Phase II Study of Pembrolizumab for PD-L1 Gene-Altered, Relapsed/Refractory DLBCL
Phase: PHASE2
Conditions: Diffuse Large B Cell Lymphoma, Lymphoma
Sponsor: University of Chicago

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SPONSOR: Institution 
 
PRINCIPAL INVESTIGATOR: 
Justin Kline, MD 
Assistant Professor of Medicine 
Section of Hematology/Oncology, University of Chicago Medical Center 
5841 S. Maryland Avenue, MC2115 
Chicago, IL 60637 
Tel: (773) 702-5550 / Fax: (773) 702-3163 
Email: jkline@medicine.bsd.uchicago.edu  
 
CO-PRINCIPAL INVESTIGATOR: 
James Godfrey, M.D. 
Assistant Professor 
Department of Hematology and Hematopoietic Cell Transplantation 
City of Hope National Medical Center 
Duarte, CA 91010 
Tel: (626) 218-8779/ Fax: (626) 471-3607 
Email: jagodfrey@coh.org  
 
TITLE: Phase II study of pembrolizumab for PD-L1 gene-altered, relapsed/refractory DLBCL 
 
IND NUMBER: 132029 
 
UNIVERSITY OF CHICAGO IRB NUMBER: IRB19-0076 
 
COORDINATING SITE: The University of Chicago 
 
CO-INVESTIGATORS: 
 
 
 
 
 Sonali Smith, MD 
 
 
 
 
 Peter Riedell, MD 
 
 
 
 
 Kenneth Cohen, MD 
 
 
 
 
 Michael Bishop, MD 
 
LEAD STATISTICIAN: 
 Theodore Karrison, PhD 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL AMENDMENT VERSION 10 
 
• Pembrolizumab dose modification guidelines were updated in accordance with Version 
12 of the pembrolizumab MISP Protocol Template. 
 
• All patients with prior CAR-T will now be considered eligible provided they meet the 
remainder of the inclusion and exclusion criteria of the study. The previous protocol 
versions excluded patients who relapsed within 90 days of their CAR T-cell infusion. 
 
• The CLIA-certified cytogenetics laboratory at City of Hope is now listed as an additional 
site for the initial PD-L1 FISH screening. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
 
1.0 TRIAL SUMMARY....................................................................................................... 7 
2.0 TRIAL DESIGN............................................................................................................. 7 
2.1 Trial Design ................................................................................................................ 7 
2.2 Trial Diagram ............................................................................................................. 9 
3.0 OBJECTIVES & HYPOTHESES ................................................................................ 9 
3.1 Primary Objective & Hypothesis ............................................................................. 9 
3.2 Secondary Objectives & Hypotheses ...................................................................... 10 
3.3 Exploratory Objectives ............................................................................................ 10 
4.0 BACKGROUND & RATIONALE ............................................................................. 10 
4.1 Background .............................................................................................................. 10 
4.1.1 Pharmaceutical and Therapeutic Background .................................................... 11 
4.1.2 Preclinical and Clinical Trial Data ...................................................................... 11 
4.2 Rationale ................................................................................................................... 12 
4.2.1 Rationale for the Trial and Selected Population ................................................. 12 
4.2.2 Justification for Dose .......................................................................................... 14 
4.2.3 Rationale for Endpoints ...................................................................................... 15 
4.3 Benefit/Risk .............................................................................................................. 17 
5.0 METHODOLOGY ...................................................................................................... 17 
5.1 Study Population ...................................................................................................... 17 
5.1.1 Participant Inclusion Criteria .............................................................................. 17 
5.1.2 Participant Exclusion Criteria ............................................................................. 19 
5.1.3 Lifestyle Restrictions .......................................................................................... 21 

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5.1.4 Pregnancy ............................................................................................................ 22 
5.1.5 Use in Nursing Women ....................................................................................... 22 
5.2 Trial Treatments ...................................................................................................... 22 
5.2.1 Timing of Dose Administration ............................................................................. 22 
5.2.2 Dose Modification and toxicity management for immune-related AEs associated 
with pembrolizumab ........................................................................................... 23 
5.3 Randomization or Treatment Allocation ............................................................... 33 
5.4 Stratification ............................................................................................................. 33 
5.5 Concomitant Medications/Vaccinations (allowed & prohibited) ........................ 33 
5.5.1 Acceptable Concomitant Medications ................................................................ 33 
5.5.2 Prohibited Concomitant Medications.................................................................. 33 
5.5.3 Rescue Medications & Supportive Care ............................................................. 34 
5.6 Participant Withdrawal/Discontinuation Criteria ............................................... 35 
5.7 Participant Replacement Strategy ......................................................................... 36 
5.8 Criteria for Early Trial Termination ..................................................................... 36 
6.0 TRIAL FLOW CHART .............................................................................................. 37 
6.1 Study Flow Chart ..................................................................................................... 37 
7.0 TRIAL PROCEDURES .............................................................................................. 39 
7.1 Trial Procedures ...................................................................................................... 39 
7.1.1 Administrative Procedures .................................................................................. 39 
7.1.2 Clinical Procedures/Assessments ........................................................................ 41 
7.1.3 Laboratory Procedures/Assessments .................................................................. 44 
7.1.4 Other Procedures ................................................................................................. 46 
7.1.5 Visit Requirements .............................................................................................. 47 
7.2 Assessing and Recording Adverse Events ............................................................. 48 

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7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck ......................................................................................... 49 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck ................. 50 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck.............. 50 
7.2.4 Evaluating Adverse Events ................................................................................. 52 
7.2.5 Sponsor Responsibility for Reporting Adverse Events ...................................... 56 
8.0 STATISTICAL ANALYSIS PLAN ........................................................................... 56 
8.1 Statistical Analysis Plan Summary ........................................................................ 56 
8.1.1 Efficacy Analyses ............................................................................................... 56 
8.1.2 Safety Analyses ................................................................................................... 56 
8.1.3 Power and Sample Size ....................................................................................... 56 
8.2 Statistical Analysis Plan .......................................................................................... 57 
8.2.1 Responsibility of Analyses ................................................................................. 57 
8.2.2 Hypotheses/Estimation ....................................................................................... 57 
8.2.3 Analysis Endpoints ............................................................................................. 57 
8.2.4 Analysis Populations ........................................................................................... 58 
8.2.5 Statistical Methods .............................................................................................. 58 
8.2.6 Compliance (Medication Adherence) ................................................................. 59 
8.2.7 Extent of Exposure .............................................................................................. 59 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 59 
9.1 Investigational Product ........................................................................................... 59 
9.2 Packaging and Labeling Information .................................................................... 60 
9.3 Clinical Supplies Disclosure .................................................................................... 60 
9.4 Storage and Handling Requirements ..................................................................... 60 
9.5 Returns and Reconciliation ..................................................................................... 60 

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10.0 ADMINISTRATIVE AND REGULATORY DETAILS ........................................ 60 
10.1 Confidentiality ........................................................................................................ 60 
10.1.1 Confidentiality of Data ....................................................................................... 60 
10.1.2 Confidentiality of Subject Records ..................................................................... 61 
10.1.3 Confidentiality of Investigator Information ........................................................ 61 
10.1.4 Confidentiality of IRB/IEC Information ............................................................. 61 
10.2 Compliance with Financial Disclosure Requirements ........................................ 62 
10.3 Compliance with Law, Audit, and Debarment ................................................... 62 
10.4 Compliance with Trial Registration and Results Posting Requirements ......... 64 
10.5 Quality Management System ................................................................................ 64 
10.6 Data Management .................................................................................................. 64 
10.7 Publications ............................................................................................................ 64 
11.0 References ................................................................................................................... 66 
Appendix 1: Detection of PD-L1 alerations by Flourescent in-situ Hybridization 
(FISH) .................................................................................................................... 70 
Appendix 2: ECOG Performance Status ........................................................................ 71 
Appendix 3: Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ..... 72 
Appendix 4: Contraceptive Guidance and Pregnancy Testing .................................... 73 
Contraception Requirements ........................................................................................... 73 
Pregnancy Testing ........................................................................................................... 74 
Appendix 5:  LYRIC Response Criteria ......................................................................... 76 
Appendix 6: Collection and Management of Specimens for Biomedical Research .... 77 
 

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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab for PD-L1 gene-altered, relapsed/refractory DLBCL 
Trial Phase 
II 
Clinical Indication 
PD-L1 gene-altered relapsed/refractory diffuse large B cell lymphoma 
(DLBCL) 
Trial Type 
Interventional, single-arm, biomarker-driven 
Type of control 
Historical (DLBCL patients enrolled on KEYNOTE-013 study) 
Route of administration 
Intravenous 
Trial Blinding 
Unblinded Open-label 
Treatment Groups  
1 
Number of trial participants 
13-29 
Estimated enrollment period 
2 years 
Estimated duration of trial 
3-4 years 
Duration of Participation 
Each subject will participate in the trial from the time he or she signs the 
Informed Consent Form (ICF) through the final protocol-specified 
contact. 
After the initial pre-screening and screening phases, eligible subjects will 
receive pembrolizumab treatment at a dose of 200 mg IV every 3 weeks 
(Q3W) for a duration of 2 years (35 cycles).  Treatment with 
pembrolizumab will continue until documented disease progression, 
unacceptable adverse event(s), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the 
subject, subject withdraws consent, pregnancy of the subject, 
noncompliance with trial treatment or procedure requirements, or 
administrative reasons reuiring cessation of treatment.  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 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 overall survival until death, withdrawal of 
consent, or the end of the study.  
Estimated average length of 
treatment per patient 
1 year 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a nonrandomized, unblinded, open-label, phase II study designed to investigate the efficacy 
of pembrolizumab in patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) 
that harbors genetic alterations (copy number alterations or chromosomal translocations) involving 
the programmed death – ligand 1 (PD-L1) locus. Patients having received ≥2 lines of prior 
systemic therapy, or ≥1 line of prior systemic therapy but are either ineligible or have refused 
autologous stem cell transplantation, are considered eligible. Furthermore, patients with primary 
refractory disease or who relapse within 12 months of initial diagnosis, are also eligible for 

