Conditions: Composite Lymphoma Grade 3b Follicular Lymphoma Stage I Diffuse Large B-Cell Lymphoma Stage I Follicular Lymphoma Stage II Diffuse Large B-Cell Lymphoma Stage II Follicular Lymphoma Stage III Diffuse Large B-Cell Lymphoma Stage III Follicular Lymphoma Stage IV Diffuse Large B-Cell Lymphoma Stage IV Follicular Lymphoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
This pilot phase I trial studies the side effects of pembrolizumab and combination chemotherapy in treating patients with previously untreated diffuse large B-cell lymphoma or grade 3b follicular lymphoma. Monoclonal antibodies, such as pembrolizumab and rituximab, may interfere with the ability of cancer cells to grow and spread. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pembrolizumab together with combination chemotherapy may be with a better treatment for diffuse large B-cell lymphoma or follicular lymphoma.

Detailed description:
PRIMARY OBJECTIVES:

I. To measure the toxicity profile of pembrolizumab (MK-3475) when co-administered with full-course RCHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone) in subjects with previously untreated diffuse large B-cell lymphoma (DLBCL).

SECONDARY OBJECTIVES:

I. To assess clinical outcomes including response rate, event-free survival, and overall survival after MK-3475 + RCHOP induction for subjects with previously untreated DLBCL.

TERTIARY OBJECTIVES:

I. To measure baseline expression of proteins in the programmed death-1 (PD-1) family on tumor cells and coexisting immune infiltrates, using archival tissue when available.

II. To measure peripheral blood T cell subsets before and after treatment using flow cytometry, and to measure baseline vitamin D (25-hydroxy, total).

III. To explore relationships with these parameters and likelihood of response to therapy and outcomes.

OUTLINE:

Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1 and prednisone orally (PO) on days 1-5. Patients also receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 2 of course 1 and on day 1 of subsequent courses. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of the study treatment, patients are followed up to 5 years.

Arms:
arm 1: Patients receive pembrolizumab IV over 30 minutes on day 1 and prednisone PO on days 1-5. Patients also receive rituximab IV, cyclophosphamide IV, doxorubicin hydrochloride IV, and vincristine sulfate IV on day 2 of course 1 and on day 1 of subsequent courses. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Cyclophosphamide intervention 2: Doxorubicin Hydrochloride intervention 3: Laboratory Biomarker Analysis intervention 4: Pembrolizumab intervention 5: Prednisone intervention 6: Rituximab intervention 7: Vincristine Sulfate
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Correlative studies intervention 4: Given IV intervention 5: Given PO intervention 6: Given IV intervention 7: Given IV

Protocol document:
Prot_SAP_000.pdf: 
Product: MK-3475 
Protocol/Amendment No: CC9291 
REGD JUL S 0 2019 
UNIVERSITY OF WASHINGTON SCHOOL OF MEDICINE 
FRED HUTCHINSON CANCER RESEARCH CENTER 
SEATTLE CANCER CARE ALLIANCE 
Protocol Title: MK-3475 in Combination with Standard RCHOP Therapy for Previously 
Untreated Diffuse Large B-Cell Lymphoma 
Version Date: 10AUG2017 
Version Number: 4.0 
Principal Investigator and Sponsor-Investigator: 
Stephen D. Smith, MD 
Associate Professor, UW 
Associate Member, FHCRC 
Seattle Cancer Care Alliance 
825 Eastlake Avenue East, Mailstop G3-200 
Seattle, WA 98109 
Telephone: (206) 288-6546. 
FHCRC IRB Approval 
SEP 11 2019 
Document Released Date 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
CONTENTS 
1.0 	
TRIAL SUMMARY 	
5 
2.0 	
TRIAL DESIGN 	
5 
2.1 	
Trial Design: 	
5 
2.2 	
Trial Diagram 	
6 
3.0 	
OBJECTIVES & HYPOTHESIS 	
6 
3.1 	
Primary Objective 	
6 
3.2 	
Exploratory Objective: 	
6 
4.0 	
BACKGROUND & RATIONALE 	
7 
4.1 	
Background 	
7 
4.1.1 MK-3475 (Pembrolizumab): Pharmaceutical and Therapeutic Background 	
7 
4.2 	
Rationale for MK-3475 (Pembrolizumab) in Lymphoma 	
9 
4.2.1 Rationale for Dose Selection/Regimen/Modification 	
10 
4.2.2 Rationale for Endpoints: 	
11 
5.0 METHODOLOGY 	
12 
5.1.1 Subject Inclusion Criteria 	
12 
5.1.2 Subject Exclusion Criteria 	
14 
5.2 	
Study Treatments 	
15 
5.2.1 Dose Modification (Escalation/Titration/Other) 	
15 
5.2.2 Timing of Dose Administration 	
17 
5.2.3 Trial Blinding/Masking 	
17 
5.3 	
Concomitant Medications/Vaccinations (allowed & prohibited) 	
17 
5.3.1 Acceptable Concomitant Medications 	
17 
5.3.2 Prohibited Concomitant Medications 	
18 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
5.4 	
Supportive Care 	
19 
5.4.1 Additional Events of Clinical Interest 	
22 
5.5 	
Diet/Activity/Other Considerations 	
22 
5.5.1 Diet 	
22 
5.5.2 Contraception 	
22 
5.5.3 Use in Pregnancy 	
23 
5.5.4 Use in Nursing Women 	
23 
5.6 	
Subject Withdrawal/Discontinuation Criteria 	
23 
5.7 	
Subject Replacement Strategy 	
24 
5.8 	
Clinical Criteria for Early Trial Termination 	
24 
6.0 	
TRIAL FLOW CHART 	
24 
6.1 	
Study Flow Chart 	
24 
7.0 	
TRIAL PROCEDURES 	
26 
7.1 	
Trial Procedures 	
26 
7.1.1 Administrative and Study-Related Procedures 	
26 
7.1.2 Clinical Procedures/Assessments 	
28 
7.1.3 Laboratory Procedures/Assessments 	
30 
7.1.4 Other Procedures 	
33 
7.1.5 Withdrawal/Discontinuation 	
33 
7.1.6 Visit Requirements 	
33 
7.2 	
Assessing and Recording Adverse Events 	
34 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to 
Merck 	
35 
7.2.2 Reporting of Pregnancy and Lactation to Merck 	
35 
7.2.3 Reporting Requirements for Adverse Events/Adverse Reactions 	
36 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
7.2.4 Evaluating Adverse Events 	
38 
7.2.5 Sponsor-Investigator Responsibility for Reporting Adverse Events 	41 
8.0 	
STATISTICAL ANALYSIS PLAN: Study Design and Statistical Analysis Plan 	
42 
8.1 	
Stopping Rule 	
43 
9.0 	
LABELING, PACKAGING, STORAGE AND RETURN OF investigational product 	
44 
9.1 	
Investigational Product 	
44 
9.2 	
Packaging and Labeling Information 	
44 
9.3 	
Clinical Supplies Disclosure 	
44 
9.4 	
Storage and Handling Requirements 	
44 
9.5 	
Returns and Reconciliation 	
44 
10.0 Data AND SAFETY MONITORING PLAN 	
45 
12.0 REGULATORY RESPONSIBILITIES OF SPONSOR-INVESTIGATOR 	
46 
13.0 REFERENCES 	
46 
14.0 APPENDICES 	
51 
14.1 ECOG Performance Status 	
51 
14.2 Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 	 51 
14.3 	
Response Criteria: "The Lugano Classification" 38 	
51 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
1.0 TRIAL SUMMARY 
Abbreviated Title 
MK-3475 (Pembrolizumab) +RCHOP in untreated DLBCL 
Trial Phase 
Pilot Study 
Clinical Indication 
Diffuse large B cell lymphoma patients who have not 
received prior systemic therapy 
Trial Type 
Nonrandomized, prospective trial 
Type of control 
N/a 
Route of administration 
IV 
Trial Blinding 
n/a 
Treatment Groups 
n/a 
Number of trial subjects 
30 
Estimated duration of trial 36 months (enrollment) 
Duration of Participation 
48 months 
2.0 TRIAL DESIGN 
2.1 Trial Design: 
This is a nonrandomized, single-arm pilot study which will evaluate the safety 
and tolerability of MK-3475 (pembrolizumab) in combination with standard, full-
course RCHOP chemoimmunotherapy in untreated DLBCL 
Study duration: Subjects will be enrolled over 36 months. Last subject out 
(completing study follow-up) is projected to occur at 48 months. Subsequently, 
patients may be followed for outcomes for up to 5 years using standard-of-care 
assessments. 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
2.2 Trial Diagram 
IN 
! 
Untreated 
DLBCL 
(n=30) 
RCHOP+ 
MK3475 
q3 wksx 6 
Remission 
status visit 
4-6 wks from 
cycle 6 
Off-study 
visit 
10-14 wks from 
cycle 6 
3.0 OBJECTIVES & HYPOTHESIS 
3.1 	
Primary Objective 
To measure the toxicity profile of MK-3475 (pembrolizumab) when co-
administered with full-course RCHOP in subjects with previously untreated 
DLBCL. 
Hypothesis: The addition of MK-3475 to 6 cycles of induction RCHOP for 
subjects with previously untreated DLBCL will not result in a significant increase 
in toxicity and treatment-related mortality beyond that which is expected using 
RCHOP alone. 
Secondary Objective: To assess clinical outcomes including response rate, event-
free survival, and overall survival after MK-3475 + RCHOP induction for subjects 
with previously untreated DLBCL. 
3.2 Exploratory Objective: 
To measure baseline expression of proteins in the programmed death-1 (PD-1) 
family on tumor cells and coexisting immune infiltrates, using archival tissue when 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
available, to measure peripheral blood T cell subsets before and after treatment 
using flow cytometry, and to measure baseline Vitamin D (25-hydroxy, total); and 
to explore relationships with these parameters and likelihood of response to therapy 
and outcomes. 
4.0 BACKGROUND & RATIONALE 
4.1 Background 
Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoid malignancy 
comprised of large, transformed B cells. DLBCL is the most common B-cell lymphoid 
neoplasm in the United States and Europe and accounts for approximately 28 percent of 
all mature B-cell lymphomas.' It most commonly presents in older adults, with a median 
age at diagnosis of 65 years, and exhibits an aggressive course with a variable prognosis. 
