Phase II Study of Rituximab Plus Pembrolizumab (MK-3475) in Subjects With Relapsed Follicular Lymphoma
Phase: PHASE2
Conditions: Recurrent Diffuse Large B-Cell Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3a Follicular Lymphoma
Sponsor: M.D. Anderson Cancer Center

MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2014-0539 
Protocol Title 
Phase II Study of Rituximab Plus Pembrolizumab (MK-3475) In Subjects with 
Relapsed Follicular Lymphoma 
Protocol Phase 
II 
Protocol Version 
Version Date 
6/10/2024 
Protocol PI 
Ranjit Nair, M.D. 
Department 
Lymphoma/Myeloma 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
126,511 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
 
 
 
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Phase II study of rituximab plus pembrolizumab (MK-3475) in subjects with 
relapsed follicular lymphoma 
 
 
 
 
Principal Investigator: 
Ranjit Nair, M.D. 
Assistant Professor 
Department of Lymphoma and Myeloma 
Division of Cancer Medicine 
 
The University of Texas M.D. Anderson Cancer Center 
 
1515 Holcombe Blvd, Unit 903 
Houston, TX - 77030 
USA 
 
Tel: (713)  792-3510 
Fax: (713) 563 3469 
 
Co-Principal Investigator: 
Sattva S. Neelapu, M.D. 
Associate Professor 
Department of Lymphoma and Myeloma 
Division of Cancer Medicine 
 
 
Investigational Drug: Pembrolizumab 
 
 
Source of Investigational Drug: Merck 
 
IND NUMBER: 126511 
 
 
Revised: 6/10/2024 
 
 
 
 
 
 
 
 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
 
 
 
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TABLE OF CONTENTS 
 
Page 
1.0 
TRIAL SUMMARY  
 
 
 
 
 
 
 
  3 
2.0 
TRIAL DESIGN 
 
 
 
 
 
 
 
 
  5 
3.0 
OBJECTIVES AND HYPOTHESIS 
 
 
 
 
 
  8 
4.0 
BACKGROUND AND RATIONALE 
 
 
 
 
 
  9 
5.0 
METHODOLOGY  
 
 
 
 
 
 
 
18 
6.0 
TRIAL FLOW CHART 
 
 
 
 
 
 
 
39 
7.0 
TRIAL PROCEDURES 
 
 
 
 
 
 
 
43 
8.0 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
 
53 
9.0 
LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL 
SUPPLIES 
 
 
 
 
 
 
 
 
 
59 
10.0 
ADMINISTRATIVE AND REGULATORY DETAILS  
 
 
60 
11.0 
REFERENCES 
 
 
 
 
 
 
 
 
62 
12.0 
APPENDICES 
 
 
 
 
 
 
 
 
66 
 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
 
 
 
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1.0 TRIAL SUMMARY 
Abbreviated Title 
Rituximab plus pembrolizumab (MK-3475) in relapsed follicular 
lymphoma 
Trial Phase 
II 
Clinical Indication 
The treatment of subjects with relapsed/refractory follicular and 
diffuse large B-cell lymphoma. 
Trial Type 
Interventional 
Type of control 
Historical control 
Route of administration 
Intravenous and po 
Trial Blinding 
Unblinded, open-label 
Treatment Groups  
Cohort 1: Rituximab (375 mg/m2 weekly x 4 weeks) and 
pembrolizumab (200 mg every 3 weeks for up to 16 infusions) in 
subjects with relapsed or refractory follicular lymphoma. Cohort 2: 
Rituximab (375 mg/m2 weekly x 4 weeks), pembrolizumab (200 mg 
every 3 weeks for up to 2 years) and lenalidomide (days 1-14 of a 3 
week cycle for 12 cycles in relapsed/refractory follicular lymphoma 
or diffuse large B-cell lymphoma patients who have failed CAR T cell 
therapy  
Number of trial subjects 
Cohort 1: 32, Cohort 2: 40 
Estimated duration of trial It is estimated that the trial will require approximately 60 months from 
the time the first subject signs the informed consent until the last 
subject’s last visit. 
Duration of Participation 
Each subject will participate in the trial from the time the subject signs 
the Informed Consent Form through the final protocol-specified 
contact. After a screening phase of 28 days, eligible subjects in cohort 
1 will receive treatment with rituximab (375 mg/m2) on day 1, 8, 15, 
and 22 of cycle 1. Pembrolizumab (200 mg) will begin on Day 2 of 
cycle 1 and repeated every 3 weeks for up to 16 infusions.  
 
In cohort 2, subjects will receive treatment with rituximab (375 
mg/m2) on day 1, 8, and 15 of cycle 1 and Day 1 of cycle 2. 
Pembrolizumab (200 mg) will begin on day 1 of cycle 1 and repeated 
every 3 weeks for up to 2 years. Per the investigator’s discretion, 
subjects who attain an investigator-determined confirmed complete 
response (CR) may consider stopping pembrolizumab treatment after 
receiving at least 24 weeks of pembrolizumab therapy. At least two 
doses must be received after CR is documented. The phase II dose of 
lenalidomide will be determined following a dose escalation of 
lenalidomide, starting at 2.5 mg on days 1-14 of each cycle for up to 
12 cycles.  
 
Study treatment will continue until documented confirmed disease 
progression, unacceptable adverse event(s), intercurrent illness that 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
 
 
 
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prevents further administration of treatment, investigator’s decision 
to withdraw the subject, subject withdraws consent, pregnancy of the 
subject, 
noncompliance 
with 
trial 
treatment 
or 
procedure 
requirements, administrative reasons, or the subject has completed the 
planned therapy.  
 
After the end of treatment, adverse events will be collected for 30 
days and serious adverse events for 90 days. Subjects who discontinue 
for reasons other than disease progression will have post-treatment 
follow-up for disease status until disease progression, initiating a non-
study cancer treatment, withdrawing consent, or becoming lost to 
follow-up. Disease assessment will be performed every 3 months 
during therapy and for the first year after discontinuation of therapy, 
and every 6 months thereafter. 
 
 
 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
 
 
 
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2.0 TRIAL DESIGN 
2.1 
Trial Design 
This is a single center, nonrandomized trial of rituximab in combination with pembrolizumab 
in subjects with relapsed follicular lymphoma (FL). Cohort 1 will consist of 32 subjects 
enrolled to examine the safety and efficacy of rituximab in combination with pembrolizumab 
in patients with relapsed FL with rituximab-sensitive FL. Rituximab will be administered at 
a dose of 375 mg/m2 weekly for 4 weeks and pembrolizumab administered at a dose of 200 
mg every 3 weeks (Q3W) for a maximum of 16 infusions.  
Cohort 2 has been added to examine the safety and efficacy of rituximab in combination with 
pembrolizumab and lenalidomide in approximately 40 subjects with relapsed/refractory FL 
and DLBCL patients who have progressed following chimeric antigen receptor (CAR) T cell 
therapy. Patients will receive rituximab at a dose of 375 mg/m2 weekly for 4 weeks, 
pembrolizumab administered at a dose of 200 mg every 3 weeks for a maximum of 2 years, 
and lenalidomide will be dose escalated from 2.5mg to a maximum of 10mg on days 1-14 of 
cycles 1-12. The prolonged course of pembrolizumab in this cohort is based on observations 
of delayed responses with pembrolizumab in patients with lymphoma enrolled in other 
prospective studies observed beyond the 16 doses planned in the original cohort.  The 
rationale for the combination is to explore the efficacy and safety of this novel immune 
therapy combination in patients with refractory disease with limited treatment options and 
very poor outcomes. The addition of lenalidomide to the combination of rituximab and 
pembrolizumab is anticipated to provide synergism by further activating the innate and 
adaptive immune response. Patients who fail to respond to CAR T cell therapy have a very 
poor outcome. Mechanisms of resistance are actively being explored, but PD-L1 expression 
has been reported as one potential mechanism and prospective studies are underway 
exploring the combination of anti PD-1 or PD-L1 therapies with CAR T cell therapy. We 
also have anecdotal experience in our department with patients achieving a response post 
CAR T cell failure with lenalidomide. Therefore, the combination may be an effective 
strategy to overcome resistance to CAR T cell therapy in high risk patients.   
Adverse events (AEs) will be monitored throughout the trial and graded in severity according 
to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0. Response will be determined according to the Recommendations for 
Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin 
Lymphoma: The Lugano Classification.[1] Study treatment will continue until documented 
progression of disease (PD), unacceptable AE(s), intercurrent illness that prevents further 
administration of treatment, investigator’s decision to withdraw the subject, subject 
withdraws consent, pregnancy of the subject, noncompliance with trial treatment or 
procedure requirements, administrative reasons, or the subject has completed 16 cycles. After 
the end of treatment, each subject will be followed for 30 days for AE monitoring (serious 
adverse events (SAEs) will be collected for 90 days after the end of treatment). Subjects who 
discontinue treatment for reasons other than disease progression will have post-treatment 
follow-up for disease status until disease progression, initiating a non-study cancer treatment, 
withdrawing consent, or becoming lost to follow-up. 
The primary objective of the trial is to determine the overall response rate (ORR) in subjects 
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with relapsed FL and DLBCL treated with rituximab, pembrolizumab ± lenalidomide. 
Secondary objectives include assessment of safety, complete response rate (CRR), 
progression-free survival (PFS), compare PFS between patients relapsing ≤ one year vs > 
one year after last prior therapy, and overall survival (OS). Exploratory objectives include 
evaluation of immunological effects of therapy and determination of the relationship of 
candidate efficacy/resistance biomarkers and anti-tumor activity of pembrolizumab.  
This study will be conducted in conformance with Good Clinical Practices. 
Specific procedures to be performed during the trial, as well as their prescribed times and 
associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each 
procedure are provided in Section 7.0 – Trial Procedures. 
2.2 
Trial Diagram 
The trial design is depicted in Figure 1. 
 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
 
 
 
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Figure 1. Clinical trial schema. Eligible subjects in Cohorts 1 will receive treatment with rituximab at 375 
mg/m2 on day 1, 8, 15, and 22 of cycle 1. *Subjects with also receive pembrolizumab at 200 mg infusion 
every 3 weeks starting on day 2 of cycle 1 for up to 16 infusions. A time window of +/- 1 day for rituximab 
infusions on days 8, 15, and 22, and +/- 3 days for 2nd through 16th infusion of pembrolizumab is allowed. 
A minimum of 18 hours interval is required between the end of rituximab infusion and beginning of 
pembrolizumab infusion on days 2 and 23.  
Cohort 2 was added with the amendment. Subjects will receive 4 weekly doses of rituximab 375 mg/m2 
starting on day 1 of cycle 1. ±Subjects will also receive pembrolizumab 200 mg infusion starting on day 1 
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of cycle 1 and continued every 3 weeks starting for up to 2 years. Per the investigator’s discretion, subjects 
who attain an investigator-determined CR may consider stopping pembrolizumab treatment after receiving 
at least 24 weeks of pembrolizumab therapy. At least two doses must be received after CR is documented. 
A time window of +/- 1 day for rituximab infusions on doses 2, 3, and 4day 1, and +/- 3 days for 2nd 
through the remaining infusions of pembrolizumab is allowed.  Subjects will also receive lenalidomide on 
days 1-14 of cycles 1-12.  
3.0 OBJECTIVE(S) & HYPOTHESIS(ES) 
3.1 
Primary Objective(s) & Hypothesis(es) 
(1) Objective: The primary objective of the study is to determine the ORR in subjects with 
relapsed FL treated with rituximab plus pembrolizumab. 
Hypothesis: Therapy with rituximab plus pembrolizumab in subjects with relapsed FL will result 
in improvement in ORR by at least 20% as compared with historical results with rituximab 
monotherapy.  
3.2 Secondary Objective(s) & Hypothesis(es) 
(1) Objective:  To determine the safety and toxicity. 
(2) Objective: To determine the CRR. 
(3) Objective: To determine the overall PFS. 
(4) Objective: To compare PFS between patients relapsing ≤ one year vs > one year after last prior 
therapy. 
(5) Objective: To determine the OS. 
Hypothesis:  Therapy with rituximab plus pembrolizumab in subjects with relapsed FL will be 
safe and well tolerated and result in clinically meaningful improvement in CRR and PFS as 
compared with historical results with rituximab monotherapy.  
3.3 Exploratory Objective 
(1) 
Objective: To determine effects of rituximab plus pembrolizumab therapy on peripheral 
blood T cells. 
(2) 
Objective: To correlate features of peripheral blood T cells with toxicities after rituximab 
plus pembrolizumab therapy. 
(3) 
Objective: To correlate features of peripheral blood T cells with response and PFS after 
rituximab plus pembrolizumab therapy. 
(4) 
Objective: To correlate baseline tumor characteristics with response and PFS after rituximab 
plus pembrolizumab therapy. 
3.4 
Objective(s) & Hypothesis(es) of Cohort 2 
(1)  Objective: To determine the ORR in subjects with relapsed/refractory FL and 
relapsed/refractory DLBCL who have failed CAR T cell therapy and are treated with 
rituximab in combination with pembrolizumab and lenalidomide. 
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(2) 
Objective:  To determine the safety and toxicity. 
(3) 
Objective:  To determine the CRR. 
(4) 
Objective:  To determine the overall PFS. 
(5) 
Objective:  To compare PFS between patients relapsing ≤ one year vs > one year after last 
prior therapy. 
(6) 
Objective:  To determine the OS. 
(7) 
Objective: To determine effects of rituximab, pembrolizumab, and lenalidomide therapy on 
peripheral blood T cells. 
(8) 
Objective: To correlate features of peripheral blood T cells with toxicities after rituximab, 
pembrolizumab, and lenalidomide therapy. 
(9) 
Objective: To correlate features of peripheral blood T cells with response and PFS after 
rituximab, pembrolizumab, and lenalidomide therapy. 
(10) Objective: To correlate baseline tumor characteristics with response and PFS after 
rituximab, pembrolizumab, and lenalidomide therapy 
Hypothesis: Therapy with rituximab, pembrolizumab, and lenalidomide in subjects with 
relapsed/refractory FL and DLBCL who have failed CAR T cell therapy (Cohort 2) will be 
safe and well tolerated and will result in improvement in ORR by at least 10% as compared 
with historical results with rituximab and lenalidomide. 
 
