti-cancer therapy).  
All trough samples should be drawn within 24 hours before infusion of pembrolizumab.  All peak samples should be drawn within 30 minutes after the end of the infusion. 
Anti-pembrolizumab antibodies should be drawn with all pre-dose trough PK samples, 30 days after discontinuation of study drug or until the subject starts new anti-cancer 
therapy.  Procedures for sample collection are described in the Procedures Manual. 
cc. An additional single PK sample should be drawn between 24 to 96 hours after Cycle 1 dosing.
dd. Informed consent for future biomedical research samples must be obtained before the DNA sample. DNA sample for analysis should be obtained predose, on Day 1 (or with 
the next scheduled blood draw) as the last sample drawn or at a later date as soon as the informed consent is obtained. Detailed instructions for the collection and management 
of specimens for FBR are provided in the Procedures Manual and Section 12.2.
 
 
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6.2
Study Flow Chart B:  Cohort 2-Multiple Myeloma (Subjects allocated to 10mg/kg Q2W)
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Administrative Procedures
Informed Consent
Xe
Informed Consent for Future Biomedical 
Research
Xf
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Review g
X
X
X
X
X
X
X
X
X
X
X
International Staging System Criteria h
X
Trial Treatment Administration 
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events i
X
X
X
X
X
X
X
X
X
X
X j
X j
Full Physical Examination
X
 
X k
X
Directed Physical Examination
X
X
X
Vital Signs and Weight l
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Skeletal survey m
X
MRI/CT/PET m
X
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
89
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
International Myeloma Working Group 
Uniform Response Criteria n
X
X
Xo
Xp
Xb
Laboratory 
Procedures/Assessments:  
analysis performed by local laboratory
Pregnancy Test – Urine or Serum -HCG q
X
PT/INR and aPTT r
Xs
CBC with Differential t
Xs
X
X
X
X
Xu
Comprehensive Chemistry Panel t
Xs
X
X
X
X
Xu
LDH t
Xs
X
X
X
X
Xu
Urinalysis t
Xs
X v
Xu
T3 (or FT3 per local standard), FT4 and TSH
t
Xs
X
X w
Xu
Viscosity t
Xs
Quantitative Serum Immunoglobulin 
Xs
X
X
X
Serum protein electrophoresis and serum 
immunofixation 
Xs
X
X
X
Serum free light chain assay 
Xs
X
X
X
24 hr urine protein electrophoresis and urine 
immunofixation 
Xs
X
X
X
M-protein quantitation (urine and serum)
Xs
X
X
X
2 microglobulin 
Xs
Archival Bone Marrow Biopsy Collection x
X
Bone Marrow Biopsy & Aspirate x,y
X
X
X
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
90
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Bone 
marrow 
morphology, 
IHC, 
Cytogenetics by standard karyotyping, FISH 
panel z,aa
X
X
X
Laboratory 
Procedures/Assessments: 
analysis performed by central laboratory
Correlative Studies Blood /Bone Marrow 
Collection x,bb
X
X
X
Anti-pembrolizumab Antibodies cc
Xcc
Xcc
Xcc
Xcc
Xcc
Pharmacokinetics cc
Xcc,dd
Xcc
Xcc
Xcc
Xcc
Blood for Future Biomedical Research ee
X
Abbreviations: AE=adverse event; AP=anteroposterior; aPTT=activated partial thromboplastin time; -HCG=beta human chorionic gonadotropin; CBC=complete blood cell 
count; CT=computed tomography; CTCAE=Common Terminology Criteria for Adverse Events; DNA=deoxyribonucleic acid; Discon=discontinuation; ECOG=Eastern 
Cooperative Oncology Group; ECI=events of clinical interest; FISH=fluorescence in situ hybridization; FT3=free triiodothyronine; FT4=free thyroxine; 
IHC=immunohistochemistry; INR=International Normalized Ratio; LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; NCI=National Cancer Institute; 
PA=posterior-anterior; PD=progressive disease; PET=positron emission tomography; PK=pharmacokinetic; PT=prothrombin time; Q2W=every 2 weeks; SAE=serious 
adverse event; T3=triiodothyronine; TSH=thyroid stimulating hormone.
a.
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.  Treatment cycles are 2 
weeks.
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status 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.
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for 
survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will 
not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death 
event previously recorded).
d.
In general, the window for each visit is ± 3 days unless otherwise noted. 
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
91
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
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 collection and 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.
Use the International Staging System (ISS) at Screening for subject classification.
i.
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.
j.
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.
k.
To be repeated every 6 cycles after cycle 6.
l.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at visit 1 only.  
m.
Skeletal survey should include a chest (PA or AP; lateral), skull (lateral), upper extremities (shoulder to elbow), lower extremities (hip to knee; AP), pelvis (AP), 
cervical/thoracic/lumbar spine (AP and lateral).  A skeletal survey and/or MRI/CT/PET (MRI for subjects with bone disease and CT/PET for plasmacytomas) performed 
as standard of care prior to signing consent can be used for screening if performed within 28 days of Day 1.  For suspected progression to bone disease bidirectional 
measurement of the target lytic lesions must be performed.  During the course of the study or if a subject develops bone pain a skeletal survey and/or MRI/CT/PET (MRI 
for subjects with bone disease and CT/PET for plasmacytomas) should be performed annually or as clinically indicated.  Subjects with measurable plasmacytomas at 
baseline should have imaging performed every 8 weeks.
n.
Disease response assessment is based upon the multiple myeloma response criteria.  Disease assessments should occur at Screening and every 4 weeks (± 7 days) while
on study treatment.  For subjects who discontinue for reasons other than PD, assessments should continue until the subject has documented PD.  Parameters assessed 
should include serum protein electrophoresis and serum immunofixation, serum free light chain assay, 24 hr urine protein electrophoresis and urine immunofixation, M-
protein quantitation (urine and serum),  and urine protein electrophoresis.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
92
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
o.
Subjects who have progressive disease at the Wk 12 assessment (Cycle 7) should have a confirmation assessment performed at least 28 days later (after Wk 16).  
Additionally, for subjects who have progressive disease at the Wk 12 assessment, a bone marrow biopsy/aspirate should be performed as part of the Wk 16 confirmation 
assessment.  See Section 7.1.2.7.7 for additional details regarding confirmation assessments.
p.
In subjects who discontinue study therapy without confirmed disease progression, a response assessment should be performed at the time of treatment discontinuation 
(i.e., date of discontinuation ±4 week window).  If previous assessment was performed within 4 weeks prior to the date of discontinuation, then a repeat assessment at 
treatment discontinuation is not mandatory.  
q.
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.
r.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Any subject receiving anticoagulant therapy should have 
coagulation factors monitored closely throughout the trial.  
s.
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.  
t.
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests.  Viscosity 
should be performed at Screening and as clinically necessary during the trial.  
u.
Unresolved abnormal laboratory tests that are drug related AEs should be followed until resolution.  Laboratory tests do not need to be repeated after the end of treatment 
if laboratory tests are within normal range.
v.
To be repeated every 4 cycles after Cycle 5.
w.
To be repeated every 3 cycles after cycle 7.
x.
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.
y.
Bone marrow biopsy/aspirate should be performed at Screening, Cycle 1 Day 1 (Cycle 1 Day 1 only if Screening Bone Marrow Aspirate/Biopsy was performed greater 
than 28 days from Day 1 Cycle 1), week 4 (± 7 days), Week 12 (± 7 days), to confirm sCR and CR, or as clinically indicated. For subjects who have progressive disease 
at the Wk 12 assessment, a bone marrow biopsy/aspirate should be performed as part of the Wk 16 confirmation assessment.  A bone marrow biopsy/aspirate performed 
as part of standard of care prior to signing informed consent may be used for screening if performed within 28 days of Day 1.  When a bone marrow biopsy is performed, 
the paraffin-embedded block must be sent to the central laboratory.  
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
93
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
z.
Bone marrow morphology and IHC should be performed with each bone marrow biopsy. Cytogenetics by standard karyotyping, and FISH panel should be performed at 
screening only.  
aa.
FISH panel should include del 1p, del 13, del 17p13, t(4;14), t(11;14), t(14;16), and 1q21 amplification.
bb. Correlative study samples should be collected at Screening, at the time of the Wk 4 and Wk 12 disease response assessments, and upon progression.
cc.
Pre-dose trough and post-dose peak PK samples will be collected at Cycles 1 and 2.  Pre-dose trough samples only will be collected at Cycle 4, Cycle 7, every 6 cycles 
thereafter, 30 days after discontinuation of study drug, and 3 months and 6 months after discontinuation of study drug (or until the subject starts new anti-cancer therapy).  
All trough samples should be drawn within 24 hours before infusion of pembrolizumab.  All peak samples should be drawn within 30 minutes after the end of the infusion. 
Anti-pembrolizumab antibodies should be drawn with all pre-dose trough PK samples, 30 days after discontinuation of study drug or until the subject starts new anti-
cancer therapy.  Procedures for sample collection are described in the Procedures Manual.  
dd. An additional single PK sample should be drawn between 24 to 96 hours after Cycle 1 dosing.
ee.
Informed consent for future biomedical research samples must be obtained before the DNA sample.  DNA sample for analysis should be obtained predose, on Day 1 (or 
with the next scheduled blood draw) as the last sample drawn or at a later date as soon as the informed consent is obtained. Detailed instructions for the collection and 
management of specimens for FBR are provided in the Procedures Manual and Section 12.2.
Note: Cohort 2 has completed enrollment and there will be no further enrollment of subjects. All subjects in Cohort 2 have previously discontinued study treatment and must 
transition into long-term safety and survival follow-up.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
94
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
6.3
Study Flow Chart C:  Cohort 3, 4A, & 4B-Hodgkin Lymphoma, Mediastinal Large B-Cell Lymphoma, & any-other PD-L1 
Positive Non-Hodgkin Lymphoma (Subjects allocated to 10mg/kg Q2W).  
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-upc
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 8 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
Administrative Procedures
Pre-screening Informed Consent 
X e
Informed Consent 
X f
Informed Consent for Future Biomedical 
Research g
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Review 
h
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events i
X
X
X
X
X
X
X
X
X
X
X j
X
Full Physical Examination 
X
X
X k
X
Directed Physical Examination
X
X
Vital Signs and Weight l
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
95
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-upc
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 8 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Pulmonary Function Test m
X
Neck, Chest, Abdominal, Pelvic PET/CT n
X
X n
X o
X p
X b
Disease Response Assessment by Revised 
Response 
Criteria 
for 
Malignant 
Lymphoma
X n
X
X
X
Assessment of Lymphoma B Symptoms n
X
X n
X
X
X
Laboratory 
Procedures/Assessments:  
analysis performed by local laboratory
Pregnancy Test – Urine or Serum -HCG q
X
PT/INR and aPTT r
X s
CBC with Differential t
X s
X
X
X
X
X u
Comprehensive Chemistry Panel t
X s
X
X
X
X
X u
LDH t
X s
X
X
X
X
X u
Urinalysis t
X s
X v
X u
T3 (or FT3 per local standard), FT4 and 
TSHt
X s
X
X w
X u
2 microglobulin t,x
X s
X
Bone Marrow Biopsy & Aspirate y,z
X
Bone 
marrow 
morphology, 
IHC, 
Cytogenetics aa
X
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
96
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-upc
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 8 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
Laboratory 
Procedures/Assessments: 
analysis 
performed 
by 
central 
laboratory
Archival Lymph Node Biopsy z
X
Lymph Node Biopsy z, bb
X
X
Correlative Studies Blood Collection z,cc
X
X
Anti-pembrolizumab Antibodies dd
Xdd
Xdd
Xdd
Xdd
Xdd
Pharmacokinetics dd
Xdd, 
ee
Xdd
Xdd
Xdd
Xdd
Blood for Future Biomedical Research ff
X
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; -HCG=beta human chorionic gonadotropin; CBC=complete blood cell count; 
CR=complete response; CT=computed tomography; CTCAE=Common Terminology Criteria for Adverse Events; DNA=deoxyribonucleic acid; Discon=discontinuation; 
ECOG=Eastern Cooperative Oncology Group; ECI=events of clinical interest; FDG=fludeoxyglucose; FEF=forced expiratory flow; FT3=free triiodothyronine; FT4=free 
thyroxine; FVC=forced vital capacity; HL=Hodgkin lymphoma; IHC=immunohistochemistry; INR=International Normalized Ratio; LDH=lactate dehydrogenase; 
MLBCL=mediastinal large B-cell lymphoma; NCI=National Cancer Institute; NHL=non-Hodgkin lymphoma; PD=progressive disease; PD-L1=programmed cell death 
ligand 1; PET=positron emission tomography; PK=pharmacokinetic; PT=prothrombin time; Q2W=every 2 weeks; SAE=serious adverse event; T3=triiodothyronine; 
TSH=thyroid stimulating hormone.
a.
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.  Treatment cycles are 
2 weeks.
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 8 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.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
97
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess 
for survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do 
not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who 
have a death event previously recorded).
d.
In general, the window for each visit is ± 3 days unless otherwise noted. 
e.
For Cohort 4B (any-other PD-L1 positive NHL) (Prior to Amendment 013-04):  For subjects that have an archival biopsy sample available, pre-screening consent must 
be obtained prior to sending a biopsy sample to the laboratory for characterization.  Subjects that do not have an archival sample available must sign the main study 
consent prior to undergoing a newly obtained biopsy.
f.
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. 
g.
Signing the informed consent for future biomedical research (FBR) samples is optional.  Detailed instructions for the collection and management of specimens for FBR 
are provided in the Procedures Manual and Section 12.2.
h.
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.
i.
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.
j.
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.
k.
To be repeated every 6 cycles after cycle 7.
l.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at visit 1 only.  
m.
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.
n.
Disease response assessment is based upon Revised Response Criteria for Malignant Lymphoma.  “Diagnostic quality” CT and PET should be performed at Screening 
and both should be repeated for subsequent assessments.  For lymphomas that are not FDG-avid at screening, PET does not need to be repeated in subsequent 
assessments.   Response assessments should occur at Screening (within 28 days prior to first dose of trial treatment), Wk 12, and every 8 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 subject is clinically progressing.  Assessment of lymphoma B symptoms should occur with each 
disease response assessment.
o.
Subjects who have progressive disease at the Wk 12 assessment should have a confirmation assessment performed at least 28 days later (after Wk 16) (+7 days). See 
Section 7.1.2.7.7 for additional details regarding confirmation assessments.
p.
In subjects who discontinue study therapy without confirmed disease progression, a radiological assessment should be performed at the time of treatment discontinuation 
(i.e. date of discontinuation ± 4 week window).  If previous scan was obtained within 4 weeks prior to the date of discontinuation, then a repeat scan at treatment 
discontinuation is not mandatory.  
q.
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.
 
 
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r.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Any subject receiving anticoagulant therapy should have 
coagulation factors monitored closely throughout the trial.  
s.
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.  
t.
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests.  
u.
Unresolved abnormal laboratory tests that are drug related AEs should be followed until resolution.  Laboratory tests do not need to be repeated after the end of treatment 
if laboratory tests are within normal range.
v.
To be repeated every 4 cycles after Cycle 5.
w.
To be repeated every 3 cycles after Cycle 7.
x.
If 2 microglobulin is elevated at baseline, testing should be repeated every 12 weeks. 
y.
All subjects will have bone marrow biopsy/aspirate performed at baseline.  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. 
z.
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.
aa.
Bone marrow morphology, IHC, and Cytogenetics should be performed with each bone marrow biopsy. Cytogenetics is done to evaluate whether genetic variation 
within a clinical trial population correlates with response to the treatment(s) under evaluation.  If it is not a standard procedure in your region, this test does not need to
be performed.
bb. Cohort 3 & 4A:  Tumor biopsies are required for HL/MLBCL subjects at Screening and Week 12 (± 7 days). If an archival biopsy is not available a new biopsy must 
be obtained. Cohort 4B: Tumor biopsies are required at Screening and Week 12 (± 7 days). A newly obtained biopsy is required for Cohort 4B even if a subject has 
been determined to be PD-L1 positive based on archival material. Tumors that are inaccessible or contraindicated due to subject safety concerns are exempt from this 
requirement at the Week 12 assessment. 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. Tumors that are inaccessible or biopsy contraindicated due to 
subject safety concerns are exempt from this requirement at the Week 12 assessment. 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 preferable to obtain a new baseline scan. 
cc.
Correlative study samples should be collected at Screening, at the time of the Week 12 disease response assessment, and upon progression.  
dd. Pre-dose trough and post-dose peak PK samples will be collected at Cycles 1 and 2. Pre-dose trough samples only will be collected at Cycle 4, Cycle 7, every 6 cycles 
thereafter, 30 days after discontinuation of study drug, and 3 months and 6 months after discontinuation of study drug (or until the subject starts new anti-cancer therapy).  
All trough samples should be drawn within 24 hours before infusion of pembrolizumab. All peak samples should be drawn within 30 minutes after the end of the 
infusion. Anti-pembrolizumab antibodies should be drawn with all pre-dose trough PK samples, 30 days after discontinuation of study drug or until the subject starts 
new anti-cancer therapy.  Procedures for sample collection are described in the Procedures Manual.  
ee.
An additional single PK sample should be drawn between 24 to 96 hours after Cycle 1 dosing.
ff.
Informed consent for future biomedical research samples must be obtained before the DNA sample.  DNA sample for analysis should be obtained predose, on Day 1 
(or with the next scheduled blood draw) as the last sample drawn or at a later date as soon as the informed consent is obtained. Detailed instructions for the collection 
and management of specimens for FBR are provided in the Procedures Manual and Section 12.2.
 
 
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6.4
Study Flow Chart D:  Cohort 2 Multiple Myeloma (Subjects allocated to 200 mg Q3W) 
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 
3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Administrative Procedures
Informed Consent
Xe
Informed Consent for Future Biomedical 
Research
Xf
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior and Concomitant Medication Review 
g
X
X
X
X
X
X
X
X
X
X
X
International Staging System Criteria h
X
Trial Treatment Administration 
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events i
X
X
X
X
X
X
X
X
X
X
X j
X j
Full Physical Examination
X
X
X k
X
Directed Physical Examination
X
X
X
X
Vital Signs and Weight l
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Skeletal survey m
X
MRI/CT/PET m
X
 
 
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Product:  MK-3475 (SCH 900475)
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Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 
3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
International Myeloma Working Group 
Uniform Response Criteria n 
X
X
X
Xo
X
X
X
Xp
Xb
Laboratory 
Procedures/Assessments:  
analysis performed by local laboratory
Pregnancy Test – Urine or Serum -HCG q
X
PT/INR and aPTT r
Xs
CBC with Differential t
Xs
X
X
X
X
X
X
X
X
Xu
Comprehensive Chemistry Panel t
Xs
X
X
X
X
X
X
X
X
Xu
LDH t
Xs
X
X
X
X
X
X
X
X
Xu
Urinalysis t
Xs
X v
X
Xu
T3 (or FT3 per local standard), FT4 and 
TSH t
Xs
X
X w
X
Xu
Viscosity t
Xs
Quantitative Serum Immunoglobulin 
Xs
X
X
X
X
X
X
X
Serum protein electrophoresis and serum 
immunofixation 
Xs
X
X
X
X
X
X
X
Serum free light chain assay 
Xs
X
X
X
X
X
X
X
24 hr urine protein electrophoresis and urine 
immunofixation 
Xs
X
X
X
X
X
X
X
M-protein quantitation (urine and serum)
Xs
X
X
X
X
X
X
X
2 microglobulin 
Xs
Archival Bone Marrow Biopsy Collection x
X
Bone Marrow Biopsy & Aspirate x,y
X
X
X
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
101
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 
3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Bone 
marrow 
morphology, 
IHC, 
Cytogenetics by standard karyotyping, 
FISH panel z,aa
X
X
X
Laboratory 
Procedures/Assessments: 
analysis performed by central laboratory
Correlative Studies Blood /Bone Marrow 
Collection x,bb
X
X
X
Anti-pembrolizumab Antibodies cc
Xcc
Xcc
Xcc
X
cc
Xcc
Pharmacokinetics cc
Xcc,dd
Xcc
Xcc
X
cc
Xcc
Blood for Future Biomedical Research ee
X
Abbreviations: AE=adverse event; AP=anteroposterior; aPTT=activated partial thromboplastin time; -HCG=beta human chorionic gonadotropin; CBC=complete blood cell 
count; CT=computed tomography; CTCAE=Common Terminology Criteria for Adverse Events; DNA=deoxyribonucleic acid; Discon=discontinuation; ECOG=Eastern 
Cooperative Oncology Group; ECI=events of clinical interest; FISH=fluorescence in situ hybridization; FT3=free triiodothyronine; FT4=free thyroxine; 
IHC=immunohistochemistry; INR=International Normalized Ratio; LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; NCI=National Cancer Institute; 
PA=posterior-anterior; PD=progressive disease; PET=positron emission tomography; PK=pharmacokinetic; PT=prothrombin time; Q3W=every 3 weeks; SAE=serious adverse 
event; T3=triiodothyronine; TSH=thyroid stimulating hormone.
a.
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.  Treatment cycles are 3 
weeks. 
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status 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.
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for 
survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will 
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
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Protocol/Amendment No.: 013-09 
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16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 
3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death 
event previously recorded).
d.
In general, the window for each visit is ± 3 days unless otherwise noted. 
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 collection and 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.
Use the International Staging System (ISS) at Screening for subject classification.
i.
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.
j.
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.
k.
To be repeated every 4 cycles after cycle 5.
l.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at visit 1 only.  
m.
Skeletal survey should include a chest (PA or AP; lateral), skull (lateral), upper extremities (shoulder to elbow), lower extremities (hip to knee; AP), pelvis (AP), 
cervical/thoracic/lumbar spine (AP and lateral).  A skeletal survey and/or MRI/CT/PET (MRI for subjects with bone disease and CT/PET for plasmacytomas) performed as 
standard of care prior to signing consent can be used for screening if performed within 28 days of Day 1.  For suspected progression to bone disease bidirectional measurement 
of the target lytic lesions must be performed.  During the course of the study or if a subject develops bone pain a skeletal survey and/or MRI/CT/PET (MRI for subjects with 
bone disease and CT/PET for plasmacytomas) should be performed annually or as clinically indicated.  Subjects with measurable plasmacytomas at baseline should have 
imaging performed every 9 weeks. 
n.
Disease response assessment is based upon the multiple myeloma response criteria.  Disease assessments should occur at Screening and every 3 weeks (± 7 days) while on 
study treatment.  For subjects who discontinue for reasons other than PD, assessments should continue until the subject has documented PD.  Parameters assessed should 
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
103
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 
3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
include serum protein electrophoresis and serum immunofixation, serum free light chain assay, 24 hr urine protein electrophoresis and urine immunofixation, M-protein 
quantitation (urine and serum),  and urine protein electrophoresis.
o.
Subjects who have progressive disease at the Wk 12 assessment (Cycle 5) should have a confirmation assessment performed at least 21 days later (after Wk 15).  Additionally, 
for subjects who have progressive disease at the Wk 12 assessment, a bone marrow biopsy/aspirate should be performed as part of the Wk 15 confirmation assessment.  See 
Section 7.1.2.7.7 for additional details regarding confirmation assessments.
p.
In subjects who discontinue study therapy without confirmed disease progression, a response assessment should be performed at the time of treatment discontinuation (i.e.,
date of discontinuation ± 4 week window).  If previous assessment was performed within 4 weeks prior to the date of discontinuation, then a repeat assessment at treatment 
discontinuation is not mandatory.  
q.
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.
r.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Any subject receiving anticoagulant therapy should have 
coagulation factors monitored closely throughout the trial.  
s.
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.  
t.
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests.  Viscosity should 
be performed at Screening and as clinically necessary during the trial.  
u.
Unresolved abnormal laboratory tests that are drug related AEs should be followed until resolution.  Laboratory tests do not need to be repeated after the end of treatment if 
laboratory tests are within normal range.
v.
To be repeated every 3 cycles after Cycle 4.
w.
To be repeated every 2 cycles after cycle 5
x.
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.
y.
Bone marrow biopsy/aspirate should be performed at Screening, Cycle 1 Day 1 (Cycle 1 Day 1 only if Screening Bone Marrow Aspirate/Biopsy was performed greater than 
28 days from Day 1 Cycle 1), Week 6 (± 7 days), Week 12 (± 7 days), to confirm sCR and CR, or as clinically indicated. For subjects who have progressive disease at the 
Wk 12 assessment, a bone marrow biopsy/aspirate should be performed as part of the Wk 15 confirmation assessment.  A bone marrow biopsy/aspirate performed as part of 
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
104
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 
3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
standard of care prior to signing informed consent may be used for screening if performed within 28 days of Day 1.  When a bone marrow biopsy is performed, the paraffin-
embedded block must be sent to the central laboratory.  
z.
Bone marrow morphology and IHC should be performed with each bone marrow biopsy.  Cytogenetics by standard karyotyping, and FISH panel should be performed at 
screening only.
aa.
FISH panel should include del 1p, del 13, del 17p13, t(4;14), t(11;14), t(14;16), and 1q21 amplification.
bb. Correlative study samples should be collected at Screening, at the time of the Wk 6 and Wk 12 disease response assessments, and upon progression.
cc.
Pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, 8 and every 4 cycles thereafter, 30 days 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. Additional post-dose 
peak PK samples will be drawn within 30 minutes after end of pembrolizumab infusion at Cycles 1 and 8. Procedures for sample collection are described in the Procedures 
Manual.
dd. An additional single PK sample should be drawn between 72 to 168 hours after Cycle 1 dosing.
ee.
Informed consent for future biomedical research samples must be obtained before the DNA sample.  DNA sample for analysis should be obtained predose, on Day 1 (or with 
the next scheduled blood draw) as the last sample drawn or at a later date as soon as the informed consent is obtained. Detailed instructions for the collection and management 
of specimens for FBR are provided in the Procedures Manual and Section 12.2.
Note: Cohort 2 has completed enrollment and there will be no further enrollment of subjects. All subjects in Cohort 2 have previously discontinued study treatment and must 
transition into long-term safety and survival follow-up.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
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Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
6.5
Study Flow Chart E:  Cohort 4A, 4C, 4D Mediastinal Large B-Cell Lymphoma, Follicular Lymphoma (FL), and Diffuse 
Large B-Cell Lymphoma (DLBCL) (Subjects allocated to 200 mg Q3W)  
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-upc
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 9 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the Sponsor
Administrative Procedures
Informed Consent 
X e
Informed Consent for Future Biomedical 
Research f
X
Inclusion/Exclusion Criteria
X
Subject Identification Card
X
Demographics and Medical History
X
Prior 
and 
Concomitant 
Medication 
Reviewg
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events h
X
X
X
X
X
X
X
X
X
X
X i
X
Full Physical Examination 
X
X
X j
X
Directed Physical Examination
X
X
X
X
Vital Signs and Weight k
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Pulmonary Function Test l
X
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
106
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-upc
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 9 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the Sponsor
Neck, Chest, Abdominal, Pelvic PET/CT m
X
X
X n
X 
X o
X b
Disease Response Assessment by Revised 
Response 
Criteria 
for 
Malignant 
Lymphoma
X
X
X
X
X
Assessment of Lymphoma B Symptoms m
X
X
X
X
X
X
Laboratory 
Procedures/Assessments:  
analysis performed by local laboratory
Pregnancy Test – Urine or Serum -HCG p
X
PT/INR and aPTT q
X r
CBC with Differential s
X r
X
X
X
X 
X
X
Xu
X
X t
Comprehensive Chemistry Panel s
X r
X
X 
X 
X
X
X
Xu
X
X t
LDH s
X r
X
X
X 
X
X 
X
Xu
X
X t
Urinalysis s
X r
Xv
X t
T3 (or FT3 per local standard), FT4 and 
TSHs
X r
X
X w
X
X t
2 microglobulins,x
X r
X x
Epstein-Barr virus (Cohort D)y
X
Bone Marrow Biopsy & Aspirate z, aa
X
Bone 
marrow 
morphology, 
IHC, 
Cytogenetics bb
X
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
107
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-upc
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 9 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the Sponsor
Laboratory 
Procedures/Assessments: 
analysis 
performed 
by 
central 
laboratory
Lymph Node Biopsy aa, cc
X
X
Correlative Studies Blood Collection aa, dd
X
X
Anti-pembrolizumab Antibodies ee
Xee
Xee
Xee
Xee
Xee
Pharmacokinetics ee
X
ee,ff
Xee
Xee
Xee
Xdd
Blood for Future Biomedical Research gg
X
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; -HCG=beta human chorionic gonadotropin; CBC=complete blood cell count; CR=complete 
response; CT=computed tomography; CTCAE=Common Terminology Criteria for Adverse Events; DNA=deoxyribonucleic acid; Discon=discontinuation; ECOG=Eastern 
Cooperative Oncology Group; ECI=events of clinical interest; FDG=fludeoxyglucose; FEF=forced expiratory flow; FT3=free triiodothyronine; FT4=free thyroxine; FVC=forced 
vital capacity; IHC=immunohistochemistry; INR=International Normalized Ratio; LDH=lactate dehydrogenase; NCI=National Cancer Institute; PD=progressive disease; 
PET=positron emission tomography; PK=pharmacokinetic; PT=prothrombin time; Q3W=every 3 weeks; SAE=serious adverse event; T3=triiodothyronine; TSH=thyroid 
stimulating hormone.
 