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enrollment. Pembrolizumab will be administered at a fixed dose of 200 mg IV every 3 weeks 
(Q3W).  A Simon two-stage design will be employed, and approximately 13-29 patients will be 
enrolled.  Treatment with pembrolizumab will continue for up to 24 months.  Reasons for 
discontinuing study treatment prior to 24 months include: 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 
reason requiring cessation of treatment. Adverse events will be monitored throughout the trial, and 
graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0. This trial will be conducted in accordance with Good 
Clinical Practices. 
Patients will undergo an initial pre-screening phase within 28 days prior to treatment allocation.  
This will include a review of the patient’s medical history to determine potential study eligibility, 
and an evaluation for the presence of PD-L1 gene alterations utilizing fluorescent in-situ 
hybridization (FISH) on archived formalin-fixed paraffin-embedded (FFPE) tissue (ideally 
obtained at the time of most recent relapse).  PD-L1 FISH will be performed at The University of 
Chicago or at City of Hope in a CLIA-certified laboratory using a previously validated technique 
(see Appendix 1).  Patients fulfilling pre-screening criteria will proceed to a screening phase to 
determine whether they meet the remainder of the study entry criteria (see Section 5.1), and will 
undergo a baseline evaluation, including evaluation of disease status by positron emission 
tomography (PET) and diagnostic computerized tomography (CT) scans (bone marrow exam will 
also be performed for patients with a history of prior bone marrow involvement).  Patients meeting 
enrollment criteria will be allocated to trial treatment by non-random assignment. 
Patients enrolled on this study will undergo serial peripheral blood samples for correlative 
analyses, and archived FFPE specimens will be collected and stored for future exploratory 
research.  Disease response to pembrolizumab will be determined using the LYRIC response 
criteria (1), and will be performed at designated timepoints outlined in the Trial Flow Chart in 
Section 6.0, and any time disease progression is clinically suspected.  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.  After 24 months, ongoing disease re-assessments will be performed at the 
discretion of the treating physician. Any patient who experiences disease progression at any time 
will be removed from study, and alternative treatment can be pursued at the discretion of the 
treating physician. After the end of treatment, each subject will be followed for the occurrence of 
adverse events and spontaneously reported pregnancy as described in Section 7.2 of the protocol. 
Subjects who discontinue treatment for reasons other than disease progression will undergo post-
treatment follow-up for disease status until disease progression, initiation of a non-study cancer 
treatment, withdrawal of consent, or becoming lost to follow-up. All subjects will be followed by 
telephone contact for overall survival until death, withdrawal of consent, or the end of the study, 
whichever comes first. 
Adverse events associated with pembrolizumab often represent immune-related toxicities.  These 
adverse events may occur shortly after the first dose or several months after the last dose of 
treatment.  Pembrolizumab must be held for drug-related toxicities and severe or life-threatening 

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adverse events as per Table 3.  See Section 5.2 for supportive care guidelines including use of 
corticosteroids. 
The primary objective of this trial is to determine whether the overall response rate (ORR) of 
pembrolizumab is significantly higher in relapsed/refractory DLBCL patients harboring PD-L1 
gene alterations compared to the ORR of unselected relapsed/refractory DLBCL patients enrolled 
on KEYNOTE-013 Cohort 4D (15% ORR).  Secondary objectives include analysis of additional 
efficacy parameters (progression-free survival (PFS), duration of response (DOR), and overall 
survival (OS)).  Correlative studies are also planned, and will serve as exploratory analyses.  These 
will include an in-depth analysis of the immunogenomic landscape of PD-L1 gene-altered 
DLBCLs, an examination of the influence of the intestinal microbiota on endogenous anti-
lymphoma immunity and on response to anti-PD-1 antibody therapy, as well as a detailed 
investigation of the clonal evolution of DLBCL in response to pembrolizumab through serial 
analysis of circulating tumor DNA (ctDNA).  
If this study confirms an improved ORR in PD-L1 gene-altered DLBCL patients compared to 
historical controls, then an expansion cohort may be considered if deemed appropriate by the 
principal investigator and study sponsor. 
2.2 
Trial Diagram 
 
Figure 1. Trial Diagram. 
3.0 OBJECTIVES & HYPOTHESES 
3.1 
Primary Objective & Hypothesis 
(1) Objective: To determine whether the overall response rate (ORR) to pembrolizumab treatment 
is significantly higher in PD-L1 gene-altered, relapsed/refractory DLBCL patients compared 
to the ORR of unselected relapsed/refractory DLBCL patients enrolled on KEYNOTE-013 
Cohort 4D (15% ORR). 
Hypothesis:  Relapsed/refractory DLBCL patients harboring PD-L1 gene alterations will 
exhibit a significantly higher ORR to pembrolizumab compared to unselected 
relapsed/refractory DLBCL patients enrolled onto Cohort 4D of the KEYNOTE-013 study 
(ORR 15%). 

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3.2 
Secondary Objectives & Hypotheses 
(1) Objective:  To determine whether the median duration of response (DOR), median 
progression-free survival (PFS), and median overall survival (OS) of PD-L1 gene-altered, 
relapsed/refractory DLBCL patients to pembrolizumab treatment is significantly higher in PD-
L1 
gene-altered, 
relapsed/refractory 
DLBCL 
patients 
compared 
to 
unselected 
relapsed/refractory DLBCL patients enrolled onto Cohort 4D of the KEYNOTE-013 study. 
Hypothesis:  Relapsed/refractory DLBCL patients harboring PD-L1 gene alterations will have 
a significantly longer DOR, PFS, and OS compared to unselected relapsed/refractory DLBCL 
patients enrolled on KEYNOTE-013 Cohort 4D. 
3.3 
Exploratory Objectives 
(1) Objective: To compare the immune landscape of DLBCLs with and without PD-L1 gene 
alterations (non-PD-L1 gene-altered DLBCLs will consist of previously identified patient 
samples stored in The University of Chicago Lymphoma Biobank). 
(2) Objective: To compare gene expression signatures of DLBCLs with and without PD-L1 gene 
alterations. 
(3) Objective: To compare genomic mutational profiles and neo-antigen load of DLBCLs with 
and without PD-L1 gene alterations.    
(4) Objective: To determine whether the degree of PD-L1 gene alterations in DLBCL (amplified 
= translocated > relative copy gain > polysomy) correlates with response and survival to 
pembrolizumab. 
(5) Objective: To determine the impact of PD-L1 protein expression as assessed by 
immunohistochemistry (IHC) (both on malignant tumor cell and within the tumor 
microenvironment using Dako PD-L1 IHC 22C3 pharmDx)) on the ORR to pembrolizumab 
treatment in patients with PD-L1 gene-altered DLBCLs. 
(6) Objective: To compare the intestinal microbiota diversity and composition between DLBCL 
patients with and without PD-L1 gene alterations, and to determine if the composition and/or 
diversity of the host microbiome predicts for response to pembrolizumab in PD-L1 gene-
altered DLBCL patients. 
(7) Objective: To identify the feasibility of monitoring clonal tumor evolution in response to 
pembrolizumab using ctDNA, and to determine the utility of measuring ctDNA burden in 
predicting clinical outcomes (PFS, DOR, OS) following pembrolizumab treatment. 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus inhibiting its 

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interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-
L2).  Based on preclinical in vitro data, pembrolizumab has high affinity and potent receptor 
blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical safety profile and is in 
clinical development as an intravenous (IV) immunotherapy for advanced malignancies.  
Keytruda® (pembrolizumab) is indicated for the treatment of patients across a number of 
indications because of its mechanism of action to bind the PD-1 receptor on the T cell.  For more 
details on specific indications refer to the Investigator brochure. 
4.1.1 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades (2).  Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in various 
malignancies.  In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T-cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; hepatocellular 
carcinoma; malignant melanoma; and renal cell carcinoma.  Tumor-infiltrating lymphocytes can 
be expanded ex vivo and reinfused, inducing durable objective tumor responses in cancers such as 
melanoma (3, 4). 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress immune 
control.  The normal function of PD-1, expressed on the cell surface of activated T-cells under 
healthy conditions, is to down-modulate unwanted or excessive immune responses, including 
autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) superfamily 
member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-associated 
protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor signaling upon 
engagement of its ligands (PD-L1 and/or PD-L2) (5, 6). 
The structure of murine PD-1 has been resolved (7).  PD-1 and its family members are type I 
transmembrane glycoproteins containing an Ig-variable–type (IgV-type) domain responsible for 
ligand binding and a cytoplasmic tail responsible for the binding of signaling molecules.  The 
cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, an immunoreceptor tyrosine-
based inhibition motif, and an immunoreceptor tyrosine-based switch motif.  Following T-cell 
stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and SHP-2, to the immunoreceptor 
tyrosine-based switch motif within its cytoplasmic tail, leading to the dephosphorylation of 
effector molecules such as CD3 zeta (CD3ζ), protein kinase C-theta (PKCθ), and zeta-chain-
associated protein kinase (ZAP70), which are involved in the CD3 T-cell signaling cascade (6, 8-
10). The mechanism by which PD-1 down-modulates T-cell responses is similar to, but distinct 
from, that of CTLA-4, because both molecules regulate an overlapping set of signaling proteins 
(11, 12). As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in DLBCL.  
4.1.2 Preclinical and Clinical Trial Data 
Refer to the Investigator’s Brochure for Preclinical and Clinical data. 

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4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Population 
4.2.1.1 Outcomes of Patients with Relapsed/Refractory DLBCL 
Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma 
(NHL) diagnosed in the United States (13).  Although a majority of DLBCL patients are cured 
with modern chemo-immunotherapy, approximately 40% will have primary-refractory or relapsed 
disease (14), which is difficult to eradicate, and associated with high rates of early mortality (15).  
Even in the era of CD19-directed CAR T cell therapy, which is effective in this patient population, 
the reality remains that the majority of patients are not candidates for this aggressive therapy, or 
will benefit briefly from it (16).  Moreover, autologous hematopoietic stem cell transplantation, 
another potentially curative treatment option for relapsed/refractory DLBCL, is associated with 
poor long-term survival, particularly in the rituximab era (17).  New approaches are therefore 
needed to both prevent and effectively treat relapsed disease. 
4.2.1.2 PD-1 Blockade Therapy in Lymphoma 
PD-L1 expression on malignant cells potently down-regulates the function of PD-1 receptor-
expressing tumor antigen-specific T cells (18-20). Interference with PD-1/PD-L1 interactions can 
“re-awaken” existing, but ineffective anti-tumor T cell responses. PD-1 blockade has demonstrated 
remarkable clinical efficacy in a number of solid tumors (21, 22), and has created a new paradigm 
for cancer treatment.  
PD-1 blockade therapy has also been effective in select lymphomas, particularly classical Hodgkin 
lymphoma (cHL) (23-25), in which the genetic loci that encode the PD-1 ligands on chromosome 
9p24.1 are commonly amplified (26, 27). In patients with relapsed/refractory cHL, treatment with 
PD-1 blocking antibodies has been associated with objective response rates (ORR) of 65-87% in 
phase 1 and 2 studies, with approximately 16-22% of patients achieving a complete remission 
(CR).  The median duration of response (DOR) to PD-1 blockade therapy in relapsed/refractory 
cHL patients is encouraging at 16.6 months. 
With regard to NHL, anti-PD-1 therapies have demonstrated promising activity in select 
aggressive B cell lymphomas.  For example, there was a 41% ORR in patients with 
relapsed/refractory primary mediastinal B cell lymphoma (PMBL) in a phase 1b study of 
pembrolizumab (28).  Notably, many of these patients experienced long-lasting responses. In the 
pivotal study, the median DOR was not reached at 11.3 months.  Early reports have also 
demonstrated high response rates to PD-1 blockade therapy in Richter’s transformation of CLL, 
primary CNS lymphoma, as well as gray zone lymphoma (29-31).  Importantly, across all of these 
studies, treatment with anti-PD-1 antibodies has been generally safe, with only rare grade 3 or 4 
toxicities reported.  Immune-related adverse events (irAEs) do occur with PD-1 blockade therapy, 
but at a lower incidence and severity compared to what has been reported after treatment with the 
CTLA-4 blocking antibody, ipilimumab (32).  
In contrast to the impressive response rates to PD-1 blockade therapy in the aforementioned 
lymphomas, the activity of anti-PD-1 therapy in patients with relapsed/refractory DLBCL has been 