Standard therapy for DLBCL was defined in 1993 as the CHOP regimen 
(cyclophosphamide, doxorubicin, vincristine, and prednisone).2 Standard induction 
therapy subsequently evolved to include rituximab (RCHOP), after a prospective 
randomized trial found improved survival without significantly increased toxicity could 
be achieved with addition of rituximab immunotherapy.3  
However, since the development of RCHOP, further efforts to improve upon the 
therapeutic index of modern therapy by adding chemotherapy agents, increasing dose 
density, or consolidating first-line therapy with high-dose chemotherapy and stem cell 
transplantation have shown limited success.4-7 These therapies have failed to improve 
the therapeutic index of RCHOP overall, resulting in increased toxicity and modest or 
absent impact on efficacy. This suggests that increasing chemotherapy intensity—
through either dose density or adding additional agents or high-dose consolidation with 
autologous stem cell rescue—is unlikely the best strategy for improving patient 
outcomes with DLBCL. Currently, 33-55% patients with high-risk clinical features are 
either refractory to initial induction RCHOP or relapse soon after therapy, typically 
within 2 years after its completion.8-1°  
Novel treatment approaches, with mechanisms of action and toxicity profiles distinct 
from those of cytotoxic chemotherapy, are clearly needed for DLBCL. In light of the 
high incidence of DLBCL, development of such therapies represents a global unmet 
medical need. Furthermore, since radiographic complete remission after induction is 
required for a high probability of disease control, novel therapies focused 6n the 
induction phase warrant the highest priority for further evaluation. 
4.1.1 MK-3475 (Pembrolizumab): Pharmaceutical and Therapeutic Background 
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 
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Product: MK-3475 
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cancer tissue and favorable prognosis in various malignancies. 12-16  In particular, 
the presence of CD8+ T-cells and the ratio of CD8+ effector T-cells / FoxP3+ 
regulatory T-cells seems to correlate with improved prognosis and long-term 
survival in many solid tumors. 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to 
suppress immune control. The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate 
unwanted or excessive immune responses, including autoimmune reactions. 
PD-1 (encoded by the gene Pdcdl) 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).17' 18  
The structure of murine PD-1 has been resolved.19  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 CD3; PKCO and ZAP70 
17 
which are involved in the CD3 T-cell signaling cascade. ,20,21,22  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.23'24 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. 25' 26 Expression has also been shown during thymic development on CD4-
CD8- (double negative) T-cells as well as subsets of macrophages and dendritic 
cells [17]. The ligands for PD-I (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.23,28,29,30  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.23 Although healthy organs express little (if any) PD-L I , 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).31 This suggests that the PD-1/PD-L I 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
pathway plays a critical role in tumor immune evasion and should be considered 
as an attractive target for therapeutic intervention. 
MK-3475 (Pembrolizumab; previously known as SCH 900475) is a potent and 
highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa 
isotope designed to directly block the interaction between PD-1 and its ligands, 
PD-L1 and PD-L2. 
4.2 	
Rationale for MK-3475 (Pembrolizumab) in Lymphoma 
PDL1 is expressed by a subset of immune suppressor and tumor cells in non-
Hodgkin lymphomas.32 Tumor cell PD-L1 expression, which is proposed to cause 
T-cell exhaustion and defective immune surveillance, is associated with likelihood 
of clinical response to anti-PD-1 therapy in solid tumors, but such a relationship has 
not been defined in in lymphoma.33 One clinical trial of anti-PD-1 blockade in 
DLBCL has been reported, using the monoclonal antibody pidilizumab as 
maintenance after autologous transplant for relapsed or refractory disease.34 In that 
single-arm study, PD I blockade was safe, with 19% experiencing grade 3-4 
neutropenia (without symptoms or complications) the most notable high-grade 
toxicity; there was a 3% rate of drug-related SAE's. Notably, 70% of subjects with a 
positive post-salvage PET CT scan-- typically associated with a poor outcome after 
transplant35-- remained in remission 16 months after their first dose. Treatment 
with pidilizumab resulted in a significant increase in the absolute number of PDL I - 
bearing activated helper T cells in the peripheral blood, and changes in PD-1 
bearing monocytes. In addition, an increase in the absolute number of circulating 
CD8 positive and central memory T cells, as well as CD4 positive central memory 
T cells, were observed. While exploratory and hypothesis generating, these 
findings supported an on-target and immunomodulatory effect of anti-PD-1 
blockade in the setting of DLBCL. 
A second trial of PD I blockade in B-cell lymphomas, specifically relapsed or 
refractory follicular lymphoma, was subsequently reported.36 In that study, 
pidilizumab was tested in conjunction with rituximab in treating 32 subjects. A 
median 10 pidilizumab treatments were given, and in conjunction with rituximab 
produced an overall response rate of 66%; median time to observed response was 
88 days (range, 53-392). It was observed that neve, effector memory, and central 
memory CD4+ T cells were increased post-treatment compared to baseline. In 
2014, a study of nivolumab (a fully human anti-PD1 antibody) in relapsed 
lymphoma including a cohort with DLBCL was reported.37 In that study, 36% 
(4/1 1) of patients with DLBCL responded to nivolumab as a single agent. 
To date, no studies of PD I blockade in treatment-naive lymphoma subjects have 
been reported, although this setting may represent a more opportune stage for 
immunomodulatory therapy. As opposed to the relapsed/refractory or post-
transplant setting, in which prior cytotoxic therapy or absent and minimal tumor 
burden may present suboptimal conditions for generation of a robust immune 
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Product: MK-3475 
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response, treatment-naive patients have relatively intact immunity, and tumor and 
immune infiltrate coexist in nodal tissue. In addition, certain therapies may 
enhance T cell antitumor immunity when combined with anti-PD-I blockage. In 
the case of DLBCL, the standard RCHOP regimen contains cyclophosphamide, 
which has been shown to induce T lymphocyte homeostatic proliferation, and 
enhance antigen-driven proliferation of tumor-immune lymphocytes.38 PD1 
blockade concomitant with cyclophosphamide-containing chemotherapy may 
therefore result in additive augmentation of T cell antitumor immunity, although 
concomitant prednisone use may exert a suppressive effect. Further investigation of 
changes in T-cell subsets over time, and clinical outcomes when combining MK-
3475 with chemotherapy, are underway in the solid tumor setting and proposed 
herein. 
Given evidence of tolerability and immune activation in lymphoma patients 
receiving anti-PD-1 therapy to date, and in light of the high worldwide incidence of 
DLBCL and its incurability in particular subsets, anti-PD-1 blockade in conjunction 
with standard chemoimmunotherapy for DLBCL represents an important avenue for 
further research. 
The selected subject population includes any patient with diffuse large B-cell 
lymphoma who are planned to receive 6 courses of R CHOP chemoimmunotherapy. 
The safety of co-administered PD I -blockade using MK-3475 and RCHOP 
chemoimmunotherapy is unknown. However, its unique and relatively favorable 
adverse effect profile to date suggest that such a combination may be feasible 
without expectation for significant additive toxicity. 
Therefore, this study proposes to assess the safety, tolerability, and immune 
activation of MK-3475, when co-administered with rituximab CHOP during 
induction in subjects with previously untreated DLBCL. 
4.2.1 Rationale for Dose Selection/Regimen/Modification 
Available PK results in subjects with melanoma, NSCLC, and other solid 
tumor types support a lack of meaningful difference in PK exposures 
obtained at a given dose among tumor types. An open-label Phase 1 trial 
(PN001) in melanoma subjects is being conducted to evaluate the safety 
and clinical activity of single agent pembrolizumab. The dose escalation 
portion of this trial evaluated three dose levels, I mg/kg, 3 mg/kg, and 10 
mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid 
tumors. All three dose levels were well tolerated and no dose-limiting 
toxicities were observed. This first in human study of pembrolizumab 
showed evidence of target engagement and objective evidence of tumor 
size reduction at all dose levels (1 mg/kg, 3 mg/kg and 10 mg/kg Q2W). 
No maximum tolerated dose (MTD) has been identified. 
In KEYNOTE-001, two randomized cohort evaluations of melanoma 
subjects receiving pembrolizumab at a dose of 2 mg/1<g versus 10 mg/kg 
Q3W have been completed. The clinical efficacy and safety data 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
demonstrate a lack of clinically important differences in efficacy response 
or safety profile at these doses. For example, in Cohort B2, advanced 
melanoma subjects who had received prior ipilimumab therapy were 
randomized to receive pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W. 
The overall response rate (ORR) was 26% (21/81) in the 2mg/kg group and 
26% (25/79) in the 10 mg/kg group (full analysis set (FAS)). The 
proportion of subjects with drug-related adverse events (AEs), grade 3-5 
drug-related AEs, serious drug-related AEs, death or discontinuation due to 
an AE was comparable between groups or lower in the 10 mg/kg group. 
Population PK analysis has been performed and has confirmed the 
expectation that intrinsic factors do not affect exposure to pembrolizumab 
to a clinically meaningful extent. Taken together, these data support the 
use of lower doses (with similar exposure to 2 mg/kg Q3W) in all solid 
tumor indications. 2 mg/kg Q3W is being evaluated in NSCLC in PN001, 
Cohort F30 and PN010, and 200 mg Q3W is being evaluated in head and 
neck cancer in PN012, which are expected to provide additional data 
supporting the dose selection. 
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is 
based on simulation results indicating that 200 mg will provide exposures 
that are reasonably consistent with those obtained with 2 mg/kg dose and 
importantly will maintain individual patient exposures within the exposure 
range established in melanoma as associated with maximal clinical 
response. A population PK model, which characterized the influence of 
body weight and other patient covariates on exposure, has been developed 
using available data from 476 subjects from PN001. The distribution of 
exposures from the 200 mg fixed dose are predicted to considerably 
overlap those obtained with the 2 mg/kg dose, with some tendency for 
individual values to range slightly higher with the 200 mg fixed dose. The 
slight increase in PK variability predicted for the fixed dose relative to 
weight-based dosing is not expected to be clinically important given that 
the range of individual exposures is well contained within the range of 
exposures shown in the melanoma studies of 2 and 1 0 mg/kg to provide 
similar efficacy and safety. The population PK evaluation revealed that 
there was no significant impact of tumor burden on exposure. In addition, 
exposure was similar between the NSCLC and melanoma indications. 
Therefore, there are no anticipated changes in exposure between different 
tumor types and indication settings. 
4.2.2 Rationale for Endpoints: 
The primary endpoint is estimation of clinically relevant toxicity and 
treatment-related mortality which result from the addition of MK-3475 to 
RCHOP chemoimmunotherapy (see section 8.0, Statistical Analysis Plan). 
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Protocol/Amendment No: CC9291 
4.2.2.1 	
Exploratory Endpoints: 
Overall response rate, event-free and overall survival. Event-free survival 
(EFS) is defined as time from diagnosis until relapse or progression, non-
protocol re-treatment of lymphoma, or death as a result of any cause. 
Overall survival is defined as survival from date of diagnosis to death from 
any cause. 
4.2.2.2 Biomarker Research: 
Tissue-based assays for tumor and immune infiltrate will be conducted 
centrally when archival tissue is available. 
In addition, we propose flow cytometric evaluation of CD3, CD4, CD8, 
CD14, PD-1, PD-L1, PD-L2 on peripheral blood mononuclear cells at 
several time points (see section 7.1.2.7). In previous studies of lymphoma 
patients treated with PD1 blockade, alterations in both PD LI and PD 1 
bearing monocytes have been observed in the peripheral blood. However 
neither of these studies were performed before or during first-line 
treatment. These analyses will seek to identify alterations in T cell subsets 
for comparison with these historical studies, and exploration of association 
with treatment outcomes achieved with study therapy. 