 
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a.
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.  Treatment cycles are 3 
weeks.
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 9 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.
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for 
survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will 
not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death 
event previously recorded).
d.
In general, the window for each visit is ± 3 days unless otherwise noted. 
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 collection and 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.
j.
To be repeated every 4 cycles after cycle 5.
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.
Disease response assessment is based upon Revised Response Criteria for Malignant Lymphoma.  “Diagnostic quality” CT and PET should be performed at Screening and 
both should be repeated for subsequent assessments.  For lymphomas that are not FDG-avid at screening, PET does not need to be repeated in subsequent assessments.  
Response assessments should occur at Screening (within 28 days prior to first dose of trial treatment), Wk 6, Wk 12, and every 9 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.  Assessment of lymphoma B symptoms should occur with 
each disease response assessment. The first assessment may be performed earlier than 12 weeks if in the opinion of the investigator the subject is clinically progressing.  
n.
Subjects who have progressive disease at the Wk 12 assessment should have a confirmation assessment performed at least 21 days later (after Wk 15) (+7 days). See Section 
7.1.2.7.7 for additional details on confirmation assessments.
o.
In subjects who discontinue study therapy without confirmed disease progression, a radiological assessment should be performed at the time of treatment discontinuation 
(i.e., date of discontinuation ± 4 week window).  If previous scan was obtained within 4 weeks prior to the date of discontinuation, then a repeat scan at treatment 
discontinuation is not 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.
 
 
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q.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Any subject receiving anticoagulant therapy should have 
coagulation factors monitored closely throughout the trial.  
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, laboratory 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 laboratory tests that are drug related AEs should be followed until resolution.  Laboratory tests do not need to be repeated after the end of treatment if 
laboratory tests are within normal range.
u.
CBC with Differential, Comprehensive Chemistry Panel, and LDH should be performed every 6 weeks after Cycle 8.
v.
To be repeated every 3 cycles after Cycle 4.
w.
To be repeated every 2 cycles after cycle 5. 
x.
If 2 microglobulin is elevated at baseline, testing should be repeated every 12 weeks. 
y.
Cohort 4D subjects will have Epstein-Barr virus status collected at Screening.
z.
All subjects will have bone marrow biopsy/aspirate performed at baseline.  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. 
aa.
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.
bb. Bone marrow morphology, IHC, and Cytogenetics should be performed with each bone marrow biopsy.  Cytogenetics is done to evaluate whether genetic variation within 
a clinical trial population correlates with response to the treatment(s) under evaluation.  If it is not a standard procedure in your region, this test does not need to be performed.
See Section 7.1.2.7.8 for additional details.
cc.
Tumor biopsies are required for subjects at Screening and Week 12 (± 7 days). If an archival biopsy is not available a new biopsy must be obtained. Tumors that are 
inaccessible or contraindicated due to subject safety concerns are exempt from this requirement at the Week 12 assessment. 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 preferable to obtain a new baseline scan.  
dd. Correlative study samples should be collected at Screening, at the time of the Week 12 disease response assessment, and upon progression. See Section 7.1.2.7.8 and the 
Procedures Manual for additional details.  
ee.
Pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, 8 and every 4 cycles thereafter, 30 days 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. Additional post-dose 
peak PK samples will be drawn within 30 minutes after end of pembrolizumab infusion at Cycles 1 and 8. Procedures for sample collection are described in the Procedures 
Manual.  
ff.
An additional single PK sample should be drawn between 72 and 168 hours after Cycle 1 dosing. 
gg. Informed consent for future biomedical research samples must be obtained before the DNA sample. DNA sample for analysis should be obtained predose, on Day 1 (or with 
the next scheduled blood draw) as the last sample drawn or at a later date as soon as the informed consent is obtained. Detailed instructions for the collection and management 
of specimens for FBR are provided in the Procedures Manual and Section 12.2.
 
 
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6.6
Study Flow Chart F: Cohort 5 Diffuse Large B-Cell Lymphoma (DLBCL) (Subjects allocated to pembrolizumab 200 mg 
administered intravenously once every 21 days in combination with lenalidomide taken orally once daily for 21 days + 
7 days off.  The cycle length is 28 days.)
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 3 cycles
Treatment Cycle/Title:
(28-day cycles)
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Discon
Post-
Treatment 
Safety 
Follow-up
Visitb
Efficacy 
Follow-up 
Visitsc
Survival 
Follow-upd
Cycle Day (visit day)
(± 3 days after Day 1 of Cycle 1 
unless otherwise specified)
(-28 to -1 
days)
1
22
1
15
1
8
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Administrative Procedures
Informed consente
X
Informed consent for future biomedical 
researchf
X
Inclusion/exclusion criteria
X
Subject identification card
X
Demographics and medical history
X
Prior and concomitant medication reviewg
X
X
X
X
X
X
X
X
X
Register subject in REVLIMID REMS™ 
program where applicableh
X
Combination treatments
Pembrolizumab administrationi
See Section 6.6.1
Lenalidomide administrationj
Post-study anticancer therapy status 
X
X
Survival status 
X
Clinical Procedures/Assessments
Review adverse eventsk
X
X
X
X
X
X
X
X
X
X
Full physical examinationl
X
X
X
Directed physical examinationl
X
 
 
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Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 3 cycles
Treatment Cycle/Title:
(28-day cycles)
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Discon
Post-
Treatment 
Safety 
Follow-up
Visitb
Efficacy 
Follow-up 
Visitsc
Survival 
Follow-upd
Cycle Day (visit day)
(± 3 days after Day 1 of Cycle 1 
unless otherwise specified)
(-28 to -1 
days)
1
22
1
15
1
8
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Vital signs and heightm
X
X
X
X
X
X
X
X
12-lead electrocardiogram
X
Pulmonary function testn
X
ECOG performance statuso
X
X
X
X
X
X
Neck, chest, abdominal, pelvic PET/CTp
X
X
±7 days
X
X
Lymphoma disease response assessment by 
Revised Response Criteria for Malignant 
Lymphoma [87]q, r
Xs
±7 days
X
X
Assessment of lymphoma B symptomst
X
X
±7 days
X
X
Laboratory Procedures/Assessments:  analysis performed by local laboratoryu
Pregnancy test – urine or serum -HCGv,w
Xv
Xw
PT/INR and aPTTx
X
X
X
X
CBC with differentialy
X
X
X
X
Comprehensive blood chemistry panelz
X
X
X
X
LDHz
X
X
X
X
Urinalysisz
X
X
X
T3, (or FT3 per local standard), FT4 and 
TSHaa
X
X
X
Creatinine clearance
X
2 microglobulinbb
X
Epstein-Barr viruscc
X
Bone marrow biopsy & aspiratedd
X
 
 
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Product:  MK-3475 (SCH 900475)
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Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 3 cycles
Treatment Cycle/Title:
(28-day cycles)
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Discon
Post-
Treatment 
Safety 
Follow-up
Visitb
Efficacy 
Follow-up 
Visitsc
Survival 
Follow-upd
Cycle Day (visit day)
(± 3 days after Day 1 of Cycle 1 
unless otherwise specified)
(-28 to -1 
days)
1
22
1
15
1
8
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Bone marrow morphology, IHC, 
cytogeneticsdd
X
Laboratory Procedures/Assessments: analysis performed by central laboratory
Lymph node biopsyee
X
X
Correlative studies blood collectionff
X
X
Anti-pembrolizumab antibodiesgg
X
X
X
X
Pembrolizumab pharmacokineticsgg
X
X
X
X
Blood for Future Biomedical Researchhh
X
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; -HCG=beta human chorionic gonadotropin; CBC=complete blood cell count; CT=computed 
tomography; CTCAE=Common Terminology Criteria for Adverse Events; DNA=deoxyribonucleic acid; Discon=discontinuation; ECOG=Eastern Cooperative Oncology 
Group; FDG=fludeoxyglucose; FT3=free triiodothyronine; FT4=free thyroxine; IHC=immunohistochemistry; INR=International Normalized Ratio; LDH=lactate 
dehydrogenase; NCI=National Cancer Institute; PD=progressive disease; PET=positron emission tomography; PK=pharmacokinetic; PT=prothrombin time; REMS=Risk 
Evaluation and Mitigation Strategy; RP2D=recommended Phase II dose; SAE=serious adverse event; T3=triiodothyronine; TSH=thyroid stimulating hormone.
a.
Treatments and assessments are based on 28-day cycles.
b.
After the end of treatment, each subject will be followed for 30 days for AE monitoring.  Serious adverse events will be collected for 90 days after the end of treatment or 
30 days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, and spontaneously reported pregnancy will be collected for 
120 days after the end of treatment.  Serious adverse events and spontaneously reported pregnancy will be reported for 30 days after the end of treatment if the subject 
initiates new anticancer therapy.  See Section 7.2 for additional details.
c.
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.
d.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for 
survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will 
not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death 
event previously recorded).
 
 
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Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 3 cycles
Treatment Cycle/Title:
(28-day cycles)
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Discon
Post-
Treatment 
Safety 
Follow-up
Visitb
Efficacy 
Follow-up 
Visitsc
Survival 
Follow-upd
Cycle Day (visit day)
(± 3 days after Day 1 of Cycle 1 
unless otherwise specified)
(-28 to -1 
days)
1
22
1
15
1
8
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
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 samples is optional.  Detailed instructions for the collection and management of specimens for future 
biomedical research 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.
Lenalidomide must be prescribed through and in compliance with the REVLIMID REMSTM program or protocol specified requirements.  Refer to local prescribing 
information.
i.
Pembrolizumab will be given by intravenous infusion over 30 minutes at a fixed dose of 200 mg.  Each dose will be administered once every 3 weeks within each 28-day 
cycle.  See Section 5.2 and Section 7.1.5.2 for additional details.  See Section 12.9 for additional dose timing details.
j.
Lenalidomide will be given orally once daily at the RP2D established during the safety run-in.  Each dose will be administered for the first 21 consecutive days of each 28-
day cycle.  See Section 5.2 and Section 7.1.5.2 for additional details.  See Section 12.9 for additional dose timing details.
k.
Adverse events 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.  See Section 7.1.2.1 and Section 7.2 for additional details.
l.
A physical examination will be performed before each administration of pembrolizumab.  A full physical examination will be performed at Week 12, and every 12 weeks 
thereafter, and directed physical exams will be conducted before administration of pembrolizumab at each of the other visits.
m.
Vitals signs will include temperature, pulse, respiratory rate, weight, and blood pressure.  Height will be measured at Screening only.
n.
Pulmonary function tests should include an assessment of forced vital capacity, forced expiratory flow between 25 and 75 percent of forced vital capacity, forced 
expiratory volume in 1 second, peak expiratory flow, 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.
o.
ECOG performance status will be performed before administration of each dose of pembrolizumab.
p.
Diagnostic quality CT and PET should be performed at Screening, Week 12, and every 12 weeks following Week 12. For lymphomas that are not FDG-avid at screening, 
PET does not need to be repeated in subsequent assessments. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts or extension 
of treatment cycle frequencies.  In subjects who discontinue study therapy without confirmed disease progression, a radiological assessment should be performed at the 
 
 
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Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 3 cycles
Treatment Cycle/Title:
(28-day cycles)
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Discon
Post-
Treatment 
Safety 
Follow-up
Visitb
Efficacy 
Follow-up 
Visitsc
Survival 
Follow-upd
Cycle Day (visit day)
(± 3 days after Day 1 of Cycle 1 
unless otherwise specified)
(-28 to -1 
days)
1
22
1
15
1
8
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
time of treatment discontinuation (i.e., date of discontinuation ±4 week window).  If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then 
a repeat scan at treatment discontinuation is not mandatory. See Section 7.1.2.7 and the Site Imaging Manual for additional details regarding scan requirements and timing.
q.
Lymphoma disease response assessments [87]should occur at Week 12, and every 12 weeks (±7 days) following the Week 12 assessment.  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 subject is clinically progressing.  See Section 7.1.2.7 for additional details regarding assessment requirements and timing.
r.
Subjects who have progressive disease at the Week 12 assessment should have a confirmation assessment performed at least 4-6 weeks later.  See Section 7.1.2.7.7 for 
additional details on confirmation assessments.
s.
Lymphoma disease response assessments [87]should occur at Week 12, and every 12 weeks (±7 days) following the Week 12 assessment. Disease assessments or scans 
should not be delayed for delays in cycle starts.
t.
Lymphoma B assessments should be performed at Screening and at the time of each disease response assessment.  See Section 7.1.2.7.6 for additional details.
u.
Laboratory tests for screening that are performed at a local laboratory should be completed within 7 days prior to the first dose (Cycle 1) of trial treatment.  Subsequent 
laboratory safety evaluations should be completed within 72 hours of any subsequent trial treatments (i.e., should be available before the subject receives the scheduled 
dose).  See Section 7.1.3.1 for details regarding laboratory safety evaluations.
v.
In females of childbearing potential, two negative pregnancy tests (sensitivity of at least 25 mIU/mL) must be obtained prior to initiating therapy in female subjects 
enrolled in Cohort 5 (DLBCL). The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing lenalidomide therapy.
w.
Females of childbearing potential with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 
28 days while taking lenalidomide, at study discontinuation, and at Day 28 following the last dose of lenalidomide.  Females of childbearing potential with irregular 
menstrual cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 14 days while taking lenalidomide, at study 
discontinuation, and at Days 14 and 28 following the last dose of lenalidomide.
x.
Coagulation factors will be obtained at Screening and repeated during the trial as per the prescribing information for the selected thromboprophylaxis/thromboembolism 
therapy.
y.
CBC with differential is performed weekly for Cycle 1, every 2 weeks for Cycles 2-4, and on Day 1 of each cycle thereafter (monthly). Subjects may require dose 
interruption and/or dose reduction.
z.
LDH, comprehensive chemistry panel, and urinalysis should be performed on Day 1 of Cycles 1-8, and every 8 weeks thereafter. Tests may be performed within ±7 days 
after Day 1 of Cycle 1.
 
 
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Product:  MK-3475 (SCH 900475)
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Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 3 cycles
Treatment Cycle/Title:
(28-day cycles)
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Discon
Post-
Treatment 
Safety 
Follow-up
Visitb
Efficacy 
Follow-up 
Visitsc
Survival 
Follow-upd
Cycle Day (visit day)
(± 3 days after Day 1 of Cycle 1 
unless otherwise specified)
(-28 to -1 
days)
1
22
1
15
1
8
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
aa.
Thyroid function tests (T3, FT4, and TSH) should be performed at Week 4, Week 8, Week 12, and every 12 weeks thereafter. Tests may be performed within ±7 days after 
Day 1 of Cycle 1.
bb. If 2 microglobulin is elevated at baseline, testing should be repeated every 12 weeks.
cc.
All subjects will have Epstein-Barr virus status collected at Screening.
dd. All subjects will have a bone marrow biopsy/aspirate, bone marrow morphology, IHC, and cytogenetics performed at baseline. Cytogenetics is done to evaluate whether 
genetic variation within a clinical trial population correlates with response to the treatment(s) under evaluation.  If it is not a standard procedure in your region, this test 
does not need to be performed. See Section 7.1.2.7.8 for additional details.
ee.
Tumor biopsies are required for subjects at Screening and Week 12 (± 7 days).  If an archival biopsy is not available a new biopsy must be obtained. See Section 7.1.2.7.8
and the Procedures Manual for additional details. Tumors that are inaccessible or contraindicated due to subject safety concerns are exempt from this requirement at the 
Week 12 assessment. 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 preferable to obtain a new baseline scan.
ff.
Correlative study samples should be collected at Screening, at the time of the Week 12 lymphoma disease response assessment, and upon progression. See Section 
7.1.2.7.8 and the Procedures Manual for additional details.
gg. Pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Day 1 of Cycle 1, Day 22 of Cycle 1, Day 15 of Cycle 2, Day 15 of Cycle 5, every 4th
pembrolizumab infusion thereafter, and 30 days after discontinuation of study drug (or until the subject starts new anti-cancer therapy).
hh. Informed consent for future biomedical research samples must be obtained before the DNA sample.  DNA sample for analysis should be obtained predose on Day 1 (or 
with the next scheduled blood draw) as the last sample drawn or at a later date as soon as the informed consent is obtained. Detailed instructions for the collection and 
management of specimens for future biomedical research are provided in the Procedures Manual and Section 12.2.
Note: Cohort 5 has been discontinued and there will be no further enrollment of subjects. All subjects in Cohort 5 must stop combination treatment immediately, complete the 
discontinuation visit and move into the long-term safety and survival follow-up per protocol. If clinically benefitting at time of stopping combination therapy, subjects may enter 
a transition period remaining on single agent lenalidomide or pembrolizumab for up to 90 days from 15-SEP-2017 and then must transition into long-term survival and safety 
follow-up.
 
 
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MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Study Dose Chart F2: Cohort 5 Diffuse Large B-Cell Lymphoma (DLBCL) (Subjects allocated to pembrolizumab 200 
mg administered intravenously once every 21 days in combination with lenalidomide taken orally once daily for 21 days 
+ 7 days off.  The cycle length is 28 days.)
Each Cycle = 28 Days (To be repeated beyond 3 cycles)
Cycle 1
Cycle 2 
Cycle 3
Trial Treatment/ Cycle Day
(± 3 days)
Days
1-7
Days
8-14
Days
15-21
Days
22-28
Days
1-7
Days
8-14
Days
15-21
Days
22-28
Days
1-7
Days
8-14
Days
15-21
Days
22-28
Pembrolizumab (Q3W)a
1
22
15
8
Lenalidomideb
1 to 21
1 to 21
1 to 21
Pill count for Lenalidomidec
1
1
1
Pregnancy Prevention Counseling and 
Dispensing of Lenalidomided
X
Abbreviations: IV=intravenous; PO=per orem; Q3W=every 3 weeks; REMS=Risk Evaluation and Mitigation Strategy; RP2D=recommended Phase II dose.
a.
Pembrolizumab will be administered as 200 mg every 21 days (3 weeks) as an IV infusion over 30 minutes. 
b.
Lenalidomide will be administered as RP2D PO, once daily on Days 1 to 21 of repeated 28-day cycles.  Lenalidomide must be prescribed through and in compliance with 
the REVLIMID REMSTM program.  Refer to local prescribing information.
c.
Site should document drug accountability as per their institutional guidelines.
d.
The Lenalidomide Education and Counseling Guidance Document must be completed for all subjects and signed by a trained counselor prior to each dispensing of 
lenalidomide (see Section 12.10). A copy of this document must be maintained in the subject’s records for each dispense. Lenalidomide will be dispensed every 3-4 weeks 
as per local requirements.
Note: Cohort 5 has been discontinued and there will be no further enrollment of subjects. All subjects in Cohort 5 must stop combination treatment immediately, complete the 
discontinuation visit and move into the long-term safety and survival follow-up per protocol. If clinically benefitting at time of stopping combination therapy, subjects may enter 
a transition period remaining on single agent lenalidomide or pembrolizumab for up to 90 days from 15-SEP-2017 and then must transition into long-term survival and safety 
follow-up.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
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MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
6.7
Study Flow Chart G:  Cohort 1-MDS Second Course Phase (Retreatment for Post-Complete Response Relapse Only) 
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 6 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
Administrative Procedures
Eligibility Criteria
X
Interim Medical History
X
Prior and Concomitant Medication 
Review
Xe
X
X
X
X
X
X
X
X
X
X
Review Transfusion History f
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events g
X
X
X
X
X
X
X
X
X
X
X h
X h
Full Physical Examination
X
X
Xi
X
Directed Physical Examination
X
X
X
X
X
X
Vital Signs and Weight j
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Determine FAB classification, WHO 
Classification, IPSS Score, and IPSS-R 
Score
X
X
X
International Working Group criteria for 
MDS k
X
Xl
Xm
Xb
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
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Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 6 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
Laboratory Procedures/Assessments:  
analysis 
performed 
by 
local 
laboratory
Pregnancy Test – Urine or Serum -
HCG n
X
PT/INR and aPTT o
Xp
CBC with Differential q
Xp
X
X
X
X
X
X
X
X
Xr
Comprehensive Chemistry Panel q
Xp
X
X
X
X
Xr
Reticulocyte Count q
Xp
X
X
X
X
X
X
X
X
Xr
LDH q
Xp
X
X
X
X
Xr
Urinalysis q
Xp
Xs
Xr
T3 (or FT3 per local standard), FT4 and 
TSH q
Xp
X
Xt
Xr
Bone Marrow Biopsy & Aspirate u,v
X
X
X
Bone marrow morphology, Iron stain (at 
screening 
only), 
Blast 
percentage, 
Cytogenetics w
X
X
X
Laboratory Procedures/Assessments: 
analysis 
performed 
by 
central 
laboratory
Correlative Studies Blood/Bone Marrow 
Collection v,x
Xx
Xx
Xx
Anti-pembrolizumab Antibodies y
X x
X x
X y
X y
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
119
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 6 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
Pharmacokinetics y
X y
X y
X y
X y
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; -HCG=beta human chorionic gonadotropin; CBC=complete blood cell count; CTCAE=Common 
Terminology Criteria for Adverse Events; Discon=discontinuation; ECOG=Eastern Cooperative Oncology Group; ECI=events of clinical interest; FAB=French-American-
British; FT3=free triiodothyronine; FT4=free thyroxine; INR=International Normalized Ratio; IPSS= International Prognostic Scoring System; IPSS-R=Revised International 
Prognostic Scoring System; LDH=lactate dehydrogenase; MDS=myelodysplastic syndrome; NCI=National Cancer Institute; PD=progressive disease; PK=pharmacokinetic; 
PT=prothrombin time; SAE=serious adverse event; T3=triiodothyronine; TSH=thyroid stimulating hormone; WHO=World Health Organization.
a.
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. Treatment cycles are 
2 weeks.
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status every 6 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.
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for 
survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will 
not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death 
event previously recorded).
d.
In general, the window for each visit is ± 3 days unless otherwise noted. 
e.
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.
f.
Transfusion history should be documented for 3 months prior to start of study and every 6 weeks during response assessment.  Transfusion history should be obtained from 
subject medical records and/or blood bank records.  
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.
i.
To be repeated every 6 weeks after cycle 6.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
120
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 6 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
j.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at visit 1 only.  
k.
Disease response assessment is made based upon the MDS response criteria and includes CBC and documentation of transfusions. Response assessments should occur at 
screening, Week 6, Week 12, and every 6 weeks (+/- 7 days).  For subjects who discontinue for reasons other than PD, assessments should continue until the subject has 
documented PD.  Bone marrow assessments should be performed at Screening, Week 6 (± 7 days), Week 12 (± 7 days), and then every 12 weeks or as clinically indicated.  
l.
Subjects who have progressive disease at the Week 12 assessment should have a confirmation assessment performed at least 28 days later (after Week 16). See Section 
7.1.2.7.7 for additional details regarding confirmation assessments.
m.
In subjects who discontinue study therapy without confirmed disease progression, a response assessment should be performed at the time of treatment discontinuation (i.e. 
date of discontinuation ± 4 week window). If previous assessment was performed within 4 weeks prior to the date of discontinuation, then a repeat assessment at treatment 
discontinuation is not 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.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. Any subject receiving anticoagulant therapy should have 
coagulation factors monitored closely throughout the trial.  
p.
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.  
q.
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time point. See Section 7.1.3 for details regarding laboratory tests.  
r.
Unresolved abnormal laboratory tests that are drug related AEs should be followed until resolution. Laboratory tests do not need to be repeated after the end of treatment if 
laboratory tests are within normal range.
s.
To be repeated every 4 cycles after Cycle 5.
t.
To be repeated every 3 cycles after Cycle 7.
u.
Detailed instructions for bone marrow collection, processing and shipment are provided in the Procedures Manual.  Bone marrow biopsy and aspirate should be collected at 
screening, Wk 6 (± 7 days), Wk 12 (± 7 days), and every 12 weeks while on study treatment or as clinically indicated.  If a subject has disease progression at Wk 12 and a 
confirmatory assessment is performed at Wk 16, a biopsy and aspirate should be performed as part of the confirmation assessment.  A confirmation biopsy does not need to 
be performed for subjects who have stable disease, partial response, or complete response at Wk 12.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
121
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 6 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed by 
the 
Sponsor
v.
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.
w.
Bone marrow morphology, Blast percentage, and Cytogenetics should be performed with each bone marrow biopsy/aspirate procedure.  Iron stain is performed at screening 
only.  Cytogenetics is done to evaluate whether genetic variation within a clinical trial population correlates with response to the treatment(s) under evaluation.  If it is not a 
standard procedure in your region, this test does not need to be performed.
x.
Correlative study samples should be collected at Screening, at the time of the Wk 6/Wk 12 disease response assessments, and upon progression.
y.
Pre-dose trough PK samples will be collected at Cycles 1, 2, 7, every 6 cycles thereafter, 30 days after discontinuation of study drug, and 3 months and 6 months after 
discontinuation of study drug (or until the subject starts new anti-cancer therapy).  All trough samples should be drawn within 24 hours before infusion of pembrolizumab.  
Anti-pembrolizumab antibodies should be drawn with all pre-dose trough PK, 30 days after discontinuation of study drug or until the subject starts new anti-cancer therapy.  
Procedures for sample collection are described in the Procedures Manual.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
122
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
6.8
Study Flow Chart H:  Cohort 2-Multiple Myeloma Second Course Phase (Retreatment for Post-Stringent Complete 
Response (sCR) Relapse Only) (Subjects allocated to 10mg/kg Q2W)  
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy
Follow-up 
Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 12 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or as 
directed by the 
Sponsor
Administrative Procedures
Eligibility Criteria
X
Interim Medical History
X
Prior and Concomitant Medication 
Review e
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
Post-study 
anticancer 
therapy 
status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events f
X
X
X
X
X
X
X
X
X
X
X g
X g
Full Physical Examination
X
 