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less encouraging.  For example, the investigator-assessed ORR to the anti-PD-1 antibodies, 
nivolumab and pembrolizuamb, have ranged between 10-36% (33, 34).  That said, DLBCL 
patients who achieve a response to PD-1 blockade therapy derive meaningful clinical benefit, with 
a median DOR of 11.3 months. This compares very favorably to other common agents prescribed 
for relapsed/refractory DLBCL, such as lenalidomide and ibrutinib, which have a median DOR of 
4.6 and 4.8 months, respectively (35, 36).  Therefore, PD-1 blockade remains a promising therapy 
in DLBCL given the potential for achieving durable responses in relapsed/refractory patients; 
however, the identification of reliable predictive biomarkers of response are needed in order to 
identify a subset of patients likely to derive meaningful benefit from treatment. 
4.2.1.3 Predictive Biomarkers to PD-1 Blockade Therapy 
The heterogenous nature of DLBCL was initially demonstrated through gene expression profiling, 
which identified 3 unique molecular disease subsets: 1) germinal center B cell-like, 2) activated 
peripheral blood B cell-like, and 3) unclassifiable (37). More recently, a number of large genomic 
analyses have identified over 150 genetic drivers of DLBCL that can be grouped into several 
unique clusters (38-40). Importantly, these studies demonstrate that unique biological DLBCL 
subsets are associated with widely disparate clinical outcomes following treatment with upfront 
chemo-immunotherapy, and in the relapsed disease setting, may also be associated with 
responsiveness to particular targeted therapies (35, 41).  Whether there exists a subset of DLBCL 
patients that will be more responsive to PD-1 blockade therapy, however, is not known.    
In solid cancers, infiltration and local activation of T cells indicates the presence of a spontaneous 
anti-tumor immune response, and enriches for the subset of patients benefitting from PD-1 
blockade therapy (42-44). This so-called “T cell-inflamed” phenotype may also be a prerequisite 
for response to anti-PD-1 therapy in lymphoma, as exemplified by cHL, which is characterized by 
pronounced T cell infiltration and exquisite sensitivity to PD-1 blockade therapy (24, 25). cHL 
also universally exploits genetic immune escape mechanisms, most notably copy gains of the PD-
L1 locus on chromosome 9p24.1 (27).  Importantly, from a biomarker perspective, studies have 
demonstrated that the degree of PD-L1 amplification in cHL is predictive of best overall response 
and PFS to anti-PD-1 therapy (45).  These findings prompted us to evaluate the incidence and 
immune landscape of PD-L1 gene alterations (copy number alterations and translocations) in 
DLBCL, which revealed that PD-L1 gene alterations occur in approximately 25% of de novo 
DLBCLs, and that these lymphomas are associated with heightened levels of T cells reminiscent 
of the “T cell-inflamed” phenotype that has been previously associated with responsiveness to PD-
1 blockade in solid tumors (unpublished observation).  Additionally, our retrospective analysis of 
relapsed/refractory DLBCL patients enrolled on the pembrolizumab, KEYNOTE-013 study 
revealed that the presence of PD-L1 gene alterations was potentially associated with 
responsiveness to anti-PD-1 antibody therapy (unpublished observation).  Collectively, these 
observations provide the rationale for this clinical study, which aims to prospectively validate the 
utility of PD-L1 gene alterations as a predictive biomarker of response to pembrolizumab in 
relapsed/refractory DLBCL patients.  If PD-L1 gene alterations are confirmed to be a reliable 
predictive biomarker of response to pembrolizumab, this finding could expand the use of 
pembrolizumab to a genetically-defined subset of DLBCL patients, and would also inform the 
design of future clinical trials exploring the use of PD-L1 gene alterations as a tissue agnostic 
genetic biomarker of responsiveness to PD-1 blockade, similar to the current use of microsatellite 
instability testing to identify neo-antigen high solid tumors. 

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4.2.2 Justification for Dose  
The planned dose of pembrolizumab for this study is 200 mg every 3 weeks (Q3W).  Based on the 
totality of data generated in the Keytruda development program, 200 mg Q3W is the appropriate 
dose of pembrolizumab for adults across all indications and regardless of tumor type.  As outlined 
below, this dose is justified by: 
• Clinical data from 8 randomized studies demonstrating flat dose- and exposure-efficacy 
relationships from 2 mg/kg Q3W to 10 mg/kg every 2 weeks (Q2W),  
• Clinical data showing meaningful improvement in benefit-risk including overall survival 
at 200 mg Q3W across multiple indications, and 
• Pharmacology data showing full target saturation in both systemic circulation (inferred 
from pharmacokinetic [PK] data) and tumor (inferred from physiologically-based PK 
[PBPK] analysis) at 200 mg Q3W 
Among the 8 randomized dose-comparison studies, a total of 2262 participants were enrolled with 
melanoma and non-small cell lung cancer (NSCLC), covering different disease settings (treatment 
naïve, previously treated, PD-L1 enriched, and all-comers) and different treatment settings 
(monotherapy and in combination with chemotherapy).  Five studies compared 2 mg/kg Q3W 
versus 10 mg/kg Q2W (KN001 Cohort B2, KN001 Cohort D, KN002, KN010, and KN021), and 
3 studies compared 10 mg/kg Q3W versus 10 mg/kg Q2W (KN001 Cohort B3, KN001 Cohort F2 
and KN006).  All of these studies demonstrated flat dose- and exposure-response relationships 
across the doses studied representing an approximate 5- to 7.5-fold difference in exposure.  The 2 
mg/kg (or 200 mg fixed-dose) Q3W provided similar responses to the highest doses studied.  
Subsequently, flat dose-exposure-response relationships were also observed in other tumor types 
including head and neck cancer, bladder cancer, gastric cancer and classical Hodgkin Lymphoma, 
confirming 200 mg Q3W as the appropriate dose independent of the tumor type.  These findings 
are consistent with the mechanism of action of pembrolizumab, which acts by interaction with 
immune cells, and not via direct binding to cancer cells. 
Additionally, pharmacology data clearly show target saturation at 200 mg Q3W.  First, PK data in 
KN001 evaluating target-mediated drug disposition (TMDD) conclusively demonstrated 
saturation of PD-1 in systemic circulation at doses much lower than 200 mg Q3W.  Second, a 
PBPK analysis was conducted to predict tumor PD-1 saturation over a wide range of tumor 
penetration and PD-1 expression.  This evaluation concluded that pembrolizumab at 200 mg Q3W 
achieves full PD-1 saturation in both blood and tumor. 
Finally, population PK analysis of pembrolizumab, which characterized the influence of body 
weight and other participant covariates on exposure, has shown that the fixed-dosing provides 
similar control of PK variability as weight based dosing, with considerable overlap in the 
distribution of exposures from the 200 mg Q3W fixed dose and 2 mg/kg Q3W dose.  Supported 
by these PK characteristics, and given that fixed-dose has advantages of reduced dosing 
complexity and reduced potential of dosing errors, the 200 mg Q3W fixed-dose was selected for 
evaluation across all pembrolizumab protocols. 

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4.2.3 Rationale for Endpoints 
4.2.3.1 Efficacy Endpoints 
The primary efficacy objective of this study is to determine if the ORR of patients with PD-L1 
gene-altered DLBCL to pembrolizumab monotherapy is higher than that of a historical cohort of 
unseleted DLBCL patients.  Response in this study will be assessed according to  LYRIC criteria 
(modified from Lugano response criteria) (1).  If the primary hypothesis is proven correct, then a 
confirmatory, retrospective radiographic review of response in each patient will be performed in 
collaboration with an outside vendor.   
The LYRIC criteria were chosen for designating response in this clinical trial because 
immunotherapeutic agents such as pembrolizumab mediate anti-tumor effects by potentiating 
endogenous cancer-specific immune responses. Responses to immunotherapeutic agents 
occasionally occur in a delayed fashion - often beyond the typical time frame of that expected 
following treatment with classical cytotoxic agents. Furthermore, in the context of checkpoint 
blockade immunotherapy, clinical responses can occur even after an initial increase in tumor 
burden is observed, or even after the appearance of new lesions on imaging studies, due to 
inflammation in sites of tumor activity and in areas uninvolved by malignancy.  The LYRIC 
criteria represent the most up-to-date consensus guidelines for response assessment of lymphomas 
treated with immunomodulatory agents such as pembrolizumab, and were created by international 
experts. Importantly, the LYRIC criteria incorporate an indeterminate response category that 
allows for continued treatment in clinically stable/improving patients who would otherwise be 
deemed to have progressive disease using conventional response criteria.  This is a significant 
addition to standard response criteria for immune-based therapies as evidenced by a recent study 
of PD-1 blockade in cHL, in which 61% of patients treated beyond conventional disease 
progression demonstrated stable or further reduced target tumor burdens (25).  Therefore, patients 
with an indeterminate response in the current study will be able to continue treatment with 
pembrolizumab if deemed appropriate by the treating physician.  These patients must undergo 
repeat imaging within 12 weeks to either confirm that an objective tumor response has occurred, 
or to unequivocably document disease progression.  Overall, the LYRIC criteria are anticipated to 
allow for a more accurate assessment of the true clinical benefit from immunotherapies such as 
pembrolizumab, and are now recommended to be utilized as the standard response criteria for 
lymphoma clinical trials incorporating immunotherapies (1). 
4.2.3.2 Biomarker Research 
4.2.3.2.1   Utility of PD-L1 gene alterations to predict ORR and PFS to pembrolizumab in 
DLBCL.  The ORR of unselected relapsed/refractory DLBCL patients to PD-1 blockade is low 
(33).  Predictive biomarkers of response are therefore needed in order for pembrolizumab to have 
a clinically meaningful impact in the treatment of DLBCL.  Based on our preliminary data, we 
hypothesize that the identification and selection of patients with PD-L1 gene-altered DLBCLs for 
pembrolizumab therapy will enrich for treatment responseiveness compared to what has been 
observed in unselected DLBCL patients.  This hypothesis is based upon our findings indicating 
that PD-L1 gene-altered lymphomas are associated with robust anti-tumor immune responses. In 
this clinical trial, the presence of PD-L1 gene alterations will be determined using a validated 
fluorescent in-situ hybridization (FISH) assay (Appendix 1).  In order to determine the utility of 