5.0 METHODOLOGY 
Entry Criteria: Previously untreated diffuse large B cell lymphoma or grade 3B follicular 
lymphoma (of any stage). Subjects must be planned to receive full course (6 cycles) of 
RCHOP chemoimmunotherapy as per clinical standard of care. Patients may have de 
novo DLBCL, and /or any of the following:- 
- Composite lymphomas, which include both diffuse DLBCL and another histology 
(most commonly follicular lymphoma) in the same lymph node 
- Transformed lymphoma with DLBCL histology, as long as the patient has not received 
prior therapy for lymphoma 
- Discordant presentations, such as DLBCL in a lymph node and low-grade lymphoma 
such as follicular lymphoma in the bone marrow. 
5.1.1 	
Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
I. Be willing and able to provide written informed consent/assent for the trial. 
2. 	
Be 18 years of age on day of signing informed consent. 
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Product: MK-3475 
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3. Have measurable nodal disease, including at least 1 disease site measuring 1.5 cm in 
longest dimension on CT or FDG-PET 
4. Have a performance status of 0 or 1 on the ECOG Performance Scale (PS) 
5. Demonstrate adequate organ function as defined in Table 1 below: 
Table 1: Ade uate Or an Function Laboratory Values 
System 
Laboratory Value 
Hematological 
Absolute neutrophil count 
(ANC) 
>1,500 /mcL except in cases of marrow 
infiltration by lymphoma 
Platelets 
>100,000 / mcL except in cases of marrow 
infiltration by lymphoma 
Hemoglobin 
>9 g/dL or >5.6 mmol/L except in cases of 
marrow infiltration by lymphoma 
Renal 
Serum creatinine OR 
5_1.5 X upper limit of normal (ULN) OR 
Measured or calculateda 
creatinine clearance 
(GFR can also be used in place 
of creatinine or CrC1) 
>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 
Coagulation 
International Normalized Ratio 
([NR) 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, or subject is 
shown to have an antiphospholipid antibody on 
workup 
aCreatinine clearance should be calculated per institutional standard. 
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6. 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. 
7. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication. Subjects of 
childbearing potential are those who have not been surgically sterilized or have not 
been free from menses for > I year. 
8. Male subjects should agree to use an adequate method of barrier contraception starting 
with the first dose of study therapy through 120 days after the last dose of study 
therapy. 
5.1.2 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of 
an investigational agent and received study drug or using an investigation device within 
4 weeks of the first dose of treatment. 
2. 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. 
3. Has a known additional, malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the 
skin, or in situ cervical cancer that has undergone potentially curative therapy. 
4. Has known active central nervous system (CNS) metastases and/or carcinomatous 
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. 
5. No active autoimmune disease that has required systemic treatment in past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment 
6. Has a history of (non-infectious) pneumonitis that required steroids or current 
pneumonitis. 
7. Has an active infection requiring intravenous antibiotic therapy. 
8. 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. 
9. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
10. 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. 
11. Has received prior therapy with an anti-PD-1, anti-PD-L I, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or 
checkpoint pathways). 
12. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
13. Has known active Hepatitis B (e.g., HBsAg reactive or HBV DNA detectable) or 
Hepatitis C (e.g., HCV RNA [qualitative] is detected). 
14. Has received a live vaccine within 30 days prior to the first dose of trial treatment. 
5.2 	
Study Treatments 
The experimental treatment MK-3475 is outlined below in Table 2. RCHOP is to be 
administered at standard doses which may be adjusted at clinician discretion at baseline 
and during treatment (rituximab 375 mg/m2 day 1, cyclophosphamide 750 mg/m2 day 
1 , doxorubicin 50 mg/m2 day 1, vincristine 2 mg capped dose day 1 , prednisone 100 
mg PO daily day 1-5). 
Institutional guidelines and clinical judgment will be followed with regard to 
administration of RCHOP. 
MK-3475 is to be administered on the same day or within 3 days of RCHOP for each 
cycle. 
Table 2: Trial Treatment 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administration 
Regimen/Treatment 
Period 
Use 
MK- 
3475 
200 mg 
Q3 wks 
induction* 
IV infusion 
Induction 
Experimental 
5.2.1 	
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 Table 3 below. 
Table 3 Dose Modification Guidelines for Pembrolizumab-Related Adverse Events 
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Toxicity 
Hold 
Treatment 
For Grade 
Timing for Restarting Treatment 
Treatment Discontinuation 
Diarrhea/Colitis 
2-3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
AST, ALT, or 
Increased 
Bilirubin 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose 
3-4 
Permanently discontinue 
(see exception below)0 
Permanently discontinue 
Type I diabetes 
mellitus (if new 
onset) or 
Hyperglycemia 
T I DM or 
3-4 
Hold pembrolizumab for new onset 
Type 1 diabetes mellitus or Grade 3-4 
hyperglycemia associated with 
evidence of beta cell failure 
Resume pembrolizumab when patients are clinically and 
metabolically stable 
Hypophysitis 
2-4 
Toxicity resolves to Grade 0-1. 
Therapy with pembrolizumab can be 
continued while endocrine 
replacement therapy is instituted 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
Hyperthyroidis 
m 
3 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Hypothyroidism 
Therapy with pembrolizumab can be 
continued while thyroid replacement 
therapy is instituted 
Therapy with pembrolizumab can be continued while 
thyroid replacement therapy is instituted 
Infusion 
Reaction 
2' 
Toxicity resolves to Grade 0-1 
Permanently discontinue if toxicity develops despite 
adequate premedication 
3-4 
Permanently discontinue 
Permanently discontinue 
Pneumonitis 
2 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks. 
Recurrent 
grade 2, or 
grade 3-4 
Permanently discontinue 
Permanently discontinue 
Renal Failure or 
Nephritis 
2 
"Foxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
3-4 
Permanently discontinue 
Permanently discontinue 
All Other Drug- 
Related 
Toxicity' 
3 or Severe 
Toxicity resolves to Grade 0-1 
Toxicity does not resolve within 12 weeks of last dose or 
inability to reduce corticosteroid to 10 mg or less of 
prednisone or equivalent per day within 12 weeks 
4 
Permanently discontinue 
Permanently discontinue 
Note: Permanently discontinue for any severe or Grade 3 drug-related AE that recurs or any life-threatening event. 
' For patients with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST or ALT increases by greater than or equal to 50% 
relative to baseline and lasts for at least 1 week then patients should be discontinued. 
'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 
mUhr to 50 mUhr). Otherwise dosing will be held until symptoms resolve and the subject should be premedicatcd for the next scheduled dose; 
Refer to Section 5.4: Infusion Treatment Guidelines for further management details. 
' Patients with intolerable or persistent Grade 2 drug-related AE may hold study medication at physician discretion. Permanently discontinue study 
drug for persistent Grade 2 adverse reactions for which treatment with study drug has been held, that do not recover to Grade 0-I within 12 weeks 
of the last dose. 
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Subjects who require delay in any RCHOP cycle for more than 14 days during the induction 
period (for any reason other than disease progression) will receive no further study therapy, 
and count toward the study stopping rule (see section 8.1) RCHOP administration may 
continue if pembrolizumab is held due to drug-related toxicity as per Dose Modification 
guidelines (Table 3) Subjects who discontinue study therapy will remain in follow-up as per 
protocol for improvement or stabilization of study drug-related toxicities. 
5.2.2 	
Timing of Dose Administration 
Trial treatment should be generally be administered on the day before 
(cycle I) or concurrently (cycles 2-6) with RCHOP, every 3 weeks, after 
completion of baseline procedures/assessments Trial Flow Chart 
(Section 6.1). Note that MK-3475 may be administered within 3 days of 
RCHOP if indicated. Missed doses of MK-3475 will not be made up. 
MK-3475 and RCHOP may both be delayed for up to 14 days if 
clinically indicated. However, as noted in in section 5.2.1, ,any subject 
who requires a delay in any RCHOP cycle for more than 14 days (e.g. 5 
weeks from a prior dose on a planned 3 week cycle) requires 
discontinuation from therapy. 
MK-3475 will be administered as a 30 minute IV infusion. Sites should 
make every effort to target infusion timing to be as close to 30 minutes 
as possible. The Pharmacy Manual contains specific instructions for 
MK-3475 reconstitution, preparation of the infusion fluid, and 
administration. 
5.2.3 	
Trial Blinding/Masking 
This is an open-label, single arm prospective trial; therefore, the 
investigator and subject will know the treatment administered. 
5.3 	
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing trial. If there is a clinical indication for one of these or 
other medications or vaccinations specifically prohibited during the trial, 
discontinuation from trial therapy or vaccination may be required. The final decision 
on any supportive therapy or vaccination rests with the investigator and/or the subject's 
primary physician. However, the decision to continue the subject on trial therapy or 
vaccination schedule requires the mutual agreement of the Investigator and the subject. 
5.3.1 	
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 
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Product: MK-3475 
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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. 
Use of filgrastim (GCSF, Neupogen) or peg-filgrastim (peg-GCSF, 
Neulasta) is permitted at the clinician's discretion. 
Intrathecal methotrexate or cytarabine may be administered for central 
nervous system prophylaxis at the clinician's discretion. 
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 are to be 
recorded after 30 days after the last dose of trial treatment should be 
recorded for SAEs and ECIs as defined in Section 7.2. 
5.3.2 	
Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the 
Screening and Induction Phase of this trial: 
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than MK-3475 
• Radiation therapy (may be administered more than 30 days after last 
dose of study therapy if planned for consolidation) 
• Live vaccines within 30 days prior to the first dose of trial treatment 
and while participating in the trial. Examples of live vaccines 
include, but are not limited to, the following: measles, mumps, 
rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) 
vaccine. Seasonal influenza vaccines for injection are generally 
killed virus vaccines and are allowed; however intranasal influenza 
vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not 
allowed. 
• Glucocorticoids for any purpose other than as prescribed with the 
RCHOP regimen, or for management of rituximab or study-drug 
related infusion reactions, or if indicated to modulate symptoms 
from an event of clinical interest of suspected immunologic etiology. 
The use of physiologic doses of corticosteroids is permitted 
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. 
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5.4 	
Supportive Care 
Subjects should receive appropriate supportive care measures as deemed necessary by 
the treating investigator. Suggested supportive care measures for the management of 
adverse events with potential immunologic etiology are outlined below. Where 
appropriate, these guidelines include the use of oral or intravenous treatment with 
corticosteroids as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is decreased. 
For each disorder, attempts should be made to rule out other causes such as metastatic 
disease or bacterial or viral infection, which might require additional supportive care. 
The treatment guidelines are intended to be applied when the investigator determines the 
events to be related to pembrolizumab. 
Note: if after the evaluation the event is determined not to be related, the investigator is 
instructed to follow the ECI reporting guidance but does not need to treat as 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. 
