Phase II Study of Pembrolizumab and Fractionated External Beam Radiotherapy in Patients With Relapsed and Refractory Non-Hodgkin Lymphoma
Phase: PHASE2
Conditions: Primary Mediastinal (Thymic) Large B-Cell Lymphoma, Recurrent Aggressive Non-Hodgkin Lymphoma, Recurrent Mature T- Cell and NK-Cell Non-Hodgkin Lymphoma, Recurrent Non-Hodgkin Lymphoma, Recurrent T-Cell Non-Hodgkin Lymphoma, Recurrent Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma, Refractory Aggressive Non-Hodgkin Lymphoma, Refractory Non-Hodgkin Lymphoma, Refractory T-Cell Non-Hodgkin Lymphoma, Refractory Transformed Follicular Lymphoma to Diffuse Large B-Cell Lymphoma, Transformed Marginal Zone Lymphoma to Diffuse Large B-Cell Lymphoma
Sponsor: M.D. Anderson Cancer Center

MD Anderson Protocol Number: 2017-0341
[2017-0341]
Version [13] Version Date [09/24/2021]
PROTOCOL TITLE: Phase II Study of Pembrolizumab and Fractionated External Beam Radiotherapy in Patients with 
Relapsed and Refractory Non-Hodgkin Lymphoma
Protocol Number:  2017-0341
ClinicalTrials.gov Identifier:  NCT03210662
Principal Investigator:  Chelsea Pinnix
Version Number:  13
Date:  09/24/2021
CONFIDENTIALITY STATEMENT 
This document is confidential communication. Acceptance of this document constitutes agreement by the recipient 
that no unpublished information contained herein will be published or disclosed without prior approval of the Principal 
Investigator.

 
 
 
 
Phase II Study of Pembrolizumab and Fractionated External Beam Radiotherapy in 
Patients with Relapsed and Refractory Non-Hodgkin Lymphoma 
 
 
 
Principal Investigator 
Chelsea C. Pinnix MD, PhD 
Associate Professor 
Department of Radiation Oncology 
Hematologic Malignancies Section 
The University of Texas MD Anderson Cancer Center 
1515 Holcolmbe Blvd. 
Houston, TX 77030 
USA 
 
 
 
 
 
 
Table of Contents 
 
 
 
 
 
 
 
 
 
Page 
1. Trial Summary 
 
 
 
 
 
2 
2. Trial Design  
 
 
 
 
 
3 
3. Objectives and Hypotheses 
 
 
 
 
5 
4. Background and Rationale 
 
 
 
 
6 
5. Methodology  
 
 
 
 
 
18 
6. Trial Flow Chart 
 
 
 
 
 
35 
7. Trial Procedures 
 
 
 
 
 
39 
8. Statistical Analysis Plan 
 
 
 
 
60 
9. Administrative and Regulatory Details 
 
 
69 
10. Appendices 
 
 
 
 
 
11. References 
 
 
 
 
 
 
73 
 

 
 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Pembrolizumab (MK-3475) and radiation for relapsed and refractory Non-
Hodgkin Lymphoma 
Trial Phase 
II 
Clinical Indication 
Refractory Non-Hodgkin Lymphoma  
Trial Type 
Treatment (Interventional)  
Type of control 
Historical Control 
Route of administration 
Intravenous and external beam radiation 
Trial Blinding 
Unblinded, open label 
Treatment Groups  
MK-3475 200 mg every 21 days with concurrent  External beam radiation 
therapy (EBRT) 
Number of trial subjects 
21 
Estimated enrollment period 
20 months 
Estimated duration of trial 
48 months 
Duration of Participation 
1.5 years 
Estimated average length of 
treatment per patient 
24 months 
 
 
 
 
2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a single center, open label, unblinded phase II trial to determine the efficacy of 
concurrent MK-3475 administered at a dose of 200 mg every 21 days with concurrent 
low to moderate dose external beam radiation therapy (EBRT) to 1-2 lesions in patients 
with relapsed and refractory Non-Hodgkin Lymphoma (NHL).  Patients with NHL that 
have failed 2 or more lines of therapy (including autologous stem cell transplant) or are 
not candidates for additional cytotoxic chemotherapy are eligible if they have 1-2 lesions 
amenable to EBRT.  This phase II trial will evaluate the efficacy and safety of systemic 
MK-3475 administered concurrently with low to moderate dose EBRT.  Pembrolizumab 
will be given at a fixed dose of 200 mg to be administered intravenously every 21 days for 
up to 24 months (total of 35 infusions).  Adverse events (AE) will be monitored 
throughout the trial and severity grading will be performed according to the NCI 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.  Response to 
therapy will be assessed according to the Recommendation for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The 
Lugano Classification 1.   
Treatment with Pembrolizumab will continue until documented progression of disease, 
unacceptable AE(s), intercurrent illness that prevents continuation with therapy, 
withdrawal of consent by the patient or investigator, non-compliance with treatment 
requirements, administrative reasons or completion of all 35 infusions.   Upon completion 
of therapy, each patient will be monitored for 30 days and 90 days for AE and serious 

 
 
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Hypotheses:  Combination therapy with MK-3475 and EBRT will result in clinically 
meaningful CRR, PFS, and OS rates.  Combination therapy with MK-3475 and EBRT is 
safe. 
3.3 
Exploratory Objectives and Hypotheses 
1) Objective: To identify tumor and peripheral blood markers predictive of response to 
concurrent Pembrolizumab and low to moderate dose EBRT in the setting of relapsed 
and refractory NHL. 
2) Objective: To determine if a course of hypo-fractionated EBRT can improve 
response after progressive disease among patients treated with fractionated EBRT and 
Pembrolizumab. 
 
Hypotheses: Hypo-fractionated EBRT and MK-3475 will result in disease response 
when tumor progression occurs with Pembrolizumab and fractionated EBRT. 
 
 
4.0 BACKGROUND & RATIONALE 
4.1 
Background 
4.1.1 Pharmaceutical and Therapeutic Background 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody 
(mAb) with high specificity of binding to the programmed cell death 1 (PD-1) receptor, thus 
inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell 
death ligand 2 (PD-L2).  Based on preclinical in vitro data, pembrolizumab has high affinity 
and potent receptor blocking activity for PD-1.  Pembrolizumab has an acceptable preclinical 
safety profile and is in clinical development as an intravenous (IV) immunotherapy for 
advanced malignancies.  Keytruda® (pembrolizumab) is indicated for the treatment of 
patients across a number of indications because of its mechanism of action to bind the PD-1 
receptor on the T cell.  For more details on specific indications refer to the Investigator 
brochure. 
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.  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, 

 
 
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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 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. As a consequence, the PD-1/PD-L1 pathway is an attractive target for therapeutic 
intervention in relapsed or refractory Non-Hodgkin Lymphoma.   PD-1 was shown to be 
expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-cells, T 
regs and Natural Killer cells.  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 (MEL).  This suggests that the PD-1/PD-L1 pathway plays a critical 
role in tumor immune evasion and should be considered as an attractive target for therapeutic 
intervention. 
Pembrolizumab is a potent and highly selective humanized monoclonal antibody (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 been approved in the United Stated for 
the treatment of patients with unresectable or metastatic melanoma and disease progression 
following ipilumumab and, if BRAF V600 mutation positive, a BRAF inhibitor.  Recently in 
March 2017, the Food and Drug Administration (FDA) granted accelerated approval for 
pembrolizumab for pediatric and adult patients with relapsed or refractory classical Hodgkin 
lymphoma (HL) who have progressive disease after 3 or more lines of therapy.   
4.1.2 Preclinical and Clinical Trial Data 
P001 is an open-label, Phase I, first-in-human (FIH) study of IV MK-3475 in subjects with 
progressive locally advanced or metastatic carcinomas, especially melanoma or NSCLC. Part 

 
 
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A of the study involved dose escalation that used a traditional 3+3 design. Cohorts of 3 to 6 
subjects were enrolled sequentially at escalating doses of 1, 3, or 10 mg/kg administered Q2W. 
Once the dose escalation was completed, additional subjects were enrolled into Parts A1 and 
A2 to further characterize the PK and pharmacodynamics of pembrolizumab. In Parts B and 
D, subjects with metastatic melanoma were enrolled to assess the safety and antitumor activity 
of pembrolizumab. Additionally, Part B explored 3 different dose regimens in subjects with 
metastatic melanoma: 10 mg/kg Q2W, 10 mg/kg Q3W, and 2 mg/kg Q3W. In Part C, subjects 
with NSCLC (with prior systemic therapy) were enrolled at 10 mg/kg Q3W to assess the 
tolerability, safety, and antitumor activity of pembrolizumab in NSCLC. In Part F, subjects 
with NSCLC in Cohort F-1 (without prior systemic therapy) and Cohort F-2 (with prior 
systemic therapy), whose tumors expressed PD-L1, were enrolled at 10 mg/kg Q2W and 10 
mg/kg Q3W to characterize the tolerability, safety, and antitumor activity of pembrolizumab. 
A small cohort of previously treated subjects with NSCLC and at least 2 lines of systemic 
therapy, whose tumors did not express PD-L1, were enrolled and treated at a dose of 10 mg/kg 
Q2W in Cohort F-2. In Cohort F-3, previously treated subjects with NSCLC whose tumors 
express PD-L1 were enrolled at 2 mg/kg Q3W to better characterize the efficacy, safety, and 
antitumor activity of pembrolizumab. Each of the 2 disease specific cohorts (melanoma and 
NSCLC) were enrolled to confirm tolerability and evaluate tumor response to pembrolizumab.  
The overall response rates for pembrolizumab treatment in P001 compared favorably to 
historical response rates for available treatments for melanoma, particularly in subjects who 
have progressed after multiple prior therapies (Investigator’s Brochure, Version 10, August 
31, 2015). 
The primary efficacy endpoint of P001 is ORR. A secondary efficacy endpoint is disease 
control rate (DCR). The efficacy analysis was based upon the All Patients as Treated (APaT) 
population—all subjects who received at least 1 dose of study treatment and may or may not 
have had measurable disease at baseline per independent central review. For subjects without 
measurable disease at baseline, a partial response was not possible (even if there was a 
reduction in tumor burden) per RECIST 1.1, and non–complete response (CR)/non–
progressive disease (PD) was equivalent to stable disease (SD) in subjects with measurable 
disease at baseline. The ORR and DCR analysis for 655 melanoma subjects who received 
pembrolizumab in Parts B1, B2, B3, and D, regardless of prior exposure to IPI and across all 
dose levels tested, is displayed in Table 30. Overall there were 44 complete responses and 159 
partial responses. The ORR was 31% (95% CI: 28% to 35%). DCR was achieved in 51% of 
all subjects. 
P002 is a partially blinded, randomized, Phase II pivotal study of pembrolizumab 2 mg/kg 
Q3W and 10 mg/kg Q3W versus investigator-choice (standard-of-care) chemotherapy in a 
1:1:1 ratio in subjects with IPI-refractory metastatic melanoma.  There are 2 co-primary 
efficacy endpoints for this study: progression-free survival (PFS) and overall survival (OS). A 
secondary efficacy endpoint is ORR.  The data cutoff date for efficacy events included in the 
efficacy analysis was 12-May-2014.  The analysis was based upon the Intention-to-Treat (ITT) 
population – subjects were included in the treatment group to which they were randomized. A 
primary censoring rule, which censored at the last disease assessment without PD, when PD 
or death was documented after more than 1 missed disease assessment, was applied for the 
analysis.  The hazard ratio was 0.57 and 0.50 in the pembrolizumab 2 mg/kg Q3W arm and 10 
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(the one-sided p-value was <0.0001  in both comparisons). This met prespecified criteria for a 
positive study.  The PFS rate at Month 6 was 34.3% (95% CI: 27.4 to 41.3%) and 37.7% (95% 
CI: 30.6% to 44.8%) for pembrolizumab 2 mg/kg and 10 mg/kg, respectively, versus 15.6% 
(95% CI: 10.5% to 21.5%) for the control arm. The median PFS was 2.9 months in both 
pembrolizumab arms and 2.7 months in the control arm.  The PFS data show that 
administration of pembrolizumab (both dose regimens) resulted in a clinically meaningful 
improvement in PFS versus treatment with chemotherapy.  The ORR per RECIST 1.1 by IRO 
is shown in Table 32: 21% in the pembrolizumab 2 mg/kg arm, 25% in the 10 mg/kg arm, and 
4% in the chemotherapy arm (p<0.0001 for each pembrolizumab dose versus chemotherapy).  
A preliminary analysis of OS indicated that the hazard ratio was 0.88 in the pembrolizumab 2 
mg/kg Q3W arm over the control arm and 0.78 in the pembrolizumab 10 mg/kg Q3W arm over 
the control arm. The one-sided p-value was 0.229 and 0.066 in 2 mg/kg Q3W and 10 mg/kg 
Q3W over the control arm, respectively, both favoring pembrolizumab. The pre-specified final 
analysis of OS will be performed after 370 deaths have occurred. 
 