X h
X
Directed Physical Examination
X
X
X
Vital Signs and Weight i
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Skeletal survey j
X
MRI/CT/PET (only for subjects 
with bone disease/plasmacytoma) j
X
International Myeloma Working 
Group Uniform Response Criteria k  
X
X
Xl
Xm
Xb
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
123
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy
Follow-up 
Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 12 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or as 
directed by the 
Sponsor
Laboratory 
Procedures/Assessments:  
analysis performed by local 
laboratory
Pregnancy Test – Urine or Serum 
-HCG n
X
PT/INR and aPTT o
Xp
CBC with Differential q
Xp
X
X
X
X
Xr
Comprehensive Chemistry Panel q
Xp
X
X
X
X
Xr
LDH q
Xp
X
X
X
X
Xr
Urinalysis q
Xp
X s
Xr
T3 (or FT3 per local standard), FT4 
and TSH q
Xp
X
X t
Xr
Viscosity q
Xp
Quantitative 
Serum 
Immunoglobulin 
Xp
X
X
X
Serum protein electrophoresis and 
serum immunofixation 
Xp
X
X
X
Serum free light chain assay 
Xp
X
X
X
24 hr urine protein electrophoresis 
and urine immunofixation 
Xp
X
X
X
M-protein quantitation (urine and 
serum) 
Xp
X
X
X
2 microglobulin 
Xp
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
124
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy
Follow-up 
Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 12 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or as 
directed by the 
Sponsor
Bone Marrow Biopsy & Aspirate u, 
v
X
X
X
Bone marrow morphology, IHC, 
Cytogenetics 
by 
standard 
karyotyping, FISH panel w,x
X
X
X
Laboratory 
Procedures/Assessments: 
analysis performed by central 
laboratory
Correlative Studies Blood /Bone 
Marrow Collection u,y
X
X
X
Anti-pembrolizumab Antibodies z
X z
X z
X z
X z
Pharmacokinetics z
X z
X z
X z
X z
Abbreviations: AE=adverse event; AP=anteroposterior; aPTT=activated partial thromboplastin time; -HCG=beta human chorionic gonadotropin; CBC=complete blood cell 
count; CT=computed tomography; CTCAE=Common Terminology Criteria for Adverse Events; Discon=discontinuation; ECOG=Eastern Cooperative Oncology Group; 
ECI=events of clinical interest; FISH=fluorescence in situ hybridization; FT3=free triiodothyronine; FT4=free thyroxine; IHC=immunohistochemistry; INR=International 
Normalized Ratio; LDH=lactate dehydrogenase; MRI=magnetic resonance imaging; NCI=National Cancer Institute; PA=posterior-anterior; PD=progressive disease; 
PET=positron emission tomography; PK=pharmacokinetic; PT=prothrombin time; Q2W=every 2 weeks; SAE=serious adverse event; T3=triiodothyronine; TSH=thyroid 
stimulating hormone.
a.
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.  Treatment cycles are 2 
weeks.
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status 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.
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for 
survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will 
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
125
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy
Follow-up 
Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 12 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or as 
directed by the 
Sponsor
not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death 
event previously recorded).
d.
In general, the window for each visit is ± 3 days unless otherwise noted. 
e.
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.
f.
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.
g.
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.
h.
To be repeated every 6 cycles after cycle 6.
i.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure.  Height will be measured at visit 1 only.  
j.
Skeletal survey should include a chest (PA or AP; lateral), skull (lateral), upper extremities (shoulder to elbow), lower extremities (hip to knee; AP), pelvis (AP), 
cervical/thoracic/lumbar spine (AP and lateral).  A skeletal survey and/or MRI/CT/PET (MRI for subjects with bone disease and CT/PET for plasmacytomas) performed as 
standard of care prior to signing consent can be used for screening if performed within 28 days of Day 1.  For suspected progression to bone disease bidirectional measurement 
of the target lytic lesions must be performed.  During the course of the study or if a subject develops bone pain a skeletal survey and/or MRI/CT/PET (MRI for subjects with 
bone disease and CT/PET for plasmacytomas) should be performed annually or as clinically indicated.  Subjects with measurable plasmacytomas at baseline should have 
imaging performed every 8 weeks.   
k.
Disease response assessment is based upon the multiple myeloma response criteria.  Disease assessments should occur at Screening and every 4 weeks (± 7 days) while on 
study treatment.  For subjects who discontinue for reasons other than PD, assessments should continue until the subject has documented PD.  Parameters assessed should 
include serum protein electrophoresis and serum immunofixation, serum free light chain assay, 24 hr urine protein electrophoresis and urine immunofixation,  M-protein 
quantitation (urine and serum),  and urine protein electrophoresis.
l.
Subjects who have progressive disease at the Wk 12 assessment should have a confirmation assessment performed at least 28 days later (after Wk 16).  Additionally, for 
subjects who have progressive disease at the Wk 12 assessment, a bone marrow biopsy/aspirate should be performed as part of the Wk 16 confirmation assessment.  See 
Section 7.1.2.7.7 for additional details regarding confirmation assessments.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
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Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy
Follow-up 
Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 12 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or as 
directed by the 
Sponsor
m.
In subjects who discontinue study therapy without confirmed disease progression, a response assessment should be performed at the time of treatment discontinuation (i.e. 
date of discontinuation ± 4 week window).  If previous assessment was performed within 4 weeks prior to the date of discontinuation, then a repeat assessment at treatment 
discontinuation is not 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.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects.  Any subject receiving anticoagulant therapy should have coagulation 
factors monitored closely throughout the trial.  
p.
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.  
q.
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time point.  See Section 7.1.3 for details regarding laboratory tests.  Viscosity should be 
performed at Screening and as clinically necessary during the trial.
r.
Unresolved abnormal laboratory tests that are drug related AEs should be followed until resolution.  Laboratory tests do not need to be repeated after the end of treatment if laboratory 
tests are within normal range.
s.
To be repeated every 4 cycles after Cycle 5.
t.
To be repeated every 3 cycles after Cycle 7.
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.
Bone marrow biopsy/aspirate should be performed at Screening, Cycle 1 Day 1 (Cycle 1 Day 1 only if Screening Bone Marrow Aspirate/Biopsy was performed greater than 28 days 
from Day 1 Cycle 1), Week 4 (± 7 days), Week 12 (± 7 days),  to confirm sCR and CR, or as clinically indicated. For subjects who have progressive disease at the Week 12 assessment, 
a bone marrow biopsy/aspirate should be performed as part of the Week 16 confirmation assessment. A bone marrow biopsy/aspirate performed as part of standard of care prior to 
signing informed consent may be used for screening if performed within 28 days of Day 1. When a bone marrow biopsy is performed, the paraffin-embedded block must be sent to 
the central laboratory.
w.
Bone marrow morphology and IHC should be performed with each bone marrow biopsy. Cytogenetics by standard karyotyping and FISH panel should be performed at screening 
only.
x.
FISH panel should include del 1p, del 13, del 17p13, t(4;14), t(11;14), t(14;16), and 1q21 amplification.
y.
Correlative study samples should be collected at Screening, at the time of the Week 4 and Week 12 disease response assessments, and upon progression.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
127
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy
Follow-up 
Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 12 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or as 
directed by the 
Sponsor
z.
Pre-dose trough PK samples will be collected at Cycles 1, 2, 7, every 6 cycles thereafter, 30 days after discontinuation of study drug, and 3 months and 6 months after discontinuation 
of study drug (or until the subject starts new anti-cancer therapy). All trough samples should be drawn within 24 hours before infusion of pembrolizumab.  Anti-pembrolizumab
antibodies should be drawn with all pre-dose trough PK, 30 days after discontinuation of study drug or until the subject starts new anti-cancer therapy.  Procedures for sample collection 
are described in the Procedures Manual.  
Note: Cohort 2 subjects are no longer eligible for second course treatment phase.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
128
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
6.9
Study Flow Chart I:  Cohort 3, 4A, 4B Hodgkin Lymphoma, Mediastinal Large B-Cell Lymphoma, & any-other PD-L1 
Positive Non-Hodgkin Lymphoma Second Course Phase (Retreatment for Post-Complete Response Relapse Only) 
(Subjects allocated to 10 mg/kg Q2W)
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 8 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
Administrative Procedures
Eligibility Criteria
X
Interim Medical History
X
Prior and Concomitant Medication Review e
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events f
X
X
X
X
X
X
X
X
X
X
X g
X
Full Physical Examination 
X
X
X h
X
Directed Physical Examination
X
X
Vital Signs and Weight i
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Pulmonary Function Test j
X
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
129
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 8 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
Neck, Chest, Abdominal, Pelvic PET/CT k
X
X
k
X l
X m
X b
Disease Response Assessment by Revised 
Response Criteria for Malignant Lymphoma
X
k
X
X
X
Assessment of Lymphoma B Symptoms k
X
X
k
X
X
X
Laboratory 
Procedures/Assessments:  
analysis performed by local laboratory
Pregnancy Test – Urine or Serum -HCG n
X
PT/INR and aPTT o
X p
CBC with Differential q
X p
X
X
X
X
X r
Comprehensive Chemistry Panel q
X p
X
X
X
X
X r
LDH q
X p
X
X
X
X
X r
Urinalysis q
X p
X s
X r
T3 (or FT3 per local standard), FT4 and TSH
q
X p
X
X t
X r
2 microglobulin q,u
X p
X u
Bone Marrow Biopsy & Aspirate v,w
X
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
130
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 8 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
Bone 
marrow 
morphology, 
IHC, 
Cytogenetics x
X
Laboratory 
Procedures/Assessments: 
analysis performed by central laboratory
Lymph Node Biopsy w, y
X
X
Correlative Studies Blood Collection w,z
X
X
Anti-pembrolizumab Antibodies aa
Xaa
Xaa
Xaa
Xaa
Pharmacokinetics aa
Xaa
Xaa
Xaa
Xaa
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; -HCG=beta human chorionic gonadotropin; CBC=complete blood cell count; CR=complete 
response; CT=computed tomography; CTCAE=Common Terminology Criteria for Adverse Events; Discon=discontinuation; ECOG=Eastern Cooperative Oncology Group; 
ECI=events of clinical interest; FDG=fludeoxyglucose; FEF=forced expiratory flow; FT3=free triiodothyronine; FT4=free thyroxine; FVC=forced vital capacity; 
IHC=immunohistochemistry; INR=International Normalized Ratio; LDH=lactate dehydrogenase; NCI=National Cancer Institute; PD=progressive disease; PD-L1=programmed 
cell death ligand 1; PET=positron emission tomography; PK=pharmacokinetic; PT=prothrombin time; Q2W=every 2 weeks; SAE=serious adverse event; T3=triiodothyronine; 
TSH=thyroid stimulating hormone.
a.
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. Treatment cycles are 2 
weeks.
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 8 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.
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for 
survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will 
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
131
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 8 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death 
event previously recorded).
d.
In general, the window for each visit is ± 3 days unless otherwise noted. 
e.
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.
f.
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.
g.
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.
h.
To be repeated every 6 cycles after cycle 7.
i.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at visit 1 only.  
j.
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.
k.
Disease response assessment is based upon Revised Response Criteria for Malignant Lymphoma. “Diagnostic quality” CT and PET should be performed at Screening and 
both should be repeated for subsequent assessments. For lymphomas that are not FDG-avid at screening, PET does not need to be repeated in subsequent assessments.  
Response assessments should occur at Screening (within 28 days prior to first dose of trial treatment), Week 12, and every 8 weeks (7 days) following the Week 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.  Assessment of lymphoma B symptoms should occur with 
each disease response assessment. The first assessment may be performed earlier than 12 weeks if in the opinion of the investigator the subject is clinically progressing.  
l.
Subjects who have progressive disease at the Week 12 assessment should have a confirmation assessment performed at least 28 days later (after Week 16) (+7 days). See 
Section 7.1.2.7.7 for additional details regarding confirmation assessments.  
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
132
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 8 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
m.
In subjects who discontinue study therapy without confirmed disease progression, a radiological assessment should be performed at the time of treatment discontinuation 
(i.e. date of discontinuation ± 4 week window). If previous scan was obtained within 4 weeks prior to the date of discontinuation, then a repeat scan at treatment 
discontinuation is not 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.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. Any subject receiving anticoagulant therapy should have 
coagulation factors monitored closely throughout the trial.  
p.
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.  
q.
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time point. See Section 7.1.3 for details regarding laboratory tests.  
r.
Unresolved abnormal laboratory tests that are drug related AEs should be followed until resolution. Laboratory tests do not need to be repeated after the end of treatment if 
laboratory tests are within normal range.
s.
To be repeated every 4 cycles after Cycle 5.
t.
To be repeated every 3 cycles after Cycle 7.
u.
If 2 microglobulin is elevated at baseline, testing should be repeated every 12 weeks. 
v.
All subjects will have bone marrow biopsy/aspirate performed at baseline.  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. 
w.
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.
x.
Bone marrow morphology, IHC, and Cytogenetics should be performed with each bone marrow biopsy. Cytogenetics is done to evaluate whether genetic variation within a 
clinical trial population correlates with response to the treatment(s) under evaluation. If it is not a standard procedure in your region, this test does not need to be performed.
y.
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 
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
133
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 8 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
assessment, it is preferred to obtain a new baseline scan. Newly obtained tumor biopsies are required for all lymphoma subjects at Screening and Week 12 (± 7 days).  Tumors 
that are inaccessible or contraindicated due to subject safety concerns are exempt from this requirement.    
z.
Correlative study samples should be collected at Screening, at the time of the Wk 12 disease response assessment, and upon progression.
aa.
Pre-dose trough PK samples will be collected at Cycles 1, 2, 7, every 6 cycles thereafter, 30 days after discontinuation of study drug, and 3 months and 6 months after 
discontinuation of study drug (or until the subject starts new anti-cancer therapy). All trough samples should be drawn within 24 hours before infusion of pembrolizumab.  
Anti-pembrolizumab antibodies should be drawn with all pre-dose trough PK, 30 days after discontinuation of study drug or until the subject starts new anti-cancer therapy.  
Procedures for sample collection are described in the Procedures Manual.  
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
134
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
6.10 Study Flow Chart J:  Multiple Myeloma (Cohort 2) Second Course Phase (Retreatment for Post-Stringent Complete 
Response (sCR) Relapse Only) (For subjects allocated to 200 mg Q3W)
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Administrative Procedures
Eligibility Criteria
X
Interim Medical History
X
Prior and Concomitant Medication Review 
e
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration 
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events f
X
X
X
X
X
X
X
X
X
X
X g
X g
Full Physical Examination
X
X 
X h
X
Directed Physical Examination
X
X
X
X
Vital Signs and Weight i
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Skeletal survey j
X
MRI/CT/PET j
X
International Myeloma Working Group 
Uniform Response Criteria k
X
X
X
Xl
X
X
X
Xm
Xb
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
135
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Laboratory 
Procedures/Assessments:  
analysis performed by local laboratory
Pregnancy Test – Urine or Serum -HCG n
X
PT/INR and aPTT o
Xp
CBC with Differential q
Xp
X
X
X
X
X
X
X
X
Xr
Comprehensive Chemistry Panel q
Xp
X
X
X
X
X
X
X
X
Xr
LDH q
Xp
X
X
X
X
X
X
X
X
Xr
Urinalysis q
Xp
X s
X
Xr
T3 (or FT3 per local standard), FT4 and 
TSH q
Xp
X
X t
X
Xr
Viscosity q
Xp
Quantitative Serum Immunoglobulin 
Xp
X
X
X
X
X
X
X
Serum protein electrophoresis and serum 
immunofixation 
Xp
X
X
X
X
X
X
X
Serum free light chain assay 
Xp
X
X
X
X
X
X
X
24 hr urine protein electrophoresis and urine 
immunofixation 
Xp
X
X
X
X
X
X
X
M-protein quantitation (urine and serum)
Xp
X
X
X
X
X
X
X
2 microglobulin 
Xp
Bone Marrow Biopsy & Aspirate u,v
X
X
X
Bone 
marrow 
morphology, 
IHC, 
Cytogenetics by standard karyotyping, 
FISH panel w,x
X
X
X
 
 
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Product:  MK-3475 (SCH 900475)
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Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
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Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
Laboratory 
Procedures/Assessments: 
analysis performed by central laboratory
Correlative Studies Blood /Bone Marrow 
Collection u,y
X
X
X
Anti-pembrolizumab Antibodies z
Xz
Xz
Xz
Xz
Xz
Pharmacokinetics z
Xz
Xz
Xz
Xz
Xz
Abbreviations: AE=adverse event; AP=anteroposterior; aPTT=activated partial thromboplastin time; -HCG=beta human chorionic gonadotropin; CBC=complete blood 
cell count; CT=computed tomography; CTCAE=Common Terminology Criteria for Adverse Events; Discon=discontinuation; ECOG=Eastern Cooperative Oncology Group; 
ECI=events of clinical interest; FISH=fluorescence in situ hybridization; FT3=free triiodothyronine; FT4=free thyroxine; IHC=immunohistochemistry; INR=International 
Normalized Ratio; LDH=lactate dehydrogenase; NCI=National Cancer Institute; PA=posterior-anterior; PD=progressive disease; PET=positron emission tomography; 
PK=pharmacokinetic; PT=prothrombin time; Q3W=every 3 weeks; SAE=serious adverse event; T3=triiodothyronine; TSH=thyroid stimulating hormone.
a.
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. Treatment cycles are 3 weeks. 
b.
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status 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.
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for survival 
status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will not have a 
scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death event previously 
recorded).
d.
In general, the window for each visit is ± 3 days unless otherwise noted. 
e.
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.
f.
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.
 
 
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Product:  MK-3475 (SCH 900475)
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Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
g.
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.
h.
To be repeated every 4 cycles after cycle 5.
i.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at visit 1 only.  
j.
Skeletal survey should include a chest (PA or AP; lateral), skull (lateral), upper extremities (shoulder to elbow), lower extremities (hip to knee; AP), pelvis (AP), 
cervical/thoracic/lumbar spine (AP and lateral). A skeletal survey and/or MRI/CT/PET (MRI for subjects with bone disease and CT/PET for plasmacytomas) performed as 
standard of care prior to signing consent can be used for screening if performed within 28 days of Day 1. For suspected progression to bone disease bidirectional measurement 
of the target lytic lesions must be performed. During the course of the study or if a subject develops bone pain a skeletal survey and/or MRI/CT/PET (MRI for subjects with bone
disease and CT/PET for plasmacytomas) should be performed annually or as clinically indicated. Subjects with measurable plasmacytomas at baseline should have imaging 
performed every 9 weeks. 
k.
Disease response assessment is based upon the multiple myeloma response criteria. Disease assessments should occur at Screening and every 3 weeks (± 7 days) while on study 
treatment. For subjects who discontinue for reasons other than PD, assessments should continue until the subject has documented PD.  Parameters assessed should include serum 
protein electrophoresis and serum immunofixation, serum free light chain assay, 24 hr urine protein electrophoresis and urine immunofixation,  M-protein quantitation (urine and 
serum),  and urine protein electrophoresis.
l.
Subjects who have progressive disease at the Week 12 assessment (Cycle 5) should have a confirmation assessment performed at least 21 days later (after Week 15).  Additionally, 
for subjects who have progressive disease at the Week 12 assessment, a bone marrow biopsy/aspirate should be performed as part of the Week 15 confirmation assessment. See 
Section 7.1.2.7.7 for additional details regarding confirmation assessments.
m.
In subjects who discontinue study therapy without confirmed disease progression, a response assessment should be performed at the time of treatment discontinuation (i.e. date 
of discontinuation ± 4 week window).  If previous assessment was performed within 4 weeks prior to the date of discontinuation, then a repeat assessment at treatment 
discontinuation is not 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.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
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Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-
up Visitsb
Survival 
Follow-upc
Scheduling Window (Days)d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 12 
weeks 
post 
Discon
(±7 days)
Every 12 
weeks
(±7 days) or 
as directed 
by the 
Sponsor
o.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. Any subject receiving anticoagulant therapy should have coagulation 
factors monitored closely throughout the trial.  
p.
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.  
q.
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time point. See Section 7.1.3 for details regarding laboratory tests. Viscosity should be 
performed at Screening and as clinically necessary during the trial.  
r.
Unresolved abnormal laboratory tests that are drug related AEs should be followed until resolution. Laboratory tests do not need to be repeated after the end of treatment if 
laboratory tests are within normal range.
s.
To be repeated every 3 cycles after Cycle 4.
t.
To be repeated every 2 cycles after cycle 5
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.
Bone marrow biopsy/aspirate should be performed at Screening, Cycle 1 Day 1 (Cycle 1 Day 1 only if Screening Bone Marrow Aspirate/Biopsy was performed greater than 28 
days from Day 1 Cycle 1), Week 6 (± 7 days), Week 12 (± 7 days), to confirm sCR and CR, or as clinically indicated. For subjects who have progressive disease at the Week 12 
assessment, a bone marrow biopsy/aspirate should be performed as part of the Week 15 confirmation assessment. A bone marrow biopsy/aspirate performed as part of standard 
of care prior to signing informed consent may be used for screening if performed within 28 days of Day 1. When a bone marrow biopsy is performed, the paraffin-embedded 
block must be sent to the central laboratory.  
w.
Bone marrow morphology and IHC should be performed with each bone marrow biopsy. Cytogenetics by standard karyotyping, and FISH panel should be performed at screening 
only.
x.
FISH panel should include del 1p, del 13, del 17p13, t(4;14), t(11;14), t(14;16), and 1q21 amplification.
y.
Correlative study samples should be collected at Screening, at the time of the Week 6 and Week 12 disease response assessments, and upon progression.
z.
Pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, 8 and every 4 cycles thereafter, 30 days 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. Additional post-dose peak PK 
samples will be drawn within 30 minutes after end of pembrolizumab infusion at Cycles 1 and 8. Procedures for sample collection are described in the Procedures Manual.
Note: Cohort 2 subjects are no longer eligible for second course treatment phase.
 
 
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Product:  MK-3475 (SCH 900475)
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Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
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Confidential
6.11 Study Flow Chart K:  Cohort 4A, 4C, 4D Mediastinal Large B-Cell Lymphoma, Follicular Lymphoma (FL), and Diffuse 
Large B-Cell Lymphoma (DLBCL) Second Course Phase (Retreatment for Post-Complete Response Relapse Only)
(Subjects allocated to 200 mg Q3W).  
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 
3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 9 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
Administrative Procedures
Eligibility Criteria
X
Interim Medical History
X
Prior 
and 
Concomitant 
Medication 
Review e
X
X
X
X
X
X
X
X
X
X
X
Trial Treatment Administration
X
X
X
X
X
X
X
X
Post-study anticancer therapy status
X
X
Survival Status
X
Clinical Procedures/Assessments
Review Adverse Events f
X
X
X
X
X
X
X
X
X
X
X g
X
Full Physical Examination 
X
X
X h
X
Directed Physical Examination
X
X
X
X
Vital Signs and Weight i
X
X
X
X
X
X
X
X
X
X
12-Lead Electrocardiogram
X
ECOG Performance Status
X
X
X
X
X
X
X
X
X
X
Pulmonary Function Test j
X
Neck, Chest, Abdominal, Pelvic PET/CT k
X
X
X l
X 
X m
X b
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
140
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 
3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 9 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
Disease Response Assessment by Revised 
Response 
Criteria 
for 
Malignant 
Lymphoma
X
X
X
X
X
Assessment of Lymphoma B Symptoms k
X
X
X
X
X
X
Laboratory 
Procedures/Assessments:  
analysis performed by local laboratory
Pregnancy Test – Urine or Serum -HCG 
n
X
PT/INR and aPTT o
X p
CBC with Differential q
X p
X
X
X
X 
X
X
Xs
X
X r
Comprehensive Chemistry Panel q
X p
X
X 
X 
X
X
X
Xs
X
X r
LDH q
X p
X
X
X 
X
X 
X
Xs
X
X r
Urinalysis q
X p
Xt
X r
T3 (or FT3 per local standard), FT4 and 
TSHq
X p
X
X u
X
X r
2 microglobulinq,v
X p
X v
Bone Marrow Biopsy & Aspirate w,x
X
Bone 
marrow 
morphology, 
IHC, 
Cytogenetics y
X
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
141
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 
3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 9 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
Laboratory 
Procedures/Assessments: 
analysis 
performed 
by 
central 
laboratory
Lymph Node Biopsy x, z
X
X
Correlative Studies Blood Collectionx, aa
X
X
Anti-pembrolizumab Antibodies bb
Xbb
Xbb
Xbb
Xb
b
Xbb
Pharmacokinetics bb
Xbb
Xbb
Xbb
Xb
b
Xbb
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; -HCG=beta human chorionic gonadotropin; CBC=complete blood cell count; CR=complete 
response; CT=computed tomography; CTCAE=Common Terminology Criteria for Adverse Events; Discon=discontinuation; ECOG=Eastern Cooperative Oncology Group; 
ECI=events of clinical interest; FDG=fludeoxyglucose; FEF=forced expiratory flow; FT3=free triiodothyronine; FT4=free thyroxine; FVC=forced vital capacity; 
IHC=immunohistochemistry; INR=International Normalized Ratio; LDH=lactate dehydrogenase; NCI=National Cancer Institute; PD=progressive disease; PET=positron 
emission tomography; PK=pharmacokinetic; PT=prothrombin time; Q3W=every 3 weeks; SAE=serious adverse event; T3=triiodothyronine; TSH=thyroid stimulating 
hormone.
a.
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. Treatment cycles are 
3 weeks.
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 9 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.
 