• Diarrhea/Colitis: 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
o All subjects who experience diarrhea/colitis should be advised to drink liberal 
quantities of clear fluids. If sufficient oral fluid intake is not feasible, fluid and 
electrolytes should be substituted via IV infusion. For Grade 2 or higher diarrhea, 
consider GI consultation and endoscopy to confirm or rule out colitis. 
o For Grade 2 diarrhea/colitis that persists greater than 3 days, administer oral 
corticosteroids. 
o For Grade 3 or 4 diarrhea/colitis that persists > 1 week, treat with intravenous 
steroids followed by high dose oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
• Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis IDKAJ) or > Grade 
3 Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
o For T1 DM or Grade 3-4 Hyperglycemia 
• Insulin replacement therapy is recommended for Type I diabetes mellitus and 
for Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 
• Evaluate patients with serum glucose and a metabolic panel, urine ketones, 
glycosylated hemoglobin, and C-peptide. 
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 or 
less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate hormones 
may be required as the steroid dose is tapered. 
• 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 3-4 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 I 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: 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
o For Grade 2 events, treat with corticosteroids. 
o 
For Grade 3-4 events, treat with systemic corticosteroids. 
o 
When symptoms improve to Grade 1 or less, steroid taper should be started and continued over 
no less than 4 weeks. 
• 
Management of Infusion Reactions: Signs and symptoms usually develop during or shortly 
after drug infusion and generally resolve completely within 2 business days of completion of 
infusion. 
4 below shows treatment guidelines for subjects who experience an infusion reaction 
associated with administration of pembrolizumab (MK-3475). 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Mild reaction; infusion interruption 
not indicated; intervention not 
indicated 
Grade 2 
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 
mUhr to 50 mUhr). Otherwise dosing will be 
held until symptoms resolve and the subject 
should be premedicated for the next scheduled 
dose.  • 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be 
permanently discontinued from further trial 
treatment administration. 
Subject may be premedicatcd 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). 
Requires infusion interruption but 
responds promptly to symptomatic 
treatment (e.g., antihistamines, 
NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for 
<=24 hrs 
Grades 3 or 4 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDS 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Epinephrine 
No subsequent dosing 
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. 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
Table 4 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Life-threatening; pressor or ventilatory 
support indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from 
further trial treatment administration. 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug 
administration. 
I 
5.4.1 Additional Events of Clinical Interest 
An overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an 
Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is 
not associated with clinical symptoms or abnormal laboratory results. 
5.5 	
Diet/Activity/Other Considerations 
5.5.1 Diet 
Subjects should maintain a normal diet unless modifications are required to 
manage an AE such as diarrhea, nausea or vomiting. 
5.5.2 Contraception 
MK-3475 may have adverse effects on a fetus in utero. Furthermore, it is not 
known if MK-3475 has transient adverse effects on the composition of sperm. 
Non-pregnant, non-breast-feeding women may be enrolled if they are willing to 
use 2 methods of birth control or are considered highly unlikely to conceive. 
Highly unlikely to conceive is defined as 1) surgically sterilized, or 2) 
postmenopausal (a woman who is >45 years of age and has not had menses for 
greater than 1 year will be considered postmenopausal), or 3) not heterosexually 
active for the duration of the study. The two birth control methods can be either 
two barrier methods or a barrier method plus a hormonal method to prevent 
pregnancy. Subjects should start using birth control from study Visit 1 
throughout the study period up to 120 days after the last dose of study therapy. 
The following are considered adequate barrier methods of contraception: 
diaphragm, condom (by the partner), copper intrauterine device, sponge, or 
spermicide. Appropriate hormonal contraceptives will include any registered 
and marketed contraceptive agent that contains an estrogen and/or a 
progestational agent (including oral, subcutaneous, intrauterine, or 
intramuscular agents). 
Subjects should be informed that taking the study medication may involve 
unknown risks to the fetus (unborn baby) if pregnancy were to occur during the 
study. In order to participate in the study they must adhere to the contraception 
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Product: MK-3475 
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requirement (described above) for the duration of the study and during the 
follow-up period defined in section 7.2.2-Reporting of Pregnancy and Lactation 
to Merck. If there is any question that a subject will not reliably comply with 
the requirements for contraception, that subject should not be entered into the 
study. 
5.5.3 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with MK-3475, 
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 Merck without delay and within 2 business days of 
investigator knowledge 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 Merck. If a male subject 
impregnates his female partner the study personnel at the site must be informed 
immediately and the pregnancy reported to Merck and followed as described 
above and in Section 7.2.2. 
5.5.4 Use in Nursing Women 
It is unknown whether MK-3475 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. 
5.6 	
Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be discontinued from the 
trial at the discretion of the investigator. In addition, a subject may be withdrawn by 
the investigator if enrollment into the trial is inappropriate, the trial plan is violated, or 
for administrative and/or other safety reasons. Subjects who require cessation of study 
therapy but do not withdraw consent may remain in standard follow-up for up to 5 
years. 
A subject must be discontinued from study therapy for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed disease progression 
Note: A subject may be granted an exception to continue on treatment with 
radiographic progression if clinically stable or clinically improved, at clinician 
discretion 
• A required dose delay of RCHOP of more than 14 days (past the typical 3 weekly 
cycle) during the Induction Period 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
• Adverse experiences deemed unacceptable by the investigator, including those 
described in Section 5.2 and Table 3 
• Intercurrent illness that does not recover within 12 weeks, preventing further 
administration of treatment 
• Investigator's decision WI withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Administrative reasons 
Subjects who discontinue for reasons other than progressive disease will complete off-
study visit at 12 weeks after the last dose of MK3475 (+/- 14 days). However, all 
patients may have post-treatment follow-tip for disease status up to 5 years at longest-- or 
until disease progression, initiating a non-study cancer treatment, withdrawing consent, 
or becoming lost to follow-up. 
(For those with unacceptable adverse experiences grade 3 or higher, as described in 
section 5.2.1,follow-up on study until resolution or stabilization of toxicities is required 
up to a maximum of 1 year from occurrence of the toxicity.) 
5.7 	
Subject Replacement Strategy 
Subjects who fail to complete study therapy during induction will not be replaced. 
5.8 	
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. 
6.0 	
TRIAL FLOW CHART 
.1 Study Flow Chart 
- 
Induction Treatment 
Off- 
Long 
term 
Screening 
CI 
CI 
Cycles 
Remission 
Study 
follow up 
Treatment Cycleffitle 
Period 
Day 1 
Day 2 
2-61 
Status visit 
Visits  
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Product: MK-3475 
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Scheduling Timing and Window 
42 to -Id 
± 3d 
± 3d 
4-6 weeks after 
Cycle 6 
± 7d 
12 weeks 
after cycle 
6 
± I4d 
Informed Consent 
x 
Inclusion/Exclusion Criteria 
x 
Medical History 
x 
Prior and Concomitant Medication 
Review 
x 
x 
x 
x 
x 
Trial Treatment Administration 
X 
(RCHOP 
ONLY) 
X 
Post-study anticancer therapy status 
x 
Survival Status 
x 
Review Adverse Events' 
X 
X 
X 
x 
X' 
Physical Examination 
x 
x 
x 
x 
x 
Vital Signs and Weight 
X 
x 
x 
x 
X 
Height 
x 
ECOG Performance Status 
x 
x 
x 
x 
x 
Pregnancy Test — Urine or Serum 0- 
IiCG2 
X 
PT/INR and aPTT 
x 
CBC with Differentiar 
x 
x 
x 
x 
x 
Comprehensive Serum Chemistry 
Pane' and IDE! 
X 
x 
x 
x 
x 
HepB S Ag, Core Ah I lep C and HIV 
screen 
x 
Urinalysis 
X 
T3, FT4 and TSH 
X 
x 
x 
x 
Vitamin D level (25-hydroxy 
Vitamin D, total) 
X 
Tumor Imaging^ 
x 
x 
Bone Marrow Biopsy and Aspirate' 
x 
x 
Other Procedures (Optional)' 
x 
Archival Tissue Collection, if 
Feasible' 
x 
Correlative Studies Blood Collection' 
X 
x 
x 
x 
i . On Cycles 2-6, MK-3475 and RCHOP may be administered on the same day if scheduling/administrative factors permit. MK-3475 and 
RCHOP should be co-administered within 3 days. RCHOP+MK-3475 cycles may be delayed as clinically indicated. 
2. For women of child-bearing potential only. 
3. AL will be recorded from the time of a subject signing consent, up until 90 days after the last dose of MK-3475. 
4. See Section 7.1.2.5: Tumor Imaging: Baseline and Remission Status imaging is mandatory. Other interim and surveillance scans are 
performed at clinician discretion. Baseline imaging must be performed within 8 weeks of initiating study drug therapy. Remission status 
imagine should be performed using FDG PET-CT, 
5. Screening bone marrow biopsy and aspirate may be completed up to 12 weeks prior to study enrollment, and at time of CR. Bone marrow 
requirements may be waived at the discretion of the Sponsor-Investigator. 
6. See Section 7.1.4. Other procedures during screening are at the discretion of the treating investigator and may include standard-of-care 
assessments of cardiac function, central venous access device placement, other laboratory studies, or other measures. 
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Product: MK-3475 
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Treatment Cycle/Title 
Screening 
Period 
Induction Treatment 
, 
Remission 
Status visit 
Off- 
Study 
Visit8  
Long 
term 
follow up 
CI 
Day I 
CI 
Day 2 
Cycles 
2-61 
Scheduling Timing and Window 
-42 to-Id 
± 3d 
± 3d 
4-6 weeks after 
Cycle 6 
± 7d 
12 weeks 
after cycle 
6 
± 14d 
7. The presence of archival tissue will be assessed during screening. When available this tissue will be provided for central biomarker analysis. 
8. Baseline correlative blood draw may be done at any time prior to the CID1 dose. Induction Treatment blood draw is completed only during 
C3D1, prior to study dosing. Off study blood draw should be done at time of disease progression or prior to start of second-line anticancer 
therapy, if possible, See Section 7.1.2.7. for discussion of correlative study blood draws. 
9. The Off-Study visit is performed 12 weeks after the last dose of study drug, irrespective of the reason drug is stopped (completion of 
therapy, discontinuation for toxicity, other reason). It may be performed earlier in subjects who require additional antilymphoma therapy. 
10. Sec Table 6 for details of these tests. Mid-cycle CBC with differential and CMP (without LDH) are lobe performed as in section 7.1.3. 
7.0 TRIAL PROCEDURES 
7.1 Trial Procedures 
The Trial Flow Chart - Section 6.1 summarizes the trial procedures to be performed at 
each visit. Individual trial procedures are described in detail below. Laboratory and 
imaging studies performed for standard of care purposes may be used to satisfy screening 
requirements, if they are performed within the appropriate timeframe noted in Section 6.1. 
It may be necessary to perform these procedures at unscheduled time points if deemed 
clinically necessary by the investigator. 
Furthermore, additional evaluations/testing may be deemed necessary by the Investigator 
and/or 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 and Study-Related Procedures 
7.1.1.1 Informed Consent 
The Investigator must obtain documented consent from each potential 
subject prior to participating in a clinical trial. 
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. 
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The initial informed consent form, any subsequent revised written 
informed consent form and any written information provided to the 
subject must receive the IRB/ERC's approval/favorable opinion in 
advance of use. The subject or his/her legally acceptable representative 
should be informed in a timely manner if new information becomes 
available that may be relevant to the subject's willingness to continue 
participation in the trial. The communication of this information will be 
provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject's dated signature or by 
the subject's legally acceptable representative's dated signature. 