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PD-L1 gene alterations to predict for response to pembrolizumab, the ORR to pembrolizumab in 
this study will be compared to that of a historical cohort of 40 unselected DLBCL patients treated 
with pembrolizumab in the KEYNOTE-013 study, where the ORR was 13%.  Additionally, we 
will determine whether a correlation exists between the degree of PD-L1 alteration 
(amplification/translocation > relative copy gain > chromosome 9 polysomy) and best overall 
response (BOR) and PFS, as was the case in cHL patients treated with PD-1 blockade therapy (45).  
Finally, as our preliminary data reveal that only ~65% of PD-L1 altered DLBCLs are PD-L1 
positive by immunohistochemistry, we will compare the ORR of DLBCLs with positive PD-L1 
protein expression on malignant cells as assessed by IHC versus those with absent PD-L1 staining 
in order to ascertain whether PD-L1 protein expression should be considered as a companion 
diagnostic with FISH for PD-L1 gene alterations to improve the positive predictive value of this 
biomarker moving forward. 
4.2.3.2.2 Effect of tumor cell intrinsic and environmental factors on responsiveness to 
pembrolizumab in DLBCL.  Previous studies have demonstrated an impact of both tumor cell 
intrinsic and environmental factors, as well as other host variables, such as the intestinal 
microbiome, on responsiveness to anti-PD-1 therapies in a variety of solid tumor malignancies 
(46-48).  To determine whether these features also influence responsiveness to PD-1 blockade in 
DLBCL, whole exome sequencing (WES) and RNA sequencing (seq) will be performed on pre-
treatment biopsies, and baseline stool samples will be collected prior to commencing study therapy 
with pembrolizumab.  WES of tumor samples will be performed through Theragen Etex, while 
RNA-seq, bioinformatics analysis, and microbiome analysis will all be conducted in core facilities 
at The University of Chicago. 
4.2.3.2.3 Feasibility of utilizing circulating tumor DNA (ctDNA) to predict early response to 
pembrolizumab in DLBCL, and to identify genetic mechanisms that underlie acquired 
resistance to therapy.  The quantification of ctDNA can be a sensitive marker of response to a 
wide array of therapies in a number of tumor types while also providing valuable prognostic 
information (49, 50).  Furthermore, ctDNA offers a non-invasive method of serially monitoring 
the clonal evolution of tumors responding to a particular therapy, and may also identify mutations 
or other genomic alterations associated with emerging resistance.  Currently, there are no data on 
the use of ctDNA to monitor response, clonal evoluation or resistance to  anti-PD-1 therapy, and 
the mechanisms of acquired resistance to pembrolizumab in DLBCL are unknown.  To investigate 
the hypothesis that serial ctDNA monitoring will provide early response information to 
pembrolizumab, and will identify mutations in genes critical for maintaining immune surveillance 
in patients developing acquired resistance to therapy, plasma will be collected for ctDNA analysis 
at baseline and after every 4 cycles of therapy (in parallel with disease response assessment via 
conventional imaging).  All ctDNA analyses will be performed using a customized lymphoma 
panel created at the Cancer Precision Medicine Center in the Cancer Institute of Japanese 
Foundation for Cancer Research. 
4.2.3.3 Future Biomedical Research 
It is possible that Future Biomedical Research will be conducted on blood and lymph node 
specimens collected during this clinical trial.  This research may include genetic analyses (DNA), 
gene expression profiling (RNA), proteomics, metabolomics (serum, plasma), and/or the 
measurement of other analytes.   

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Such research is for biomarker testing to address emergent questions not described elsewhere in 
the protocol (as part of the main trial).  The objective of collecting specimens for Future 
Biomedical Research will be to explore and identify biomarkers that inform the scientific 
understanding of diseases and/or their therapeutic treatments.  The details of Future Biomedical 
Research are presented in Appendix 6 – Collection and Management of Specimens for Future 
Biomedical Research.   
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. 
Effiacy and safety information in regards to pembrolizumab are provided in the current version of 
the IB. 
5.0 METHODOLOGY 
5.1 
Study Population 
Relapsed/refractory DLBCL patients with evidence of PD-L1 gene alterations (copy number 
alterations or translocations) as determined by FISH. 
5.1.1 Participant Inclusion Criteria 
Participants are eligible to be included in the study if all of the following criteria apply: 
1. Male/female participants who are at least 18 years of age on the day of signing informed 
consent with a histologically confirmed diagnosis of DLBCL will be enrolled in this study.   
Note: Patients with high-grade B cell lymphomas not otherwised specified and those with 
MYC and BCL2 translocations (double hit lymphoma) are eligible, as are patients with 
transformed indolent lymphoma, so long as PD-L1 gene alterations are present. 
2. A male participant must agree to use a contraception as detailed in Appendix 4 of this 
protocol during the treatment period, and for at least 120 days after the last dose of study 
treatment and refrain from donating sperm during this period. 
3. A female participant is eligible to participate if she is not pregnant (see Appendix 4), not 
breastfeeding, and at least one of the following conditions applies:  
a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix 4  
b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 during 
the treatment period and for at least 120 days after the last dose of study treatment. 
C.) patient must have negative pregnancy test within 72 hours of beginning treatment 
if WOCBP 
4. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial.    

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5. Have measurable disease, defined as at least one lesion that can be accurately measured in 
at least two dimensions by CT scan.  Minimum measurement must be >15 mm in the 
longest diameter by >10 mm in the short axis.  Lesions situated in a previously irradiated 
area are considered measurable if radiographic progression has been demonstrated in such 
lesions. 
 
6. Particpants must have available archived biopsy material (ideally to be performed shortly 
before enrollment at the time of most recent relapse) for PD-L1 FISH and correlative 
studies.  Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides.   
Note: If submitting unstained cut slides, newly cut slides should be submitted within 14 
days from the date slides are cut if possible. 
7. There is evidence of a PD-L1 gene alteration within lymphoma cells as assessed by FISH.  
See Appendix 1 for detailed description of what constitutes the presence of a PD-L1 gene 
alteration. 
8. Participants must have received either: 
a. ≥ 2 lines of prior systemic therapy 
b. ≥ 1 line of prior systemic therapy with documented comborbidities that preclude 
eligbility for standard salvage chemotherapy and autologous stem cell transplant , 
or  
c. 1 line of prior therapy with documented disease relapse within 12 months of initial 
diagnosis. 
Note: patients having undergone prior CAR T cell therapy are eligible, as are patients 
having received a prior allogeneic transplantation, provided they do not meet any of the 
exclusionary GVHD criteria, and are at least 5 years removed from the date of their 
transplant. 
9. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
Evaluation of ECOG performance status is to be performed within 14 days prior to the date 
of treatment allocation. 
10. Have adequate organ function as defined in Table 1 within 10 days prior to the date of 
treatment allocation. 
 
Table 1.  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1,000/µL 

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5.1.2 Participant Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. A WOCBP who has a positive urine pregnancy test within 72 hours prior to treatment 
allocation (see Appendix 3).  If the urine test is positive or cannot be confirmed as negative, 
a serum pregnancy test will be required. 
Note: in the event that 72 hours have elapsed between the screening pregnancy test and 
the first dose of study treatment, another pregnancy test (urine or serum) must be 
performed and must be negative in order for subject to start receiving study medication. 
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
 
3. Has received chemotherapy, monoclonal antibody therapy, or targeted small molecule 
therapy within 4 weeks prior to the first dose of study medication. Subjects must have 
recovered (≤ Grade 1) from adverse events related to a previously administered agent 
(patients with ≤ Grade 2 neuropathy are eligible). Subjects who have previously received 
CAR T cell therapy are eligible.  
Note: If a participant received major surgery, he or she must have recovered adequately 
from complications from the intervention prior to starting study treatment. 
Platelets 
≥50,000/µL 
Hemoglobin 
≥8.0 g/dLa 
Renal 
 
Creatinine OR 
Measured or calculatedb creatinine clearance 
(GFR can also be used in place of creatinine or 
CrCl) 
≤1.5 × ULN OR 
≥30 mL/min for participant with creatinine 
levels >1.5 × institutional ULN 
Hepatic 
 
Total bilirubin 
≤1.5 ×ULN OR direct bilirubin ≤ULN for 
participants 
with 
total 
bilirubin 
levels 
>1.5 × ULN 
AST (SGOT) and ALT (SGPT) 
≤2.5 × ULN (≤5 × ULN for participants with 
liver metastases) 
Coagulation 
 
International normalized ratio (INR) OR 
prothrombin time (PT) 
≤1.5 × ULN unless participant is receiving 
anticoagulant therapy as long as PT or aPTT 
is within therapeutic range of intended use of 
anticoagulants 
Activated partial thromboplastin time (aPTT) 

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4. Has received prior radiotherapy within 1 week of start of study treatment.  Participants 
must have recovered from all radiation-related toxicities, not require corticosteroids, and 
not have had radiation pneumonitis.   
 
5. Has a histologic diagnosis of primary mediastinal lymphoma or gray zone lymphoma. 
 
6. Has known active CNS lymphoma and/or lymphomatous meningitis.  Participants with 
previously treated brain metastases may participate provided they are radiologically stable, 
i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the 
repeat imaging should be performed during study screening),  clinically stable and without 
requirement of steroid treatment for at least 14 days prior to first dose of study treatment. 
 
7. Has received a live vaccine within 30 days prior to the first dose of study drug.  Examples 
of live vaccines include, but are not limited to, the following:  measles, mumps, rubella, 
varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guérin (BCG), and 
typhoid vaccine.  Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live 
attenuated vaccines and are not allowed. 
 
8. Is currently participating in or has participated in a study of an investigational agent or has 
used an investigational device within 4 weeks prior to the first dose of study treatment. 
9. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug.  Short 
courses of corticosteroids will be allowed for palliation of symptoms related to lymphoma, 
but must be discontinued within 7 days prior to the first dose of study drug. 
10. Subjects having received prior allogeneic stem cell transplant, must be at least 5 years 
removed from the date of their transplant. The also must have no history of severe (grade 
3-4) acute GVHD, and/or current > grade 1 acute GHVD.  Subjects must not have active 
chronic GVHD that requires active immune suppression or more than 10 mg of 
prednisone/day or equivalent.  
11. Has a history of a solid organ transplant. 
12. Has a known additional malignancy that is progressing or has required active treatment 
within the past 3 years.  Note:  Participants with basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in 
situ) that have undergone potentially curative therapy are not excluded 
13. Has severe hypersensitivity (≥Grade 3) to pembrolizumab and/or any of its excipients. 
 
14. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 

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Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
15. Has a history of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis. 
16. Has an active infection requiring systemic therapy. 
17. Has a known history of Human Immunodeficiency Virus (HIV) infection.   
     
18. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] 
reactive) or known active Hepatitis C virus (defined as detection of HCV RNA) infection.  
19. Has a known history of active TB  (Bacillus Tuberculosis).   
 
 
     
 
20. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the study, interfere with the subject’s participation for the 
full duration of the study, or is not in the best interest of the subject to participate, in the 
opinion of the treating investigator.   
21. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
22. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the study, starting with the screening visit through 120 days after the 
last dose of trial treatment. 
23. Patient is in need of immediate cytoreductive therapy 
5.1.3 Lifestyle Restrictions 
5.1.3.1 Meals and Dietary Restrictions 
Participants should maintain a normal diet unless modifications are required to manage an AE such 
as diarrhea, nausea or vomiting. 
5.1.3.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Refer to Appendix 4 for approved 
methods of contraception. 
For this study, male participants will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to prior vasectomy or to an underlying medical condition).   