 
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Product:  MK-3475 (SCH 900475)
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Confidential
c.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess 
for survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do 
not/will not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who 
have a death event previously recorded).
d.
In general, the window for each visit is ± 3 days unless otherwise noted. 
e.
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.
f.
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.
g.
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.
h.
To be repeated every 4 cycles after cycle 5.
i.
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at visit 1 only. 
j.
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.
k.
Disease response assessment is based upon Revised Response Criteria for Malignant Lymphoma. “Diagnostic quality” CT and PET should be performed at Screening 
and both should be repeated for subsequent assessments. For lymphomas that are not FDG-avid at screening, PET does not need to be repeated in subsequent 
assessments.  Response assessments should occur at Screening (within 28 days prior to first dose of trial treatment), Week 6, Week 12, and every 9 weeks (7 days) 
following the Week 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. Assessment of lymphoma 
B symptoms should occur with each disease response assessment. The first assessment may be performed earlier than 12 weeks if in the opinion of the investigator the 
subject is clinically progressing.  
l.
Subjects who have progressive disease at the Week 12 assessment should have a confirmation assessment performed at least 21 days later (after Week 15) (+7 days). 
See Section 7.1.2.7.7 for additional information on confirmation assessments. See Section 7.1.2.7.7 for additional details regarding confirmation assessments.
m.
In subjects who discontinue study therapy without confirmed disease progression, a radiological assessment should be performed at the time of treatment discontinuation 
(i.e. date of discontinuation ± 4 week window). If previous scan was obtained within 4 weeks prior to the date of discontinuation, then a repeat scan at treatment 
discontinuation is not 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.
Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. Any subject receiving anticoagulant therapy should have 
coagulation factors monitored closely throughout the trial.  
p.
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.  
q.
After Cycle 1, laboratory samples can be collected up to 72 hours prior to the scheduled time point. See Section 7.1.3 for details regarding laboratory tests.  
r.
Unresolved abnormal laboratory tests that are drug related AEs should be followed until resolution. Laboratory tests do not need to be repeated after the end of treatment 
if laboratory tests are within normal range.
s.
CBC with Differential, Comprehensive Chemistry Panel, and LDH should be performed every 6 weeks after Cycle 8.
t.
To be repeated every 3 cycles after Cycle 4.
u.
To be repeated every 2 cycles after cycle 5. 
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
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Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cycles a
End of 
Treatment
Post-treatment
To be repeated beyond 8 
cycles
Treatment Cycle/Title:
Screening
(Visit 1)
1
2
3
4
5
6
7
8
Discon
Post-
Treatment 
Safety 
Follow-up
Visit
Efficacy 
Follow-up 
Visits b
Survival 
Follow-up 
c
Scheduling Window (Days) d:
-28 to -1
± 3
± 3
± 3
± 3
± 3
± 3
± 3
± 
3
At time of 
Discon
30 days 
post 
Discon
(±3 days)
Every 9 
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
v.
If 2 microglobulin is elevated at baseline, testing should be repeated every 12 weeks. 
w.
All subjects will have bone marrow biopsy/aspirate performed at baseline. 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. 
x.
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.
y.
Bone marrow morphology, IHC, and Cytogenetics should be performed with each bone marrow biopsy. Cytogenetics is done to evaluate whether genetic variation 
within a clinical trial population correlates with response to the treatment(s) under evaluation. If it is not a standard procedure in your region, this test does not need to 
be performed. See section 7.1.2.7.8 for additional details. 
z.
Tumor biopsies are required for subjects at Screening and Week 12 (± 7 days).  If an archival biopsy is not available a new biopsy must be obtained.  
aa.
Correlative study samples should be collected at Screening, at the time of the Week 12 disease response assessment, and upon progression. See section 7.1.2.7.8 and 
the Procedures Manual for additional details.   
bb. Pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Cycles 1, 2, 4, 8 and every 4 cycles thereafter, 30 days 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. 
Additional post-dose peak PK samples will be drawn within 30 minutes after end of pembrolizumab infusion at Cycles 1 and 8. Procedures for sample collection are 
described in the Procedures Manual.
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
144
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
6.12 Study Flow Chart L:  Cohort 5 Diffuse Large B-Cell Lymphoma (DLBCL) Second Course Phase (Retreatment for Post-
Complete Response Relapse Only) (Subjects allocated to pembrolizumab 200 mg administered intravenously once every 
21 days in combination with lenalidomide taken orally once daily for 21 days + 7 days off.  The cycle length is 28 days.)
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 3 cycles
Treatment Cycle/Title:
(28-day cycles)
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Discon
Post-
Treatment 
Safety 
Follow-up
Visitb
Efficacy 
Follow-up 
Visitsc
Survival 
Follow-
upd
Cycle Day (visit day)
(± 3 days after Day 1 of Cycle 1 
unless otherwise specified)
(-28 to -1 
days)
1
22
1
15
1
8
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 12
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
Administrative Procedures
Inclusion/exclusion criteria
X
Subject identification card
X
Demographics and interim medical history
X
Prior and concomitant medication reviewe
X
X
X
X
X
X
X
X
X
Reconfirm subject registration in REVLIMID 
REMS™ program where applicablef
X
Combination treatments
Pembrolizumab administrationg
See Section 6.12.1
Lenalidomide administrationh
Post-study anticancer therapy status
X
X
Survival status 
X
Clinical Procedures/Assessments
Review adverse eventsi
X
X
X
X
X
X
X
X
X
X
Full physical examinationj
X
X
X
Directed physical examinationj
X
Vital signsk
X
X
X
X
X
X
X
X
12-lead electrocardiogram
X
 
 
05GL8N

Product:  MK-3475 (SCH 900475)
145
Protocol/Amendment No.: 013-09 
MK-3475-013-09 Final Protocol
16-Apr-2020
Confidential
Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 3 cycles
Treatment Cycle/Title:
(28-day cycles)
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Discon
Post-
Treatment 
Safety 
Follow-up
Visitb
Efficacy 
Follow-up 
Visitsc
Survival 
Follow-
upd
Cycle Day (visit day)
(± 3 days after Day 1 of Cycle 1 
unless otherwise specified)
(-28 to -1 
days)
1
22
1
15
1
8
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 12
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
Pulmonary function testl
X
ECOG performance statusm
X
X
X
X
X
X
Neck, chest, abdominal, pelvic PET/CTn
X
X
±7 days
X
X
Lymphoma disease response assessment by 
Revised Response Criteria for Malignant 
Lymphoma [87]o,p
Xq
±7 days
X
X
Assessment of lymphoma B symptomsr
X
X
±7 days
X
X
Laboratory Procedures/Assessments:  analysis performed by local laboratorys
Pregnancy test – urine or serum -HCGt,u
Xt
Xu
PT/INR and aPTTv
X
X
X
X
CBC with differentialw
X
X
X
X
Comprehensive blood chemistry panelx
X
X
X
X
LDHx
X
X
X
X
Urinalysisx
X
X
X
T3, (or FT3 per local standard), FT4 and 
TSHy
X
X
X
Creatinine clearance
X
2 microglobulinz
X
Epstein-Barr virusaa
X
Bone marrow biopsy & aspiratebb
X
Bone marrow morphology, IHC, 
cytogeneticsbb
X
 
 
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Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 3 cycles
Treatment Cycle/Title:
(28-day cycles)
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Discon
Post-
Treatment 
Safety 
Follow-up
Visitb
Efficacy 
Follow-up 
Visitsc
Survival 
Follow-
upd
Cycle Day (visit day)
(± 3 days after Day 1 of Cycle 1 
unless otherwise specified)
(-28 to -1 
days)
1
22
1
15
1
8
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 12
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
Laboratory Procedures/Assessments: analysis performed by central laboratory
Lymph node biopsycc
X
X
Correlative studies blood collectiondd
X
X
Anti-pembrolizumab antibodiesee
X
X
X
X
Pembrolizumab pharmacokineticsee
X
X
X
X
Abbreviations: AE=adverse event; aPTT=activated partial thromboplastin time; -HCG=beta human chorionic gonadotropin; CBC=complete blood cell count; CT=computed 
tomography; CTCAE=Common Terminology Criteria for Adverse Events; Discon=discontinuation; ECOG=Eastern Cooperative Oncology Group; FDG=fludeoxyglucose; 
FT3=free triiodothyronine; FT4=free thyroxine; IHC=immunohistochemistry; INR=International Normalized Ratio; LDH=lactate dehydrogenase; NCI=National Cancer 
Institute; PD=progressive disease; PET=positron emission tomography; PK=pharmacokinetic; PT=prothrombin time; REMS=Risk Evaluation and Mitigation Strategy; 
RP2D=recommended Phase II dose; SAE=serious adverse event; T3=triiodothyronine; TSH=thyroid stimulating hormone.
a.
Treatments and assessments are based on 28-day cycles.
b.
After the end of treatment, each subject will be followed for 30 days for AE monitoring. Serious adverse events will be collected for 90 days after the end of treatment or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, and spontaneously reported pregnancy will be collected for 120 
days after the end of treatment. Serious adverse events and spontaneously reported pregnancy will be reported for 30 days after the end of treatment if the subject initiates 
new anticancer therapy. See Section 7.2 for additional details.
c.
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.
d.
After the start of new anti-cancer treatment or documented disease progression, the subject should be contacted by telephone approximately every 12 weeks to assess for 
survival status. Updated survival status may be requested by the Sponsor at any time during the course of the study. Upon Sponsor notification, all subjects who do not/will 
not have a scheduled study visit or study contact during the Sponsor-defined time period will be contacted for their survival status (excluding subjects who have a death 
event previously recorded).
e.
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.
 
 
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Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 3 cycles
Treatment Cycle/Title:
(28-day cycles)
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Discon
Post-
Treatment 
Safety 
Follow-up
Visitb
Efficacy 
Follow-up 
Visitsc
Survival 
Follow-
upd
Cycle Day (visit day)
(± 3 days after Day 1 of Cycle 1 
unless otherwise specified)
(-28 to -1 
days)
1
22
1
15
1
8
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 12
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
f.
Lenalidomide must be prescribed through and in compliance with the REVLIMID REMSTM program or protocol-specified requirements. Refer to local prescribing 
information.
g.
Pembrolizumab will be given by intravenous infusion over 30 minutes at a fixed dose of 200 mg. Each dose will be administered once every 3 weeks within each 28-day 
cycle. See Section 5.2 and Section 7.1.5.2 for additional details. See Section 12.9 for additional dose timing details.
h.
Lenalidomide will be given orally once daily at the RP2D established during the safety run-in. Each dose will be administered for the first 21 consecutive days of each 28-
day cycle. See Section 5.2 and Section 7.1.5.2 for additional details. See Section 12.9 for additional dose timing details.
i.
Adverse events 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. See Section 7.1.2.1 and Section 7.2 for additional details.
j.
A physical examination will be performed before each administration of pembrolizumab. A full physical examination will be performed at Week 12, and every 12 weeks 
thereafter, and directed physical exams will be conducted before administration of pembrolizumab at each of the other visits.
k.
Vitals signs will include temperature, pulse, respiratory rate, weight, and blood pressure.  
l.
Pulmonary function tests should include an assessment of forced vital capacity, forced expiratory flow between 25 and 75 percent of forced vital capacity, forced expiratory 
volume in 1 second, peak expiratory flow, 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.
ECOG performance status will be performed before administration of each dose of pembrolizumab.
n.
Diagnostic quality CT and PET should be performed at Screening, Week 12, and every 12 weeks following Week 12. For lymphomas that are not FDG-avid at screening, 
PET does not need to be repeated in subsequent assessments. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts or extension 
of treatment cycle frequencies.  In subjects who discontinue study therapy without confirmed disease progression, a radiological assessment should be performed at the time 
of treatment discontinuation (i.e., date of discontinuation ±4 week window).  If a previous scan was obtained within 4 weeks prior to the date of discontinuation, then a repeat 
scan at treatment discontinuation is not mandatory.  See Section 7.1.2.7 and the Site Imaging Manual for additional details regarding scan requirements and timing.  
o.
Lymphoma disease response assessments [87] should occur at Week 12, and every 12 weeks (±7 days) following the Week 12 assessment.  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 subject is clinically progressing.  See Section 7.1.2.7 for additional details regarding assessment requirements and timing.
p.
Subjects who have progressive disease at the Week 12 assessment should have a confirmation assessment performed 4-6 weeks later.  See Section 7.1.2.7.7 for additional 
details on confirmation assessments.
 
 
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Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 3 cycles
Treatment Cycle/Title:
(28-day cycles)
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Discon
Post-
Treatment 
Safety 
Follow-up
Visitb
Efficacy 
Follow-up 
Visitsc
Survival 
Follow-
upd
Cycle Day (visit day)
(± 3 days after Day 1 of Cycle 1 
unless otherwise specified)
(-28 to -1 
days)
1
22
1
15
1
8
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 12
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
q.
Lymphoma disease response assessments [87] should occur at Week 12, and every 12 weeks (±7 days) following the Week 12 assessment. Disease assessments or scans 
should not be delayed for delays in cycle starts.
r.
Lymphoma B assessments should be performed at Screening and at the time of each disease response assessment.
s.
Laboratory tests for screening that are performed at a local laboratory should be completed within 7 days prior to the first dose (Cycle 1) of trial treatment.  Subsequent 
laboratory safety evaluations should be completed within 72 hours of any subsequent trial treatments (i.e., should be available before the subject receives the scheduled 
dose).  See Section 7.1.3.1 for details regarding laboratory safety evaluations.
t.
In females of childbearing potential, two negative pregnancy tests (sensitivity of at least 25 mIU/mL) must be obtained prior to initiating therapy in female subjects enrolled 
in Cohort 5 (DLBCL). The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing lenalidomide therapy.
u.
Females of childbearing potential with regular or no menstrual cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 
28 days while taking lenalidomide, at study discontinuation, and at Day 28 following the last dose of lenalidomide. Females of childbearing potential with irregular menstrual 
cycles must agree to have pregnancy tests weekly for the first 28 days of study participation and then every 14 days while taking lenalidomide, at study discontinuation, and 
at Days 14 and 28 following the last dose of lenalidomide.
v.
Coagulation factors will be obtained at Screening and repeated during the trial as per the prescribing information for the selected thromboprophylaxis/thromboembolism 
therapy. 
w.
CBC with differential is performed weekly for Cycle 1, every 2 weeks for Cycles 2-4, and on Day 1 of each cycle thereafter (monthly).
x.
LDH, comprehensive chemistry panel, and urinalysis should be performed on Day 1 of Cycles 1-8, and every 8 weeks thereafter. Tests may be performed within ±7 days 
after Day 1 of Cycle 1.
y.
Thyroid function tests (T3, FT4, and TSH) should be performed at Week 4, Week 8, Week 12, and every 12 weeks thereafter. Tests may be performed within ±7 days after 
Day 1 of Cycle 1.
z.
If 2 microglobulin is elevated at baseline, testing should be repeated every 12 weeks.
aa.
All subjects will have Epstein-Barr virus status collected at Screening.
bb. All subjects will have a bone marrow biopsy/aspirate, bone marrow morphology, IHC, and cytogenetics performed at baseline. Cytogenetics is done to evaluate whether 
genetic variation within a clinical trial population correlates with response to the treatment(s) under evaluation. If it is not a standard procedure in your region, this test does 
not need to be performed. See Section 7.1.2.7.8 for additional details.  
 
 
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Trial Period:
Screening 
Phase
Treatment Cyclesa
End of 
Treatment
Post-treatment
To be repeated beyond 3 cycles
Treatment Cycle/Title:
(28-day cycles)
Screening
(Visit 1)
Cycle 1
Cycle 2
Cycle 3
Discon
Post-
Treatment 
Safety 
Follow-up
Visitb
Efficacy 
Follow-up 
Visitsc
Survival 
Follow-
upd
Cycle Day (visit day)
(± 3 days after Day 1 of Cycle 1 
unless otherwise specified)
(-28 to -1 
days)
1
22
1
15
1
8
At time of 
Discon
30 days post 
Discon
(±3 days)
Every 12
weeks post 
Discon
(±7 days)
Every 12 
weeks
(±7 days)
or as 
directed 
by the 
Sponsor
cc.
Tumor biopsies are required for subjects at Screening and Week 12 (± 7 days). If an archival biopsy is not available a new biopsy must be obtained. See Section 7.1.2.7.8
and the Procedures Manual for additional details. 
dd. Correlative study samples should be collected at Screening, at the time of the Week 12 lymphoma disease response assessment, and upon progression. See Section 7.1.2.7.8
and the Procedures Manual for additional details.  
ee.
Pre-dose trough PK and anti-pembrolizumab antibody samples will be collected at Day 1 of Cycle 1, Day 22 of Cycle 1, Day 15 of Cycle 2, Day 15 of Cycle 5, every 4th
pembrolizumab infusion thereafter, and 30 days after discontinuation of study drug (or until the subject starts new anti-cancer therapy).
Note: Cohort 5 has been discontinued and there will be no further enrollment of subjects. All subjects in Cohort 5 must stop combination treatment immediately, complete the 
discontinuation visit and move into the long-term safety and survival follow-up per protocol. If clinically benefitting at time of stopping combination therapy, subjects may enter 
a transition period remaining on single agent lenalidomide or pembrolizumab for up to 90 days from 15-SEP-2017 and then must transition into long-term survival and safety 
follow-up. Cohort 5 subjects are no longer eligible for second course treatment phase.
 
 
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Study Dose Chart L2: Cohort 5 Diffuse Large B-Cell Lymphoma (DLBCL) (Retreatment for Post-Complete Response 
Relapse Only) (Subjects allocated to pembrolizumab 200 mg administered intravenously once every 21 days in 
combination with lenalidomide taken orally once daily for 21 days + 7 days off.  The cycle length is 28 days.) 
Each Cycle = 28 Days (To be repeated beyond 3 cycles)
Cycle 1
Cycle 2 
Cycle 3
Trial Treatment/ Cycle Day
(± 3 days)
Days
1-7
Days
8-14
Days
15-21
Days
22-28
Days
1-7
Days
8-14
Days
15-21
Days
22-28
Days
1-7
Days
8-14
Days
15-21
Days
22-28
Pembrolizumab (Q3W)a
1
22
15
8
Lenalidomideb
1 to 21
1 to 21
1 to 21
Pill count for Lenalidomidec
1
1
1
Pregnancy Prevention Counseling and 
Dispensing of Lenalidomided
X
Abbreviations: IV=intravenous; PO=per orem; Q3W=every 3 weeks; REMS=Risk Evaluation and Mitigation Strategy; RP2D=recommended Phase II dose.
a.
Pembrolizumab will be administered as 200 mg every 21 days (3 weeks) as an IV infusion over 30 minutes. 
b.
Lenalidomide will be administered as RP2D PO, once daily on Days 1 to 21 of repeated 28-day cycles.  Lenalidomide must be prescribed through and in compliance with 
the REVLIMID REMSTM program.  Refer to local prescribing information.
c.
Site should document drug accountability as per their institutional guidelines.
d.
The Lenalidomide Education and Counseling Guidance Document must be completed for all subjects and signed by a trained counselor prior to each dispensing of 
lenalidomide (see Section 12.10). A copy of this document must be maintained in the subject’s records for each dispense. Lenalidomide will be dispensed every 3-4 weeks 
as per local requirements. 
Note: Cohort 5 has been discontinued and there will be no further enrollment of subjects. All subjects in Cohort 5 must stop combination treatment immediately, complete the 
discontinuation visit and move into the long-term safety and survival follow-up per protocol. If clinically benefitting at time of stopping combination therapy, subjects may enter 
a transition period remaining on single agent lenalidomide or pembrolizumab for up to 90 days from 15-SEP-2017 and then must transition into long-term survival and safety 
follow-up. Cohort 5 subjects are no longer eligible for second course treatment phase.
 
 
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7.0 TRIAL PROCEDURES
7.1
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 must obtain documented consent from each potential subject 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 after the subject provides written 
informed consent.
Medical History
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.
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.  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, radiation, and surgeries.  For MDS subjects, transfusion history should be 
documented for 3 months prior to start of study and every 6 weeks during response assessment.  
Transfusion history should be obtained from patient medical records and/or blood bank 
records.  
7.1.1.6.3 Subsequent Antineoplastic Therapy Status
The investigator or qualified designee will review all new antineoplastic therapy initiated after 
the last dose of trial treatment, and collect transplant parameters (e.g., date and type of 
transplant, conditioning regimen) when applicable.  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 treatment allocation. Each 
subject will be assigned only one screening number.  Screening numbers must not be re-used 
for different subjects.  Any subject who is screened multiple times will retain the original 
screening number assigned at the initial screening visit.
Assignment of Randomization Number
All eligible subjects will be allocated, by non-random assignment, to trial treatment and will 
receive a randomization number.  The randomization number identifies the subject for all 
procedures occurring after treatment allocation.  This unique number is termed a randomization 
number throughout the protocol for operational purposes. 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.
Trial Compliance (Medication/Diet/Activity/Other)
Interruptions from the protocol specified treatment plan for > 12 weeks between doses of
pembrolizumab or lenalidomide + pembrolizumab combination due to toxicity, require 
 
 
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consultation between the investigator and the Sponsor and written documentation of the 
collaborative decision on subject management.
Administration of pembrolizumab will be witnessed by the investigator and/or trial staff.  The 
total volume of pembrolizumab infused will be compared to the total volume prepared to 
determine compliance with each dose administered.  Because subjects will self-administer 
lenalidomide, pill counts will be conducted on Day 1 of each cycle.
The instructions for preparing and administering pembrolizumab and for appropriate self-
administration of lenalidomide 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 12.5).  Toxicities will be 
characterized in terms regarding seriousness, causality, toxicity grading, and action taken with 
regard to trial treatment. 
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 Trial Flow Chart (Section 6.0).  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 (Section 6.0), the 
investigator or qualified designee will perform a directed physical exam as clinically indicated 
prior to trial treatment administration.  New clinically significant abnormal findings should be 
recorded as AEs.  
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 
 
 
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rate, weight and blood pressure. Height will be measured at screening only and will not be 
repeated for second course treatment.
Electrocardiogram
A standard 12-lead electrocardiogram will be performed using local standard procedures at 
screening.  Clinically significant abnormal findings should be recorded as medical history.  
Pulmonary Function Testing
Pulmonary function tests should include an assessment of forced vital capacity, forced 
expiratory flow between 25 and 75 percent of forced vital capacity, forced expiratory volume 
in 1 second, peak expiratory flow, 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.
Eastern Cooperative Oncology Group (ECOG) Performance Scale
The investigator or qualified designee will assess ECOG status (see Section 12.4) at screening, 
prior to the administration of each dose of pembrolizumab infusion and discontinuation of trial 
treatment as specified in the Trial Flow Chart (Section 6.0).
Assessment of Disease and Tumor Imaging
7.1.2.7.1 Criteria for Assessment of Disease
Anti-tumor activity of pembrolizumab will be evaluated using the following criteria:

MDS:  Clinical application and proposal for modification of the IWG response criteria 
in myelodysplasia. [88]

MM:  International uniform response criteria for multiple myeloma [89]

HL/NHL:  Revised Response Criteria for Malignant Lymphoma.  [87]
The IWG 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 (e.g., discontinuation 
of study therapy).  
7.1.2.7.2 Hodgkin and Non-Hodgkin Lymphoma Disease Response Assessment
Lymphoma (HL/NHL) response assessment by CT/positron emission tomography (PET) is 
based on the Revised Response Criteria for Malignant Lymphoma [87]. 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 performed by a central 
 
 
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vendor if the primary efficacy endpoint is met.  Assessment of lymphoma B symptoms should 
occur with each lymphoma disease response assessment.
7.1.2.7.3 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 lymphoma 
disease response assessment criteria may not provide a comprehensive response assessment of 
immunotherapeutic agents such as pembrolizumab.  Therefore, in the setting where a subject’s 
lymphoma disease response assessment shows PD, trial treatment may be continued at the 
discretion of the principal investigator in a subject whose clinical condition is stable until 
repeat imaging performed to 6 weeks later confirms progression.  However, imaging should 
occur at any time where there is clinical suspicion of progression.  See Section 7.1.2.7.7 for 
additional information about the timing of the disease response assessment after PD.
NOTE: If a subject with confirmed progression according to response criteria for each cohort 
is clinically stable or clinically improved, an exception may be considered to continue 
treatment upon consultation with the Sponsor.
7.1.2.7.4 Timing of Disease Assessments
Uniform disease response assessments will occur at Week 12 for all indications (see Table 10
below).  One additional disease assessment for MDS will occur after 6 weeks. Additional 
assessments for MM subjects will occur on therapy per the frequency in Table 10 to assess for 
kinetics of response. One additional disease assessment for FL and DLBCL subjects receiving 
200 mg Q3W will occur at Week 6, with the exception of Cohort 5 (DLBCL).  Treatment
decisions will not be based on these additional assessments prior to Week 12.
 
 
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Table 10
Disease Response Assessments
Indication
Assessment Frequency
MDS
Every 6 weeks
MM (Cohort 2 for subjects 
receiving 10 mg/kg Q2W)
Every 4 weeks 
MM (Cohort 2 for subjects 
receiving 200 mg Q3W)
Every 3 weeks 
HL/NHL (Cohort 3, 4A, 4B) 
for 
subjects 
receiving 
10 
mg/kg Q2W
Every 8 weeks following 
first assessment at Wk 12
NHL (Cohort 4A, 4C, 4D) for 
subjects receiving 200 mg 
Q3W
Wk 6, Wk 12, every 9 weeks 
following Wk 12
NHL (Cohort 5) for subjects 
receiving lenalidomide + 
pembrolizumab 
Wk 12 and every 12 weeks 
following Wk 12.
Abbreviations: HL=Hodgkin lymphoma; MDS=myelodysplastic 
syndrome; MM=multiple myeloma; NHL=non-Hodgkin lymphoma; 
Q2W=every 2 weeks; Q3W=every 3 weeks.
7.1.2.7.5 Initial Disease Assessment
Initial disease assessment or tumor imaging must be performed within 28 days prior to the first 
dose of trial treatment.  For lymphoma the site study team must review pre-trial images to 
confirm the subject has measurable disease as defined in the inclusion criteria.  The baseline 
imaging scan must be submitted to the central imaging vendor for a retrospective analysis of 
this eligibility criterion. 
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.  For lymphoma, CT and PET should be used throughout 
the study.  For lymphomas that are not fludeoxyglucose-avid at screening, PET does not need 
to be repeated in follow-up assessments.   
7.1.2.7.6 Disease Assessment During Trial
Disease assessments should be performed per the frequency defined in Table 10 above.  There 
is a ± 7 day window for assessments performed after Day 1. Lymphoma tumor imaging should 
be performed by CT and PET throughout the trial (after Screening scan, PET is repeated to 
confirm response). Disease assessments or scans should not be delayed for delays in cycle 
starts.  
 
 
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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.  See Section 7.1.2.7.7 for confirmation assessment 
requirements when a subject’s disease response assessment shows disease progression at the 
Week 12 assessment.  
Assessment of Lymphoma B symptoms should occur at Screening (Visit 1) and with each 
lymphoma disease response assessment.  These symptoms include the following:

Unexplained weight loss of more than 10% of the body weight during the 6 months 
before initial staging investigation; 

Unexplained, persistent, or recurrent fever with temperatures above 38°C during the 
previous month; and 

Recurrent drenching night sweats during the previous month [90].
7.1.2.7.7 Confirmation Assessments 
Because a subject treated with PD-1 inhibitors may have pseudoprogression of disease (there 
is progression per imaging, but the subject is clinically stable or improving), confirmation of 
progression should be conducted as follows:
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 a disease response 
assessment performed 4-6 weeks later confirms progression. 
Clinical stability may be defined as:
1) Absence of symptoms and signs indicating clinically significant progression of 
disease (including worsening of laboratory values) with the exception of M-protein 
elevation for the multiple myeloma cohort.
2) No decline in ECOG performance status.
3) Absence of rapid progression of disease or progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent medical intervention.
Subjects that are deemed clinically unstable are not required to have a repeat disease response 
assessment 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
no other anti-tumor therapy (e.g., chemotherapy, radiation, etc.) has been administered.
 