Efficacy data are available for a total of 655 P001 melanoma subjects treated with 
pembrolizumab and 540 P002 melanoma subjects treated with either pembrolizumab or 
chemotherapy. The data cutoff dates are 18-Apr-2014 for P001 melanoma subjects and 12-
May-2014 for P002 subjects.  For both clinical studies, assessment of overall response rate 
(ORR) was based on RECIST 1.1 and performed by blinded central reviewers. 
The P001 overall response rate (ORR) demonstrated the antitumor activity of pembrolizumab 
in subjects with melanoma (ipilimumab-naïve and previously treated with ipilimumab). 
P002 demonstrated superior PFS for both pembrolizumab treatment arms compared to the 
chemotherapy control arm. Treatment with pembrolizumab lead to an ORR that was >4 fold 
higher than the response rate of the chemotherapy control arm. This difference was highly 
statistically significant, with a one sided p-value of <0.0001.  The overall response rates for 
pembrolizumab treatment in P001 and P002 compared favorably to historical response rates 
for available treatments for melanoma, particularly in subjects who had progressed after 
multiple prior therapies. For example, the largest randomized clinical trial in previously treated 
advanced melanoma subjects, in which carboplatin and paclitaxel were used in the control arm, 
and sorafenib plus carboplatin and paclitaxel in the experimental arm, produced a response rate 
of 11% and 12%, respectively. 
 
The approval for pembrolizumab among patients with relapsed and refractory HL was based 
on the KEYNOTE 087 trial, a nonrandomized, open-label study of 210 patients with refractory 
HL or relapsed disease after 3 or more prior lines of therapy.  The ORR for pembrolizumab 
was 69% (95% CI 62-75) at a median follow up of 9.4 months.  Of these overall responses, 
complete responses were reported among 22% of patients and partial responses on 47%.  
Among the 145 responding patients, the median duration of response was 11.1 months (range 
0+ to 11.1).  The median number of prior therapies was 4 (range of 1-12). Serious adverse side 
effects were reported in 16% of patients (most frequently pneumonia, Graft versus host disease 
(GVHD), herpes zoster, pyrexia, pneumonitis and dyspnea).  Corticosteroids were required for 
adverse reactions in 15% of patients.  Two patient deaths occurred that were unrelated to 
disease in a patient that died of  septic shock and a patient that died of GVHD after undergoing 
subsequent allogeneic hematopoietic stem cell transplantation.   
 

 
 
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In regards to patients with non-Hodgkin lymphoma and other hematologic malignancies, there 
are two ongoing trials evaluating the safety and efficacy of pembrolizumab among patients 
with hematologic malignancies.  The P013 trial is a Phase Ib, Multi-Cohort Trial of MK-3745 
in patients with Hematologic Malignancies.  P023 is a phase I dose escalation trial of 
Pembrolizumab, lenalinomide and dexamethasone in patients with multiple myeloma.  In the 
P013 trial among 88 trial subjects, 73 (83.0%) experienced AEs of which 35 (39.8%) were 
considered drug related.  Serious AEs were reported in 36.4% of subjects, and SAEs that were 
considered by Investigators to be drug related were reported in 4.5% of subjects overall. Three 
subjects (3.4%) died within 30 days of the last dose of pembrolizumab; none of the deaths were 
considered drug related. Deaths reported due to MedDRA preferred terms “Neoplasm 
Progression,” “Malignant Neoplasm Progression,” and “Disease Progression” not related to 
the drug are excluded from this count of subjects that died. Most subjects continued treatment 
despite AEs, with 9.1% discontinuing due to an AE. Only 4.5% of subjects discontinued study 
treatment due to an AE that was considered related to study treatment by Investigators. 
 
Of the 10 subjects on the P023 trial, 8 (80.0%) experienced AEs of which 6 (60.0%) were 
considered drug related. Serious AEs were reported in 30.0% of subjects, and SAEs that were 
considered by Investigators to be drug related were reported in 20.0% of subjects overall. No 
subjects died within 30 days of the last dose of pembrolizumab and no subjects discontinued 
due to an AE. Due to the fact that this was a combination study, and also because of the small 
sample size, comparative evaluation of the AE profile of pembrolizumab combination therapy 
from this protocol to pembrolizumab monotherapy or to chemotherapy monotherapy in other 
studies cannot be made. 
 
4.1.3 Radiation Therapy 
Along with surgery and chemotherapy, radiation has long been regarded as one of the pillars 
of oncology.  Radiation therapy is often utilized when local control is desired.  In patients with 
solid tumors, radiation is often used before or after surgery to improve loco-regional control.  
In contrast, surgery has little role in the management of hematologic malignancies.  The role 
of RT in the management of NHL has evolved over the course of history 2.  The initial curative 
approach for patients with Hodgkin’s lymphoma and NHL was with RT.  Long term disease 
control was achieved with radiation alone, especially for patients with limited stage I and II 
disease.   In a study of 655 patients with stage I and stage II NHL  treated  in the 1970’s, RT 
was found to be curative in a significant proportion of patients 3.  RT to moderate doses of 25-
30 Gy in 10-25 fractions produced local control rates in excess of 90% for most patients with 
low grade NHL.  Patients with diffuse large B cell lymphoma treated with radiation therapy 
for gross disease required higher doses to 40-50 Gy in 20-25 fractions to achieve local control 
greater than 75%.  Prior to the widespread introduction of systemic therapy, extended field RT 
that included prophylactic radiation of all major lymph node regions above and below the 
diaphragm, afforded patients increased progression free survival and overall survival 4-7.  With 
the introduction of systemic therapy (mainly anthracycline containing regimens) in the 1980’s 
as the primary treatment for patients with NHL, RT was used mainly as consolidation to 
improve local control and disease free survival 8.   

 
 
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Long term follow up of patients treated with extensive radiation fields with outdated techniques 
have demonstrated significant long term morbidity and in some cases, mortality.  Radiation 
toxicity has been widely investigated and reported, especially among young Hodgkin 
lymphoma patients 9-11.  Through knowledge of this long term toxicity coupled with the 
recognition that prophylactic nodal radiation is unnecessary in patients that receive 
consolidative RT after a good response to chemotherapy, radiation fields have dramatically 
evolved.  Extended field RT gave way to involved field RT (IFRT) introduced in 2002, where 
fewer prophylactic nodal basins were included in the radiation field 12.  Current “involved site” 
radiation therapy guidelines mandate that only sites of pre-chemotherapy disease involvement 
should be included in consolidative RT fields 13.  The reduced normal tissue exposure should 
result in lower treatment related morbidity as suggested by modeling studies 14,15. 
It is widely accepted that lymphoma cells are particularly sensitive to radiation therapy.  In 
1928 James Ewing recognized various degrees of radio-sensitivity and classified lymphoma as 
the most radiosensitive tumor16.   Curative therapy with RT for patients with NHL requires low 
to moderate doses of radiation, from 20-50 Gy, as compared to 65-70 Gy required for definitive 
management of solid tumors.   
In patients that are treated with radiation for consolidation after systemic therapy for aggressive 
NHL, a randomized trial conducted in the UK demonstrated that 30 Gy in 2 Gy fractions was 
equivalent to 40-45 Gy in similar fraction sizes, with no significant differences in local control, 
progression free survival or overall survival.  Patients with gross, chemo-refractory aggressive 
NHL at the time of RT, however require increased final doses of RT.  Studies suggest that 
doses greater than 40 Gy improve local control in the management of chemo-resistant 
intermediate to high grade NHL17,18,40.   
For patients with indolent NHL, curative RT is possible with lower doses of radiotherapy.  A 
large, randomized trial established lower doses of 24 Gy in 12 fractions as standard of care for 
the definitive management of low grade NHL19.  This treatment approach was associated with 
trends towards reduced toxicity as compared to the higher dose 40-45 Gy arm.  Strategies with 
ultra-low dose RT, referred to as “boom” where 4 Gy administered in 2 fractions of 2 Gy per 
fraction over 2 consecutive days, offers an attractive palliative approach for patients with low 
grade NHL20.  When 4 Gy was compared in a randomized fashion with 24 Gy however, local 
control and progression free survival was inferior in the low dose arm and 24 Gy was 
recommended for patients treated with curative intent.   
 
4.2 
Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
Immune Checkpoint Therapy in Malignant Disease.  Cancer immunotherapy has been 
investigated as a viable anti-tumor therapy for several decades but only recently has been 
accepted as a pillar of cancer therapy 21.  That the immune system is an effective treatment 
against hematologic malignancies is evidenced by the utilization of allogeneic stem cell 
transplantation, where graft versus lymphoma/leukemia effects result in valuable therapy.  The 

 
 
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programmed death (PD-1) pathway is involved in potent inhibition of immune activation, 
especially through inhibition of effector T cell function.  The PD-1 receptor is a transmembrane 
protein expressed on activated T cells and other immune cells.  T cell exhaustion occurs when 
PD-1 ligands (PD-L1, PD-L2) activate their receptors, initiating an inhibitory signaling 
network that results in apoptosis of activated T cells.  PD ligand expression is minimal in 
normal tissues, but markedly upregulated in acute inflammatory environments, implicating its 
role in peripheral tolerance.  Recent pre-clinical and clinical studies suggest that the PD-1/PD-
ligand pathway plays a pivotal role in tumor immune evasion, as PD-1 receptor and ligand 
expression is increased in several malignancies.  Encouraging responses have been 
demonstrated in patients with advanced diseases treated with antibodies targeting PD-1 and 
PD-L1 leading to FDA approval of two antibodies against PD1 for the treatment of melanoma 
in 2014.   
PD-1 blockade for lymphoma.  Manipulation of the PD-1/PDL-1 pathway is of recent interest 
in patients with classical Hodgkin lymphoma (cHL) and several non-Hodgkin lymphomas 
(NHLs) including follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) 22.  
Indeed in cHL, two distinct phase 1 clinical trials evaluating single agent PD-1 blockade with 
a monoclonal antibody demonstrated impressive overall response rates (ORR) of 87% and 53% 
among patients with refractory cHL, of whom the majority failed autologous stem cell 
transplantation as well as brentuximab23,24.  Complete response (CR) rates were 17% and 20% 
in these studies.  Data is also emerging regarding the clinical utility of immune checkpoint 
inhibition in NHL.  We have recently demonstrated that in FL, PD-1 blockade in combination 
with anti-CD20 targeting agent rituximab was well tolerated and resulted in an ORR of 66% 
and CR in 52% of patients treated with this approach 25.  A recent publication in Blood revealed 
that among patients with DLBCL, tumor biopsy expression of PD-L1 negatively impacted 
overall survival suggesting a potential role for the PD-1/PD-L1 pathway in this patient 
population 26. 
Preliminary data from an ongoing trial evaluating PD-1 blockade in NHLs, however suggests 
that the full potential of immune checkpoint blockage will not be reached with anti-PD-1 
monotherapy 27,28.  In this study of 81 patients, including 31 and 23 patients with B-cell NHL 
and T-cell NHL respectively, the ORR was 26% among patients with B cell NHL and 17% 
among patients with T-cell NHL (Figure 3).  The compete response rate was 10% among the 
B cell NHL subjects and 0% for those with T cell NHL.  This suggests that effective cancer 
immunotherapy likely requires cooperation with other anti-tumor modalities for improved 

 
 
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Recent clinical and pre-clinical data suggests that EBRT induces a tumor specific immune 
response in irradiated and non-irradiated tumors that is mediated by PD-1 blockade 34.     
While stereotactic ablative radiation doses have been used primarily to this effect in 
patients with known radio-resistant tumor histologies such as melanoma, lower radiation doses 
may have similar efficacy in patients with hematologic malignancies given the inherent 
radiosensitivity of these tumors 35.  Utilization of lower doses also has the potential to decrease 
treatment related toxicity.  Furthermore lower radiation doses may be more effective in 
preserving normal tissue and lymph nodes that are required for the most effective immune 
response.  While there is ongoing controversy regarding the optimal dose and fractionation of 
RT required for anti-tumor immune responses, some preclinical data suggests that fractionated 
RT is more immunogenic and leads to increased immune mediated abscopal effects compared 
with large ablative doses of RT36,37.  Indeed in the mammary model described above where 
treatment with Flt-3 Ligand and RT led to growth delay of both irradiated and non-irradiated 
tumors, single doses of 2 Gy and 6 Gy were evaluated for ability to induce an abscopal effect.  
The study investigators found that 2 Gy and 6 Gy both led to tumor growth impairment, 
however there was no significant difference in the level of growth delay of the irradiated or 
non-irradiated tumors based on these two doses.  This prompted the authors to conclude that 
“a single clinically relevant RT dose is unlikely to trigger an abscopal effect without the 
addition of FLT3-Ligand” and that “a low RT dose may be as effective as a higher dose in 
inducing the abscopal effect”.  Indeed, in a phase I/II study evaluating in situ tumor vaccination 
with a Toll-like receptor 9 (TLR9) agonist and low dose fractionated radiation therapy in 2 Gy 
fractions in patients with low grade B-cell lymphoma, systemic clinical responses were 
detected 38. Fifteen patients with relapsed low grade B cell lymphoma (13 with FL and 2 with 
MZL) were treated with an in situ vaccination approach with an intra-tumoral Toll-like 
receptor 9 (TLR9) ligand coupled with low dose RT at the same tumor site to a dose of 4 Gy 
in 2 fractions over two consecutive days.   The overall response rate in this small study was 
27%, with one patient experiencing a complete response, three patients with partial response 
and stable disease observed in 8 patients.  Taken together, these data suggest that radiation 
with standard fractionation of 2 Gy and at lower total radiation doses can be immunogenic and 
sufficient to support immune mediated, radiation induced distant tumor death.  Radiation at 
ablative doses administered on a hypo-fractionated schedule are likely not required for eliciting 
an abscopal effect in radiosensitive tumor types, such as lymphoma.   
We propose a phase II open label, unblinded single arm trial to evaluate the potential 
for fractionated radiation therapy to augment responses with PD-1 inhibitor Pembrolizumab.  
Among patients with progressive disease outside of the radiation therapy field after concurrent 
fractionated EBRT and pembrolizumab, a second course of EBRT administered on a hypo-
fractionated schedule of at least 4 Gy per fraction with pembrolizumab will be evaluated,  This 
approach will afford the ability to 1) assess the potential added efficacy of fractionated EBRT 
(as opposed to stereotactic body radiation therapy) to PD-1 immunotherapy in this refractory 
patient population 2) assess the ability of hypo-fractioned EBRT to offer salvage therapy to 
patients with progression after initial therapy with pembrolizumab and fractionated EBRT and 

 
 
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3) identify tumor and peripheral blood markers that correlate with response and/or toxicity 
based on serial specimens collected over the course of the trial. 
 