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5.1.4 Pregnancy 
If a participant inadvertently becomes pregnant while on treatment with pembrolizumab, the 
participant will be immediately discontinued from study treatment.  The site will contact the 
participant at least monthly and document the participant’s status until the pregnancy has been 
completed or terminated.  The outcome of the pregnancy will be reported to Merck within 2 
working days if the outcome is a serious adverse experience (eg, death, abortion, congenital 
anomaly, or other disabling or life-threatening complication to the mother or newborn).  The study 
Investigator will make every effort to obtain permission to follow the outcome of the pregnancy 
and report the condition of the fetus or newborn to Merck.  If a male participant impregnates his 
female partner, the study personnel at the site must be informed immediately and the pregnancy 
must be reported to Merck and followed as described in Section 7.2.2. 
5.1.5 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are excreted 
in human milk, and because of the potential for serious adverse reactions in the nursing infant, 
participants who are breast-feeding are not eligible for enrollment. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2.  Trial Treatment 
Drug 
Dose/Potency Dose 
Frequency 
Route 
of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 200 mg 
Q3W 
IV infusion 
Day 1 of each 3 
week cycle 
Experimental 
 
Trial treatment should begin on or as close as possible to the day of allocation. 
5.2.1 Timing of Dose Administration 
Trial treatment should be administered on day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the Trial Flow Chart (Section 6.0).  Trial treatment may be 
administered up to 3 days before or after the scheduled day 1 of each cycle due to administrative 
reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks.  Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 

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The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
5.2.2 Dose Modification and toxicity management for immune-related AEs associated with 
pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. These 
immune-related AEs (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 study data, most irAEs are reversible and can 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 3. 

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Table 3 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab  
General instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks of 
the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Add prophylactic antibiotics for 
opportunistic infections 
•  Monitor participants for signs and symptoms of 
pneumonitis 
•  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Recurrent 
Grade 
3 
or 
Grade 4 
Permanently 
discontinue 
 
and of bowel perforation (ie, peritoneal signs 
and ileus) 
•  Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis 
•  Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion 
AST or ALT 
Elevation 
or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
•  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
T1DM 
or 
Hyperglycemia 
New 
onset 
T1DM 
or  
Grade 3 or 4 
hyperglycemia 
associated with 
Withhold d 
•  Initiate insulin replacement therapy for 
participants with T1DM 
•  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
evidence 
of 
β-cell failure 
•  Administer antihyperglycemic in 
participants with hyperglycemia 
 
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 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 
•  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate 
•  Monitor for signs and symptoms of thyroid 
disorders 
Grade 3 or 4 
Withhold 
or 
permanently 
discontinue d 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
•  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care 
•  Monitor for signs and symptoms of thyroid 
disorders 
Nephritis: 
grading 
according 
to 
increased 
creatinine 
or 
acute 
kidney 
injury 
Grade 2 
Withhold 
•  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper 
•  Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Grade 2 
Withhold 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
Neurological 
Toxicities 
Grade 3 or 4 
Permanently 
discontinue 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Myocarditis 
Grade 1 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All Other irAEs 
Persistent Grade 2 Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Grade 3 
Withhold 
or 
discontinue based 
on the event e  
Recurrent 
Grade 3 
or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal 

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irAEs 
Toxicity 
Grade 
(CTCAE v5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other 
Therapies 
Monitoring and Follow-up 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
 
 
Dose modification and toxicity management of infusion-reactions related to pembrolizumab 
Pembrolizumab may cause severe or life threatening infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and 
symptoms usually develop during or shortly after drug infusion and generally resolve completely within 24 hours of completion of 
infusion. Dose modification and toxicity management guidelines on pembrolizumab associated infusion reaction are provided in Table 
4.  
 
Table 4  Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 

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Confidential 
 
NCI CTCAE Grade 
Treatment 
Premedication at Subsequent Dosing 
Grade 1 
Mild 
reaction; 
infusion 
interruption 
not 
indicated; 
intervention not indicated 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption 
but 
responds 
promptly 
to 
symptomatic 
treatment (e.g., antihistamines, 
NSAIDs, narcotics, IV fluids); 
prophylactic 
medications 
indicated for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion 
may be restarted at 50% of the original infusion rate (e.g. from 100 mL/hr 
to 50 mL/hr).  Otherwise dosing will be held until symptoms resolve and 
the participant should be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate 
premedication should be permanently discontinued from further study 
drug treatment 
Participant may be premedicated 1.5h (± 
30 minutes) prior to infusion of _____ 
with: 
Diphenhydramine 
50 
mg 
po 
(or 
equivalent dose of antihistamine). 
Acetaminophen 500-1000 mg po (or 
equivalent dose of analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (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: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the 
participant is deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug 
treatment. 
No subsequent dosing 

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Confidential 
 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at http://ctep.cancer.gov 

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Confidential 
 
 

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Other allowed dose interruption for pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants 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 patient's 
study record. 
 
5.2.3 Second Course * 
All participants who stop study treatment with SD or better may be eligible for up to an 
additional 17 cycles (approximately 1 year) of pembrolizumab treatment if they progress 
after stopping study treatment from the initial treatment phase.  This retreatment is termed 
the Second Course Phase of this study and is only available if the study remains open and the 
participant meets the following conditions: 
Either 
• Stopped initial treatment with study treatment after attaining an 
investigator-determined confirmed CR, and 
o Was treated with at least 8 cycles of study treatment before discontinuing 
treatment, and 
o Received at least 2 treatments with pembrolizumab beyond the date when the 
initial CR was declared 
OR 
• Had SD, PR, or CR and stopped study treatment after completion of 
35 administrations (approximately 2 years) of study treatment for reasons other than 
disease progression or intolerability 
AND 
• Experienced an investigator-determined radiographic disease progression by LYRIC 
critria after stopping initial treatment, and 
o No new anticancer treatment was administered after the last dose of study 
treatment, and 
o The participant meets all of the safety parameters listed in the inclusion criteria 
and none of the safety parameters listed in the exclusion criteria, and 
o The study is ongoing 
An objective response or disease progression that occurs during the Second Course Phase for 
a participant will not be counted as an event for the primary analysis of either endpoint in this 
study. 

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*Note: patients must have measurable disease at the start of protocol treatment to be eligible 
for this provision. 
 
5.3 
Randomization or Treatment Allocation 
Subjects participating in this trial will be allocated to trial treatment by non-random 
assignement. 
5.4 
Stratification 
No stratification 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.  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 final decision on any supportive therapy or vaccination rests 
with the investigator and/or the participants's primary physician.  
5.5.1 Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the standards of medical care.  
All concomitant medication will be recorded on the case report form (CRF) including all 
prescription, over-the-counter (OTC), herbal supplements, and IV medications and fluids.  If 
changes occur during the trial period, documentation of drug dosage, frequency, route, and 
date may also be included on the CRF. 
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. 
5.5.2 Prohibited Concomitant Medications 
Parcticipants are prohibited from receiving the following therapies during the screening and 
treatment phase of this trial: 
• Anti-neoplastic biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy  
• Investigational agents other than pembrolizumab 
• Radiation therapy  

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o Note:  Radiation therapy to a symptomatic solitary lesion may be allowed at the 
investigator’s discretion, provided that study treatment is initiated at least 7 
days after completion of all palliative radiation..   
• Live vaccines within 30 days prior to the first dose of study treatment and while 
participating in the study.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus 
vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are 
live attenuated vaccines and are not allowed.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
immune-related adverse event, or the use of palliative glucocorticoids during the 
screening phase of the study (steroids however must be discontinued within 7 days of 
the first dose of pembrolizumab treatment).  The use of physiologic doses of 
corticosteroids may be approved after consultation with the sponsor. 
Participants who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  All 
treatments that the investigator considers necessary for a participant’s welfare may be 
administered at the discretion of the investigator in keeping with the standards of medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing study.  If there is a clinical indication for any medication or vaccination 
specifically prohibited during the study, discontinuation from study therapy or vaccination may 
be required.  The final decision on any supportive therapy or vaccination rests with the 
investigator and/or the participant's primary physician.  However, the decision to continue the 
participant on study treatment requires the mutual agreement of the investigator, the Sponsor 
and the participant. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.5.3 Rescue Medications & Supportive Care 
Participants should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of AEs with 
potential immunologic etiology are outlined along with the dose modification guidelines in 
Section 5.2.2, [Table 3].  Where appropriate, these guidelines include the use of oral or IV 
treatment with corticosteroids, as well as additional anti-inflammatory agents if symptoms do 
not improve with administration of corticosteroids.  Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased.  For 
each disorder, attempts should be made to rule out other causes such as metastatic disease or 
bacterial or viral infection, which might require additional supportive care.  The treatment 
guidelines are intended to be applied when the investigator determines the events to be related 
to pembrolizumab.  

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Note: If after the evaluation of the event, it is determined not to be related to pembrolizumab, 
the investigator does not need to follow the treatment guidance.  Refer to [Table 3] in Section 
5.2.2 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.  
5.6 
Participant Withdrawal/Discontinuation Criteria 
Participants may discontinue study treatment at any time for any reason, and may also be 
discontinued from study treatment at the discretion of the investigator should any untoward 
effect occur.  In addition, a participant may be discontinued from study treatment by the 
investigator or sponsor if study treatment is inappropriate, the trial plan is violated, or for 
administrative and/or other safety reasons.  Specific details regarding procedures to be 
performed at study treatment discontinuation are provided in Section 7.1.4 – Other Procedures. 
A participant must be discontinued from study treatment but continue to be monitored in the 
study for any of the following reasons: 
• The participant or participant’s legally acceptable representative requests to 
discontinue study treatment 
• Confirmed radiographic disease progression outlined in Section 7.1.2.6 
• Any progression or recurrence of any malignancy, or any occurrence of another 
malignancy that requires active treatment 
• Unacceptable adverse events as described in Section 5.2.2 
• The participant has a medical condition or personal circumstance which, in the opinion 
of the investigator and/or sponsor, placed the participant at unnecessary risk from 
continued administration of study treatment. 
• The participant  has a confirmed positive serum pregnancy test 
• Noncompliance with study treatment or procedure requirements 
• Recurrent Grade 2 pneumonitis 
• Discontinuation of treatment may be considered for participants who have attained a 
confirmed complete response (CR) and have been treated for at least 8 cycles (at 
least 24 weeks), receiving at least 2 doses of pembrolizumab beyond the date when 
the initial CR was declared. These participants may be eligible for second course 
treatment described in Section 5.2.3. 
• The participant is lost to follow-up 
• Completion of 35 treatments (approximately 2 years) with pembrolizumab 

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Note: The number of treatments is calculated starting with the first dose.  Participants 
who stop the combination or pembrolizumab after receiving 35 doses may be eligible 
for retreatment if they progress after stopping study treatment provided they meet the 
requirements detailed in Section 5.2.3. Participants may be retreated in the Second 
Course Phase (Retreatment) for up to an additional 17 cycles (approximately 1 year). 
• Administrative reasons 
5.7 
Participant Replacement Strategy 
Subjects may be replaced in the trial as needed to ensure that the required number of evaluable 
subjects is achieved for the desiginated statistical analyses as put forth in section 8.0. 
5.8 
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. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to participants 
4. Plans to modify or discontinue the development of the study drug 
5. The ORR does not meet stated hypothesis upon completion of the first phase of the study 
(< 3/13 responders) 
In the event that Merck decides to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to participant treatment can be made. 
 