 
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Subjects should have their next disease response assessment as detailed in the Trial Flow Chart 
(see Section 6.0).  When feasible, subjects should not be discontinued until progression is 
confirmed.
For subjects who have SD, partial response, or CR following the disease response assessment
at Week 12, a confirmation assessment is not required.  Disease assessments and imaging 
should continue per the regular frequency.  
Subjects who have a CR for at least 18 months, irrespective of continued or discontinued trial 
treatment, may have subsequent imaging done every 6 months according to institutional 
standards until confirmed progression.
NOTE: If a subject with confirmed progression according to response criteria for each cohort 
is clinically stable or clinically improved, an exception may be considered to continue 
treatment upon consultation with the Sponsor.
7.1.2.7.8 Biopsy Collection and Correlative Studies Blood Collection
All subjects enrolled into this study must be able to provide an archived formalin-fixed 
paraffin-embedded biopsy sample or newly obtained core or excisional biopsy (fine needle 
aspiration not adequate) to be submitted for characterization at a central lab.  FL and DLBCL 
subjects (Cohort 4C, 4D, and 5) are not required to have PD-L1 testing to determine eligibility;
regardless, an archived formalin-fixed paraffin-embedded biopsy sample or newly obtained 
core or excisional biopsy needs to be submitted at screening.
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. 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.
 
 
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Bone marrow and lymph node biopsies will be collected as per Table 11 below.
Table 11
Bone Marrow and Lymph Node Biopsy Assessments
Indication
Timing of Biopsy
MDS (Cohort 1)
(Bone marrow biopsy/aspirate)
Screening, Wk 6 (± 7 days), Wk 12 (± 7 days), then 
every 12 weeks or as clinically indicated.  If subject has 
PD at Wk 12, repeat bone marrow aspiration/biopsy at 
WK 16 to confirm PD.
MM (Cohort 2) subjects receiving 10 mg/kg Q2W
(Bone marrow biopsy/aspirate)
Screening, Wk 4 (± 7 days), Wk 12 (± 7 days), to 
confirm CR, and sCR, and as clinically indicated.  If 
subject has PD at Wk 12, repeat bone marrow/aspiration 
biopsy at WK 16 to confirm PD.
MM (Cohort 2) subjects receiving 200 mg Q3W
(Bone marrow biopsy/aspirate)
Screening, Wk 6 (± 7 days), Wk 12 (± 7 days), to 
confirm CR, and sCR, and as clinically indicated.  If 
subject has PD at Wk 12, repeat bone marrow/aspiration 
biopsy at WK 15 to confirm PD.
HL (Cohort 3)
(Lymph node biopsy)
Screening and Wk 12 (± 7 days).  [Screening biopsy may 
be archival (from recent relapse, if available) or newly 
obtained].
MLBCL (Cohort 4A)
(Lymph node biopsy)
Screening and Wk 12 (± 7 days).  [Screening biopsy may 
be archival (from recent relapse, if available) or newly 
obtained).
NHL (Cohort 4B)
(Lymph node biopsy)
Screening (archival and newly obtained), and Wk 12 (± 
7 days).  (A newly obtained biopsy is required at 
Screening for all NHL subjects even if they have already 
been determined to be PD-L1 positive based on archival 
material.)
FL (Cohort 4C) and DLBCL (Cohort 4D) and 
(Cohort 5)
(Lymph node biopsy) 
Screening and Wk 12 (± 7 days).  [Screening biopsy may 
be archival (from recent relapse, if available) or newly 
obtained.
HL/NHL (Cohort 3, 4A, 4B, 4C, 4D, and 5)
(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.
Abbreviations: CR=complete response; DLBCL=diffuse large B-cell lymphoma; FL=follicular lymphoma; 
HL=Hodgkin lymphoma; MDS=myelodysplastic syndrome; MLBCL=mediastinal large B-cell lymphoma; 
MM=multiple myeloma; NHL=non-Hodgkin lymphoma; PD=progressive disease; PD-L1=programmed cell 
death ligand 1; Q2W=every 2 weeks; Q3W=every 3 weeks; sCR=stringent complete response.
 
 
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Blood for correlative biomarker studies should be collected as per Table 12 below.
Table 12
Blood Collection for Correlative Biomarkers Studies
Indication
Timing of Correlative Blood Collection
MDS (Cohort 1)
Screening, Wk 6, Wk 12, and upon progression.
MM (Cohort 2) subjects receiving 10 mg/kg 
Q2W
Screening, Wk 4, Wk 12, and upon progression.
MM (Cohort 2) subjects receiving 200 mg Q3W
Screening Wk 6, Wk 12 and upon progression
HL (Cohort 3)/NHL (Cohort 4A, 4B, 4C, 4D,
and 5)
Screening, Wk 12, and upon progression. 
Abbreviations: HL=Hodgkin lymphoma; MDS=myelodysplastic syndrome; MM=multiple myeloma; 
NHL=non-Hodgkin lymphoma; Q2W=every 2 weeks; Q3W=every 3 weeks.
Laboratory Procedures/Assessments
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood/tissue to be drawn/collected over the course of the 
trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes 
drawn/collected by visit and by sample type per subject can be found in the Procedures Manual.
Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis)
Laboratory tests for hematology, chemistry, and urinalysis are specified in Table 13.  
 
 
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Table 13
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 a
Alanine aminotransferase (ALT)
Protein
aPTT
Platelet count
Aspartate 
aminotransferase 
(AST)
Specific gravity 
Total Triiodothyronine (T3)
(or FT3) b
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); if these evaluations 
are not performed as part of 
standard of care in your region, 
then these tests do not need to be 
performed
Urine pregnancy test c
Thyroid 
stimulating 
hormone (TSH)
Absolute 
Neutrophil Count
Creatinine
Anti-pembrolizumab
Antibodies
Absolute 
Lymphocyte Count
Uric Acid
PK
Reticulocyte Count 
(MDS cohort only)
Calcium
Blood for FBR
Chloride
Blood for correlative studies
Glucose
Viscosity (MM cohort only)
Phosphorus
2 
microglobulin 
(MM, 
HL/NHL cohorts)
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
Abbreviations: aPTT=activated partial thromboplastin time; CBC=complete blood cell count; FBR=Future Biomedical 
Research; HL=Hodgkin lymphoma; INR=International Normalized Ratio; MDS=myelodysplastic lymphoma; MM=multiple 
myeloma; NHL=non-Hodgkin lymphoma; PK=pharmacokinetics; PT=prothrombin time; WBC=white blood cell count.
a  CBC differential should include blast percentage for MDS subjects.
b  Free T3 may be performed instead of T3 per local standard of care.
c  Perform on women of childbearing potential only.  If urine pregnancy results cannot be confirmed as negative, a serum 
pregnancy test will be required.
 
 
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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 7 days prior to the first dose of treatment. After Cycle 1, pre-dose laboratory procedures 
can be conducted up to 72 hours prior to dosing. Results must be reviewed by the investigator 
or qualified designee and found to be acceptable prior to each dose of trial treatment.
Pharmacokinetic/Pharmacodynamic Evaluation
7.1.3.2.1 Blood Collection for Serum MK-3475
Sample collection, storage and shipment instructions for serum samples will be provided in the
operations/laboratory manual. 
The time points for PK blood sampling are described in Section 6.0 – Trial Flow Chart.
7.1.3.2.2 Blood Collection for Anti-pembrolizumab Antibodies 
Sample collection, storage, and shipment instructions for blood samples will be provided in 
the operations/laboratory manual.
The time points for anti-pembrolizumab antibodies are described in Section 6.0 – Trial Flow 
Chart.
Future Biomedical Research
The following specimens are to be obtained as part of Future Biomedical Research:

Blood for genomics use

Leftover bone marrow biopsy/aspirate samples

Leftover lymph node biopsies

Leftover correlative blood samples
Other Procedures
Withdrawal/Discontinuation
When a subject discontinues/withdraws prior to trial completion, 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 or sCR (MM) may discontinue treatment with the option of restarting 
treatment if they meet the criteria specified in Section 7.1.5.2.1.  After discontinuing treatment 
following assessment of CR or sCR, 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 7.1.5.3.2).
 
 
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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 writing to the 
principal investigator for the main trial.  If medical records for the main trial are still available, 
the 
investigator 
will 
contact 
the 
Sponsor 
using 
the 
designated 
mailbox 
(clinical.specimen.management@merck.com), and a form will be provided by the Sponsor to 
obtain appropriate information to complete specimen withdrawal.  Subsequently, the subject's 
specimens will be removed from the biorepository and be destroyed.  A letter will be sent from 
the Sponsor to the investigator confirming the destruction. It is the responsibility of the 
investigator to inform the subject of completion of destruction.  Any analyses in progress at 
the time of request for destruction or already performed prior to the request being received by 
the Sponsor will continue to be used as part of the overall research trial data and results.   No 
new analyses would be generated after the request is received.
In the event that the medical records for the main trial are no longer available (e.g., if the 
investigator is no longer required by regulatory authorities to retain the main trial records) or 
the specimens have been completely anonymized, there will no longer be a link between the 
subject’s personal information and their specimens.  In this situation, the request for specimen 
destruction cannot be processed.
Blinding/Unblinding
This is an open label trial; there is no blinding for this trial.
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 Period
Approximately 28 days prior to enrollment, potential subjects will be evaluated to determine 
that they fulfill the entry requirements as set forth in Section 5.1.  Visit requirements are 
outlined in Section 6.0 – Trial Flow Chart.
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.
 
 
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
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).

In females of childbearing potential, two negative pregnancy tests (sensitivity of at least 
25 mIU/mL) must be obtained prior to initiating therapy in female subjects enrolled in 
Cohort 5 (DLBCL).  The first test should be performed within 10-14 days and the 
second test within 24 hours prior to prescribing lenalidomide therapy.

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 
of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met.
7.1.5.1.1 Prospective Enrollment of PD-L1 Positive Subjects (Cohort 4B:  Any-other 
NHL Only)
Subjects with a NHL subtype other than MLBCL require characterization of PD-L1 to 
determine eligibility.  Subjects that have an archival lymph node biopsy sample available may 
sign a pre-screening consent to determine the PD-L1 status. After providing a pre-screening 
consent, subjects will be assigned a screening number. 
Subjects that do not have an archival lymph node biopsy sample available must provide written 
consent for the main study before the lymph node biopsy or any other protocol-specified 
procedures can occur.  
FL (Cohort 4C), DLBCL (Cohort 4D), and DLBCL (Cohort 5) subjects are not required to 
have PD-L1 testing to determine eligibility.
Treatment Period
Cohort 5 has been discontinued with no further enrollment of subjects. All subjects in Cohort 
5 must stop combination treatment immediately, complete the discontinuation visit, and move 
into the long-term safety and survival follow-up per protocol. If clinically benefitting at time 
of stopping combination therapy, subjects may enter a transition period remaining on single 
agent lenalidomide or pembrolizumab for up to 90 days from 15-SEP-2017 and then must 
transition into long-term survival and safety follow-up. Additionally, enrollment in Cohort 2 
has been completed; all subjects have previously discontinued study treatment and must 
transition into long-term safety and survival follow-up. There will be no further enrollment of 
subjects in this cohort.
 
 
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7.1.5.2.1 Second Course Phase (Retreatment Period for Post-Complete Remission 
Relapse ONLY) 
Subjects may be eligible to receive pembrolizumab or lenalidomide + pembrolizumab 
combination in the Retreatment Period of this study if the study remains open and the subject 
meets the following conditions:

Stopped initial treatment with pembrolizumab or lenalidomide + pembrolizumab 
combination after attaining an investigator-determined confirmed CR or sCR (MM) 
according to respective response criteria

Was treated for at least 24 weeks with pembrolizumab or lenalidomide + 
pembrolizumab combination before discontinuing therapy

Received at least 2 treatments with pembrolizumab or for subjects enrolled in Cohort 5
(DLBCL) an additional 21 consecutive daily doses of lenalidomide + 2 doses of 
pembrolizumab beyond the date when the initial CR or sCR was declared

Experienced an investigator-determined confirmed disease progression after stopping 
their initial treatment with pembrolizumab or lenalidomide + pembrolizumab 
combination

Did not receive any anti-cancer treatment since the last dose of pembrolizumab or 
lenalidomide + pembrolizumab combination

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 subjects 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 
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have not been free from menses for > 2 years. 

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.  

Subjects enrolled in Cohort 5 (DLBCL) must meet the criteria for eligibility related to 
pregnancy and contraception as described in Section 5.1.2, and must be willing to 
follow the requirements for contraception as described in Section 5.7.2 and Section 
5.7.3.  Subjects must be enrolled in the REVLIMID REMS program.
 
 
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
Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator.
Subjects who restart treatment will be retreated at the same dose frequency as when they last 
received pembrolizumab for a treatment duration of a maximum of 17 cycles for subjects 
receiving pembrolizumab Q3W or 26 cycles for subjects receiving pembrolizumab Q2W.  
Subjects in Cohort 5 (DLBCL) will be retreated at the same dose frequency as when they last 
received lenalidomide + pembrolizumab combination for a treatment duration of a maximum 
of 13 cycles.  
Note: Subjects in Cohort 2 and Cohort 5 are no longer eligible for second course treatment 
phase.
Visit requirements are outlined in Section 6.0 – 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 to 
1 or until the beginning of a new antineoplastic therapy, whichever occurs first.  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.
Subjects who are eligible for retreatment with pembrolizumab or lenalidomide + 
pembrolizumab combination (as described in Section 7.1.5.2.1) may have up to two safety 
follow-up visits, one after the Treatment Period and one after the Second Course Phase.
7.1.5.3.2 Efficacy 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 to monitor disease status as follows:

Every 6 weeks (±7 days) (MDS); every 12 weeks (±7 days) (MM); every 8 weeks 
(±7 days) (HL/NHL Cohorts 3, 4A, and 4B) and receiving pembrolizumab 10 mg/kg 
Q2W 
 
 
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
Every 9 weeks (±7 days) for NHL Cohorts 4A, 4C, and 4D and receiving 
pembrolizumab 200 mg Q3W

Every 12 weeks (±7 days) for NHL Cohort 5 (DLBCL) and receiving pembrolizumab 
200 mg administered intravenously once every 21 days in combination with 
lenalidomide taken orally once daily for 21 days + 7 days off
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 or lenalidomide + pembrolizumab combination as detailed in 
Section 7.1.5.2.1.  Information regarding post-study antineoplastic treatment will be collected 
if new treatment is initiated.
Note: For subjects who discontinue due to CR, modifications or extensions to the disease status 
assessment requirements during the Follow-Up Phase may be permitted following Sponsor 
Consultation.
Subjects who are eligible to receive retreatment with pembrolizumab or lenalidomide + 
pembrolizumab combination according to the criteria in Section 7.1.5.2.1 will move from the 
follow-up phase to the Second Course Phase when they experience disease progression.  
Details are provided in Section 6.0 – Trial Flow Chart for Retreatment.   
7.1.5.3.3 Survival Follow-up
Once a subject experiences confirmed disease progression or starts a new antineoplastic 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone approximately every 12 weeks to assess for survival status until death, withdrawal 
of consent, or the end of the study, whichever occurs first. Survival follow-up information may 
be collected from a subject in-person if a non-study clinic visit falls within the survival follow-
up window in lieu of contacting the subject by telephone.
Subjects who discontinue treatment to receive stem cell transplant are transitioned into survival 
follow-up. The conditioning regimen and the stem cell transplant procedure are collected as 
part of the survival follow-up.  Additional parameters (see Section 7.2.3.2) are collected for 
subjects who receive allogeneic stem cell transplant.  Subjects entering survival follow-up for 
other reasons (PD or starting new anti-cancer treatment) may also receive a stem cell 
transplant. The information for all stem cell transplants will be collected as described in this 
paragraph.
Survival Status
To ensure current and complete survival data is available at the time of database locks, updated 
survival status may be requested during the course of the study by the Sponsor. For example, 
updated survival status may be requested prior to but not limited to an interim database lock, 
interim, and/or final analysis. Upon Sponsor notification, all subjects who do not/will not have 
a scheduled study visit or study contact during the Sponsor-defined time period will be 
 
 
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contacted for their survival status (excluding subjects who have a previously recorded death 
event in the collection tool).
7.2
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 Cohort 1, 2, 3, 4A, 4B (in subjects receiving pembrolizumab 10 mg/kg Q2W): For purposes 
of this trial, an overdose will be defined as any dose exceeding the prescribed dose for 
pembrolizumab by 20% over the prescribed dose. 
For Cohort 2, 4A, 4C, 4D, and 5 (in subjects receiving pembrolizumab 200 mg Q3W): For 
purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg 
or greater.  
For Cohort 5 (DLBCL), an overdose for lenalidomide will be defined as any dose exceeding 
the prescribed dose. 
No specific information is available on the treatment of overdose of pembrolizumab or 
lenalidomide.  In the event of overdose, 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
The following reporting requirements apply to Cohorts 1, 2, 3, and 4:
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.
 
 
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Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator. All reported pregnancies must be followed to the completion/termination 
of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
The following reporting requirements apply to Cohort 5:
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), including the pregnancy of a male subject's female partner that occurs during 
the trial.
Pregnancies and lactations of subjects and female partners of male subjects from the time the 
consent form is signed but before treatment allocation/randomization must be reported by the 
investigator if they cause the subject to be excluded from the trial, or are the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. Pregnancies and lactations of subjects and female 
partners of male subjects that occur from the time of treatment allocation/randomization 
through 120 days following cessation of study treatment, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, must be reported. All reported 
pregnancies must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, 
fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events 
(Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) 
must also be reported.
Such events must be reported within 24 hours to the Sponsor either by electronic media or 
paper. Electronic reporting procedures can be found in the EDC data entry guidelines. Paper 
reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
 
 
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Immediate Reporting of Adverse Events to the Sponsor
Serious Adverse Events
A serious adverse event is any adverse event occurring at any dose or during any use of 
Sponsor's product that:
●
Results in death;
●
Is life threatening;
●
Results in persistent or significant disability/incapacity;
●
Results in or prolongs an existing inpatient hospitalization;
●
Is a congenital anomaly/birth defect;
●
Is an other important medical event. 
Note: In addition to the above criteria, adverse events meeting either of the below criteria, 
although not serious per ICH definition, are reportable to the Sponsor in the same timeframe 
as SAEs to meet certain local requirements. Therefore, these events are considered serious by 
the Sponsor for collection purposes.
●
Is a new cancer (that is not a condition of the study);
●
Is associated with an overdose.
Refer to Table 14 for additional details regarding each of the above criteria.
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details), that occurs to any subject must be reported within 24 
hours to the Sponsor if it causes the subject to be excluded from the trial, or is the result of a 
protocol-specified intervention, including but not limited to washout or discontinuation of 
usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study (reference Section 7.2.3.3 for additional details), whether or not related to the Sponsor's 
product, must be reported within 24 hours to the Sponsor either by electronic media or paper. 
Electronic reporting procedures can be found in the EDC data entry guidelines. Paper reporting 
procedures can be found in the Investigator Trial File Binder (or equivalent).
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to the Sponsor's product that is brought to the attention of the 
investigator at any time following consent through the end of the specified safety follow-up 
period specified in the paragraph above, or at any time outside of the time period specified in 
the previous paragraph also must be reported immediately to the Sponsor.  
 
 
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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 treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor if it causes the subject to be excluded from the trial, 
or is the result of a protocol-specified intervention, including but not limited to washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure.
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to the Sponsor’s product, must be reported within 24 hours to the Sponsor, either by electronic 
media or paper.  Electronic reporting procedures can be found in the EDC data entry guidelines. 
Paper reporting procedures can be found in the Investigator Trial File Binder (or equivalent).
Events of clinical interest for this trial include:
1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not 
associated with clinical symptoms or abnormal laboratory results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the 
upper limit of normal and, at the same time, an alkaline phosphatase lab value that is 
less than 2X the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing.*
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for assessment 
and follow up of these criteria can be found in the Investigator Trial File Binder.
3. Follow-up Post-Allogeneic Stem Cell Transplantation
In the event a subject receives an allogeneic SCT within 24 months of the last dose of 
pembrolizumab, or before the end of the trial, the following events will be collected as 
ECIs through 18 months from the date of allogeneic SCT or until the end of the trial: 
GVHD, febrile syndrome treated with steroids, pulmonary complications, hepatic veno-
occlusive disease and/or sinusoidal syndrome, immune-mediated AEs, critical illness, and 
transplant-related mortality. Post-allogeneic-SCT ECIs that occur after the normal safety 
follow-up period must be assessed for seriousness and causality and reported to the Sponsor 
as follows: within 24 hours if serious regardless of causality, or if non-serious and 
 
 
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considered to be drug-related; and 5 calendar days if non-serious and not considered to be 
drug-related. Guidance on details to be collected and suggested events to be reported can 
be found in the procedure manual.
If available and relevant to an event post allo-SCT, concomitant medications and/or 
laboratory results may be reported. Additional medically important AEs may be submitted 
at the Investigator’s discretion. 
Protocol-Specific Exceptions to Serious Adverse Event Reporting
Efficacy endpoints 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 14
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 [including hospitalization for an elective procedure] for a preexisting 
condition which has not worsened does not constitute a serious adverse event.); or
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours to meet certain local 
requirements); or
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.
Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed 
previously (designated above by a †).
Duration
Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and units
Action taken 
Did the adverse event cause the Sponsor’s product to be discontinued?
Relationship to 
Sponsor’s 
Product
Did the Sponsor’s product cause the adverse event? The determination of the likelihood that the Sponsor’s product caused the adverse event will be provided by an 
investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, 
ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below 
are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the 
available information.
The following components are to be used to assess the relationship between the Sponsor’s product and the AE; the greater the correlation with the components 
and their respective elements (in number and/or intensity), the more likely the Sponsor’s product caused the adverse event (AE):
Exposure
Is there evidence that the subject was actually exposed to the Sponsor’s product such as: reliable history, acceptable compliance assessment (pill 
count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?
Time Course
Did the AE follow in a reasonable temporal sequence from administration of the Sponsor’s product?
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?
Likely Cause
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors
 
 
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Relationship
The following components are to be used to assess the relationship between the test drug and the AE: (continued)
to 
Sponsor's 
Product
(continued) 
Dechallenge
Was the Sponsor’s product discontinued or dose/exposure/frequency reduced?
If yes, did the AE resolve or improve?
If yes, this is a positive dechallenge. If no, this is a negative dechallenge.
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation 
of the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.)
Rechallenge
Was the subject re-exposed to the Sponsor’s product in this study?
If yes, did the AE recur or worsen?
If yes, this is a positive rechallenge. If no, this is a negative rechallenge.
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or 
(3) Sponsor’s product(s) is/are used only one time).
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY THE SPONSOR'S PRODUCT, OR IF REEXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE U.S. CLINICAL 
MONITOR 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
8.1
Statistical Analysis Plan Summary
This section contains a brief summary of the statistical analyses for this trial. Full detail is in 
the Statistical Analysis Plan (SAP) (Section 8.2).
The primary purpose of this study is to investigate the safety, tolerability, and anti-tumor 
activity of pembrolizumab administered intravenously to subjects in the following disease 
cohorts:

Intermediate-1, intermediate-2, or high risk MDS (Cohort 1)

Relapse refractory or refractory MM (Cohort 2)

Lymphoma, evaluated separately according to the following groups:
o
Relapsed / refractory nodular sclerosing or mixed cellularity HL (Cohort 3)
o
NHL – monotherapy (Cohort 4)

Relapsed / refractory MLBCL that have failed, are ineligible for, or 
refused a stem cell transplant (Cohort 4A)

Relapsed / refractory PD-L1 positive NHL (excluding MLBCL) that 
have failed, are ineligible for, or refused a stem cell transplant (Cohort 
4B)

Irrespective of PD-L1 status, NHL subjects with relapsed / refractory 
FL that have failed, are ineligible for, or refused a stem cell transplant
(Cohort 4C)

Irrespective of PD-L1 status, NHL subjects with relapsed / refractory 
DLBCL that have failed, are ineligible for, or refused a stem cell 
transplant (Cohort 4D)
For the purposes of disease subtype analysis within Cohort 4, analyses for

“MLBCL” will consist of Cohort 4A subjects
 
 
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
“FL” will consist of Cohort 4C subjects plus any PD-L1 positive FL subject in 
Cohort 4B

“DLBCL” will consist of Cohort 4D subjects plus any PD-L1 positive DLBCL 
subjects in Cohort 4B

“Other” will consist of Cohort 4B subjects excluding FL and DLBCL subjects
Cohort analyses, unless otherwise specified, will be conducted regardless of PD-L1 
status or whether the subject received pembrolizumab given either as weight-based or 
fixed-dose.
o
NHL – combination therapy (Cohort 5)

Irrespective of PD-L1 status, NHL subjects with relapsed / refractory DLBCL 
that have failed, are ineligible for, or refused a stem cell transplant
Due to the current status of the study, statistical analyses of this section for Cohorts 2 and 5 
may be modified and changes will be reported in the Clinical Study Report (CSR).
Efficacy Analyses
The FAS population (defined as all subjects with a baseline efficacy evaluation and at least 
one post-baseline efficacy evaluation) will serve as the primary population for the analyses of 
efficacy data in this trial.  Supportive analyses of efficacy will be conducted in the intention to 
treat (ITT) population.  An outline of the efficacy analysis strategy is presented in Table 15
below.  For Cohorts 1 thru 4, a 90% CI (two-sided) along with a one-sided p-value for testing 
the null hypothesis based on the binomial distribution will be provided for the rate in each 
cohort. The respective cohort is considered to have reached the efficacy objective if the 
corresponding one-sided p-value for testing the respective null hypothesis is less than 5%.  For 
Cohort 5 (DLBLC), a 90% CI (two-sided) will be presented.
 