4.0 BACKGROUND & RATIONALE 
4.1 Background 
4.1.1 Current therapy and prognosis of FL. In 2014, it is estimated that 70,800 patients will be 
diagnosed, and an estimated 18,990 will die due to non-Hodgkin’s lymphoma (NHL) in the 
United States. Follicular lymphoma is the most common low-grade lymphoma and 
comprises 22% of all NHL cases worldwide.[2] Stage I or II FL is potentially curable with 
radiation therapy but is present in only 10-15% of patients at the time of initial diagnosis. 
Greater than 85% of patients with FL have advanced stage disease at the time of initial 
diagnosis. Although advanced stage FL has a generally indolent course and a median 
survival of over 12 years, it is considered incurable with the available treatment options. It 
is highly responsive to various therapies such as chemotherapy, radiation therapy, and/or 
biologic therapy, but is characterized by repeated remissions and relapses and most patients 
eventually die of their disease.[3] The inclusion of rituximab, in combination chemotherapy 
regimens has improved the response rates, PFS, and OS of patients with FL. However, even 
these combinations do not appear to be curative since no plateau in the survival curves has 
been demonstrable.[4-6] Therefore, novel treatment options are needed to improve clinical 
outcome in these patients. 
Immunotherapy for FL. Several studies have demonstrated that immunotherapy could induce 
meaningful and durable clinical remissions in FL. First, treatment with custom-made anti-
idiotype antibodies generated against the clonal tumor immunoglobulin expressed on the 
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surface of FL induced clinical responses in 66% of the patients with 13% experiencing 
complete remission lasting many years.[7] Second, administration of rituximab, an anti-
CD20 monoclonal antibody, as a single agent induced clinical remission in a significant 
proportion of patients with FL.[8-11] Third, a high PFS of 83% was observed after a median 
follow-up of five years following non-myeloablative allogeneic stem cell transplantation 
suggesting that a graft versus tumor effect mediated by the immune system can lead to 
prolonged clinical remission in FL.[12, 13] Fourth, immunization with customized 
therapeutic vaccines in FL has been shown to improve disease-free survival when 
administered in the setting of minimal residual disease.[14] Taken together, these results 
suggest that immunotherapy involving the humoral and/or the cellular arms of the immune 
system may induce durable clinical responses in FL.  
Rituximab monotherapy in FL. Rituximab, a chimeric anti-CD20 monoclonal antibody has 
been shown to induce a 48% response rate in relapsed indolent lymphomas in the pivotal 
phase II study.[10] The median time to progression was 13 months in responders and 9 
months for all evaluable patients. Rituximab was also effective when used in indolent 
lymphoma patients who relapsed after a prior response to rituximab. Re-treatment with 
rituximab induced responses in 40% of patients and median time-to-progression among 
responders was 17.8 months.[15] Rituximab as single agent first-line therapy has been shown 
to induce response rates in 47% to 73% of patients in previously untreated indolent 
lymphomas. Median time-to-progression was 18 months to 2.2 years.[11, 16] Taken together, 
these results suggest that rituximab has significant clinical activity as single agent in FL 
patients either previously untreated or treated with rituximab.  
Rituximab plus lenalidomide in FL. Lenalidomide, a thalidomide derivative, is a second 
generation immunomodulatory drug, proposed to have multiple mechanisms of action, 
including beneficial effects on both tumor and the microenvironment. Lenalidomide has been 
shown to induce growth arrest and apoptosis of lymphoma cell lines and enhance the NK-
cell–mediated antibody-dependent cellular cytotoxicity (ADCC) of rituximab [17], 
suggesting lenalidomide and rituximab could be a synergistic immune therapy approach in 
FL. Witzig et al reported a phase II study of lenalidomide (25 mg/d for 21 of 28 days) in 
patients with relapsed or refractory indolent NHL.[18] Among 27 assessable patients with a 
median of three (range, 1-17) prior therapies, the ORR was 26% (n = 7) including 2 CRs, 
whereas the overall clinical benefit (stable disease or better response) was observed in 59% 
of the patients. Investigators within our department conducted a phase II study with 
lenalidomide and rituximab in relapsed/refractory DLBCL and FL including patients with 
transformed lymphoma. Patients received lenalidomide 20 mg/day on days 1-21 of each 28 
day cycle. Rituximab was given weekly during cycle 1 at 375 mg/m2. ORR in this study was 
33%, with a median duration of response of 10.2 months.[19] We also conducted a phase II 
study of the combination of lenalidomide and rituximab in patients with untreated indolent 
NHL.[20] We reported high overall response rates in this untreated population, with a 
complete response rate of 87% in patients with follicular lymphoma. Toxicity was mild to 
moderate, with the most common non-hematologic adverse event reported as grade 1-2 
fatigue and rash. Hematologic toxicity included 35% ≥ grade 3 neutropenia and 4% with ≥ 
grade 3 thrombocytopenia. These results suggest that enhancing the innate immune system 
as a therapeutic target can be effective in FL.  
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Effects of immune system on cancer. A series of elegant studies in mouse cancer models 
conducted over the past decade has provided strong and convincing data that the innate and 
adaptive immune systems can not only prevent development of tumors (cancer 
immunosurveillance or cancer elimination), but can also participate in the generation of a 
sculpted tumor cell repertoire that displays either reduced immunogenicity or an increased 
capacity to inhibit protective antitumor immune responses (cancer immunoediting).[21, 22] 
The recognition of the dual effects of the immune system on developing tumors has evolved 
into the “cancer immunoediting hypothesis” that suggests three phases in the tumor 
development process termed the “three Es of cancer immunoediting”: elimination, 
equilibrium, and escape.[21, 22] 
Endogenous anti-tumor immunity in FL. The natural history of FL characterized by stable 
disease or spontaneous remissions[23] lasting months to years while on observation in a 
significant proportion of patients, suggests that it may go through a phase of equilibrium 
where the tumor is probably kept in check by the immune system before escape mechanisms 
develop resulting in progression of the tumor. Recent studies support the notion that the 
immune system may play a significant role in the control of this tumor. First, the survival of 
patients with FL appeared to correlate with the gene expression signatures of infiltrating 
nonmalignant immune cells in the tumor.[24] Second, high levels of CD8+ T-cell content in 
diagnostic lymph nodes correlated with better prognosis.[25] Third, the presence of an 
immunosurveillance pattern (CD8+ T cells) or an immune-escape pattern (CD57+ T cells), 
correlated with good or poor prognosis, respectively.[26] Finally, tumor-specific T cells 
could be easily isolated from the peripheral blood and tumor microenvironment in FL.[27, 
28] Together, these results suggest that endogenous antitumor immune responses are 
naturally induced in patients with FL but these immune responses eventually become 
ineffective to control the tumor presumably due to development of various 
immunosuppressive mechanisms in the tumor microenvironment.  
Immunosuppressive mechanisms. Recently, several immunosuppressive mechanisms were 
shown to impair the function of tumor-specific effector T cells in the tumor 
microenvironment in various animal models and in some human cancers.[29] Development 
of such immunosuppressive mechanisms could result in the progression of FL and other 
cancers from an “equilibrium” phase to the “escape” phase. Important negative regulatory 
pathways that inhibit T-cell function include extrinsic suppression by regulatory T cells 
(Tregs); direct inhibition through inhibitory ligands such as programmed death-ligand 1 (PD-
L1), PD-L2, and B7-H4; soluble factors such as transforming growth factor β and interleukin 
(IL)-10; and metabolic dysregulation of essential amino acids such as tryptophan.[29] In the 
current trial, we intend to reverse the inhibitory effects of one of these mechanisms, the PD-
1/PD-ligand pathway, on tumor-specific effector T cells in FL. 
Immunotherapy for DLBCL. There is more evidence for targeting the immune 
microenvironment via the PD-1/PD-ligand pathway in Hodgkin and FL, but may be less well 
understood in other lymphoma subtypes.[30] T cell exhaustion via the PD-1 pathway is often 
exploited by tumors to evade immune surveillance.  Immune blockade of PD-1/PD-L1 by 
monoclonal antibodies can restore the antitumor activity of cytotoxic T-cells and attenuate 
T-cell mediated immune responses across malignancies.[31] A phase I, open-label, dose-
escalation study of nivolumab (anit-PD-1 monoclonal antibody) reported an objective 
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response of 36% in 11 subjects with relapsed/refractory DLBCL. [32] Though small number 
of subjects, the results are encouraging particularly if the responses are durable. In an 
international phase II trial of single agent lenalidomide, patients with relapsed or refractory 
DLBCL (n=108) had an ORR of 28%.[33] In our own single-center phase II study, with the 
rationale to increase antibody-dependent cell-mediated cytotoxicity, lenalidomide in 
combination with rituximab in relapsed or refractory DLBCL (n=32) or transformed 
lymphoma (n=9), we observed an ORR of 28% and 56%.[19] An analysis of the international 
CORAL Study which reported on the outcomes for patients (n=203) who were ineligible for 
autologous stem cell transplant, ORR with third-line chemotherapy was 39%, with a median 
overall survival of 4.4 months.[34] There is an unmet need for patients with 
relapsed/refractory DLBCL who fail to respond to standard chemotherapy based approaches. 
Rationale immune therapy combinations appear promising, hence the rationale for rituximab, 
pembrolizumab and lenalidomide in relapsed/refractory DLBCL. 
4.1.2 Pharmaceutical and Therapeutic Background 
PD-1/PD-ligand pathway. The PD-1 receptor-ligand interaction is a major pathway hijacked 
by tumors to suppress immune control. The normal function of PD-1, expressed on the cell 
surface of activated T-cells under healthy conditions, is to down-modulate unwanted or 
excessive immune responses, including autoimmune reactions. PD-1 (encoded by the gene 
Pdcd1) is an 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).[35]  The structure of murine PD-1 has been resolved.  PD-1 and family 
members are type I transmembrane glycoproteins containing an Ig Variable-type (V-type) 
domain responsible for ligand binding and a cytoplasmic tail which is responsible for the 
binding of signaling molecules.  The cytoplasmic tail of PD-1 contains 2 tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an 
immunoreceptor tyrosine-based switch motif (ITSM). Following T-cell stimulation, PD-1 
recruits the tyrosine phosphatases SHP-1 and SHP-2 to the ITSM motif within its 
cytoplasmic tail, leading to the dephosphorylation of effector molecules such as CD3ζ, PKCθ 
and ZAP70 which are involved in the CD3 T-cell signaling cascade.[35] 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.[36] PD-1 was shown 
to be expressed on activated lymphocytes including peripheral CD4+ and CD8+ T-cells, B-
cells, Tregs and Natural Killer cells.[35] Expression has also been shown during thymic 
development on CD4-CD8- (double negative) T-cells as well as subsets of macrophages and 
dendritic cells.[35] The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or 
can be induced in a variety of cell types, including non-hematopoietic tissues as well as in 
various tumors.[35, 37] 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 
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peripheral tissues.[35-37]  Although healthy organs express little (if any) PD-L1, a variety 
of cancers were demonstrated to express abundant levels of this T-cell inhibitor.  
PD-1 is markedly upregulated on intratumoral and peripheral blood CD4+ and CD8+ T cells 
of patients with FL. More importantly, PD-1 expression is associated with impaired T-cell 
function, and blocking PD-1 restores the function of these T cells against autologous tumor 
cells.[38, 39] Although FL tumor cells do not express PD-L1, its expression was observed 
on T cells and other stromal cells in the tumor microenvironment.[40] These data suggest 
that the PD-1/PD-ligand pathway plays a critical role in tumor immune evasion and should 
be considered as an attractive target for therapeutic intervention in FL. 
Pembrolizumab. Pembrolizumab (previously known as MK-3475 and SCH 900475) is a 
potent and highly selective humanized monoclonal antibody (mAb) of the IgG4/kappa 
isotype designed to directly block the interaction between PD-1 and its ligands, PD-L1 and 
PD-L2 without ADCC or CDC activity.   
Rituximab. Rituximab is an FDA approved drug for the treatment of relapsed FL and will be 
obtained through standard commercial sources. Rituximab (Rituxan®) is a chimeric 
monoclonal antibody against CD20 a receptor on the surface of malignant B-cell 
lymphocytes. The drug has activity against aggressive and indolent NHL of B-cell origin, 
and has been used in combination with chemotherapy. The drug is administered 
intravenously at doses of 375 mg mg/m².  Side effects are as follows: 
In clinical trials, Grade 3 and 4 cytopenias were reported in 48% of patients treated with 
Rituximab; these include: lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia 
(3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 
1 to 588 days) and of neutropenia was 13 days (range, 2 to 116 days).  A single occurrence 
of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia 
following Rituximab therapy were reported.  
In addition, there have been a limited number of post-marketing reports of prolonged 
pancytopenia, marrow hypoplasia, progressive multifocal leucoencephalopathy, and late 
onset neutropenia (defined as occurring 40 days after the last dose of Rituximab) in patients 
with hematologic malignancies. In reported cases of late onset neutropenia (Grade 3 and 4), 
the median duration of neutropenia was 10 days (range 3 to 148 days). Documented 
resolution of the neutropenia was described in approximately one-half of the reported cases; 
of those with documented recovery, approximately half received growth factor support. In 
the remaining cases, information on resolution was not provided. More than half of the 
reported cases of delayed onset neutropenia occurred in patients who had undergone prior 
autologous stem cell transplantation. 
Lenalidomide. Lenalidomide, an oral agent, is a thalidomide derivative that belongs to a class 
of agents known as immunomodulatory drugs (IMiDs). Lenalidomide has clinical activity in 
NHL and has been shown to possess several immunomodulatory properties. It enhances the 
proliferative and functional capacity of T cells, repairs effector T-cell synapses, increases 
NK cell mediated ADCC, upregulates costimulatory molecules on the tumor cell surface, 
and has non-immunomodulatory actions that include inhibition of angiogenesis.[17, 41-44] 
The molecular action of lenalidomide, and the related development of resistance, involve its 
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14 
binding to protein targets cereblon, Ikaros, and Aiolos, and subsequent effects on protein 
ubiquitination and degradation.[45, 46] 
Lenalidomide is available in 2.5mg, 5 mg, 10 mg, 15mg, 20mg, and 25mg capsules for oral 
administration. Each capsule contains lenalidomide as the active ingredient and the following 
inactive ingredients: lactose anhydrous, microcrystalline cellulose, croscarmellose sodium, 
and magnesium stearate. 
4.1.3 Preclinical and Clinical Trial Data with Pembrolizumab 
Therapeutic studies in mouse models have shown that administration of antibodies blocking 
PD-1/PD-L1 interaction enhances infiltration of tumor-specific CD8+ T-cells and leads 
ultimately to tumor rejection, either as a monotherapy or in combination with other treatment 
modalities. Anti-mouse PD-1 or anti-mouse PD-L1 antibodies have demonstrated anti-tumor 
responses as a monotherapy in models of squamous cell carcinoma, pancreatic carcinoma, 
melanoma, and colorectal carcinoma. Blockade of the PD-1 pathway effectively promoted 
CD8+ T-cell infiltration into the tumor and the presence of IFN-γ, granzyme B, and perforin, 
indicating that the mechanism of action involved local infiltration and activation of effector 
T-cell function in vivo.[35-37] Experiments have confirmed the in vivo efficacy of PD-1 
blockade as a monotherapy as well as in combination with chemotherapy in syngeneic mouse 
tumor models (see the Investigator’s Brochure). 
Recent clinical data of nivolumab (MDX-1106, BMS-936558), an IgG4 monoclonal 
antibody against PD-1, have validated PD-1 as an attractive target for clinical therapeutic 
intervention. Nivolumab was tested in multiple solid tumors and promising clinical activity 
was noted in melanoma, renal cell carcinoma (RCC), and non-small cell lung cancer 
(NSCLC) at multiple doses.[47] Similarly, treatment with pembrolizumab resulted in high 
rate of sustained tumor regression in patients with advanced melanoma and NSCLC.[48, 49] 
The most common adverse events (AEs) with pembroliuzmab included fatigue, fever, chills, 
myalgias, and headaches. Observed immune-related AEs (irAEs) included pruritus, skin 
rash, pneumonitis, transaminitis, hypothyroidism, vitiligo, and diarrhea. Please refer to the 
Investigator’s Brochure for complete details on Clinical data. 
4.1.4 Ongoing Pembrolizumab Clinical Trials 
Ongoing clinical trials are being conducted in advanced melanoma, non-small cell lung 
cancer, head and neck cancer, urothelial tract cancer, triple negative breast cancer, gastric 
cancer, and hematological malignancies. For study details please refer to the Investigator’s 
Brochure. 
4.2 Rationale 
4.2.1 Rationale for the Trial and Selected Subject Population 
As described above, we and others have observed that PD-1 is markedly overexpressed on 
intratumoral CD4+ and CD8+ T cells in FL. Its expression is associated with impaired T-cell 
function and blocking PD-1 enhanced the function of intratumoral CD4+ and CD8+ T-cells 
in FL. Therefore, administration of pembrolizumab may augment the naturally induced 
endogenous antitumor immunity in patients with FL. Rituximab targets CD20 on the tumor 
cells and induces apoptosis via antibody-dependent cellular cytotoxicity (ADCC) mediated 
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by NK cells and/or macrophages. By blocking PD-1, pembrolizumab activates antitumor T 
cells and therefore would induce complementary effects to rituximab. Furthermore, the 
apoptosis of tumor cells induced by rituximab might result in release of tumor antigens and 
lead to activation of additional T cells, the function of which might be enhanced by 
pembrolizumab. Therefore, the combination of rituximab and pembrolizumab might even 
have synergistic effects. Furthermore, activating multiple arms of the immune system is 
likely to minimize the emergence of immune escape variants and recurrence of lymphoma 
in these patients. Based on the known mechanisms of action of rituximab and pembrolizumab 
and the established safety profile of the two agents, the combination is not expected to 
increase the toxicity of either agent.   
Indeed, in a recent single arm phase II trial, we showed that the use of rituximab in 
combination with another immune checkpoint inhibitor, pidilizumab was safe and induced 
an ORR of 66%, CRR of 52%), and improved PFS in patients with relapsed FL compared to 
historical controls of rituximab monotherapy (ORR of 40% and CRR of 11%).[50] The 
reported affinity of pembrolizumab to PD-1 is almost 3 logs higher compared to pidilizumab 
and the reported efficacy of pembrolizumab is much higher than pidilizumab in melanoma 
patients.[48, 51] Therefore, the combination of rituximab and pembrolizumab is likely to be 
highly effective and possibly superior to what was observed with rituximab plus pidilizumab. 
Furthermore, based on the known mechanisms of actions of the two agents and based on the 
observation that the combination of rituximab plus pidilizumab was well tolerated, we do 
not expect to see any increased toxicity with the combination of rituximab plus 
pembrolizumab. Given that the median age at diagnosis for FL is 60 years, development of 
such therapeutic strategies that increase efficacy without increasing toxicity is highly 
desirable. 
A recent analysis of the National LymphoCare study revealed a high risk group of patients 
with FL in need of novel therapies as their median survival was approximately five years.[52] 
These high risk patients were characterized as having an early progression event within two 
years of diagnosis. The eligibility criteria in the initial design of this study restricted inclusion 
to patients that were sensitive to rituximab similar to our previous phase II study 
investigating rituximab in combination with pidilizumab. This restricted eligibility to 
patients with longer remission durations following therapy and inadvertently, excluded many 
of these high risk patients in which a non-chemotherapy approach may be appealing. 
Therefore, we are proposing to explore this novel immune therapy combination in patients 
with both rituximab sensitive and refractory disease and we aim to explore whether the 
addition of an additional immune therapy agent, lenalidomide will result in added efficacy 
without additional toxicity in comparison to historical controls.  
We have extensive experience with lenalidomide and rituximab in lymphoma, having 
completed phase I/II investigator initiated studies [19, 20, 53] and several ongoing trials with 
this combination. Pembrolizumab has been combined with lenalidomide and dexamethasone 
in relapsed/refractory multiple myeloma (KEYNOTE-023, NCT02036502) with preliminary 
findings suggesting the combination was tolerable and efficacy was promising with the 
recommended phase II dose of 200mg of pembrolizumab and lenalidomide dose as high as 
25mg.[54] It is important to note, KEYNOTE-185 (NCT02579863) is a randomized study 
examining pembrolizumab (200mg), plus lenalidomide (25mg) and dexamethasone (40mg) 
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versus lenalidomide and dexamethasone in untreated multiple myeloma. The preliminary 
safety data reported at ASCO 2018 was concerning for a death rate of 13% in the 
pembrolizumab containing arm (13 deaths due to AEs) and 6% in the control arm (8 deaths 
due to AEs) suggesting the efficacy-safety profile was unfavorable for pembrolizumab in 
combination with lenalidomide and dexamethasone in untreated multiple myeloma. This 
safety concern was not observed in the relapsed/refractory setting suggesting that treatment 
status may be associated with toxicity with the combination. 
We have experience with lenalidomide and rituximab in a similar patient population 
(relapsed/refractory FL and DLBCL), and understand the safety profile of lenalidomide and 
rituximab. We will perform a dose escalation in cohort 2 to ensure adequate safety of the 
triplet combination starting with lenalidomide at 2.5 mg on days 1-14 of cycles 1-12 and 
escalating to a maximum of 10mg if the maximum tolerated dose (MTD) is not reached. 
Once the recommended phase II dose (R2PD) has been established, we will complete the 
dose expansion at the RP2D of lenalidomide.  
 