The effect of external beam radiation therapy fractionation on radiation induced 
augmentation of immune checkpoint therapy is unclear 39.  Most studies in solid tumors have 
utilized ablative stereotactic dose of RT.  While we hypothesize that fractionated RT at 2 Gy 
per fraction will be effective for eliciting tumor responses (as supported by data stated above), 
it is plausible that hypo-fractionation is essential for synergy between checkpoint blockade 
immunotherapy and radiation.  In an effort to identify the potential benefit of hypo-
fractionation, among patients treated with standard fractionated EBRT and pembrolizumab 
that progress after combination therapy, we propose a second course of EBRT to be 
administered with a high dose per fraction, hypo-fractionated approach (of at least 4 Gy per 
fraction) , to be administered with continued pembrolizumab therapy.   
 
It is likely that the timing of immune checkpoint blockade and EBRT influence the 
effectiveness of therapy.  In a pre-clinical model of melanoma, breast and colorectal cancer, 
the anti-tumor activity of low dose fractionated RT was enhanced through the combination of 
a monoclonal antibody targeting PD-L135.  In this mouse model, treatment timing and 
scheduling was significantly affected treatment efficacy; with concurrent RT and PD-L1 
therapy but not sequential therapy resulting in beneficial local control and survival.  Based on 
these data we propose that pembrolizumab and fractionated RT should be administered 
concurrently.     
 
The overall response rates of refractory NHL to single modality radiation therapy are 
relatively high but often not durable.  In a retrospective study from the Dana-Farber Cancer 
Institute of 110 patients treated with a course of salvage radiation therapy for relapsed or 
refractory aggressive NHL, the overall response rate was 78% among refractory patients 
treated with curative intent and 81% for those refractory patients treated with palliative 
intent40.  Among living patients the 5 year rate of progression free survival however was only 
34%.  Furthermore even among patients treated with doses greater than 40 Gy with curative 
intent the 2 year local control rate was only 61%.  This highlights 1) the need for effective 
systemic therapies to pair with salvage radiation therapy and 2) the room for improvement in 
long term local control that for patients with refractory NHL that may be accomplished with 
concurrent systemic therapy.   
 
Given this data this study will address the role of pembrolizumab and concurrent RT 
in two patient populations.  The first eligible cohort will include patients with more 
disseminated disease where all disease will not be included in the radiation field and there 
will be an “unirradiated lesion”. The second cohort of eligible patients will be those with 
relapsed/refractory aggressive NHL where all sites of disease can be encompassed in 1-2  
radiation therapy fields.  We hypothesize that 1) the response rates of the unirradiated lesion 
will be higher than reported ORR among patients treated previously with PD-1 blockade 
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with pembrolizumab and RT fields encompassing all sites of disease will be also be 
improved over rates reported for salvage RT alone.  
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 dose-limiting 
toxicities 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 MTD has been identified to date.  10.0 mg/kg Q2W, the 
highest dose tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and 
D of this protocol to test for initial tumor activity.  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 provides 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 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 is 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 

 
 
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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 of 200 mg of pembrolizumab administered every 21 days (q3weeks) is 
planned for this study.  Available PK results in patients with NSCLC, melanoma, classical HL 
and other solid tumor types support a lack of meaningful difference in PK exposures obtained 
at a given dose among tumor types.  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. 
4.2.2 Rationale for Endpoints 
The primary endpoint of this phase II trial is to determine the ORR fortreatment with 
pembrolizumab and concurrent EBRT. For patients in Cohort 1 with multiple sites of relapsed 
or refractory disease, the ORR of an unirradiated lesion to pembrolizumab with EBRT will be 
determined. For Cohort 2 eligible patients all sites of radiographic lymphoma will be included 
in 1-2 RT fields and the ORR will be determined.  Secondary endpoints include the 
determination of CRR, PFS, OS and duration of response of irradiated and non-irradiated 
lesions among patients treated with pembrolizumab with fractionated EBRT.   
Disease response will be according to standard response criteria for NHL that was revised in 
2014 (Appendix 11.3) 1.  For patients with FDG-avid disease, the Deauville Criteria will be 
utilized for PET-CT scoring on a 5 point scale, in accordance with standard response criteria.  
The 5 point scale is as follows, with score of 1-3 considered negative and 4-5 considered 
positive: 
1. No uptake 
2. Uptake less than or equal to the mediastinum 
3. Uptake greater than the mediastinum but less than or equal to the liver 
4. Moderately increased compared with the liver 
5. Markedly increased compared with the liver 
X.  New Areas of uptake unlikely to be related to lymphoma 
 
While the immune related response criteria (irRC) are often utilized for immunotherapy trials, 
these criteria are best suited for assessing responses among patients with solid tumors and not 
in the setting of lymphoma.  As we are interested in assessing the responses inside and outside 
of the irradiated field, in addition to determining overall response rates and overall complete 
response rates, we will also divide disease response into local (within the radiation field) and 
systemic (outside of the radiation field). 
An ongoing challenge in assessing response to immunotherapy lies in the ability to distinguish 
true disease progression from immune induced inflammatory changes, i.e. pseudo-progression 
41,42.  Given that disease response may only become apparent radiographically following a 

 
 
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period of initial disease stability or progression, early evidence of clinically asymptomatic 
disease progression or new lesions detected in less than 3 months will not be criteria for study 
removal.  While the first efficacy evaluation will occur at 8 weeks, if the study investigators 
suspect radiographic pseudo-progression in the absence of definitive clinical proof of disease 
progression, a subject may be granted an exception to continue on treatment until progression 
is confirmed at least 4 weeks later, provided that the subject’s clinical condition is stable as 
detailed in Section 7.1.2.6.4. 
Efficacy Endpoints 
Disease response will be assessed via revised Lugano classification for the response 
assessment of Hodgkin and non-Hodgkin lymphoma 1. The end of treatment assessment is 
determined by positron emission tomography (PET)-computed tomography (CT) imaging for 
patients with fluoro-deoxyglucose (FDG) avid hematologic malignancies.  Responses are 
designated, complete response (CR), partial response (PR) stable disease (SD) or progressive 
disease (PD).  For disease histologies with low or variable FDG avidity, CT based response 
will be utilized.  Disease response will be divided into local and systemic response and will be 
determined beginning at 3 months after treatment initiation.   
4.2.2.1 Biomarker Research 
Blood samples and tumor biopsies will be obtained from consenting patients at baseline and/or 
on treatment from subjects enrolled on the study at the indicated time points shown in the Trial 
Flow Chart under Section 6.0. The overall goal of the biomarker studies is to identify 
predictive, surrogate, mechanistic, and pharmacodynamic biomarkers of pembrolizumab and 
EBRT combination therapy. Peripheral blood mononuclear cells (PBMC) and serum will be 
isolated from blood samples and cryopreserved for batched analysis. 
PBMC samples will be analyzed by up to 10-color multiparametric flow cytometry to 
determine alteration in effector and regulatory T cell subsets and to determine expression of 
various co-stimulatory and co-inhibitory receptors on T cells. Serum samples will be analyzed 
for alteration in various cytokines and chemokines. Tumor biopsies will be analyzed by whole 
genome gene expression profiling (GEP), immunohistochemistry (IHC), and/or flow 
cytometry. Immunohistochemical and flow cytometric analyses will be performed on baseline 
tumor biopsy specimens to evaluate for baseline levels of PD-L1, PD-1, CD4+ and CD8+ 
Tumor Infiltrating Lymphocytes (TILs) and regulatory T cells (Tregs) within the tumor.  Gene 
expression profiling will also be performed on baseline tumor biopsy samples.  We will also 
assess the predictive significance of the intra-tumoral effector T cell gene signature that was 
associated with clinical outcome in follicular lymphoma patients treated with rituximab plus 
pidilizumab therapy that was recently described by us 25. The same analyses will be conducted 
on tumor biopsy samples obtained post-RT.   Immunophenotyping via flow cytometry will be 
performed on peripheral blood mononuclear cells obtained from baseline and serial post-
treatment samples to determine alteration in effector and regulatory T cell subsets and to 
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5.0 METHODOLOGY 
5.1 
Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
Male or female subjects with histologic evidence of aggressive Non-Hodgkin lymphoma 
(NHL) who have relapsed or progressive disease after 2 prior systemic therapies (including 
autologous stem cell transplant) or have relapsed/refractory disease and are no longer 
candidates for cytotoxic chemotherapy are eligible for this study.   
5.1.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Have at least one site of lymphomatous disease amenable to external beam radiation 
therapy (EBRT) 
2. Have pathologic confirmation of aggressive Non-Hodgkin Lymphoma (including 
diffuse large B cell lymphoma, transformed follicular lymphoma, transformed 
marginal zone lymphoma, primary mediastinal B-cell lymphoma, T cell lymphoma and 
NK T-cell lymphoma). Patients with indolent B cell lymphoma are excluded.  
3. Be willing and able to provide written informed consent/assent for the trial. 
4. Be ≥ 18 years of age on day of signing informed consent. 
5. Have measurable disease (≥ 1.5 cm in the longest diameter for nodal or extranodal   
disease) 
6. Have provided archival tumor tissue sample or newly obtained core or excisional 
biopsy of a tumor lesion not previously irradiated.  Formalin-fixed, paraffin embedded 
(FFPE) tissue blocks are preferred to slides.  Newly obtained biopsies are preferred to 
archived tissue. Newly-obtained is defined as a specimen obtained up to 6 weeks (42 
days) prior to initiation of treatment on Day 1.  Subjects for whom newly-obtained 
samples cannot be provided (e.g. inaccessible or subject safety concern) may submit 
an archived specimen. Note: If submitting unstained cut slides, newly cut slides should 
be submitted to the testing laboratory within 14 days from the date slides are cut. 
7. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 
Evaluation of ECOG is to be performed within 7 days prior to the date of 
allocation/randomization. 
8. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 10 days of treatment initiation.   
Table 1  Adequate Organ Function Laboratory Values 
System 
Laboratory Value 

 
 
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Hematological 
 
Absolute neutrophil count (ANC) 
≥1,000 /mcL 
Platelets 
≥ 50,000/ mcL 
Hemoglobin 
≥ 8 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency 
(within 7 days of assessment) 
Renal 
 
Serum creatinine OR 
Measured or calculateda creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X 
institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN  OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>2.5 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 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance should be calculated per institutional standard. 
 
9. Female subject of childbearing potential should have a negative urine or serum 
pregnancy within 72 hours prior to receiving the first dose of study medication.  If the 
urine test is positive or cannot be confirmed as negative, a serum pregnancy test will 
be required.   
10. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an 
adequate method of contraception as outlined in Section 5.7.2 – Contraception,  for the 
course of the study through 120 days, corresponding to time needed to eliminate any 
Merck study treatment(s) and/or any active comparator/combination, plus 30 days (a 
menstruation cycle) for study treatments with risk of genotoxicity after the last dose of 
study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for 
the subject. 
11. A male participant must agree to use a contraception as detailed in Appendix 3 of this 
protocol during the treatment period and for at least the entire period during which the 
male participant receives the study drug pembrolizumab, corresponding to time needed 
to eliminate any Merck study treatment(s)  and/or any active comparator/combination, 
plus an additional 120 days (a spermatogenesis cycle) for study treatments with 
evidence of genotoxicity at any dose, after the last dose of study treatment and refrain 
from donating sperm during this period. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception 
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5.1.3 Subject Exclusion Criteria  
The subject must be excluded from participating in the trial if the subject: 
1. Has had prior radiation therapy to the potential radiation target such that additional 
radiation therapy is considered unsafe by the treating radiation oncologist 
2. Has a history of allogeneic stem cell transplantation. 
3. Has a diagnosis of active scleroderma or lupus or any other autoimmune disease that 
by the opinion of the treating radiation oncologist would put the patient at unacceptable 
risk of toxicity. 
4. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study therapy or used an investigational device 
within 4 weeks of the first dose of treatment. 
5. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any 
other form of immunosuppressive therapy within 7 days prior to the first dose of trial 
treatment. 
 