 
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Table 15
Primary Analysis Strategy for Efficacy Endpoints
Endpoint/Variable
(Description, Time Point)
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Primary
1.
MDS (Cohort 1): ORR based on 
IWG (2006 criteria for MDS 
(investigator-assessed)
2.
MM (Cohort 2): ORR based on 
IMWG criteria (investigator-
assessed)
3.
HL (Cohort 3): Complete 
Remission Rate (CRR) based IWG 
criteria (investigator-assessed)
4.
NHL monotherapy (Cohort 4): 
ORR based on IWG criteria 
(investigator-assessed)
5.
NHL combination therapy 
(Cohort 5): ORR based on IWG 
criteria (investigator-assessed)
Exact test of 
binomial 
parameter
(Cohorts 1 thru 
4); Descriptive 
statistics 
(Cohort 5)
FAS
Subjects with missing 
data are considered 
non-responders
Secondary binary endpoints

MDS (Cohort 1): 
a.
Bone marrow response by 
IWG criteria (investigator 
assessed)
b.
Hematologic 
improvement by IWG 
criteria (investigator-
assessed)
c.
Cytogenetic response by 
IWG criteria (investigator 
assessed)

MM (Cohort 2):
a.
CR + sCR by IMWG 
criteria (investigator 
assessed)

HL (Cohort 3):
a.
ORR

NHL monotherapy (Cohort 4): 
none

NHL combination therapy 
(Cohort 5): none
Exact test of 
binomial 
parameter
FAS
Subjects with missing 
data are considered 
non-responders
 
 
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Endpoint/Variable
(Description, Time Point)
Statistical 
Method
Analysis 
Population
Missing Data 
Approach
Secondary time-to-event endpoints
1.
MDS (Cohort 1):
a.
OS
b.
DOR
2.
MM (Cohort 2):
a.
TTP
b.
DOR
c.
PFS
d.
OS
3.
HL (Cohort 3):
a.
PFS
b.
OS
c.
DOR
4.
NHL monotherapy (Cohort 4):
a.
PFS
b.
OS
c.
DOR
5.
NHL combination therapy 
(Cohort 5):
a.
PFS
b.
OS
c.
DOR
Summary 
statistics using 
Kaplan-Meier 
method
OS, TTP, 
PFS: FAS
DOR: all 
responders
Censored at last 
assessment
Secondary descriptive analyses
Response by PD-L1 expression change 
before and after HMA treatment in each 
population separately:
1.
MDS (Cohort 1)
2.
MM (Cohort 2)
3.
HL (Cohort 3)
4.
NHL monotherapy (Cohort 4)
5.
NHL combination therapy 
(Cohort 5)
Descriptive 
statistics
FAS
Safety Analyses
The All-Subjects-as-Treated population will be employed for safety analyses.  
Power and Sample Size 
The calculation of power and sample size for each cohort does not account for an interim 
analysis.  
 
 
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MDS (Cohort 1)
With approximately 25 subjects with intermediate-1, intermediate-2, or high risk MDS, the 
study has ~80% power to detect a 20% difference in ORR under the null hypothesis of 
ORR=10% with a one-sided type I error rate of 5% if the true ORR is 30%.  Success for this 
hypothesis requires at least 6/25 responses.  The actual number of subjects enrolled may be 
larger than 25 to ensure that at least 25 subjects are evaluable for analysis. 
MM (Cohort 2)
With approximately 28 subjects with relapse refractory or refractory Multiple Myeloma, the 
study has ~80% power to detect a 25% difference in ORR under the null hypothesis of 
ORR=25% with a one-sided type I error rate of 5% if the true ORR is 50%.  Success for this 
hypothesis requires at least 12/28 responses.  The actual number of subjects enrolled may be 
larger than 28 to ensure that at least 28 subjects are evaluable for analysis. 
Lymphoma – HL (Cohort 3)
With approximately 25 subjects with HL, the study has ~80% power to detect a 20% difference 
in CRR under the null hypothesis of CRR=10% with a one-sided type I error rate of 5% if the 
true CRR is 30%.  Success for this hypothesis requires at least 6/25 responses.  The actual 
number of subjects enrolled may be larger than 25 to ensure that at least 25 subjects are 
evaluable for analysis.
Lymphoma –NHL monotherapy (Cohort 4)
With approximately 78 subjects with NHL, the study has ~80% power to detect a 14% 
difference in ORR under the null hypothesis of ORR=25% with a one-sided type I error rate 
of 5% if the true ORR is 39%.  Success for this hypothesis requires at least 27/78 responses.  
The actual number of subjects enrolled may be larger than 78 to ensure that at least 78 subjects 
are evaluable for analysis.
The maximum half-width of the 2-sided 90% CI will be 16% for the DLBCL and FL subtypes 
with a targeted number of 30 subjects each, and wider CIs for the MLBCL and Other subtypes.
Lymphoma –NHL combination therapy (Cohort 5)
Approximately 30 to 66 subjects will be evaluated in this cohort, depending on the number of 
dose levels of lenalidomide assessed during safety run-in; subjects treated at the confirmed 
RP2D during safety run-in will be included among the 30 subjects assessed during dose 
expansion (see Section 5.2.1.3 for details).
The maximum half-width of the 2-sided 90% CI will be 16% with a targeted number of 30 
subjects treated at the RP2D.
 
 
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Interim Analysis
Unless otherwise indicated, an interim analysis will be performed if fewer than 10 subjects are 
enrolled in a cohort 6 months after the time that the first subject is treated in the respective 
cohort. The interim analysis will take place after 10 subjects have reached the Week 12 
assessment. Results will be reviewed by the study team.  
See Section 12.8 for further details regarding the decision rules for resuming enrollment 
following the interim analysis.
Table 16 summarizes the strategy and timing of the potential interim analysis for each cohort.
For the MDS and HL cohorts, if an interim analysis is conducted and 1 or fewer subjects out 
of the first 10 subjects with a post-baseline (Week 12) assessment/imaging scan have a 
confirmed or unconfirmed primary endpoint response (OR or CR respectively), then 
enrollment will
be paused
until response data for the subsequent (Week 24) 
assessment/imaging scan are reviewed for all subjects already enrolled in the trial (including 
those enrolled who have not reached the first post-baseline assessment/imaging scan).  
Enrollment will be resumed if the observed responses (confirmed or unconfirmed) for the 
primary endpoint in the respective cohort among subjects who are still enrolled in the trial 
indicates that the probability of the response for the primary endpoint >10% is at least 80% 
(e.g., ≥3/16 confirmed or unconfirmed responses). See Section 12.8 for further details 
regarding the decision rules for resuming enrollment following the interim analysis.
For the MM and NHL Cohorts 4A and 4B combined, if an interim analysis is conducted and 3
or fewer subjects out of the first 10 subjects with a post-baseline (Week 12) imaging scan have 
a confirmed or unconfirmed primary endpoint response, then enrollment will be paused until 
response data for the subsequent imaging scan (Week 24) are reviewed for all subjects already 
enrolled in the trial (including those enrolled who have not reached the first post-baseline scan).  
Enrollment will be resumed if the observed responses (confirmed or unconfirmed) for the 
primary endpoint in the respective cohort among subjects who are still enrolled in the trial 
indicates that the probability of the response for the primary endpoint >25% is at least 80% 
(e.g., ≥5/16 confirmed or unconfirmed responses). See Section 12.8 for further details 
regarding the decision rules for resuming enrollment following the interim analysis.
No interim analysis is planned for subjects with unselected PD-L1 status with relapsed /
refractory FL, DLBCL receiving monotherapy (Cohort 4C and 4D, or DLBCL subjects 
receiving combination therapy (Cohort 5).
 
 
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Table 16
Summary of Interim Analysis Strategy
Interim Analysis 
Number
Key Endpoints 
for Interim 
Analysis
Timing (Sample 
size) for analysis 
Purpose of Analysis
Interim Analysis 
MDS (Cohort 1)
ORR
≥10 subjects 
with 1st post-
baseline (Week 
12) disease 
assessment 
Pause enrollment 
until further 
evidence of efficacy
Interim Analysis
MM (Cohort 2)
ORR
≥10 subjects 
with 1st post-
baseline (Week 
12) disease 
assessment
Pause enrollment 
until further 
evidence of efficacy
Interim Analysis 
Hodgkin Lymphoma
(Cohort 3)
CRR
≥10 subjects 
with 1st post-
baseline  
(Week 12) 
imaging scan
Pause enrollment 
until further 
evidence of efficacy 
Interim Analysis 
NHL monotherapy
(Cohorts 4A and 4B)
ORR
≥10 subjects 
with 1st post-
baseline (Week 
12) imaging  
scan
Pause enrollment 
until further 
evidence of efficacy 
8.2
Statistical Analysis Plan
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 an open-label study, i.e., subjects, investigators, and SPONSOR 
personnel will be aware of subject treatment assignments after each subject is enrolled and 
treatment is assigned.
The Clinical Biostatistics department will generate the allocation schedule(s) for study 
treatment assignment.  
Hypotheses/Estimation
Objectives and hypotheses of the study are stated in Section 3.0.
Analysis Endpoints
Efficacy and safety endpoints that will be evaluated for within-treatment differences are listed 
below, followed by the descriptions of the derivations of selected endpoints.
 
 
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Efficacy/Immunogenicity/Pharmacokinetics Endpoints
Efficacy and safety endpoints that will be evaluated for are listed below, followed by the 
descriptions of the derivations of selected endpoints.
MDS (Cohort 1)
The primary efficacy endpoint for the MDS cohort is ORR, defined as the proportion of 
subjects in the analysis population who have response according to the IWG 2006 criteria at 
any time during the study.  Response for the primary analysis will be determined by the
investigator.  
Key secondary efficacy endpoints for the MDS cohort include:

OS

Bone Marrow Response based on IWG criteria for MDS (investigator-assessed)

Hematologic improvement based on IWG criteria for MDS (investigator-assessed)

Cytogenetic response based on IWG criteria for MDS (investigator-assessed)

DOR

Response by PD-L1 expression change before and after HMA treatment
Additional analyses of efficacy endpoints in MDS based on central review of bone marrow 
assessment may be conducted at the end of the trial and will be considered exploratory.
MM (Cohort 2)
The primary efficacy endpoint for the MM cohort is ORR, defined as the proportion of subjects 
in the analysis population who have response according to the IMWG criteria at any time 
during the study.  Response for the primary analysis will be determined by the investigator.
Key secondary efficacy endpoints for the MM cohort include:

CR + sCR rate based on IMWG criteria (investigator-assessed)

TTP

DOR

PFS

OS

PD-L1 expression at baseline among responders/non-responders
 
 
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Lymphoma – HL (Cohort 3)
The primary efficacy endpoint for the HL cohort is CRR, defined as the proportion of subjects 
meeting the Revised Response Criteria for Malignant Lymphoma for a CR at any time during 
the study.  Response for the primary analysis will be assessed by the investigator.
Key secondary endpoints in the HL cohort include:

PFS

OS

ORR

DOR

PD-L1 expression at baseline among responders/non-responders
Additional analyses of HL efficacy endpoints based on central imaging assessment may be 
conducted at the end of the trial and will be considered exploratory.
Lymphoma –NHL monotherapy (Cohort 4)
The primary efficacy endpoint for the NHL monotherapy cohort is ORR, defined as the 
proportion of subjects meeting the IWG criteria for an OR at any time during the study.  
Response for the primary analysis will be assessed by the investigator.
Key secondary endpoints in the NHL cohort include:

PFS

OS

DOR

PD-L1 expression at baseline among responders/non-responders
These endpoints will also be assessed separately for subjects with relapsed / refractory MLBCL 
(Cohort 4A), FL (Cohort 4C + FL subjects in Cohort 4B), DLBCL (Cohort 4D + DLBCL 
subjects in Cohort 4B), DLBCL combo (Cohort 5) and Other (non-FL and non-DLBCL Cohort 
4B subjects).
Additional analyses of NHL monotherapy efficacy endpoints based on central imaging 
assessment may be conducted at the end of the trial and will be considered exploratory.
 
 
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Lymphoma –NHL combination therapy (Cohort 5)
The primary efficacy endpoint for the NHL combination therapy cohort is ORR, defined as the 
proportion of subjects meeting the IWG criteria for an OR at any time during the study.  
Response for the primary analysis will be assessed by the investigator.
Key secondary endpoints in the NHL cohort include:

PFS

OS

DOR

PD-L1 expression at baseline among responders/non-responders
Additional analyses of NHL combination therapy efficacy endpoints based on central imaging 
assessment may be conducted at the end of the trial and will be considered exploratory.
Safety Endpoints
A description of safety measures is provided in Section 4.2.3.1.  
The primary safety endpoints are AEs graded using CTCAE (Version 4.0) criteria. Safety will 
be assessed by quantifying the toxicities and grades experienced by subjects who have received 
pembrolizumab (Cohorts 1 thru 4) or lenalidomide + pembrolizumab (Cohort 5), including 
SAEs and ECIs.  Other safety endpoints include laboratory safety assessments, ECOG 
performance status, vital signs and physical examinations.
Analysis Populations
Efficacy Analysis Populations
The FAS population will serve as the primary population for the analysis of efficacy data in 
this study.  The FAS population consists of all randomized subjects in each disease cohort who:

Receive at least one dose of study treatment,

Have a baseline disease assessment, and 

Have a post baseline disease assessment OR discontinue the trial due to PD/drug related 
AE
Supportive analyses will be conducted in the ITT population, defined as all randomized 
subjects.  
For MDS cohort only, two additional subpopulations FAS/WHO-Classification and
ITT/WHO-Classification will be used. These two populations have the same definition as 
above except for requiring the baseline disease assessment to satisfy WHO criteria. 
 
 
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Subjects will be included in the treatment group to which they are randomized for the analysis 
of efficacy data.  Details on the approach to handling missing data are provided in Section
8.2.5 Statistical Methods.
Safety Analysis Populations
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 allocated subjects who received at least one 
dose of study treatment. 
At least one laboratory or vital sign measurement obtained subsequent to at least one dose of 
study treatment is required for inclusion in the analysis of each specific parameter.  To assess 
change from baseline, a baseline measurement is also required.
Details on the approach to handling missing data for safety analyses are provided in Section 
8.2.5 Statistical Methods.
Statistical Methods
Statistical testing and inference for safety analyses are described in 8.2.5.2. 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 8.2.6, 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
Efficacy will be evaluated separately in each disease cohort.  For the primary efficacy endpoint, 
the point estimate, 90% CI, and p-value for testing primary endpoint rate is greater than the 
historical control for each cohort will be provided using exact binomial distribution. Subjects 
in the primary analysis population (FAS) without response data will be counted as non-
responder.
 
 
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Table 17 summarizes the key efficacy analyses.
Table 17
Analysis Strategy for Key Efficacy Variables
Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Primary
1.
MDS (Cohort 1): ORR based 
on IWG (2006) criteria for 
MDS (investigator-assessed)
2.
MM (Cohort 2): ORR based 
on IMWG criteria 
(investigator-assessed)
3.
HL (Cohort 3): Complete 
Remission Rate (CRR) based 
IWG criteria (investigator-
assessed)
4.
NHL monotherapy (Cohort 
4): ORR based on IWG 
criteria (investigator-
assessed)
5.
NHL combination therapy 
(Cohort 5): ORR based on 
IWG criteria (investigator-
assessed)
Exact test of 
binomial parameter
(Cohorts 1 thru 4); 
Descriptive 
statistics (Cohort 5)
FAS (P)
ITT (S)
Subjects with missing 
data are considered 
non-responders
Secondary binary endpoints
1.
MDS (Cohort 1): 
a.
ORR based on IWG 
(2006) criteria for 
MDS (investigator-
assessed)
b.
Bone marrow response 
by IWG criteria 
(investigator assessed)
c.
Hematologic 
improvement  by IWG 
criteria (investigator-
assessed)
d.
Cytogenetic response 
by IWG criteria 
(investigator assessed)
2.
MM (Cohort 2):
a.
CR + sCR by IMWG 
criteria (investigator 
assessed)
3.
HL (Cohort 3):
a.
ORR
4.
NHL monotherapy (Cohort 
4): none
5.
NHL combination therapy 
(Cohort 5): none
Exact test of 
binomial parameter
MDS ORR: 
FAS/WHO-
Classification 
(P)   
ITT/WHO-
Classification 
(S)
All Others:
FAS (P)
ITT (S)
Subjects with missing 
data are considered 
non-responders
 
 
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Endpoint/Variable
(Description, Time Point)
Statistical Method
Analysis 
Population
Missing Data 
Approach
Secondary time-to-event endpoints
1.
MDS (Cohort 1):
a.
OS
b.
DOR
2.
MM  (Cohort 2):
a.
TTP
b.
DOR
c.
PFS
d.
OS
3.
HL (Cohort 3):
a.
PFS
b.
OS
c.
DOR
4.
NHL monotherapy (Cohort 
4):
a.
PFS
b.
OS
c.
DOR
5.
NHL combination therapy 
(Cohort 5):
a.
PFS
b.
OS
c.
DOR
Summary statistics 
using Kaplan-Meier 
method
OS, TTP, PFS: 
FAS (P)      
ITT (S)
DOR: all 
responders
Censored at last 
assessment
Secondary descriptive analyses
Response by PD-L1 expression 
change before and after HMA 
treatment in each population 
separately:
1.
MDS (Cohort 1)
2.
MM (Cohort 2)
3.
HL (Cohort 3)
4.
NHL monotherapy (Cohort 
4)
5.
NHL combination therapy 
(Cohort 5)
Descriptive 
statistics
FAS (P)
ITT (S)
P=Primary approach; S=Supportive approach; FAS=Full Analysis Set; ITT=Intention to treat
In addition to the analyses specified above for overall cohort 4, separate efficacy analyses, 
descriptive in nature, will be performed with subjects with relapsed / refractory MLBCL 
(Cohort 4A), FL (Cohort 4C + FL subjects in Cohort 4B), DLBCL (Cohort 4D + DLBCL 
subjects in Cohort 4B), and Other (Cohort 4B excluding FL and DLBCL subjects).
The strategy to address multiplicity issues with regard to multiple efficacy endpoints is 
described in Section 8.2.6, Multiplicity and Section 8.2.9, Interim Analyses.
Exploratory objectives in each cohort will be evaluated using descriptive statistics.
 
 
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Statistical Methods for Safety Analyses
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
AEs, laboratory tests, and vital signs. 
Summary statistics (counts, percentage, mean, standard deviation, etc.) will be provided for 
the safety endpoints as appropriate. The 95% CI for the incidence rate of Grade 2 or higher 
adverse events with an immune etiology and the incidence rate of Grade 4/5 AEs will be 
provided as appropriate.  
Safety analysis will be performed separately for Cohorts 1 through 5 as well as the subtypes 
within Cohort 4.
Summaries of Baseline Characteristics, Demographics, and Other Analyses
8.2.5.3.1
Demographic and Baseline Characteristics
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, randomized, the primary reasons for screening failure, and the 
primary reason for discontinuation will be displayed.  Demographic variables (e.g., age, 
gender), baseline characteristics, primary and secondary diagnoses, and prior and concomitant 
therapies will be summarized by treatment either by descriptive statistics or categorical tables.
Multiplicity
The false positive rate for testing the primary efficacy endpoint in each disease cohort (MDS,
MM, HL, and NHL monotherapy is controlled at 0.05 (1-sided) for each cohort.  No additional 
multiplicity adjustment is required because each disease cohort will be evaluated 
independently.  No statistical testing will be performed for Cohort 5 (NHL combination 
therapy).
Sample Size and Power Calculations
The calculation of power and sample size for each cohort does not account for an interim 
analysis.  
MDS (Cohort 1)
With approximately 25 subjects with intermediate-1, intermediate-2, or high risk MDS, the 
study has ~80% power to detect a 20% difference in ORR under the null hypothesis of 
ORR=10% with a one-sided type I error rate of 5% if the true ORR is 30%.  Success for this 
hypothesis requires at least 6/25 responses.  The null hypothesis ORR of 10% is based on the 
historic response rate in phase I/II trials of chemotherapy in MDS (Table 18).  The actual 
number of subjects enrolled may be larger than 25 to ensure that at least 25 subjects are 
evaluable for analysis. 
 
 
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MM (Cohort 2)
With approximately 28 subjects with MM, the study has ~80% power to detect a 25% 
difference in ORR under the null hypothesis of ORR=25% with a one-sided type I error rate 
of 5% if the true ORR is 50%.  Success for this hypothesis requires at least 12/28 responses.  
The null hypothesis ORR of 25% is based on the historic OR rate for MM (Table 18). The 
actual number of subjects enrolled may be larger than 28 to ensure that at least 28 subjects are 
evaluable for analysis.
Lymphoma – HL (Cohort 3)
With approximately 25 subjects with HL, the study has ~80% power to detect a 20% difference 
in CRR under the null hypothesis of CRR=10% with a one-sided type I error rate of 5% if the 
true CRR is 30%.  Success for this hypothesis requires at least 6/25 responses.  The null 
hypothesis CRR of no greater than 10% is estimated based on CR rate observed in prior studies 
of single agents in relapsed / refractory HL combined with the assumption that the HL 
population enrolled in the current trial would have failed prior brentuximab vedotin treatment
(Table 18). The actual number of subjects enrolled may be larger than 25 to ensure that at least 
25 subjects are evaluable for analysis.
Table 18
Historic Response Rates for Hematologic Malignancies
Disease
Reference
Agents
N
Response rate
Timing of Response 
Assessment
MDS
Bhatnagor [91]
Decitabine
13
0% ORR
Best objective response
Silverman [92]
5-Aza
191
23% ORR
Best objective response
MM
Siegel [93]
Carfilzomib
257
23.7%
Best objective response
Richardson [94]
Pomalidomide w/ 
low-dose 
Dexamethasone
113
33%
Best objective response
HL
Devizzi [95]
Vinorelbine
22
14% CR
Best objective response
Savage [96]
Gemcitabine
29
0% CR
Best objective response
Younes [39]
Brentuximab
102
34% CR
Best objective response
NHL
Churpek [97]
Epothilone
51
27% ORR 
Best objective response
Goy [98]
Bortezomib
27
19%
Best objective response
Wiernik [54]
Lenalidomide
49
35%
Best objective response
Lymphoma –NHL monotherapy (Cohort 4)
With approximately 78 subjects with NHL, the study has ~80% power to detect a 14% 
difference in ORR under the null hypothesis of ORR=25% with a one-sided type I error rate 
of 5% if the true ORR is 39%.  Success for this hypothesis requires at least 27/78 responses.  
The null hypothesis ORR of 25% is based on the historic OR rate from chemotherapy trials in 
NHL and MLBCL (Table 18).  The actual number of subjects enrolled may be larger than 78
to ensure that at least 78 subjects are evaluable for analysis.
 
 
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The maximum half-width of the 2-sided 90% exact CI will be 16% for the DLBCL and FL 
subtypes with a targeted number of 30 subjects each, and wider CIs for the MLBCL and Other 
subtypes.
Lymphoma –NHL combination therapy (Cohort 5)
Approximately 30-66 subjects will be evaluated in this cohort, depending on the number of 
dose levels of lenalidomide assessed during safety run-in.  Subjects in the safety run-in treated 
at the RP2D will be included in the dose expansion evaluation of 30 subjects for efficacy (see 
Section 5.2.1.3 for details).
The maximum half-width of the 2-sided 90% exact CI will be 16% with a targeted number of 
30 subjects. Table 19 describes examples of 90% CIs across a possible range of ORRs. 
Table 19
Precision (90% Confidence Intervals) for range of observed ORR (33% - 83%)
Number of responses/Number of treated subjects (ORR) 
90% 2-sided Confidence Interval*
10/30 (33%)
15/30 (50%)
20/30 (67%)
25/30 (83%)
(19, 50)
(34, 66)
(50, 81)
(68, 93)
*exact (Clopper-Pearson) confidence limit for the binomial proportion
Subgroup Analyses and Effect of Baseline Factors
No other subgroup analysis is planned.
Interim Analyses
Unless otherwise indicated, an interim analysis will be performed if fewer than 10 subjects are 
enrolled in a cohort 6 months after the time that the first subject is treated in the respective 
cohort. The interim analysis will take place after 10 subjects have reached the Week 12 
assessment. Results will be reviewed by the study team.  
MDS/HL (Cohorts 1 and 3)
For the MDS and HL cohorts, if an interim analysis is conducted and 1 or fewer subjects out 
of the first 10 subjects with a post-baseline (Week 12) assessment/imaging scan have a 
confirmed or unconfirmed primary endpoint response (OR or CR respectively), then 
enrollment will
be paused until response data for the subsequent (Week 24) 
assessment/imaging scan are reviewed for all subjects already enrolled in the trial (including 
those enrolled who have not reached the first post-baseline assessment/imaging scan).  
Enrollment will be resumed if the observed responses (confirmed or unconfirmed) for the 
primary endpoint in the respective cohort among subjects who are still enrolled in the trial 
indicates that the probability of the response for the primary endpoint >10% is at least 80% 
 
 
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(e.g., ≥3/16 confirmed or unconfirmed responses). See Section 12.8 for further details 
regarding the decision rules for resuming enrollment following the interim analysis. If the 
required number of responses is observed, enrollment will be resumed in the respective cohort 
regardless of whether all subjects have had disease assessments through Week 24.  Table 20
provides the operating characteristics for the interim analysis rule in MDS and HL.
Table 20
Operating Characteristics of Interim Analysis Rule for MDS and HL –  Pause 
Enrollment if ≤1/10 Subjects Achieve an Overall Response (MDS) or a Complete Response 
(HL); Final Analysis with 25 Subjects
True ORR
Probability of Pausing 
Enrollment
Probability of 
Passing the IA and 
Achieving Study 
Success
10%
0.73
0.03
15%
0.54
0.14
20%
0.37
0.34
25%
0.25
0.55
30%
0.15
0.74
35%
0.09
0.87
40%
0.05
0.93
MM (Cohort 2) and NHL (Cohorts 4A and 4B)
For the MM (Cohort 2) and combined MLBCL and PD-L1 positive NHL Cohorts 4A and 4B, 
respectively), if an interim analysis is conducted and 3 or fewer subjects out of the first 10 
subjects with a post-baseline (Week 12) imaging scan have a confirmed or unconfirmed 
primary endpoint response, then enrollment will be paused until response data for the 
subsequent imaging scan (Week 24) are reviewed for all subjects already enrolled in the trial 
(including those enrolled who have not reached the first post-baseline scan).  Enrollment will 
be resumed if the observed responses (confirmed or unconfirmed) for the primary endpoint in 
the respective cohort among subjects who are still enrolled in the trial indicates that the 
probability of the response for the primary endpoint >25% is at least 80% (e.g., ≥5/16 
confirmed or unconfirmed responses). See Section 12.8 for further details regarding the 
decision rules for resuming enrollment following the interim analysis. If the required number 
of responses is observed, enrollment will be resumed in the respective cohort regardless of 
whether all subjects have had disease assessments through Week 24. Table 21 provides the 
operating characteristics for this interim analysis rule in MM and MLBCL and PD-L1 Positive 
NHL Cohorts, respectively. 
 