Rationale for Dose Selection/Regimen/Modification  
The dose regimen of 200 mg Q3W of pembrolizumab is planned for this study. 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, 1 mg/kg, 3 mg/kg, and 10 mg/kg, administered every 2 
weeks (Q2W) in subjects with advanced solid tumors.  All three dose levels were well 
tolerated and no dose-limiting toxicities were observed.  This first in human study of 
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/kg versus 10 mg/kg Q3W have been completed.  The 
clinical efficacy and safety data demonstrate a lack of clinically important differences in 
efficacy response or safety profile at these doses. For example, in Cohort B2, advanced 
melanoma subjects who had received prior ipilimumab therapy were randomized to receive 
pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W.  The 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.   
Available pharmacokinetic results in subjects with melanoma, NSCLC, and other solid tumor 
types support a lack of meaningful difference in pharmacokinetic exposures obtained at a 
given dose among tumor types. 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 
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(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 10 mg/kg 
to provide similar efficacy and safety.  The population PK evaluation revealed that there was 
no significant impact of tumor burden on exposure. In addition, exposure was similar 
between the NSCLC and melanoma indications. Therefore, there are no anticipated changes 
in exposure between different tumor types and indication settings. 
 
4.2.2 Rationale for Endpoints 
4.2.2.1 Efficacy Endpoints 
The primary efficacy endpoint is to determine the ORR in subjects with relapsed/refractory 
FL or DLBCL. Secondary efficacy endpoints include assessment of safety and toxicity, CRR, 
PFS, compare PFS between patients relapsing ≤ one year vs > one year after last prior 
therapy, and OS. Cheson 2014 Lugano Classification response criteria for malignant 
lymphoma will be used to assess clinical responses.[1] Subjects enrolled on this study are 
expected to have relapsed after responding to prior rituximab-based therapies. Retreatment 
with rituximab in such patients induces an ORR of 40% and CRR of 11%.[15] Since the 
combination of rituximab plus pembrolizumab is likely to be complementary and possibly 
synergistic, we expect to observe an improvement in ORR by at least 20% in cohort 1 of this 
trial. We may also observe an improvement in CRR and PFS as compared with rituximab 
monotherapy. 
Among patients in cohort 2 with relapsed/refractory FL or DLBCL, ORR of approximately 
30% have been observed with lenalidomide and rituximab [19] and PD-1 antibodies [32]. 
Standard of care third-line chemotherapy has been associated with an ORR of 39%, with a 
median duration of response of less than 5 months and an unfavorable toxicity profile.[34] 
With the combination of rituximab, pembrolizumab, and lenalidomide we expect to observe 
an improvement in ORR by at least 10% in cohort 2 which is a higher risk population than 
cohort 1.  
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4.2.2.2 Biomarker Research 
Blood samples and tumor biopsies will be obtained from consenting patients at baseline 
and/or on treatment from subjects enrolled on the study at the indicated time points shown 
in the Trial Flow Chart under Section 6.0. The overall goal of the biomarker studies is to 
identify predictive, surrogate, mechanistic, and pharmacodynamic biomarkers of rituximab 
plus pembrolizumab therapy. Peripheral blood mononuclear cells (PBMC) and serum will 
be isolated from blood samples and cryopreserved for batched analysis.  
PBMC samples will be analyzed by up to 10-color multiparametric flow cytometry to 
determine alteration in effector and regulatory T cell subsets and to determine expression of 
various co-stimulatory and co-inhibitory receptors on T cells. Serum samples will be 
analyzed for alteration in various cytokines and chemokines. Tumor biopsies will be 
analyzed by whole genome gene expression profiling (GEP), immunohistochemistry (IHC), 
and/or flow cytometry. IHC/flow cytometry assessment will include PD-1, PD-L1, and PD-
L2 expression besides evaluation of effector and regulatory T cell subsets. We will also 
assess the predictive significance of the intratumoral effector T cell gene signature that was 
associated with clinical outcome in FL patients treated with rituximab plus pidilizumab 
therapy that was recently described by us.[50] 
5.0 METHODOLOGY 
5.1 Entry Criteria 
5.1.1 Diagnosis/Condition for Entry into the Trial 
5.1.2 In order to be eligible for participation in this trial, the subject must: 
1. For cohort 1: Male or female subjects with histologic proof of follicular lymphoma 
grade 1, 2, or 3a relapsing after at least one prior systemic therapy that included 
rituximab (or other monoclonal CD20 antibody). Patients should have documented 
rituximab-sensitive disease defined as a documented complete or partial response 
lasting at least 6 months after the last rituximab-containing therapy.  
2. For cohort 2: Male or female subjects with histologic proof of follicular lymphoma 
grade 1, 2, or 3a relapsing after at least two prior systemic therapies, which must include 
CAR T cell therapy or histologic proof of DLBCL relapsing after at least two prior 
systemic therapies, which must include CAR T cell therapy.  
3. Either the subject or his/her legally authorized representative be willing and able to 
provide written informed consent for the trial. 
4. Be ≥ 18 years of age on day of signing informed consent. 
5. Have measurable disease (≥ 1.5 cm in the longest diameter for nodal or extranodal 
disease).   
6. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
7. Demonstrate adequate organ function as defined in Table 1, all screening labs should 
be performed within 28 days of treatment initiation.   
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8. Female subject of childbearing potential should have a negative urine or serum 
pregnancy test within 72 hours prior to receiving the first dose of study medication. If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test 
will be required.   
9. Female subjects of childbearing potential should be willing to use 2 methods of birth 
control or be surgically sterile, or abstain from heterosexual activity for the course of 
the study through 120 days after the last dose of study medication (Reference Section 
5.5.1).  Female subjects of childbearing potential are those who have not been 
surgically sterilized or have not been free from menses for > 1 year. 
a.  Females of reproductive potential enrolled in the lenalidomide cohort must 
adhere to the scheduled pregnancy testing as required in the Revlimid REMS® 
program.  
10. Male subjects should agree to use two methods of contraception starting with the first 
dose of study therapy through 120 days after the last dose of study therapy. 
11. All study participants enrolled in the lenalidomide containing cohort (cohort 2) must 
be registered into the mandatory Revlimid REMS® program, and be willing and able 
to comply with the requirements of the REMS® program. 
Table 1. Adequate Organ Function Laboratory Values. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System 
Laboratory Value 
Hematological 
 
Absolute neutrophil count (ANC) 
≥1.0 × 109/L 
Platelets 
≥50 × 109/L 
Hemoglobin 
≥8.0 g/dL 
Renal 
 
Serum creatinine OR 
Measured 
or 
calculateda 
creatinine 
clearance 
(GFR can also be used in place of 
creatinine or CrCl) 
≤1.5 × upper limit of normal (ULN) OR 
 
≥60 mL/min GFR or CrCl for subjects with creatinine levels > 
1.5 × institutional ULN 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 × ULN OR 
 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 
1.5 ULN 
AST (SGOT) and ALT (SGPT) 
≤ 2.5 × ULN  OR 
≤ 5 × ULN for subjects with lymphoma in the liver 
Coagulation 
International Normalized Ratio (INR) or 
Prothrombin Time (PT) 
 
Activated Partial Thromboplastin Time 
(aPTT) 
≤1.5 × ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
≤1.5 × ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
aCreatinine clearance will be calculated per institutional standard. 
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5.1.3 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 had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has 
not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to agents administered more 
than 4 weeks earlier.  
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy 
within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at 
baseline) from AEs due to a previously administered agent. 
- 
Note:  Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study. 
- 
Note:  If subject received major surgery, they must have recovered adequately 
from the toxicity and/or complications from the intervention prior to starting 
therapy.   
5. Has a known additional malignancy that is progressing and 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.   
6. Has known active central nervous system (CNS) lymphoma and/or lymphomatous 
meningitis. Subjects with previously treated CNS lymphoma and/or lymphomatous 
meningitis 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.   
7. 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 (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. Subjects with vitiligo or resolved childhood asthma/atopy would be an 
exception to this rule. Subjects that require intermittent use of bronchodilators, local 
steroid injections or inhaled or topical steroids would not be excluded from the study. 
Subjects with hypothyroidism stable on hormone replacement or Sjorgen’s syndrome 
will not be excluded from the study. 
8. Has evidence of interstitial lung disease or active, non-infectious pneumonitis that 
required steroids or current pneumonitis. 
9. Has an active infection requiring systemic therapy. 
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10. 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.   
11. Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the trial. 
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 
120 days after the last dose of trial treatment. 
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or 
anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including 
ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation 
or checkpoint pathways). 
- 
Note: Subjects that received prior therapy with pidilizumab are an exception 
to this criterion and may qualify for the study. 
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
16. Has received a live vaccine within 30 days prior to the first dose of trial treatment.   
5.2 Trial Treatments 
The treatment to be used in this trial is outlined below in Table 2. There will be 2 cohorts. 
Cohort 1 will include patients with relapsed FL with rituximab-sensitive and rituximab-refractory 
disease. Treatment will consist of rituximab + pembrolizumab. Cohort 2 will include patients with 
relapsed/refractory FL or DLBCL and will consist of rituximab + pembrolizumab + lenalidomide. 
Table 2.  Trial Treatment 
Drug 
Dose/Potenc
y 
Dose 
Frequenc
y 
Route 
of 
Administratio
n 
Regimen/ 
Treatment 
Period 
Use 
Cohort 1: Relapsed FL 
Rituximab 
375 mg/m2 
weekly 
IV infusion 
4 infusions over 
4 weeks 
Standard 
Pembrolizumab 
200 mg 
Q 
3 
weeks 
IV infusion 
16 
infusions 
over 1 year 
Experimental 
Cohort 2: Relapsed/refractory FL or DLBCL 
Rituximab 
375 mg/m2 
weekly 
IV infusion 
4 infusions over 
4 weeks 
Standard 
Pembrolizumab 
200 mg 
Q 
3 
weeks 
IV infusion 
up to 2 years* 
Experimental 
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Drug 
Dose/Potenc
y 
Dose 
Frequenc
y 
Route 
of 
Administratio
n 
Regimen/ 
Treatment 
Period 
Use 
Lenalidomide  
2.5mg± 
Days 
1-
14 
of 
cycles 1-
12 
PO 
Days 1-14 of 
cycles 1-12 
Experimental 
*Pembrolizumab will be administered every 3 weeks starting on day 1  up to 2 years of therapy. 
Per the investigator’s discretion, subjects who attain an investigator-determined CR may consider 
stopping pembrolizumab treatment after receiving at least 24 weeks of pembrolizumab therapy. 
At least two doses must be received after CR is documented. 
± There will be a dose escalation phase of lenalidomide in cohort 2 as outlined in Section 
5.2.1.2.2.1. Dose level 1 will include lenalidomide 2.5mg on days 1-14 of cycles 1-12. Dose level 
2 will include lenalidomide 5mg on days 1-14 of cycles 1-12. Dose level 3 will include 
lenalidomide 10mg on days 1-14 of cycles 1-12. The dosing of pembrolizumab and/or 
lenalidomide may be altered due to toxicity as described in Section 5.2.1.2. 
5.2.1 Dose Selection/Modification 
5.2.1.1 Dose Selection 
The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale.  There is no dose modification for rituximab.  
5.2.1.2 Guidelines for Dose Modification  
5.2.1.2.1 Pembrolizumab 
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Subjects should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless 
otherwise discussed with the PI. The reason for interruption should be documented in the 
patient's study record. Pembrolizumab may be restarted when clinically indicated 
according to any applicable dose modification guidelines and the dosing schedule conforms 
to the schedule of the normal dosing Cycle. Pembrolizumab will be withheld for drug-
related Grade 4 hematologic toxicities, non-hematological toxicity ≥ Grade 3 including 
laboratory abnormalities, and severe or life-threatening AEs as per Table 3 and Table 4 
below. 
Table 3: Dose modification guidelines for Hematological drug-related AEs. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing 
for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject  
Hematological Toxicity 
 
1, 2, 3 
No 
N/A 
N/A 
N/A 
 
4  
Yes 
Toxicity 
resolves 
to 
May 
restart 
pembrolizumab 
Toxicity does 
not 
resolve 
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Grade 0-1 or 
baseline 
at 200 mg Q 3 
weeks 
within 4 weeks 
of last infusion 
Permanent 
discontinuation 
should 
be 
considered for 
any severe or 
life-threatening 
event 
 
Table 4: Dose modification guidelines for Non-Hematological drug-related AEs. 
Toxicity 
Grade 
Hold 
Treatment 
(Y/N) 
Timing for 
restarting 
treatment 
Dose/Schedule 
for restarting 
treatment 
Discontinue 
Subject  
Non-hematological 
toxicity 
 
Note:  Exception to be 
treated similar to Grade 1 
toxicity  
• Grade 2 alopecia 
• Grade 2 fatigue 
 
For additional information 
regarding Adverse Events 
with a potential Immune-
Etiology reference Section 
5.4.1.1 and 5.4.1.2. 
1 
No 
N/A 
N/A 
N/A 
2 
Consider 
withholding 
for 
persistent 
symptoms 
1,2 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
Clinical AE 
resolves within 4 
weeks:  Same 
dose and 
schedule 
(reference 
Section 5.4.1.2 
for 
recommendations 
regarding 
pneumonitis) 
Toxicity does 
not resolve 
within 4 weeks 
of last infusion 
3 
Yes 3 
Toxicity 
resolves to 
Grade 0-1 or 
baseline 
May restart 
pembrolizumab 
at 200 mg Q 3 
weeks 
Toxicity does 
not resolve 
within 4 weeks 
of last infusion 
4 
NA 
NA 
NA 
Pembrolizumab 
will be 
permanently 
discontinued  
1 
During DLT evaluation period, depending on the nature of AE, for subjects who develop Grade 2 non-heme drug-
related AE, MK-3475 will not be held, if symptoms improve with appropriate supportive care and symptomatic 
treatment within 3 days.   
2 
During DLT evaluation period, depending on the nature of AE, for subjects who develop Grade 2 non-heme drug-
related AE, MK-3475 will be held, if symptoms do not improve with appropriate supportive care and symptomatic 
treatment within 3 days and it will be considered DLT. 
3 
During DLT evaluation period, for subjects who develop Grade 3 non-heme drug-related AE, MK-3475 will be 
held (except for inadequately treated nausea, hypersensitivity reactions, or fatigue lasting less than 3 days) and it 
will be considered DLT. 
 
For toxicity related to pembrolizumab that does not resolve to Grade 0-1 within 4 weeks after last 
infusion, trial treatment should be discontinued. For information on the management of AEs, see 
Section 5.4.   
For subjects who experience a recurrence of the same AE(s) at the same grade or greater with 
rechallenge of pembrolizumab, the subject must discontinue trial treatment 
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Subjects who experience a recurrence of the same severe or life-threatening event at the same 
grade or greater with re-challenge of pembrolizumab should be discontinued from trial treatment. 
 
5.2.1.2.2 Lenalidomide 
Patients in cohort 2 with creatinine clearance (CrCl) >60 mL/min as determined by modified 
Crockcroft-Gault (see Appendix ) will receive a total of 12 cycles of lenalidomide as outlined in 
Section 5.2, Table 2. Subjects with renal impairment (CrCl ≤ 60 ml/min) will be dosed based on 
Table 5.  CrCL assessment will occur on: Day 1 of each cycle. However, if a subject has a 
creatinine obtained at any time during the administration of lenalidomide on study because it was 
clinically indicated, a dose reduction based on CrCL and Table 5 should be performed.  
For subjects with renal impairment (CrCl ≤ 60 ml/min) necessitating dose adjustment on Day 1 of 
a cycle according to Table 5, but then stably improves, a dose increase based on CrCL will not 
occur until day 1 of the next cycle. At any point, should a patient require dose reduction due to 
reduced CrCl, and the CrCl then stably improves, dose escalation will not occur until day 1 of the 
next cycle.   
 