6. Has a known history of active TB   (Bacillus Tuberculosis) 
 
7. Hypersensitivity to pembrolizumab or any of its excipients. 
8. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study 
Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due 
to agents administered more than 4 weeks earlier. 
9. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from adverse events due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
10. Has a known additional malignancy that is progressing or requires active treatment 
within the past 3 years.  Exceptions include basal cell carcinoma of the skin or 
squamous cell carcinoma of the skin that has undergone potentially curative therapy or 
in situ cervical cancer. 
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11. Has known active central nervous system (CNS) lymphoma or lymphomatous 
meningitis.  Subjects with previously treated brain metastases may participate provided 
they are stable (without evidence of progression by imaging for at least four weeks 
prior to the first dose of trial treatment and any neurologic symptoms have returned to 
baseline), have no evidence of new or enlarging brain metastases, and are not using 
steroids for at least 7 days prior to trial treatment.   
12. Has active autoimmune disease that has required systemic treatment in the past 2 years 
(i.e. with use of disease modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid 
replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form 
of systemic treatment.  
13. Has history of (non-infectious) pneumonitis that required steroids, evidence of 
interstitial lung disease or active, non-infectious pneumonitis. 
14. Has an active infection requiring systemic therapy. 
15. Has a history or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the trial, interfere with the subject’s participation for 
the full duration of the trial, or is not in the best interest of the subject to participate, in 
the opinion of the treating investigator.   
16. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
17. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
18. A WOCBP who has a positive urine pregnancy test within 72 hours prior to receiving 
the first dose of study medication (see Appendix 3).  If the urine test is positive or 
cannot be confirmed as negative, a serum pregnancy test will be required. 
Note: in the event that 72 hours have elapsed between the screening pregnancy test and the 
first dose of study treatment, another pregnancy test (urine or serum) must be performed and 
must be negative in order for subject to start receiving study medication. 
 
19. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent directed 
to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137). 
20. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
21. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
22. Has received a live vaccine within 30 days of planned start of study therapy. 

 
 
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Note:  Seasonal influenza vaccines for injection are generally inactivated flu vaccines 
and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live 
attenuated vaccines, and are not allowed. 
5.2 
Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2 
Table 2  Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
Pembrolizumab 
200 mg 
Q3Wa 
IV infusion 
Day 1 of each 3 week 
cycle 
Experimental 
External Beam 
Radiation 
Therapy 
20-50 Gy in 
≤ 3 Gy 
fractions 
 
Daily 
External 
Beam 
5 days per week 
consecutively until 
treatment is complete 
(not including 
holidays and 
weekends) 
Standard of 
Care 
bThe MK-3475 dosing interval may be modified secondary to toxicity as described in Section 5.2.1.2  
 
Trial treatment should begin on the day of randomization or as close as possible to the date on 
which treatment is allocated/assigned. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection  
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.  Details on preparation and administration of pembrolizumab (MK-
3475) are provided in the Pharmacy Manual.   
Radiation will be given as per our instuitional standard for NHL.  Fractionation schedules 
include 40-50 Gy in 3 Gy fractions or less, which are acceptable doses for salvage RT for 
patients with aggressive NHL.  Hypofractionated radiation therapy when given to patients with 
progressive disease will be given at fraction sizes of at least 4 Gy per fractions.  All radiation 
therapy will be administered daily (likely excluding weekends and holidays when applicable).  
All radiation therapy will be standard of care.   
5.2.1.2 Dose Modification (Escalation/Titration/Other) 
Adverse events (both non-serious and serious) associated with pembrolizumab exposure may 
represent an immunologic etiology.  These adverse events may occur shortly after the first dose 
or several months after the last dose of treatment. Pembrolizumab must be withheld for drug-
related toxicities and severe or life-threatening AEs as per 3 below. See Section 5.6 for 
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Table 3 Dose modification and toxicity management guidelines for immune-related AEs associated with pembrolizumab  
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has been reduced to Grade 1 or 0 and 
corticosteroid has been tapered. Pembrolizumab should be permanently discontinued if AE does not resolve within 12 weeks of last dose or 
corticosteroids cannot be reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment 
should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade or 
conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management with 
corticosteroid and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and 
symptoms of pneumonitis 
• 
Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
• 
Add prophylactic antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms 
of enterocolitis (ie, diarrhea, abdominal 
pain, blood or mucus in stool with or 
without fever) and of bowel perforation 
(ie, peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea 
suspecting colitis should consider GI 
consultation and performing endoscopy to 
rule out colitis.  
• 
Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids.  If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion. 
Grade 4 
Permanently 
discontinue 

 
 
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AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider 
weekly or more frequently until liver 
enzyme value returned to baseline or is 
stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-cell 
failure 
Withhold 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or 
other signs and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated.   
 
• 
Monitor for signs and symptoms of 
hypophysitis (including hypopituitarism and 
adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (eg, propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (eg, levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid 
disorders.  
 
Nephritis and 
Renal 
dysfunction 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Myocarditis 
Grade 1 or 2 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 or 4 
Permanently 
discontinue 

 
 
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All other 
immune-related 
AEs 
Intolerable/ 
persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm 
etiology and/or exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event.  Events that 
require 
discontinuation 
include and not 
limited to:  
Gullain-Barre 
Syndrome, 
encephalitis 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician.   
NOTE:  
For participants with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, pembrolizumab may be resumed 
when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement therapy or achieved metabolic control (in case of T1DM).   
 
 
 
 
 

 
Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient vacation, 
and/or holidays). Subjects should be placed back on study therapy within 3 weeks of the 
scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered on Day 2 of the first cycle and Day 1 of cycles 2-25 
after all procedures/assessments have been completed as detailed on the Trial Flow Chart 
(Section 6.0).  Trial treatment may be administered up to 3 days before or after the scheduled 
Day 1 of each cycle due to administrative reasons. 
All trial treatments will be administered on an outpatient basis. 
Pembrolizumab 200 mg will be administered as a 1 hour IV infusion every 3 weeks.  Nurses 
should make every effort to target infusion timing to be as close to 30 minutes as possible.  
However, given the variability of infusion pumps from site to site, a window of - 5 minutes 
and + 10 minutes is permitted (i.e., infusion time is 30 minutes: - 5 min/+ 10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
Computed tomography (CT) based simulation for radiation treatment planning will generally 
occur one week prior to the initiation of EBRT.  RT will be administered daily except for on 
weekends and holidays.    
A subject with unconfirmed PD may continue trial treatment until PD is confirmed at the next 
scheduled assessment.  Subjects may only receive study treatment while waiting for 
confirmation of PD of the following criteria are met: 
1) Absence of signs and symptoms indicating disease progression (including worsening 
of laboratory values) 
2) No decline in ECOG performance status 
3) Absence of rapid PD 
4) Absence of progressive tumor at a critical anatomical site (i.e. cord compression) 
requiring urgent alternative medical intervention. 
 
5.2.3 Trial Blinding/Masking 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 

 
 
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5.3 
Randomization or Treatment Allocation 
This is an unblinded, non-randomized trial among patients with relapsed and refractory 
aggressive NHL.   Trial enrollees will receive MK-3475 concurrent with fractionated EBRT.  
Patients will be stratified according to extent of disease included in the radiation therapy field 
(s)as follows: 
1) Cohort 1: Relapsed/Refractory Aggressive B-cell lymphoma with disease excluded 
from the Radiation Therapy Field (n=20) 
2) Cohort 2:  Relapsed/Refractory Aggressive B-cell lymphoma with all sites of 
radiographically evident disease treated in 1-2 radiation therapy field(s).Disease (n=20) 
5.4 
Radiation Therapy 
Radiation treatment will consist of definitive radiation therapy to a site of relapsed/refractory 
disease encompassed in one radiation therapy plan. Patients in Cohort 1 with relapsed or 
refractory lymphoma will be treated to one to two region(s) of disease with at least one 
distinct lesion excluded from the field and designated the “unirradiated lesion”. Patients in 
Cohort 2 with relapsed or refractory lymphoma will be treated with one to two  RT plan(s) 
encompassing all sites of evident active disease.  All patients (in both cohorts) will receive 
EBRT to a dose of 40-50 Gy in fractions sizes of 3 Gy or less.  Integrated boost technique is 
permitted.  Treatment will be administered 5 days per week, excluding holidays and 
weekends.  For patients that are eligible for salvage hypo-fractionated EBRT, fraction sizes 
of at least 4 Gy will be used with a conformal delivery approach.  
 
Radiation Simulation 
CT based simulation and RT planning is required for every patient.  Simulation will be 
performed roughly one week prior to initiation of therapy.  Custom immobilization should be 
used when appropriate.  During simulation, patients will be evaluated for respiration induced 
motion of the target volume.  Based on this evaluation, a 4D CT simulation or breath-hold 
may be used for motion management. The CT simulation images will be transferred over to 
the treatment planning system (Pinnacle or Eclipse) for radiation therapy planning.   
 
Radiation Technique 
The radiation technique utilized is at the discretion of the treating radiation oncologist and 
will be standard of care and institutional standards.  Priority to sparing normal tissue should 
be maintained at all times.  Potential treatment modalities include 3D conformal RT, 
Intensity Modulated Radiation Therapy (IMRT), Volumetric Arc Therapy (VMAT), Proton 
radiotherapy and Electron radiotherapy.  Utilization of daily image guidance is at the 
discretion of the treating radiation oncologist with the goal of limiting set up uncertainty to 
less than 10 mm variation.  Integrated boost technique is permitted at fractions of 3 Gy or 
less. 
 
Radiation Target Volumes and Dosimetry 
1) Gross tumor volume (GTV) is defined as the tumor bulk visible radiographically on the 
CT planning scan.   

 
 
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2) The Clinical Target Volume (CTV) and Planning Target Volume (PTV) will be 5 -15 mm 
based on the type of image guidance utilized and the planned radiation technique.  The 
prescription isodose line should cover greater than 98% of the GTV.  We recommend PTV 
coverage of >95% when possible.  
 
For patients enrolled in Cohort 1, the lesion(s) designated as the non-index lesion(s) outside 
of the radiation field should be at least 5 cm away from the radiation field. This lesion should 
be identified and documented prior to initiation of protocol therapy.  In cases where the 
lesion is within 5 cm of the field, the non-index lesion(s) should be contoured and should 
receive a dose no greater than 5 Gy over the course of the entire radiation treatment.   
 
Dose Constraints 
 
Dose constraints are according to QUANTEC as well as institutional dose constraint 
guidelines established by the Department of Radiation Oncology Hematologic Malignancy 
Section 43.  Important dose restraints include: 
 
1) Spinal cord Max point dose <45 Gy 
2) Lung: Mean lung dose (MLD) ≤13.5 Gy, V20 < 30%, V15<35%, V10 <40% and 
V55<55% 44. 
3) Heart: Mean <15 Gy 
4) Brachial Plexus: Maximum dose <66 Gy 
5) Parotid gland: Mean <26 Gy 
6) Submandibular gland: Mean <26 Gy 
7) Small Bowel: 1cc <55 Gy 45 
8) Kidney: Mean <13 Gy, V20 < 33% for at least one kidney 
9) Liver: Mean <28 Gy, V30 < 30% and V20 <50% 
10) Bone marrow: pelvic bone marrow V10 <95% and V20 <76% 46 
 
 
5.5 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial.  If there is a clinical indication for one of these or other medications 
or vaccinations specifically prohibited during the trial, discontinuation from trial therapy or 
vaccination may be required.  The investigator should discuss any questions regarding this 
with the Merck Clinical team.  The final decision on any supportive therapy or vaccination 
rests with the investigator and/or the subject's primary physician.  
5.5.1 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. 

 
 
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All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded.  Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in Section 7.2. 
5.5.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Live vaccines within 30 days prior to the first dose of trial treatment and while 
participating in the trial.  Examples of live vaccines include, but are not limited to, the 
following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG, and 
typhoid vaccine.  
• Systemic glucocorticoids for any purpose other than to modulate symptoms from an 
event of clinical interest of suspected immunologic etiology.  The use of physiologic 
doses of corticosteroids may be approved after consultation with the Sponsor. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial.  Subjects 
may receive other medications that the investigator deems to be medically necessary. 
The Exclusion Criteria describes other medications which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.6 
Rescue Medications & Supportive Care 
5.6.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator.  Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. Where appropriate, these 
guidelines include the use of oral or intravenous treatment with corticosteroids as well as 
additional anti-inflammatory agents if symptoms do not improve with administration of 
corticosteroids.   Note that several courses of steroid tapering may be necessary as symptoms 
may worsen when the steroid dose is decreased. For each disorder, attempts should be made to 
rule out other causes such as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab.  

 
 
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Note: if after the evaluation the event is determined not to be related, the investigator does not 
need to follow the treatment guidance (as outlined below). Refer to Section 5.2.1 for dose 
modification.  
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event.  
• Pneumonitis:  
o For Grade 2 events, treat with systemic corticosteroids. When symptoms 
improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
o For Grade 3-4 events, immediately treat with intravenous steroids.  
Administer additional anti-inflammatory measures, as needed. 
o Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
o If grade 2 or higher pneumonitis occurs in patients receiving concurrent 
radiation therapy to the chest, radiation therapy will be suspended immediately.   
• Diarrhea/Colitis:  
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such 
as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus).   
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids.  If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion.  For Grade 2 or higher 
diarrhea, consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis, administer oral corticosteroids.  
o For Grade 3 or 4 diarrhea/colitis, treat with intravenous steroids followed by 
high dose oral steroids.   
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
o When grade 3 or higher diarrhea or colitis occurs in a patient receiving 
concurrent radiation therapy to the abdomen or pelvis and the bowel is receiving 
radiation, then the radiation therapy will be suspended immediately. 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or 
≥ Grade 3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic 
acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 Insulin replacement therapy is recommended for Type I diabetes 
mellitus and for Grade 3-4 hyperglycemia associated with metabolic 
acidosis or ketonuria.  