 
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No interim analysis is planned for subjects with unselected PD-L1 status with relapsed /
refractory FL (Cohort 4C) or DLBCL (Cohort 4D).
Table 21
Operating Characteristics of Interim Analysis Rule for MLBCL and PD-L1 
Positive NHL subjects (Cohorts 4A and 4B) and MM (Cohort 1)– Pause Enrollment if ≤3/10 
Subjects Achieve an Overall Response (PR or better); Final Analysis with 28 Subjects
True ORR
Probability of Pausing 
Enrollment
Probability of 
Passing the IA and 
Achieving Study 
Success
25%
0.78
0.02
30%
0.65
0.08
35%
0.51
0.20
40%
0.38
0.37
45%
0.27
0.57
50%
0.17
0.74
55%
0.10
0.86
60%
0.05
0.93
Compliance (Medication Adherence)
A day within the study will be considered an On-Therapy day if the subject receives any dose 
of study medication.  The number of Days Should be on Therapy is the total number of days 
from the first day of study medication to the date of the last dose of study medication. For each 
subject, percent compliance will then be calculated (separately for pembrolizumab and 
lenalidomide for Cohort 5) using the following formula:
x 100.
Summary statistics will be provided on percent compliance for the FAS population.
Extent of Exposure
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
any dose of study medication. Summary statistics will be provided on Extent of Exposure for 
ASaT population.
Therapy
on 
be
Should
Days
of
Number 
Therapy
on 
Days
of
Number 
Compliance
Percent 

 
 
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9.0 LABELING, PACKAGING,
STORAGE AND RETURN OF CLINICAL 
SUPPLIES
9.1
Investigational Product
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations.
Clinical Supplies will be provided by the Sponsor as summarized in Table 22.  
Table 22
Product Descriptions
Product Name & Potency
Dosage Form
Source/Additional Information
pembrolizumab (MK-3475) 
50 mg
Lyophilized Powder for 
Injection
Provided centrally by the Sponsor 
(non-US).
pembrolizumab (MK-3475) 
100 mg/ 4mL
Solution for Injection
Provided centrally by the Sponsor 
(US only).
lenalidomide 5, 10, 15, 20,
and 25 mg
Capsules for Oral 
Administration
Provided centrally by the Sponsor 
except in regions that can source 
locally.
Not all dose strengths will be 
made available centrally from the 
Sponsor.  
Reference the study Pharmacy 
Manual.
9.2
Packaging and Labeling Information
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.
Vials will be provided in an open label fashion for subject dosing.  
9.3
Clinical Supplies Disclosure
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided.
 
 
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9.4
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.
9.5
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. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS
10.1 Confidentiality
Confidentiality of Data
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will be 
divulged to the institutional review board, ethics review committee (IRB/ERC) or similar or 
expert committee; affiliated institution and employees, only under an appropriate 
understanding of confidentiality with such board or committee, affiliated institution and 
employees.  Data generated by this trial will be considered confidential by the investigator, 
except to the extent that it is included in a publication as provided in the Publications section 
of this protocol.
Confidentiality of Subject Records
By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), 
IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in 
order to verify worksheet/case report form data.  By signing the consent form, the subject 
agrees to this process.  If trial documents will be photocopied during the process of verifying 
worksheet/case report form information, the subject will be identified by unique code only; 
full names/initials will be masked prior to transmission to the Sponsor.
By signing this protocol, the investigator agrees to treat all subject data used and disclosed in 
connection with this trial in accordance with all applicable privacy laws, rules and regulations.
 
 
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Confidentiality of Investigator Information
By signing this protocol, the investigator recognizes that certain personal identifying 
information with respect to the investigator, and all subinvestigators and trial site personnel, 
may be used and disclosed for trial management purposes, as part of a regulatory submissions, 
and as required by law.  This information may include:

name, address, telephone number and e-mail address;

hospital or clinic address and telephone number;

curriculum vitae or other summary of qualifications and credentials; and

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.
10.2 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 
 
 
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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.
10.3 Compliance with Law, Audit and Debarment
By signing this protocol, the investigator agrees to conduct the trial in an efficient and diligent 
manner and in conformance with this protocol; generally accepted standards of Good Clinical 
Practice (e.g., International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated 
Guideline and other generally accepted standards of good clinical practice); and all applicable 
federal, state and local laws, rules and regulations relating to the conduct of the clinical trial.
The Code of Conduct, a collection of goals and considerations that govern the ethical and 
scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -
Merck Code of Conduct for Clinical Trials.
The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory 
authority inspection of trial-related documents and procedures and provide for direct access to 
all trial-related source data and documents.
The investigator agrees not to seek reimbursement from subjects, their insurance providers or 
from government programs for procedures included as part of the trial reimbursed to the 
investigator by the Sponsor.
The investigator shall prepare and maintain complete and accurate trial documentation in 
compliance with Good Clinical Practice standards and applicable federal, state and local laws, 
rules and regulations; and, for each subject participating in the trial, provide all data, and, upon 
completion or termination of the clinical trial, submit any other reports to the Sponsor as 
required by this protocol or as otherwise required pursuant to any agreement with the Sponsor.
Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator 
upon request and also shall be made available at the trial site upon request for inspection, 
copying, review and audit at reasonable times by representatives of the Sponsor or any 
regulatory authorities.  The investigator agrees to promptly take any reasonable steps that are 
requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation 
and worksheets/case report forms.
The investigator must maintain copies of all documentation and records relating to the conduct 
of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data, correspondence 
with regulatory authorities and IRBs/ERCs, consent forms, investigator’s curricula vitae, 
monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
 
 
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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 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 discarding trial and/or subject files.  
ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s 
primary physician about the subject’s participation in the trial if the subject has a primary 
physician and if the subject agrees to the primary physician being informed.
The investigator will promptly inform the Sponsor of any regulatory authority inspection 
conducted for this trial.
Persons debarred from conducting or working on clinical trials by any court or regulatory 
authority will not be allowed to conduct or work on this Sponsor’s trials.  The investigator will 
immediately disclose in writing to the Sponsor if any person who is involved in conducting the 
trial is debarred or if any proceeding for debarment is pending or, to the best of the 
investigator’s knowledge, threatened.
In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will 
promptly notify that trial site’s IRB/IEC.
According to European legislation, a Sponsor must designate an overall coordinating 
investigator for a multi-center trial (including multinational).  When more than one trial site is 
open in an EU country, Merck, as the Sponsor, will designate, per country, a national principal 
coordinator (Protocol CI), responsible for coordinating the work of the principal investigators 
at the different trial sites in that Member State, according to national regulations.  For a single-
center trial, the Protocol CI is the principal investigator.  In addition, the Sponsor must 
designate a principal or coordinating investigator to review the trial report that summarizes the 
trial results and confirm that, to the best of his/her knowledge, the report accurately describes 
the conduct and results of the trial [Clinical Study Report (CSR) CI].  The Sponsor may 
consider one or more factors in the selection of the individual to serve as the Protocol CI and 
or CSR CI (e.g., availability of the CI during the anticipated review process, thorough 
understanding of clinical trial methods, appropriate enrollment of subject cohort, timely 
achievement of trial milestones).  The Protocol CI must be a participating trial investigator.
10.4 Compliance with Trial Registration and Results Posting Requirements
Under the terms of the Food and Drug Administration Amendments Act (FDAAA) of 2007, 
and the European Medicines Agency (EMA) clinical trial Directive 2001/20/EC, the Sponsor 
 
 
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of the trial is solely responsible for determining whether the trial and its results are subject to 
the requirements for submission to http://www.clinicaltrials.gov, www.clinicaltrialregister.eu
or other local registries. Merck, as Sponsor of this trial, will review this protocol and submit 
the information necessary to fulfill these requirements. Merck entries are not limited to 
FDAAA or the EMA clinical trials directive mandated trials. Information posted will allow 
subjects to identify potentially appropriate trials for their disease conditions and pursue 
participation by calling a central contact number for further information on appropriate trial 
locations and trial site contact information.   
By signing this protocol, the investigator acknowledges that the statutory obligations under 
FDAAA, the EMA clinical trials directive or other locally mandated registries are that of the 
Sponsor and agrees not to submit any information about this trial or its results to those 
registries.
10.5 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.
10.6 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 
by the Sponsor.
10.7 Publications
This trial is intended for publication, even if terminated prematurely. Publication may include 
any or all of the following: posting of a synopsis online, abstract and/or presentation at a 
scientific conference, or publication of a full manuscript.  The Sponsor will work with the 
authors to submit a manuscript describing trial results within 12 months after the last data 
become available, which may take up to several months after the last subject visit in some 
cases such as vaccine trials.  However, manuscript submission timelines may be extended on 
OTC trials.  For trials intended for pediatric-related regulatory filings, the investigator agrees 
to delay publication of the trial results until the Sponsor notifies the investigator that all 
relevant regulatory authority decisions on the trial drug have been made with regard to 
pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the 
 
 
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primary outcome, 12 months after the decision to discontinue development, or product 
marketing (dispensed, administered, delivered or promoted), whichever is later.
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for analysis, to protect intellectual property, or to comply with confidentiality 
agreements with other parties.  Authors of the primary results manuscript will be provided the 
complete results from the Clinical Study Report, subject to the confidentiality agreement. 
When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also include 
the protocol and statistical analysis plan to facilitate the peer and editorial review of the 
manuscript.  If the manuscript is subsequently accepted for publication, the Sponsor will allow 
the journal, if it so desires, to post on its website the key sections of the protocol that are 
relevant to evaluating the trial, specifically those sections describing the trial objectives and 
hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, 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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Feugier P, Van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, FerméC, 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 
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Coiffier P, Feugier N, Mounier N, Franchi-Rezgui P, Neste EVD, Macro M. Long-
term results of the gela study comparing r-chop and chop chemotherapy in older 
patients with diffuse large B-cell lymphoma show good survival in poor-risk 
patients: 2007 ASCO Annual Meeting Proceedings: Post-Meeting Edition. J Clin 
Oncol 2007;25(18S):1-2.
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Coiffier B, Lepage E, Brière J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP 
chemotherapy plus rituximab compared with CHOP alone in elderly patients with 
diffuse large-B-cell lymphoma. N Engl J Med 2002;346(4):235-42.
 
 
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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 
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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 
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2008;14(10):3044-51.
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Chang DH, Liu N, Klimek V, Hassoun H, Mazumder A, Nimer SD, et al. 
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lenalidomide: therapeutic implications. Blood. 2006 Jul 15;108(2):618-21. Epub 
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Gandhi AK, Kang J, Naziruddin S, Parton A, Schafer PH, Stirling DI. Lenalidomide 
inhibits proliferation of Namalwa CSN.70 cells and interferes with Gab1 
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Wu L, Adams M, Carter T, Chen R, Muller G, Stirling D, et al. Lenalidomide 
enhances natural killer cell and monocyte-mediated antibody-dependent cellular 
cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res. 2008 Jul 
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Yang Y, Shaffer AL 3rd, Emre NC, Ceribelli M, Zhang M, Wright G, et al. 
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Zhang LH, Kosek J, Wang M, Heise C, Schafer PH, Chopra R. Lenalidomide 
efficacy in activated B-cell-like subtype diffuse large B-cell lymphoma is dependent 
upon IRF4 and cereblon expression. Br J Haematol. 2013 Feb;160(4):487-502.
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Wiernik PH, Lossos IS, Tuscano JM, Justice G, Vose JM, Cole CE. Lenalidomide 
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Witzig TE, Vose JM, Zinzani PL, Reeder CB, Buckstein R, Polikoff JA, et al. An 
international phase II trial of single-agent lenalidomide for relapsed or refractory 
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Hernandez-Ilizaliturri FJ, Deeb G, Zinzani PL, Pileri SA, Malik F, Macon WR, et 
al. Higher response to lenalidomide in relapsed/refractory diffuse large B-cell 
lymphoma in nongerminal center B-cell-like than in germinal center B-cell-like 
phenotype. Cancer. 2011 Nov 15;117(22):5058-66.
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Zinzani PL, Pellegrini C, Gandolfi L, Stefoni V, Quirini F, Derenzini E, et al. 
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Wang M, Fowler N, Wagner-Bartak N, Feng L, Romaguera J, Neelapu SS, et al . 
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vanov V, Coso D, Chetaille B, Esterni B, Olive D, Aurran-Schleinitz T, et al. 
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Nowakowski GS, LaPlant B, Macon WR, Reeder CB, Foran JM, Nelson GD, et al. 
Lenalidomide combined with R-CHOP overcomes negative prognostic impact of 
non-germinal center B-cell phenotype in newly diagnosed diffuse large B-Cell 
lymphoma: a phase II study. J Clin Oncol. 2015 Jan 20;33(3):251-7.
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Vitolo U, Chiappella A, Franceschetti S, Carella AM, Baldi I, Inghirami G. et al. 
Lenalidomide plus R-CHOP21 in elderly patients with untreated diffuse large B-
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intravenous use: 2015.
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for solution for infusion: July 2015.
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Kwon D, Kim S, Kim PJ, Go H, Nam SJ, Paik JH, et al. Clinicopathological analysis 
of programmed cell death-1 and programmed cell death-ligand 1 expression in the 
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Kiyasu J, Miyoshi H, Hirata A, Arakawa F, Ichikawa A, Niino D, et al. Expression 
of programmed cell death ligand 1 is associated with poor overall survival in 
patients with diffuse large B-cell lymphoma. Blood. 2015 Nov 5;126(19):2193-201.
 
 
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Several immune escape patterns in non-Hodgkin's lymphomas. Oncoimmunology. 
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Miguel JS, Mateos MV, Shah JJ, Ocio EM, Rodriguez-Otero P, Reece D, et al. 
Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for 
elapsed/Refractory Multiple Myeloma (RRMM): KEYNOTE-023 [abstract]. 
Abstracts of the American Society of Hematology 57th Annual Meeting and 
Exposition; 2015 Dec 5-8; Orlando, FL: ASH; 2015. p. 3.
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Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013 
Jan;63(1):11-30.
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Phekoo KJ, Schey SA, Richards MA, Bevan DH, Bell S, Gillett D, et al. A 
population study to define the incidence and survival of multiple myeloma in a 
National Health Service Region in UK. Br J Haematol 2004;127:299-304.
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Sant M, Allemani C, Tereanu C, De Angelis R, Capocaccia R, Visser O. et al. 
Incidence of hematologic malignancies in Europe by morphologic subtype: results 
of the HAEMACARE project. Blood. 2010 Nov 11;116(19):3724-34.
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Smith A, Howell D, Patmore R, Jack A, Roman E. Incidence of haematological 
malignancy by sub-type: a report from the Haematological Malignancy Research 
Network. Br J Cancer. 2011 Nov 22;105(11):1684-92.
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Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012 
Jan-Feb;62(1):10-29.
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Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008 Mar 15;111(6):2962-72.
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Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. 
Lancet 2009;374:324-39.
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Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. 
Improved survival in multiple myeloma and the impact of novel therapies. Blood 
2008;111(5):2516-20.
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multiple myeloma: an overview of 6,633 patients from 27 randomized trials. 
Myeloma Trialists' Collaborative Group. J Clin Oncol. 1998 Dec;16(12):3832-42.
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Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, et al. Risk 
of progression and survival in multiple myeloma relapsing after therapy with IMiDs 
and bortezomib: a multicenter international myeloma working group study. 
Leukemia. 2012 Jan;26(1):149-57.
 
 
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Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, et al. 
Plasma cells from multiple myeloma patients express B7-H1 (PD-L1) and increase 
expression after stimulation with IFN-gamma and TLR ligands via a MyD88-, 
TRAF6-, and MEK-dependent pathway. Blood 2007;110(1):296-304
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Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-
L1 on tumor cells in the escape from host immune system and tumor 
immunotherapy by PD-L1 blockade. Proc Natl Acad Sci U S A 2002;99(19):12293-
7.
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Hallett WH, Jing W, Drobyski WR, Johnson BD. Immunosuppressive effects of 
multiple myeloma are overcome by PD-L1 blockade. Biol Blood Marrow 
Transplant. 2011 Aug;17(8):1133-45.
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Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD. 
Clinical application and proposal for modification of the international working 
group (IWG) response criteria in myelodysplasia. Blood 2006;108(2):419-25.
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Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007;25(5):579-86.
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Durie BGM, Harousseau J-L, Miguel JS, BladéJ, Barlogie B, Anderson K. 
International uniform response criteria for multiple myeloma. Leukemia 
2006;20:1467-73.
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Durie BG. Staging and kinetics of multiple myeloma. Semin Oncol. 1986 
Sep;13(3):300-9.
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Ji Y, Li Y, Bekele BN. Dose-finding in phase I clinical trials based on toxicity 
probability intervals. Clin Trials J 2007;4:235-44.
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Ji Y, Li Y, Bekele BN. Dose-finding in phase l clinical trials based on toxicity 
probability intervals. Clin Trials 2007;4:235-44.
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Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. 
Revised response criteria for malignant lymphoma. J Clin Oncol 2007;25:579-86.
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Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, 
et al. Clinical application and proposal for modification of the International 
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International uniform response criteria for multiple myeloma. Leukemia 
2006;20:1467-73.
 
 
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3858: Lack of response of myelodysplastic syndrome (MDS) and acute myeloid: 
Leukemia (AML) to decitabine after failure of azacitidine: 54th ASH annual 
meeting and exposition.
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Reissig R. Randomized controlled trial of azacitidine in patients with the 
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Pomalidomide alone or in combination with low-dose dexamethasone in relapsed 
and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014 
Mar20;123(12):1826-32.
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of epothilone B analog bms-247550 (nsc 710428) in patients with relapsed 
aggressive non-hodgkin lymphomas. Cancer 2013;*(*):1-7.
 
 
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12.0 APPENDICES
12.1 Merck Code of Conduct for Clinical Trials
Merck*
Code of Conduct for Clinical Trials
I.
Introduction
A. Purpose
Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our 
products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in 
compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in the 
design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or national 
regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki. 
B. Scope
Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the 
party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This 
Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code 
does not apply to investigator-initiated trials which are not under the control of Merck.
II. Scientific Issues
A. Trial Conduct
i.
Trial Design
Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy and/or 
pharmacokinetic or pharmacodynamic indices of Merck or comparator products.  Alternatively, Merck may conduct 
outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine subject
preferences, etc.  
The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose of 
the trial.  Research subjects must meet protocol entry criteria to be enrolled in the trial. 
ii.
Site Selection
Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities 
and staff, previous performance in Merck trials, as well as budgetary considerations.  Prior to trial initiation, sites 
are evaluated by Merck personnel to assess the ability to successfully conduct the trial.
iii.
Site Monitoring/Scientific Integrity
Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical 
Practice.  Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source 
documentation according to standard operating procedures.  Per Merck policies and procedures, if fraud, misconduct 
or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, the clinical 
site will be closed, the responsible regulatory authorities and ethics review committees notified and data disclosed 
accordingly. 
B. Publication and Authorship
To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts.  Some early phase or 
pilot trials are intended to be hypothesis-generating rather than hypothesis testing.  In such cases, publication of results 
may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues of 
multiplicity.
Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice guidelines. 
In summary, authorship should reflect significant contribution to the design and conduct of the trial, performance or 
interpretation of the analysis, and/or writing of the manuscript.  All named authors must be able to defend the trial
results and conclusions.  Merck funding of a trial will be acknowledged in publications. 
 
 
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III. Subject Protection
bb. IRB/ERC review
All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site.  
Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that 
changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC approval. 
For each site, the IRB/ERC and Merck will approve the subject informed consent form. 
cc.
Safety
The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance.  Potential 
subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trial
designs will take into account the local standard of care.  Subjects are never denied access to appropriate medical care 
based on participation in a Merck clinical trial. 
All participation in Merck clinical trials is voluntary.  Subjects are enrolled only after providing informed consent for 
participation.  Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or receipt 
of, medical care that may otherwise be available to them.
dd. Confidentiality
Merck is committed to safeguarding subject confidentiality, to the greatest extent possible.  Unless required by law, 
only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical 
records that might identify the research subject by name.  
ee.
Genomic Research
Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by an 
Ethics Committee.
IV. Financial Considerations
ff.
Payments to Investigators
Clinical trials are time- and labor-intensive.  It is Merck’s policy to compensate investigators (or the sponsoring 
institution) in a fair manner for the work performed in support of Merck trials.   Merck does not pay incentives to 
enroll subjects in its trials.  However, when enrollment is particularly challenging, additional payments may be made 
to compensate for the time spent in extra recruiting efforts.
Merck does not pay for subject referrals.  However, Merck may compensate referring physicians for time spent on 
chart review to identify potentially eligible subjects.
gg. Clinical Research Funding 
Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring 
institution is being paid or provided a grant for performing the trial.  However, the local IRB/ERC may wish to alter 
the wording of the disclosure statement to be consistent with financial practices at that institution.  As noted above, 
publications resulting from Merck trials will indicate Merck as a source of funding.
hh. Funding for Travel and Other Requests
Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be 
consistent with local guidelines and practices including, in the U.S., those established by the American Medical 
Association (AMA). 
V. Investigator Commitment
Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing 
the protocol, agree to support these ethical and scientific standards.
* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a 
subsidiary of Merck & Co., Inc.  Merck is known as MSD outside of the United States and Canada.  As warranted by 
context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."
 
 
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12.2 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 DNA, blood, lymph node and bone marrow specimen(s) collected in the current trial 
will be used to study various causes for how subjects may respond to a drug.  The DNA, 
blood, lymph node and bone marrow specimen(s) will be stored to provide a resource for 
future trials conducted by Merck focused on the study of biomarkers responsible for how 
a drug enters and is removed by the body, how a drug works, other pathways a drug 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, 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 Merck 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 to any specimens, test results, or 
medical information once the specimens have been rendered de-identified.
 
 
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Subjects are not required to participate in Future Biomedical Research in order to 
participate in the main trial. Subjects who decline to sign the Future Biomedical 
Research informed consent will not have the specimen collected nor will they be 
discontinued from the main trial.
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 Future Biomedical Research purposes. Any 
specimens for which such an informed consent cannot be verified will be destroyed.
a.
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 Merck 
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.
 
 
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To maintain privacy of information collected from specimens obtained for Future 
Biomedical Research, Merck has developed secure policies and procedures.  All specimens 
will be de-identified as described below. 
At the clinical trial site, unique codes will be placed on the Future Biomedical Research 
specimens for transfer to the storage facility.  This first code is a random number which 
does not contain any personally identifying information embedded within it. The link (or 
key) between subject identifiers and this first unique code will be held at the trial site.  No 
personal identifiers will appear on the specimen tube.  
This first code will be replaced with a second code at a Merck 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 Merck designated facility to an Entrusted Keyholder at Merck.  The 
second code will be logged into the primary biorepository database at Merck 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 
Merck Entrusted Keyholder under strict security policies and procedures.  The Merck 
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 Merck 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 
Merck, or an additional third party (e.g., a university investigator) designated by Merck.  
The investigator conducting the analysis will be provided with double coded specimens. 
 
 
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Re-association of analysis results with corresponding clinical data will only be conducted 
by the Merck Entrusted Keyholder.  Any contracted third party analyses will conform to 
the specific scope of analysis outlined in FBR protocol and consent.  Future Biomedical 
Research specimens remaining with the third party after the specific analysis is performed 
will be returned to the sponsor or destroyed and documentation of destruction will be 
reported to Merck.
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 
writing to the principal investigator for the main trial.  If medical records for the main trial 
are still available, the investigator will contact Merck using the designated mailbox 
(clinical.specimen.management@merck.com) and a form will be provided by Merck 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 Merck 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 
Merck 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 Merck 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 Merck.  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 
 
 
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network security policies and practices based in international standards (e.g., ISO17799) 
to protect against unauthorized access.  The Merck Entrusted Keyholder 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 Merck 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 Merck) 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, Merck will publish the results without revealing specific 
subject information, inform all trial sites who participated in the Merck 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 Merck 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 FBR, risks to the subject have been minimized. 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. 
Merck 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 Merck 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 
clinical.specimen.management@merck.com.
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
 
 
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12.3 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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12.4 ECOG Performance Status 
Grade
Description
0
Fully active, able to carry on all pre-disease performance 
without restriction
1
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, e.g., 
light housework, office work
2
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
Capable of only limited self-care; confined to bed or chair 
more than 50% of waking hours.
4
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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12.5 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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12.6 Multiple Myeloma Diagnostic Criteria
Durie, Seminars in Oncology, Vol 13, No 3 (September), 1986:pp300-309:
 
 
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12.7 Disease Response Criteria 
MDS Disease Response Criteria
Cheson et al.  Clinical application and proposal for modification of the International Working
Group (IWG) response criteria in myelodysplasia.  Blood.  2006; 108:419-425.
Criteria for MDS disease assessment:
 
 
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Criteria for MDS hematologic improvement assessment:
 
 
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Durie et al.  International uniform response criteria for multiple myeloma.  Leukemia.  2006; 
20:1467-1473.
Criteria for multiple myeloma disease assessment:
 
 
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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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12.8 Interim Analysis Decision Rules
The table below describes the detailed Go/No-Go decision rules for resuming enrollment (GO
= Resume enrollment; NG = do not resume enrollment) based on the number of subjects 
enrolled and number of responses following the interim analysis.
MDS/HL
Number of subjects enrolled at IA
Number of Responses
10 to 14
15 to 20
0
NG
NG
1
NG
NG
2
GO
NG
3+
GO
GO
MM and MLBCL/PD-
L1+ NHL
Number of subjects enrolled at IA
Number of Responses
10 to 11
12 to 15
16 to 18
19 to 20
0 to 3
NG
NG
NG
NG
4
GO
NG
NG
NG
5
GO
GO
NG
NG
6
GO
GO
GO
NG
7
GO
GO
GO
GO
GO = Resume enrollment; NG = do not resume enrollment
 
 
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12.9 Dose Timing Table for Lenalidomide + Pembrolizumab Combination Treatment
Cycle
Weeks
Day
Pembrolizumab 200 mg
Lenalidomide RP2D
Cycle 1
1-4
1
Dose 1
Days 1-21 + 7 days off
8
15
22
Dose 2
Cycle 2
5-8
1
Days 1-21 + 7 days off
8
15
Dose 3
22
Cycle 3
9-12
1
Days 1-21 + 7 days off
8
Dose 4
15
22
Cycle 4
13-16
1
Dose 5
Days 1-21 + 7 days off
8
15
22
Dose 6
Cycle 5
17-20
1
Days 1-21 + 7 days off
8
15
Dose 7
22
Cycle 6
21-24
1
Days 1-21 + 7 days off
8
Dose 8
15
22
Cycle 7
25-28
1
Dose 9
Days 1-21 + 7 days off
8
15
22
Dose 10
Cycle 8
29-32
1
Days 1-21 + 7 days off
8
15
Dose 11
22
Cycle 9
33-36
1
Days 1-21 + 7 days off
8
Dose 12
15
22
Cycle 10
37-40
1
Dose 13
Days 1-21 + 7 days off
8
15
22
Dose 14
Cycle 11
41-44
1
Days 1-21 + 7 days off
8
15
Dose 15
22
 
 
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Cycle
Weeks
Day
Pembrolizumab 200 mg
Lenalidomide RP2D
Cycle 12
45-48
1
Days 1-21 + 7 days off
8
Dose 16
15
22
Cycle 13
49-52
1
Dose 17
Days 1-21 + 7 days off
8
15
22
Dose 18
Cycle 14
53-56
1
Days 1-21 + 7 days off
8
15
Dose 19
22
Cycle 15
57-60
1
Days 1-21 + 7 days off
8
Dose 20
15
22
Cycle 16
61-64
1
Dose 21
Days 1-22 + 7 days off
8
15
22
Dose 22
Cycle 17
65-68
1
Days 1-21 + 7 days off
8
15
Dose 23
22
Cycle 18
69-72
1
Days 1-21 + 7 days off
8
Dose 24
15
22
Cycle 19
73-76
1
Dose 25
Days 1-21 + 7 days off
8
15
22
Dose 26
Cycle 20
77-80
1
Days 1-21 + 7 days off
8
15
Dose 27
22
Cycle 21
81-84
1
Days 1-21 + 7 days off
8
Dose 28
15
22
Cycle 22
85-88
1
Dose 29
Days 1-21 + 7 days off
8
15
22
Dose 30
 