Table 5: Lenalidomide Dose Adjustment in Cohort 2. 
Category 
Renal 
Function 
(modified 
Cockcroft-
Gault) 
Dose level 1* 
Dose level 2 
Dose level 3 
Mild or no 
renal 
impairment 
CrCl > 60 
mL/min 
2.5 mg once 
daily 
5mg once daily 
10 mg once 
daily 
Moderate renal 
impairment 
CrCl 30-60 
mL/min 
2.5 mg every 
48 hours 
2.5 mg once 
daily 
5 mg every 24 
hours 
Severe renal 
impairment 
CrCl 
<30mL/min 
(not requiring 
dialysis) 
2.5 mg every 
72 hours 
2.5 mg every 48 
hours 
5 mg every 48 
hours 
5.2.1.2.2.1 Dose Escalation Phase: Cohort 2 
The dose escalation phase of cohort 2 will assess the safety/tolerability of escalating doses of 
lenalidomide combined with rituximab and pembrolizumab as outlined in Table 2.  
All adverse events including dose limiting toxicity (DLT) will be reported according to the 
instructions in Section 7.2 and graded according to NCI CTCAE v. 4.  
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During the dose escalation phase, a DLT will be defined as any of the following adverse events 
which occur from Cycle 1 Day 1 through Cycle 1 Day 28.  
• 
Grade 4 neutropenia lasting > 7 days 
• 
Grade 3 neutropenia associated with fever (single temperature of > 38.3 ºC, or with a 
sustained temperature of ≥ 38 º C lasting > 1 hour) 
• 
Grade 4 thrombocytopenia 
• 
Grade 3 or 4 non-hematologic adverse event not considered by the investigator to be 
attributable to another clearly identifiable cause 
Patients who discontinue from the study prior to completing the DLT assessment window for 
reasons other than a DLT will be considered non-evaluable for dose-escalation decisions and will 
be replaced by an additional patient at that same dose level. Subjects must be monitored for the 
entirety of the DLT window (28 days) before the next dose level cohort can begin. 
Initial dose escalation will utilize single patient cohorts and the dose levels outlined in Table 5 
until one of the following occurs: 
1. A DLT occurs 
2. Escalation reaches a dose of 10mg of lenalidomide (level 3) 
If any one of the above conditions is met, whichever occurs first, the dose escalation will be 
modified to a standard 3+ 3 design (at the same dose level) and conducted in accordance with the 
following rules: 
1. A minimum of 3 patients will initially be enrolled in each cohort unless the first 2 
enrolled patients experience a protocol-defined DLT (see above) in which case 
enrollment into the cohort will be terminated. 
2. If none of the first 3 DLT-evaluable patients experiences a DLT, enrollment of the 
next cohort at the next highest dose level may proceed.  
3. If 1 of the first 3 DLT-evaluable patients experiences a DLT, the cohort will be 
expanded to at least 6 patients. All patients will be evaluated for DLTs before any 
dose-escalation decision. 
a. If DLTs are observed in 1 of 6 DLT-evaluable pateitns, enrollment of the 
next dose-escalation cohort may proceed.  
b. If DLTs are observed in ≥ 2 of 6 subjects, the dose-escalation will be halted 
and that dose declared as exceeding the maximum tolerated dose (MTD). 
4. The MTD will be defined as the highest dose level resulting in DLTs in ≤ 1 of 6 
patients.  
5. If the MTD is not exceeded, the highest dose administered in this study will be 
declared dose level 3.  
Once the MTD has been defined, dose-escalation will stop and enrollment at MTD or 
recommended phase 2 dose (R2PD) will commence for the dose expansion phase.  
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5.2.1.2.2.2 Dose Expansion Phase: Cohort 2 
Toxicities necessitating dose modification of lenalidomide or delay during the dose expansion 
phase will be defined as any non-hematologic or hematologic toxicity listed below. Treatment with 
rituximab, pembrolizumab, and/or lenalidomide should be discontinued in the event of a toxicity 
lasting more than 4 weeks despite appropriate medical management, unless reviewed and approved 
by the Principal Investigator. The action in Table 6 should be taken for the following lenalidomide 
toxicities: 
Non-hematologic toxicity will be defined as any of the following: 
• 
Any unmanageable Grade 3 or 4 non-hematologic toxicity with failure to improve 
(< Grade 2) or recover to baseline within 14 days of withholding drug  
• 
Grade 3 non-blistering rash that does not resolve to < Grade 2 within 14 days 
• 
Any desquamating (blistering) or grade 4 rash 
• 
Any grade Stevens-Johnson syndrome or toxic epidermal necrolysis 
• 
Grade 3 or 4 thrombosis/embolism 
• 
Grade 3 or 4 peripheral neuropathy which began or worsened while on study 
 
Hematologic toxicity will be defined as any of the following: 
• 
Grade 3 neutropenia with infection or fever (single temperature of > 38.3 ºC, or 
with a sustained temperature of ≥ 38 º C lasting > 1 hour). 
• 
Grade 4 neutropenia (ANC<500/µL) lasting > 7 days.  
• 
Grade 4 thrombocytopenia (<25,000/µL) 
 
The following action in Table 6 should be taken for any unmanageable toxicity that is consistent 
with the rules outlined above: 
 
Table 6. Dose Modification for Lenalidomide Toxicity. 
Toxicity Grade 
Action to be Taken 
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Grade 
3 
neutropenia 
associated 
with 
fever 
(single temperature of > 
38.3 ºC, or with a 
sustained temperature of 
≥ 38 º C lasting > 1 hour) 
OR 
Grade 
4 
neutropenia 
lasting > 7 days. 
• Hold lenalidomide. 
• Follow CBC weekly. 
• If neutropenia has resolved to < Grade 2 prior to Day 21 of 
the current cycle, restart lenalidomide at next lower dose 
level, (see Table 5) and continue through the scheduled 
Day 21 of the current cycle.  Otherwise, omit for 
remainder of cycle and reduce the dose of lenalidomide by 
1 dose level at the start of the next cycle.   
• Omitted doses are not made up.   
• G-CSF may be used. 
• Hold pembrolizumab and rituximab for grade 4 neutropenia 
until resolved to ≤ Grade 1. 
Grade 
3 
thrombocytopenia 
• 
Follow CBC weekly. 
• 
Hold prophylactic anti-coagulation including aspirin, if 
applicable. 
• 
Restart prophylactic anti-coagulation and/or aspirin when 
platelet count is ≥ 50,000/mm³. 
≥ 
Grade 
4 
thrombocytopenia 
• 
Hold lenalidomide. 
• 
Follow CBC weekly. 
• 
If thrombocytopenia resolves to < Grade 2 prior to Day 21 of 
the current cycle, restart lenalidomide at next lower dose 
level and continue through the scheduled Day 21 of the 
current cycle.  Otherwise, omit for remainder of cycle and 
reduce the dose of lenalidomide by 1 dose level at the start of 
the next cycle.   
• 
Omitted doses are not made up. 
• 
Hold prophylactic anti-coagulation including aspirin, if 
applicable. 
• 
Restart prophylactic anti-coagulation and/or aspirin when 
platelet count is ≥ 50,000/mm³. 
• 
Hold pembrolizumab and rituximab until resolved to ≤ Grade 
1. 
Non-blistering rash 
≥  Grade 3 
 
 
 
• 
If Grade 3, hold lenalidomide.   
• 
Follow weekly.  
• 
If the toxicity resolves to < Grade 2 prior to Day 21 of the 
current cycle, restart lenalidomide at original dose level (for 
first occurrence) and continue through the scheduled Day 21 
of the current cycle.  Otherwise, omit for remainder of cycle.   
• 
Omitted doses are not made up. 
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• 
For the second occurrence of Grade 3, hold lenalidomide, and 
follow weekly. If the toxicity resolves to ≤ Grade 2 prior to 
Day 21 of the current cycle, restart lenalidomide at next lower 
dose level and continue through the scheduled Day 21 of the 
current cycle.  Otherwise, omit for remainder of cycle and 
reduce the dose of lenalidomide by 1 dose level at the start of 
the next cycle.  Omitted doses are not made up. 
• 
Treatment with 10mg of prednisone or equivalent for 10 days 
(with or without taper) and/or antihistamines PO daily is 
recommended.  
• If Grade 3 rash has not improved to at least Grade 2 within 14 
days of drug being withheld and administration of 10mg 
of steroids and/or antihistamines daily, the subject will 
discontinue study treatment.  
• Hold pembrolizumab for grade 3 rash until resolved to ≤ 
Grade 1. 
• Permanently discontinue pembrolizumab for grade 4 rash. 
Desquamating 
(blistering) rash 
Any grade 
• 
Discontinue rituximab, pembrolizumab and lenalidomide. 
Remove patient from study. 
• 
Start supportive care: daily antihistamine, 10mg or higher of 
prednisone or corticosteroid equivalent as clinically indicated 
≥ 
Grade 
3 
thrombosis/embolism 
• Hold lenalidomide and start therapeutic anticoagulation.   
• Restart lenalidomide at investigator’s discretion (maintain 
dose level) after anticoagulation is initiated. 
Peripheral neuropathy 
Grade 3 
 
 
Grade 4 
• If Grade 3, hold lenalidomide dose.  Follow at least weekly. 
• If the toxicity resolves to ≤ grade 1 prior to Day 21 of the 
current cycle, restart lenalidomide at next lower dose level 
and continue through the scheduled Day 21 of the current 
cycle.  Otherwise, omit for remainder of cycle and reduce 
the dose of lenalidomide by 1 dose level at the start of the 
next cycle.  Omitted doses are not made up. 
• If Grade 4, discontinue lenalidomide.  Remove patient from 
study. 
Other 
non-hematologic 
toxicity ≥ Grade 3  
• 
Hold lenalidomide.  Follow at least weekly. 
• 
If the toxicity resolves to < Grade 2 prior to Day 21 of the 
current cycle, restart lenalidomide and continue through the 
scheduled Day 21 of the current cycle.  Otherwise, omit for 
remainder of cycle.  Omitted doses are not made up.  For 
toxicity attributed to lenalidomide, reduce the lenalidomide 
dose by 1 dose level when restarting lenalidomide. 
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• 
Hold pembrolizumab Grade 3 non-hematologic toxicity until 
resolved to ≤ Grade 1. 
• 
Permanently discontinue pembrolizumab for Grade 4 toxicity. 
 
The dose of lenalidomide may be reduced successively by one level from starting dose, 
Table 5. Once a patient’s dose has been reduced, no dose re-escalation is permitted. 
Patients who cannot tolerate the lowest applicable dose level are to be discontinued from 
study. Dose modification should also meet the specifications outlined for those subjects 
with renal insufficiency as outlined in Table 5.  
 
5.2.2 Timing of Dose Administration 
Trial treatment should be administered after all procedures/assessments have been 
completed as detailed on the Trial Flow Chart (Section 6.0).  A time window of +/- 1 day 
for rituximab infusions on days 8, 15, and 22, +/- 3 days for 2nd through final infusion of 
pembrolizumab and +/- 3 days for initiation of lenalidomide for cycles 1-12 is allowed.  
All trial treatments will be administered on an outpatient basis. 
Rituximab will be administered as per standard protocol. 
Pembrolizuamb will be administered as a 30 minute IV infusion. Nurses should make every 
effort to target infusion timing to be as close to 30 minutes as possible.  However, given 
the variability of infusion pumps, a window of -5 minutes and +10 minutes is permitted 
(i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Procedures Manual contains specific instructions for pembrolizumab dose calculation, 
reconstitution, preparation of the infusion fluid, and administration. 
Lenalidomide (Revlimid®) will be provided in accordance with the Celgene Corporation’s 
Revlimid REMS® program.  Per standard Revlimid REMS® program requirements,  all 
physicians who prescribe lenalidomide for research subjects enrolled into this trial, and all 
research subjects enrolled into this trial, must be registered in, and must comply with, all 
requirements of the Revlimid REMS® program. 
Further information about the Revlimid REMS® program is available at 
www.celgeneriskmanagement.com. 
Drug will be shipped on a per patient basis by the contract pharmacy to the clinic site for 
IND studies. Only enough lenalidomide for one cycle of therapy will be supplied to the 
patient each cycle. 
Lenalidomide should be taken orally at about the same time each day, either with or without 
food. Lenalidomide capsules should be swallowed whole with water, and should not be 
opened, broken, or chewed. If a dose is missed, it can be taken as soon as possible on the 
same day with a return to the normal schedule the following day. No extra capsules to make 
up the missed dose should be taken. Females of childbearing potential should not handle 
or administer lenalidomide unless they are wearing gloves. 
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Additional 
prescribing 
information 
can 
be 
found 
at 
www.revlimid.com/wp-
content/uploads/2013/11/PI.pdf 
A subject with unconfirmed PD may continue trial treatment until PD is confirmed at the 
next scheduled assessment (refer to Section 7.1.2.6.3 for details). Subjects may only 
receive study treatment while waiting for confirmation of PD if the following criteria are 
met: 
• Absence of signs and symptoms (including worsening of laboratory values) 
indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid PD 
• Absence of progressive tumor at critical anatomical sites (e.g. cord compression) 
requiring urgent alternative medical intervention 
If a subject is noted to have confirmed PD by the respective response criteria, the subject 
should not receive further treatment with study medication except if PD was at week 12 
assessment (see Section 7.1.2.6.4 for details). 
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 in the medical record 
including all prescription, over-the-counter (OTC), herbal supplements, and IV 
medications and fluids.  If changes occur during the trial period, documentation of drug 
dosage, frequency, route, and date may also be included on the CRF. Subjects may remain 
on anti-coagulation therapy as long as the PT or PTT is within therapeutic range of the 
intended use of anticoagulants. 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant 
medications administered after 30 days after the last dose of trial treatment should be 
recorded for SAEs and events of clinical interests (ECIs) as defined in Section 7.2. 
5.3.2 Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Treatment Phase 
of this trial: 
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• Antineoplastic systemic chemotherapy or biological therapy  
• Immunotherapy not specified in this protocol 
• Chemotherapy not specified in this protocol 
• Investigational agents other than pembrolizumab 
• Radiation therapy  
• 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.  
• Systemic use of glucocorticoids for any purpose other than to modulate symptoms 
from an ECI of suspected immunologic etiology or for patients undergoing CT scan 
with a contrast allergy. The use of physiologic doses of corticosteroids may be 
allowed.  
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically 
necessary. 
The Exclusion Criteria describes other medications, which are prohibited in this trial. 
There are no prohibited therapies during the Post-Treatment Follow-up Phase. 
5.4 Rescue Medications & Supportive Care 
5.4.1 Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator including but not limited to the items outlined below: 
• Diarrhea: Subjects should be carefully monitored for signs and symptoms of enterocolitis 
(such as diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of 
bowel perforation (such as peritoneal signs and ileus). In symptomatic subjects, infectious 
etiologies should be ruled out, and if symptoms are persistent and/or severe, endoscopic 
evaluation should be considered. Please refer to Table 8 for toxicity management 
guidelines for immune-related AEs. 
o In subjects with severe enterocolitis (Grade 4), pembrolizumab will be permanently 
discontinued and treatment with systemic corticosteroids should be initiated at a 
dose of 1 to 2 mg/kg/day of prednisone or equivalent. When symptoms improve to 
Grade 1 or less, corticosteroid taper should be started and continued over at least 1 
month. 
o In subjects with moderate enterocolitis (Grade 2 or 3), pembrolizumab should be 
withheld and anti-diarrheal treatment should be started. Systemic corticosteroids 
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should be initiated (e.g., 1-2 mg/kg/day of prednisone or equivalent). Consider GI 
consultation for endoscopy to rule out colitis. When symptoms improve to Grade 1 
or less, corticosteroid taper should be started and continued over at least 1 month.  
Regarding guidelines for continuing treatment with pembrolizumab, see Section 
5.2. 
o All subjects who experience diarrhea should be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes 
should be substituted via IV infusion. 
• Nausea/vomiting: Nausea and vomiting should be treated aggressively, and consideration 
should be given in subsequent cycles to the administration of prophylactic antiemetic 
therapy according to standard institutional practice. Subjects should be strongly 
encouraged to maintain liberal oral fluid intake. 
• Anti-infectives: Subjects with a documented infectious complication should receive oral or 
IV antibiotics or other anti-infective agents as considered appropriate by the treating 
investigator for a given infectious condition, according to standard institutional practice. 
• Thrombosis Prophylaxis: It is recommended that patients in cohort 2 assigned to the 
lenalidomide cohort receive prophylactic aspirin (81mg) daily unless contraindicated. If 
aspirin is contraindicated, use of low molecular weight heparin or warfarin (or equivalent 
Vitamin K antagonist) to keep the international normalized ratio (INR) in the range of 2-3, 
or use of other anti-thrombotic therapy according to hospital guidelines, or physician 
preference, is acceptable. However, the choice of anticoagulant for prophylaxis for VTE 
relies upon the investigator’s discretion and should be tailored to the patient’s individual 
risk/benefit profile by taking into account the individual thrombotic risk (e.g., history of 
venous thrombosis), bleeding risk, and the quality of compliance with antithrombotic 
treatment. In the setting of thrombocytopenia, thromboembolism prophylaxis should be 
held in accordance with the guidelines established in Table 6. All patients who develop a 
deep venous thromboembolism in any location must be treated appropriately with low 
molecular weight heparin. Heparin should continue for at least 3 months, however treating 
physician discretion is allowed. Study treatment is to continue during heparin use. For 
subjects in whom low molecular weight heparin is contraindicated (i.e., renal impairment), 
a vitamin K antagonist anti-coagulant can be used instead where medically appropriate. 
• Immune-related AEs: Please see Section 5.4.1.1 below and the separate guidance document 
regarding diagnosis and management of adverse experiences of a potential immunologic 
etiology.   
• Management of Infusion Reactions: Pembrolizumab may cause severe or life threatening 
infusion-reactions including severe hypersensitivity or anaphylaxis. Signs and symptoms 
usually develop during or shortly after drug infusion and generally resolve completely within 
24 hours of completion of infusion. Dose modification and toxicity management guidelines on 
pembrolizumab associated infusion reaction are provided below in in Table 7.  
Table 7.  Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines  
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NCI CTCAE Grade 
Treatment 
Premedication at Subsequent 
Dosing 
Grade 1 
Mild reaction; infusion 
interruption not 
indicated; intervention 
not indicated 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or 
infusion interruption but 
responds promptly to 
symptomatic treatment 
(e.g., antihistamines, 
NSAIDs, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug 
infusion, the infusion may be restarted at 50% of 
the original infusion rate (e.g. from 100 mL/hr to 50 
mL/hr).  Otherwise dosing will be held until 
symptoms resolve and the subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite 
adequate premedication should be permanently 
discontinued from further study drug treatment 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab 
with: 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
Acetaminophen 500-1000 mg 
po (or equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not 
rapidly responsive to 
symptomatic medication 
and/or brief interruption 
of infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization indicated 
for other clinical 
sequelae (e.g., renal 
impairment, pulmonary 
infiltrates) 
Grade 4: 
Life-threatening; pressor 
or ventilatory support 
indicated 
Stop Infusion. 
Additional appropriate medical therapy may 
include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically 
indicated until the subject is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be 
used immediately. 
Subject is permanently discontinued from 
further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of 
drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v4.0 (CTCAE) at 
http://ctep.cancer.gov 
 