 
 
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 Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide.  
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered. 
• Hyperthyroidism or Hypothyroidism:  
Thyroid disorders can occur at any time during treatment. Monitor patients for changes 
in thyroid function (at the start of treatment, periodically during treatment, and as 
indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid 
disorders. 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 In hyperthyroidism, non-selective beta-blockers (e.g. propranolol) are 
suggested as initial therapy. 
 In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism  
 Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid 
taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid 
dose is tapered. 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly). 
 Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 hours.  
o When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks. 
• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 

 
 
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o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks.  
• Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion.  
Table 3 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab (MK-3475). 
Table 3 Infusion Reaction Treatment Guidelines 
 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
< =24 hrs 
Stop Infusion and monitor symptoms. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within one hour of stopping 
drug infusion, the infusion may be restarted at 
50% of the original infusion rate (e.g., from 100 
mL/hr to 50 mL/hr).  Otherwise dosing will be 
held until symptoms resolve and the subject 
should be 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. 
Subject may be premedicated 1.5h 
(± 30 minutes) prior to infusion of 
pembrolizumab (MK-3475) with: 
 
Diphenhydramine 50 mg po (or 
equivalent dose of antihistamine). 
 
Acetaminophen 500-1000 mg po 
(or equivalent dose of antipyretic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or 
brief interruption of infusion); 
recurrence of symptoms following 
initial improvement; hospitalization 
indicated for other clinical sequelae 
(e.g., renal impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
 

 
 
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5.7 
Diet/Activity/Other Considerations 
5.7.1 Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE 
such as diarrhea, nausea or vomiting. 
5.7.2 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero.  Furthermore, it is not known if 
pembrolizumab has transient adverse effects on the composition of sperm.   
For this trial, male subjects will be considered to be of non-reproductive potential if they have 
azoospermia (whether due to having had a vasectomy or due to an underlying medical 
condition).   
Female subjects will be considered of non-reproductive potential if they are either:  
(1) postmenopausal (defined as at least 12 months with no menses without an alternative 
medical cause; in women < 45 years of age a high follicle stimulating hormone (FSH) level 
in the postmenopausal range may be used to confirm a post-menopausal state in women 
not using hormonal contraception or hormonal replacement therapy. In the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient.);  
OR  
(2) have had a hysterectomy and/or bilateral oophorectomy, bilateral salpingectomy or bilateral 
tubal ligation/occlusion, at least 6 weeks prior to screening;  
OR  
(3) has a congenital or acquired condition that prevents childbearing. 
Female and male subjects of reproductive potential must agree to avoid becoming pregnant or 
impregnating a partner, respectively, while receiving study drug and for 120 days after the last 
dose of study drug by complying with one of the following:   
(1) practice abstinence† from heterosexual activity;  
OR  
(2) use (or have their partner use) acceptable contraception during heterosexual activity.   
 
Acceptable methods of contraception are‡: 

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

 
 
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will not reliably comply with the requirements for contraception, that subject should not be 
entered into the study. 
5.7.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will 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 and to Merck 
without delay and within 24 hours to the Sponsor and within 2 working days to Merck if the 
outcome is a serious adverse experience (e.g., death, abortion, congenital anomaly, or other 
disabling or life-threatening complication to the mother or newborn).   
The study investigator will make every effort to obtain permission to follow the outcome of 
the pregnancy and report the condition of the fetus or newborn to the Sponsor.   If a male 
subject impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to the Sponsor and to Merck and followed as 
described above and in Section 7.2.2. 
5.7.4 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk.  Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.8 
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur.  In addition, a subject may be 
withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the 
trial plan is violated, or for administrative and/or other safety reasons.  Specific details 
regarding discontinuation or withdrawal are provided in Section 7.1.4 – Other Procedures. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 5.2.2 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.2.7.1 
• Unacceptable adverse experiences as described in Section 5.2.1.2 

 
 
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• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Completed 24 months of uninterrupted treatment with pembrolizumab or 35 
administrations of study medication, whichever is later. 
Note: 24 months of study medication is calculated from the date of first dose. Subjects 
who stop pembrolizumab after 24 months may be eligible for up to one year of 
additional study treatment if they progress after stopping study treatment provided they 
meet the requirements detailed in Section 7.1.5.5 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements).  After the end of treatment, each subject will 
be followed for 30 days for adverse event monitoring (serious adverse events will be collected 
for 90 days after the end of treatment as described in Section 7.2.3.1).  Subjects who 
discontinue for reasons other than progressive disease will have post-treatment follow-up for 
disease status until disease progression, initiating a non-study cancer treatment, withdrawing 
consent or becoming lost to follow-up.  After documented disease progression each subject 
will be followed by telephone for overall survival until death, withdrawal of consent, or the 
end of the study, whichever occurs first. 
5.8.1 Discontinuation of Study Therapy after CR  
Discontinuation of treatment may be considered for subjects who have attained a confirmed 
CR that have been treated for at least 24 weeks with pembrolizumab and had at least two 
treatments with pembrolizumab and at least 80% of the planned doses of EBRT beyond the 
date when the initial CR was declared.  Subjects who then experience radiographic disease 
progression may be eligible for up to one year of additional treatment with pembrolizumab via 
the Second Course Phase at the discretion of the investigator if no cancer treatment was 
administered since the last dose of pembrolizumab, the subject meets the safety parameters 
listed in the Inclusion/Exclusion criteria, and the trial is open.  Subjects will resume therapy at 
the same dose and schedule at the time of initial discontinuation.  Additional details are 
provided in Section 7.1.5.5. 
5.9 
Subject Replacement Strategy 
Additional subjects may be enrolled to ensure that the required number of evaluable subjects 
is achieved in the applicable analysis population. 

 
 
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5.10 Clinical Criteria for Early Trial Termination 
Early trial termination will be the result of the criteria specified below: 
1. Quality or quantity of data recording is inaccurate or incomplete 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential 
health hazard to subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of Merck decision to no longer supply study drug, ample notification will be 
provided so that appropriate adjustments to subject treatment can be made. 
 

Product:   Pembrolizumab 
39 
Protocol/Amendment No.: 1  
 
 
 
 
 
 
 
 
Page | 39 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart 
Trial Period: 
Screening Phase 
Pembrolizumab Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated up to 16 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visitsb 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days)c: 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
Every 12 
weeks post 
discon 
Every 
12 
weeks  
Administrative Procedures 
Pre-screening Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consentd 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Reviewe 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pembrolizumab Administration 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
EBRT Administration 
 
 
X 
Xf 
 
 
 
 
 
 
 
 
 
 
Post-study anticancer therapy status 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Survival Status 
 
 
 
X 
 
 
 
 
 
 
X 
X 
 
X 
Clinical Procedures/Assessments 
Review Adverse Eventsg 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Full Physical Examination 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Weighth 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
ECOG Performance Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Procedures/Assessments: analysis performed by LOCAL laboratory 
Pregnancy Test – Urine or Serum β-HCGi 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTTj 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 

Product:   Pembrolizumab 
40 
Protocol/Amendment No.: 1  
 
 
 
 
 
 
 
 
Page | 40 
Trial Period: 
Screening Phase 
Pembrolizumab Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Pre-
screening 
(Visit 1) 
Main 
Study 
Screening 
(Visit 2) 
1 
2  
3 
4 
To be repeated up to 16 
cycles 
Discon 
Safety 
Follow-up 
Follow Up 
Visitsb 
Survival 
Follow-
Up 
5 
6 
7 
8 
Scheduling Window (Days)c: 
 
-28 to -1 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discon 
30 days 
post 
discon 
Every 12 
weeks post 
discon 
Every 
12 
weeks  
HIV 1 and 2 antibody 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differentialk 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Comprehensive Serum Chemistry Panelk 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
T3, FT4 and TSH 
 
X 
 
 
X 
 
X 
 
X 
 
 
Xl 
X 
 
Quantitative immunoglobulins: IgG, IgA 
and IgM 
 
X 
 
 
 
 
Xm 
 
 
 
 
X 
X 
 
Bone Marrow Biopsy and Aspirate 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
Efficacy Measurements 
Chest X Ray, PA and Lateral 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
CT Neck, Chest, Abdomen and Pelviso 
 
 
 
 
 
Xp 
 
 
 
 
 
 
X 
 
PET-CTo 
 
X 
 
 
 
Xp 
 
 
 
X 
Xq 
 
 
 
Bio-Marker Studies 
Archival or Newly Obtained Tissue 
Collection (optional)r 
 
X 
 
 
 
Xr 
 
 
 
 
 
 
 
 
Correlative Studies Blood Collection 
(optional)r 
 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
*For patients treated with 22 fractions of EBRT, cycle#2 of pembrolizumab will occur during EBRT 
 
a.  In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified. Treatment 
cycles are 3 weeks (21 days); however the treatment cycle interval may be increased due to toxicity according to the dose modification guidelines provided in 
Section 5.2.1.2. If the interval is increased, all procedures except for response assessment should be performed based on the new dosing schedule.  

Product:   Pembrolizumab 
41 
Protocol/Amendment No.: 1  
 
 
 
 
 
 
 
 
Page | 41 
b. In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease status as 
per the follow-up schedule until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or (4) the end of the study, whichever 
occurs first.  
c. In general, the window for each visit is ± 3 days unless otherwise noted.  
d. Written consent must be obtained prior to performing any protocol specific procedure. Results of a test performed prior to the subject signing consent as part of 
routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior to the first dose of 
trial treatment). Screening number will be assigned when the study informed consent is signed.  
e. Prior medications – Record all medications taken within 28 days of screening visit. Concomitant medications – Enter new medications started during  
the trial through the Safety Follow-up visit. Record all medications taken for SAEs as defined in Section 7.2.  
f. For patients treated for aggressive NHL, cycle#2 of pembrolizumab will occur during EBRT 
g. AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All AEs, will also be evaluated for seriousness.  Record all AEs 
occurring within 30 days after the last dose of trial treatment. Report all SAEs (related and unrelated to trial treatment) and ECIs occurring up until 90 days after 
the last dose of trial treatment or the start of new anti-cancer treatment, whichever comes first. Afterwards, report only SAEs and ECIs that are related to trial 
treatment.  
h. Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at visit 1 only.  
i. For women of reproductive potential, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. If urine pregnancy results 
cannot be confirmed as negative, a serum pregnancy test will be required. 
j. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. Any subject receiving anticoagulant therapy 
should have coagulation factors monitored closely throughout the trial. 
k. After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. See Section 7.1.3 for details regarding laboratory tests. 

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l. Unresolved abnormal labs that are drug related AEs should be followed until resolution. Labs do not need to 
be repeated after the end of treatment if labs are within normal range. 
m. To be repeated every 4 cycles after Cycle 5. 
n. Subjects will have bone marrow biopsy/aspirate performed at baseline at the discretion of the treating 
physician. Subsequent bone marrow assessments will only be performed in subjects who achieved a CR by 
imaging criteria and have had bone marrow involvement at baseline. Repeat marrow assessment is not required 
in subjects who do not achieve a CR by imaging criteria. 
o. Disease response assessment is based upon Cheson 2014 lymphoma response criteria. “Diagnostic quality” 
PET-CT with oral contrast/water and IV contrast should be performed at Screening unless there is a 
contraindication. In general, follow-up assessments during therapy will be done by PET-CT scans for FDG avid 
disease. If PET-CT scans cannot be performed then contrasted CT scans will be obtained.  PET-CT scan will be 
repeated to confirm complete remission and/or at treatment discontinuation. For lymphomas that are not FDG-
avid at screening, PET does not need to be repeated in subsequent assessments. Response assessments should 
occur at Screening (within 42 days prior to first dose of trial treatment), after Wk 8 (+/- 14 days), and every 3 
months (+/- 14 days) during therapy and for one year after treatment discontinuation and then every 6 months 
(+/- 14 days) until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or 
(4) the end of the study, whichever occurs first. Imaging timing should follow calendar days and should not be 
adjusted for delays in cycle starts or extension of pembrolizumab cycle frequencies. For subjects who 
discontinue for reasons other than PD, assessments should continue until the subject has documented PD. The 
first assessment may be performed earlier than 8 weeks if in the opinion of the investigator the patient is 
clinically progressing.  
p. At the Week 8 assessment (prior to cycle #4) disease can be assessed by contrasted PET-CT scan or CT 
imaging of the neck, chest, abdomen  and pelvis.  Subjects who have progressive disease at the Wk 8 
assessment should have a confirmation assessment performed at least 28 days ( +/- 14 days) later (after Wk 9) 
(+/- 14 days). If subjects have stable disease, partial response, or complete response a confirmation assessment 
is not required, they should continue on the assessment schedule.  
q. In subjects who discontinue study therapy without confirmed disease progression, a radiological assessment 
should be performed at the time of treatment discontinuation (i.e. date of discontinuation ± 4 week window). If 
previous scan was obtained within 4 weeks prior to the date of discontinuation, then a repeat scan at treatment 
discontinuation isn’t mandatory.  
r. Blood and tumor sample collection for biomarker studies is optional. In consenting subjects, 40 ml of blood 
sample [one red top tube (10 ml) and 3 heparin containing green top tubes (30 ml)] will be collected within 28 
days prior to the first infusion of pembrolizumab, at day  9 (+/- 3 days) (during the course of EBRT) prior to the 
2nd infusion of pembrolizumab  on Day 23 (+/- 3 days) and prior to fourth infusion of pembrolizumab on Day 
64 (+/- 3 days). These samples will be transported within 6 hours of collection to Dr. Neelapu’s laboratory for 
processing at the South Campus Research Building I, Room 4.3206, at M. D. Anderson Cancer Center 
(MDACC). In consenting patients, core needle biopsies and fine needle aspirates (FNA) will be obtained by 
Interventional Radiology from accessible lymph node under ultrasound or CT-scan guidance within 28 days 
prior to the first infusion of pembrolizumab. A second set of optional core needle biopsies will be obtained with 
the same process of a non-irradiated lesion around the time of the fourth infusion of pembrolizumab on Day 64 
(+/- 4 days). 
 