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6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Treatment Cyclesa 
End 
of 
Treatment Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -11 
-10 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 
days 
post 
discon 
Every 12 
weeks post 
discon 
Every 
12 
weeks  
Administrative Procedures 
Pre-screening Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Review 
 
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 
 
Survival Status 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Full Physical Examination 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
 
 
Directed Physical Examination 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
 
Vital Signs and Weight 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ECOG Performance Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum β-HCGa 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differential 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Comprehensive Serum Chemistry Panel 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 

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Trial Period: 
Screening Phase 
Treatment Cyclesa 
End 
of 
Treatment Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated beyond 8 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visits 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days): 
-28 to -11 
-10 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 
days 
post 
discon 
Every 12 
weeks post 
discon 
Every 
12 
weeks  
LDH 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Urinalysis 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
 
 
TSH 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
 
 
Efficacy Measurements 
Tumor Imaging and bone marrow examb 
 
Xb 
 
 
 
X 
 
 
 
X 
X 
 
 
 
Tumor Biopsies/Archival Tissue Collection/Correlative Studies Blood 
PD-L1 FISH Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival 
or 
Newly 
Obtained 
Tissue 
Collection 
 
X 
 
 
 
 
 
 
 
 
Xc 
 
 
 
Correlative Studies Blood Collection 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
 
Baseline Stool Collection  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
a 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). 
bTumor imaging to consist of a PET scan and diagnostic CT scans of neck, chest, abdomen, and pelvis.  Scans performed within 28 days of treatment allocation will be allowable.  
Bone marrow biopsy to also be performed at times of tumor imaging for patients with baseline involvement (this does not need to be performed for patients with clear progression 
on diagnostic imaging, and does not need to be repeated for patients with documented bone marrow clearance unless otherwise clinically indicated). 
cA new biopsy will be performed whenever possible for patients developing progressive disease. 
 
 

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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 sponsor for 
reasons related to participant 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 participant.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The investigator must obtain documented consent from each potential participant prior to 
participating in the clinical trial. 
7.1.1.1.1 General Informed Consent 
Consent (both pre-screening and screening consent forms) must be documented by the 
participant’s dated signature or by the participant’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 participant before 
participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the participant must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The participant or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the participant’s willingness to continue participation in the 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 participant’s dated signature 
or by the participant’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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7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the participant qualifies for the trial.  
7.1.1.3 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 participant has enrolled in this study will be recorded separately and not listed as 
medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the participant 
within 28 days before starting the trial.  Treatment for the disease for which the participant has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the participant 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments, including 
systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a participant initiates a new anti-cancer 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 anti-cancer therapy has been initiated, the 
participant will move into survival follow-up.  

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7.1.1.6 Assignment of Screening Number 
All consented subjects will be assigned a unique screening number that will be used to identify 
the subject for all procedures that occur prior to 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.  
7.1.1.7 Assignment of Randomization Number 
All eligible subjects will be allocated, by non-random assignment, to trial treatment and will 
receive a unique treatment allocation number.  The allocation number identifies the subject for 
all procedures.  This unique number is termed an allocation number throughout the protocol 
for operational purposes.  Once an allocation number is assigned to a subject, it can never be 
re-assigned to another subject.  A subject cannot be assigned more than 1 allocation number. 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
Interruptions from the protocol specified treatment plan for > 12 weeks between doses of 
pembrolizumab due to toxicity require 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.  
The instructions for preparing and administering pembrolizumab will be provided in the 
Pharmacy Manual. 
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event (AE) Monitoring 
The investigator or qualified designee will assess each participant 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 Appendix 2).  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.   
7.1.2.2 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,  

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7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (Appendix 2) at screening, prior 
to the administration of each dose of trial treatment, and at discontinuation of trial treatment as 
specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
Tumor imaging will include positron emission tomography (PET) with combined diagnostic 
quality computed tomography (CT) scans throughout the study.  For the abdomen and pelvis, 
contrast-enhanced magnetic resonance imaging (MRI) may be used when CT with iodinated 
contrast is contraindicated, or when local practice mandates it.  The same imaging technique 
regarding modality, ideally the same scanner, and the use of contrast should be used in a 
participant throughout the study to optimize the reproducibility of the assessment of existing 
and new tumor burden and improve the accuracy of the assessment of response or progression 
based on imaging. 
Local reading (investigator assessment with site radiology reading) will be used in determining 
subject eligibility and response.  Response to pembrolizumab will be evaluated using LYRIC 
response criteria (1).  The sponsor will also receive radiologic images if the primary efficacy 
endpoint of the trial is met in order to retrospectively confirm subject eligibility and treatment 
response through a contracted centralized vendor.   
7.1.2.6.1 Initial Tumor Imaging 
Initial tumor imaging performed at screening must be conducted within 28 days prior to the 
date of treatment allocation, and consist of both PET and diagnostic CT scans of the neck, 
chest, abdomen and pelvis.  The site study team must review screening images to confirm the 
participant has measurable disease as defined in the inclusion criteria.  The baseline imaging 
scans must also be submitted to the central imaging vendor for a retrospective analysis of this 
eligbility criterion if the primary efficacy objective is met. 
Tumor imaging performed as part of routine clinical management is acceptable for use as 
screening tumor imaging if they are of diagnostic quality and performed within 28 days prior 
to the date of allocation and can be assessed by the central imaging vendor. 

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7.1.2.6.2 Tumor Imaging During the Study 
Imaging assessments with PET and diagnostic CT scans will be performed after every 4 cycles 
(12 weeks  ±7 days)) of therapy.  Imaging timing should follow calendar days and should not 
be adjusted for delays in cycle starts.  During the first 2 years of the study, 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 study, whichever comes first.  After 2 
years on study, further imaging is to be performed at the discretion of the treating physician. 
See Section 7.1.2.6.4 for confirmation assessment requirements when a subject’s disease 
response assessment shows an indeterminate response according to the LYRIC reposnse 
criteria.   
7.1.2.6.3 End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window).  If previous imaging was obtained within 
4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation is not 
mandatory.  In participants who discontinue study treatment due to documented disease 
progression, no further tumor imaging in the context of this trial is required. 
In participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging using 
the same imaging schedule used while receiving study treatment (every 12 weeks for up to 2 
years) to monitor disease status until the start of a new anticancer treatment, disease 
progression, pregnancy, death, withdrawal of consent, or the end of the study, whichever 
occurs first. 
7.1.2.6.4 Confirmation Assessments 
Because subjects treated with PD-1 blocking antibodies may have pseudoprogression of 
disease (there is progression on imaging per conventional response criteria, but the subject is 
clinically stable or improving), confirmation of progression should be performed in patients 
having an indeterminate response as defined by the LYRIC criteria (1).  Specifically, all 
patients having an indeterminate response can be continued on therapy at the discretion of the 
treating investigator.  However, repeat imaging must be performed within 12 weeks to either 
confirm or refute the presence of true disease progression. 
Clinical stability may be defined as: 
1) Absence of symptoms and signs indicating clinically significant progression of 
disease (including worsening of laboratory values) 
2) No decline in ECOG performance status 
3) Absence of rapid progression of disease or progressive tumor at critical 
anatomatical sites (e.g. cord compression) requiring urgent medical intervention 

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If progression is confirmed on repeat imaging without an intervening response, then the subject 
will be discontinued from trial treatment, and the initial indeterminate response will be 
recategorized as disease progression as outlined in the LYRIC criteria (1).  If progression is 
not confirmed, then the subject should continue trial treatment until disease progression is 
documented following the pre-determined response assessment dates outlined in the Trial Flow 
Chart (see Section 6.0).  Where appropriate, subjects should not be discontinued from study 
treatment with pembrolizumab until progression is confirmed.  However, the decision to 
continue or discontinue study treatment in the case of an intermediate response is that of the 
treating physician. 
7.1.2.6.5 Tumor Tissue Collection and Correlative Studies Sampling 
All subjects enrolled into this study must be able to provide an archived FFPE biopsy sample 
or preferrably a newly-obtained core needle or excisional biopsy (FNA is not adequate) to be 
submitted for characterization through the research collaborations organized by the principal 
investigator.   
Serial blood and baseline stool specimens will be collected as documented in the Trial Flow 
Chart (Section 6.0) for additional exploratory analyses.  The specific protocols for collecting 
serial blood and baseline stool samples is outlined in greater detail in the accompanying lab 
manual. Briefly however, blood will be compartmentalized into plasma, serum, and peripheral 
blood mononuclear cells on-site within 2 hours of sample collection and will be shipped to The 
University of Chicago Human Tissue Resource Center for long-term storage. Germline DNA 
will also be extracted from peripheral blood to provide a paired normal reference for tumor 
whole exome sequencing.  Correlative blood samples should be obtained at the time of routine 
blood specimens drawn for the main trial whenever possible.  Baseline stool sampling will be 
obtained using a home stool collection kit.  Once stool has been collected at home, the kit can 
either be returned by the patient at their next clinic appointment or shipped directly to The 
University of Chicago Microbiome Core Facility using the attached return address information. 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below.  
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry, and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified in Table 5.   

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Table 5. Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
Thyroid stimulating hormone (TSH) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
Blood for correlative studies 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
Urine pregnancy test † 
 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
 
 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
  
 
Total protein 
 
  
 
Blood Urea Nitrogen 
 
 
 
 
 
 
 
 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 

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Laboratory tests for the initial screening phase should be performed within 10 days prior to the 
first dose of treatment.  After cycle 1, pre-dose laboratory procedures can be conducted up to 
72 hours prior to dosing.  Results must be reviewed by the investigator or qualified designee 
and found to be acceptable prior to each dose of trial treatment. 
 
7.1.3.2 Correlative and Future Biomedical Research  
The following specimens are to be obtained as part of Correlative and Future Biomedical 
Research: 
• Blood and plasma for genomic and transcriptomic analyses 
• Archived and leftover FFPE lymph node biopsy specimens 
• Stool for microbiome analyses 
7.1.4 Other Procedures 
7.1.4.1 Withdrawal/Discontinuation 
When a participant 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.  Participants who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 5.2.3.  After discontinuing treatment following assessment of 
CR, these participants 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). 
7.1.4.1.1 Withdrawal From Correlative Biomedical Research 
Subjects may withdraw their consent for Correlative Biomedical Research and have their 
specimens and all derivatives destroyed.  Subjects may withdraw consent at any time by 
writing the principal investigator for the main trial. Subsequently, the subject’s specimens will 
be removed from the biorepository and will be destroyed. Any analyses in progress at the time 
of request for destruction or already perofmed 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 specimens have been completely anonymized, there will no longer be a 
link between the subject’s personal information and their specimens.  In this situation, the 
request for specimen destruction cannot be processed. 
7.1.4.2 Blinding/Unblinding 
This is an open label trial and therefore there will be no patient blinding. 

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7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 
7.1.5.1 Pre-screening and Screening Phases 
Approximately 28 days prior to enrollment, potential subjects interested in participating in the 
study will sign a pre-screening informed consent during a clinic visit.  Pre-screening will then 
consist of a brief review of medical history to determine potential eligibility, and an evaluation 
for the presence of a PD-L1 gene alteration using FISH on archived FFPE tissue (ideally 
obtained at the time of most recent relapse).  All FISH procedures will be performed at The 
University of Chicago or at City of Hope using a previously validated technique (Appendix 1).   
Patients fulfilling pre-screening criteria will then provide screening informed consent in order 
to proceed to the screening phase to determine full eligibility as set forth in Section 5.1.  This 
will consist of a physical examination, assessment of performance status, evaluation of 
hematology and chemistry parameters, and a baseline evaluation of disease status using results 
from positron emission tomography (PET) and diagnostic computerized tomography (CT) 
scans (a bone marrow exam will also be performed for patients with a history of prior bone 
marrow involvement). 
Written consent must be obtained prior to both the pre-screening and screening phases in order 
for a protocol specific procedure to be performed.  Results of a test conducted 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 14 days prior to the first dose of trial treatment except for the following: 
• 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). 
• Tumor imaging performed as part of routine clinical management is acceptable for use 
as baseline scans if they are of diagnostic quality and performed within 28 days of 
treatment allocation. 
Subjects may be re-screened 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 
incusion/exclusion criteria is met. When re-screening is performed, the initially assigned 
screening number will be utilized. 
7.1.5.2 Treatment Period 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 

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7.1.5.3 Post-Treatment Visits 
7.1.5.3.1 Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of study treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Participants with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 
0-1 or until the beginning of a new anti-cancer therapy, whichever occurs first.  SAEs that 
occur within 90 days of the end of treatment or before initiation of a new anti-cancer treatment 
should also be followed and recorded.  Participants who are eligible for retreatment/crossover 
with pembrolizumab (as described in Section 5.2.3) may have up to two safety follow-up visits, 
one after the Initial Treatment Period and one after the Second Course Treatment. 
7.1.5.4 Follow-up Visits 
Participants who discontinue study treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed every 12 weeks (84 ± 7 days) by 
radiologic imaging to monitor disease status for up to 2 years. Every effort should be made to 
collect information regarding disease status until the start of new anti-cancer therapy, disease 
progression, death, end of the study or if the participant begins retreatment with 
pembrolizumab as detailed in Section 5.2.3.  Information regarding post-study anti-cancer 
treatment will be collected if new treatment is initiated. 
Participants who are eligible to receive retreatment with pembrolizumab according to the 
criteria in Section 5.2.3 will move from the follow-up phase to the Second Course Phase when 
they experience disease progression.   
7.1.5.4.1 Survival Follow-up 
Participants who experience confirmed disease progression or start a new anti-cancer therapy, 
will move into the Survival Follow-Up Phase, and should be contacted by telephone every 
12 weeks to assess for survival status until death, withdrawal of consent, or the end of the trial, 
whichever occurs first.  
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment. An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the use of a medicinal product 
or protocol-specified procedure, whether or not considered related to the medicinal product or 
protocol-specified procedure.  Any worsening (i.e., any clinically significant adverse change 
in frequency and/or intensity) of a pre-existing condition that is temporally associated with the 
use of the Merck’s product, is also an adverse event. 

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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. 
Merck 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 Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse 
and from withdrawal. 
All AEs, SAEs and other reportable safety events that occur after the consent form is signed 
but before treatment allocation must be reported by the investigator if the participant is 
receiving placebo run-in or other run-in treatment, if the event cause the participant to be 
excluded from the study, or is the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, or a procedure.  
● All AEs from the time of treatment allocation through 30 days following cessation of study 
treatment must be reported by the investigator.  
● All AEs meeting serious criteria, from the time of treatment allocation through 90 days 
following cessation of study treatment, or 30 days following cessation of study treatment if the 
participant initiates new anti-cancer therapy, whichever is earlier must be reported by the 
investigator.  
● All pregnancies and exposure during breastfeeding, from the time of treatment 
allocation/randomization through 120 days following cessation of study treatment, or 30 days 
following cessation of study treatment if the participant initiates new anti-cancer therapy  must 
be reported by the investigator.  
● Additionally, any SAE brought to the attention of an investigator at any time outside of the 
time period specified above must be reported immediately by the investigator if the event is 
considered to be drug-related. 
Investigators are not obligated to actively seek AE or SAE or other reportable safety events in 
former study participants. However, if the investigator learns of any SAE, including a death, 
at any time after a participant has been discharged from the study, and he/she considers the 
event to be reasonably related to the study treatment or study participation, the investigator 
must promptly notify Merck. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor and to Merck 
For purposes of this study, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 

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treatment of overdose of pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity.  Appropriate supportive treatment should be provided if 
clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product 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 within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229) 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and infant exposure during breast feeding are not considered adverse 
events, it is the responsibility of investigators or their designees to report any pregnancy or 
lactation in a participant (spontaneously reported to them) that occurs during the study. 
Pregnancies and infant exposures during breastfeeding that occur after the consent form is 
signed but before treatment allocation/randomization must be reported by the investigator if 
they cause the participant 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 infant exposures during breastfeeding 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 participant 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 and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215-661-6229) 
7.2.3 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death 

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• 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 Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
• Is a new cancer (that is not a condition of the study) 
• Is associated with an overdose. 
Refer to Table 6 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 that occurs to any participant must be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety if it causes the 
participant 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 participant 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 whether or not related to the Merck 
product, must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck 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 Merck Global Safety. 
All participants with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-661-6229 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 

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regulators. Investigators will cross reference this submission according to local regulations to 
the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215-661-6229) at the time of submission to FDA. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 2 working days to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215-661-6229). 
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 participant must 
be reported within 2 working days to Merck Global Safety if it causes the participant 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 participant initiates 
new anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not 
related to Merck product, must be reported within 2 working days to Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  an overdose of Merck 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.  
 
7.2.4 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 6 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 Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the participant, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of participant 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 and to Merck within 2 
working days 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 to the Sponsor and to 
Merck within 2 working days.. 

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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 participant 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 Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck  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 Merck product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the participant was actually exposed to Merck 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 
Merck 
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 
Merck 
Product 
(continued)  
Dechallenge 
Was Merck 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 participant re-exposed to Merck 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 MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE PARTICIPANT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR 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 Merck 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 Merck product relationship). 
Yes, 
there 
is 
a 
reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is reasonable.  
The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Participant did not receive the Merck  product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable 
OR the AE is more likely explained by another cause than the Merck product.  (Also entered for a participant with overdose without an associated 
AE.) 

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7.2.5 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.  
8.0 STATISTICAL ANALYSIS PLAN 
8.1 
Statistical Analysis Plan Summary 
This section contains a brief summary of the statistical analysis plan for this trial.  Full details 
are provided in the Statistical Analysis Plan (SAP) (Section 8.2). 
The primary objective of this study is to identify the ORR of PD-L1 gene-altered 
relapsed/refractory DLBCL patients to pembrolizumab, and to determine whether this is 
significantly higher than a historical control of unselected relapsed/refractory DLBCL patients 
treated with pembrolizumab on the KEYNOTE-013 study. 
For the purposes of this clinical trial, the definition of relapsed/refractory disease includes 
patients who have experienced disease progression after receiving ≥ 2 lines of prior systemic 
therapy, ≥1 line of prior systemic therapy in those ineligible for or who have refused autologous 
stem cell transplantation, or patients who have received 1 line of prior therapy and have had 
primary refractory disease, or experienced a relapse within 12 months from initial diagnosis.  
The response assessment of patients enrolled on study will be determined using the LYRIC 
response criteria (1). 
8.1.1 Efficacy Analyses 
The full analysis set (FAS) population (defined as all subjects with a baseline disease burden 
assessment who receive at least one dose of study treatment will serve as the primary 
population for the analyses of efficacy data in this trial.  Subjects who withdraw prior to 
receiving any study drug will be considered non-evaluable.  Subjects in the FAS population 
with missing outcomes data will be considered as non-responders.  An exact 95% confidence 
interval (two-sided) for the response rate will be estimated based on the binomial distribution, 
along with a one-sided test of the null hypothesis (see 8.1.3).    Secondary time-to-event 
efficacy endpoints including PFS, OS, and DOR will be assessed by Kaplan-Meier survival 
analyses, and 95% confidence intervals will be calculated using Greenwood’s formula.  
8.1.2 Safety Analyses 
The FAS population will be employed for safety analyses which will be descriptive in nature. 
8.1.3 Power and Sample Size 
The sample size for this study was determined using a Simon two-stage design.  We project an 
ORR of 15%, below which the response will be unacceptable to continue the development of 
PD-L1 gene alterations as a biomarker of responsiveness to pembrolizumab based upon results 

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from unselected DLBCL patients enrolled on the KEYNOTE-013 study; an ORR of ≥40% will 
be considered worthy of further exploration of this biomarker.  The null hypothesis that the 
ORR is <15% will be tested against the alternative hypothesis that the ORR is ≥40%.  The 
sample size computations were performed assuming a 5% level of significance, 90% power, 
and an optimal two-stage design.   
Using these criteria, a maximum of 29 FAS patients will be enrolled (more than 29 patients 
may need to be enrolled to obtain the full analysis set population if there are enrolled patients 
that fail to receive a dose of study medication).  In the first stage, 13 patients will enter the 
study.  If 2 or fewer respond, the study will be terminated early and declared to have a negative 
result.  If 3 or more patients respond, enrollment will be extended to a total of 29 FAS patients.  
At Stage 2, the biomarker strategy will be declared effective and worthy of further testing if 8 
or more patients respond. 
8.2 
Statistical Analysis Plan 
8.2.1 Responsibility of Analyses 
The statistical analysis of the data obtained from this study will be the responsibility of the 
Biostatistics Laboratory of the University of Chicago. 
This trial is being conducted as an open-label study, i.e., subjects, investigators, and personell 
will be aware of subject treatment assignments after each subject is enrolled and treatment is 
allocated. 
8.2.2 Hypotheses/Estimation 
Objectives and hypotheses of the study are stated in Section 3.0. 
8.2.3 Analysis Endpoints 
8.2.3.1 Efficacy Endpoints 
Efficacy endpoints that will be evaluated are listed below followed by the desripitions of the 
derivations of selected endpoints. 
The primary efficacy endpoint is objective overall response rate (ORR), defined as the 
proportion of subjects meeting the LYRIC criteria for an objective response at any time during 
the study.  Response for the primary analysis will be assessed by the investigator. 
Key secondary endpoints include: 
• Progression-free survival (PFS) – defined as the time from treatment administration  to 
documented disease progression according to LYRIC criteria or death from any cause.  
Patients in response who elect to proceed to stem cell transplantation will be censored 
on the date of stem cell infusion. 

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• Overall survival (OS) – defined as the time from treatment administration to death from 
any cause. 
• Duration of response (DOR) – defined as the time from the first documented complete 
or partial response to disease progression or death. 
8.2.4 Analysis Populations 
8.2.4.1 Efficacy Analysis Populations 
The Full Analysis Set (FAS) population will serve as the primary population for the analysis 
of efficacy data in this study.  The FAS population consists of all allocated subjects who: 
• Receive at least one dose of study treatment, and 
• Have a baseline disease assessment 
8.2.5 Statistical Methods 
8.2.5.1 Statistical Methods for Efficacy Analyses 
Efficacy results will be considered to be statistically significant if Type I error rates are less 
than 5% per the two-stage design criteria stated above.  For the primary efficacy endpoint, the 
point estimate and 95% confidence interval will be provided using exact binomial distribution.  
Subjects in the primary analysis population (FAS) without response data will be counted as 
non-responders. 
Exploratory objectives will be evaluated using a combination of comparative and descriptive 
statistics. For example, response rates between patients with and without PD-L1 gene 
alterations will be compared using Fisher’s exact test and nonparametric, Wilcoxon rank-sum 
tests will be performed to compare PD-L1 protein expression as assessed by 
immunohistochemistry (IHC) between responders and non-responders.  Cox (50) regression 
models will be fit to determine whether other exploratory biomarkers are associated with PFS 
and OS, depending on the number of events observed. 
8.2.5.2 Statistical Methods for Safety Analyses 
Safety and tolerability will be assessed by clinical review of all relevant parameters including 
adverse events (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% confidence interval for the incidence rate of 
grade 2 or higher adverse events with an immune etiology and incidence rate of Grade 4/5 AEs 
will be provided as appropriate. 

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8.2.5.3 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.  No statistical 
hypothesis tests will be performed on these characteristics.  The number and percentage of 
subjects screened, allocated, the primary reasons for screening failure, and the primary reason 
for discontinuation will be displayed.  Demographic variables (e.g., age, gender), baseline 
characeristics, primary and secondary diagnoses, and prior and concomitant therapies will be 
summarized by descriptive statistics or categorical tables. 
8.2.6 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 using the following formula: 
 
Percent Compliance =             Number of Days on Therapy      x 100            
 
 
 
 
   Number of Days Should be on Therapy 
Summary statistics will be provided on percent complicance for the FAS population. 
8.2.7 Extent of Exposure 
Extent of Exposure for a subject is defined as number of cycles in which the subject receives 
a dose of study medication.  Summary statistics will be provided on Extent of Exposure for the 
all subjects as treated population. 
 
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. 
Pembrolizumab will be provided by Merck as summarized in Table 7. 
Table 7 Product Descriptions 

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Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Supplies will be labeled in accordance with regulatory requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the participant, 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. 
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 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the participants and the 
amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
10.1.1 Confidentiality of Data 
By signing this protocol, the investigator affirms to the Sponsor that information furnished to 
the investigator by the Sponsor will be maintained in confidence, and such information will be 
divulged to the institutional review board, ethics review committee (IRB/ERC) or similar or 
expert committee; affiliated institution and employees, only under an appropriate 

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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. 
10.1.2 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. 
10.1.3 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 email address 
• Hospital or clinic address and telephone number 
• Curriculum vitae or other summary of qualification and credentials 
• 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. 
10.1.4 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 

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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/subinvestigaor(s) agree, if requested by the Sponsor in accordance with 21 
CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to 
allow for the submission of complete and accurate certification and disclosure statements.  The 
investigator/subinvestigator(s) 
further 
agree 
to 
provide 
this 
information 
on 
a 
Certification/Disclosure Form, commonly known as a financial disclosure form proviced 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 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 representative of the Sponsor or any 

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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 worksheet/case report forms. 
The investigator must maintain copies of all documentation and records relating to the conduct 
of the trial in compliance with all applicable legal and regulatory requirements.  This 
documentation includes, but is not limited to, the protocol, worksheets/case report forms, 
advertising for subject participation, adverse event reports, subject source data correspondence 
with regulatory authorities and IRBs/ERCs, consent forms, investigator’s curricula vitae, 
monitor visit logs, laboratory reference ranges, laboratory certification or quality control 
procedures and laboratory director curriculum vitae.  By signing this protocol, the investigator 
agrees that documentation shall be retained until at least 2 years after the last approval of a 
maketing 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 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 prinicipal 
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 prinicapl 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 

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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 
of the tiral 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 

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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.  Sponsor will post a synopsis of trial results for approved 
products on www.clinicaltrials.gov by 12 months after the last subjet’s last visit for the primary 
outcome, 12 months after the decision to discontinue development, or product marketing 
(dispensed, administered, delivered or promoted), whichever is later. 
These timelines may be extended for products that are not yet marketed, if additional time is 
needed for anlaysis, 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 

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confidentiality does not include efficacy and safety results.  Sponsor review can be expedited 
to meet publication timelines. 
 
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APPENDICES 
 
Appendix 1: Detection of PD-L1 alerations by Flourescent in-situ Hybridization (FISH)  
FISH will performed utilizing a previously validated technique in a CLIA-certified 
cytogeneitcs laboratory at The University of Chicago or at City of Hope.  Briefly, de-
paraffinized FFPE slides will be incubated with FISH probes targeting PD-L1 (CD274, 
Orange, Empire Genomics) and centromere 9 (CEP9, Aqua, Abbott Molecular).  An additional 
probe targeting a region centromeric to PD-L2 (RP11-610G2, Green, Empire Genomics) will 
also be included to assess for chromosomal translocation involving PD-L1. After overnight 
hybridization at 37 °C in a humidifier chamber, slides will be washed and counterstained with 
2.5 mg/mL DAPI.  Fluorescent microscopy will then be performed to identify the presence or 
absence of PD-L1 gene alterations, and when present, to characterize the underlying 
mechanism (polysomy, relative copy gain, amplification, translocation).  30 lymphoma cells 
per sample will be analyzed.  
Nuclei will be defined as PD-L1 amplified if the PD-L1/CEP9 ratio is ≥ 3:1 or there are ≥ 6 
PD-L1 signals.  Nuclei with ≥3 PD-L1 signals and a PD-L1/CEP9  ratio of > 1:1 but < 3:1 will 
be defined as harboring PD-L1 copy gains, and those with a probe ratio of 1:1 but with more 
than 2 copies of each probe will be characterized as polysomic for chromosome 9.  PD-L1 
translocations will be called if there is evidence of a split signal between the PD-L1 and 
translocation probe centromeric to PD-L2.  The frequency of lymphoma cells harboring each 
form of PD-L1 alteration will be assessed for each sample, and samples will be considered PD-
L1 gene-altered if ≥20% of lymphoma cell nuclei exhibit any of the above-mentioned 
alterations.  For the purposes of the study, only patients with DLBCLs exhibiting PD-L1 
amplifications, translocations, or relative copy gains will be enrolled. DLBCLs exhibiting 
chromosome 9 polysomy alone without evidence of PD-L1 copy gain, amplification, and/or 
translocation are not considered PD-L1 gene-altered for the purposes of this clinical trial. 
A.  
 
 
B.  
 
  
Figure 2. A. schematic represenation of FISH probe locations on chromosome 9, and B. 
examples of PD-L1 gene alterations as determined by FISH. 

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Appendix 2: ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
 
 
 
 
 
 
 
 
 
 

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Appendix 3: 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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Appendix 4: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note:  Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
▪ 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may 
be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 
12 months of amenorrhea, confirmation with two FSH measurements in the 
postmenopausal range is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame in section 6.0:  
● Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent 
on a long term and persistent basis) and agree to remain abstinent 
● Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in Table 8 when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant. 
○ Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration. 
 
Female Participants: 

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Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 8 
during the protocol-defined time frame in Section 6.0.  
Table 8 
Highly Effective Contraception Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing ) hormonal contraception b 
○ Oral  
○ Intravaginal  
○ Transdermal  
○ Injectable 
● Progestogen-only hormonal contraception b 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant b 
● Intrauterine hormone-releasing system (IUS)  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole 
male sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional 
highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual
abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for participants
of clinical studies.  
 
a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used consistently and
correctly).  
b) If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable
hormonal contraceptives are limited to those which inhibit ovulation.  
Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.  

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Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected; at the time points 
specified in the Schedule of Activities, and as required locally. 
 

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Appendix 5:  LYRIC Response Criteria 

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Appendix 6: Collection and Management of Specimens for Biomedical Research 
1. Scope of Biomedical Research 
The blood, stool, DNA, and archival biopsy specimens collected in the current trial will 
be used to perform the exploratory research objectives listed in Section 3.3.  The 
collected biospecimens may also be used for future biomedical research focused on the 
identification of potential biomarkers of response, as well as mechanisms of acquired 
resistance to pembrolizumab therapy. 
2. Summary of Procedures for Biomedical Research 
a. Subjects for Enrollment 
All subjects enrolled in the clinical trial will be requested to provide archival 
biopsies, as well as blood and stool specimens at the timepoints outlined in the Trial 
Flowchart in Section 6.0. 
b. Informed Consent 
Informed consent to obtain archival biopsy specimens (10-20 unstained slides or a 
tissue block if available) for PD-L1 FISH experiments will be requested during a 
pre-screening trial visit by the investigator or his or her designate.  Patients 
fulfilling the pre-screening eligibility requirements will then be provided with a 
separate consent form to obtain other biospecimens (blood and stool) during the 
trial.  Informed consent must be obtained prior to collection of all biomedical 
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.  Patients unwilling to consent 
to providing the outlined biospecimens will not be eligibile for the study unless 
extenuating circumstances exist as deemed by a mutual agreement between the 
treating physician and the principal investigator. 
 
c. Biomedical Research Specimen Collection 
Serial blood, baseline stool, and archival biopsies will be collected as documented 
in the Trial Flow Chart (Section 6.0).  All blood specimens will be obtained at a 
time when the subject is having blood drawn for other trial purposes.  Baseline stool 
will be collected by the patient using a home stool collection kit. 
The protocol for serial blood and baseline stool collection is outlined in more detail 
in the accompanying lab manual. Briefly, blood will be compartmentalized into 
plasma, serum, and peripheral blood mononuclear cells at the patient’s trial site 
within 2 hours of sample collection and will be shipped to The University of 
Chicago Human Tissue Resource Center for long-term storage.  Germline DNA 
will also be extracted from peripheral blood to provide a paired normal reference 

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for tumor whole exome sequencing.  More detailed information regarding the 
specific reagents and blood processing techniques is provided in the accompanying 
lab manual.  Subjects participating in the study will be provided a home stool 
collection kit for baseline stool sampling.  After stool collection, the kit can either 
be returned by the patient at their next clinic appointment or shipped directly to The 
University of Chicago Microbiome Core Facility using the attached return address 
information. 
3. Withdrawal of Consent to Biomedical Research 
Subjects may withdraw their consent for biomedical research and have their specimens 
and all derivatives destroyed.  Subjects may withdraw consent at any time by writing 
to the principal investigator.  Subsequently, the subject’s specimens will be removed 
from the biorepository and be destroyed.  Any analyses in progress at the time of 
request for destruction or already performed prior to the request being received by the 
principal investigator will continue to be used as part of the overall research trial data 
and results.  No new analyses will be generated after the request is received. 
4. Retention of Specimens 
Archival biopsies and blood specimens will be stored at The University of Chicago 
Human Tissue Resource Center for potential analysis for up to 20 years from 
acquisition.  All baseline stool specimens will stored at The University of Chicago 
Microbiome Core Facility.  Specimens from the trial site will be shipped to the 
appropriate storage facility.  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 the storage facility’s policies and procedures 
and this destruction will be documented in the biorepository database. 
5. Reporting of Biomedical Research Data to Subjects 
There is no definitive requirement in either authoritative ethical guidelines or in 
relevant laws/regulation 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.  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 after 
completion of the clinical trial, the investigator will publish the results without 
revealing specific subject information in order for physicians and patients to pursue 
clinical diagnostic testing if they wish to do so. 
6. Risks Versus Benefits of Biomedical Research 

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For biomedical research, 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.  
Additionally, baseline stool collections will take place in the privacy of the patient’s 
home and can be shipped to the storage facility by any patient representative. 
Data privacy risks will also be 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. 
It is necessary for subject-related data (i.e., ethnicity, 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 database, and all specimens will be stripped of subject 
identifiers.  No information concerning results obtained from future biomedical 
research will be entered into clinical recoreds, nor will it be released to outside persons 
or agencies, in any way that could be tied to an individual subject.