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5.4.1.1 Dose modification and toxicity management for immune-related AEs associated 
with pembrolizumab 
AEs associated with pembrolizumab exposure may represent an immunologic etiology. 
These immune-related AEs (irAEs) may occur shortly after the first dose or several months 
after the last dose of pembrolizumab treatment and may affect more than on body system 
simultaneously. Therefore, early recognition and initiation of treatment is critical to reduce 
complications.  Based on existing clinical trial data, most irAEs were reversible and could 
be managed with interruptions of pembrolizumab, administration of corticosteroids and/or 
other supportive care. For suspected irAEs, ensure adequate evaluation to confirm etiology 
or exclude other causes. Additional procedures or tests such as bronchoscopy, endoscopy, 
skin biopsy may be included as part of the evaluation. Based on the severity of irAEs, 
withhold or permanently discontinue pembrolizumab and administer corticosteroids. Dose 
modification and toxicity management guidelines for irAEs associated with 
pembrolizumab are provided in Table 8. 
In addition, a Guidance Document for management of Events of Clinical Interest and irAEs 
is attached as an Appendix. 
Table 8.  Dose modification and toxicity management guidelines for immune-related AEs 
associated with pembrolizumab  
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over 
at least 4 weeks. 
2. For situations where pembrolizumab has been withheld, pembrolizumab can be resumed after AE has 
been reduced to Grade 1 or 0 and corticosteroid has been tapered. Pembrolizumab should be permanently 
discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be reduced to ≤ 
10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. 
Other immunosuppressive treatment should be initiated if irAEs cannot be controlled by corticosteroids. 
 
Immune-related 
AEs 
Toxicity grade 
or conditions 
(CTCAEv4.0) 
Action taken to 
pembrolizumab 
irAE management 
with corticosteroid 
and/or other 
therapies  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer 
corticosteroids 
(initial dose of 1-
2mg/kg 
prednisone or 
equivalent) 
followed by taper 
 
• 
Monitor subjects for 
signs and symptoms of 
pneumonitis 
• 
Evaluate subjects with 
suspected pneumonitis 
with radiographic 
imaging and initiate 
corticosteroid treatment 
• 
Add prophylactic 
antibiotics for 
opportunistic infections 
Grade 3 or 4, or 
recurrent grade 2 
Permanently 
discontinue 
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Diarrhea / colitis  
Grade 2 or 3 
Withhold 
• Administer 
corticosteroids 
(initial dose of 1-
2mg/kg 
prednisone or 
equivalent) 
followed by taper 
 
• 
Monitor subjects for 
signs and symptoms of 
enterocolitis (i.e. 
diarrhea, abdominal 
pain, blood or mucus in 
stool with or without 
fever) and of bowel 
perforation (i.e. 
peritoneal signs and 
ileus). 
• 
Subjects with ≥ Grade 2 
diarrhea suspecting 
colitis should consider 
GI consultation and 
performing endoscopy 
to rule out colitis.  
• 
Subjects with 
diarrhea/colitis should 
be advised to drink 
liberal quantities of 
clear fluids.  If 
sufficient oral fluid 
intake is not feasible, 
fluid and electrolytes 
should be substituted 
via IV infusion. 
Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Increased 
Bilirubin 
Grade 2 
Withhold 
• Administer 
corticosteroids 
(initial dose of 
0.5- 1mg/kg 
prednisone or 
equivalent) 
followed by taper 
• 
Monitor with liver 
function tests (consider 
weekly or more 
frequently until liver 
enzyme value returned 
to baseline or is stable 
Grade 3 or 4  
Permanently 
discontinue 
• Administer 
corticosteroids 
(initial dose of 1-
2mg/kg 
prednisone or 
equivalent) 
followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of β-
cell failure 
Withhold 
• Initiate insulin 
replacement 
therapy for 
subjects with 
T1DM  
• Administer anti-
hyperglycemic in 
subjects with 
hyperglycemia  
 
• 
Monitor subjects for 
hyperglycemia or other 
signs and symptoms of 
diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer 
corticosteroids 
• 
Monitor for signs and 
symptoms of 
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Grade 3 or 4  
Withhold or 
permanently 
discontinue1  
and initiate 
hormonal 
replacements as 
clinically 
indicated.   
 
hypophysitis (including 
hypopituitarism and 
adrenal insufficiency)  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-
selective beta-
blockers (e.g. 
propranolol) or 
thionamides as 
appropriate  
• 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Grade 3 or 4  
Withhold or  
Permanently 
discontinue1 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid 
replacement 
hormones (e.g. 
levothyroxine or 
liothyroinine) per 
standard of care 
• 
Monitor for signs and 
symptoms of thyroid 
disorders.  
 
Nephritis and 
renal dysfunction 
Grade 2 
Withhold  
• Administer 
corticosteroids 
(prednisone 1-
2mg/kg or 
equivalent) 
followed by taper. 
• 
Monitor changes of 
renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
All Other 
immune-related 
AEs 
Grade 3, or 
intolerable/ 
persistent Grade 
2 
Withhold 
• Based on severity 
of AE administer 
corticosteroids  
• 
Ensure adequate 
evaluation to confirm 
etiology or exclude 
other causes 
 
Grade 4 or 
recurrent Grade 
3  
Permanently 
discontinue 
NOTES:  
1. Withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating 
physician.   
2. For subjects with Grade 3 or 4 immune-related endocrinopathy where withhold of pembrolizumab is required, 
pembrolizumab may be resumed when AE resolves to ≤ Grade 2 and is controlled with hormonal replacement 
therapy or achieved metabolic control (in case of T1DM) 
5.5 Other Considerations 
5.5.1 Contraception 
Pembrolizumab may have adverse effects on a fetus in utero. Furthermore, it is not known 
if pembrolizumab has transient adverse effects on the composition of sperm. 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.  
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37 
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 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. 
5.5.2 Use in Pregnancy 
If a subject inadvertently becomes pregnant while on treatment with pembrolizumab, the 
subject will immediately be removed from the study. The site will contact the subject at 
least monthly and document the subject’s status until the pregnancy has been completed or 
terminated. The outcome of the pregnancy will be reported to Merck without delay and 
within 24 hours if the outcome is a serious adverse experience (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn). The study investigator will make every effort to obtain permission to follow the 
outcome of the pregnancy and report the condition of the fetus or newborn to 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. 
The pregnancy, suspected pregnancy, or positive pregnancy test must also be reported to 
Celgene Drug Safety immediately by facsimile, or other appropriate method, using the 
Pregnancy Initial Report Form, or approved equivalent form. The female subject may be 
referred to an obstetrician-gynecologist (not necessarily one with reproductive toxicity 
experience) or another appropriate healthcare professional for further evaluation. 
The Investigator will follow the female subject until completion of the pregnancy, and must 
notify Celgene Drug Safety immediately about the outcome of the pregnancy (either 
normal or abnormal outcome) using the Pregnancy Follow-up Report Form, or approved 
equivalent form.  
 
IF 
THE 
OUTCOME 
OF 
THE 
PREGNANCY 
WAS 
ABNORMAL 
(E.G., 
SPONTANEOUS OR THERAPEUTIC ABORTION), THE INVESTIGATOR SHOULD 
REPORT THE ABNORMAL OUTCOME AS AN AE.  IF THE ABNORMAL 
OUTCOME MEETS ANY OF THE SERIOUS CRITERIA, IT MUST BE REPORTED 
AS AN SAE TO CELGENE DRUG SAFETY IMMEDIATELY BY FACSIMILE, OR 
OTHERAPPROPRIATE METHOD, WITHIN 24 HOURS OF THE INVESTIGATOR’S 
KNOWLEDGE OF THE EVENT USING THE SAE REPORT FORM, OR APPROVED 
EQUIVALENT FORM. 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
 
 
 
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All neonatal deaths that occur within 28 days of birth should be reported, without regard 
to causality, as SAEs. In addition, any infant death after 28 days that the Investigator 
suspects is related to the in utero exposure to the IP should also be reported to Celgene 
Drug Safety immediately by facsimile, or other appropriate method, within 24 hours of the 
Investigator’s knowledge of the event using the SAE Report Form, or approved equivalent 
form. 
 
Male Subjects 
If a female partner of a male subject taking investigational product becomes pregnant, the 
male subject taking lenalidomide should notify the Investigator, and the pregnant female 
partner should be advised to call their healthcare provider immediately. 
 
5.5.3 Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are 
excreted in human milk, and because of the potential for serious adverse reactions in the 
nursing infant, subjects who are breast-feeding are not eligible for enrollment. 
5.6 Subject Withdrawal/Discontinuation Criteria 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the 
discretion of the investigator should any untoward effect occur. In addition, a subject may be 
withdrawn by the investigator if enrollment into the trial is inappropriate, the trial plan is 
violated, or for administrative and/or other safety reasons. Specific details regarding 
discontinuation or withdrawal are provided in Section 7.1.4. 
A subject must be discontinued from the trial for any of the following reasons: 
• The subject or legal representative (such as a parent or legal guardian) withdraws 
consent. 
• Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression, please see Section 
5.2.2 
Note: A subject may be granted an exception to continue on treatment with 
confirmed radiographic progression if clinically stable or clinically improved, 
please see Section 7.1.2.6.4 
• Unacceptable adverse experiences as described in Section 5.2.1.2 
• Intercurrent illness that prevents further administration of treatment 
• Investigator’s decision to withdraw the subject 
• The subject has a confirmed positive serum pregnancy test 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
 
 
 
39 
• Noncompliance with trial treatment or procedure requirements 
• The subject is lost to follow-up 
• Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6 (Protocol Flow 
Chart) and Section 7.1.5 (Visit Requirements). After the end of treatment, each subject will 
be followed for 30 days for AE monitoring (serious AEs will be collected for 90 days after 
the end of treatment as described in Section 7.2.3.1). Subjects who discontinue treatment for 
reasons other than progressive disease will have post-treatment follow-up for disease status 
until disease progression, initiating a non-study cancer treatment, withdrawing consent or 
becoming lost to follow-up.  
5.7 Subject Replacement Strategy 
Additional subjects may be enrolled to ensure that the required number of evaluable subjects 
is achieved in the applicable analysis population. 
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 with pembrolizumab 
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. 
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Protocol: 2014-0539                                                                                                         Phase II study of rituximab and pembrolizumab 
 
 
40 
6.0 TRIAL FLOW CHART 
6.1 
Study Flow Chart – Table 9. 
Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening 
(Visit 1) 
 
1 
2 
3 
4 
To be repeated up to 2 
years 
Discontinuation 
Safety 
Follow-up 
Follow-up 
Visitsb 
5 
6 
7 
8 
Scheduling Window (Days)c: 
-28 to -1 
 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discontinuation 
30 
days 
+/- 7 days 
Q 3 mo x 1 yr 
and then Q 6 mo 
(+/- 14 days) 
Administrative Procedures 
Informed Consentd 
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior and Concomitant Medication Reviewe 
X 
Day 1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Rituximab Administrations 
 
Days 1, 8, 15 
X 
 
 
 
 
 
 
 
 
 
Pembrolizumab Administrationt 
 
Day 1 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Lenalidomide Administrationw 
 
Days 1-14 
Days1-
14 
Days
1-14 
Days
1-14 
Days
1-14 
Days
1-14 
Days
1-14 
Days
1-14  
 
 
Clinical Assessments 
Review Adverse Eventsf 
X 
Day 1 
X 
X 
X 
X 
X 
X 
X 
X 
Xg 
X 
Full Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
Directed Physical Examination 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs and Weighth 
X 
Day 1 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ECOG Performance Status 
X 
Day 1 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Laboratory Assessments 
Pregnancy Test – Urine or Serum β-HCGl 
X 
 
 
 
 
 
 
 
 
 
 
 
PT/INR and aPTTm 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV 1 and 2 antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
HBsAg, Hep C Abu 
X 
 
 
 
 
 
 
 
 
 
 
 
CBC with Differentialo 
Xn 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xp 
X 
Comprehensive Serum Chemistry Panelo 
Xn 
 
X 
X 
X 
X 
X 
X 
X 
X 
Xp 
X 

Protocol: 2014-0539                                                                                                         Phase II study of rituximab and pembrolizumab 
 
 
41 
Trial Period: 
Screening 
Phase 
Treatment Cyclesa 
End of 
Treatment 
Post-Treatment 
Treatment Cycle/Title: 
Screening 
(Visit 1) 
 
1 
2 
3 
4 
To be repeated up to 2 
years 
Discontinuation 
Safety 
Follow-up 
Follow-up 
Visitsb 
5 
6 
7 
8 
Scheduling Window (Days)c: 
-28 to -1 
 
 
± 3 
± 3 
± 3 
± 3 
± 3 
± 3 
At time of 
Discontinuation 
30 
days 
+/- 7 days 
Q 3 mo x 1 yr 
and then Q 6 mo 
(+/- 14 days) 
Urinalysis 
X 
 
 
 
 
Xq 
 
 
 
 
Xp 
 
Free T4 and TSH 
X 
 
 
X 
 
X 
 
Xv 
 
 
Xp 
X 
β2 microglobulin 
X 
 
 
 
 
 
 
 
 
 
 
 
Quantitative immunoglobulins – IgG, IgA, 
and IgM 
X 
 
 
 
 
Xq 
 
 
 
 
X 
X 
Bone marrow biopsy and aspirater 
 
 
 
 
 
Xr 
 
 
 
 
 
 
Imaging Studies 
 
 
 
 
 
 
 
 
 
 
 
 
 
CT Neck, Chest, Abdomen, and Pelvisi 
 
 
 
 
 
Xj 
 
 
 
 
 
X 
PET-CTi 
X 
 
 
 
 
 
 
 
X 
Xk 
 
 
Biomarker Studies 
Archival 
or 
Newly 
Obtained 
Tissue 
Collection (Optional) 
X 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers Blood Collection (Optional) 
X 
Day 8 
Day 22 
 
 
X 
 
 
 
X 
 
 
 
a. 
In general, assessments/procedures are to be performed on Day 1 and prior to the first dose of treatment for each cycle unless otherwise specified.  Treatment 
cycles are 3 weeks; however the treatment cycle interval may be increased due to toxicity according to the dose modification guidelines provided in Section 
5.2.1.2. If the interval is increased, all procedures except for response assessment should be performed based on the new dosing schedule. 
b. 
In subjects who discontinue study therapy without documented disease progression, every effort should be made to continue monitoring their disease 
status as per the follow-up schedule until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or (4) the end of the 
study, whichever occurs first. 
c. 
In general, the window for each visit is ± 3 days unless otherwise noted. 
d. 
Written consent must be obtained prior to performing any protocol specific procedure. Results of a test performed prior to the subject signing consent 
as part of routine clinical management are acceptable in lieu of a screening test if performed within the specified time frame (e.g., within 28 days prior 
to the first dose of trial treatment). Screening number will be assigned when the study informed consent is signed. 
e. 
Prior medications – Record all medications taken within 28 days of screening visit. Concomitant medications – Enter new medications started during the 

Protocol: 2014-0539                                                                                                         Phase II study of rituximab and pembrolizumab 
 