Specifics about a trial and the trial population will be added to the 
consent form template at the protocol level. The informed consent will 
adhere to IRB/ERC requirements, and applicable laws and regulations. 
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. 
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7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current 
details regarding disease status. 
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer 
treatments including systemic treatments, radiation and surgeries. 
7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-
neoplastic therapy initiated after the last dose of trial treatment. 
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 Section 
12.2). Toxicities will be characterized in terms regarding seriousness, 
causality, toxicity grading, and action taken with regard to trial 
treatment. 
All AEs of unknown etiology associated with MK-3475 exposure should 
be evaluated to determine if it is possibly an event of clinical interest 
(ECI) of a potentially immunologic etiology (irAE). 
Please refer to section 7.2 for detailed information regarding the 
assessment and recording of AEs. 
7.1.2.2 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. 
7.1.2.3 Vital Signs 
The investigator or qualified designee will take vital signs at screening, 
prior to the administration of each dose of trial treatment and at 
treatment discontinuation as specified in the Trial Flow Chart (Section 
6.0). Vital signs should include temperature, pulse, respiratory rate, 
weight and blood pressure. Height will be measured at screening only. 
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7.1.2.4 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see 
Section 12.4) at screening, prior to the administration of each dose of 
trial treatment and discontinuation of trial treatment as specified in the 
Trial Flow Chart. 
7.1.2.5 Tumor Imaging and Assessment of Disease 
Tumor imaging consists of standard of care imaging at baseline during 
the screening period, including either FDG-PET/CT or contrast-
enhanced computed tomography (CT) of the chest, abdomen, and pelvis. 
FDG PET-CT scanning is preferred at baseline and required for 
determination of Remission Status visit. For measurement of response, 
2014 criteria as described in "Recommendations for Initial Evaluation, 
Staging, and Response Assessment of Hodgkin and Non-Hodgkin 
Lymphoma: The Lugano Classification" will be used (see Appendix 
14.3).39  
• Baseline imaging must be performed within 8 weeks of 
initiating study drug therapy. Additional baseline imaging may 
be performed as indicated for standard of care and clinical 
purposes including MRI, or CT imaging of the neck. 
• Remission Status tumor imaging performed 4-6 weeks, +/-7 
days, after 6 cycles of induction therapy with MK-3475 + 
RCHOP is required. 
Interim restaging using CT scan during R CHOP may be conducted as 
per standard of care but are not required. 
All CT scans should be performed with IV contrast unless 
contraindicated, and abdominal and pelvis scans should be performed 
with oral contrast. When FDG PET/CT is performed, IV and oral 
contrast are not required and the scan used for PET attenuation 
correction is adequate. 
All CT and FDG-PET/CT scans are to be interpreted locally; central 
review of radiology will not be performed. 
7.1.2.6 Bone marrow aspirate and biopsy 
A bone marrow aspirate and biopsy will be obtained up to 12 weeks 
before the first dose of study drug, and for confirmation of CR when 
indicated. FDG PET-CT may suffice for identification of bone marrow 
involvement39 and bone marrow aspirate and biopsy requirements may 
be waived by the Sponsor-Investigator. These samples will be evaluated 
locally. 
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7.1.2.7 Tumor Tissue Collection and Correlative Studies Blood Sampling 
Assessment of available archival tumor tissue for correlative study 
analysis will be performed during the screening period. Any available 
pretreatment biopsy tissue will be provided for central correlative study 
analysis. 
Peripheral blood correlative study samples will be performed at the 
following time-points (see Section 6.1, Trial Flow Chart): 
1. Baseline (collected any time prior to cycle 1 day 1 study drug 
dosing) 
2. Cycle 3 day 1 prior to drug dosing 
3. At the Response Assessment visit (4-6 weeks, +/-7 days, after cycle 
6) for subjects who complete all 6 cycles of therapy 
4. At the off-study visit, at the time of disease progression, or at time of 
initiation of second-line therapy (whichever occurs first). 
Specimen Requirements: Submission for flow cytometry 
• A 5-10 mL specimen of peripheral blood in a lavender- (EDTA) or 
green- (sodium heparin) tube is acceptable for each draw. 
• Storage/Transport Temperature: Specimens can be transported with a 
cold pack or wet ice, but do not fix or freeze specimens. 
• Unacceptable Conditions: Frozen specimens, specimens greater than 48 
hours old, specimens fixed in formalin for flow cytometry 
• Address for shipping specimens: 
Attn: Katy Dougherty, Hematopathology Lead 
Seattle Cancer Care Alliance 
Hematopathology Laboratory G7800 
825 Eastlake Ave E. 
Seattle, WA 98109 
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this 
trial are provided below and in section 6.1 (Study Flow Chart). All chemistry and 
hematology studies required to start a new cycle may be performed within 3 days of 
dosing prior to day 1 of that cycle. In addition, a CBC with differential and chemistry 
panel (excluding LDH; see Table 6) will be performed between cycles. The 
recommended timing of this mid-cycle laboratory evaluation is between day 8-15 of 
each cycle. 
7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry and Urinalysis) 
Laboratory tests for hematology, chemistry, urinalysis, and others are specified 
in Table 6 below. 
HBV Surface Antigen (Hep B S Ag), HBV Core Antibody (Hep B Core Ab), 
HIV screening, Hep C Ab screening will be performed during the screening 
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period, and reviewed and managed at the study site as per clinical standard of 
care. 
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Table 6: Laboratory Tests 
Hematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum P-human chorionic 
gonadotropint 
Hemoglobin 
Alkaline phosphatase 
Glucose 
(3-hCG)t 
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) 
Carbon Dioxide t. 
results are noted 
Free tyroxine (14) 
(CO2 or biocarbonate) 
, Urine pregnancy 	
Thyroid stimulating 
test t 	
I hormone (TSH) 
Calcium 
Chloride 
Blood for correlative studies 
Glucose 
HBV Surface Antigen, 
1 HBV Core Ab, HIV screen, 
Hep C Ab screening 
Vitamin D (25- 
hydroxyvitamin D, total) 
Potassium 
Sodium 
Total Bilirubin 
, 
Direct Bilirubin (If total 
bilirubin is elevated above 
the upper limit of normal) 
Total protein 
Blood Urea Nitrogen 
t Perform on women of childbearing potential only. If urine pregnancy results cannot be confirmed as 
negative, a serum pregnancy test will be required. , 
t. If considered standard of care in your region. 
After Cycle 1, pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. 
Results must be reviewed by the investigator or qualified designee and found to be acceptable 
prior to each dose of trial treatment. 
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7.1.4 	
Other Procedures 
Standard of care practices including baseline determination of cardiac ejection 
fraction, placement of a vascular access devices, mid-cycle analysis of 
laboratory parameters during therapy, any additional imaging, additional 
laboratory studies for evaluation or management tumor lysis, and any 
medications for management of rituximab infusion reactions may be undertaken 
as part of standard of care. Dose reductions of RCHOP may be performed at 
discretion of the treating clinician. 
7.1.5 	
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. 
7.1.6 	
Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific 
procedure-related details are provided above in Section 7.1 - Trial Procedures. 
7.1.6.1 	
Screening Period 
The screening period begins upon signing consent and includes 
evaluation of available tissue specimen for study-related, central 
review, any ancillary/staging/laboratory testing and standard-of-
care evaluations (including "Other Procedures" as in Section 7.1.4) 
prior to Cycle 1 Day 1 of study therapy. The screening period may 
last up to 42 days. 
7.1.6.2 	
Induction Treatment Period 
The induction treatment period includes RCHOP + study drug 
therapy, administered every 3 weeks for 6 cycles. MK-3475 is to 
be administered on cycle 1 day 1, and RCHOP will be given on 
Cycle 1 day 2. On future cycles, both treatments will be 
administered on the same day when feasible. However, MK-3475 
and RCHOP may be given up to 3 days apart if needed for 
scheduling or administrative reasons. Whenever RCHOP treatment 
is delayed, study drug administration will also be delayed so that 
MK-3475 and RCHOP are co-administered on the same day (or 
within 3 days). Interim restaging will be performed as clinically 
indicated (see Tumor Imaging 7.1.2.5). 
7.1.6.3 	
Remission Status Visit 
All subjects will undergo a visit for determination of remission 
status, 4-6 weeks (+/- 7 d) after completion of induction therapy. 
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This visit will include review of tumor imaging (FDG PET-CT)) as 
well as medical history, physical exam, and laboratory evaluations 
required for determination of remission status. Remission status is 
to be determined according to 2014 Criteria ("The Lugano 
Classification")39 as in Appendix 14.3. 
For patients with equivocal post-induction imaging or clinical 
findings, in whom remission status cannot be clearly ascertained, 
further workup as per clinical standard of care including tumor 
biopsy or repeat imaging should be undertaken to confirm remission 
status (PR or CR) prior to proceeding onto the Follow-Up Period 
7.1.6.4 	
Off-Study Visit 
12 weeks (+/- 14 d) after the last dose of MK-3475, irrespective of 
cause of cessation, an off-study visit should be performed. 
However, if a subject requires additional anti-lymphoma therapy, 
the off-study visit may occur earlier. The off-study visit is intended 
to coincide generally with the requirement that ECI be reported up 
to 90 days from last dose of MK-3475 except for subjects who 
require additional anticancer therapy. 
The off-study visit will include laboratory studies (CBC diff, CMP, 
LDH), medical history, physical exam, remission status, 
concomitant medications, adverse-events, and documentation of any 
ECI and subsequent management. 
After the off-study visit, additional surveillance for DLBCL relapse 
will be conducted as per routine standard of care for up to 5 years 
unless other criteria for withdrawal are met (see 
Section 5.6). 
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), 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. 
Merck product includes any pharmaceutical product, biological product, device, 
diagnostic agent or protocol-specified procedure, whether investigational (including 
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Product: MK-3475 
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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 within the follow-up period specified by the protocol, or prescribed in clinical 
practice, from overdose (whether accidental or intentional), from abuse and from 
withdrawal. 
Adverse events may also occur in screened subjects during any pre-allocation baseline 
period as a result of a protocol-specified intervention, including washout or 
discontinuation of usual therapy, diet, placebo treatment or a procedure. 
Adverse events grade 3 and higher, as well as AEs requiring clinical intervention/dose 
modification, ECIs, and SAEs of any grade, will be recorded from the time the consent 
form is signed through 90 days following cessation of MK-3475 treatment 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. 
7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose to 
Merck 
For purposes of this trial, an overdose will be defined as any dose exceeding the 
prescribed dose for MK-3475 by 20% over the prescribed dose. No specific 
information is available on the treatment of overdose of MK-3475. In the event 
of overdose, MK-3475 should be discontinued and the subject should be 
observed closely for signs of toxicity. Appropriate supportive treatment should 
be provided if clinically indicated. This reporting threshold will also be used 
for IRB reporting. 
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 (Ed), using 
the terminology "accidental or intentional overdose without adverse effect." 