 
 
 
 
 
 

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7.0 TRIAL PROCEDURES 
7.1 
Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit.  Individual trial procedures are described in detail below.  It may be necessary to perform 
these procedures at unscheduled time points if deemed clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Sponsor and/or 
Merck for reasons related to subject safety. In some cases, such evaluation/testing may be 
potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may 
require that additional informed consent be obtained from the subject.  In these cases, such 
evaluations/testing will be performed in accordance with those regulations. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial.  The informed consent will adhere to IRB requirements, 
applicable laws and regulations and Sponsor requirements. 
7.1.1.1.1  General Informed Consent 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature 
of the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB/ERC’s 
approval/favorable opinion in advance of use.  The subject or his/her legally acceptable 
representative should be informed in a timely manner if new information becomes available 
that may be relevant to the subject’s willingness to continue participation in the trial.  The 
communication of this information will be provided and documented via a revised consent 
form or addendum to the original consent form that captures the subject’s dated signature or 
by the subject’s legally acceptable representative’s dated signature. 

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Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level.   
The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations 
and Sponsor requirements. 
 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee 
to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee.  Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator.  Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as medical 
history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial.  Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial.  All medications related to reportable SAEs and ECIs should be recorded as 
defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease 
status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 

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7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment.  If a 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 anti-cancer therapy has been initiated the subject will 
move into survival follow-up.  
7.1.1.6 Assignment of Screening Number 
All patients will be assigned a screening number prior to trial initiation during the main study 
screening visit. 
7.1.1.7 Assignment of Randomization Number 
All patients that will enroll in the Phase II component of the trial will be assigned a 
randomization number prior to therapy initiation during the screening visit. 
7.1.1.8 Trial Compliance (Medication/Diet/Activity/Other) 
Patients will be monitored for systemic and radiation treatment compliance in addition to 
general compliance with clinic visits, concomitant medications and prohibited activities.  If a 
patient is unwilling or unable to maintain compliance, then the patient may be removed from 
the study based on the discretion of the trial investigators and/or treating physician.   
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 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 experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see Appendix Section 11.2).  Toxicities will 
be characterized in terms regarding seriousness, causality, toxicity grading, and action taken 
with regard to trial treatment.  
Please refer to section 7.2 for detailed information regarding the assessment and recording of 
AEs.   
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period.  Clinically significant abnormal findings should be recorded as medical 
history.  A full physical exam should be performed during screening,  

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7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Flow Chart (Section 6.0).  Vital signs should include temperature, pulse, respiratory 
rate, weight and blood pressure.  Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 11.1) at screening, 
prior to the administration of each dose of trial treatment and discontinuation of trial treatment 
as specified in the Trial Flow Chart.   
7.1.2.6 Tumor Imaging and Assessment of Disease 
Tumor response will be assessed radiographically according to the revised Lugano 
classification for response assessment of HL and NHL1.  In patients with FDG avid disease 
contrasted PET-CT will be utilized for baseline imaging as well as for determination of tumor 
response according to the standard of care.  For patients with non-FDG avid or FDG-variable 
disease, CT imaging will be utilized for baseline radiographic examination as well as for 
assessment of tumor response. 
 
7.1.2.6.1.  Measurable Disease Prior to Therapy 
Initial disease assessment or tumor imaging must be performed within 42 days prior to the first 
dose of trial therapy.  PET-CT fusion imaging scans with oral contrast/water and IV contrast 
will be used for the initial disease assessment unless there is a contraindication.  Disease 
assessments or scans performed as part of routine clinical management are acceptable for use 
as the screening scan if they are of diagnostic quality and performed within 42 days prior to 
the first dose of trial treatment.  A unilateral bone marrow aspiration and biopsy will be 
performed within 42 days prior to the first dose of trial treatment at the discretion of the treating 
physician.   
7.1.2.6.1 End of Treatment and Follow-up Tumor Imaging 
In participants who discontinue study treatment, tumor imaging should be performed at the 
time of treatment discontinuation (±4 week window).  If previous imaging was obtained 
within 4 weeks prior to the date of discontinuation, then imaging at treatment discontinuation 
is not mandatory.   

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In participants who discontinue study treatment without documented disease progression, 
every effort should be made to continue monitoring their disease status by tumor imaging 
using the same imaging schedule used while on treatment to monitor disease status until the 
start of a new anticancer treatment, disease progression, pregnancy, death, withdrawal of 
consent, or the end of the study, whichever occurs first. 
 
7.1.2.6.3.  Guidelines for Evaluation of Measurable Disease 
The initial disease response will occur at 8 weeks (+/- 14 days) after initiation of therapy.  
Subsequent disease response assessments will occur every 12 weeks (+/- 14 days) during 
therapy and for the first year after discontinuation of therapy, and then every 6 months 
thereafter. There is a ±14-day window for all imaging assessments. Disease response 
assessments will be performed by CT scans or PET-CT scan at q3 month intervals. 
In subjects achieving a complete remission by CT scan criteria, PET-CT scan will be repeated 
once to confirm response. In addition, unilateral bone marrow aspiration and biopsy will be 
repeated once in such patients if the bone marrow was involved with lymphoma at baseline. 
Disease assessments or scans should not be delayed for delays in cycle starts or extension of 
pembrolizumab cycle intervals. Disease assessments and imaging should continue to be 
performed until documented disease progression, the start of new anti-cancer treatment, 
withdrawal of consent, death, or the end of the study, whichever occurs first. Subjects who 
have unconfirmed disease progression may continue on treatment until progression is 
confirmed by imaging provided they have met the conditions detailed in Section 7.1.2.6.4. For 
lymphomas that are not FDG-avid at screening, PET-CT does not need to be repeated in 
follow-up assessments 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses, which may be functionally 
anergic. The response patterns seen with such an approach may extend beyond the typical time 
course of responses seen with cytotoxic agents, and can manifest a clinical response after an 
initial increase in tumor burden or even the appearance of new lesions. Standard response 
assessment criteria may not provide a complete response assessment of immunotherapeutic 
agents such as pembrolizumab. Therefore, in the setting where a subject’s assessment shows 
PD at the first disease response assessment at Week 8, a subject may be granted an exception 
to continue on treatment until progression is confirmed at least 4 weeks later, provided that the 
subject’s clinical condition is stable as detailed in Section 7.1.2.6.4. 
7.1.2.6.4  Confirmation Assessments 
A subject with progression of disease documented at the Week 8 (+/- 7) assessment may 
continue trial treatment at the discretion of the investigator until confirmation of progression 
of disease is documented per the response evaluation criteria at least 28 days (+/- 7) later (after 
Week 9) (+/- 7 days). When feasible, subjects should not be discontinued until repeat disease 

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response assessment is performed at least 28 days later. Subjects may only receive treatment 
while waiting for confirmation of PD 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 (defined as: rapidly growing mass that is greater than 
5 cm in the long axis, weight loss, drenching night sweats, marked fatigue, or fever in the 
absence of an infection) based on the clinical judgment of the investigator. 
• Absence of progressive tumor at critical anatomical sites (e.g. cord compression) requiring 
urgent alternative medical intervention 
Subjects that are deemed clinically unstable after first disease response assessment. 
 
7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Blood and tumor sample collection for biomarker studies is optional. In consenting subjects, 
40 ml of blood sample [one red top tube (10 ml) and 3 heparin containing green top tubes (30 
ml)] will be collected within 28 days prior to the first infusion of pembrolizumab, at day  9 (+/- 
3 days) (during the course of EBRT), prior to the 2nd infusion of pembrolizumab  Day 23 (+/- 
3 days) and prior to third infusion of pembrolizumab  Day 43 (+/- 3 days). These samples will 
be transported within 6 hours of collection to Dr. Neelapu’s laboratory for processing at the 
South Campus Research Building I, Room 4.3206, at M. D. Anderson Cancer Center 
(MDACC). Blood from red top and green top tubes will be processed for isolation of serum 
and PBMC, respectively using standard laboratory protocols. The isolation of serum and 
PBMC may also be performed at the Clinical and Translational Research Center (CTRC) 
Laboratory at MDACC using standard laboratory protocols. 
In consenting patients, core needle biopsies and fine needle aspirates (FNA) will be obtained 
by Interventional Radiology from accessible nodal or extranodal location under ultrasound or 
CT-scan guidance within 28 days prior to the first infusion of pembrolizumab. Whenever 
feasible, up to 3 cores will be obtained using 18 or 20 gauge needles as deemed appropriate by 
an Interventional Radiologist. The three cores will be processed as follows: i) the first core 
biopsy specimen will be preserved in RNAlater for microarray studies; ii) second core will be 
formalin-fixed and paraffin-embedded for IHC; and iii) third core will be snap frozen for DNA, 
RNA, or protein isolation. FNA sample will be analyzed by flow cytometry. These samples 
will be transported in RNAlater (core # i)/formalin (core # ii)/normal saline (cores # iii and 
FNA) within 6 hours of collection on ice to Dr. Neelapu’s laboratory for processing at the 
South Campus Research Building I, Room 4.3206, at MDACC. If fresh biopsies are not 
feasible, archival tissue from prior tumor biopsy may be used for biomarker studies.  A second 

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set of optional core needle biopsies will be obtained with the same process of a non-irradiated 
lesion prior to third infusion of pembrolizumab  Day 43 (+/- 3 days). 
Samples will be maintained until the study has been terminated. 
 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below in the Laboratory Safety Evaluations Section (Hematology, Chemistry and 
Urinalysis).  Laboratory tests for hematology, chemistry, urinalysis, and others are specified 
in Table 5.   
Laboratory tests for screening or entry into the trial should be performed within 28 days prior 
to the first dose of treatment. CBC with differential and serum chemistry panel will need to be 
repeated if screening tests were performed more than 7 days prior to the first dose of 
pembrolizumab as detailed under Trial Flow Chart. After Cycle 1 of pembrolizumab, 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. 
The schedule for laboratory assessments is provided under the Trial Flow Chart. CBC with 
differential should include total white count, absolute neutrophil count, absolute lymphocyte 
count, hemoglobin, and platelet count. Comprehensive serum chemistry panel should include 
sodium (Na), potassium (K), chloride (Cl), glucose, bicarbonate (CO2), blood urea nitrogen 
(BUN), creatinine (Cr), calcium (Ca), magnesium (Mg), phosphorus, total protein, albumin, 
alkaline phosphatase, aspartate transaminase (AST), alanine transaminase (ALT), total 
bilirubin, uric acid, and lactate dehydrogenase (LDH). Direct bilirubin should be obtained if 
total bilirubin is above the upper limit of normal. Urinalysis should include blood, glucose, 
protein, and specific gravity. If blood, glucose, and protein are abnormal on urinalysis, a urine 
microscopic exam should be performed. Total triiodothyronine (T3) will be performed if TSH 
is abnormal. 
 
 
 
 
 
 

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Table 5  Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic gonadotropin† 
Hemoglobin 
Alkaline phosphatase 
Glucose 
  (β-hCG)† 
Platelet count 
Alanine aminotransferase (ALT) 
Protein 
PT (INR) 
WBC (total and differential) 
Aspartate aminotransferase (AST) 
Specific gravity  
aPTT 
Red Blood Cell Count 
Lactate dehydrogenase (LDH) 
Microscopic exam (If abnormal)  
Total thriiodothyronine (T3) 
Absolute Neutrophil Count 
Carbon Dioxide ‡ 
results are noted 
Free thyroxine (T4) 
Absolute Lymphocyte Count 
  (CO2 or biocarbonate) 
Urine pregnancy test † 
Thyroid stimulating hormone (TSH) 
 
Uric Acid 
 
 
 
Calcium 
 
 
 
Chloride 
 
Blood for correlative studies 
 
Glucose 
 
  
 
Phosphorus 
 
  
 
Potassium   
 
  
 
Sodium 
 
  
 
Magnesium 
 
  
 
Total Bilirubin 
 
  
 
Direct Bilirubin (If total bilirubin is 
elevated above the upper limit of 
normal) 
 
 
 
Total protein 
 
 
 
Blood Urea Nitrogen 
 
 
† Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required.   
‡ If considered standard of care in your region. 
 
 

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Laboratory tests for screening or entry into the Second Course Phase should be performed 
within 10 days prior to the first dose of treatment.  After Cycle 1, pre-dose laboratory 
procedures can be conducted up to 72 hours prior to dosing.  Results must be reviewed by the 
investigator or qualified designee and found to be acceptable prior to each dose of trial 
treatment.  
7.1.3.1 Pharmacokinetic/Pharmacodynamic Evaluations 
7.1.3.1.1 Blood Collection for Serum Pembrolizumab 
Sample collection, storage and shipment instructions for serum samples will be provided in the 
Laboratory Manual. 
The time points for PK blood sampling are described in Section 6 – Trial Flow Chart.  
7.1.3.1.2 Blood Collection for Anti-Pembrolizumab Antibodies  
Sample collection, storage and shipment instructions for blood samples will be provided in the 
Laboratory Manual. 
Other Procedures 
7.1.3.2 Withdrawal/Discontinuation 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation.  Any 
adverse events which are present at the time of discontinuation/withdrawal should be followed 
in accordance with the safety requirements outlined in Section 7.2 - Assessing and Recording 
Adverse Events.  Subjects who a) attain a CR or b) complete 24 months of treatment with 
pembrolizumab may discontinue treatment with the option of restarting treatment if they meet 
the criteria specified in Section 7.1.5.5.  After discontinuing treatment following assessment 
of CR, these subjects should return to the site for a Safety Follow-up Visit (described in Section 
7.1.5.3.1) and then proceed to the Follow-Up Period of the study (described in Section 7.1.5.4). 
7.1.3.3 Blinding/Unblinding 
N/A 
7.1.4 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart.   Specific procedure-related 
details are provided above in Section 7.1 - Trial Procedures. 

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7.1.4.1 Screening 
7.1.4.1.1 Screening Period 
Approximately 28 days prior to enrollment, potential trial subjects will be evaluated to 
determine if they fulfill the entry requirements as set forth in Section 5.1.  Visit requirements 
are outlined in Section 6.0- Trial Flow Chart.   
Written consent for the main study must be obtained prior to performing any protocol specific 
procedure. Results of a test performed prior to the subject signing consent as part of routine 
clinical management are acceptable in lieu of a screening test if performed within the specified 
time frame. Screening procedures are to be completed within 28 days prior to the first dose of 
trial treatment except for the following: 
• Laboratory tests are to be performed within 7 days prior to the first dose of trial treatment. 
• 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. 
7.1.4.2 Treatment Period 
7.1.4.2.1 Salvage Hypo-Fractionated Radiation Therapy 
Patients that receive initial therapy with MK-3475 and fractionated EBRT that develop 
progressive disease (PD) in any of the follow up evaluations may be considered for salvage 
EBRT.  Patients will be scheduled for simulation and will initiate salvage radiation therapy as 
soon as possible (usually within 1 week).  EBRT will be given concurrently with remaining 
cycles of MK-3475 with a fraction size of at least 4 Gy (hypo-fractionated approach).  The 
final dose will be determined by the treating radiation oncologist according based on disease 
histology.   
7.1.4.3 Post-Treatment Visits 
7.1.5.3.1  Safety Follow-Up Visit 
The mandatory Safety Follow-Up Visit should be conducted approximately 30 days after the 
last dose of trial treatment or before the initiation of a new anti-cancer treatment, whichever 
comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be recorded.  
Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to Grade 0-1 
or until the beginning of a new anti-neoplastic therapy, whichever occurs first.  SAEs that occur 

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within 90 days of the end of treatment or before initiation of a new anti-cancer treatment should 
also be followed and recorded.  Subjects who are eligible for retreatment with pembrolizumab 
(as described in Section 7.1.5.5) may have up to two safety follow-up visits, one after the 
Treatment Period and one after the Second Course Phase. 
 
7.1.4.4 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 3 months (+/- 14 days) by radiologic 
imaging to monitor disease status.  After 1 year, the imaging time point will occur every 6 
months  (± 14 days). Every effort should be made to collect information regarding disease 
status until the start of new anti-neoplastic therapy, disease progression, death, end of the study 
or if the subject begins retreatment with pembrolizumab as detailed in Section 7.1.5.5.  
Information regarding post-study anti-neoplastic treatment will be collected if new treatment 
is initiated. 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 7.1.5.5 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression.  Details are provided in Section 6.2 – Trial Flow Chart for 
Retreatment.    
7.1.4.4.1 Survival Follow-up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer 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.  
7.1.4.5 Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
• Either  
o Stopped initial treatment with pembrolizumab after attaining an investigator-
determined confirmed CR and 
 Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
 Received at least two treatments with pembrolizumab beyond the date when 
the initial CR was declared 

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OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months of study 
therapy for reasons other than disease progression or intolerability 
AND 
• Experienced an investigator-determined confirmed radiographic disease progression 
after stopping their initial treatment with pembrolizumab 
• Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
• Has a performance status of 0 or 1 on the ECOG Performance Scale 
• Demonstrates adequate organ function as detailed in Section 5.1.2 
• Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study medication.   
• Female subject of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.7.2).  Subjects of child bearing potential are those who have not been surgically 
sterilized or have been free from menses for > 1 year.  
• Male subject should agree to use an adequate method of contraception starting with the 
first dose of study therapy through 120 days after the last dose of study therapy.   
• Does not have a history or current evidence of any condition, therapy, or laboratory 
abnormality that might interfere with the subject’s participation for the full duration of 
the trial or is not in the best interest of the subject to participate, in the opinion of the 
treating investigator. 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
Visit requirements are outlined in Section 6.0 – Trial Flow Chart. 
 
7.2 
Assessing and Recording Adverse Events 
An adverse event is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment. An adverse event can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), 

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symptom, or disease temporally associated with the use of a medicinal product or protocol-
specified procedure, whether or not considered related to the medicinal product or protocol-
specified procedure.  Any worsening (i.e., any clinically significant adverse change in 
frequency and/or intensity) of a preexisting condition that is temporally associated with the use 
of the Merck’s product, is also an adverse event. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events.  Examples 
of this may include, but are not limited to, teething, typical crying in infants and children and 
onset of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or distributed 
by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials, or 
as prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse 
and from withdrawal. 
Progression of the cancer under study is not considered an adverse event.  
All adverse events that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure. 
From the time of treatment allocation/randomization through 30 days following cessation of 
treatment, all adverse events must be reported by the investigator. Such events will be 
recorded at each examination on the Adverse Event case report forms/worksheets.  The 
reporting timeframe for adverse events meeting any serious criteria is described in section 
7.2.3.1. The investigator will make every attempt to follow all subjects with non-serious 
adverse events for outcome. 
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any protocol-
specified procedure or intervention.  If the subject requires a blood draw, fresh tumor biopsy 
etc., the subject is first required to provide consent to the main study and AEs will be captured 
according to guidelines for standard AE reporting.  
 
Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor and to 
Merck 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose).  No specific information is available on the 
treatment of overdose of pembrolizumab. Appropriate supportive treatment should be provided 

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if clinically indicated. In the event of overdose, the subject should be observed closely for signs 
of toxicity.  Appropriate supportive treatment should be provided if clinically indicated. 
If an adverse event(s) is associated with (“results from”) the overdose of a Merck product, the 
adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are 
met. 
If a dose of Merck’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-
serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional 
overdose without adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 2 working days hours to Merck Global Safety. (Attn: Worldwide 
Product Safety; FAX 215 993-1220) 
7.2.1 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered adverse events, it is the responsibility of 
investigators or their designees to report any pregnancy or lactation in a subject 
(spontaneously reported to them) that occurs during the trial. 
Pregnancies and lactations that occur after the consent form is signed but before treatment 
allocation/randomization must be reported by the investigator if they cause the subject to be 
excluded from the trial, or are the result of a protocol-specified intervention, including but not 
limited to washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.   
Pregnancies and lactations that occur from the time of treatment allocation/randomization 
through 120 days following cessation of Sponsor’s product, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier, must be reported 
by the investigator.  All reported pregnancies must be followed to the completion/termination 
of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign 
hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth 
must be reported as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 
Such events must be reported within 24 hours to the Sponsor and within 2 working days to 
Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.2 Immediate Reporting of Adverse Events to the Sponsor and to Merck 
7.2.2.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or during any use of 
Merck’s product that: 
• Results in death; 
• Is life threatening; 

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• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is another important medical event  
• Note: In addition to the above criteria, adverse events meeting either of the below 
criteria, although not serious per ICH definition, are reportable to the Merck in the same 
timeframe as SAEs to meet certain local requirements. Therefore, these events are 
considered serious by Merck for collection purposes. 
● 
Is a new cancer (that is not a condition of the study); 
● 
Is associated with an overdose. 
 
Refer to Table 6 for additional details regarding each of the above criteria. 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer under study (reference 
Section 7.2.3.3 for additional details) that occurs to any subject must be reported within 24 
hours to the Sponsor and within 2 working days to Merck Global Safety if it causes the subject 
to be excluded from the trial, or is the result of a protocol-specified intervention, including but 
not limited to washout or discontinuation of usual therapy, diet, placebo treatment or a 
procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any serious adverse event, or follow up to a serious 
adverse event, including death due to any cause other than progression of the cancer under 
study (reference Section 7.2.3.3 for additional details), whether or not related to the Merck 
product, must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to Merck product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified 
in the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately to the Sponsor and to Merck Global Safety. 
All subjects with serious adverse events must be followed up for outcome. 
SAE reports and any other relevant safety information are to be forwarded to the Merck 
Global Safety facsimile number:  +1-215-993-1220 
A copy of all 15 Day Reports and Annual Progress Reports is submitted as required by FDA, 
European Union (EU), Pharmaceutical and Medical Devices agency (PMDA) or other local 
regulators. Investigators will cross reference this submission according to local regulations to 

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the Merck Investigational Compound Number (IND, CSA, etc.) at the time of submission.  
Additionally investigators will submit a copy of these reports to Merck & Co., Inc. (Attn: 
Worldwide Product Safety; FAX 215 993-1220) at the time of submission to FDA. 
7.2.2.2 Events of Clinical Interest 
Selected non-serious and serious adverse events are also known as Events of Clinical Interest 
(ECI) and must be reported within 24 hours to the Sponsor and within 2 working days to Merck 
Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the consent form is signed until treatment 
allocation/randomization, any ECI, or follow up to an ECI, that occurs to any subject must be 
reported within 24 hours to the Sponsor and within 2 working days to Merck Global Safety if 
it causes the subject to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. 
For the time period beginning at treatment allocation/randomization through 90 days following 
cessation of treatment, or 30 days following cessation of treatment if the subject initiates new 
anticancer therapy, whichever is earlier, any ECI, or follow up to an ECI, whether or not related 
to Merck product, must be reported within 24 hours to the Sponsor and within 24 hours to 
Merck Global Safety. 
Events of clinical interest for this trial include: 
1.  An overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose for 
This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical 
symptoms or abnormal laboratory results.  
2.  An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X the 
upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require 
an additional evaluation for an underlying etiology.  
7.2.2.3 Protocol-Specific Exceptions to Serious Adverse Event Reporting  
Efficacy endpoints as outlined in this section will not be reported to Merck as described in 
Section 7.2.3.- Immediate Reporting of Adverse Events to the Sponsor and to Merck, unless 
there is evidence suggesting a causal relationship between the drug and the event. Any such 
event will be submitted to the Sponsor within 24 hours and to Merck Global Safety within 2 
working days either by electronic or paper media. 

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Specifically, the suspected/actual events covered in this exception include any event that is 
disease progression of the cancer under study. 
The Sponsor will monitor unblinded aggregated efficacy endpoint events and safety data to 
ensure the safety of the subjects in the trial. Any suspected endpoint which upon review is not 
progression of the cancer under study will be forwarded to Merck Global Safety as a SAE 
within 2 working days of determination that the event is not progression of the cancer under 
study 
Hospitalization related to convenience (e.g. transportation issues etc.) will not be considered a 
SAE. 
 
7.2.3 Evaluating Adverse Events 
An investigator who is a qualified physician will evaluate all adverse events according to the 
NCI Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse event 
which changes CTCAE grade over the course of a given episode will have each change of 
grade recorded on the adverse event case report forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for seriousness. 

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Table 6. Evaluating Adverse Events 
An investigator who is a qualified physician, will evaluate all adverse events as to: 
V4.0 CTCAE 
Grading 
Grade 1 
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only; intervention not indicated. 
 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental ADL. 
 
Grade 3 
Severe or medically significant but not immediately life-threatening; hospitalization or prolongation or hospitalization indicated; disabling; 
limiting self-care ADL. 
 
Grade 4 
Life threatening consequences; urgent intervention indicated. 
 
Grade 5 
Death related to AE 
Seriousness 
A serious adverse event is any adverse event occurring at any dose or during any use of Merck product that: 
 
†Results in death; or 
 
†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred (Note: This does not include an 
adverse event that, had it occurred in a more severe form, might have caused death.); or 
 
†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or 
 
†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the 
hospitalization is a precautionary measure for continued observation. (Note: Hospitalization for an elective procedure to treat a pre-existing condition that has not 
worsened is not a serious adverse event.  A pre-existing condition is a clinical condition that is diagnosed prior to the use of a Merck product and is documented in the 
patient’s medical history.); or 
 
†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis);or 
 
Is a new cancer (that is not a condition of the study) (although not serious per ICH definition, is reportable to the Sponsor within 24 hours and to Merck within 2 
working days to meet certain local requirements); or 
 
Is an overdose (whether accidental or intentional).  Any adverse event associated with an overdose is considered a serious adverse event for collection purposes. An 
overdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours to the Sponsor and to 
Merck within 2 working days.. 