 
42 
trial through the Safety Follow-up visit. Record all medications taken for SAEs as defined in Section 7.2. 
f. 
AEs and laboratory safety measurements will be graded per NCI CTCAE version 4.0. All AEs, will also be evaluated for seriousness. 
g. 
Record all AEs occurring within 30 days after the last dose of trial treatment. Report all SAEs (related and unrelated to trial treatment) and ECIs occurring 
up until 90 days after the last dose of trial treatment or the start of new anti-cancer treatment, whichever comes first. Afterwards, report only SAEs 
and ECIs that are related to trial treatment. 
h. 
Vital signs to include temperature, pulse, respiratory rate, weight and blood pressure. Height will be measured at visit 1 only. 
i. 
Disease response assessment is based upon Cheson 2014 lymphoma response criteria. “Diagnostic quality” PET-CT with oral contrast/water and IV 
contrast should be performed at Screening unless there is a contraindication. In general, follow-up assessments during therapy will be done by CT scans. 
PET-CT scan will be repeated to confirm complete remission and/or at treatment discontinuation. For lymphomas that are not FDG-avid at screening, PET 
does not need to be repeated in subsequent assessments. Response assessments should occur at Screening (within 42 days prior to first dose of trial 
treatment), after Wk 12, and every 3 months (+/- 14 days) during therapy and for one year after treatment discontinuation and then every 6 
months (+/- 14 days) until (1) the start of new anti-cancer treatment, (2) documented disease progression, (3) death, or (4) the end of the study, 
whichever occurs first. Imaging timing should follow calendar days and should not be adjusted for delays in cycle starts or extension of pembrolizumab 
cycle frequencies. For subjects who discontinue for reasons other than PD, assessments should continue until the subject has documented PD.  The first 
assessment may be performed earlier than 12 weeks if in the opinion of the investigator the patient is clinically progressing. 
j. 
Subjects who have progressive disease at the Wk 12 assessment should have a confirmation assessment performed at least 28 days later (after Wk 16) (+7 
days). If subjects have stable disease, partial response, or complete response a confirmation assessment is not required, they should continue on the 
assessment schedule. 
k. 
In subjects who discontinue study therapy without confirmed disease progression, a radiological assessment should be performed at the time of treatment 
discontinuation (i.e. date of discontinuation ± 4 week window). If previous scan was obtained within 4 weeks prior to the date of discontinuation, 
then a repeat scan at treatment discontinuation isn’t mandatory. 
l. 
For women of reproductive potential in cohort 1, a urine pregnancy test should be performed within 72 hours prior to first dose of trial treatment. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be required. For cohort 2, for females of child bearing potential, pregnancy 
tests must be done in accordance with REMS. 
m. Coagulation factors (PT/INR and aPTT) should be tested as part of the screening procedures for all subjects. Any subject receiving anticoagulant 
therapy should have coagulation factors monitored closely throughout the trial. 
n. 
These screening tests need to be repeated if performed more than 7 days prior to the first dose of rituximab. See Section 7.1.3 for details regarding laboratory 
tests. 
o. 
After Cycle 1, lab samples can be collected up to 72 hours prior to the scheduled time point. See Section 7.1.3 for details regarding laboratory tests. 
p. 
Unresolved abnormal labs that are drug related AEs should be followed until resolution. Labs do not need to be repeated after the end of treatment if labs 
are within normal range. 
q. 
To be repeated every 4 cycles after Cycle 5. 
r. 
Bone marrow assessments will only be performed in subjects who achieved a CR by imaging criteria and had known bone marrow involvement at baseline. 
Repeat marrow assessment is not required in subjects who do not achieve a CR by imaging criteria. 
s. 
Rituximab 375 mg/m2 on day 1 and +/- 1 day on days 8, 15, and 22 (for cohort 2, day 22 will be considered cycle 2, day 1).  
t. 
Pembrolizumab will be administered on day 2, day 23 and day 1 +/- 3 days for cycle 2 through16 in cohort 1. For cohort 2, pembrolizumab will be 
administered every 3 weeks starting on day 1 of cycle 1 for up to 2 years. Per the investigator’s discretion, subjects who attain an investigator-determined 
CR may consider stopping pembrolizumab treatment after receiving at least 24 weeks of pembrolizumab therapy. At least two doses must be received after 
CR is documented. A minimum of 18 hours interval is required between the end of rituximab infusion and beginning of pembrolizumab infusion on days 
2 and 23. 

Protocol: 2014-0539                                                                                                         Phase II study of rituximab and pembrolizumab 
 
 
43 
u. 
HCV RNA will be performed if Hep C Ab is positive. 
v. 
To be repeated every 2 cycles after cycle 7. 
w. Lenalidomide will be administered in cohort 2 only in combination with rituximab and pembrolizumab on days 1-14 (± 3 days) of cycles 1-12.  

Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
  
 
 
 
44 
7.0 TRIAL PROCEDURES 
7.1 Trial Procedures 
The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each 
visit. Individual trial procedures are described in detail below. It may be necessary to 
perform these procedures at unscheduled time points if deemed clinically necessary by the 
investigator. 
7.1.1 Administrative Procedures 
7.1.1.1 Informed Consent 
The informed consent will adhere to IRB requirements, applicable laws and regulations 
and Sponsor requirements. 
7.1.1.2 Inclusion/Exclusion Criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified 
designee to ensure that the subject qualifies for the trial.  
7.1.1.3 Medical History 
A medical history will be obtained by the investigator or qualified designee. Medical 
history will include all active conditions, and any condition diagnosed within the prior 10 
years that are considered to be clinically significant by the Investigator. Details regarding 
the disease for which the subject has enrolled in this study will be recorded separately and 
not listed as medical history.   
7.1.1.4 Prior and Concomitant Medications Review 
7.1.1.4.1 Prior Medications 
The investigator or qualified designee will review prior medication use, including any 
protocol-specified washout requirement, and record prior medication taken by the subject 
within 28 days before starting the trial. Treatment for the disease for which the subject has 
enrolled in this study will be recorded separately and not listed as a prior medication.  
7.1.1.4.2 Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject 
during the trial. All medications related to reportable SAEs and ECIs should be recorded 
as defined in Section 7.2. 
7.1.1.5 Disease Details and Treatments 
7.1.1.5.1 Disease Details 
The investigator or qualified designee will obtain prior and current details regarding 
disease status.  
7.1.1.5.2 Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including 
systemic treatments, radiation and surgeries. 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
  
 
 
 
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7.1.1.5.3 Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated 
after the last dose of trial treatment. If possible, the 30 day Safety Follow-up visit must 
occur before the first dose of the new therapy. Once new anti-cancer therapy has been 
initiated the subject will move into survival follow-up.  
7.1.2 Clinical Procedures/Assessments 
7.1.2.1 Adverse Event Monitoring 
The investigator or a physician 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. 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 pembrolizumab exposure should be 
evaluated to determine if it is possibly an ECI of a potentially immunologic etiology (irAE). 
See Section 5.4.1.1 and the separate guidance document regarding the identification, 
evaluation and management of AEs of a potential immunological etiology.   
Please refer to section 7.2 for detailed information regarding the assessment and recording 
of AEs. 
7.1.2.2 Full Physical Exam 
The investigator or qualified designee will perform a full physical exam during the 
screening period. After the first dose of trial treatment new clinically significant abnormal 
findings should be recorded as AEs. 
7.1.2.3 Directed Physical Exam 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator 
or qualified designee will perform a directed physical exam as clinically indicated prior to 
trial treatment administration.   
7.1.2.4 Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified 
in the Trial Flow Chart (Section 6.0). Vital signs should include temperature, pulse, 
respiratory rate, weight and blood pressure. Height will be measured at screening only. 
7.1.2.5 Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status (see Section 12.1) at 
screening, prior to the administration of each dose of trial treatment and discontinuation of 
trial treatment as specified in the Trial Flow Chart. 
7.1.2.6 Tumor Imaging and Assessment of Disease 
7.1.2.6.1 Criteria for Assessment of Disease 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
  
 
 
 
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The Recommendations for Initial Evaluation, Staging, and Response Assessment of 
Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification [1] criteria will be 
applied as the primary measure for assessment of disease response and as a basis for all 
protocol guidelines related to disease status (e.g. discontinuation of study therapy). 
7.1.2.6.2 Initial Disease Assessment 
Initial disease assessment or tumor imaging must be performed within 42 days prior to the 
first dose of trial treatment. PET-CT fusion imaging scans with oral contrast/water and IV 
contrast will be used for initial disease assessment unless there is a contraindication. 
Disease assessments or scans performed as part of routine clinical management are 
acceptable for use as the screening scan if they are of diagnostic quality and performed 
within 42 days prior to the first dose of trial treatment.  
7.1.2.6.3 Disease Assessment During Trial 
Disease response assessments will occur every 12 weeks during therapy and for the first 
year after discontinuation of therapy, and then every 6 months thereafter. There is a ±14-
day window for all imaging assessments. Disease response assessments will be performed 
by CT scans or PET-CT scan at the indicated time points (see Trial Flow Chart - Section 
6.0).  
In subjects achieving a complete remission by CT scan criteria, PET-CT scan will be 
repeated once to confirm response. In addition, unilateral bone marrow aspiration and 
biopsy will be repeated once in such patients if the bone marrow was involved with 
lymphoma at baseline. 
Disease assessments or scans should not be delayed for delays in cycle starts or extension 
of pembrolizumab cycle intervals. Disease assessments and imaging should continue to be 
performed until documented disease progression, the start of new anti-cancer treatment, 
withdrawal of consent, death, or the end of the study, whichever occurs first. Subjects who 
have unconfirmed disease progression may continue on treatment until progression is 
confirmed by imaging provided they have met the conditions detailed in Section 7.1.2.6.4. 
For lymphomas that are not FDG-avid at screening, PET does not need to be repeated in 
follow-up assessments 
Immunotherapeutic agents such as pembrolizumab may produce antitumor effects by 
potentiating endogenous cancer-specific immune responses, which may be functionally 
anergic. The response patterns seen with such an approach may extend beyond the typical 
time course of responses seen with cytotoxic agents, and can manifest a clinical response 
after an initial increase in tumor burden or even the appearance of new lesions. Standard 
response assessment criteria may not provide a complete response assessment of 
immunotherapeutic agents such as pembrolizumab. Therefore, in the setting where a 
subject’s assessment shows PD at the first disease response assessment at Week 12, a 
subject may be granted an exception to continue on treatment until progression is 
confirmed at least 4 weeks later, provided that the subject’s clinical condition is stable as 
detailed in Section 7.1.2.6.4. 
7.1.2.6.4 Confirmation Assessments 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
  
 
 
 
47 
A subject with progression of disease documented at the Wk 12 assessment may continue 
trial treatment at the discretion of the investigator until confirmation of progression of 
disease is documented per the response evaluation criteria at least 28 days later (after Wk 
16) (+ 7 day window). When feasible, subjects should not be discontinued until repeat 
disease response assessment is performed at least 28 days later. Subjects may only receive 
treatment while waiting for confirmation of PD if the following criteria are met: 
• Absence of signs and symptoms (including worsening of laboratory values) 
indicating disease progression 
• No decline in ECOG performance status 
• Absence of rapid progression of disease (defined as: rapidly growing mass that is 
greater than 5 cm in the long axis, weight loss, drenching night sweats, marked 
fatigue, or fever in the absence of an infection) based on the clinical judgment of 
the investigator. 
• Absence of progressive tumor at critical anatomical sites (e.g. cord compression) 
requiring urgent alternative medical intervention 
Subjects that are deemed clinically unstable after first disease response assessment (Week 
12) are not required to have a repeat assessment 28 days later (after Week 16). 
7.1.2.7 Blood Sampling and Tumor Tissue Collection for Correlative Studies 
Blood and tumor sample collection for biomarker studies is optional. In consenting 
subjects, 5 ml of blood sample [one purple top (5ml, EDTA) one red top tube (10 ml) and 
3 heparin containing green top tubes (30 ml)] will be collected within 28 days prior to the 
first infusion of rituximab, prior to second and fourth infusions of rituximab (days 8 and 
22), and at the time of response assessment, week 12, and at the time of disease progression. 
After collection of blood sample prior to the first infusion of rituximab, pre-dose blood 
samples can be collected up to 72 hours prior to dosing. These samples will be transported 
within 6 hours of collection to Dr. Neelapu’s laboratory for processing at the South Campus 
Research Building I, Room 4.3206, at M. D. Anderson Cancer Center (MDACC). Blood 
from red top and green top tubes will be processed for isolation of serum and PBMC, 
respectively using standard laboratory protocols. The isolation of serum and PBMC may 
also be performed at the Clinical and Translational Research Center (CTRC) Laboratory at 
MDACC using standard laboratory protocols. 
In consenting patients, core needle biopsies and fine needle aspirates (FNA) will be 
obtained by Interventional Radiology from accessible lymph node under ultrasound or CT-
scan guidance within 28 days prior to the first infusion of rituximab. Whenever feasible, 
up to 3 cores will be obtained using 18 or 20 gauge needles as deemed appropriate by an 
Interventional Radiologist. The three cores will be processed as follows: i) the first core 
biopsy specimen will be preserved in RNAlater for microarray studies; ii) second core will 
be formalin-fixed and paraffin-embedded for IHC; and iii) third core will be snap frozen 
for DNA, RNA, or protein isolation. FNA sample will be analyzed by flow cytometry. 
These samples will be transported in RNAlater (core # i)/formalin (core # ii)/normal saline 
(cores # iii and FNA) within 6 hours of collection on ice to Dr. Neelapu’s laboratory for 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
  
 
 
 
48 
processing at the South Campus Research Building I, Room 4.3206, at MDACC. If fresh 
biopsies are not feasible, archival tissue from prior tumor biopsy may be used for biomarker 
studies. 
Samples will be maintained until the study has been terminated.  
7.1.3 Laboratory Procedures/Assessments 
Details regarding specific laboratory procedures/assessments to be performed in this trial 
are provided below. The schedule for laboratory assessments is provided under the Trial 
Flow Chart. 
Laboratory tests for screening or entry into the trial should be performed within 28 days 
prior to the first dose of treatment. CBC with differential and serum chemistry panel will 
need to be repeated if screening tests were performed more than 7 days prior to the first 
dose of rituximab as detailed under Trial Flow Chart. After Cycle 1 of pembrolizumab, 
pre-dose laboratory procedures can be conducted up to 72 hours prior to dosing. Results 
must be reviewed by the investigator or qualified designee and found to be acceptable prior 
to each dose of trial treatment. 
The schedule for laboratory assessments is provided under the Trial Flow Chart. CBC with 
differential should include total white count, absolute neutrophil count, absolute 
lymphocyte count, hemoglobin, and platelet count. Comprehensive serum chemistry panel 
should include sodium (Na), potassium (K), chloride (Cl), glucose, bicarbonate (CO2), 
blood urea nitrogen (BUN), creatinine (Cr), calcium (Ca), magnesium (Mg), phosphorus, 
total protein, albumin, alkaline phosphatase, aspartate transaminase (AST), alanine 
transaminase (ALT), total bilirubin, uric acid, and lactate dehydrogenase (LDH). Direct 
bilirubin should be obtained if total bilirubin is above the upper limit of normal. Urinalysis 
should include blood, glucose, protein, and specific gravity. If blood, glucose, and protein 
are abnormal on urinalysis, a urine microscopic exam should be performed. Total 
triiodothyronine (T3) will be performed if TSH is abnormal. 
7.1.4 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, if the 
patient consents. Any AEs 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 AEs, if the patient consents. After discontinuing treatment 
following assessment of CR, these subjects should return to the site for a Safety Follow-up 
Visit (described in Section 7.1.5.2) and then proceed to the Follow-Up Period of the study 
(described in Section 7.1.5.3). However, the follow-ups do not apply when consent and/ or 
authorization are withdrawn by the subject. 
7.1.5 Visit Requirements 
Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-
related details are provided above in Section 7.1 - Trial Procedures. 
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7.1.5.1 Screening Period 
Approximately 28 days prior to enrollment, potential subjects will be evaluated to 
determine that they fulfill the entry requirements as set forth in Section 5.1. Visit 
requirements are outlined in Section 6.0 – Trial Flow Chart. 
Written consent for the main study must be obtained prior to performing any protocol 
specific procedure. Results of a test performed prior to the subject signing consent as part 
of routine clinical management are acceptable in lieu of a screening test if performed within 
the specified time frame. Screening procedures are to be completed within 28 days prior to 
the first dose of trial treatment except for the following: 
• Laboratory tests are to be performed within 7 days prior to the first dose of trial 
treatment. 
• For women of reproductive potential in cohort 1, a urine pregnancy test will be 
performed within 72 hours prior to the first dose of trial treatment. If urine 
pregnancy results cannot be confirmed as negative, a serum pregnancy test will be 
required (performed by the local study site laboratory). For women of reproductive 
potential in cohort 2, pregnancy tests will be performed in accordance with REMS. 
Subjects may be rescreened after initially failing to meet the inclusion/exclusion criteria. 
Results from assessments performed during the initial screening period are acceptable in 
lieu of a repeat screening test if performed within the specified time frame and the 
inclusion/exclusion criteria is met. 
7.1.5.2 Post-Treatment Safety Follow-Up Visit 
If possible, the Safety Follow-Up Visit should be conducted approximately 30 days after 
the last dose of trial treatment or before the initiation of a new anti-cancer treatment, 
whichever comes first. All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded. SAEs that occur within 90 days of the end of treatment or before initiation of a 
new anti-cancer treatment should be followed and recorded.   
7.1.5.3 Follow-up Visits 
Subjects who discontinue trial treatment for a reason other than disease progression will 
move into the Follow-Up Phase and should be assessed by radiologic imaging to monitor 
disease status. Imaging assessments will be performed every 3 months during therapy and 
for the first year after discontinuation of therapy, and every 6 months thereafter. Every 
effort should be made to collect information regarding disease status until the start of new 
anti-neoplastic therapy, disease progression, death, or end of the study. 
7.2 Assessing and Recording AEs 
Data will be recorded in PDMS/Core or RedCap. 
An AE 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 AE 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 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
  