All reports of overdose with and without an adverse event must be reported 
within 2 business days of investigator knowledge to Merck Global Safety. 
(Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.2 Reporting of Pregnancy and Lactation 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), including the pregnancy 
of a male subject's female partner that occurs during the trial or within 120 days 
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of completing the trial completing the trial, or 30 days following cessation of 
treatment if the subject initiates new anticancer therapy, whichever is earlier. 
All subjects and female partners of male subjects who become pregnant must be 
followed to the completion/termination of the pregnancy. Pregnancy outcomes 
of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted 
ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported 
as serious events (Important Medical Events). If the pregnancy continues to 
term, the outcome (health of infant) must also be reported. 
Such events must be reported within 2 business days of investigator knowledge 
to Merck Global Safety. (Attn: Worldwide Product Safety; FAX 215 993-1220) 
7.2.3 Reporting Requirements for Adverse Events/Adverse Reactions 
7.2.3.1 Serious Adverse Events 
A serious adverse event is any adverse event occurring at any dose or 
during any use of Merck's product that: 
• Results in death; 
• Is life threatening; 
• Results in persistent or significant disability/incapacity; 
• Results in or prolongs an existing inpatient hospitalization; 
• Is a congenital anomaly/birth defect; 
• Is a new cancer (that is not a condition of the study); 
• Is associated with an overdose; 
• Is another important medical event 
Progression of the cancer under study is not considered an adverse 
event unless it results in hospitalization or death. 
Any serious adverse event, or follow up to a serious adverse event, 
including death due to any cause other than progression of the cancer 
under study that occurs to any subject from the time the consent is 
signed through 90 days following cessation of treatment, or the 
initiation of new anti-cancer therapy, whichever is earlier, whether or 
not related to Merck product, must be reported within 2 business days 
of investigator knowledge to Merck Global Safety. 
Non-serious Events of Clinical Interest will be forwarded to Merck 
Global Safety and will be handled in the same manner as SAEs. 
Additionally, any serious adverse event, considered by a qualified 
investigator to be related to Merck product that is brought to the 
attention of the investigator at any time outside of the time period 
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Product: MK-3475 
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specified in the previous paragraph also must be reported immediately 
to Merck. 
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 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. 
All subjects with serious adverse events must be followed up for 
outcome. 
7.2.3.2  Events of Clinical Interest (ECI) 
Selected non-serious and serious adverse events are also known as 
Events of Clinical Interest (ECI) as defined below, and must be 
reported within 2 business days to Merck Global Safety. (Attn: 
Worldwide Product Safety; FAX 215 993-1220). 
For the time period beginning when the consent form is signed through 
90 days after the last dose of MK-3475, or until the initiation of new 
anticancer therapy (whichever is earlier), any ECI must be reported 
within 2 business days to Merck Global Safety. 
Events of clinical interest for this trial include: 
1. an overdose of Merck product, as defined in Section 7.2. Definition 
of an Overdose for This Protocol and Reporting of Overdose to Merck, 
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. 
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7.2.4 	
Evaluating Adverse Events 
A qualified investigator will evaluate all adverse events according to the NCI 
Common Terminology for Adverse Events (CTCAE), version 4.0. Any adverse 
event which changes CTCAE grade over the course of a given episode will have 
each change of grade recorded on the adverse event case report 
forms/worksheets. 
All adverse events regardless of CTCAE grade must also be evaluated for 
seriousness. Adverse events will be recorded, and SAE's reported, from the time 
of signed consent and for up to 90 days after the last treatment of MK-3475 is 
administered. 
Table 7:Evaluating Adverse Events 
A qualified investigator 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: 
tResults in death; or 
tls 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 
tResults in a persistent or significant disability/incapacity 
(substantial disruption of one's ability to conduct normal life functions); 
or 
tResults in or prolongs an existing inpatient hospitalization 
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(hospitalization is defined as an inpatient admission, regardless of 
length of stay, even if the hospitalization is a precautionary measure for 
continued observation. (Note: Hospitalization [including hospitalization 
for an elective procedure] for a preexisting condition which has not 
worsened does not constitute a serious adverse event.); or 
tIs a congenital anomaly/birth defect (in offspring of subject taking 
the product regardless of time to diagnosis);or 
Is a new cancer; (that is not a condition of the study) or 
Is an overdose (whether accidental or intentional). Any adverse event 
associated with an overdose is considered a serious adverse event. An 
overdose that is not associated with an adverse event is considered a 
non-serious event of clinical interest and must be reported within2 
business days of investigator knowledge.. 
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 t). 
Record the start and stop dates of the adverse event. If less than I day, 
indicate the appropriate length of time and units 
Did the adverse event cause the Merck product to be discontinued? 
Did the Merck product cause the adverse event? The determination of 
the likelihood that the 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 the Merck product and the AE; the greater the correlation 
with the components and their respective elements (in number and/or 
intensity), the more likely the Merck product caused the adverse event 
(AE): 
Duration 
Action 
taken 
Relationship 
to test drug 
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Exposure Is there evidence that the subject was actually exposed to 
the 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 
Did the AE follow in a reasonable temporal sequence from 
Course 
administration of the Merck product? 
Is the time of onset of the AE compatible with a drug-
induced effect (applies to trials with investigational 
medicinal product)? 
Likely 
Is the AE not reasonably explained by another etiology 
Cause 
such as underlying disease, other drug(s)/vaccine(s), or 
other host or environmental factors 
Relationship The following components are to be used to assess the relationship 
between the test drug and the AE: (continued) 
to Merck 
Dechallenge Was the Merck product discontinued or 
product 
dose/exposure/frequency reduced? 
(continued) 
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 Merck 
product; or (3) the trial is a single-dose drug trial); or (4) 
Merck product(s) is/are only used one time.) 
Rechallenge Was the subject re-exposed to the 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: (I) the initial AE 
resulted in death or permanent disability, or (2) the trial is a 
single-dose drug trial); or (3) Merck product(s) is/are used 
only one time). 
NOTE: IF A RECHALLENGE IS PLANNED FOR AN 
ADVERSE EVENT WHICH WAS SERIOUS AND 
WHICH MAY HAVE BEEN CAUSED BY THE MERCK 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
PRODUCT, OR IF REEXPOSURE TO THE MERCK 
PRODUCT POSES ADDITIONAL POTENTIAL 
SIGNIFICANT RISK TO THE SUBJECT, THEN THE 
RECHALLENGE MUST BE APPROVED IN ADVANCE 
BY THE U.S. CLINICAL MONITOR AS PER DOSE 
MODIFICATION GUIDELINES IN THE PROTOCOL. 
Consistency 
with Trial 
Treatment 
Profile 
Is the clinical/pathological presentation of the AE consistent 
with previous knowledge regarding the Merck product or 
drug class pharmacology or toxicology? 
The assessment of relationship will be reported on the case report forms /worksheets by a 
qualified investigator according to his/her best clinical judgment, including consideration 
of the above elements. 
Record one of the 
following 
Use the following scale of criteria as guidance (not all 
criteria must be present to be indicative of a Merck 
product relationship). 
Yes, there is a reasonable 
possibility of Merck 
product relationship, 
There is evidence of exposure to the Merck product. The 
temporal sequence of the AE onset relative to the 
administration of the Merck product is reasonable. The AE 
is more likely explained by the Merck product than by 
another cause. 
No, there is not a 
reasonable possibility 
Merck product 
relationship 
Subject did not receive the Merck product OR temporal 
sequence of the AE onset relative to administration of the 
Merck product is not reasonable OR there is another 
obvious cause of the AE. (Also entered for a subject with 
overdose without an associated AE.) 
7.2.5 	
Sponsor-Investigator Responsibility for Reporting Adverse Events 
The sponsor-investigator is required to report all problems, events and 
information that require prompt reporting to the IRB within ten (10) calendar 
days of learning of the problem. 
Adverse events grade 3 and higher, as well as AEs requiring clinical 
intervention/dose modification, ECIs, and SAEs of any grade, will be reported 
from the time of signing of consent up until 90 days following the last dose of 
MK-3475. 
If a problem, event or information is determined to be an unanticipated problem 
involving risks to participants or others, it will be reviewed by the convened 
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Product: MK-3475 
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IRB, appropriate steps will be taken and it will be reported to appropriate 
institutional and governmental officials as provided under applicable law. 
For the purposes of this protocol, the terms Adverse Event, Serious Adverse 
Event (Related, Possibly Related or Unexpected) and Unanticipated Problem 
are defined in accordance with Fred Hutchinson Cancer Research Center 
Institutional Review Board Policy 2.6, version 6.03. 
Reporting Requirements 
Expedited Reporting 
With respect to each research study he or she is conducting, the principal 
investigator must ensure that the following problems, events, and information 
involving risks to research participants or others are reported to the IRB not 
later than ten (10) calendar days after he or she first becomes aware of the 
problem, event, or information. 
Adverse Events Requiring Expedited Reporting 
Adverse events require expedited reporting if they meet all three of the 
following criteria: 
(1) unexpected, and 
(2) related or possibly related to the research and 
(3) serious or suggest that the research places research participants or others at a 
greater risk of physical or psychological harm than was previously known or 
recognized. 
Unless otherwise specified in the Protocol, therapeutic oncology protocols are 
not required to specify monitoring parameters for Grade I or 11 toxicities as 
described in the Common Terminology Criteria for Adverse Events published 
by the National Cancer Institute. These adverse events are expected and occur 
routinely in the subject population being studied. They should be monitored 
and treated in the practice of routine clinical care. 
8.0 STATISTICAL ANALYSIS PLAN: STUDY DESIGN AND STATISTICAL 
ANALYSIS PLAN 
This is a single-arm pilot study which aims to estimate the toxicity of the addition of MK-
3475 to RCHOP. Since MK-3475 possesses a novel mode of action, and a safety profile 
independent of dose and different than RCHOP, a phase I study is not planned. Rather, 
this is a pilot study of the addition of MK-3475 to standard RCHOP with a primary 
objective of measuring toxicity, with particular attention to Events of Clinical Interest 
(potential immune-mediated adverse events). 
RCHOP administered every 21 (RCHOP-21) days is associated with significant toxicity, 
especially hematologic toxicity (grade 3-4 neutropenia in 60-80%), and is associated with 
a mortality rate of 5-10% depending on age; in addition, only 80-90% complete full-course 
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Product: MK-3475 
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therapy. 3,5,6,40  Infusion reactions are common with rituximab on the first administration. 
35,6,40 About 10-13% require reduction or elimination of a chemotherapy drug, even when 
white blood cell growth factors are routinely used, due to toxicity.5,6,41 Studies of 
RCHOP-21 do not consistently parse out clinically relevant grade 3-4 toxicities from all 
high-grade toxicities, many of which are expected and relatively unimportant 
(asymptomatic grade 3-4 laboratory findings or alopecia). This poses a challenge to the 
rational design of studies seeking to identify the assess the clinically relevant, additive 
toxicity of a novel agent such as MK-3475 to standard RCHOP. One prospective study 
testing the addition of rituximab to CHOP or CHOEP (the MINT trial) showed an overall 
grade 3-4 adverse event rate of 37% when grade 3 hematologic toxicity, and grade 4 
hematologic toxicity without signs or symptoms, were excluded.40  
From this study and other available data with RCHOP-21, about 40% of patients receiving 
full-course therapy will experience at least one clinically relevant grade 3-5 toxicity — 
defined as grade 3-5 toxicity excluding alopecia, grade 3 hematologic toxicity, and grade 4 
hematologic toxicity without and signs or symptoms. Amendment 4.0 expands the trial to 
30 patients. This sample size will permit the estimation of a 40% incidence of grade 3-5 
clinically relevant toxicity with a lower bound of 23% and upper bound of 57% (95% 
confidence interval). This expansion will also enhance the ability to detect uncommon 
events and relevant patterns, including immune-related adverse events. 
Secondary endpoints include measurement of response rate, and event-free and overall 
survival. Event-free survival (EFS) is defined as time from diagnosis until relapse or 
progression, non-protocol re-treatment of lymphoma, or death as a result of any cause. 
Overall survival is defined as survival from date of diagnosis to death from any cause. 
8.1 	
Stopping Rule 
In conjunction with the amendment to expand the trial to 30 patients, if more than 3 patients fail to 
complete 6 cycles of RCHOP therapy (for any reason other than disease progression), or die during 
or within 90 days of the last dose of RCHOP (due to any cause other than disease progression or as 
a complication of subsequent, non-protocol therapy for DLBCL), enrollment will be stopped. 
Patients who require discontinuation of study therapy because they require a delay in administering 
RCHOP of more than 14 days (beyond scheduled administration, see section 5.2.1) will count 
toward the stopping threshold. Routine dose modifications, unless they result in RCHOP delay of 
more than 14 days or RCHOP discontinuation, will not count toward the stopping threshold. 
Once enrollment is held, the nature of events to leading to stopping will be assessed by the 
Principal Investigator and reported to institutional regulatory authorities, in accordance with the 
institutional Data Safety Monitoring Plan. The institutional Data Safety Monitoring Committee 
will determine whether any further accrual may proceed. 
Statistical analysis will entail descriptive statistics, and survival analysis including 
Kaplain-meier estimates, log-rank testing of univariate prognostic factors, cox 
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proportional hazards analysis, as well as T-testing and regression analysis for comparing 
continuous variables in correlative study data. 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF INVESTIGATIONAL 
PRODUCT 
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. Investigational product will be provided by Merck as summarized 
in below. 
Table 8: Product Descriptions 
_ 
Product Name & Potency 
Dosage Form 
MK-3475 100 mg/ 4mL 
Solution for Injection 
9.2 Packaging and Labeling Information 
Investigational product will be labeled in accordance with regulatory requirements. 
9.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor-
investigator 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 
Investigational product 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. 
Investigational product may not be used for any purpose other than that stated in the 
protocol. 
9.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the investigational 
product 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 
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Product: MK-3475 
Protocol/Amendment No: CC9291 
federal, state, local and institutional guidelines and procedures, and provided that 
appropriate records of disposal are kept. 
10.0 DATA AND SAFETY MONITORING PLAN 
Ongoing trial oversight is carried out by the Principal Investigator and study staff.. These 
individuals will communicate on a regular basis to review recently acquired data and 
adverse events. The data recorded within the research charts and protocol database is 
compared with the actual data that is available from the medical record and/or clinical 
histories. Data detailed in the research case report forms includes the nature and severity 
of all toxicities, which are also reported as described above. 
Institutional support of trial monitoring will be in accordance with the FHCRC/UW 
Cancer Consortium Institutional Data and Safety Monitoring Plan. Under the provisions 
of this plan, FHCRC Clinical Research Support coordinates monitoring for data accuracy 
and compliance by consultants, contract research organizations, or FHCRC employees 
unaffiliated with the conduct of the study. Independent monitoring visits occur at 
specified intervals determined by the assessed risk level of the study and the findings of 
previous visits per the institutional DSMP. 
In addition, protocols are reviewed at least annually and as needed by a the Consortium 
Data Safety Monitoring Committee (DSMC), FHCRC Scientific Review Committee 
(SRC) and the FHCRC/Cancer Consortium Institutional Review Board (IRB). The 
review committees evaluate accrual, adverse events, stopping rules, and adherence to the 
applicable data and safety monitoring plan for studies actively enrolling or treating 
patients. The IRB reviews the study progress and safety information to assess continued 
acceptability of the risk-benefit ratio for human subjects. Approval of committees as 
applicable is necessary to continue the study. 
The trial will comply with the standard guidelines set forth by these regulatory 
committees and other institutional, state and federal guidelines. 
The IRB has the authority to suspend or terminate the study should it be deemed 
necessary. 
11.0 RECORDS 
Research staff under the supervision of the investigators will maintain case report forms 
and secured databases on the relevant clinical and laboratory data. Records maintained 
in investigators' offices will be secured with access limited to study personnel. 
Authorization for access to medical records will be obtained from all patients in 
accordance with provisions of the Health Insurance Portability and Accountability Act 
(HIPAA). 
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Product: MK-3475 
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12.0 REGULATORY RESPONSIBILITIES OF SPONSOR-INVESTIGATOR 
The Sponsor-Investigator will ensure that the study is conducted in accordance with all 
applicable institutional, state, and federal regulatory requirements, including, but not 
limited to: compliance with requirements for IRB and other regulatory approvals, 
monitoring responsibilities, reporting obligations, and compliance with standards for 
written informed consent from all patients entering the study. In addition, the IND 
sponsor will ensure oversight of the study via data and safety monitoring as described 
above. 
13.0 REFERENCES 
1. Morton LM, Wang SS, Devesa SS, Hartge P. Weisenburger DD, Linet MS. Lymphoma 
incidence patterns by WHO subtype in the united states, 1992-2001. Blood. 2006 Jan 
1;107(1):265-76. 
2. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, et al. Comparison of 
a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-
hodgkin's lymphoma. N Engl J Med. 1993 Apr 8;328(14):1002-6. 
3. Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, et al. CHOP 
chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse 
large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. 
4. Recher C, Coiffier B, Haioun C, Molina Ti, Ferme C, Casasnovas 0, et al. Intensified 
chemotherapy with ACVBP plus rituximab versus standard CHOP plus rituximab for the 
treatment of diffuse large B-cell lymphoma (LNH03-2B): An open-label randomised phase 3 
trial. Lancet. 2011 Nov 26;378(9806):1858-67. 
5. Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P. et at. Rituximab plus 
cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly 
diagnosed diffuse large B-cell non-hodgkin lymphoma: A phase 3 comparison of dose 
intensification with 14-day versus 21-day cycles. Lancet. 2013 May 25;381(9880):1817-26. 
6. Delarue R, Tilly H, Mounier N, Petrella T, Salles G, Thieblemont C, et al. Dose-dense 
rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse 
large B-cell lymphoma (the LNH03-6B study): A randomised phase 3 trial. Lancet Oncol. 
2013 May;14(6):525-33. 
7. Stiff PJ, Unger JM, Cook JR, Constine LS, Couban S, Stewart DA, et al. Autologous 
transplantation as consolidation for aggressive non-hodgkin's lymphoma. N Engl J Med. 2013 
Oct 31;369(18):1681-90. 
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8. Maurer MJ, Ghesquieres H, Jais JP, Witzig TE, Haioun C, Thompson CA, et at. Event-free 
survival at 24 months is a robust end point for disease-related outcome in diffuse large B-cell 
lymphoma treated with immunochemotherapy. J Clin Oncol. 2014 Apr 1;32(10):1066-73. 
9. Zhou Z, Sehn LH, Rademaker AW, Gordon LI, Lacasce AS, Crosby-Thompson A, et at. An 
enhanced international prognostic index (NCCN-IPI) for patients with diffuse large B-cell 
lymphoma treated in the rituximab era. Blood. 2014 Feb 6;123(6):837-42. 
10. Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, et at. The revised 
international prognostic index (R-IPI) is a better predictor of outcome than the standard IPI for 
patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007 Mar 
1;109(5):1857-61. 
11. Disis ML. Immune regulation of cancer. J Clin Oncol 2010; 28(29):4531-8. 
12. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated 
B74-11 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 
2002;8(8):793-800. 
13. Sharpe AH, Freeman GJ. The B7-CD28 superfamily. Nature 2002;2:116-26. 
14. Brown JA, Dorfman DM, Ma F-R, Sullivan EL, Munoz 0, Wood CR, et at. Blockade of 
programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine 
production. J Immunol 2003;170:1257-66. 
15. Francisco LM, Sage PT, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. 
Immunol Rev 2010;236:219-42. 
16. Thompson RH, Dong H, Lohse CM, Leibovich BC, Blute ML, Cheville JC, et al. PD-1 
expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients 
with renal cell carcinoma. Clin Caner Res 2007;13(6):1757-61. 
17. Talmadge JE, Donkor M, Scholar E. Inflammatory cell infiltration of tumors: Jekyll or 
Hyde. Cancer Metastasis Rev 2007;26:373-400. 
18. Usubuttin A, Ayhan A, Uygur MC, zen H, klu C, acan S. Prognostic factors in renal cell 
carcinoma. J Exp Clin Cancer Res 1998;17(1):77-81. 
19. Al-Shibli KI, Donnem T, Al-Saad S, Persson M, Bremnes RM, Busund L-T. Prognostic 
effect of epithelial and stromal symphocyte infiltration in non-small cell lung cancer. Clin 
Cancer Res 2008;14(16):5220-7. 
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20. Deschoolmeester V, Baay M, Van Marck E, Weyler J, Vermeulen p, Lardon F, et al. 
Tumor infiltrating lymphocytes: an intriguing player in the survival of colorectal cancer 
patients. BMC Immunol 2010;11:19. 
21. Diez M, Pollan M, Enriquez JM, Dominguez P, Santana A, Tobaruela E, et at. 
Histopathologic prognostic score in colorectal adenocarcinomas. Anticancer Res 1998;18:689-
94. 
22. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. 
Type, density, and location of immune cells within human colorectal tumors predict clinical 
outcome. Science 2006;313:1960-4. 
23. Hiraoka N. Tumor-infiltrating lymphocytes and hepatocellular carcinoma: molecular 
biology. Int J Clin Oncol 2010;15:544-51. 
24. Nobili C, Degrate L, Caprotti R, Franciosi C, Leone BE, Trezzi R, et al. Prolonged survival 
of a patient affected by pancreatic adenocarcinoma with massive lymphocyte and dendritic cell 
infiltration after interleukin-2 immunotherapy. Report of a case. Tumori 2008;94:426-30. 
25. Hodi FS, Dranoff G. The biologic importance of tumor-infiltrating lymphocytes. J Cutan 
Pathol 2010;37(Suppl 1):48-53. 
26. Kloor M. Lymphocyte infiltration and prognosis in colorectal cancer. Lancet 
2009;10(840):841. 