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Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, the event may jeopardize the 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 Merck product to be discontinued? 
Relationship to 
Merck Product  
Did Merck product cause the adverse event? The determination of the likelihood that Merck  product caused the adverse event will be provided by an investigator who 
is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a 
medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended 
as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available 
information. 
The following components are to be used to assess the relationship between Merck product and the AE; the greater the correlation with the components and their 
respective elements (in number and/or intensity), the more likely Merck product caused the adverse event (AE): 
 
Exposure 
Is there evidence that the subject was actually exposed to Merck product such as: reliable history, acceptable compliance assessment (pill count, 
diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen? 
 
Time Course 
Did 
the 
AE 
follow 
in 
a 
reasonable 
temporal 
sequence 
from 
administration 
of 
Merck 
product?  
Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)? 
 
Likely Cause 
Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental factors 
 

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Relationship 
The following components are to be used to assess the relationship between the test drug and the AE: (continued) 
to Merck 
Product 
(continued)  
Dechallenge 
Was Merck product discontinued or dose/exposure/frequency reduced? 
If yes, did the AE resolve or improve? 
If yes, this is a positive dechallenge. If no, this is a negative dechallenge. 
(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of 
the Sponsor’s product; or (3) the trial is a single-dose drug trial); or (4) Sponsor’s product(s) is/are only used one time.) 
 
Rechallenge 
Was the subject re-exposed to Merck product in this study? 
If yes, did the AE recur or worsen? 
If yes, this is a positive rechallenge. If no, this is a negative rechallenge. 
(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) 
Sponsor’s product(s) is/are used only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN 
CAUSED BY MERCK PRODUCT, OR IF REEXPOSURE TO MERCK PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK 
TO THE SUBJECT, THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSOR AS PER DOSE MODIFICATION 
GUIDELINES IN THE PROTOCOL. 
 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding Merck product or drug class pharmacology or 
toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including 
consideration of the above elements. 
Record one of the following 
Use the following scale of criteria as guidance (not all criteria must be present to be indicative of Merck product relationship). 
Yes, there is a reasonable 
possibility of Merck product 
relationship. 
There is evidence of exposure to Merck product.  The temporal sequence of the AE onset relative to the administration of Merck product is reasonable.  
The AE is more likely explained by Merck product than by another cause. 
No, there is not a reasonable 
possibility of Merck product 
relationship 
Subject did not receive the Merck product OR temporal sequence of the AE onset relative to administration of Merck product is not reasonable OR 
the AE is more likely explained by another cause than the Merck product.  (Also entered for a subject with overdose without an associated AE.) 

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The overall response (OR: complete response + partial response) of non-irradiated lesion(s) at 
three months and dose limiting toxicity (DLT) at one cycles (3 weeks) will be monitored 
simultaneously using the Bayesian stopping boundaries calculated based on beta-binomial 
distributions. Independence is assumed between OR and DLT.  
DLT is defined as the following toxicities observed during cycle one of the treatment that are 
considered by the investigator to be related to therapy: 
1. Grade 4 neutropenia (ANC < 500/mm3) lasting more than 7 consecutive days. 
2. Grade 3 neutropenia with fever and/or infection, where fever is defined as an oral 
Temperature ≥ 38.5°C. 
3. Grade 4 thrombocytopenia (platelets < 25,000/mm3) lasting more than 7 consecutive 
Days.  
4. Grade 3 thrombocytopenia with clinically significant bleeding. 
5. A platelet count < 10,000/mm3 at any time. 
6. Grade 3 or greater nausea and/or emesis despite the use of optimal anti-emetic 
Prophylaxis. Optimal anti-emetic prophylaxis is defined as an anti-emetic regimen that 
employs a 5-HT3 antagonist given in standard doses and according to standard 
schedules. 
7. Grade 3 or greater diarrhea that occurs despite maximal supportive therapy. 
8. Any other Grade 3 or greater non-hematologic toxicity with the following exceptions: 
Grade 3 arthralgia/myalgia or brief (< 1 week) Grade 3 fatigue. 
9. A delay of more than 2 weeks in the initiation of Cycle 2 of treatment because of a lack 
of adequate recovery of therapy related hematological or non-hematologic toxicities. 
In cohort 1 for the patients with multiple sites of aggressive NHL, we will consider that the 
regimen is promising if the OR rate of the non-irradiated lesion (s) at 3 months is at least 35% 
and the DLT rate at cycle one is below 30%.  A sample size of 20 ensures that, if the trial is 
not terminated early, a posterior 90% credibility interval for OR rate at 3 months will have 
width of 0.335 at most, when 7 responses are observed out of the 20 patients, under the 
assumption of 35% OR rate. The prior probability of OR and DLT for the regimen are modeled 
by beta distribution (Beta(0.35, 0.65) and Beta(0.3, 0.7), respectively). Denoting the 
probability of OR and DLT by {θOR, θDLT}, and they are compared to fixed targets of OR and 
DLT rates. The following decision criteria will be applied: 
 
1) Stop if Prob{ θOR <  0.35 | data} > 0.95, and  
2) Stop if Prob{ θDLT > 0.30 | data} > 0.95 

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Patients will be monitored by a cohort size of 10 according to the following stopping 
boundaries for OR at 3 months and DLT at cycle one.  If the number of responses required for 
moving the trial to next stage has not been achieved, the patient enrollment will be halted until 
enough responses observed. 
Number 
of 
patients 
evaluated 
Stop if <= OR observed 
Stop if >= DLT observed 
10 
0-1 
6-10 
20 
Always stop with this many patients 
 
The operating characteristics are summarized in the following table (based on simulations from 
10,000 trials). 
True DLT Rate 
True OR Rate 
Prob (stop the trial 
early) 
Average number of 
patients treated 
0.1 
0.15 
0.5444 
14.56 
 
0.25 
0.2441 
17.56 
 
0.35 
0.0861 
19.14 
 
0.45 
0.0234 
19.77 
 
0.55 
0.0046 
19.95 
0.2 
0.15 
0.5472 
14.53 
 
0.25 
0.2488 
17.51 
 
0.35 
0.0918 
19.08 
 
0.45 
0.0295 
19.71 
 
0.55 
0.0108 
19.89 
0.3 
0.15 
0.5659 
14.34 
 
0.25 
0.2798 
17.20 
 
0.35 
0.1292 
18.71 

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0.45 
0.0695 
19.31 
 
0.55 
0.0516 
19.48 
0.4 
0.15 
0.6201 
13.80 
 
0.25 
0.3697 
16.30 
 
0.35 
0.2379 
17.62 
 
0.45 
0.1856 
18.14 
 
0.55 
0.1700 
18.30 
0.5 
0.15 
0.7161 
12.84 
 
0.25 
0.5290 
14.71 
 
0.35 
0.4305 
15.69 
 
0.45 
0.3914 
16.09 
 
0.55 
0.3798 
16.20 
 
In cohort 2 patients will be treated to all sites of relapsed or refractory NHL that can  be 
completely included in 1-2 RT field(s), we will consider that the regimen is promising if the 
OR rate of the radiated disease at 3 months is at least 90% and the DLT rate at cycle one is 
below 30%. A sample size of 20 ensures that, if the trial is not terminated early, a posterior 
90% credibility interval for OR rate at 3 months will have width of 0.203 at most, when 18 
responses are observed out of the 20 patients, under the assumption of 90% OR rate. The prior 
probability of OR and DLT for the regimen are modeled by beta distribution (Beta(0.9,0.1) 
and Beta(0.3,0.7), respectively). Denoting the probability of OR and DLT by {θOR, θDLT}, and 
they are compared to fixed targets of OR and DLT rates. The following decision criteria will 
be applied: 
 
1) Stop if Prob{ θOR <  0.90 | data} > 0.95, and  
2) Stop if Prob{ θDLT > 0.30 | data} > 0.95 
 
Patients will be monitored by a cohort size of 10 according to the following stopping 
boundaries for OR at 3 months and DLT at cycle one. If the number of responses required for 

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moving the trial to next stage has not been achieved, the patient enrollment will be halted until 
enough responses observed. 
Number 
of 
patients 
evaluated 
Stop if <= OR observed 
Stop if >= DLT observed 
10 
0-6 
6-10 
20 
Always stop with this many patients 
 
The operating characteristics are summarized in the following table (based on simulations from 
10,000 trials). 
True DLT Rate 
True OR Rate 
Prob (stop the trial 
early) 
Average number of 
patients treated 
0.1 
0.6 
0.6178 
13.82 
 
0.7 
0.3505 
16.50 
  
0.8 
0.1210 
18.79 
 
0.9 
0.0129 
19.87 
 
0.95 
0.0012 
19.99 
0.2 
0.6 
0.6202 
13.80 
 
0.7 
0.3545 
16.45 
 
0.8 
0.1265 
18.74 
 
0.9 
0.0191 
19.81 
 
0.95 
0.0074 
19.93 
0.3 
0.6 
0.6358 
13.64 
 
0.7 
0.3811 
16.19 
 
0.8 
0.1625 
18.38 
 
0.9 
0.0595 
19.40 
 
0.95 
0.0483 
19.52 

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0.4 
0.6 
0.6813 
13.19 
 
0.7 
0.4584 
15.42 
 
0.8 
0.2670 
17.33 
 
0.9 
0.1769 
18.23 
 
0.95 
0.1671 
18.33 
0.5 
0.6 
0.7618 
12.38 
 
0.7 
0.5953 
14.05 
 
0.8 
0.4523 
15.48 
 
0.9 
0.3849 
16.15 
 
0.95 
0.3776 
16.22 
 
The above stopping boundaries and operating characteristics are calculated using MultcLean 
(v.2.1.0) design software downloaded from 
http://biostatistics.mdanderson.org/SoftwareDownload. 
 
ANALYSIS PLANS 
For each patient cohort, summary statistics will be provided for continuous variables such as 
age. Frequency tables will be used to summarize categorical variables such as gender, 
histology, response, toxicity type and severity.  Response rate and its 95% confidence interval 
will be estimated for each patient cohort separately.  The distribution of time-to-event 
endpoints, such as time to progression and overall survival, will be estimated using the method 
of Kaplan and Meier.  Comparison of time-to-event endpoints by important patient 
characteristics will be made using the log-rank test.   
Time-to-event outcomes, including PFS and OS will be estimated using the Kaplan-Meier 
method, with analysis beginning at the receipt of the first dose of MK-3475.  The log-rank 
test will be performed to test the difference in time-to-event distributions between patient 
groups.  Cox proportional hazards model may be used to include multiple covariates in the 
time-to-event analysis.   
 
Assuming an accrual rate of 2 patients per month, we anticipate an accrual period of roughly 
20 months.  Data from all subjects who receive any study drug will be included in the safety 

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analyses.  Subjects who entered the study and did not take any of the study drug and had this 
confirmed, will not be evaluated for safety.   
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
9.1 
Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies will be provided by Merck as summarized in Table 7. 
Table 7.  Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 50 mg 
Lyophilized Powder for Injection 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 
Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 
Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 
Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication must be recorded by an authorized person at the 
trial site. 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 

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9.5 
Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies received 
from Merck or designee, the amount dispensed to and returned by the subjects and the amount 
remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s 
responsibility to arrange for disposal of all empty containers, provided that procedures for 
proper disposal have been established according to applicable federal, state, local and 
institutional guidelines and procedures, and provided that appropriate records of disposal are 
kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 Confidentiality 
Confidentiality will be maintained throughout this study in accordance without the Health 
Insurance Portability and Accountability Act.  This study will be presented and approved by 
the Internal Review Board at MD Anderson Cancer Center. 
10.2 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the 
Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely 
responsible for determining whether the trial and its results are subject to the requirements for 
submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov.  Information posted 
will allow subjects to identify potentially appropriate trials for their disease conditions and 
pursue participation by calling a central contact number for further information on appropriate 
trial locations and trial site contact information.     
10.3 Quality Management System 
10.3.1 IND Safety Report 
The investigator will be notified by Merck via an IND Safety Report of the following: 1) 
serious and/or unexpected adverse events associated with pembrolizumab n this study or other 
studies or 2) any findings from studies in lab animals suggesting a significant risk for human 
patients including reports of carcinogenicity or teratogenicity.  The Investigator will notify the 
IRB promptly of new unexpected and/or serious adverse event(s) or potential serious risks to 
patients.  The investigator will keep copies of all adverse event information on file.   
10.4 Data Confidentiality Plan 
All information, including but not limited to patient data/information, biomarker research data, 
and information related to the conduct of the study will be kept confidential. Blood and tissue 
samples will be identified by coded numbers. Data will be stored in password-protected 

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databases, protected by an institutional firewall. All data collected for this project, including 
all clinical information, will be kept confidential by limiting access only to the investigators 
and collaborators involved in the study. In order to maintain confidentiality, the investigator 
will maintain a personal patient identification list (coded numbers for blood and tissue samples 
corresponding with patient identifiers) to enable records to be identified and verified as 
authentic. This list will be maintained at the study site with other study records under adequate 
security and restricted access. 
 

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11.0 APPENDICES 
11.1 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. 
 
11.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 

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