 
 
 
50 
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 AE. 
Changes resulting from normal growth and development that do not vary significantly in 
frequency or severity from expected levels are not to be considered AEs. Examples of this 
may include, but are not limited to, teething, typical crying in infants and children and onset 
of menses or menopause occurring at a physiologically appropriate time. 
Merck product includes any pharmaceutical product, biological product, device, diagnostic 
agent or protocol-specified procedure, whether investigational (including placebo or active 
comparator medication) or marketed, manufactured by, licensed by, provided by or 
distributed by Merck for human use. 
Adverse events may occur during the course of the use of Merck product in clinical trials 
or 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. 
All AEs will be recorded from the time the consent form is signed through 30 days 
following cessation of treatment and at each examination on the AE CRFs/worksheets. The 
reporting timeframe for AEs meeting any serious criteria is described in Section 7.2.3.1.  
Adverse events will not be collected for subjects during the pre-screening period (for 
determination of archival tissue status) as long as that subject has not undergone any 
protocol-specified procedure or intervention.  If the subject requires a blood draw, fresh 
tumor biopsy etc., the subject is first required to provide consent to the main study and AEs 
will be captured according to guidelines for standard AE reporting. The AE reporting 
guidelines are detailed in the Table 10 below: 
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7.2.1 Definition of an Overdose for This Protocol and Reporting of Overdose  
For purposes of this trial, an overdose will be defined as any dose exceeding the prescribed 
dose for pembrolizumab by 20% over the prescribed dose. No specific information is 
available on the treatment of overdose of pembrolizumab. In the event of overdose, 
pembrolizumab should be discontinued and the subject should be observed closely for 
signs of toxicity. Appropriate supportive treatment should be provided if clinically 
indicated. 
If an AE(s) is associated with (“results from”) the overdose of a Merck product, the AE(s) 
is reported as a serious AE, 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 ECI, using the terminology “accidental or intentional overdose without 
adverse effect.” 
On a per dose basis, an overdose of lenalidomide is defined as any amount over the 
protocol-specified dose. 
Overdoses must be reported within 2 working days to MD Anderson Cancer Center IND 
Office (IND Sponsor) and Merck Global Safety (Attn: Worldwide Product Safety; FAX 
215 993-1220), unless they are life threatening or result in an SAE in which case they will 
be reported within 24 hours to MD Anderson Cancer Center IND Office (IND Sponsor). 
7.2.2 Reporting of Pregnancy and Lactation to the Sponsor and to Merck 
Although pregnancy and lactation are not considered AEs, 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 of completing the trial completing 
the trial, or 30 days following cessation of treatment if the subject initiates new anticancer 
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Definitive Phase I          
Phase II
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I          
Phase II
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Phase I         
Phase II  
Phase III
Unlikely
Possible
Phase I          
Phase II
Probable
Grade 4
Phase I
Phase I
Phase I
Phase I
Phase I         
Phase II  
Grade 5
Recommended Adverse Event Recording Guidelines 
Unrelated
Phase I         
Phase II  
Phase III
Attribution
Grade 1
Grade 2
Grade 3
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52 
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 working days to MD Anderson Cancer Center IND 
Office (IND Sponsor) and Merck Global Safety (Attn: Worldwide Product Safety; FAX 
215 993-1220), unless they are life threatening or result in an SAE in which case they will 
be reported within 24 hours to MD Anderson Cancer Center IND Office (IND Sponsor).  
7.2.3 Immediate Reporting of AEs to the Sponsor and to Merck 
7.2.3.1 Serious Adverse Events (SAEs) 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of 
either the investigator or the sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the 
patient, in the view of the initial reporter, at immediate risk of death from the 
adverse experience as it occurred. It does not include an adverse experience that 
had it occurred in a more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may 
require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in inpatient hospitalization, or the development of drug dependency 
or drug abuse (21 CFR 312.32). 
• Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as 
an SAE if deemed appropriate by the Principal Investigator or the IND 
Sponsor, IND Office. 
 
• All events occurring during the conduct of a protocol and meeting the definition of 
a SAE must be reported to the IRB in accordance with the timeframes and 
procedures outlined in “The University of Texas M. D. Anderson Cancer Center 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
  
 
 
 
53 
Institutional Review Board Policy for Investigators on Reporting Unanticipated 
Adverse Events for Drugs and Devices”.  Unless stated otherwise in the protocol, 
all SAEs, expected or unexpected, must be reported to the IND Office, regardless 
of attribution (within 5 working days of knowledge of the event). 
 
• All life-threatening or fatal events, that are unexpected, and related to the study 
drug, must have a written report submitted within 24 hours (next working day) of 
knowledge of the event to the Safety Project Manager in the IND Office and within 
2 working days to Merck Global Safety.   
 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized 
for safety reporting to the IND Office and MDACC IRB.  
 
• Serious adverse events will be captured from the time of the first protocol-
specific intervention, until 90 days after the last dose of drug, or the initiation 
of new anti-cancer therapy, whichever is earlier, whether or not related to 
Merck product, unless the participant withdraws consent. Serious adverse 
events must be followed until clinical recovery is complete and laboratory tests 
have returned to baseline, progression of the event has stabilized, or there has 
been acceptable resolution of the event. 
 
• Additionally, any serious adverse events that occur after the 30 day time 
period that are related to the study treatment must be reported to the IND 
Office. This may include the development of a secondary malignancy. 
 
 
Reporting to FDA: 
• Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety 
Project Manager IND Office) according to 21 CFR 312.32. 
 
It is the responsibility of the PI and the research team to ensure serious adverse events 
are reported according to the Code of Federal Regulations, Good Clinical Practices, 
the protocol guidelines, the sponsor’s guidelines, and Institutional Review Board 
policy. 
Investigator Communication with Supporting Companies: 
All SAEs will be reported within 2 working days to Merck Global Safety (Attn: Worldwide 
Product Safety; FAX 215 993-1220). Non-serious Events of Clinical Interest (see section 
7.2.3.2) will be forwarded to Merck Global Safety and will be handled in the same manner as 
SAEs.  
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A copy of all 15-Day Reports and Annual Progress Reports is submitted as required by 
FDA. 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. 
7.2.3.2 Events of Clinical Interest 
Selected non-serious Events of Clinical Interest (ECI) must be recorded as such on the AE 
CRFs/worksheets and reported within 2 working days to MD Anderson Cancer Center IND 
Office (IND Sponsor) and Merck Global Safety. (Attn: Worldwide Product Safety; FAX 
215 993-1220), unless they are life threatening or result in an SAE in which case they will 
be reported within 24 hours to MD Anderson Cancer Center IND Office (IND Sponsor). 
Events of clinical interest for this trial include: 
1.  an overdose of Merck product, as defined in Section 7.2.1 - Definition of an Overdose 
for This Protocol and Reporting of Overdose to the IND Sponsor, that is not associated 
with clinical symptoms or abnormal laboratory results.  
2.  an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 
2X the upper limit of normal, as determined by way of protocol-specified laboratory testing 
or unscheduled laboratory testing.* 
*Note:  These criteria are based upon available regulatory guidance documents. The 
purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology. 
A separate guidance document has been provided entitled “Event of Clinical Interest and 
Immune-Related Adverse Event Guidance Document.” This document provides guidance 
regarding identification, evaluation and management of ECIs and irAEs. Additional ECIs 
are identified in this guidance document and also need to be reported to MD Anderson 
Cancer Center IND Office (IND Sponsor) and to Merck Global Safety within 2 working 
days of the event.   
Subjects should be assessed for possible ECIs prior to each dose. Lab results should be 
evaluated and subjects should be asked for signs and symptoms suggestive of an immune-
related event.  Subjects who develop an ECI thought to be immune-related should have 
additional testing to rule out other etiologic causes. If lab results or symptoms indicate a 
possible immune-related ECI, then additional testing should be performed to rule out other 
etiologic causes. If no other cause is found, then it is assumed to be immune-related.  
ECIs that occur in any subject from the date of first dose through 90 days following 
cessation of treatment, or the initiation of a new anticancer therapy, whichever is earlier, 
whether or not related to the Merck’s product, must be reported to MD Anderson Cancer 
Center IND Office (IND Sponsor) and to Merck Global Safety within 2 working days. 
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7.2.4 Evaluating AEs 
AEs will be evaluated according to the NCI Common Terminology for Adverse Events 
(CTCAE), version 4.0. Any AE which changes CTCAE grade over the course of a given 
episode will have each change of grade recorded on the AE CRFs/worksheets. All AEs 
regardless of CTCAE grade must also be evaluated for seriousness. 
8.0 STATISTICAL ANALYSIS PLAN 
This is an investigator-initiated, open label, Phase II clinical trial to evaluate the efficacy 
and safety of pembrolizumab given in combination with rituximab in patients with 
relapsed/refractory FL (cohort 1, maximum of 32 subjects) and in combination with 
lenalidomide in relapsed/refractory FL and DLBCL who have failed CAR T cell therapy 
(cohort 2, maximum of 40).  The maximum number of patients to be recruited for the study 
is 72.  
8.1 Power and Sample Size 
Cohort 1: Rituximab plus pembrolizumab in rituximab-sensitive  and rituximab-
refractory FL 
The primary objective of Cohort 1 is to determine the overall response (OR) rate (complete 
+ partial responses) in patients with relapsed FL with rituximab-sensitive disease who 
receive pembrolizumab in combination with rituximab. The secondary objectives are to 
determine the safety and toxicity, CRR, PFS, compare PFS between patients relapsing ≤ 
one year vs > one year after last prior therapy, and OS.  
 
 
Cohort 1 
It is expected for the cohort 1 that the two-drug combination will achieve an OR rate of 50% 
while the toxicity rate is under 30%. A sample size of 32 ensures that, if the trial is not 
terminated early, a posterior 90% credibility interval for response rate will have width of 0.254 at 
most, under the assumption of a 50% OR. The prior probabilities of OR and toxicity for the 
regimen are modeled by beta distributions (Beta(.5, .5) and Beta(.3, .7), respectively).  Denoting 
the probabilities of OR rate and toxicity rate by {p(OR) , p(TOX)}, the following decision 
criteria will be applied: 
 
1) Stop if Prob{p(OR) < 50% | data} > 0.985, and  
2) Stop if Prob{p(TOX) > 30% | data} > 0.975 
 
Patients will be monitored according to the following stopping boundaries for OR.  If the number 
of responses required for moving the trial to next stage has not been achieved, the patient 
enrollment will be halted until enough responses observed. 
 
Number of patients 
Stop if < OR 
Stop if > study drug-
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56 
evaluated 
observed 
related toxicity observed 
5 
0 
5 
10 
0-1 
7-10 
15 
0-3 
9-15 
20 
0-5 
11-20 
25 
0-7 
13-25 
30 
0-9 
15-30 
35 
0-11 
17-35 
40 
Always stop with this many patients 
 
The operating characteristics are summarized in the following table (based on simulations from 
10,000 trials). 
True Toxicity Rate 
True OR Rate 
Prob(stop the trial 
early) 
Average number of 
patients treated 
0.10 
0.30 
0.7350 
23.74 
 
0.40 
0.3079 
33.34 
 
0.50 
0.0726 
38.15 
 
0.60 
0.0138 
39.56 
 
0.70 
0.0026 
39.91 
0.20 
0.30 
0.7355 
23.72 
 
0.40 
0.3094 
33.30 
 
0.50 
0.0746 
38.09 
 
0.60 
0.0159 
39.51 
 
0.70 
0.0047 
39.85 
0.30 
0.30 
0.7466 
23.35 
 
0.40 
0.3383 
32.64 
 
0.50 
0.1135 
37.28 
 
0.60 
0.0572 
38.65 
 
0.70 
0.0465 
38.99 
0.40 
0.30 
0.8096 
21.50 
 
0.40 
0.5026 
29.23 
 
0.50 
0.3336 
33.08 
 
0.60 
0.2913 
34.23 
 
0.70 
0.2833 
34.52 
0.50 
0.30 
0.9222 
17.58 
 
0.40 
0.7969 
22.22 
 
0.50 
0.7279 
24.50 
 
0.60 
0.7106 
25.22 
 
0.70 
0.7073 
25.41 
 
 
 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
  
 
 
 
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Cohort 2 
 
Promising results have been observed with rituximab plus pembrolizumab for the patients with  
rituximab-sensitive disease in the existing study.  We would like to explore the efficacy with the 
addition of lenalidomide (a triplet combination).  We will add the following cohort to the existing 
study: Pembrolizumab + rituximab + lenalidomide in refractory DLBCL and FL to CAR T cell 
therapy. 
 
The added cohort consists of two parts: Part 1 – dose escalation to determine the MTD of 
lenalidomide when given in combination with pembrolizumab and rituximab, and Part 2 – dose 
expansion to determine the efficacy and safety of the triplet combination.     
 
A maximum of 40 patients that will be recruited for the additional cohort. 
 
Part 1: Dose escalation 
The modified “3+3” design is applied with 3 pre-defined dose levels for lenalidomide while the 
standard dosing for the other two drugs remains.  
 
Dose level 
Lenalidomide (mg) 
1 
2.5 
2 
5 
3 
10 
                  
Dose limiting toxicity (DLT) is defined as the following toxicities observed during cycle 1 of the 
treatment: 
• 
Grade 4 neutropenia lasting > 7 days 
• 
Grade 3 neutropenia associated with fever (single temperature of > 38.3 ºC, or with a 
sustained temperature of ≥ 38 º C lasting > 1 hour) 
• 
Grade 4 thrombocytopenia 
• 
Grade 3 or 4 non-hematologic adverse event not considered by the investigator to be 
attributable to another clearly identifiable cause 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
  
 
 
 
58 
Applying the 3+3 design, the first cohort of 3 patients will be treated at dose level 1 and evaluated 
for DLT at the end of first cycle (28 days).  The algorithm is as follows: (1) If 0 out of 3 patients 
experiences dose-limiting toxicity (DLT), the next cohort of 3 patients will be treated at the next 
higher dose level.  (2) If 1 out of 3 patients develop a DLT, an additional 3 patients will be treated 
at the same dose level.  If no more DLTs develop at this dose, i.e. 1 out of a total of 6 patients 
develops a DLT, the dose escalation continues for the next cohort of 3 patients.  (3) At any given 
dose, if greater than 1 out 3 patients or 1 out of 6 patients experience DLT, the dose level exceeds 
the MTD and 3 more patients will be treated at the next lower dose if there are less than 6 patients 
already treated at that dose. Following the above scheme, MTD is defined as the highest dose level 
in which 6 patients have been treated with less than 2 instances of DLT.  It is anticipated that up 
to 12 eligible patients are required for Part 1.   
 
 
 
Part 2: Dose expansion 
The primary objective for Part 2 is to further evaluate the safety and efficacy of the three–drug 
combination at the MTD determined in Part 1.  The 6 patients treated at the MTD in Part 1 will 
be counted as the first group of patients in Part 2.  Additional 24 patients will be enrolled if the 
trial is not terminated early due to futility or excessive toxicity.    
 
The overall response (OR) and toxicity assessed after completion of 8 treatments with 
pembrolizumab and 4 doses of rituximab will be monitored simultaneously using the Bayesian 
stopping boundaries calculated based on beta-binomial distributions. Toxicity is defined as any 
grade 3 or 4 non-hematologic toxicity that in the opinion of the PI is at least possibly related to 
study treatment. Independence was assumed between OR and toxicity.  
 
It is expected that the three-drug combination will achieve an OR rate of 40% while the toxicity 
rate is under 30% for the patients. A sample size of 40 ensures that, if the trial is not terminated 
early, a posterior 90% credibility interval for response rate will have width of 0.285 at most, 
under the assumption of a 40% OR. The prior probabilities of OR and toxicity for the regimen 
are modeled by beta distributions (Beta(.4, .6) and Beta(.3, .7), respectively).  Denoting the 
probabilities of OR rate and toxicity rate by {p(OR) , p(TOX)}, the following decision criteria 
will be applied: 
 
1) Stop if Prob{p(OR) < 40% | data} > 0.975, and  
2) Stop if Prob{p(TOX) > 30% | data} > 0.975 
 
After the first 10 patients are treated in Part 2 (including the 6 patients treated at the MTD in Part 
1), patients will be monitored in a cohort size of 5 according to the following stopping 
boundaries for OR and toxicity.  If the number of responses required for moving the trial to next 
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Protocol: 2014-0539                                             Phase II study of rituximab and pembrolizumab 
 
  
 
 
 
59 
stage has not been achieved, the patient enrollment will be halted until enough responses 
observed.   
 