27. Hillen F, Baeten CIM, van de Winkel A, Creytens D, van der Schaft DWJ, 
Winnepenninckx V, et al. Leukocyte infiltration and tumor cell plasticity are parameters of 
aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 2008;57:97-
106. 
28. Lee HE, Chae SW, Lee YJ, Kim MA, Lee HS, Lee BL, et al. Prognostic implications of 
type and density of tumour-infiltrating lymphocytes in gastric cancer. Br J Cancer 
2008;99(10):1704-11. 
29. Leffers N, Gooden MJM, de Jong RA, Hoogeboom B-N, ten Hoor KA, Hollema H, et at. 
Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions 
of advanced stage ovarian cancer. Cancer Immunol Immunother 2009;58:449-59. 
30. Nishimura H, Honjo T, Minato N. Facilitation of f3 selection and modification of positive 
selection in the thymus of PD-1-deficient mice. J Exp Med 2000;191(5):891-7. 
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31. Liotta F, Gacci M, Frosali F, Querci V. Vittori G, Lapini A, et al. Frequency of regulatory 
T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor 
prognosis in renal cell carcinoma. BJU Intern 2010;107:1500-6. 
32. Andorsky DJ, Yamada RE, Said J, Pinkus GS, Betting DJ, Timmerman JM. Programmed 
death ligand 1 is expressed by non-hodgkin lymphomas and inhibits the activity of tumor-
associated T cells. Clin Cancer Res. 2011 Jul 1;17(13):4232-44. 
33. Taube JM, Klein AP, Brahmer JR, Xu H, Pan X, Kim JH, et al. Association of PD-1, PD-1 
ligands, and other features of the tumor immune microenvironment with response to anti-PD-1 
therapy. Clin Cancer Res. 2014 Apr 8. 
34. Armand P, Nagler A, Weller EA, Devine SM, Avigan DE, Chen YB, et al. Disabling 
immune tolerance by programmed death-1 blockade with pidilizumab after autologous 
hematopoietic stem-cell transplantation for diffuse large B-cell lymphoma: Results of an 
international phase II trial. J Clin Oncol. 2013 Nov 20;31(33):4199-206. 
35. Dickinson M, Hoyt R, Roberts AW, Grigg A, Seymour JF, Prince HM, et al. Improved 
survival for relapsed diffuse large B cell lymphoma is predicted by a negative pre-transplant 
FDG-PET scan following salvage chemotherapy. Br J Haematol. 2010 Jul;150(1):39-45. 
36. Westin JR, Chu F, Zhang M, Fayad LE, Kwak LW, Fowler N, et al. Safety and activity of 
PD1 blockade by pidilizumab in combination with rituximab in patients with relapsed 
follicular lymphoma: A single group, open-label, phase 2 trial. Lancet Oncol. 2014 
Jan; 15(1):69-77. 
37. Lesokhin AM, Ansel! SM, Armand P. Preliminary Results of a Phase I Study of Nivolumab 
(BMS-936558) in Patients with Relapsed or Refractory Lymphoid Malignancies. ASH Annual 
Meeting Abstracts. 2014;Abstract 291. 
38. Bracci L, Moschella F, Sestili P, La Sorsa V, Valentini M, Canini I, et al. 
Cyclophosphamide enhances the antitumor efficacy of adoptively transferred immune cells 
through the induction of cytokine expression, B-cell and T-cell homeostatic proliferation, and 
specific tumor infiltration. Clin Cancer Res. 2007 Jan 15;13(2 Pt I):644-53. 
39. Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano 
classification. J Clin Oncol. 2014;32(27):3059-3068. 
40. Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Treneny M, et al. CHOP-like 
chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with 
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good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera 
International Trial (MInT) Group. Lancet Oncol. 2006 May;7(5):379-391. 
41. Balducci L, Mo M, AbeIla E, Saven A. Retrospective analysis of relative dose intensity in 
patients with non-Hodgkin lymphoma receiving CHOP-based chemotherapy and pegfilgrastim. 
Am J Clin Oncol. 2014;37(6):603-610. 
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14.0 APPENDICES 
14.1 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, • MM., 	
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. 
14.2 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.govireportingictc.html) 
14.3 Response Criteria: "The Lugano Classification" 38  
Response and 
Site 	
PET-CT—Based Response 	
CT-Based Response 
Complete radiologic response (all of the 
Complete 	Complete metabolic response 	
following) 
Target nodes/nodal masses must regress 
Score 1, 2, or 3 with or without a residual mass on 513St 	
to 1.5 cm in LDi 
It is recognized that in Waldeyer's ring or extranodal sites 
with high physiologic uptake or with activation within 
spleen or marrow (eg, with chemotherapy or myeloid 
colony-stimulating factors). uptake may be greater than 
normal mediastinum and/or liver. In this circumstance, 
complete metabolic response may be inferred if uptake at 
Lymph nodes and sites of initial involvement is no greater than surrounding 
extralymphatic 	
normal tissue even if the tissue has high physiologic 
sites 	
uptake 
No extralymphatic sites of disease 
Nonmeasured 
lesion 	
Not applicable 	
Absent 
Organ 
enlargement 	
Not applicable 	
Regress to normal 
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Product: MK-3475 
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Response and 
Site 	
PET-CT—Based Response 	
CT-Based Response 
New lesions 	
None 	
None 
r- 
Normal by morphology; if 
Bone marrow 	
No evidence of FDG-avid disease in marrow 	
indeterminate, IHC negative 
L'artial 
Partial remission (all of the 
Partial metabolic response 	
following) 
Lymph 
nodes and 
extralymphatic 	
Score 4 or 5' with reduced uptake compared with baseline > 50% decrease in SPD of up to 6 target 
sites 	
and residual mass(es) of any size 	
measurable nodes and extranodal sites 
At interim, these findings suggest responding disease 
When a lesion is too small to measure 
on CT, assign 5 mm x 5 mm as the 
default value 
At end of treatment, these findings indicate residual 
disease 	
When no longer visible. 0 x 0 mm 
For a node > 5 mm x 5 mm. but smaller 
than normal, use actual measurement 
for calculation 
Nonmeasured 	
Absent/normal. regressed, but no 
lesions 	 Not applicable 	
increase 
Organ 	
Spleen must have regressed by > 50% 
enlargement 	
Not applicable 	
in length beyond normal 
New lesions 	
None 	
None 
Bone marrow 
Residual uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake 
compatible with reactive changes from chemotherapy 
allowed). If there are persistent focal changes in the 
marrow in the context of a nodal response, consideration 
should be given to further evaluation with MRI or biopsy 
or an interval scan 
Not applicable 
No response or 
stable disease 	
No metabolic response 	
Stable disease 
Target 	
<50% decrease from baseline in SPD 
nodes/nodal 	
of up to 6 dominant, measurable nodes 
masses. 	 Score 4 or 5 with no significant change in FDG uptake 	
and extranodal sites; no criteria for 
extranodal lesions from baseline at interim or end of treatment 	
progressive disease are met 
Nonmeasured 
lesions 	 Not applicable 	
No increase consistent with progression 
Organ 
enlargement 	
Not applicable 	
No increase consistent with progression 
New lesions 	
None 	
None 
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Product: MK-3475 
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Response and 
Site 
PET-CT—Based Response 
CT-Based Response 
Not applicable 
Bone marrow 
No change from baseline 
Progressive 	
Progressive disease requires at least 1 
disease 	 Progressive metabolic disease 	
of the following 
Individual target 
nodes/nodal 
masses 
Score 4 or 5 with an increase in intensity of uptake from 
baseline and/or 
PPD progression: 
Extranodal lesions 
New FDG-avid foci consistent with lymphoma at interim 
or end-of-treatment assessment 
An individual node/lesion must be 
abnormal with: 
LDi > 1.5 cm and 
Increase by > 50% from PPD nadir and 
An increase in LDi or SDi from nadir 
0.5 cm for lesions < 2 cm 
1.0 cm for lesions >2 cm 
In the setting of splenomegaly, the 
splenic length must increase by > 50% 
of the extent of its prior increase 
beyond baseline (eg. a 15-cm spleen 
must increase to > 16 cm). If no prior 
splenomegaly. must increase by at least 
2 cm from baseline 
New or recurrent splenomegaly 
Nonmeasured 	
New or clear progression of preexisting 
lesions 	 None 	
nonmeasured lesions 
New lesions 
New FDG-avid foci consistent with lymphoma rather than 
another etiology (eg, infection, inflammation). If uncertain 
regarding etiology of new lesions, biopsy or interval scan 
may be considered 
Regrowth of previously resolved 
lesions 
A new node > 1.5 cm in any axis 
A new extranodal site > 1.0 cm in any 
axis; if < 1.0 cm in any axis, its 
presence must be unequivocal and must 
be attributable to lymphoma 
Assessable disease of any size 
unequivocally attributable to lymphoma 
Bone marrow 	
New or recurrent MG-avid foci 	
New or recurrent involvement 
• 
Abbreviations: 5PS. 5-point scale; CT, computed tomography: FDG. fluorodeoxyglucose; II IC, 
immunohistochemistry; LDi, longest transverse diameter of a lesion; MRI. magnetic resonance imaging; 
PET, positron emission tomography; PPD. cross product of the LDi and perpendicular diameter; SDi. 
shortest axis perpendicular to the LDi; SPD, sum of the product of the perpendicular diameters for 
multiple lesions. 
• 
+1* A score of 3 in many patients indicates a good prognosis with standard treatment, especially if at the 
time of an interim scan. However, in trials involving PET where de-escalation is investigated, it may be 
preferable to consider a score of 3 as inadequate response (to avoid undertreatment). Measured dominant 
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Protocol/Amendment No: CC9291 
lesions: Up to six of the largest dominant nodes, nodal masses. and extranodal lesions selected to be 
clearly measurable in two diameters. Nodes should preferably be from disparate regions of the body and 
should include, where applicable, mediastinal and retroperitoneal areas. Non-nodal lesions include those 
in solid organs (eg, liver, spleen, kidneys, lungs). GI involvement. cutaneous lesions, or those noted on 
palpation. Nonmeasured lesions: Any disease not selected as measured, dominant disease and truly 
assessable disease should be considered not measured. These sites include any nodes, nodal masses, and 
extranodal sites not selected as dominant or measurable or that do not meet the requirements for 
measurability but are still considered abnormal, as well as truly assessable disease, which is any site of 
suspected disease that would be difficult to follow quantitatively with measurement, including pleural 
effusions. ascites, bone lesions, leptomeningeal disease, abdominal masses, and other lesions that cannot 
be confirmed and followed by imaging. In Waldeyer's ring or in extranodal sites (eg, GI tract, liver, bone 
marrow), FDG uptake may be greater than in the mediastinum with complete metabolic response, but 
should be no higher than surrounding normal physiologic uptake (eg. with marrow activation as a result of 
chemotherapy or myeloid growth factors). 
• 
ot PET 5PS: I. no uptake above background; 2. uptake < mediastinum; 3. uptake > mediastinum but < 
liver: 4: uptake moderately > liver; 5, uptake markedly higher than liver and/or new lesions; X. new areas 
of uptake unlikely to be related to lymphoma. 
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