 
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Cycle
Weeks
Day
Pembrolizumab 200 mg
Lenalidomide RP2D
Cycle 23
89-92
1
Days 1-21 + 7 days off
8
15
Dose 31
22
Cycle 24
93-96
1
Days 1-21 + 7 days off
8
Dose 32
15
22
Cycle 25
97-100
1
Dose 33
Days 1-21 + 7 days off
8
15
22
Dose 34
Cycle 26
101-104
1
Days 1-21 + 7 days off
8
15
Dose 35
22
 
 
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12.10 Lenalidomide Pregnancy Prevention Plan for Subjects in Clinical Trials
The Pregnancy Prevention Plan (PPP) applies to all subjects receiving lenalidomide within a 
clinical trial. The following PPP documents are included: 
1. The Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods document (Section 12.10.1) provides the following 
information:

Potential risks to the fetus associated with lenalidomide exposure

Definition of female of childbearing potential (FCBP)/female not of childbearing 
potential (FNCBP)

Requirements for counseling of all subjects receiving lenalidomide about 
pregnancy precautions and the potential risks of fetal exposure to lenalidomide

Acceptable birth control methods for both female subjects of childbearing potential 
and male subjects receiving lenalidomide in the study

Pregnancy testing requirements for subjects receiving lenalidomide who are FCBP
2. The Lenalidomide Education and Counseling Guidance Document for each gender 
(female and male; Sections 12.10.6 and Section 12.10.7, respectively) must be 
completed and signed by a trained counselor at the participating clinical center prior to 
each dispensing of lenalidomide. A copy of this document must be maintained in the 
subject’s records for each dispense.
3. The Lenalidomide Information Sheet (Section 12.10.8) will be given to each subject 
receiving lenalidomide. The subject must read this document prior to starting 
lenalidomide and each time the subject receives a new supply of lenalidomide.
Lenalidomide Risks of Fetal Exposure, Pregnancy Testing Guidelines and 
Acceptable Birth Control Methods
Risks Associated with Pregnancy
Lenalidomide is structurally related to thalidomide. Thalidomide is a known human teratogenic 
active substance that causes severe life-threatening birth defects. An embryofetal development 
study in animals indicates that lenalidomide produced malformations in the offspring of female 
monkeys who received the drug during pregnancy. A teratogenic effect of lenalidomide in 
humans cannot be ruled out. Therefore, a pregnancy prevention program must be followed.
Definition of Females of Childbearing Potential
A FCBP is a female who: 1) has achieved menarche at some point, 2) has not undergone a 
hysterectomy or bilateral oophorectomy or 3) has not been naturally postmenopausal 
(amenorrhea following cancer therapy does not rule out childbearing potential) for at least 
 
 
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24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive 
months).
Definition of Females Not of Childbearing Potential
Females who do not meet the above definition of FCBP should be classified as FNCBP.
Counseling
Females of Childbearing Potential
For a FCBP, lenalidomide is contraindicated unless all of the following are met (ie, all FCBP 
must be counseled concerning the following risks and requirements prior to the start of 
lenalidomide): 

She understands the potential teratogenic risk to the unborn child

She understands the need for effective contraception, without interruption, 28 days 
before starting lenalidomide, throughout the entire duration of lenalidomide, during 
dose interruptions and for at least 28 days after the last dose of lenalidomide

She understands and agrees to inform the Investigator if a change or stop of method 
of contraception is needed

She must be capable of complying with effective contraceptive measures

She is informed and understands the potential consequences of pregnancy and the 
need to notify her study doctor immediately if there is a risk of pregnancy

She understands the need to commence lenalidomide as soon as it is dispensed 
following a negative pregnancy test

She understands and accepts the need to undergo pregnancy testing based on the 
frequency outlined in this plan (Section 12.10.4) and in the Informed Consent

She acknowledges that she understands the hazards lenalidomide can cause to an 
unborn fetus and the necessary precautions associated with the use of lenalidomide.
The Investigator must ensure that a FCBP:

Complies with the conditions of the pregnancy prevention plan, including 
confirmation that she has an adequate level of understanding

Acknowledges the aforementioned requirements.
Females Not of Childbearing Potential
For a FNCBP, lenalidomide is contraindicated unless all of the following are met (ie, all 
FNCBP must be counseled concerning the following risks and requirements prior to the start 
of lenalidomide): 

She acknowledges she understands the hazards lenalidomide can cause to an unborn 
fetus and the necessary precautions associated with the use of lenalidomide.
 
 
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Males
Traces of lenalidomide have been found in semen. Male subjects taking lenalidomide must 
meet the following conditions (ie, all males must be counseled concerning the following risks 
and requirements prior to the start of lenalidomide):

Understand the potential teratogenic risk if engaged in sexual activity with a 
pregnant female or a FCBP

Understand the need for the use of a condom even if he has had a vasectomy, if 
engaged in sexual activity with a pregnant female or a FCBP

Understand the potential teratogenic risk if the subject donates semen or sperm.
Contraception
Female Subjects of Childbearing Potential
Females of childbearing potential enrolled in this protocol must agree to use two reliable forms 
of contraception simultaneously or to practice complete abstinence (True abstinence is 
acceptable when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence [eg, calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal 
are not acceptable methods of contraception.) from heterosexual contact during the following 
time periods related to this study: 1) for at least 28 days before starting lenalidomide; 2) while 
taking lenalidomide; 3) during dose interruptions; and 4) for at least 28 days after the last dose 
of lenalidomide. 
The two methods of reliable contraception must include one highly effective method and one 
additional effective (barrier) method. If the below contraception methods are not appropriate 
for the FCBP, she must be referred to a qualified provider of contraception methods to 
determine the medically effective contraception method appropriate to the subject. The 
following are examples of highly effective and additional effective methods of contraception:

Examples of highly effective methods:

IUD

Hormonal (birth control pills, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, 
ovulation inhibitory progesterone-only pills [e.g. desogestrel])

Tubal ligation

Partner’s vasectomy

Examples of additional effective methods:

Male condom
 
 
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
Diaphragm

Cervical Cap
Implants and levonorgestrel-releasing intrauterine systems are associated with an increased 
risk of infection at the time of insertion and irregular vaginal bleeding. Prophylactic antibiotics 
should be considered particularly in subjects with neutropenia. 
Male Subjects
Male subjects must practice complete abstinence (True abstinence is acceptable when this is 
in line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, 
ovulation, symptothermal or post-ovulation methods] and withdrawal are not acceptable 
methods of contraception.) or agree to use a condom during sexual contact with a pregnant 
female or a FCBP while taking lenalidomide, during dose interruptions and for at least 28 days 
after the last dose of lenalidomide, even if he has undergone a successful vasectomy. 
Pregnancy Testing
Medically supervised pregnancy tests with a minimum sensitivity of 25 mIU/mL must be 
performed for FCBP.
Females of childbearing potential must have two negative pregnancy tests (sensitivity of at 
least 25 mIU/mL) prior to starting lenalidomide. The first pregnancy test must be performed 
within 10 to 14 days prior to the start of lenalidomide and the second pregnancy test must be 
performed within 24 hours prior to the start of lenalidomide. The subject may not receive 
lenalidomide until the study doctor has verified that the results of these pregnancy tests are 
negative.
Females of childbearing potential with regular or no menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 28 days while 
taking lenalidomide, at study discontinuation, and at Day 28 following the last dose of 
lenalidomide. 
Females of childbearing potential with irregular menstrual cycles must agree to have 
pregnancy tests weekly for the first 28 days of study participation and then every 14 days while 
taking lenalidomide, at study discontinuation, and at Days 14 and 28 following the last dose of 
lenalidomide.
 
 
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Pregnancy Precautions for Lenalidomide Use
Before Starting Lenalidomide
12.10.5.1.1
Female Subjects of Childbearing Potential
Females of childbearing potential must have two negative pregnancy tests (sensitivity of at 
least 25 mIU/mL) prior to starting lenalidomide. The first pregnancy test must be performed 
within 10 to 14 days prior to the start of lenalidomide and the second pregnancy test must be 
performed within 24 hours prior to the start of lenalidomide. The subject may not receive 
lenalidomide until the study doctor has verified that the results of these pregnancy tests are 
negative.
Females of childbearing potential must use two reliable forms of contraception simultaneously, 
or practice complete abstinence (True abstinence is acceptable when this is in line with the 
preferred and usual lifestyle of the subject. Periodic abstinence [eg calendar, ovulation, 
symptothermal or post-ovulation methods] and withdrawal are not acceptable methods of 
contraception.) from heterosexual contact for at least 28 days before starting lenalidomide.
12.10.5.1.2
Male Subjects
Male subjects must agree to practice complete abstinence (True abstinence is acceptable when 
this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg 
calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal are not 
acceptable methods of contraception.) or agree to use a condom during sexual contact with a 
pregnant female or a FCBP while taking lenalidomide, during dose interruptions and for at 
least 28 days after the last dose of lenalidomide, even if he has undergone a successful 
vasectomy. 
During and After Study Participation
12.10.5.2.1
Female Subjects

Females of childbearing potential with regular or no menstrual cycles must agree 
to have pregnancy tests weekly for the first 28 days of study participation and then 
every 28 days while taking lenalidomide, at study discontinuation, and at Day 28 
following the last dose of lenalidomide. 

Females of childbearing potential with irregular menstrual cycles must agree to 
have pregnancy tests weekly for the first 28 days of study participation and then 
every 14 days while taking lenalidomide, at study discontinuation, and at Days 14 
and 28 following the last dose of lenalidomide.  

At each visit, the Investigator must confirm with the FCBP that she is continuing 
to use two reliable methods of birth control if not committing to complete 
abstinence, or confirm commitment to complete abstinence.
 
 
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
If a FCBP considers the need to change or to stop a method of contraception, the 
Investigator must be notified immediately.

Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted at a minimum of every 28 days. 

If pregnancy or a positive pregnancy test does occur in a subject, lenalidomide must 
be immediately discontinued.

Pregnancy testing and counseling must be performed if a subject misses her period 
or if her pregnancy test or her menstrual bleeding is abnormal. Lenalidomide must 
be discontinued during this evaluation.

Females must agree to abstain from breastfeeding while taking lenalidomide and 
for at least 28 days after the last dose of lenalidomide.
12.10.5.2.2
Male Subjects

Must practice complete abstinence (True abstinence is acceptable when this is in 
line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg 
calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal are 
not acceptable methods of contraception.) or use a condom during sexual contact 
with a pregnant female or a FCBP while taking lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide, even if he 
has undergone a successful vasectomy.

Must not donate semen or sperm while receiving lenalidomide, during dose 
interruptions or for at least 28 days after the last dose of lenalidomide.

Counseling about pregnancy precautions and the potential risks of fetal exposure 
must be conducted at a minimum of every 28 days.

If pregnancy or a positive pregnancy test does occur in the partner of a male subject 
while taking lenalidomide, the Investigator must be notified immediately.
 
 
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Lenalidomide Education and Counseling Guidance Document for Female 
Subjects
To be completed prior to each dispensing of lenalidomide.
Protocol Number: ____________________________________________
Subject Name (Print): __________________ DOB: _____/_____/_____ (dd/mmm/yyyy)
Check one risk category:
FCBP (Female of childbearing potential): a female who: 1) has achieved menarche 
(first menstrual cycle) at some point, 2) has not undergone a hysterectomy (the 
surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of 
both ovaries) or 3) has not been naturally postmenopausal (amenorrhea following 
cancer therapy does not rule out childbearing potential) for at least 24 consecutive 
months (ie, has had menses at any time during the preceding 24 consecutive 
months)
NOT FCBP
Female of Childbearing Potential:
1. I have verified and counseled the subject regarding the following:
Potential risk of fetal exposure to lenalidomide: A teratogenic potential of 
lenalidomide in humans cannot be ruled out. If lenalidomide is taken during
pregnancy, it may cause birth defects or death to any unborn baby. Females are 
advised to avoid pregnancy while taking lenalidomide. Females of childbearing 
potential must agree not to become pregnant while taking lenalidomide. 
That the required pregnancy tests performed are negative.
The subject confirmed that she is using TWO reliable methods of birth control at 
the same time, or complete abstinence (True abstinence is acceptable when this is 
in line with the preferred and usual lifestyle of the subject. Periodic abstinence [eg 
calendar, ovulation, symptothermal or post-ovulation methods] and withdrawal are 
not acceptable methods of contraception.) from heterosexual contact (at least 
28 days prior to receiving lenalidomide, while receiving lenalidomide, during dose 
interruptions and for at least 28 days after the last dose of lenalidomide). 
One highly effective method and one additional method of birth control must be 
used AT THE SAME TIME. The following are examples of highly effective and 
additional effective methods of contraception:

Examples of highly effective methods:
o
IUD
 
 
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o
Hormonal (birth control pills, injections, implants, levonorgestrel-releasing 
intrauterine system [IUS], medroxyprogesterone acetate depot injections, 
ovulation inhibitory progesterone-only pills [e.g. desogestrel])
o
Tubal ligation
o
Partner’s vasectomy

Examples of additional effective methods:
o
Male condom
o
Diaphragm
o
Cervical Cap
The subject confirmed that even if she has amenorrhea she must comply with advice 
on contraception.
Pregnancy tests before, during administration of lenalidomide and at the last dose 
of lenalidomide, even if the subject agrees not to have reproductive heterosexual 
contact.
Frequency of pregnancy tests to be done:

Two pregnancy tests will be performed prior to receiving lenalidomide, one 
within 10 to 14 days, and a second within 24 hours of the start of lenalidomide.

Every week during the first 28 days of this study and a pregnancy test every 
28 days while the subject is taking lenalidomide if menstrual cycles are regular. 

Every week during the first 28 days of this study and a pregnancy test every 
14 days while the subject is taking lenalidomide if menstrual cycles are 
irregular.

If the subject missed a period or has unusual menstrual bleeding.  

When the subject is discontinued from the study and at Day 28 after the last 
dose of lenalidomide if menstrual cycles are regular. If menstrual cycles are 
irregular, pregnancy tests will be done at discontinuation from the study and at 
Days 14 and 28 after the last dose of lenalidomide.
The subject confirmed that she will stop taking lenalidomide immediately in the 
event of becoming pregnant and to call her study doctor as soon as possible. 
The subject confirmed that she has not and will not breastfeed a baby while taking 
lenalidomide and for at least 28 days after the last dose of lenalidomide.
The subject has not and will never share lenalidomide with anyone else.
The subject has not and will not donate blood while taking lenalidomide, during 
dose interruptions and for at least 28 days after the last dose of lenalidomide.
 
 
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The subject has not and will not break, chew, or open lenalidomide capsules at any 
point.
The subject confirmed that she will return unused lenalidomide capsules to the 
study doctor.
2. I have provided the Lenalidomide Information Sheet to the subject.
Female Not of Childbearing Potential (Natural Menopause for at Least 24 
Consecutive Months, a Hysterectomy, or Bilateral Oophorectomy):
1. I have verified and counseled the subject regarding the following:
Potential risk of fetal exposure to lenalidomide: A teratogenic potential of 
lenalidomide in humans cannot be ruled out. If lenalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby.
The subject has not and will never share lenalidomide with anyone else.
The subject has not and will not donate blood while taking lenalidomide, during 
dose interruptions and for at least 28 days after the last dose of lenalidomide.
The subject has not and will not break, chew, or open lenalidomide capsules at any 
point.
The subject confirmed that she will return unused lenalidomide capsules to the 
study doctor.
2. I have provided the Lenalidomide Information Sheet to the subject.
 
 
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Do Not Dispense Lenalidomide if:

The subject is pregnant.

No pregnancy tests were conducted for a FCBP.

The subject states she did not use TWO reliable methods of birth control 
(unless practicing complete abstinence from heterosexual contact) at least 28 
days prior to receiving lenalidomide, while receiving lenalidomide and during 
dose interruptions.

The subject stated that she has or does not want to adhere to pregnancy 
precautions outlined within this PPP.
Counselor Name (Print): ____________________
Counselor Signature: _______________________ Date: 
_____/_____/_____(dd/mmm/yyyy)
**Maintain a copy of the Education and Counseling Guidance Document in the subject’s records.**
 
 
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Lenalidomide Education and Counseling Guidance Document for Male Subjects
To be completed prior to each dispensing of lenalidomide.
Protocol Number: ____________________________________________
Subject Name (Print): __________________ DOB: _____/_____/_____ (dd/mmm/yyyy)
1. I have verified and counseled the subject regarding the following:
Potential risk of fetal exposure to lenalidomide: A teratogenic potential of 
lenalidomide in humans cannot be ruled out. If lenalidomide is taken during 
pregnancy, it may cause birth defects or death to any unborn baby.
The subject confirmed that he has practiced complete abstinence (True abstinence 
is acceptable when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence [eg calendar, ovulation, symptothermal or post-ovulation 
methods] and withdrawal are not acceptable methods of contraception.) or used a 
condom when engaging in sexual contact (including those who have had a 
vasectomy) with a pregnant female or FCBP, while taking lenalidomide, during 
dose interruptions and for at least 28 days after the last dose of lenalidomide.
The subject confirmed that he has not impregnated his female partner while in the 
study.
The subject confirmed that he will notify his study doctor if his female partner 
becomes pregnant and the female partner of a male subject taking lenalidomide 
confirmed that she will call her healthcare provider immediately if she becomes 
pregnant.
The subject has not and will never share lenalidomide with anyone else.
The subject confirmed that he has not donated and will not donate semen or sperm 
while taking lenalidomide or during dose interruptions and that he will not donate 
semen or sperm for at least 28 days after the last dose of lenalidomide.
The subject has not and will not donate blood while taking lenalidomide, during 
dose interruptions and for at least 28 days after the last dose of lenalidomide.
The subject has not and will not break, chew, or open lenalidomide capsules at any 
point.
The subject confirmed that he will return unused lenalidomide capsules to the study 
doctor.
2. I have provided the Lenalidomide Information Sheet to the subject.
 
 
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Do Not Dispense Lenalidomide if:

The subject stated that he has or does not want to adhere to pregnancy 
precautions outlined within this PPP.
Counselor Name (Print): ____________________
Counselor Signature: _______________________ Date: 
_____/_____/_____(dd/mmm/yyyy)
**Maintain a copy of the Education and Counseling Guidance Document in the subject’s records.**
 
 
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Lenalidomide Information Sheet 
For subjects enrolled in clinical research studies 
Please read this Lenalidomide Information Sheet before you start taking lenalidomide and each 
time you get a new supply. This Lenalidomide Information Sheet does not take the place of an 
informed consent to participate in clinical research or talking to your study doctor or healthcare 
provider about your medical condition or your treatment.  
What is the most important information I should know about lenalidomide?
1. Lenalidomide may cause birth defects (deformed babies) or death of an unborn 
baby. Lenalidomide is similar to the medicine thalidomide. It is known that 
thalidomide causes life-threatening birth defects.
If you are a female who is able to become pregnant:

Do not take lenalidomide if you are pregnant or plan to become pregnant

You must practice complete abstinence from sexual contact with a male or use 
two reliable, separate forms of effective birth control at the same time: 

for 28 days before starting lenalidomide

while taking lenalidomide 

during breaks (dose interruptions) of lenalidomide 

for at least 28 days after the last dose of lenalidomide 

You must have pregnancy testing done at the following times:

within 10 to 14 days prior to the first dose of lenalidomide

24 hours prior to the first dose of lenalidomide 

weekly for the first 28 days

if you have regular menstrual periods: every 28 days after the first month 

if you have irregular menstrual periods: every 14 days after the first month

if you miss your period or have unusual menstrual bleeding

28 days after the last dose of lenalidomide (14 and 28 days after the last dose if 
menstrual periods are irregular)

Stop taking lenalidomide if you become pregnant while taking lenalidomide

If you suspect you are pregnant at any time during the study, you must stop 
lenalidomide immediately and immediately inform your study doctor. Your 
study doctor will report all cases of pregnancy to Celgene Corporation.
 
 
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
Do not breastfeed while taking lenalidomide and for at least 28 days after the 
last dose of lenalidomide

The study doctor will be able to advise you where to get additional advice on 
contraception.
If you are a female not able to become pregnant:
In order to ensure that an unborn baby is not exposed to lenalidomide, your study doctor 
will confirm that you are not able to become pregnant.
If you are a male:
A small amount of lenalidomide is found in human semen. The risk to an unborn baby 
in females whose male partner is receiving lenalidomide is unknown at this time.  

Male subjects (including those who have had a vasectomy) must practice complete 
abstinence or must use a condom during sexual contact with a pregnant female or 
a female that can become pregnant:

While you are taking lenalidomide 

During breaks (dose interruptions) of lenalidomide 

For at least 28 days after the last dose of lenalidomide  

Male subjects should not donate sperm or semen while taking lenalidomide, 
during breaks (dose interruptions) and for at least 28 days after the last dose of 
lenalidomide. 

If you suspect that your partner is pregnant any time during the study, you 
must immediately inform your study doctor. The study doctor will report all 
cases of pregnancy to Celgene Corporation. Your partner should call their 
healthcare provider immediately if they become pregnant.
2. All subjects:

Do not share lenalidomide with other people. It must be kept out of the reach 
of children and should never be given to any other person.

Do not donate blood while you take lenalidomide, during breaks (dose 
interruptions) and for at least 28 days after the last dose of lenalidomide. 

Do not break, chew, or open lenalidomide capsules at any point.

You will get no more than a 28-day supply of lenalidomide at one time.

Return unused lenalidomide capsules to your study doctor.
Additional information is provided in the informed consent form and you can ask your 
study doctor for more information.
 
 
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12.11 List of Abbreviations
Abbreviation/Term
Definition
5-Aza
5-Azacytidine
ABC
Activated B-cell-like
ADCC
Antibody-dependent cellular cytotoxicity
AE
Adverse event
Allo-SCT
Allogeneic stem cell transplantation
ALT
Alanine transferase
AML
Acute myeloid leukemia
aPTT
Activated partial thromboplastin time
ASaT
All Subjects as Treated
AST
Aspartate transferase
auto-SCT
Autologous stem-cell transplantation
-HCG
Beta human chorionic gonadotropin
CBC
Complete blood cell count
CFR
Code of Federal Regulations
CHL
Classical Hodgkin lymphoma
CI
Confidence interval 
CLL
Chronic lymphocytic leukemia
CNS
Central nervous system
CR
Complete response/remission
CRAB
Hypercalcemia, renal failure, anemia, or bone destruction
CrCl
Creatinine clearance
CRF
Case report form
CRR
Complete response rate
CSR
Clinical Study Report
CSR CI
Clinical Study Report Coordinating Investigator
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTL
Cytotoxic T lymphocytes
CTLA-4
Cytotoxic T-lymphocyte-associated antigen-4
D
De-escalate
DLBCL
Diffuse large B-cell lymphoma
DLT
Dose limiting toxicity
DNA
Deoxyribonucleic acid
DOR
Duration of response
DU
Current dose level is considered unacceptably toxic
E
Escalate
ECI
Events of clinical interest
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDC
Electronic Data Capture
EMA
European Medicines Agency
ERC
Ethics Review Committee
EU
European Union
FAB
French-American-British
FAS
Full Analysis Set
FBR
Future Biomedical Research
FDA
Food and Drug Administration
 
 
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Abbreviation/Term
Definition
FDAAA
Food and Drug Administration Amendments Act
FEF
Forced expiratory flow
FL
Follicular lymphoma
FLC
Free light chain
FT3
Free triiodothyronine
FVC
Forced vital capacity
GCB
Germinal center B-cell-like
GCP
Good Clinical Practice
G-CSF
Granulocyte colony stimulating factor
GFR
Glomerular filtration rate
GM-CSF
Granulocyte/macrophage colony stimulating factor
GVHD
Graft-versus-host-disease
HBsAg
Hepatitis B surface antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C virus
Hgb
Hemoglobin
HIV
Human immunodeficiency virus
HL
Hodgkin lymphoma
HMA
Hypomethylating agent
IB
Investigator’s Brochure
ICH
International Council for Harmonization
IFN
Interferon
Ig
Immunoglobulin
IHC
Immunohistochemistry
IMiD
Immunomodulatory imide drug
IMWG
International Myeloma Working Group
INR
International Normalized Ratio
IPSS
International Prognostic Scoring System
IPSS-R
Revised International Prognostic Scoring System
irAE
Immune-related adverse event
IRB
Institutional Review Board
IRF
Interferon regulatory factor
ITSM
Immunoreceptor tyrosine-based switch motif
ITT
Intention to Treat
IUD
Intrauterine device
IV
Intravenous
IWG
International Working Group
LDH
Lactate dehydrogenase
MDS
Myelodysplastic syndrome
MLBCL
Mediastinal large B-cell lymphoma
MM
Multiple myeloma
MSD
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
NCI
National Cancer Institute
NHL
Non-Hodgkin lymphoma
NK
Natural killer
NSAID
Non-steroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
ORR
Objective response rate
OS
Overall survival
 
 
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Abbreviation/Term
Definition
OTC
Over-the-counter
PD
Progressive disease
PD-1
Programmed cell death 1 receptor
PD-L1
Programmed cell death ligand 1 receptor
PD-L2
Programmed cell death ligand 2 receptor
PET
Positron emission tomography
PEF
Peak expiratory flow
PFS
Progression-free survival
PGt
Pharmacogenetic
PK
Pharmacokinetic
PK/PD
Pharmacokinetic/pharmacodynamic
PMLBCL
Primary mediastinal large B-cell lymphoma
POEMS
Polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin 
changes
PR
Partial response
Protocol CI
Protocol Coordinating Investigator
PT
Prothrombin time
Q2W
Every 2 weeks
Q3W
Every 3 weeks
R-CHOP-21
Rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, 
and prednisone every 3 weeks
REMS
Risk Evaluation and Mitigation Strategy
RNA
Ribonucleic acid
RP2D
Recommended Phase II dose
S
Stay
SAE
Serious adverse events
SAP
Statistical Analysis Plan
sCR
Stringent complete response
SCT
stem cell transplant
SD
Stable disease
SFU
Survival follow-up
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SOP
Standard Operating Procedures
T3
Triiodothyronine
T4
Thyroxine
TSH
Thyroid stimulating hormone
TTP
Time to progression
ULN
Upper limit of normal
US
United States
WBC
White blood cell count
WHO
World Health Organization
 
 
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13.0 SIGNATURES
13.1 Sponsor's Representative
TYPED NAME                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
13.2 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                                 SIGNATURE                                   DATE
_________________________      ____________________________     __________
 
 
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