Number of patients 
evaluated 
Stop if < OR 
observed 
Stop if > study drug-
related toxicity observed 
10 
0-1 
7-10 
15 
0-2 
9-15 
20 
0-3 
11-20 
25 
0-5 
13-25 
40 
Always stop with this many patients 
 
The operating characteristics are summarized in the following table (based on simulations from 
10,000 trials). 
True Toxicity Rate 
True OR Rate 
Prob(stop the trial 
early) 
Average number of 
patients treated 
0.10 
0.20 
0.6829 
19.65 
 
0.30 
0.2773 
25.87 
 
0.40 
0.0715 
28.83 
 
0.50 
0.0134 
29.76 
 
0.60 
0.0018 
29.96 
0.20 
0.20 
0.6835 
19.64 
 
0.30 
0.2786 
25.85 
 
0.40 
0.0732 
28.81 
 
0.50 
0.0152 
29.73 
 
0.60 
0.0036 
29.94 
0.30 
0.20 
0.6938 
19.44 
 
0.30 
0.3021 
25.51 
 
0.40 
0.1034 
28.40 
 
0.50 
0.0473 
29.30 
 
0.60 
0.0361 
29.50 
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0.40 
0.20 
0.7482 
18.49 
 
0.30 
0.4262 
23.81 
 
0.40 
0.2629 
26.34 
 
0.50 
0.2167 
27.13 
 
0.60 
0.2075 
27.31 
0.50 
0.20 
0.8603 
16.31 
 
0.30 
0.6816 
19.99 
 
0.40 
0.5909 
21.73 
 
0.50 
0.5653 
22.28 
 
0.60 
0.5602 
22.41 
The above stopping boundaries and operating characteristics are calculated using MultcLean 
(v.2.0.0) 
design 
software 
downloaded 
from 
http://biostatistics.mdanderson.org/SoftwareDownload.   
Cohort 2: 
• 
Escalation Phase: 
               A toxicity summary will be submitted after the first evaluable subject completes cycle 
one of study treatment, and every evaluable subject thereafter. IND Office approval must be 
obtained prior to advancing/changing dose levels. If a DLT occurs during the single subject 
escalation portion, or if the dose escalation reaches a dose of 10mg of lenalidomide (level 3), the 
statistical design will switch to a standard 3+3 design and the summaries for the escalation phase 
will be submitted every three evaluable subjects when the third subject completes cycle one, with 
IND Office approval prior to advancing or changing dose levels.  
• 
Expansion Phase: 
After the first five evaluable subjects complete 24 weeks of study treatment, and every five 
evaluable subjects thereafter.  
 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 
8.2 Analysis Plans 
The analysis on each patient cohort will be performed separately.  Summary statistics including 
mean, standard deviation, median, and range for continuous variables, and frequency count and 
percentage for categorical variables will be provided.  Response rate and its 95% confidence 
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interval will be reported.  Logistic regression will be utilized to assess the effect of patient 
prognostic factors on the response rate and the toxicity rate.  The distribution of time-to-event 
endpoints including overall survival and progression free survival will be estimated using the 
method of Kaplan and Meier.  Comparison of time-to-event endpoints by important subgroups will 
be made using the log-rank test.   
 
Toxicity data will be summarized by frequency tables for all patients.  For the efficacy endpoints, 
intend-to-treat analysis will be applied to the eligible patients.  For the toxicity endpoint, per-
treated analysis will be performed to include any patient who received the treatment regardless of 
the eligibility nor the duration or dose of the treatment received. 
 
9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
9.1 Investigational Product  
The investigator shall take responsibility for and shall take all steps to maintain appropriate 
records and ensure appropriate supply, storage, handling, distribution and usage of 
investigational product in accordance with the protocol and any applicable laws and 
regulations. 
Clinical Supplies of pembrolizumab will be provided by Merck as summarized in Table 
17. Rituximab will be obtained through standard commercial sources. 
Table 17.  Investigational Product Descriptions 
Product Name & Potency 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
Solution for Injection 
 
9.2 Packaging and Labeling Information 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements. 
9.3 Clinical Supplies Disclosure 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded to treatment. Drug identity (name, strength) is included in the label 
text; random code/disclosure envelopes or lists are not provided. 
9.4 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label.   
Receipt and dispensing of trial medication will be recorded by an authorized person at the 
trial site. 
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Clinical supplies may not be used for any purpose other than that stated in the protocol. 
9.5 Returns and Reconciliation 
The investigator is responsible for keeping accurate records of the clinical supplies 
received from Merck or designee, the amount dispensed to and returned by the subjects 
and the amount remaining at the conclusion of the trial.  
Upon completion or termination of the study, all unused and/or partially used 
investigational product will be destroyed at the site per institutional policy. It is the 
Investigator’s responsibility to arrange for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable federal, 
state, local and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
10.0 ADMINISTRATIVE AND REGULATORY DETAILS 
10.1 IND Annual Reports 
If the FDA has granted an IND number, it is a requirement of 21 CFR 312.33, that an 
annual report is provided to the FDA within 60-days of the IND anniversary date.  21 CRF 
312.33 provides the data elements that are to be submitted in the report. The Annual Report 
should be filed with MD Anderson Cancer Center IND Office (IND Sponsor), who will 
then forward to FDA. An additional copy should be placed in the study's Regulatory Binder 
and a copy must be sent to Merck as a supporter of this study. 
10.2 IND Safety Reports 
Merck shall notify the Investigator via an IND Safety Report of the following information: 
• 
Any AE associated with the use of study drug in this study or in other studies that is 
both serious and unexpected. 
• 
Any finding from tests in laboratory animals that suggests a significant risk for human 
subjects including reports of mutagenicity, teratogenicity, or carcinogenicity. 
The Investigator shall notify his IRB promptly of these new serious and unexpected AE(s) 
or significant risks to subjects. 
The Investigator must keep copies of all AE information, including correspondence with 
Merck and the IRB on file. 
10.3 Compliance with Trial Registration and Results Posting Requirements 
Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and 
the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is 
solely responsible for determining whether the trial and its results are subject to the 
requirements 
for 
submission 
to 
the 
Clinical 
Trials 
Data 
Bank, 
http://www.clinicaltrials.gov. Information posted will allow subjects to identify potentially 
appropriate trials for their disease conditions and pursue participation by calling a central 
contact number for further information on appropriate trial locations and trial site contact 
information.     
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10.4 Data Confidentiality Plan 
All information, including but not limited to patient data/information, biomarker research 
data, and information related to the conduct of the study will be kept confidential. Blood 
and tissue samples will be identified by coded numbers. Data will be stored in password-
protected databases, protected by an institutional firewall. All data collected for this project, 
including all clinical information, will be kept confidential by limiting access only to the 
investigators involved in the study. In order to maintain confidentiality, the investigator 
will maintain a personal patient identification list (coded numbers for blood and tissue 
samples corresponding with patient identifiers) to enable records to be identified and 
verified as authentic. This list will be maintained at the study site with other study records 
under adequate security and restricted access. 
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11.0 REFERENCES 
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Westin, J.R. and S.S. Neelapu, Therapy of Newly Diagnosed Follicular Lymphoma. 
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Fisher, R.I., et al., New treatment options have changed the survival of patients with 
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Marcus, R., et al., Phase III study of R-CVP compared with cyclophosphamide, vincristine, 
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Hiddemann, W., et al., Frontline therapy with rituximab added to the combination of 
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Davis, T.A., et al., Anti-idiotype antibodies can induce long-term complete remissions in 
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Hainsworth, J.D., et al., Maximizing therapeutic benefit of rituximab: maintenance therapy 
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9. 
Colombat, P., et al., Rituximab (anti-CD20 monoclonal antibody) as single first-line 
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10. 
McLaughlin, P., et al., Rituximab chimeric anti-CD20 monoclonal antibody therapy for 
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Witzig, T.E., et al., Rituximab therapy for patients with newly diagnosed, advanced-stage, 
follicular grade I non-Hodgkin's lymphoma: a phase II trial in the North Central Cancer 
Treatment Group. J Clin Oncol, 2005. 23(6): p. 1103-8. 
12. 
Khouri, I.F., et al., Nonmyeloablative allogeneic transplantation with or without 90yttrium 
ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. 
Blood, 2012. 119(26): p. 6373-8. 
13. 
Khouri, I.F., et al., Eight-year experience with allogeneic stem cell transplantation for 
relapsed follicular lymphoma after nonmyeloablative conditioning with fludarabine, 
cyclophosphamide, and rituximab. Blood, 2008. 111(12): p. 5530-6. 
14. 
Schuster, S.J., et al., Vaccination with patient-specific tumor-derived antigen in first 
remission improves disease-free survival in follicular lymphoma. J Clin Oncol, 2011. 29(20): p. 
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15. 
Davis, T.A., et al., Rituximab anti-CD20 monoclonal antibody therapy in non-Hodgkin's 
lymphoma: safety and efficacy of re-treatment. J Clin Oncol, 2000. 18(17): p. 3135-43. 
16. 
Hainsworth, J.D., et al., Rituximab as first-line and maintenance therapy for patients with 
indolent non-hodgkin's lymphoma. J Clin Oncol, 2002. 20(20): p. 4261-7. 
17. 
Wu, L., et al., lenalidomide enhances natural killer cell and monocyte-mediated antibody-
dependent cellular cytotoxicity of rituximab-treated CD20+ tumor cells. Clin Cancer Res, 2008. 
14(14): p. 4650-7. 
18. 
Witzig, T.E., et al., Lenalidomide oral monotherapy produces durable responses in 
relapsed or refractory indolent non-Hodgkin's Lymphoma. J Clin Oncol, 2009. 27(32): p. 5404-9. 
19. 
Wang, M., et al., Oral lenalidomide with rituximab in relapsed or refractory diffuse large 
cell, follicular and transformed lymphoma: a phase II clinical trial. Leukemia, 2013. 27(9): p. 
1902-9. 
20. 
Fowler, N.H., et al., Safety and activity of lenalidomide and rituximab in untreated indolent 
lymphoma: an open-label, phase 2 trial. Lancet Oncol, 2014. 15(12): p. 1311-8. 
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Schreiber, R.D., L.J. Old, and M.J. Smyth, Cancer immunoediting: integrating immunity's 
roles in cancer suppression and promotion. Science, 2011. 331(6024): p. 1565-70. 
22. 
Dunn, G.P., L.J. Old, and R.D. Schreiber, The three Es of cancer immunoediting. Annu 
Rev Immunol, 2004. 22: p. 329-60. 
23. 
Horning, S.J. and S.A. Rosenberg, The Natural History of Initially Untreated Low-Grade 
Non-Hodgkin's Lymphomas. New England Journal of Medicine, 1984. 311(23): p. 1471-1475. 
24. 
Dave, S.S., et al., Prediction of survival in follicular lymphoma based on molecular 
features of tumor-infiltrating immune cells. N Engl J Med, 2004. 351(21): p. 2159-69. 
25. 
Wahlin, B.E., et al., CD8+ T-cell content in diagnostic lymph nodes measured by flow 
cytometry is a predictor of survival in follicular lymphoma. Clin Cancer Res, 2007. 13(2 Pt 1): p. 
388-97. 
26. 
Alvaro, T., et al., Immunohistochemical patterns of reactive microenvironment are 
associated with clinicobiologic behavior in follicular lymphoma patients. J Clin Oncol, 2006. 
24(34): p. 5350-7. 
27. 
Lee, S.T., et al., A novel strategy for rapid and efficient isolation of human tumor-specific 
CD4(+) and CD8(+) T-cell clones. J Immunol Methods, 2008. 331(1-2): p. 13-26. 
28. 
Schultze, J.L., et al., Autologous tumor infiltrating T cells cytotoxic for follicular lymphoma 
cells can be expanded in vitro. Blood, 1997. 89(10): p. 3806-16. 
29. 
Zou, W., Immunosuppressive networks in the tumour environment and their therapeutic 
relevance. Nat Rev Cancer, 2005. 5(4): p. 263-74. 
30. 
Yang, Z.Z., et al., PD-1 expression defines two distinct T-cell sub-populations in follicular 
lymphoma that differentially impact patient survival. Blood Cancer J, 2015. 5: p. e281. 
31. 
Reiss, K.A., P.M. Forde, and J.R. Brahmer, Harnessing the power of the immune system 
via blockade of PD-1 and PD-L1: a promising new anticancer strategy. Immunotherapy, 2014. 
6(4): p. 459-75. 
32. 
Lesokhin, A.M., et al., Nivolumab in Patients With Relapsed or Refractory Hematologic 
Malignancy: Preliminary Results of a Phase Ib Study. J Clin Oncol, 2016. 34(23): p. 2698-704. 
33. 
Witzig, T.E., et al., An international phase II trial of single-agent lenalidomide for relapsed 
or refractory aggressive B-cell non-Hodgkin's lymphoma. Ann Oncol, 2011. 22(7): p. 1622-7. 
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34. 
Van Den Neste, E., et al., Outcome of patients with relapsed diffuse large B-cell lymphoma 
who fail second-line salvage regimens in the International CORAL study. Bone Marrow 
Transplant, 2016. 51(1): p. 51-7. 
35. 
Keir, M.E., et al., PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol, 
2008. 26: p. 677-704. 
36. 
Okazaki, T., et al., A rheostat for immune responses: the unique properties of PD-1 and 
their advantages for clinical application. Nat Immunol, 2013. 14(12): p. 1212-8. 
37. 
Zou, W. and L. Chen, Inhibitory B7-family molecules in the tumour microenvironment. Nat 
Rev Immunol, 2008. 8(6): p. 467-77. 
38. 
Nattamai D, N.S., PD-1 expression is markedly upregulated on intratumoral CD4+ and CD8+ T cells in 
follicular lymphoma and is associated with T-cell exhaustion. . Blood (ASH Annual Meeting Abstracts), Nov 
2007; 110: 2749. 
39. 
Yang, Z.Z., et al., Intratumoral CD4+CD25+ regulatory T-cell-mediated suppression of 
infiltrating CD4+ T cells in B-cell non-Hodgkin lymphoma. Blood, 2006. 107(9): p. 3639-46. 
40. 
Myklebust, J.H., et al., High PD-1 expression and suppressed cytokine signaling 
distinguish T cells infiltrating follicular lymphoma tumors from peripheral T cells. Blood, 2013. 
121(8): p. 1367-76. 
41. 
Chang, D.H., et al., Enhancement of ligand-dependent activation of human natural killer 
T cells by lenalidomide: therapeutic implications. Blood, 2006. 108(2): p. 618-21. 
42. 
Ramsay, A.G., et al., Follicular lymphoma cells induce T-cell immunologic synapse 
dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment 
and immunotherapy. Blood, 2009. 114(21): p. 4713-20. 
43. 
Chanan-Khan, A.A., et al., Biological effects and clinical significance of lenalidomide-
induced tumour flare reaction in patients with chronic lymphocytic leukaemia: in vivo evidence of 
immune activation and antitumour response. Br J Haematol, 2011. 155(4): p. 457-67. 
44. 
Reddy, N., et al., Immunomodulatory drugs stimulate natural killer-cell function, alter 
cytokine production by dendritic cells, and inhibit angiogenesis enhancing the anti-tumour activity 
of rituximab in vivo. Br J Haematol, 2008. 140(1): p. 36-45. 
45. 
Gandhi, A.K., et al., Immunomodulatory agents lenalidomide and pomalidomide co-
stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of 
the E3 ubiquitin ligase complex CRL4(CRBN.). Br J Haematol, 2014. 164(6): p. 811-21. 
46. 
Lu, G., et al., The myeloma drug lenalidomide promotes the cereblon-dependent 
destruction of Ikaros proteins. Science, 2014. 343(6168): p. 305-9. 
47. 
Topalian, S.L., et al., Safety, activity, and immune correlates of anti-PD-1 antibody in 
cancer. N Engl J Med, 2012. 366(26): p. 2443-54. 
48. 
Hamid, O., et al., Safety and tumor responses with lambrolizumab (anti-PD-1) in 
melanoma. N Engl J Med, 2013. 369(2): p. 134-44. 
49. 
Rizvi NA, G.E., Patnaik A, et al., Safety and clinical activity of MK-3475 as initial therapy 
in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol, 2014. 32:5s, (suppl; 
abstr 8007). 
50. 
Westin, J.R., 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. 15(1): p. 69-77. 
51. 
Atkins MB, K.R., Sznol M, et al., Phase 2, multicenter, safety and efficacy study of 
pidilizumab in patients with metastatic melanoma. J Clin Oncol, 2014. 32:5s, (suppl; abstr 9001). 
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52. 
Casulo, C., et al., Early Relapse of Follicular Lymphoma After Rituximab Plus 
Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for 
Death: An Analysis From the National LymphoCare Study. J Clin Oncol, 2015. 33(23): p. 2516-
22. 
53. 
Wang, M., et al., Lenalidomide in combination with rituximab for patients with relapsed 
or refractory mantle-cell lymphoma: a phase 1/2 clinical trial. Lancet Oncol, 2012. 13(7): p. 716-
23. 
54. 
San Miguel, J., Mateos, M., Shah, J. J., et. al, Pembrolizumab in Combination with 
Lenalidomide and Low-Dose Dexamethasone for Relapsed/Refractory Multiple Myeloma 
(RRMM): Keynote-023. Blood  2015  126:505, 2015. 
55. 
Thall, P.F., R.M. Simon, and E.H. Estey, Bayesian sequential monitoring designs for 
single-arm clinical trials with multiple outcomes. Stat Med, 1995. 14(4): p. 357-79. 
56. 
Thall, P.F., R.M. Simon, and E.H. Estey, New statistical strategy for monitoring safety and 
efficacy in single-arm clinical trials. J Clin Oncol, 1996. 14(1): p. 296-303. 
57. 
Thall, P.F. and H.G. Sung, Some extensions and applications of a Bayesian strategy for 
monitoring multiple outcomes in clinical trials. Stat Med, 1998. 17(14): p. 1563-80. 
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12.0  APPENDICES 
12.1 ECOG Performance Status 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
* As published in Am. J. Clin. Oncol.:  Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative Oncology Group, