Clinical trial NCT02981914
Conditions: Classical Hodgkin Lymphoma B-cell Non-Hodgkin Lymphoma Acute Myeloid Leukemia Myelodysplastic Syndromes
Keywords: Classical Hodgkin Lymphoma B-cell Non-Hodgkin Lymphoma Acute Myeloid Leukemia Myelodysplastic Syndromes pembrolizumab
Sponsor: University of Chicago
Start date: 2017-03-07; Completion date: 2020-11-01
Enrollment: 12 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot study has been designed to investigate the safety of pembrolizumab treatment for disease relapse following allogeneic stem cell transplant (alloSCT). Pembrolizumab will be administered at a fixed dose of 200 mg IV every 3 weeks. Approximately 12-26 patients with relapsed MDS, AML, or mature B cell (B-NHL, cHL) malignancies that have relapsed following alloSCT will be enrolled on this trial. Pembrolizumab treatment will be administered for up to 24 months, provided that neither disease progression, nor development of a dose-limiting toxicity (DLT), has occurred. Adverse events will be monitored every three weeks throughout the trial and graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. This trial will be conducted in accordance with Good Clinical Practices.

Detailed description:

Arms: arm 1: Pembrolizumab will be administered at a fixed dose of 200 mg IV every 3 weeks. Treatment will be administered for up to 24 months, provided that neither disease progression, nor development of a dose-limiting toxicity (DLT), has occurred.
Interventions: intervention 1: Pembrolizumab
Intervention descriptions: intervention 1: Pembrolizumab will be administered at a fixed dose of 200 mg IV every 3 weeks for a max of 24 months, so long as there is no disease progression.

Protocol documents:
Prot_SAP_000.pdf: 
1 
TITLE: Pilot study of pembrolizumab treatment for disease relapse after allogeneic 
stem cell transplantation 
IND NUMBER: 132029 
IRB#: 16-1195 
NCT#: NCT02981914
SPONSOR-INVESTIGATOR:  Justin Kline, MD 
Coordinating Center: The University of Chicago 
Principal Investigator: Dr. Justin Kline 
Address: The University of Chicago Medicine 
5841 S. Maryland Avenue, MC 2115   
Chicago, IL 60637 
Telephone: +1 (773) 702-5550 
Fax: +1 (773) 702-3163 
E-mail: jkline@medicine.bsd.uchicago.edu
Lead Co-Investigator: Dr. Hongtao Liu 
Address: The University of Chicago Medicine 
5841 S. Maryland Avenue, MC 2115   
Chicago, IL 60637 
Telephone:  
 
Fax:  
E-mail: hliu2@medicine.bsd.uchicago.edu
Version #/Date: Version 3 (July 14, 2017) 


                                                                                                                                 
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CONTENTS 
1.0 
TRIAL SUMMARY.................................................................................................... 6 
2.0 
TRIAL DESIGN.......................................................................................................... 6 
 
Trial design .............................................................................................................. 6 
 
Trial overview ......................................................................................................... 8 
3.0 
OBJECTIVES & HYPOTHESES ............................................................................. 8 
 
Primary Objective & Hypothesis .......................................................................... 8 
 
Secondary Objectives & Hypotheses ..................................................................... 9 
 
Exploratory Objectives & Hypotheses .................................................................. 9 
4.0 
BACKGROUND ....................................................................................................... 10 
 
Disease relapse after alloSCT. ............................................................................. 10 
 
Immune checkpoint blockade in hematological malignancies. ......................... 10 
 
PD-1/PD-L1 interactions, graft-versus-host disease (GVHD) and the graft-
versus-tumor effect (GVT). .................................................................................. 11 
 
Post-alloSCT immunotherapy. ............................................................................ 11 
 
Pembrolizumab (MK-3475). ................................................................................ 12 
 
Pharmaceutical and therapeutic background of pembrolizumab (MK-
3475). ...................................................................................................................... 12 
 
Pre-clinical and clinical trial data. ...................................................................... 13 
5.0 
Rationale .................................................................................................................... 13 
 
Rationale for the trial and selected subject population. .................................... 13 
 
Rationale for pembrolizumab dose and schedule. ............................................. 14 
 
Rationale for tolerability endpoints. ................................................................... 15 
 
Rationale for efficacy endpoints. ......................................................................... 16 
 
Rationale for biomarker research. ...................................................................... 16 
6.0 
Methodology .............................................................................................................. 17 
 
Entry criteria ......................................................................................................... 17 
6.1.1  Diagnosis for study entry .................................................................................. 17 
6.1.2  Subject inclusion criteria .................................................................................. 17 
6.1.3  Subject exclusion criteria ................................................................................. 19 
 
Trial treatments .................................................................................................... 21 
6.2.1  Dose selection/modification .............................................................................. 21 
6.2.2  Timing of dose administration ......................................................................... 24 


                                                                                                                                 
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6.2.3  Extent of trial treatment ................................................................................... 26 
6.2.4  Trial blinding/masking ..................................................................................... 26 
 
Randomization or treatment allocation .............................................................. 26 
 
Stratification .......................................................................................................... 26 
 
Concomitant medications and vaccines. ............................................................. 26 
6.5.1  Acceptable concomitant medications .......................................................... 2726 
6.5.2  Prohibited concomitant medications and treatments .................................... 27 
 
Rescue medications and supportive care ........................................................ 2827 
6.6.1  Supportive care guidelines ........................................................................... 2827 
 
Contraception, pregnancy and nursing mothers ............................................... 33 
6.7.1  Contraception .................................................................................................... 33 
6.7.2  Use during pregnancy ................................................................................... 3534 
6.7.3  Use in nursing women ....................................................................................... 35 
 
Subject withdrawal/discontinuation criteria ...................................................... 35 
6.8.1  Discontinuation of pembrolizumab after achievement of a complete 
response (CR) .................................................................................................... 36 
 
Beginning and end of trial .................................................................................... 36 
 
Criteria for early trial termination ..................................................................... 36 
7.0 
TRIAL FLOW CHART ........................................................................................... 37 
 
Screening and Cycles 1-4 ...................................................................................... 37 
 
Cycles 5-12 ............................................................................................................. 39 
427.3  Cycles 13-19 ........................................................................................................... 41 
 
Cycle 20-26 ............................................................................................................. 43 
 
Cycle 27-33 ............................................................................................................. 45 
 
Cycle 34 – Post Treatment ................................................................................... 47 
8.0 
TRIAL PROCEDURES ........................................................................................... 49 
 
Trial procedures .................................................................................................... 49 
8.1.1  Administrative procedures ............................................................................... 49 
8.1.2  Clinical procedures/assessments ...................................................................... 51 
8.1.3  Laboratory procedures/assessments ............................................................... 55 
8.1.4  Other procedures .............................................................................................. 57 
8.1.5  Visit requirements ............................................................................................. 57 
8.1.6  Post-treatment assessments .............................................................................. 59 
 
Assessing and recording adverse events ............................................................. 61 
8.2.1  Definition of an overdose for this protocol and reporting of overdose to 
the sponsor ......................................................................................................... 62 
8.2.2  Reporting of pregnancy and lactation ............................................................. 62 
8.2.3  Immediate reporting of adverse events ........................................................... 63 


                                                                                                                                 
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8.2.4  Evaluating adverse events ................................................................................ 65 
 
Adverse Event Reporting Requirements ............................................................ 68 
8.3.1  Routine Adverse Event Reporting ................................................................... 68 
8.3.2  Serious Adverse Event Reporting to the Coordinating Center .................... 68 
 
Trial governance and oversight ........................................................................... 68 
8.4.1  Data monitoring committee ............................................................................. 68 
9.0 
STATISTICAL ANALYSIS PLAN ........................................................................ 69 
 
Statistical analysis plan summary ....................................................................... 69 
9.1.1  Safety analyses ................................................................................................... 69 
9.1.2  Efficacy analyses ............................................................................................... 69 
9.1.3  Interim analysis ................................................................................................. 69 
 
Statistical analysis plan ........................................................................................ 69 
9.2.1  Hypotheses ......................................................................................................... 69 
9.2.2  Analysis endpoints ............................................................................................ 69 
9.2.3  Analysis population ........................................................................................... 70 
9.2.4  Statistical methods ............................................................................................ 70 
10.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES ................................................................................................................. 72 
 
Investigational product ......................................................................................... 72 
 
Packaging and labeling information ................................................................... 72 
 
Clinical supplies disclosure .............................................................................. 7372 
 
Storage and handling requirements ................................................................ 7372 
 
Discard/destruction/returns and reconciliation ................................................. 73 
11.0 
ADMINISTRATIVE AND REGULATORY DETAILS ....................................... 73 
 
Confidentiality ....................................................................................................... 73 
11.1.1  Confidentiality of data ...................................................................................... 73 
11.1.2  Confidentiality of subject records ................................................................... 73 
 
Obligations of Site Investigator ........................................................................... 73 
 
Auditing ................................................................................................................. 74 
 
Data management ................................................................................................. 74 
 
Publication ............................................................................................................. 74 
12.0 
APPENDICES ........................................................................................................... 74 
 
ECOG Performance Status .................................................................................. 75 
 
Common Terminology Criteria for Adverse Events V4.0 (CTCAE) ............... 75 
 
Response Evaluation of Hodgkin and non-Hodgkin lymphoma. ..................... 75 


                                                                                                                                 
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12.3.1  Criteria for lymphoma disease assessment ..................................................... 76 
 
International Prognostic Scoring System (IPSS) for MDS Prognostic 
Variable .................................................................................................................. 76 
 
MDS Response Criteria: ...................................................................................... 77 
12.5.1  Complete Remission (CR) ................................................................................ 77 
12.5.2  Partial Remission (PR) ..................................................................................... 77 
12.5.3  Stable Disease .................................................................................................... 77 
12.5.4  Failure ................................................................................................................ 77 
12.5.5  Relapse (following a CR or PR) ....................................................................... 78 
12.5.6  Disease Progression ........................................................................................... 78 
12.5.7  Disease Transformation .................................................................................... 78 
12.5.8  Cytogenetic Response ....................................................................................... 78 
 
Identification and Follow-up of Lesions in AML ............................................... 79 
12.6.1  Complete Remission (CR) ................................................................................ 79 
12.6.2  Complete Remission with Incomplete Platelet Recovery (CRp) .................. 79 
12.6.3  Complete Remission with Incomplete Hematological Recovery (CRi) ........ 79 
12.6.4  Partial Remission (PR) ..................................................................................... 79 
12.6.5  Relapse ............................................................................................................... 79 
12.6.6  Definitive Progression ....................................................................................... 79 
12.6.7  Acute GVHD grading 42 .................................................................................... 80 
13.0 
REFERENCES .......................................................................................................... 82 
 
 
 
 
 


                                                                                                                                 
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1.0 
TRIAL SUMMARY 
Abbreviated Title 
Pilot study of pembrolizumab treatment for disease 
relapse after allogeneic stem cell transplantation 
Trial Phase 
Pilot study 
Clinical Indication 
Classical Hodgkin lymphoma (cHL), B cell non-
Hodgkin lymphoma (B-NHL), acute myeloid leukemia 
(AML), myelodysplastic syndromes (MDS) 
Trial Type 
Interventional 
Type of control 
None 
Route of 
administration 
Intravenous 
Trial Blinding 
None 
Treatment Groups 
1 
Number of trial 
subjects 
12-26 
Estimated enrollment 
period 
10-20 months 
Estimated duration of 
trial 
36-48 months 
Duration of 
Participation 
35 cycles (up to 2 years) 
 
2.0 
TRIAL DESIGN 
 
TRIAL DESIGN 
This pilot study has been designed to investigate the safety of pembrolizumab treatment 
for disease relapse following allogeneic stem cell transplant (alloSCT). Pembrolizumab 
will be administered at a fixed dose of 200 mg IV every 3 weeks. Approximately 12-26 
patients with relapsed MDS, AML, or mature B cell (B-NHL, cHL) malignancies that 


                                                                                                                                 
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have relapsed following alloSCT will be enrolled on this trial. Pembrolizumab treatment 
will be administered for up to 24 months, provided that neither disease progression, nor 
development of a dose-limiting toxicity (DLT), has occurred. Adverse events will be 
monitored every three weeks throughout the trial and graded in severity according to the 
guidelines outlined in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. This trial will be conducted in accordance with Good Clinical 
Practices. 
Briefly, patients will undergo baseline eligibility screening within 2 weeks prior to 
enrollment, including a medical history, physical examination, and assessment of 
performance status and hematology and chemistry parameters. Baseline assessment of 
disease status will be based on results of a bone marrow aspirate and biopsy for patients 
with AML and MDS, and a CT/PET scan (with a bone marrow exam for history of 
disease involvement) for patients with lymphoma. Baseline and subsequent bone marrow 
and peripheral blood samples will be obtained for correlative assays. Disease response 
assessment (bone marrow aspirate and biopsy and/or CT/PET) will be performed at 
baseline, and then every 3 months for 2 years, as well as any time if relapse is 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 7.0.  Details of 
each procedure are provided in Section 8.0 – trial procedures. After 24 months, ongoing 
disease re-assessments will be performed at the discretion of the treating physician. Any 
patient who experiences biopsy-proven disease progression at any time will be removed 
from study, and alternative treatment can be recommended at the treating physician’s 
discretion. Subjects are not eligible for re-treatment on with pembrolizumab in the setting 
of this protocol should they experience a disease relapse after completing 24 months of 
therapy. After the end of treatment, each subject will be followed for 30 days for adverse 
event monitoring (serious adverse events will be collected for 90 days after the end of 
treatment). Subjects who discontinue treatment for reasons other than disease progression 
will have post-treatment follow-up for disease status until disease progression, initiating a 
non-study cancer treatment, 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. 
The primary objective of this trial is to determine whether administration of 
pembrolizumab is tolerable in patients who have experienced disease relapse following 
alloSCT. Secondary objectives include analysis of efficacy parameters (ORR, DOR, OS).  
Correlative studies to examine the effect of PD-1 blockade therapy on T cell parameters 
and clonality, as well as on donor chimerism are planned as exploratory analyses. 
A DLT is defined as the development of grade 3 or 4 acute GVHD (defined by the 
Gluckenberg scale), graft rejection, the development of any unexpected grade > 2 toxicity 
felt to be related to pembrolizumab, or the development of > grade 2 dysfunction of a 
vital organ felt to be secondary to an immune-related adverse event within 90 days 
following the initiation of pembrolizumab treatment.  For immune-related adverse events 
that do not meet criteria for a DLT, but do meet criteria for a treatment-limiting toxicity 
(TLT), for example grade 2 acute GVHD, pembrolizumab will held until the toxicity has 


                                                                                                                                 
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decreased to ≤ grade 1. It will be permanently discontinued if delayed for >12 weeks. For 
patients who develop GVHD or an immune-related adverse event while on 
pembrolizumab, corticosteroid therapy and potentially other immunomodulatory agents 
will be initiated. 
If the safety and feasibility of pembrolizumab is confirmed in this patient cohort, a phase 
II expansion cohort may be considered, particularly for disease subtypes where objective 
responses have been observed.  
 
TRIAL OVERVIEW 
The trial overview is depicted in Table 1. 
Table 1. Trial overview 
 
Initial treatment 
Pembrolizumab 200 mg IV on day 1 of each 21 day 
cycle 
Treatment-limiting 
toxicity 
(TLT) (for example, grade 2 
acute GVHD) 
Hold treatment for up to 12 weeks.. For immune-
related adverse events that do not meet criteria for a 
DLT, but do meet criteria for a treatment-limiting 
toxicity (TLT), for example grade 2 acute GVHD,  
pembrolizumab can be restarted provided that the 
toxicity has decreased to < grade 2. For patients who 
develop GVHD or an immune-related adverse event 
while on pembrolizumab, corticosteroid therapy and 
potentially other immunomodulatory agents will be 
initiated. Re-start treatment with pembrolizumab 200 
mg IV on day 1 of each 21 day cycle, provided that 
the TLT has resolved to ≤ grade 1. Permanently 
discontinue if no improvement in toxicity to ≤ grade 
1 in 12 weeks. 
Dose-limiting toxicity (DLT) 
Discontinue treatment. Remove patient from study 
 
3.0 
OBJECTIVES & HYPOTHESES 
 
PRIMARY OBJECTIVE & HYPOTHESIS 
Objective: To determine the tolerability of pembrolizumab treatment in the setting of 
relapsed myeloid malignancies and mature B cell lymphomas following alloSCT. 
Hypothesis: Pembrolizumab administered for disease relapse following alloSCT will be 


                                                                                                                                 
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tolerable with an acceptable incidence of immune-related adverse events, including 
GVHD. 
 
SECONDARY OBJECTIVES & HYPOTHESES 
Objective 1: To determine the overall response rate (ORR) of patients treated with 
pembrolizumab in the setting of relapsed myeloid malignancies and mature B cell 
lymphomas following alloSCT, stratified by disease type. ORR is defined as the first 
documentation of CR or PR (by IRC) to the first documentation of disease progression or 
death by any cause. 
Objective 2: To determine the duration of response (DOR) of patients treated with 
pembrolizumab in the setting of relapsed myeloid malignancies and mature B cell 
lymphomas following alloSCT. DOR is defined as the time between the initial response 
to therapy and subsequent disease progression or relapse. 
Objective 3: To determine the overall survival (OS) of patients treated with 
pembrolizumab in the setting of relapsed myeloid malignancies and mature B cell 
lymphomas following alloSCT. OS is defined as the interval from the start of the study 
treatment to death from any cause. 
Hypothesis 1: Pembrolizumab will have anti-tumor activity in the defined patient 
population as measured by ORR.  
 
EXPLORATORY OBJECTIVES & HYPOTHESES 
Objective 1: To determine the effect of pembrolizumab on restoring donor chimerism in 
patients with relapsed myeloid malignancies and mature B cell lymphomas following 
alloSCT.    
Objective 2: To determine the effect of pembrolizumab on the numbers and activations 
status of peripheral blood T cells. 
Objective 3: To compare PD-L1 expression on malignant cells at initial diagnosis and at 
disease relapse following alloSCT. 
Objective 4: To examine the effect of pembrolizumab on the T cell receptor (TCR) 
repertoire in the peripheral blood, and where available, tumor environment, following 
alloSCT. 
Hypothesis 1: Pembrolizumab treatment will restore donor chimerism when 
administered to patients with relapsed myeloid malignancies and mature B cell 
lymphomas following alloSCT. 
Hypothesis 2: Pembrolizumab treatment will be associated with enhanced expression of 
activation markers on peripheral blood T cells in patients with relapsed myeloid 
malignancies and mature B cell lymphomas following alloSCT. 


                                                                                                                                 
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Hypothesis 3: PD-L1 expression will be increased on malignant cells following disease 
relapse after alloSCT compared to diagnosis. 
Hypothesis 4: Pembrolizumab treatment will be associated with clonal expansion of 
conventional and regulatory T cell subsets in peripheral blood as measured by TCR-β 
deep sequencing and Simpson’s index of diversity analysis. 
4.0 
BACKGROUND 
 
DISEASE RELAPSE AFTER ALLOSCT.  
AlloSCT remains the only curative treatment modality for many high-risk and relapsed 
hematological malignancies. The widespread use of reduced-intensity conditioning (RIC) 
regimens has expanded patient eligibility for alloSCT due to reduced rates of transplant-
related mortality (TRM).  However, disease relapse remains the major cause of mortality 
following alloSCT 1.  The infusion of T cell-depleted allografts, a common practice at 
some institutions to reduce the risk of graft-versus-host disease (GVHD), has also been 
associated with a higher risk of disease recurrence following alloSCT 2, 3, 4.  Prognosis of 
patients with aggressive hematological cancers that relapse following alloSCT is abysmal 
5, 6, 7, 8, 9. Treatment options for this patient population are extremely limited, and new 
therapeutic approaches are needed. 
 
IMMUNE CHECKPOINT BLOCKADE IN HEMATOLOGICAL 
MALIGNANCIES.  
PD-L1 expression on malignant and non-malignant cells in the tumor environment 
potently down-regulates the function of PD-1-expressing tumor antigen-specific T cells 
10, 11, 12. Interference with PD-1/PD-L1 interactions can “re-awaken” previously 
generated, but ineffective anti-tumor T cell responses. PD-1 blockade has demonstrated 
remarkable clinical efficacy in a number of solid tumors 13, 14, and has created a new 
paradigm for cancer treatment.  
PD-1 blockade has also been effective in some hematological cancers, particularly 
Hodgkin lymphoma (HL) 15, in which the genetic loci that encode the PD-1 ligands are 
commonly amplified 16. In patients with relapsed/refractory HL, treatment with the PD-1 
blocking antibody, nivolumab, led to an objective response rate (ORR) of 87% (70% 
partial responses – PR, and 17% complete responses – CR).  At 24 weeks, 86% of 
responding patients were progression-free 15. Pembrolizumab, a similar PD-1 blocking 
antibody, induced ORR and CR rates of 53% and 20%, respectively, in a heavily pre-
treated group of HL patients 17. An updated abstract presented at ASCO 2016 showed 
that in patients refractory to brentuximab vedotin, pembrolizumab treatment was 
associated with a 65% ORR. Many of the responses observed were durable 18. 
With regard to NHL, a phase II study of a third PD-1 blocking antibody, pidilizumab, in 
combination with the anti-CD20 antibody, rituximab, was conducted in patients with 
relapsed follicular lymphoma. ORR and CR rates were impressive at 66% and 52 % 19. 
Preliminary results of a phase I study of nivolumab in patients with refractory 


                                                                                                                                 
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hematological malignancies demonstrated a 36% and 40% ORR in diffuse large B cell 
lymphoma and follicular lymphoma, respectively. There were also responses in patients 
with peripheral and cutaneous T cell lymphomas 20.  Therapy with anti-PD-1 antibodies 
has been generally safe, and only a few grade 3 or 4 toxicities were reported.  Immune-
related adverse events can occur following PD-1 blockade, but are less common and 
severe than what has been observed with the CTLA-4 blocking antibody, ipilimumab 21.  
Clinical studies of PD-1 blockade are currently ongoing in other hematological cancers, 
such as AML and myelodysplastic syndrome (MDS) (MK3475 KEYNOTE 013; 
NCT01096602; NCT02532231), and the results are eagerly awaited. Our group has 
demonstrated that PD-1/PD-L1 interactions promote immune evasion in a pre-clinical 
AML model 22, and our preliminary data indicates that human AML blasts from a 
fraction of patients express PD-L1 when analyzed by flow cytometry, arguing that 
interfering with PD-1/PD-L1 interactions may be therapeutically efficacious in human 
myeloid malignancies as well. 
 
PD-1/PD-L1 INTERACTIONS, GRAFT-VERSUS-HOST DISEASE (GVHD) 
AND THE GRAFT-VERSUS-TUMOR EFFECT (GVT).  
Acute GVHD is influenced by factors that either positively or negatively modulate donor 
T cell activation, and the PD-1/PD-L1 pathway has been previously implicated in 
exacerbating acute GVHD in pre-clinical models. For example, in a MHC-mismatched 
murine alloSCT model, acute GVHD was enhanced in transplant recipients treated with a 
PD-L1 blocking antibody 23. Additional studies in animals have found elevated 
expression of PD-L1 and PD-L2 in GVHD target organs following alloSCT. 
Interestingly, PD-1/PD-L1, but not PD-1/PD-L2 blockade markedly accelerated GVHD-
related lethality 24. Although PD-1 blockade has not formally been tested in humans in 
the post-transplant setting, results in animal models do raise concern that by attempting to 
harness a GVT effect via PD-1 blockade, GVHD could develop as a complicating factor.  
In addition, a recent presentation at the 2015 meeting of the American Society of 
Hematology, Herbeux and colleagues presented a retrospective analysis of nivolumab 
treatment for patients with Hodgkin lymphoma who had relapsed following alloSCT. Of 
8 evaluable patients, acute GVHD occurred in 2 (grades 3 and 4 acute GVHD of the 
skin). Both patients had a history of acute GVHD in the 3 months prior to receiving 
nivolumab.  Seven of 8 nivolumab-treated patients derived clinical benefit, with 4 
achieving a partial response (PR), and 3 a complete response (CR).  Furthermore, both 
patients who developed GVHD improved with treatment 25. 
 
POST-ALLOSCT IMMUNOTHERAPY.  
Unfortunately, patients who relapse after alloSCT have few treatment options and dismal 
outcomes. Withdrawal of immunosuppression to unleash a GVT effect has been effective 
in CML, but rarely in other diseases 26. Chemotherapy may be an option, although 
responses are not often durable 27, and most patients do not have sufficient performance 
status or hematological reserve to tolerate cytotoxic therapies. Cellular-based 
immunotherapies, including donor lymphocyte infusion (DLI), as well as adoptive T and 
NK cell therapy, have been employed to treat disease relapse following allo-SCT with 


                                                                                                                                 
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variable efficacies 28, 29, 30, including a 2-year survival of only 21% following DLI in an 
EBMT study 31. In addition, acute GVHD develops in up to 40–60% of patients who 
receive DLI, and pancytopenia, infections, current GVHD, and donor availability at the 
time of relapse are major impediments to its use 30, 31. 
The anti-CTLA-4 antibody, ipilimumab, was administered in the context of a phase 1 
study to 29 patients with relapsed malignancies after alloSCT 32. No dose-limiting 
toxicities (DLT) or grade 3-4 GVHD were observed. Chronic GVHD, present in 2 
patients at the time of anti-CTLA-4 therapy, did not flare. One patient developed grade 1 
GVHD two months after receiving ipilimumab, which occurred only after a DLI was 
administered for progressive disease. A CR was achieved in 2 patients with HL, and a PR 
was observed in a patient with NHL. These results suggest that checkpoint blockade 
therapy can be safely administered to patients with disease relapse following alloSCT. 
A prospective trial was recently published utilizing ipilimumab in 28 patients with 
various hematologic malignancies including relapsed AML, MDS, NHL, and HL 
following allogeneic transplant. Patients had no history of grade III or IV acute GVHD 
and were off immunosuppression. for at least 4 weeks 21% of patients had immune-
related adverse events and 14% had GVHD precluding further treatment.  ORR was 32% 
(23% CR) at the 10 mg/kg dose, with 18% of patients achieving a durable remission for 
more than 1 year 33. 
 
PEMBROLIZUMAB (MK-3475).  
Please refer to the IB / approved labeling for detailed background information on 
pembrolizumab (MK-3475). 
 
PHARMACEUTICAL AND THERAPEUTIC BACKGROUND OF 
PEMBROLIZUMAB (MK-3475).  
The importance of intact immune surveillance in controlling outgrowth of neoplastic 
transformation has been known for decades. Accumulating evidence shows a correlation 
between tumor-infiltrating lymphocytes (TILs) in cancer tissue and favorable prognosis 
in various malignancies.  In particular, the presence of CD8+ T-cells and the ratio of 
CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control 34, 35. The normal function of PD-1, expressed on the cell surface of 
activated T-cells under healthy conditions, is to down-modulate unwanted or excessive 
immune responses, including autoimmune reactions.  PD-1 (encoded by the gene Pdcd1) 
is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to 
negatively regulate antigen receptor signaling upon engagement of its ligands (PD-L1 
and/or PD-L2). The structure of murine PD-1 has been resolved.  PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) 
domain responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based 


                                                                                                                                 
13 
 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, 
PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade.  
The mechanism by which PD-1 down modulates T-cell responses is similar to, but 
distinct from that of CTLA-4 as both molecules regulate an overlapping set of signaling 
proteins.  PD-1 was shown to be expressed on activated lymphocytes including peripheral 
CD4+ and CD8+ T-cells, B-cells, Tregs and Natural Killer cells. Expression has also 
been shown during thymic development on CD4-CD8- (double negative) T-cells as well 
as subsets of macrophages and dendritic cells. The ligands for PD-1 (PD-L1 and PD-L2) 
are constitutively expressed or can be induced in a variety of cell types, including non-
hematopoietic tissues as well as in various tumors. Both ligands are type I transmembrane 
receptors containing both IgV- and IgC-like domains in the extracellular region and 
contain short cytoplasmic regions with no known signaling motifs. Binding of either PD-
1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is 
expressed at low levels on various non-hematopoietic tissues, most notably on vascular 
endothelium, whereas PD-L2 protein is only detectably expressed on antigen-presenting 
cells found in lymphoid tissue or chronic inflammatory environments. PD-L2 is thought 
to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves to 
dampen unwarranted T-cell function in peripheral tissues. Although healthy organs 
express little (if any) PD-L1, a variety of cancers were demonstrated to express abundant 
levels of this T-cell inhibitor. PD-1 has been suggested to regulate tumor-specific T-cell 
expansion in subjects with melanoma.  
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (mAb) 
of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and its 
ligands, PD-L1 and PD-L2.  KeytrudaTM (pembrolizumab) has recently been approved in 
the United States for the treatment of patients with unresectable or metastatic melanoma 
and disease progression following ipilimumab and, if BRAF V600 mutation positive, a 
BRAF inhibitor. It has also been FDA approved for patients with metastatic non-small 
cell lung cancer (NSCLC) who have progressed on standard chemotherapy and whose 
tumor expresses PD-L1. It has also been FDA approved for patients with recurrent or 
metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on 
or after platinum-containing chemotherapy. 
 
PRE-CLINICAL AND CLINICAL TRIAL DATA.  
Refer to the IB for details. 
5.0 
RATIONALE 
 
RATIONALE FOR THE TRIAL AND SELECTED SUBJECT POPULATION.  
Checkpoint blockade therapy with anti-PD-1 antibodies has demonstrated remarkably 
broad therapeutic success as cancer immunotherapy. The efficacy of PD-1 blockade 


                                                                                                                                 
14 
 
appears to be greater in neo-antigen rich and “inflamed” tumors. However, in the post-
alloSCT setting, immune-mediated elimination of malignant cells is driven by a 
mismatch in minor histocompatibility antigens (miHA) between donor and recipient. It is 
not known whether donor T cells recognize neo-antigens displayed on recipient-derived 
malignant cells.  
Examining the safety of anti-PD-1 antibodies following disease relapse after alloSCT is 
critical for several reasons. First, the “off-protocol” use of anti-PD-1 antibodies following 
alloSCT will rise due to the general excitement around them and due to lack of other 
treatment options.  Even a small study such as the one proposed here could go a long way 
in generating a safety signal for PD-1 blockade following alloSCT.  Second, given that 
PD-1 expression is common on donor T cells following alloSCT 36, 37, and has been 
associated with leukemia relapse after transplantation 38, it is not unreasonable to 
speculate that the clinical activity of ant-PD-1 therapy post-alloSCT will be high. 
 
RATIONALE FOR PEMBROLIZUMAB DOSE AND SCHEDULE.   
An open-label Phase I trial (Protocol 001) was conducted to evaluate the safety and 
clinical activity of single agent MK-3475. The dose escalation portion of this trial 
evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 weeks 
(Q2W) in subjects with advanced solid tumors. All three dose levels were well tolerated 
and no DLTs were observed. This first in human study of MK-3475 showed evidence of 
target engagement and objective evidence of tumor size reduction at all dose levels (1 
mg/kg, 3 mg/kg and 10 mg/kg Q2W). No maximum-tolerated dose (MTD) has been 
identified to date; however, recent data from other clinical studies within the MK-3475 
program has shown that a lower dose of MK-3475 and a less frequent schedule may be 
sufficient for target engagement and clinical activity. 
PK data analysis of MK-3475 administered Q2W and Q3W showed slow systemic 
clearance, limited volume of distribution, and a long half-life (refer to IB). 
Pharmacodynamic data (IL-2 release assay) suggested that peripheral target engagement 
is durable (>21 days). This early PK and pharmacodynamic data has provided scientific 
rationale for testing a Q2W and Q3W dosing schedule.   
A population pharmacokinetic analysis has been performed using serum concentration 
time data from 476 patients. Within the resulting population PK model, clearance and 
volume parameters of MK-3475 were found to be dependent on body weight. The 
relationship between clearance and body weight, with an allometric exponent of 0.59, is 
within the range observed for other antibodies and would support both body weight 
normalized dosing or a fixed dose across all body weights. MK-3475 has been found to 
have a wide therapeutic range based on the melanoma indication. The differences in 
exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based 
regimen are anticipated to remain well within the established exposure margins of 0.5 – 
5.0 for MK-3475 in the melanoma indication. The exposure margins are based on the 
notion of similar efficacy and safety in melanoma at 10 mg/kg Q3W vs. the proposed 
dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and exposure). The population PK 
evaluation revealed that there was no significant impact of tumor burden on exposure. In 


                                                                                                                                 
15 
 
addition, exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different indication 
settings. 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab 
in solid tumors was based on: 1) similar efficacy and safety of pembrolizumab when 
dosed at either 2 mg/kg or 10 mg/kg Q3W in melanoma patients, 2) the flat exposure-
response relationships of pembrolizumab for both efficacy and safety in the dose ranges 
of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumor burden or indication on 
distribution behavior of pembrolizumab (as assessed by the population PK model) and 4) 
the assumption that the dynamics of pembrolizumab target engagement will not vary 
meaningfully with tumor type. 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is 
based on simulations performed using the population PK model of pembrolizumab 
showing that the fixed dose of 200 mg every 3 weeks will provide exposures that 1) are 
optimally consistent with those obtained with the 2 mg/kg dose every 3 weeks, 2) will 
maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients 
exposure in the exposure range established in melanoma that are well tolerated and safe.  
A fixed dose regimen will simplify the dosing regimen to be more convenient for 
physicians and to reduce potential for dosing errors. A fixed dosing scheme will also 
reduce complexity in the logistical chain at treatment facilities and reduce wastage. 
Therefore 200mg pembrolizumab Q3W will be used in the current study.  
 
RATIONALE FOR TOLERABILITY ENDPOINTS.  
The primary endpoint of this trial is to determine whether pembrolizumab administration 
is safe and tolerable in patients with relapsed AML, MDS, and mature B cell lymphomas 
following alloSCT.  The safety analysis will be based on subjects who experience 
toxicities following treatment with pembrolizumab as defined by CTCAE criteria. Safety 
will be assessed by quantifying and grading the toxicities experienced by subjects who 
have received pembrolizumab, including serious adverse events (SAEs) and events of 
clinical interest (ECIs). Safety will be assessed by reported adverse events using CTCAE, 
version 4.0. The attribution to drug, timing of onset, event duration, event resolution, and 
any concomitant medications administered will be recorded. AEs will be analyzed, 
including but not limited to all AEs, SAEs, fatal AEs, and laboratory changes. Further, 
the occurrence of a grade 2 or higher immune-related AE will be collected and designated 
as an immune-related event of clinical interest (irAE) as well as veno-occlusive disease 
(VOD) and steroid-requiring febrile syndrome. Special attention will be paid in this 
patient population, to the development and severity of acute GVHD, which will be 
appropriately staged and graded according to accepted criteria (see Appendix, Section 
13.6). 
Given that a standard, phase I dose-escalation approach is not warranted given the 
discussion in Section 5.2, the investigators feel it is reasonable to perform a pilot study to 


                                                                                                                                 
16 
 
explore if the chosen pembrolizumab dose and schedule (i.e. 200 mg Q3W) is safe in this 
patient population.   
 
RATIONALE FOR EFFICACY ENDPOINTS.  
The secondary objective of this study (primary efficacy endpoints) is to determine the 
anti-tumor activity of pembrolizumab treatment in subjects with relapsed AML, MDS or 
mature B cell lymphomas following alloSCT. The overall response rate (ORR) will be 
the most valuable and primary efficacy endpoint. ORR for B cell lymphoma patients will 
be assessed according to the International Working Group criteria 39.  ORR for AML and 
MDS patients will be assessed according to the European Leukemia Net and International 
Working Group response criteria, respectively 40, 41.  ORR is defined as the proportion of 
subjects who achieve an objective disease response, as defined in Section 3.2. 
Secondary efficacy endpoints include duration of response (DOR) and overall survival 
(OS). DOR is defined as the interval from the first documentation of an objective disease 
response, as defined in Section3.2, to the documentation of disease progression, as 
defined in Section 3.2.  OS is defined as the interval from the date of study enrollment to 
death from any cause. 
 
RATIONALE FOR BIOMARKER RESEARCH. 
Effect of pembrolizumab treatment on restoring donor chimerism. Disease relapse 
following alloSCT is commonly associated with a decline in donor chimerism. By 
stimulating donor-derived T cells, it is hypothesized that pembrolizumab will improve or 
even completely restore full donor chimerism in patients will relapsed disease after 
alloSCT (where loss or decline in donor chimerism has been documented to occur).  
Donor chimerism in both the entire WBC population and in the CD3+ cell compartment 
will be analyzed by short tandem repeat analysis on 10 pre-defined loci by PCR and a 
capillary amplifier.  Analyses on peripheral blood (all patients) and bone marrow 
aspirates (in AML and MDS patients only) will be performed at baseline (pre-treatment) 
and at 3, 6, 9, 12, 15, 18, 21 and 24 months of pembrolizumab treatment.  It is expected 
that pembrolizumab treatment will improve or completely restore donor chimerism in 
treated patients.  A correlation between donor chimerism status and objective response 
will be sought, although patient number may be too small to make any definitive 
conclusion. 
Effect of pembrolizumab on T cell number and activation status.  Pembrolizumab, by 
interrupting PD-1/PD-L1 interactions, may affect not only numbers of T cells present in 
peripheral blood (and bone marrow), but may also lead to upregulation of activation 
markers on peripheral blood T cells. To explore this hypothesis, the frequencies and 
absolute numbers of T cell subsets (conventional CD4+ and CD8+ and 
CD4+CD25+CD127- regulatory T cells (Tregs)) will be enumerated in the peripheral 
blood (all patients) and bone marrow (AML and MDS patients only) at several defined 
time points prior to and following pembrolizumab treatment (pre-treatment, and at 3, 6, 9, 
12, 15, 18, and 24 months of treatment). Peripheral blood mononuclear cells (PBMC) or 
bone marrow cells will be stained with anti-CD3, anti-CD8, anti-CD4, anti-CD25, and 


                                                                                                                                 
17 
 
anti-CD127 antibodies and analyzed by flow cytometry to define specific T cell subsets.  
Conventional CD4+ T cells will be defined as CD3+CD4+CD25-/low cells, while 
conventional CD8+ T cells will be defined as CD3+CD8+ cells.  Tregs will be defined as 
CD3+CD4+CD25hiCD127- cells. Frequencies will be calculated by sub-gating on the 
lymphocyte population as appropriate. Absolute numbers of T cells in each subset will be 
enumerated by multiplying the frequency of each T cell subset by the total white blood 
count from each sample.  T cell activation status will be analyzed by co-staining cells 
with antibodies directed against the following markers: HLA-DR, CD69, ICOS and 
CD25 (others may be added).  Descriptive statistics will be utilized to compare pre- and 
post-treatment frequencies, absolute numbers and activation status of T cells in enrolled 
patients.  The goal would be to define potential biomarkers associated with 
responsiveness to pembrolizumab treatment that could be verified in larger studies in a 
similar patient population. 
Detection of PD-L1 and PD-L2 expression. To determine whether expression of PD-1 
ligands on malignant or non-malignant cells in the tumor environment may be a driver of 
disease relapse following alloSCT, PD-L1 and PD-L1 expression will be analyzed and 
compared between diagnostic samples and post-alloSCT relapse samples.  This assay will 
be performed in collaboration with Merck using in-house protocols.   
TCR sequencing. To investigate the hypothesis that pembrolizumab treatment will be 
associated with clonal expansion of antigen-specific T cells, the peripheral blood TCR 
repertoires will be compared in each patient prior to and at defined time points following 
pembrolizumab treatment (see above) using TCR-β deep sequencing.  These studies will 
be performed by Adaptive Biotechnologies, and data analyzed internally.  Simpson’s 
index of diversity will be utilized to compare the diversity of TCR repertoires prior to and 
following pembrolizumab treatment 
6.0 
METHODOLOGY 
 
ENTRY CRITERIA 
6.1.1 DIAGNOSIS FOR STUDY ENTRY 
Male or female subjects with AML, MDS or mature B cell lymphomas that have relapsed 
following matched-related donor (MRD) or matched unrelated donor (MUD) (HLA-A -B 
-C -DR -DQ) alloSCT are eligible for enrollment. 
6.1.2 SUBJECT INCLUSION CRITERIA 
1. Signed written informed consent 
a) Subjects must have signed and dated an IRB-approved written informed 
 
consent form in accordance with regulatory and institutional guidelines. This 
must be obtained before the performance of any protocol-related procedures 
that are not part of normal subject care. 


                                                                                                                                 
18 
 
b) Subjects must be willing and able to comply with scheduled visits, treatment 
schedule, laboratory tests and other requirements of the study. 
2. Target population 
a) Subjects must be ≥ 18 years of age. 
b) Subjects must have an ECOG performance status of 0-1 (Appendix). 
c) Subjects have undergone alloSCT > 90 days prior to enrollment from a 
matched-related donor (MRD), matched-unrelated donor (MUD), cord blood 
donor, or haplo-identical and cord blood donor. 
d) There must be histological confirmation of relapse after alloSCT of any of the 
following diseases: any mature B cell lymphoma (cHL or NHL), AML or 
MDS. 
e) Subjects must be off of all immunosuppressive medications for a minimum of 
2 weeks with the exception of physiologic doses of corticosteroids. 
f) Subjects with B cell lymphoma must have measurable disease, defined as at 
least 1 lesion that can be accurately measured in at least 2 dimensions with CT 
scan.  Minimum measurement must be > 15 mm in the longest diameter and > 
10 mm in the short axis. 
g) Subjects must not have had any prior investigational agents or devices within 
4 weeks of beginning study drug 
h) Subjects must have no prior history of VOD 
i) Subjects must demonstrate adequate organ function as defined in Table 2. All 
screening labs should be performed within 10 days of treatment initiation.   
Table 2. Adequate Organ Function Laboratory Values 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil    
count (ANC) 
≥ 500 /mcL 
Platelets 
≥ 20,000 /mcL 
Hemoglobin 
≥ 8 g/dL (RBC transfusions are OK) 
Renal 
 
Serum creatinine OR 
Measured or calculateda  
creatinine clearance 
(GFR can also be used in  
place of creatinine or  
≤ 1.5 X upper limit of normal (ULN) or 
≥ 60 mL/min for subject with creatinine levels > 1.5 
X institutional ULN 


                                                                                                                                 
19 
 
CrCl) 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN or direct bilirubin ≤ ULN for 
subjects with total bilirubin levels > 1.5X ULN 
AST (SGOT) and ALT 
(SGPT) 
≤ 2.5 X ULN  
Albumin 
> 2.0 mg/dL 
Coagulation 
International Normalized 
Ratio (INR) or  
Prothrombin Time (PT) 
 
 
Activated Partial  
Thromboplastin Time  
(aPTT) 
≤ 1.5 X ULN unless subject is receiving 
anticoagulant 
therapy, 
in 
which 
case, 
the 
PT/INR should be within therapeutic range for 
intended use. 
 
≤ 1.5 X ULN unless subject is receiving 
anticoagulant 
therapy, 
in 
which 
case, 
the 
PTT should be within therapeutic range for 
intended use. 
aCreatinine clearance should be calculated per institutional standard. 
 
j) Female subjects of childbearing potential should have a negative urine or 
serum pregnancy test (β-hCG) within 72 hours prior to receiving the first dose 
of study medication.  
k) Female subjects with childbearing potential should be willing to use 2 
methods of contraception, be surgically sterile, or abstain from heterosexual 
activity throughout the course of the study, until 120 days after the final dose 
of study medication. Subjects with childbearing potential are those who have 
not been surgically sterilized or have not been free from menses for > 1 year. 
Abstinence is acceptable if this is the established and preferred contraceptive 
method for the subject (see Section 6.7.1). 
l) Male subjects should agree to use an adequate method of contraception 
starting with the first dose of study medication until 120 days after the final 
dose of study medicine. Abstinence is acceptable if this is the established and 
preferred contraceptive method for the subject (see Section 6.7.1). 
6.1.3 SUBJECT EXCLUSION CRITERIA 
1. Target disease exclusions 
a) Subjects must not have known central nervous system involvement by disease 
(parenchymal, meningeal or cerebrospinal fluid) 
2. Medical history, concurrent diseases, and prior treatments 
a) Subjects must not have a history of any positive test for hepatitis B or hepatitis 


                                                                                                                                 
20 
 
C indicating active disease or previous exposure. 
b) Subjects must not have a history of human immunodeficiency virus (HIV) 
infection. 
c) Subjects must not be receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 2 weeks prior to the first dose of study 
medication. The use of physiologic doses of corticosteroids is acceptable. 
d) Subjects must not be concurrently receiving disease-modifying therapy in 
another therapeutic investigational study.  
e) Subjects must not have received a prior monoclonal antibody within 4 weeks 
prior to the first dose of study medication, and must have recovered (≤ grade 
1) from adverse events related to any anti-cancer agent administered > 4 
weeks previous to the first dose of study medication. 
f) Subjects must not have received chemotherapy or targeted small molecule 
therapy within 4 half-lives of the specific agent(s), or radiation therapy within 
2 weeks prior to the first dose of study medication, and must have recovered 
(≤ grade 1) from adverse events related to a previously administered agent. 
g) Subjects must not have received a donor lymphocyte infusion (DLI) within 8 
weeks prior to the first dose of study medication. 
h) Subjects must not have a history of severe (grade 3-4) acute GVHD, and/or 
current > grade 1 acute GHVD.  Subjects must not have a history of active 
chronic GVHD (whether limited or extensive stage).   
i) Subjects must not have autoimmune disease that has required systemic 
treatment in the past 2 years (i.e. with use of disease modifying agents, 
corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., 
thyroxine, insulin, or physiologic corticosteroid replacement therapy for 
adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment.  
j) Subjects must not have a known history of congestive heart failure, unstable 
angina pectoris, or cardiac arrhythmia (with the exception of chronic and rate-
controlled atrial fibrillation). 
k) Subjects must not have a history of other serious underlying medical or 
psychiatric condition that, in the opinion of the investigator, would impair the 
ability to receive, tolerate and or comply with the planned treatment and 
follow-up. 
l) Subjects must not have a history of a known secondary primary malignancy 
that is not in remission and/or that requires active therapy. Exceptions include 
non-melanoma skin cancers and in situ cervical cancer that has undergone 


                                                                                                                                 
21 
 
curative-intent local therapy. 
m) Subjects must not have a known active infection requiring intravenous 
antibiotic therapy. 
n) Subjects must not have a history of (non-infectious) pneumonitis that required 
steroid treatment, evidence of interstitial lung disease, or active, non-
infectious pneumonitis.  Subjects must not have active, non-infectious colitis. 
o) Subjects must not be pregnant or breastfeeding, or expecting to conceive or 
father children within the projected duration of the trial, starting with the 
screening visit through 120 days after the final dose of study medication. 
p) Subjects must not have received a live vaccine within 30 days prior to the first 
dose of study medication. 
q) Subjects must not be or have an immediate family member (spouse, parent, 
legal guardian, sibling or child) who is an investigational site sponsor or staff 
directly involved with the trial, unless IRB approval is granted previously. 
 
TRIAL TREATMENTS 
The treatment to be used in this trial is outlined below in Table 3. 
Table 3. Trial treatments 
Study Drug 
Dose 
Cycle 
duration 
Route 
of 
administration
Treatment 
period  
Use  
Pembrolizumab 
200 mg in 
100 mL of 
normal 
saline 
21 days 
IV 
infusion 
(0.2 
micron 
in-line filter) 
over 
30 
minutes 
Day 1 of each 
treatment cycle 
Experimental 
 
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 the study medication in accordance with the study protocol and any applicable 
laws and regulations. 
6.2.1 DOSE SELECTION/MODIFICATION 
6.2.1.1 
DOSE SELECTION (PREPARATION) 
All subjects will receive 200 mg of pembrolizumab via IV infusion every 21 days. 
Details on preparation and administration are provided in the pharmacy manual. 


                                                                                                                                 
22 
 
The rationale for selection of pembrolizumab dose to be used in this trial is provided in 
Section 5.2. There are no specific clarifications or evaluations required to be performed 
in order to administer the proper dose to each subject. 
6.2.1.2 
DOSE MODIFICATION 
Pembrolizumab will be withheld for drug-related, grade 4 hematologic toxicities and 
drug-related  ≥ grade 2 or 3 toxicities including laboratory abnormalities, as outlined in 
Tables 4 and 5. Attribution of events to drug will be per investigator/physician 
discretion. 
Table 4. Dose modification guidelines for hematological drug-related adverse events 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Discontinue 
Subject 
(after consultation with 
the 
Principal 
Investigator) 
Hematological 
Toxicity 
 
1, 2, 3 
No 
N/A 
N/A 
4 
Yes 
Toxicity 
resolves to 
Grade 
0-1 
or baseline 
Toxicity does not resolve 
within 12 weeks of last 
infusion 
Permanent 
discontinuation should be 
considered for any life-
threatening event 
 
Table 5. Dose modification guidelines for non-hematological drug-related adverse events 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Acute GVHD 
(as defined by 
the Gluckenberg 
scale 
- 
see 
appendix)  
21 
Toxicity 
resolves 
to 
grade 0-1. 
Re-start 
pembrolizumab at 200 
mg IV q21 days. 
Toxicity 
does 
not 
resolved 
within 12 weeks of last dose or 
inability to reduce corticosteroid 
to 10 mg or less of prednisone 
equivalent per day within 12 
weeks. 
3-41 
Permanently 
discontinue 
Permanently discontinue 


                                                                                                                                 
23 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
Diarrhea/Colitis 
21 
 
Toxicity 
resolves 
to 
Grade 
0-1. 
Re-start 
pembrolizumab at 200 
mg IV q21 days. 
Toxicity does not resolve within 
12 weeks of last dose or 
inability to reduce corticosteroid 
to 10 mg or less of prednisone 
or equivalent per day within 12 
weeks. 
3-41 
Permanently 
discontinue 
Permanently discontinue 
Hypophysitis 
2-31 
Toxicity 
resolves 
to 
Grade 0-1. 
Toxicity does not resolve within 
12 weeks of last dose or 
inability to reduce corticosteroid 
to 10 mg or less of prednisone 
or equivalent per day within 12 
weeks. 
41 
Toxicity 
resolves 
to 
Grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose or 
inability to reduce corticosteroid 
to 10 mg or less of prednisone 
or equivalent per day within 12 
weeks. 
AST, ALT, or 
Increased 
Bilirubin 
21 
Toxicity 
resolves 
to 
Grade 
0-1. 
Re-start 
pembrolizumab at 200 
mg IV q21 days. 
Toxicity does not resolve within 
12 weeks of last dose. 
3-41 
Permanently 
discontinue 
(see exception below)2 
Permanently discontinue 
Hyperthyroidism 
or 
Hypothyroidism 
31 
Toxicity 
resolves 
to 
Grade 0-1 
Toxicity does not resolve within 
12 weeks of last dose or 
inability to reduce corticosteroid 
to 10 mg or less of prednisone 
or equivalent per day within 12 
weeks. 
41 
Permanently 
Permanently discontinue 


                                                                                                                                 
24 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
discontinue 
Infusion 
Reaction 
3-4 
Permanently 
discontinue 
Permanently discontinue 
Neurologic 
events (including 
myasthenia 
gravis) 
21 
Toxicity 
resolves 
to 
Grade 
0-1. 
Re-start 
pembrolizumab at 200 
mg IV q21 days. 
Toxicity does not resolve within 
12 weeks of last dose or 
inability to reduce corticosteroid 
to 10 mg or less of prednisone 
or equivalent per day within 12 
weeks. 
3-41 
Permanently 
discontinue 
Permanently discontinue  
Pneumonitis 
21 
Toxicity 
resolves 
to 
Grade 
0-1. 
Re-start 
pembrolizumab at 200 
mg IV q21 days. 
Toxicity does not resolve within 
12 weeks of last dose or 
inability to reduce corticosteroid 
to 10 mg or less of prednisone 
or equivalent per day within 12 
weeks. 
3-41 
Permanently 
discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
21 
Toxicity 
resolves 
to 
Grade 
0-1. 
Re-start 
pembrolizumab at 200 
mg IV q21 days. 
Toxicity does not resolve within 
12 weeks of last dose or 
inability to reduce corticosteroid 
to 10 mg or less of prednisone 
or equivalent per day within 12 
weeks. 
3-41 
Permanently 
discontinue 
Permanently discontinue 
All Other Drug-
Related 
Toxicity3 
3 
or 
Severe1 
Toxicity 
resolves 
to 
Grade 
0-1. 
Re-start 
pembrolizumab at 200 
mg IV q21 days. 
Toxicity does not resolve within 
12 weeks of last dose or 
inability to reduce corticosteroid 
to 10 mg or less of prednisone 
or equivalent per day within 12 
weeks. 


                                                                                                                                 
25 
 
Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting 
Treatment 
Discontinue Subject 
4 
Permanently 
discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any 
life-threatening event. 
1 Administer corticosteroid (See also Events of Clinical Interest Guidance Document and 
Section 8.2.3.2 Events of Clinical Interest). 
2 For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST 
or ALT increases by greater than or equal to 50% relative to baseline and lasts for at least 1 
week then patients should be discontinued. 
3 Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication 
at physician discretion.  Permanently discontinue study drug for persistent Grade 2 adverse 
reactions for which treatment with study drug has been held, that do not recover to Grade 0-
1 within 12 weeks of the last dose.   
* Attribution of events to drug will be per investigator/physician discretion; in case of DLT 
grade toxicity that is deemed to be unrelated to drug, patient can continue on trial with 
appropriate treatment 
 
6.2.2 TIMING OF DOSE ADMINISTRATION 
Trial treatment should be administered on day 1 of each treatment cycle after all 
procedures/assessments have been completed as detailed on the trial flow chart (Section 
7.0). Trial treatment may be administered up to 3 days before or after the scheduled day 1 
of each cycle due to administrative reasons. Interruptions from the treatment plan for > 3 
days and up to 3 weeks may be allowed, but require consultation between the principal 
investigator and treating investigator, and written documentation of the collaborative 
decision on subject management. 
Pembrolizumab will be administered as a 30 minute (+/- 5 minute) IV infusion every 21 
days, unless a treatment-limiting toxicity (TLT), as defined in Section 6.2.1.2 and as 
outlined in Table 5, has occurred.  In this case, provided that the patient has sufficiently 
recovered, pembrolizumab will be restarted as a 30 minute (+/- 5 minute) IV infusion 
every 21 days.  All trial treatments will be administered on an outpatient basis. 
In the setting where a subject assessment is consistent with progressive disease (PD) at 
the 3 month disease response assessment, study drug may be continued until next disease 
response assessment provided the subjects’ clinical condition is stable. If progressive 


                                                                                                                                 
26 
 
disease is noted on imaging and patient is clinically stable or improved, repeat imaging 
should be obtained 4-6 weeks later. This exception pertains to B cell lymphoma 
patients only. 
If a subject is noted to have progression of disease at a time point beyond the 3 month 
disease response assessment, a repeat assessment may not be performed and the subject 
should not receive further treatment with the study medication.   
Subjects may only receive study treatment if the following criteria are met: 
 Absence of signs and symptoms (including worsening of laboratory values 
indicative of disease progression) 
 No decline in ECOG performance status 
 Absence of rapid disease progression 
6.2.3 EXTENT OF TRIAL TREATMENT 
All subjects who experience a partial response or have stable disease may remain on 
treatment for up to 2 years, or until progression.  
Subjects who achieve a complete response may choose to discontinue pembrolizumab 
therapy. However, they will not be eligible for re-treatment on this study should the 
disease recur before or after the planned 2 year treatment period. 
6.2.4 TRIAL BLINDING/MASKING 
This is an open-label trial. The investigator and subject will be aware of the study 
treatment administered. 
 
RANDOMIZATION OR TREATMENT ALLOCATION 
Subjects participating in this trial will be allocated by non-random assignment. 
 
STRATIFICATION 
No stratification based on age, sex or other characteristics will be used in this trial. 
 
CONCOMITANT MEDICATIONS AND VACCINES. 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed.  If there is a clinical indication for any medication or vaccination specifically 
prohibited during the trial, discontinuation from trial therapy or vaccination may be 
required.  The treating investigator should discuss any questions regarding this with the 
principal investigator and drug manufacturer, Merck (as appropriate).  The final decision 
on any supportive therapy or vaccination rests with the investigator and/or the subject's 
primary physician.  However, the decision to continue the subject on trial therapy or 


                                                                                                                                 
27 
 
vaccination schedule requires the mutual agreement of the investigator, the principal 
investigator and the subject. 
6.5.1 ACCEPTABLE CONCOMITANT MEDICATIONS 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community 
standards of medical care. All concomitant medication will be recorded on the case report 
form (CRF) including all prescription, over-the-counter (OTC), herbal supplements, and 
IV medications and fluids.  If changes occur during the trial period, documentation of 
drug dosage, frequency, route, and date may also be included on the CRF.  Subject may 
remain on anti-coagulation therapy as long as the PT or PTT is within therapeutic range 
of the intended use of anticoagulants 
All concomitant medications received within 28 days before the first dose of trial 
treatment and 30 days after the last dose of trial treatment should be recorded.  
Concomitant medications administered after 30 days after the last dose of trial treatment 
should be recorded for SAEs and ECIs as defined in Section 8.2. 
6.5.2 PROHIBITED CONCOMITANT MEDICATIONS AND TREATMENTS 
 Anti-neoplastic systemic chemotherapy or biological therapy 
 GM-CSF 
 Immunotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy (Radiation therapy to a symptomatic solitary lesion may be 
allowed after consultation with the investigator. 
 Live vaccines within 30 days prior to the first dose of pembrolizumab and through 
the duration of the study. Examples include, but are not limited to: measles, 
mumps, rubella, chicken pox, yellow fever, rabies, BCG, oral typhoid, and 
intranasal influenza vaccines (e.g. Flu-Mist®).  Seasonal influenza vaccines for 
injection are generally acceptable. 
 Immunosuppressive medications including, but not limited to, systemic 
corticosteroids 
(>10 
mg/day 
prednisone 
or 
equivalent), 
methotrexate, 
azathioprine, and tumor necrosis factor alpha (TNF-α) blockers. Use of 
immunosuppressive medications for the management of investigational product-
related AEs and in subjects with contrast allergies is permitted.  The use of 
physiologic steroid replacement may be approved after consultation with the 
investigator, study PI, and sponsor. In addition, use of inhaled and intranasal 
corticosteroids is permitted.  


                                                                                                                                 
28 
 
 Other medications as outlined in the exclusion criteria (Section 6.1.3). 
 
RESCUE MEDICATIONS AND SUPPORTIVE CARE 
6.6.1 SUPPORTIVE CARE GUIDELINES 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating physician, including but not limited to the items outlined below: 
 Diarrhea: Subjects should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or 
without fever) and bowel perforation (such as peritoneal signs and ileus). Diarrhea 
in this particular patient population may be due either to acute GVHD or to 
classical pembrolizumab-induced enterocolitis, and the differentiation between 
the two may be difficult or impossible. In symptomatic subjects, infectious 
etiologies should be evaluated, and if symptoms are persistent and/or severe, 
endoscopic evaluation should be performed. 
 In subjects with severe enterocolitis (grade 3 or 4) caused by acute GVHD or 
classical pembrolizumab-associated enterocolitis, pembrolizumab will be 
permanently discontinued, and treatment with systemic corticosteroids should be 
initiated at a dose of 1-2 mg/kg/day of prednisone or equivalent. When symptoms 
improve to ≤ grade 1, a corticosteroid taper should be started and continued for > 
1 month. 
 In subjects with moderate enterocolitis (grade 2) caused by acute GVHD or 
classical pembrolizumab-associated enterocolitis, pembrolizumab will be 
withheld and corticosteroids should be initiated at a dose of 1 mg/kg/day of 
prednisone or equivalent. When symptoms improve to ≤ grade 1, a corticosteroid 
taper should be started and continued for > 1 month.  Pembrolizumab may be re-
started at 200 mg IV every 21 days, as outlined in Section 6.2.1.2. 
 All subjects who experience diarrhea should be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolyte 
repletion (IV) is appropriate.  Other treatments, including loperamide, oral non-
absorbable corticosteroids and octreotide may be administered according to 
institutional guidelines for the treatment of acute GVHD. 
 GVHD: Subjects should be carefully monitored for signs and symptoms of 
GVHD (including diarrhea, transaminitis, rash). These symptoms will be treated 
aggressively 
with 
topical 
and/or 
systemic 
steroids 
and 
additional 
immunosuppressants per institutional guidelines. 
 Nausea/vomiting: These symptoms should be treated aggressively, and 
consideration should be given in subsequent cycles to the administration of 
prophylactic anti-emetics according to institutional practice. 


                                                                                                                                 
29 
 
 Antibiotics:  Antibiotics, either prophylactic or therapeutic, are allowed as 
considered appropriate by the treating physician. Appropriate antibiotics (i.e. 
PCP prophylaxis) should be initiated for patients who are on longer courses 
of corticosteroids. 
 Immune-related adverse events: Please see Table 5 above and separate guidance 
document regarding diagnosis and treatment of adverse events of a potential 
immunologic etiology. 
 Infusion reactions: Acute infusion reactions (which include cytokine release 
syndrome, angioedema, or anaphylaxis) are unique from allergic/hypersensitive 
reactions, although some of the manifestations are common to both.  Signs and 
symptoms usually develop during or shortly after pembrolizumab infusion and 
generally resolve completely within 24 hours of completion of infusion. 
Signs/symptoms may include: allergic reaction/hypersensitivity (including fever), 
arthralgia, bronchospasm, cough, dizziness, dyspnea, fatigue, headache, 
hypertension, hypotension, tachycardia, rigors or chills, myalgia, nausea, 
vomiting, pruritus, rash or urticaria, and tumor pain.  See Table 6 below for 
management guidelines for pembrolizumab-associated infusion reactions. 
 Respiratory/Pulmonary adverse events: Investigators should maintain a high index 
of suspicion for pneumonitis and initiate treatment with corticosteroids in a timely 
manner.  Additional supportive care guidance for pneumonitis can be found in 
Section 6.6.1.2. 
Table 6. Infusion reaction treatment guidelines 
NCI CTCAE Grade 
Treatment 
Premedication 
at 
subsequent dosing 
Grade 1 
Mild reaction; infusion 
interruption and 
intervention not 
indicated. 
Increase monitoring of vital 
signs as medically indicated until 
the subject is deemed medically 
stable in the opinion of the 
investigator. 
None 
Grade 2 
Requires infusion 
interruption but responds 
promptly to treatment 
(e.g., antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated for 
Stop Infusion.  
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Subject may be pre-
medicated 1.5h (± 30 
minutes) prior to 
infusion of 
pembrolizumab with: 
 
Diphenhydramine 50 
mg PO (or equivalent 


                                                                                                                                 
30 
 
NCI CTCAE Grade 
Treatment 
Premedication 
at 
subsequent dosing 
≤ 24 hrs 
 
Increase monitoring of vital 
signs as medically indicated until 
the subject is deemed medically 
stable in the opinion of the 
investigator. 
 
If symptoms resolve within one 
hour of stopping drug infusion, 
the infusion may be restarted at 
50% of the original infusion rate 
(e.g. from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will 
be held until symptoms resolve 
and the subject should be pre-
medicated for the next scheduled 
dose. 
Subjects who develop Grade 2 
toxicity despite adequate 
premedication should be 
permanently discontinued from 
further trial treatment 
administration. 
antihistamine dose). 
 
Acetaminophen 500-
1000 mg PO (or 
equivalent dose of 
antipyretic). 
Grade 3 or 4 
Grade 3: 
Prolonged (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) 
Stop Infusion. 
Additional appropriate medical 
therapy may include but is not 
limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital 
No subsequent dosing 


                                                                                                                                 
31 
 
NCI CTCAE Grade 
Treatment 
Premedication 
at 
subsequent dosing 
 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
signs as medically indicated until 
the subject is deemed medically 
stable in the opinion of the 
investigator. 
 
Hospitalization 
may 
be 
indicated. 
 
Subject 
is 
permanently 
discontinued from further trial 
treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician 
readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse 
Events v4.0 (CTCAE) at http://ctep.cancer.gov 
 
6.6.1.1 
SUPPORTIVE CARE GUIDELINES FOR ADVERSE EVENTS OF 
CLINICAL INTEREST WITH AN IMMUNE ETIOLOGY (IRAES) 
AND EVENTS OF CLINICAL INTEREST (ECI) 
Immune-related adverse events (irAE) 
 
irAEs are defined as an adverse event associated with pembrolizumab exposure and 
mediated through an immune mechanism.  irAEs may be predicted based on the nature of 
the known mechanism of action of pembrolizumab, as well as experience with other 
immunotherapies with a similar mechanism of action. Special attention should be paid to 
AEs that are suggestive of potential irAEs.  An irAE can occur shortly after the first dose, 
or several months after the final dose of pembrolizumab.  If an irAE is suspected, effort 
should be made to rule out other potential etiologic causes prior to labeling an AE as an 
irAE.  Information on how to identify and evaluate irAEs is included in the event of 
clinical interest and immune-related adverse event guidance document located in the 
administrative binder. 
Events of clinical interest (ECI) 
ECIs are non-serious and serious AEs that may or may not be irAEs. ECIs must be 
reported to Merck within 24 hours regardless of attribution to pembrolizumab.  


                                                                                                                                 
32 
 
Information on how to identify and report ECIs can be referenced in Section 8.2.3.2. 
6.6.1.2 
SUPPORTIVE CARE GUIDELINES FOR PNEUMONITIS 
Pembrolizumab treatment should be immediately held in subjects with symptomatic 
pneumonitis, and a clinical evaluation should be performed. The evaluation may include 
bronchoscopy and pulmonary function tests to rule out other causes. If the subject is 
determined to have pembrolizumab-associated pneumonitis, a treatment plan is outlined 
in Table 7.  
Table 7. Recommended approach to the management of pneumonitis 
Study drug 
associated 
pneumonitis 
Withhold/Discontinue 
pembrolizumab? 
Supportive Care 
Grade 1 
Asymptomatic; 
clinical or diagnostic 
observations 
No 
Intervention not indicated 
Grade 2 
Symptomatic; 
medical intervention 
indicated; 
limiting 
instrumental ADL 
Yes 
May 
re-treat 
with 
pembrolizumab 
200 
mg every 21 days if 
improves to grade ≤ 1 
within 12 weeks 
Systemic corticosteroids are indicated.  
Grade 3 and 4 
Grade 
3- 
Severe 
symptoms; limiting 
self-care; 
oxygen 
indicated 
 
Grade 
4 
- 
Life-
threatening 
respiratory 
compromise; urgent 
intervention 
indicated 
(e.g., 
tracheotomy 
or 
Yes 
Discontinue 
pembrolizumab 
permanently 
Systemic corticosteroids are indicated.  
The use of infliximab may be indicated 
as appropriate. Refer to the Event of 
Clinical Interest Guidance Document 
for additional recommendations.  


                                                                                                                                 
33 
 
intubation) 
 
For grade 2 pneumonitis that improves to ≤ 1 grade 1 within 12 weeks, the following 
rules should apply: 
 First episode of pneumonitis 
o May return to treatment (pembrolizumab 200 mg IV every 21 days) 
 Second episode of pneumonitis - permanently discontinue pembrolizumab if upon 
re-challenge, subject develops recurrent pneumonitis ≥ grade 2. 
 
CONTRACEPTION, PREGNANCY AND NURSING MOTHERS 
6.7.1 CONTRACEPTION 
Pembrolizumab may have adverse effects on a fetus. It is not known if pembrolizumab 
has transient adverse effects on the composition of sperm.  For this trial, male subjects 
will be considered to be of no reproductive potential if they are azospermic (whether due 
to having a vasectomy or an underlying medical condition). 
Female subjects will be considered of non-reproductive potential if they are either: 
1. postmenopausal (defined by at least 12 months with no menses without an 
alternative medical cause; in women <45 years of age a high follicle stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a post-
menopausal state in women not using hormonal contraception or hormonal 
replacement therapy. In the absence if 12 months of amenorrhea, a single FSH 
measurement is insufficient); 
OR 
2. have had a hysterectomy and/or bilateral oppherectomy, bilateral salpingectomy 
or bilateral tubal ligation/occlusions, at least 6 weeks prior to screening; 
OR 
3. have a congentially-acquired condition that prevents childbearing. 
 
Female and male subjects of reproductive potential must agree to avoid becoming 
pregnant or impregnating a partner, respectively, while receiving study drug and for 120 
days after the last dose of drug by complying with one of the following: 
1. practice abstinence from heterosexual activity; 


                                                                                                                                 
34 
 
 
OR 
2. 2) use (or have their partner use) acceptable contraception during heterosexual 
activity 
Acceptable methods of contraception are: 
 Single method (one of the following is acceptable): 
o intrauterine device (IUD) 
o vasectomy of a female subject’s male partner 
o contraceptive rod implanted into the skin 
 Combination method (requires use of two of the following): 
o diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide) 
o cervical cap with spermicide (nulliparous women only) 
o contraceptive sponge (nulliparous women only) 
o male condom or female condom (cannot be used together) 
o hormonal contraceptive: oral contracceptive pill (estrogen/progestin pill or 
rogestin-only pill), contraceptive skin patch,  
vaginal 
contraceptive 
ring, or subcutaneous contraceptive injection. 
Abstinence (relative to heterosexual activity) can be used as the sole method of 
contraception if it is consistently employed as the subjected preferred and usual lifestyle 
and is considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic 
abstinence (e.g., calendar, ovulation, symptom-thermal, post-ovulation methods, etc.) and 
withdrawal are not acceptable methods of contraception. 
If a contraceptive method listed above is restricted by local regulations/guidelines, then it 
does not qualify as an acceptable method of contraception for subjects participating at 
sites in this country/region. 
Subjects should be informed that taking the study medication may involve unknown risks 
to the fetus (unborn baby) if pregnancy were to occur during the study. In order to 
participate in the study, they must adhere to the contraception requirement (described 
above) from the day of study medication initiation (or 14 days prior to the initiation of a 
study medication for oral contraception) throughout the study period up to 120 days after 
the last dose of trial therapy. If there is any question that a subject will not reliably 
comply with the requirements for contraception, that subject should not be entered into 
the study. 


                                                                                                                                 
35 
 
6.7.2 USE DURING PREGNANCY 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, she 
will immediately be removed from the study.  The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been completed or 
terminated.  The outcome of the pregnancy will be reported to the sponsor without delay 
and within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  The study investigator will make every effort to obtain permission to follow 
the outcome of the pregnancy and report the condition of the fetus or newborn to the 
sponsor. 
6.7.3 USE IN NURSING WOMEN 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
 
SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA    
Subjects may withdraw consent at any time for any reason or be removed from the trial at 
the discretion of the investigator should any untoward effect occur.  In addition, a subject 
may be withdrawn by the investigator or the sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons.  
A subject must be discontinued from the trial for any of the following reasons: 
 The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
A subject must be discontinued from treatment (but may continue to be monitored in the 
trial) for any of the following reasons: 
 The subject or legal representative withdraws consent for treatment 
 Disease progression occurs 
 Unacceptable AEs develop as described in Tables 5 and 6, and Sections 6.6.1.1 
and 6.6.1.2 
 Intercurrent 
illness 
develops 
that 
prevents 
further 
administration 
of 
pembrolizumab 
 Investigator’s decision 
 The subject becomes pregnant 
 The subject is non-compliant with the treatment or trial requirements 


                                                                                                                                 
36 
 
 The subject is lost to follow-up 
 Administrative reasons 
The end of treatment and follow-up visit procedures are listed in Section 7.0 (Trial flow 
chart) and Section 8.1.5 (Visit Requirements).  After the end of treatment, each subject 
will be followed for 30 days for adverse event monitoring (serious adverse events will be 
collected for 90 days after the end of treatment.  Subjects who discontinue for reasons 
other than progressive disease will have post-treatment follow-up for disease status until 
disease progression, initiating a non-study cancer treatment, withdrawing consent or 
becoming lost to follow-up.  After documented disease progression or the start of new 
anti-cancer therapy, each subject will be followed by telephone for overall survival until 
death, withdrawal of consent, or the end of the study, whichever occurs first. 
6.8.1 DISCONTINUATION OF PEMBROLIZUMAB AFTER ACHIEVEMENT 
OF A COMPLETE RESPONSE (CR) 
Per the discretion of the investigator (and patient), subjects who achieve a CR following 
pembrolizumab treatment after a minimum of 6 months of treatment with at least 2 doses 
of pembrolizumab after confirmation of CR status may elect to discontinue 
pembrolizumab treatment. However, subjects who are discontinued from pembrolizumab 
treatment are not eligible for re-treatment on this trial should disease relapse occur. 
 
BEGINNING AND END OF TRIAL 
The overall trial begins when the first subject signs the informed consent form. The 
overall trial ends when the last subject completes the last study-related phone-call or visit, 
discontinues from the trial or is lost to follow-up (unable to be contacted by the 
investigator). 
 
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 the protocol and regulatory requirements 
3. Plans to modify or discontinue the development of the study drug 
4. Early stopping rule(s) are met 


                                                                                                                                 
37 
 
7.0 
TRIAL FLOW CHART 
 
SCREENING AND CYCLES 1-4 
Trial Period 
Screening Phase 
  
  
  
  
  
  
Weeks of treatment/cycle# 
Main Study Screening Visit 
1(D1C1) 2(D8C1)
3(D15C1)
4(D1C2) 
7(D1C3)
10(D1C4) 
Scheduling Window (days): 
(Day -28 to -1) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
Administrative Procedures 
Informed Consent 
X 
  
  
  
  
  
  
Inclusion/Exclusion Criteria 
X 
  
  
  
  
  
  
Demographics and Medical History 
X 
  
  
  
  
  
  
Prior and Concomitant Medication Review 
X 
  
  
  
  
  
  
Trial Treatment Administration 
  
X 
  
  
X 
X 
X 
Post-Study anticancer therapy status 
X 
  
  
  
  
  
  
Survival status 
X 
X 
X 
X 
X 
X 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Full Physical Examination 
X 
  
  
  
  
  
  
Directed Physical Examination 
  
X 
X 
X 
X 
X 
X 
Vital Signs and Weight 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 


                                                                                                                                 
38 
 
Trial Period 
Screening Phase 
  
  
  
  
  
  
Weeks of treatment/cycle# 
Main Study Screening Visit 
1(D1C1) 2(D8C1)
3(D15C1)
4(D1C2) 
7(D1C3)
10(D1C4) 
Scheduling Window (days): 
(Day -28 to -1) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
Laboratory Procedures/Assessments: analysis performed by local laboratory 
Pregnancy Test- Urine or Serum b-HCG 
X 
  
  
  
  
  
  
PT/INR and aPTT 
X 
  
  
  
  
  
  
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
  
  
  
  
  
  
T3, FT4, and TSH 
X 
  
  
  
X 
  
X 
HIV, CMV 
X 
  
  
  
  
  
  
HBV core antibody, anti-HCV antibody 
X 
  
  
  
  
  
  
Peripheral blood chimerism 
X 
 
 
 
 
 
 
Efficacy Measurements 
Tumor Imaging* 
X 
  
  
  
  
  
  
BM Biopsy** 
X 
  
  
  
  
  
  
Tumor Biopsies/Archival Tissue Collection Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection 
X 
  
  
  
  
  
  
Correlative Studies Blood Collection 
X 
  
  
  
  
  
  
 
*Tumor imaging only for HL and NHL 
**BM biopsy only for AML, MDS patients. For HL and NHL patients, a bone marrow is required only in patients with a prior 
history of marrow involvement 
 


                                                                                                                                 
39 
 
 
 CYCLES 5-12 
Trial Period 
  
  
  
  
  
  
  
  
Weeks of treatment/cycle# 
13(D1C5)
16(D1C6)
19(D1C7) 22(D1C8)
25(D1C9)
28(D1C10)
31(D1C11)
34(D1C12) 
Scheduling Window (days): 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
Administrative Procedures 
Informed Consent 
  
  
  
  
  
  
  
  
Inclusion/Exclusion Criteria 
  
  
  
  
  
  
  
  
Demographics and Medical History 
  
  
  
  
  
  
  
  
Prior and Concomitant Medication Review 
  
  
  
  
  
  
  
  
Trial Treatment Administration 
X 
X 
X 
X 
X 
X 
X 
X 
Post-Study anticancer therapy status 
  
  
  
  
  
  
  
  
Survival status 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
Full Physical Examination 
  
  
  
  
  
  
  
  
Directed Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs and Weight 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Procedures/Assessments: analysis performed by local laboratory 
Pregnancy Test- Urine or Serum b-HCG 
  
  
  
  
  
  
  
  
PT/INR and aPTT 
  
  
  
  
  
  
  
  
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
  
  
  
  
  
  
  
  
T3, FT4, and TSH 
  
X 
  
X 
  
X 
  
X 
HIV, CMV 
  
  
  
  
  
  
  
  


                                                                                                                                 
40 
 
Trial Period 
  
  
  
  
  
  
  
  
Weeks of treatment/cycle# 
13(D1C5)
16(D1C6)
19(D1C7) 22(D1C8)
25(D1C9)
28(D1C10)
31(D1C11)
34(D1C12) 
Scheduling Window (days): 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
HBV core antibody, anti-HCV antibody 
  
  
  
  
  
  
  
  
Peripheral blood chimerism 
X 
 
 
 
X 
 
 
 
Efficacy Measurements 
Tumor Imaging* 
X 
  
  
  
X 
  
  
  
BM Biopsy** 
X 
  
  
  
X 
  
  
  
Tumor Biopsies/Archival Tissue Collection Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection 
X 
  
  
  
X 
  
  
  
Correlative Studies Blood Collection 
X 
  
  
  
X 
  
  
  
 
*Tumor imaging only for HL and NHL 
**BM biopsy only for AML, MDS patients. For HL and NHL patients, a bone marrow is required only in patients with a prior 
history of marrow involvement 
 
 
 


                                                                                                                                 
41 
 
 
 
CYCLES 13-19 
Trial Period 
  
  
  
  
  
  
  
Weeks of treatment/cycle# 
37(D1C13)
40(D1C14)
43(D1C15) 46(D1C16)
49(D1C17)
52(D1C18)
55(D1C19)
Scheduling Window (days): 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
Administrative Procedures 
Informed Consent 
  
  
  
  
  
  
  
Inclusion/Exclusion Criteria 
  
  
  
  
  
  
  
Demographics and Medical History 
  
  
  
  
  
  
  
Prior and Concomitant Medication Review 
  
  
  
  
  
  
  
Trial Treatment Administration 
X 
X 
X 
X 
X 
X 
X 
Post-Study anticancer therapy status 
  
  
  
  
  
  
  
Survival status 
X 
X 
X 
X 
X 
X 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Full Physical Examination 
  
  
  
  
  
  
  
Directed Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Vital signs and Weight 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
Laboratory Procedures/Assessments: analysis performed by local laboratory 
Pregnancy Test- Urine or Serum b-HCG 
  
  
  
  
  
  
  
PT/INR and aPTT 
  
  
  
  
  
  
  
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 


                                                                                                                                 
42 
 
Trial Period 
  
  
  
  
  
  
  
Weeks of treatment/cycle# 
37(D1C13)
40(D1C14)
43(D1C15) 46(D1C16)
49(D1C17)
52(D1C18)
55(D1C19)
Scheduling Window (days): 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
Urinalysis 
  
  
  
  
  
  
  
T3, FT4, and TSH 
  
X 
  
X 
  
X 
  
HIV, CMV 
  
  
  
  
  
  
  
HBV core antibody, anti-HCV antibody 
  
  
  
  
  
  
  
Peripheral blood chimerism 
X 
 
 
 
X 
 
 
Efficacy Measurements 
Tumor Imaging* 
X 
  
  
  
X 
  
  
BM Biopsy** 
X 
  
  
  
X 
  
  
Tumor Biopsies/Archival Tissue Collection Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection 
X 
  
  
  
X 
  
  
Correlative Studies Blood Collection 
X 
  
  
  
X 
  
  
 
*Tumor imaging only for HL and NHL 
**BM biopsy only for AML, MDS patients. For HL and NHL patients, a bone marrow is required only in patients with a prior 
history of marrow involvement 
 
 


                                                                                                                                 
43 
 
 
CYCLE 20-26 
Trial Period 
  
  
  
  
  
  
  
Weeks of treatment/cycle# 
58(D1C20)
61(D1C21)
64(D1C22) 67(D1C23)
70(D1C24)
73(D1C25)
76(D1C26)
Scheduling Window (days): 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
Administrative Procedures 
Informed Consent 
  
  
  
  
  
  
  
Inclusion/Exclusion Criteria 
  
  
  
  
  
  
  
Demographics and Medical History 
  
  
  
  
  
  
  
Prior and Concomitant Medication Review 
  
  
  
  
  
  
  
Trial Treatment Administration 
X 
X 
X 
X 
X 
X 
X 
Post-Study anticancer therapy status 
  
  
  
  
  
  
  
Survival status 
X 
X 
X 
X 
X 
X 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Full Physical Examination 
  
  
  
  
  
  
  
Directed Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Vital signs and Weight 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
Laboratory Procedures/Assessments: analysis performed by local laboratory 
Pregnancy Test- Urine or Serum b-HCG 
  
  
  
  
  
  
  
PT/INR and aPTT 
  
  
  
  
  
  
  
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
  
  
  
  
  
  
  


                                                                                                                                 
44 
 
Trial Period 
  
  
  
  
  
  
  
Weeks of treatment/cycle# 
58(D1C20)
61(D1C21)
64(D1C22) 67(D1C23)
70(D1C24)
73(D1C25)
76(D1C26)
Scheduling Window (days): 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
T3, FT4, and TSH 
X 
  
X 
  
X 
  
X 
HIV, CMV 
  
  
  
  
  
  
  
HBV core antibody, anti-HCV antibody 
  
  
  
  
  
  
  
Peripheral blood chimerism 
 
X 
 
 
 
X 
 
Efficacy Measurements 
Tumor Imaging* 
  
X 
  
  
  
X 
  
BM Biopsy** 
  
X 
  
  
  
X 
  
Tumor Biopsies/Archival Tissue Collection Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection 
  
X 
  
  
  
X 
  
Correlative Studies Blood Collection 
  
X 
  
  
  
X 
  
 
*Tumor imaging only for HL and NHL 
**BM biopsy only for AML, MDS patients. For HL and NHL patients, a bone marrow is required only in patients with a prior 
history of marrow involvement 
 
 
 


                                                                                                                                 
45 
 
 
CYCLE 27-33 
Trial Period 
  
  
  
  
  
  
  
Weeks of treatment/cycle# 
79(D1C27)
82(D1C28)
85(D1C29) 88(D1C30) 91(D1C31) 94(D1C32)
97(D1C33)
Scheduling Window (days): 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
Administrative Procedures 
Informed Consent 
  
  
  
  
  
  
  
Inclusion/Exclusion Criteria 
  
  
  
  
  
  
  
Demographics and Medical History 
  
  
  
  
  
  
  
Prior and Concomitant Medication Review 
  
  
  
  
  
  
  
Trial Treatment Administration 
X 
X 
X 
X 
X 
X 
X 
Post-Study anticancer therapy status 
  
  
  
  
  
  
  
Survival status 
X 
X 
X 
X 
X 
X 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Full Physical Examination 
  
  
  
  
  
  
  
Directed Physical Examination 
X 
X 
X 
X 
X 
X 
X 
Vital signs and Weight 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
Laboratory Procedures/Assessments: analysis performed by local laboratory 
Pregnancy Test- Urine or Serum b-HCG 
  
  
  
  
  
  
  
PT/INR and aPTT 
  
  
  
  
  
  
  
CBC with differential 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
  
  
  
  
  
  
  


                                                                                                                                 
46 
 
Trial Period 
  
  
  
  
  
  
  
Weeks of treatment/cycle# 
79(D1C27)
82(D1C28)
85(D1C29) 88(D1C30) 91(D1C31) 94(D1C32)
97(D1C33)
Scheduling Window (days): 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
(+/- 3) 
T3, FT4, and TSH 
  
X 
  
X 
  
X 
  
HIV, CMV 
  
  
  
  
  
  
  
HBV core antibody, anti-HCV antibody 
  
  
  
  
  
  
  
Peripheral blood chimerism 
 
 
X 
 
 
 
X 
Efficacy Measurements 
Tumor Imaging* 
  
  
X 
  
  
  
X 
BM Biopsy** 
  
  
X 
  
  
  
X 
Tumor Biopsies/Archival Tissue Collection Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection 
  
  
X 
  
  
  
X 
Correlative Studies Blood Collection 
  
  
X 
  
  
  
X 
 
*Tumor imaging only for HL and NHL 
**BM biopsy only for AML, MDS patients. For HL and NHL patients, a bone marrow is required only in patients with a prior 
history of marrow involvement 
 
 


                                                                                                                                 
47 
 
 
CYCLE 34 – POST TREATMENT 
Trial Period 
  
  
  
  
Weeks of treatment/cycle# 
100(D1C34)
103(D1C35)
End of Treatment*** 
Post-Treatment*** 
Scheduling Window (days): 
(+/- 3) 
(+/- 3) 
(+/- 7) 
(+/- 7) 
Administrative Procedures 
Informed Consent 
  
  
  
  
Inclusion/Exclusion Criteria 
  
  
  
  
Demographics and Medical History 
  
  
  
  
Prior and Concomitant Medication Review 
  
  
  
  
Trial Treatment Administration 
X 
X 
  
  
Post-Study anticancer therapy status 
  
  
  
X 
Survival status 
X 
X 
X 
X 
Clinical Procedures/Assessments 
Review Adverse Events 
X 
X 
X 
X 
Full Physical Examination 
  
  
  
  
Directed Physical Examination 
X 
X 
X 
X 
Vital signs and Weight 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
Laboratory Procedures/Assessments: analysis performed by local laboratory 
Pregnancy Test- Urine or Serum b-HCG 
  
  
  
  
PT/INR and aPTT 
  
  
  
  
CBC with differential 
X 
X 
X 
X 
Comprehensive Serum Chemistry Panel 
X 
X 
X 
X 
Urinalysis 
  
  
  
  


                                                                                                                                 
48 
 
Trial Period 
  
  
  
  
Weeks of treatment/cycle# 
100(D1C34)
103(D1C35)
End of Treatment*** 
Post-Treatment*** 
Scheduling Window (days): 
(+/- 3) 
(+/- 3) 
(+/- 7) 
(+/- 7) 
T3, FT4, and TSH 
X 
  
X 
X 
HIV, CMV 
  
  
  
  
HBV core antibody, anti-HCV antibody 
  
  
  
  
Peripheral blood chimerism 
 
 
 
X 
Efficacy Measurements 
Tumor Imaging* 
  
  
  
X 
BM Biopsy** 
  
  
  
X 
Tumor Biopsies/Archival Tissue Collection Correlative Studies Blood 
Archival or Newly Obtained Tissue 
Collection 
  
  
  
X 
Correlative Studies Blood Collection 
  
  
  
X 
 
*Tumor imaging only for HL and NHL 
**BM biopsy only for AML, MDS patients. For HL and NHL patients, a bone marrow is required only in patients with a prior 
history of marrow involvement 
***The safety visit (Section 8.1.6.3) can be completed on the same date as the initial end of treatment or post-treatment visit.  
Follow-up visits should occur every 12 weeks until initiation of a new anti-cancer therapy, disease progression, withdrawal of 
consent or death, whichever comes first.  
 
 


                                                                                                                                 
49 
 
 
8.0 
TRIAL PROCEDURES 
 
TRIAL PROCEDURES 
The trial flow chart (Section 7.0) 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 as unscheduled time points if deemed clinically necessary by 
the investigator. 
Additional evaluations/testing may be deemed necessary by the investigator or the 
sponsor for reasons related to subject safety. In some cases, such evaluations may be 
potentially sensitive in nature (e.g, HIV, hepatitis C), and thus local regulations may 
require that additional informed consent be obtained from the subject. In these cases, 
such evaluations will be performed in accordance with these regulations. 
8.1.1 ADMINISTRATIVE PROCEDURES 
8.1.1.1 
INFORMED CONSENT 
The investigator or qualified designee must obtain documented consent from each 
potential subject or each subject’s legal representative prior to his or her participation in 
this clinical trial. 
8.1.1.1.1 
GENERAL INFORMED CONSENT 
Consent must be documented by the subject’s dated signature or by the subject’s legal 
representative’s dated signature on a consent form along with the dated signature of the 
person conducting the consent discussion. A copy of the signed and dated consent form 
should be given to the subject before participation in the trial. 
The initial informed consent form, any subsequent revised written informed consent form 
and any written information provided to the subject must receive IRB approval in 
advance of use.  The subject or his/her legal representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s 
willingness to continue participation in the trial. The communication of this information 
will be provided and documented in a revised consent form or addendum to the original 
consent form that captures the subject’s dated signature or by the subject’s legal 
representative’s dated signature. The informed consent will adhere to IRB requirements, 
applicable laws and regulations and sponsor requirements. 
8.1.1.2 
INCLUSION/EXCLUSION CRITERIA 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified 
designee to ensure that the subject qualifies for the trial. 


                                                                                                                                 
50 
 
8.1.1.3 
MEDICAL HISTORY 
A medical history will be obtained by the investigator or qualified designee. 
8.1.1.4 
PRIOR AND CONCOMITANT MEDICATION REVIEW 
8.1.1.4.1 
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 subject 
within 28 days before starting the trial. Treatment for the disease for which the subject 
has enrolled in the study will be recorded separately and not listed as a prior medication 
8.1.1.4.2 
CONCOMITANT MEDICATIONS 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. 
8.1.1.5 
DISEASE DETAILS AND TREATMENTS 
8.1.1.5.1 
DISEASE DETAILS 
The investigator or qualified designee will obtain prior and current details regarding 
disease status.   
8.1.1.5.2 
PRIOR TREATMENT DETAILS 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation, and surgeries and record in the trial database.  
8.1.1.5.3 
SUBSEQUENT ANTI-CANCER THERAPY STATUS 
The investigator or qualified designee will review all new anti-cancer therapy initiated 
after the last dose of trial treatment.  If a subject 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 antineoplastic therapy has been 
initiated the subject will move into survival follow-up.    
8.1.1.6 
ASSIGNMENT OF STUDY IDENTIFICATION NUMBER 
All eligible subjects will be assigned a study identification number.  The subject 
identification number identifies the subject for all procedures occurring after start of 
study.  Once a subject identification number is assigned to a subject, it can never be re-
assigned to another subject. 
8.1.1.7 
TRIAL COMPLIANCE (MEDICATION/DIET/ACTIVITY/OTHER) 
Interruptions from the protocol specified treatment for > 12 weeks between 


                                                                                                                                 
51 
 
pembrolizumab doses due to toxicity require consultation between the principal and 
treating investigators and written documentation of the collaborative decision on subject 
management. 
Administration of trial medication will be witnessed by the investigator and/or trial staff. 
The total volume of trial treatment infused will be compared to the total volume prepared 
to determine compliance with each dose administered. The instructions for preparing and 
administering pembrolizumab will be provided in the Pharmacy Manual. 
8.1.2 CLINICAL PROCEDURES/ASSESSMENTS 
8.1.2.1 
ADVERSE EVENT (AE) MONITORING 
The investigator or qualified designee will assess each subject to evaluate for potential 
new or worsening AEs as specified in the trial flow chart, and more frequently if 
clinically indicated.  Adverse events will be graded and recorded throughout the study 
and during the follow-up period according to NCI CTCAE Version 4.0. All AEs of 
unknown etiology associated with pembrolizumab exposure should be evaluated to 
determine if they are possibly events of clinical interest (ECI) of a potentially 
immunologic etiology (irAE).  See Section 6.6.1.1 and the separate guidance document in 
the administrative binder regarding the identification, evaluation, and management of 
AEs of a potential immunological etiology. Please refer to Section 8.2 for detailed 
information regarding the assessment and recording of AEs. 
8.1.2.2 
PHYSICAL EXAMINATION 
The investigator or qualified designee will perform a complete physical examination 
during the screening period.  Clinically significant abnormal findings should be recorded 
as medical history.  A complete physical examination should be performed during 
screening and repeated as per the frequency defined in the Study Flow Chart.  After the 
first dose of trial treatment, new clinically significant abnormal findings should be 
recorded as AEs. 
8.1.2.3 
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 7.0).  Vital signs should include temperature, 
pulse, respiratory rate, weight and blood pressure.  Height will be measured at screening 
only. 
8.1.2.4 
ELECTROCARDIOGRAM 
A standard 12-lead ECG will be performed using local standard procedures at screening.  
Clinically significant abnormal findings should be recorded as medical history.   


                                                                                                                                 
52 
 
8.1.2.5 
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
The investigator or qualified designee will assess ECOG status (Appendix) at screening, 
prior to the administration of each dose of pembrolizumab, and at discontinuation of trial 
treatment as specified in the trial flow chart. 
8.1.2.6 
ASSESSMENT OF DISEASE  
8.1.2.6.1 
CRITERIA FOR ASSESSMENT OF DISEASE 
The efficacy of pembrolizumab will be evaluated using the following disease-specific 
criteria 
 B cell lymphomas - The International Working Group response criteria will be 
utilized as the primary means to assess disease response to pembrolizumab in B 
cell lymphoma patients 39, and is the basis for all protocol guidelines related to 
disease status. 
 MDS - The International Working Group response criteria in myelodysplasia will 
be utilized as the primary means to assess disease response to pembrolizumab in 
MDS patients 40, and is the basis for all protocol guidelines related to disease 
status. 
 AML - The European LeukemiaNet guidelines will be utilized as the primary 
means to assess disease response to pembrolizumab in AML patients 41, and is the 
basis for all protocol guidelines related to disease status. 
8.1.2.6.2 
B CELL LYMPHOMA SUBJECT DISEASE RESPONSE 
ASSESSMENT 
Response in B cell lymphoma patients using bone marrow analysis (where applicable), as 
well as PET/CT (aggressive B cell lymphomas and Hodgkin lymphoma) or CT (low-
grade B cell lymphomas) is based on the International Working Group criteria 39. Local 
reading (investigator assessment with site radiology reading) will be used to determine 
subject eligibility and for subject management. No central radiology review will be 
performed. Assessment of lymphoma-related B symptoms should occur with each disease 
response assessment. 
8.1.2.6.3 
DISEASE ASSESSMENT OF IMMUNOTHERAPEUTIC AGENTS 
Note - this section pertains to subjects with B cell lymphomas only. 
Immunotherapeutic agents such as pembrolizumab may produce anti-tumor effects by 
potentiating endogenous cancer-specific immune responses, which may be functionally 
anergic.  The response patterns seen with such an approach may extend beyond the 
typical time course of responses seen with cytotoxic agents, and can manifest a clinical 
response after an initial increase in tumor burden or even the appearance of new lesions.  


                                                                                                                                 
53 
 
Standard response assessment criteria may not provide a complete response assessment 
of immunotherapeutic agents such as pembrolizumab. Therefore in the setting where a 
subject assessment shows PD, study drug may be continued until next disease response 
assessment provided that the subjects’ clinical condition is stable. Repeat scans after 
suspected "pseudoprogression" should be obtained in 4-6 weeks; if scans confirm 
progression, pembrolizumab will be discontinued. If progression is not confirmed on 
repeat imaging, the patient may continue on therapy. However, imaging should occur at 
any time where there is clinical suspicion of progression. 
Note - with the next disease response assessment if the disease is clinically stable or 
clinically improved, an exception may be considered to continue treatment upon 
consultation with the principal investigator. 
8.1.2.6.4 
AML SUBJECT DISEASE RESPONSE ASSESSMENT 
Response in AML patients using peripheral blood and bone marrow analysis is based on 
the European LeukemiaNet guidelines 41. Local review by a site hematopathologist will 
be used to determine subject eligibility and management. No central pathology review 
will be performed.  
8.1.2.6.5 
MDS SUBJECT DISEASE RESPONSE ASSESSMENT 
Response in MDS patients using peripheral blood and bone marrow analysis is based on 
the International Working Group response criteria in myelodysplasia 40. Local review by 
a site hematopathologist will be used to determine subject eligibility and management. 
No central pathology review will be performed.  
8.1.2.6.6 
TIMING OF DISEASE ASSESSMENTS 
Uniform disease response assessments in all subjects will occur every 12 weeks 
following the first disease response assessment at week 12 (see Table 8).  
Table 8. Disease response assessments 
Indication 
Assessment Frequency 
B cell lymphoma, AML and 
MDS 
Every 12 weeks following first assessment 
at week 13 up to 12 months. Subsequent 
disease response assessments are at the 
discretion of the treating physician. 
 
8.1.2.6.7 
INITIAL DISEASE ASSESSMENT  
Initial disease assessment must be performed within 28 days prior to the first dose of trial 
treatment.  The site study team must review pre-trial images to confirm that the subject 
has measurable disease as defined in the inclusion criteria.  


                                                                                                                                 
54 
 
8.1.2.6.8 
DISEASE ASSESSMENT DURING THE TRIAL 
Disease assessments should be performed as outlined in Table 8. There is a +/- 7 day 
window for assessments performed after Day 1. For MDS and AML patients, bone 
marrow biopsy will be the method of assessing disease response (along with peripheral 
blood counts).  For subjects with lymphoma, PET and diagnostic CT scans will be 
performed for aggressive B cell lymphoma and Hodgkin lymphoma subjects, while CT 
scans alone will be performed for subjects with low-grade lymphomas. Disease 
assessments and imaging should continue to be performed on protocol for 2 years after 
initiation of pembrolizumab treatment, and then until documented disease progression, 
the start of new anti-cancer treatment, withdrawal of consent, death, or the end of the 
study, whichever occurs first.   
8.1.2.6.9 
DISEASE PROGRESSION ASSESSMENTS 
A subject with B cell lymphoma ONLY with evidence of progressive disease 
documented at the week 12 assessment may continue trial treatment until next response 
assessment provided the subjects’ clinical condition is stable. However, imaging should 
occur at any time where there is clinical suspicion of progression. Repeat scans after 
suspected "pseudoprogression" should be obtained in 4-6 weeks; if scans confirm 
progression, pembrolizumab will be discontinued. If progression is not confirmed on 
repeat imaging, the patient may continue on therapy.  Subjects may only receive 
treatment if the following criteria are met: 
 Absence of signs and symptoms (including worsening of laboratory values) 
indicating disease progression 
 No decline in ECOG performance status 
 Absence of rapid progression of disease  
 Absence of progressive tumor at critical anatomical sites (e.g. cord compression) 
requiring urgent alternative medical intervention 
After the first disease response assessment, it is at the discretion of the investigator to 
keep a clinically stable subject on trial treatment or to stop trial treatment until a repeat 
assessment is performed.  Subjects that are deemed clinically unstable after first disease 
response assessment at week 13 should not continue trial treatment and must be 
discontinued from the trial.  
For subjects who have stable disease, partial response, or complete response following 
the first disease response assessment (at week 13), disease assessments and imaging 
should continue per the regular frequency every 12 weeks as outlined in the trial flow 
chart.   
For subjects noted to have progression of disease at a time point beyond the week 13 
initial disease response assessment, it is at the discretion of the investigator to keep a 


                                                                                                                                 
55 
 
clinically stable subject on trial treatment or to stop trial treatment until a repeat 
assessment is performed. 
8.1.2.6.10 
COLLECTION OF SAMPLES FOR COLLABORATIVE STUDIES 
All subjects enrolled onto this trial must consent to provide extra samples of peripheral 
blood and bone marrow at screening and at the 3, 6, 9, 12, 15, 18, 21 and 24 month visits. 
See Table 9. 
Table 9. Bone marrow and peripheral blood collection for correlative assays. 
Subjects 
Timing of correlative blood and bone 
marrow collection 
B cell lymphoma, MDS and AML  
At screening and 13 weeks, 25 weeks, 37 
weeks, 49 weeks, 61 weeks, 73 weeks,, 
85 
weeks 
 
and 
post-treatment 
assessments. Blood will be collected 
from all subjects.  Bone marrow aspirate 
samples will be collected from AML and 
MDS subjects at all time points.  Bone 
marrow aspirate samples will be collected 
from B cell lymphoma patients at 
screening, and 3 month, 6 month, 9 
month and 12 month assessments only 
for B cell lymphoma patients with 
marrow involvement at screening. 
 
8.1.3 LABORATORY PROCEDURES/ASSESSMENTS 
Samples will be drawn for our institutional lab. Local laboratory testing will include 
institutional standard tests for evaluating safety and making clinical decisions. The following 
laboratory assessments will be performed by the institutional lab to evaluate safety at 
scheduled timepoints during the course of the study. To contact the hematology lab for 
marrow/aspirate collection, dial 773-702-1314. 
8.1.3.1 
 LABORATORY EVALUATIONS 
Laboratory tests for hematology, chemistry and urinalysis are specified in Table 10. 
Table 10. Laboratory tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum 
β-human 


                                                                                                                                 
56 
 
Hematology 
Chemistry 
Urinalysis 
Other 
chorionic gonadotropin 
(β-hCG) 
Hemoglobin 
Alkaline phosphatase 
Glucose 
PT (INR) 
CBC 
with 
differential a  
Alanine 
aminotransferase 
(ALT) 
Protein 
aPTT 
Platelet count 
Aspartate aminotransferase 
(AST) 
Specific gravity  
Total 
Thriiodothyronine (T3) 
(or FT3) b 
WBC (total and 
differential) 
Lactate 
dehydrogenase 
(LDH) 
Microscopic exam, 
if abnormal results 
are noted  
Free thyroxine (T4) 
Red Blood Cell 
Count 
Carbon Dioxide (CO2 or 
bicarbonate) 
Urine 
pregnancy 
testc  
 Thyroid 
stimulating 
hormone (TSH) 
Absolute 
Neutrophil 
Count 
Creatinine 
 
Anti-pembrolizumab 
Antibodies 
Absolute 
Lymphocyte 
Count 
Uric Acid 
 
  
 
Calcium 
 
 Blood for FBR 
 
Chloride 
 
 Blood for correlative 
studies 
(donor 
chimerism, 
T 
cell 
receptor sequencing, T 
cell activation markers)
 
Glucose 
 
 
 
Phosphorus 
 
 
 
Potassium 
 
  
 
Sodium 
 
  


                                                                                                                                 
57 
 
Hematology 
Chemistry 
Urinalysis 
Other 
 
Magnesium   
 
  
 
Total Bilirubin   
 
  
 
Direct 
and 
Indirect 
Bilirubin, if total bilirubin 
is elevated above the upper 
limit of normal 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
Laboratory tests for screening 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. 
8.1.4 OTHER PROCEDURES 
8.1.4.1 
WITHDRAWAL/DISCONTINUATION 
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits. 
When a subject discontinues/withdraws from participation in the trial, all applicable 
activities scheduled for the final trial visit should be performed at the time of 
discontinuation. 
Any 
adverse 
events 
which 
are 
present 
at 
the 
time 
of 
discontinuation/withdrawal should be followed in accordance with the safety 
requirements outlined in Section 8.2 - Assessing and recording adverse events.  Subjects 
who attain a CR may discontinue treatment without the option of restarting treatment. 
After discontinuing treatment following assessment of CR, these subjects should return to 
the site for a safety follow-up visit (Section 8.1.6.3), and then proceed to the follow-up 
period of the study (Section 8.1.6.4).   
8.1.4.2 
BLINDING/UNBLINDING 
This is an open label trial; there is no blinding for this trial. 
8.1.5 VISIT REQUIREMENTS 
Visit requirements are outlined in Section 7.0 - trial flow chart.   Specific procedure-
related details are provided above in Section 8.1 - trial procedures. 


                                                                                                                                 
58 
 
8.1.5.1 
SCREENING 
Approximately 28 days prior to start of study drug dosing, potential subjects will be 
evaluated to determine that they fulfill the entry requirements as set forth in Section 6.1.  
Screening procedures may be repeated after consultation with the principal investigator.  
Written consent for the main study must be obtained prior to performing any protocol 
specific procedure.  Results of a test performed prior to the subject signing consent as 
part of routine clinical management are acceptable in lieu of a screening test if performed 
within the specified time frame.  Screening procedures are to be completed within 28 
days prior to the first dose of trial treatment except for the following: 
Laboratory tests are to be performed within 10 days prior to the first dose of trial 
treatment. 
For women of reproductive potential, a urine pregnancy test will be performed within 72 
hours prior to the first dose of trial treatment.  If urine pregnancy results cannot be 
confirmed as negative, a serum pregnancy test will be required (performed by the local 
study site laboratory). 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria.  
Results from assessments performed during the initial screening period are acceptable in 
lieu of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. 
8.1.5.2 
TREATMENT PERIOD 
Visit requirements are outlined in Section 7.0 – trial flow chart.  Specific procedure-
related details are provided above in Section 8.1 – trial Procedures. Each on-study visit 
will be scheduled based on the date of the week 0 (day 1) visit. Required visits are 
outlined below. The treatment period commences on the day of the first dose of 
pembrolizumab, and ends following a 21 day cycle. During the study treatment period, 
subjects will be regularly monitored to assess the safety and anti-tumor activity of the 
treatment. 
Baseline/Week 0 
Subjects who meet all of the inclusion criteria and none of the exclusion criteria will 
return to the clinic within 28 days after screening for baseline assessments. 
The following baseline assessments will be completed prior to the first dose of 
pembrolizumab: 
 Physical examination and vital signs, including ECOG performance status 
 Laboratory assessments and blood sampling: 
 Chemistry 


                                                                                                                                 
59 
 
 TSH, T3, FT4  
 Hematology: CBC and differential 
 Urine pregnancy test, if applicable 
 Correlative studies 
 Confirmation of Medical History 
 Assessment of AEs 
 Recording of concomitant medications 
Weeks 1, 2, 3 
Clinic/laboratory visits will occur every week through the Week 4 visit. The following 
procedures will be completed at each visit, unless otherwise specified: 
 Physical examination and vital signs, including ECOG performance status 
 Laboratory assessments and blood sampling: 
 Chemistry 
 Hematology: CBC and differential 
 Assessment of AEs 
 Recording of concomitant medications 
Weeks 4, 7, 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55, 58, 61, 64, 67, 
70, 73, 76, 79, 82, 85, 88, 91, 94, 97, 100, 103 
Subjects continuing on study past Week 4 will have visits every 3 weeks through Week 
49, and then at physician discretion. The following procedures will be completed at each 
visit, unless otherwise specified: 
 Physical examination and vital signs, including ECOG performance status 
 Laboratory assessments and blood sampling: 
 Chemistry 
 TSH, T3, FT4 (every 6 weeks) 
 Hematology: CBC and differential 


                                                                                                                                 
60 
 
 Assessment of adverse events 
 Recording of concomitant medications 
Weeks 13, 25, 37, 49, 61, 73, 85, 97 - Disease assessments  
 Bone marrow aspirate and biopsy for all patients with AML and MDS and B cell 
lymphoma patients with bone marrow involvement 
 Correlative studies  
 Radiology assessment (CT or CT/PET) for B cell lymphoma patients only 
8.1.6 POST-TREATMENT ASSESSMENTS 
8.1.6.1 
END OF TREATMENT VISIT 
If a subject permanently discontinues pembrolizumab, every attempt should be made to 
keep the subject in the study and continue to perform the required study-related follow-up 
and procedures. 
The following procedures will be completed at the time of study treatment 
discontinuation for patients who elect to discontinue or are required to discontinue study 
treatment prior to the end of the planned study duration: 
 Physical examination vital signs, including ECOG performance status 
 Laboratory assessments and blood sampling: 
 Chemistry 
 TSH, T3, FT4 
 Hematology: CBC and differential 
 Assessment of adverse events 
 Recording of concomitant medications 
 Assessment of disease status if disease progression is suspected. 
8.1.6.2 
END OF STUDY VISIT (WEEK 104-105) 
The following procedures will be completed at the end of study visit: 
 Physical examination vital signs, including ECOG performance status 
 Laboratory assessments and blood sampling: 


                                                                                                                                 
61 
 
 Chemistry 
 TSH, T3, FT4 
 Hematology: CBC and differential 
 Assessment of adverse events 
 Recording of concomitant medications 
8.1.6.3 
SAFETY FOLLOW-UP VISIT 
The mandatory safety follow-up visit should be conducted approximately 30 days after 
the last dose of pembrolizumab treatment or before the initiation of a new anti-cancer 
treatment, whichever comes first.  The safety follow-up visit can be done on the same day 
as the end of study visit (Section 8.1.6.2) or the end of treatment visit (Section 8.1.6.1). 
All AEs that occur prior to the safety follow-up visit should be recorded.  Subjects with 
an AE of grade > 1 will be followed until the resolution of the AE to grade 0-1, or until 
the beginning of a new 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.   
8.1.6.4 
FOLLOW-UP VISITS 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the follow-up phase and should be assessed every 12 weeks (+/- 7 days) to 
monitor disease status.  Every effort should be made to collect information regarding 
disease status until the start of new anti-cancer therapy, disease progression, death, or end 
of the study.  Information regarding post-study anti-cancer treatment will be collected if 
new treatment is initiated. 
8.1.6.4.1 
SURVIVAL FOLLOW-UP 
Once a subject experiences confirmed disease progression or starts a new antineoplastic 
therapy, the subject moves into the survival follow-up phase and should be contacted by 
telephone every 12 weeks to assess for survival status until death, withdrawal of consent, 
or the end of the study, whichever occurs first. 
 
ASSESSING AND RECORDING ADVERSE EVENTS 
The rate of subject entry and expansion will depend upon assessment of the safety profile 
of patients entered at the previous dose level. Toxicity will be evaluated according to the 
NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 (see 
Appendix E). If at least 5 of the first 12 patients complete pembrolizumab treatment 
without developing a DLT, we will open an expansion cohort to enroll with plans to 
enroll 14 additional patients should DLT-associated stopping rule not be met in the first 
12 patients. If at least 14 of the 26 patients remain DLT-free, we would have sufficient 


                                                                                                                                 
62 
 
evidence to warrant further study of pembrolizumab in a future trial. 
This particular safety stopping rule is based on the expected 50% rate of GVHD that has 
been reported to develop after DLI therapy 30. The inclusion of an expansion cohort will 
enable a further and more robust safety signal, as well as provide a larger cohort of 
patients in whom to assess clinical response, especially given the mixture of diseases that 
are being included in this study.  
8.2.1 DEFINITION OF AN OVERDOSE FOR THIS PROTOCOL AND 
REPORTING OF OVERDOSE TO THE SPONSOR 
For purposes of this trial, an overdose will be defined as any dose exceeding the 
prescribed dose for pembrolizumab will be defined as any dose of 1000 mg or greater. No 
specific information is available on the treatment of overdose of pembrolizumab. In the 
event of overdose, pembrolizumab should be discontinued and the subject should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be 
provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of pembrolizumab, 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
If a dose of pembrolizumab according to the definition of overdose is administered 
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 either by electronic media or paper.   
8.2.2 REPORTING OF PREGNANCY AND LACTATION 
Although pregnancy and lactation are not considered adverse events, it is the 
responsibility of investigators or their designees to report any pregnancy or lactation in a 
subject (spontaneously reported to them) that occurs during the trial or within 120 days of 
completing the trial or 30 days following cessation of treatment if the subject initiates 
new anticancer therapy, whichever is earlier.  All subjects who become pregnant 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 principal investigator and Merck 
either by electronic media or paper.   


                                                                                                                                 
63 
 
8.2.3 IMMEDIATE REPORTING OF ADVERSE EVENTS 
8.2.3.1 
SERIOUS ADVERSE EVENTS 
A serious adverse event is any adverse event occurring at any dose or during any use of 
pembrolizumab that: 
 Results in death; 
 Is life threatening; 
 Results in persistent or significant disability/incapacity; 
 Results in or prolongs an existing inpatient hospitalization; 
 Is a congenital anomaly/birth defect; 
 Is a new cancer (that is not a condition of the study); 
 Is associated with an overdose; 
 Is another important medical event  
Refer to Table 11 for additional details regarding each of the above criteria. 
Progression of the cancer under study is not considered an adverse event unless it results 
in hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, including death due to 
any cause other than progression of the cancer under study (reference Section 7.2.3.3 for 
additional details) that occurs to any subject from the time the consent is signed through 
90 days following cessation of treatment, or 30 days following cessation of treatment if 
the subject initiates new anticancer therapy, whichever is earlier, whether or not related to 
pembrolizumab, must be reported within 24 hours to the principal investigator and Merck 
either by electronic media or paper.   
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to pembrolizumab that is brought to the attention of the 
investigator at any time outside of the time period specified in the previous paragraph 
also must be reported immediately to the principal investigator and Merck.   
All subjects with serious adverse events must be followed up for outcome. 
8.2.3.2 
EVENTS OF CLINICAL INTEREST  
Selected non-serious and serious adverse events are also known as Events of Clinical 
Interest (ECI) and must be recorded as such on the adverse event case report 
forms/worksheets and reported within 24 hours to the principal investigator and Merck 


                                                                                                                                 
64 
 
either by electronic media or paper. 
Events of clinical interest for this trial include: 
1. an overdose of pembrolizumab, as defined in Section 8.2.1, that is not associated 
with clinical symptoms or abnormal laboratory results.  
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper 
limit of normal and an elevated total bilirubin lab value that is greater than or equal 
to 2X the upper limit of normal and, at the same time, an alkaline phosphatase lab 
value that is less than 2X the upper limit of normal, as determined by way of 
protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  The trial site guidance for 
assessment and follow up of these criteria can be found in the Investigator Trial File 
Binder (or equivalent). 
3. Early transplant-related events such as veno-occlusive disease (VOD) and steroid-
requiring febrile syndrome. 
A separate guidance document has been provided entitled “Event of Clinical Interest 
Guidance Document.”  This document can be found in the administrative binder and 
provides guidance regarding identification, evaluation and management of ECIs and 
irAEs.   
ECIs identified in this guidance document from the date of first dose through 90 days 
following cessation of treatment, or 30 days after the initiation of a new anticancer 
therapy, whichever is earlier need to be reported to the SPONSOR within 24 hours of the 
event consistent with standard SAE reporting guidelines and either by electronic media or 
paper.  Sponsor Contact information can be found in the administrative binder. 
Subjects should be assessed for possible ECIs prior to each dose.  Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an 
immune-related event.  Subjects who develop an ECI thought to be immune-related 
should have additional testing to rule out other etiologic causes.  If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be 
performed to rule out other etiologic causes.  If no other cause is found, then it is 
assumed to be immune-related. 
8.2.3.3 
PROTOCOL-SPECIFIC EXCEPTIONS TO SERIOUS ADVERSE 
EVENT REPORTING 
Efficacy endpoints as outlined in this section will not be reported as described in Section 
8.2.3, unless there is evidence suggesting a causal relationship between the drug and the 
event.  Any such event will be submitted to the principal investigator and Merck. 


                                                                                                                                 
65 
 
Specifically, the suspected/actual events covered in this exception include disease 
progression of the cancer during the study period.   
The principal investigator will monitor aggregated efficacy endpoint events and safety 
data to ensure the safety of the subjects in the trial.   
8.2.4 EVALUATING ADVERSE EVENTS 
A qualified investigator 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. 
Table 11. Evaluating adverse events 
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 pembrolizumab that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at 
immediate risk of death from the event as it occurred (Note: This does not include 
an adverse event that, had it occurred in a more severe form, might have caused 
death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial 
disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is 
defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: 
Hospitalization for an elective procedure to treat a pre-existing condition that has 
not worsened is not a serious adverse event.  A pre-existing condition is a clinical 
condition that is diagnosed prior to the use of a Merck product and is documented 
in the patient’s medical history.); or 


                                                                                                                                 
66 
 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product 
regardless of time to diagnosis);or 
 
Is a new cancer; (that is not a condition of the study) or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated 
with an overdose is considered a serious adverse event. An overdose that is not 
associated with an adverse event is considered a non-serious event of clinical 
interest and must be reported within 24 hours. 
 
Other important medical events that may not result in death, not be life 
threatening, or not require hospitalization may be considered a serious adverse 
event when, based upon appropriate medical judgment, the event may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed previously (designated above by a †). 
Duration 
Record the start and stop dates of the adverse event. If less than 1 day, indicate the 
appropriate length of time and units 
Action taken  
Did the adverse event cause pembrolizumab to be discontinued? 
Relationship to 
test drug  
Did pembrolizumab product cause the adverse event? The determination of the 
likelihood that pembrolizumab caused the adverse event will be provided by the 
investigator. 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 
pembrolizumab and the AE; the greater the correlation with the components and 
their respective elements (in number and/or intensity), the more likely 
pembrolizumab caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to 
pembrolizumab 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 
pembrolizumab? 
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 
Relationship 
The following components are to be used to assess the relationship between the test 
drug and the AE: (continued) 
pembrolizumab 
(continued)  
Dechallenge 
Was pembrolizumab discontinued or dose/exposure/frequency 
reduced? 
If yes, did the AE resolve or improve? 


                                                                                                                                 
67 
 
If yes, this is a positive dechallenge. If no, this is a negative 
dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in 
death or permanent disability; (2) the AE resolved/improved 
despite continuation of the Sponsor’s product; or (3) the trial is 
a single-dose drug trial); or (4) Sponsor’s product(s) is/are only 
used one time.) 
 
Rechallenge 
Was the subject re-exposed to pembrolizumab in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative 
rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE 
resulted in death or permanent disability, or (2) the trial is a 
single-dose drug trial); or (3) Sponsor’s product(s) is/are used 
only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN 
ADVERSE EVENT WHICH WAS SERIOUS AND WHICH 
MAY HAVE BEEN CAUSED BY THE SPONSOR'S 
PRODUCT, OR IF REEXPOSURE TO PEMBROLIZUMAB 
POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE SUBJECT, THEN THE RECHALLENGE MUST BE 
APPROVED 
IN 
ADVANCE 
BY 
THE 
PRINCIPAL 
INVESTIGATOR 
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 pembrolizumab or drug 
class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator 
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 pembrolizumab 
relationship). 
Yes, 
there 
is 
a 
reasonable 
possibility 
of 
pembrolizumab 
relationship. 
There is evidence of exposure to pembrolizumab.  The 
temporal sequence of the AE onset relative to the 
administration of pembrolizumab is reasonable.  The AE is 
more likely explained by pembrolizumab than by another 
cause. 
No, there is not a reasonable 
possibility 
of 
pembrolizumab 
relationship 
Subject did not receive pembrolizumab OR temporal sequence 
of 
the 
AE 
onset 
relative 
to 
administration 
of 
the 
pembrolizumab is not reasonable OR there is another obvious 
cause of the AE.  (Also entered for a subject with overdose 
without an associated AE.) 


                                                                                                                                 
68 
 
 
 
ADVERSE EVENT REPORTING REQUIREMENTS 
8.3.1 ROUTINE ADVERSE EVENT REPORTING 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
using the Serious Event Reporting Form and/or MedWatch Form discussed below 
must also be reported in routine study data submissions.   
8.3.2 SERIOUS ADVERSE EVENT REPORTING TO THE COORDINATING 
CENTER 
All serious adverse events (as defined in section 8.2.3.1) and all adverse events that have 
been specified to require expedited reporting in the section 8.2.3.2 occurring on this study 
require expedited reporting to the University of Chicago Comprehensive Cancer Center 
(UC CCC).  The responsible Research Nurse or other designated individual at the treating 
site should report the SAE to the Principal Investigator and the CCTO by the end of the 
business day when s/he becomes aware of the event.  Events occurring after business 
hours should be reported to the CCTO by 12pm (noon) the next business day.  Reports 
should be made using the ‘Serious Event Report’ Form.   
All unexpected adverse reactions must be reported to the IND holder so that the 
University of Chicago CCTO can inform the FDA.  The responsible Research Nurse or 
other designated individual at the treating site should provide a complete written report 
using the FDA MedWatch 3500A form.  The completed form should be sent to the 
CCTO at qaccto@bsd.uchicago.edu within the specified timelines below regardless of 
whether all information regarding the event is available.  If applicable, a follow-up report 
should be provided to the CCTO if additional information on the event becomes 
available.   
Study staff should not forward any adverse event reports directly to the FDA.  The CCTO 
will report all events to the FDA as per the current FDA guidelines.   
Fatal or Life-threatening Events: within 4 calendar days from treating investigator 
knowledge of the event 
All Other Reportable Events: within 10 calendar days of treating investigator 
knowledge of the event 
All serious adverse events should also be reported to the local IRB of record according to 
their policies and procedures.   
 
TRIAL GOVERNANCE AND OVERSIGHT 
8.4.1 DATA MONITORING COMMITTEE 
The principal investigator will ensure that trial is conducted and data are generated, 


                                                                                                                                 
69 
 
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. The trial will specifically be evaluated by the 
principal investigator after the first 12 patients are enrolled to assess if the trial should be 
continued. 
A quality assurance audit/inspection of this study may be conducted by regulatory 
authorities. The quality assurance auditor will have access to all medical records, the 
investigator’s study-related files and correspondence, and the informed consent 
documentation of this clinical study.  
9.0 
STATISTICAL ANALYSIS PLAN 
 
STATISTICAL ANALYSIS PLAN SUMMARY 
This section contains a brief summary of the statistical analysis for this trial. Full details 
can be found in the statistical analysis plan (SAP) in Section 8.2. 
9.1.1 SAFETY ANALYSES 
The study will initially enroll 12 patients in the first stage of the two-stage trial design. 
The accrual rate will be 1 patient/month in relapsed/refractory myeloid and B cell 
malignancies following allogeneic stem cell transplant to assess the safety and feasibility 
of pembrolizumab. If at least 5 of the first 12 patients complete pembrolizumab treatment 
without developing a DLT, we will open an expansion cohort to enroll with plans to 
enroll 14 additional patients should DLT-associated stopping rule not be met in the first 
12 patients.  Specifically, if 5 or more of the first 12 enrolled patients develop a DLT, 
including grade 3-4 GHVD, then the study will be halted.  If at least 14 of the 26 patients 
remain DLT-free, we would have sufficient evidence to warrant further study of 
pembrolizumab in a future trial.  Furthermore, if severe GVHD (grade 3-4) develops 
within the first 90 days of pembrolizumab treatment in each of the first 5 patients treated 
on the study (i.e. develop a DLT), it will be permanently closed to accrual as a measure to 
ensure safety. 
Toxicity will be graded per the CTCAE guidelines and the maximally tolerated dose will 
be defined a less or equal than 1 in 6 patients with DLTs. All patients who receive any 
amount of the study drug will be evaluable for toxicity. 
9.1.2 EFFICACY ANALYSES 
The intention-to-treat population, defined as subjects who received at least one dose of 
pembrolizumab, will serve as the primary analysis population in this study. The primary 
efficacy endpoint is the overall response rate (ORR), defined as those patients who 
achieve a PR or CR (lymphoma), PR or CR (MDS), or a CR, CRp, CRi or PR (AML).  
Secondary efficacy endpoints include duration of response (DOR) and overall survival 
(OS). 


                                                                                                                                 
70 
 
An outline of the efficacy analysis strategy is shown in Table 12 below.   
Table 12. Primary analysis strategy for efficacy endpoints 
Endpoint/Variable 
(Description, Time 
Point) 
Statistical Method 
Analysis 
Population 
Missing 
Data 
Approach 
Primary: 
Overall response 
rate (ORR) using  
defined criteria 
Exact test of binomial 
parameter 
ITT 
Subjects 
with 
missing data 
are 
considered 
non-
responders 
Secondary: 
Duration of 
response (DOR) 
Summary statistics 
using Kaplan-Meier 
method 
All 
responders 
Non-
responders 
are 
excluded in 
analysis 
Overall survival 
(OS) 
Summary statistics 
using Kaplan-Meier 
method 
ITT 
Censored at 
last 
assessment 
 
9.1.3 INTERIM ANALYSIS 
After the first 12 patients have been enrolled and have received at least 1 dose of 
pembrolizumab, an interim safety analysis will be performed.  If < 5 of the first 12 
patients develop a DLT (including grade 3-4 acute GVHD) following pembrolizumab 
treatment, an expansion cohort of 14 additional patients will be enrolled in order to obtain 
a more robust safety signal, as well as to enhance numbers of treated patients for efficacy 
analyses, given that patients with a wide variety of hematological malignancies will be 
enrolled.  However, if  ≥ 5 of the first 12 enrolled patients develop a DLT, then the study 
will be permanently closed to accrual. Furthermore, if severe GVHD (grade 3-4) 
develops in each of the first 5 patients treated on the study, it will be permanently closed 
to accrual as a measure to ensure safety. 
 
STATISTICAL ANALYSIS PLAN 
9.2.1 HYPOTHESES 
The objectives and hypotheses of the study are stated in Section 3. 


                                                                                                                                 
71 
 
9.2.2 ANALYSIS ENDPOINTS 
9.2.2.1 
SAFETY ENDPOINTS 
Safety measurements are described in Section 8. 
9.2.2.2 
EFFICACY ENDPOINTS 
Efficacy endpoints that will be evaluated for are listed below. 
The primary efficacy endpoint is the overall response rate (ORR), defined as the 
proportion of subjects in the analysis population who achieve at least a partial response to 
pembrolizumab. Specifically, for B cell lymphoma patients, partial and complete 
responses will be defined according to the International Working Group criteria 39 
(Appendix). For MDS patients, partial and complete responses (including cytogenetic 
responses) will be defined according to the International Working Group criteria 40. 
Lastly, for AML patients, complete (including CR, CRp, CRi), and partial responses will 
be defined according to the European Leukemia Net response criteria (Appendix) 41. 
9.2.3 ANALYSIS POPULATION 
9.2.3.1 
SAFETY ANALYSIS POPULATION 
The All Patients as Treated (APaT) population will be used for the analysis of safety data 
in this study. The APaT population consists of all enrolled subjects who received at least 
1 dose of study treatment. At least one laboratory or vital sign measurement obtained 
subsequent to at least one dose of trial treatment is required for inclusion in the analysis 
of each specific parameter. To assess change from baseline, a baseline measurement is 
also required. 
9.2.3.2 
EFFICACY ANALYSIS POPULATION 
The analysis of primary efficacy endpoints are based on the intention-to-treat (ITT) 
population, i.e., subjects will be included if they receive at least one dose of study 
medication.  
9.2.4 STATISTICAL METHODS 
9.2.4.1 
STATISTICAL METHODS FOR TOLERABILITY ANALYSES 
The trial will feature a two-stage minimax trial design (Simon 1989, A’hern, 2001) which 
tests for futility in a smaller sample of patients before proceeding with treatment of the 
full cohort. The accrual rate will be 1 patient/month in relapsed/refractory myeloid and B 
cell malignancies following allogeneic stem cell transplant to assess the safety and 
feasibility of pembrolizumab. The primary outcome is whether the patient remains DLT-
free at the end of treatment.  A priori, we expect 40% or fewer patients on an unsafe 
treatment would finish without experiencing a DLT, and at least 65% of patients would 
be DLT-free on a safe treatment. For α = 0.05 and 80% power, we would need to observe 


                                                                                                                                 
72 
 
at least 5 DLT-free treatments out of a small sub-sample of 12 patients before we would 
consider evaluating pembrolizumab in the full sample of 26 patients. If at least 14 of the 
26 patients respond remain DLT-free, we would have sufficient evidence to warrant 
further study of pembrolizumab in a future trial.  
9.2.4.2 
STATISTICAL METHODS FOR EFFICACY ANALYSES 
9.2.4.2.1 
OVERALL RESPONSE RATE (ORR) 
ORR will be summarized as a proportion. ORR will depend on the tumor type, and we 
will analyze for HL NHL, MDS, and AML individually, acknowledging that the numbers 
will be small. Descriptive statistics will be used to test the hypothesis that the ORR 
exceeds 10%. 
9.2.4.2.2 
DURATION OF RESPONSE (DOR) 
DOR will be summarized using a Kaplan-Meier survival curve.  
9.2.4.2.3 
OVERALL SURVIVAL (OS) 
OS will be summarized using a Kaplan-Meier survival curve.  
10.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
 
INVESTIGATIONAL PRODUCT 
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution and 
usage of investigational product in accordance with the protocol and any applicable laws 
and regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 13. 
Table 13. Product description 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/4mL 
Solution for Injection 
 
 
PACKAGING AND LABELING INFORMATION 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. Subjects will receive open label pembrolizumab (MK-3475) vials. 


                                                                                                                                 
73 
 
 
CLINICAL SUPPLIES DISCLOSURE 
This trial is open-label.  
 
STORAGE AND HANDLING REQUIREMENTS 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.  Receipt and dispensing of trial medication must be 
recorded by an authorized person at the trial site. Clinical supplies may not be used for 
any purpose other than that stated in the protocol. 
 
DISCARD/DESTRUCTION/RETURNS AND RECONCILIATION 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from the sponsor, the amount dispensed to and returned by the subjects and the 
amount remaining at the conclusion of the trial. Where local discard and destruction is 
appropriate, the investigator is responsible for ensuring that a local discard/destruction 
procedure is documented. 
11.0 
ADMINISTRATIVE AND REGULATORY DETAILS 
 
CONFIDENTIALITY 
11.1.1 CONFIDENTIALITY OF DATA 
All study records will be maintained in confidence, and such information will be divulged 
to the institutional review board, ethics review committee (IRB/ERC) or similar or expert 
committee; affiliated institution and employees, only under an appropriate understanding 
of confidentiality with such board or committee, affiliated institution and employees.  
Data generated by this trial will be considered confidential by the investigator, except to 
the extent that it is included in a publication as provided in the Publications section of this 
protocol. 
11.1.2 CONFIDENTIALITY OF SUBJECT RECORDS 
The study team, Merck, 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 any party outside of the coordinating site. All subject data will be used 
and disclosed in connection with this trial in accordance with all applicable privacy laws, 
rules and regulations. 
 
OBLIGATIONS OF SITE INVESTIGATOR 
The Principal Investigator is responsible for the conduct of the clinical trial at the site in 
accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 


                                                                                                                                 
74 
 
Helsinki.  The Study Site Principal Investigator is responsible for personally overseeing 
the treatment of all study patients.  He/she must assure that all study site personnel, 
including sub-investigators and other study staff members, adhere to the study protocol 
and all FDA/GCP/NCI regulations and guidelines regarding clinical trials both during 
and after study completion. 
The Principal Investigator will be responsible for assuring that all the required data will 
be collected and entered into the CRFs. Periodically, monitoring visits or audits will be 
conducted and he/she must provide access to original records to permit verification of 
proper entry of data.  
 
AUDITING 
The University of Chicago Comprehensive Cancer Center will perform routine Quality 
Assurance Audits of investigator-initiated clinical trials as described in the NCI-approved 
UC CCC DSM Plan. Audits provide assurance that trials are conducted and study data are 
collected, documented and reported in compliance with the protocol. Further, quality 
assurance audits ensure that study data are collected, documented and reported in 
compliance with Good Clinical Practices (GCP) Guidelines and regulatory requirements. 
The audit will review subjects enrolled at the University of Chicago in accordance with 
audit procedures specified in the UC CCC Data and Safety Monitoring plan.  
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, 
during its conduct or even after its completion. If an inspection has been requested by a 
regulatory authority, the site investigator must immediately inform the University of 
Chicago Cancer Clinical Trials Office and Regulatory Manager that such a request has 
been made. 
 
DATA MANAGEMENT 
The investigator or qualified designee is responsible for recording and verifying the 
accuracy of subject data.   
 
PUBLICATION 
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.   
12.0 
APPENDICES 
 


 
 
 
 
 
 
75 
 
 
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. 
 
 
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) 
 
RESPONSE EVALUATION OF HODGKIN AND NON-HODGKIN LYMPHOMA.  
Response Evaluation of Hodgkin and non-Hodgkin lymphoma will occur via the 2007 
International Working Group criteria (Cheson et al.); MDS response evaluation by 
International Working Group (IWG) criteria (Cheson et al.); AML evaluation via an 
international expert panel, on behalf of the European LeukemiaNet (Dohner et al.) (43-45). 


 
 
 
 
 
 
76 
 
12.3.1 CRITERIA FOR LYMPHOMA DISEASE ASSESSMENT 
 
 
 
 
INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS) FOR MDS 
PROGNOSTIC VARIABLE 
       Survival and MDS Evolution Score Value  
 
 


 
 
 
 
 
 
77 
 
 
MDS RESPONSE CRITERIA:  
Modified International MDS Working Group (IWG) Criteria for Measurement of 
Response/Treatment Effect in MDS will be used to assess response.  
12.5.1 COMPLETE REMISSION (CR)  
Bone marrow evaluation: Bone marrow showing < 5% myeloblasts with normal maturation 
of all cell lines, with no evidence for dysplasia (see dysplasia qualifier under peripheral blood 
evaluation). When erythroid precursors constitute < 50% of bone marrow nucleated cells, the 
percent of blasts is based on all nucleated cells; when there are ≥ 50% erythroid cells, the 
percent blasts should be based on the non-erythroid cells.  
 Peripheral Blood Counts (Absolute values must last ≥ 8 weeks). 
 Hemoglobin greater than 11 g/dL.  
 Neutrophils 1500/mm3 or more (not on a myeloid growth factor).  
 Platelets 100 000/mm3 or more (not on a thrombopoetic agent).  
 Blasts ≤ 5%.  
 No dysplasia. The presence of mild megaloblastoid changes may be permitted if they 
are thought to be consistent with treatment effect. However, persistence of 
pretreatment abnormalities (e.g., pseudo-Pelger Huet cells, ringed sideroblasts, 
dysplastic megakaryocytes) is not consistent with CR.  
12.5.2 PARTIAL REMISSION (PR)  
 All of the CR criteria (if abnormal prior to treatment), except:  
 Bone marrow evaluation: Blasts decreased by 50% over pretreatment, or a less 
advanced MDS WHO classification than pretreatment. Cellularity and morphology 
are not relevant.  
12.5.3 STABLE DISEASE  
Failure to achieve at least a PR, but with no evidence of progression for ≥ 2 months.  
12.5.4 FAILURE  
Death during treatment or disease progression characterized by worsening of cytopenias, 
with increase in the percent of bone marrow blasts (as defined in Section 6 below), and/or 
progression to an MDS FAB subtype more advanced than pretreatment.  


 
 
 
 
 
 
78 
 
12.5.5 RELAPSE (FOLLOWING A CR OR PR)  
One or more of the following:  
 Return to pretreatment bone marrow blast percentage. 
 Decrement of > 50% from maximum remission response levels in neutrophils or 
platelets  
 RBC transfusion dependence (≥ 2 units RBC transfusions over an 8 week period) or a 
reduction in hemoglobin concentration by ≥ 2 g/dL in the absence of acute infection, 
gastrointestinal bleeding, hemolysis, treatment hiatus etc. 
12.5.6 DISEASE PROGRESSION  
 A 50 % increase in blasts, depending on baseline blast percent.  
 For patients with < 5% blasts: increase to ≥ 10% blasts.  
 For patients with 5% to 10% blasts: ≥ 50% increase to > 10% blasts.  
 For patients with 10% to 20% blasts: ≥ 50% increase to ≥ 20% blasts.  
12.5.7 DISEASE TRANSFORMATION  
 Transformation to AML (≥ 20% blasts).  
12.5.8 CYTOGENETIC RESPONSE  
Requires 20 analyzable metaphases when using conventional techniques. Analysis of data 
will require 20 metaphases before and after treatment, which must be done on bone marrow 
only (peripheral blood is not a substitute). Fluorescent in situ hybridization (FISH) may be 
used as a supplement to follow a specifically defined cytogenetic abnormality, but it is not a 
substitute for conventional cytogenetic studies. Cytogenetic response is defined as follows:  
12.5.8.1 
COMPLETE CYTOGENETIC RESPONSE:  
Restoration of a normal karyotype in patients with a documented pre-existing clonal (>2 
metaphases abnormal) chromosome abnormalities.  
12.5.8.2 
PARTIAL RESPONSE:  
 50% reduction in the percentage of Hematologic Improvement.  
 Improvements must last ≥ 8 consecutive weeks.  
12.5.8.3 
ERYTHROID RESPONSE  
Major Erythroid Response: Transfusion-independence for ≥ 8 consecutive weeks for patients 


 
 
 
 
 
 
79 
 
who were RBC transfusion-dependent at baseline AND a ≥ 1 g/dL hemoglobin rise 
compared to mean pre-transfusion baseline value; or a > 2 g/dL rise in hemoglobin without 
transfusion for non-transfusion dependent patients.  
Minor Erythroid Response: The mean hemoglobin is sustained 1.0 to 2.0 g/dL above the 
baseline value for a minimum of 8 weeks; or a 50% or greater decrease in 8-week RBC 
transfusion requirements compared to baseline.  
12.5.8.4 
PLATELET RESPONSE  
Major Platelet Response: For patients with a pretreatment count < 100,000/mm3, an absolute 
increase of ≥ 30,000/mm3; for platelet transfusion-dependent patients, stabilization of 
platelet counts and platelet transfusion independence.  
Minor Platelet Response: For patients with a pretreatment platelet count < 100,000/mm3, a > 
50% increase in platelet count with a net increase > 10,000/mm3 but < 30,000/mm3. 
12.5.8.5 
NEUTROPHIL RESPONSE  
Major Neutrophil Response: For pretreatment ANC < 1500/mm3, ≥ 100% increase, or an 
absolute increase of ≥ 500/mm3, whichever is greater.  
Minor Neutrophil Response: For ANC > 1500/mm3 before therapy, ANC increase of at least 
100%, but absolute increase less than 500/mm3, lasting greater than 8 weeks (56 days).  
12.5.8.6 
PROGRESSION/RELAPSE FOLLOWING ERYTHROID 
HEMATOLOGIC IMPROVEMENT  
For patients who achieve RBC transfusion independence: requirement for ≥ 2 units RBC 
transfusion in an 8 week period or a reduction in hemoglobin concentration by ≥ to 2 g/dL in 
the absence of acute infection, gastrointestinal bleeding, hemolysis, etc., reaching a 
hemoglobin < 9.5 g/dL. 
For patients who achieve ≥ 50% decrease in RBC transfusions: return to pre-treatment RBC 
transfusion requirement over an 8 week period.  
12.5.8.7 
DURATION OF RESPONSE  
Time to disease progression (as per Bone Marrow Responses above) or progression/relapse 
following hematologic improvement (as per Hematologic Improvement above). 
 
IDENTIFICATION AND FOLLOW-UP OF LESIONS IN AML 
12.6.1 COMPLETE REMISSION (CR) 
For subjects to be classified as being in CR, they must have bone marrow regenerating 
normal hematopoietic cells and achieve a morphologic leukemia-free state (<5% bone 
marrow blasts in bone marrow, no blasts with Auer rods and no persistence of 
extramedullary disease) and must have an ANC ≥1 × 109/L and platelet count >100 × 109/L 


 
 
 
 
 
 
80 
 
and they will be RBC and platelet transfusion independent (defined as 4 weeks without RBC 
transfusions and 1 week without platelet transfusion). 
12.6.2 COMPLETE REMISSION WITH INCOMPLETE PLATELET RECOVERY 
(CRP) 
For subjects to be classified as being in CRp, they must achieve CR except for incomplete 
platelet recovery (<100 × 109/L). 
12.6.3 COMPLETE REMISSION WITH INCOMPLETE HEMATOLOGICAL 
RECOVERY (CRI) 
For subjects to be classified as being in CRi, they must fulfill all the criteria for CR except 
for incomplete hematological recovery with residual neutropenia <1 × 109/L and/or platelet 
count >100 × 109/L. RBC and platelet transfusion independence is not required. 
12.6.4 PARTIAL REMISSION (PR) 
For subjects to be classified as being in PR, they must meet the criteria for CRi but only 
require a decrease of at least 50% in the percentage of blasts in the bone marrow with the 
total marrow blasts between 5% and 25% inclusive. 
12.6.5 RELAPSE 
Relapse after CR, CRp, or CRi is defined as a reappearance of leukemic blasts in the 
peripheral blood or ≥5% blasts in the bone marrow aspirate or biopsy not attributable to any 
other cause or reappearance or new appearance of extramedullary leukemia. Relapse after PR 
is similarly defined with reappearance of significant numbers of peripheral blasts and an 
increase in the percentage of blasts in the bone marrow aspirate to >25% not attributable to 
any other cause or reappearance or new appearance of extramedullary leukemia. 
12.6.6 DEFINITIVE PROGRESSION 
NHL, HL, MDS, and AML response and progression data will be subjected to IRC review. 
The subject should continue on study pending confirmation of progression by the IRC.  


 
 
 
 
 
 
81 
 
12.6.7 ACUTE GVHD GRADING 42  
The Gluckenberg scale will be used to grade and stage acute GVHD. 
 
 
 


 
 
 
 
 
 
82 
 
 
13.0 
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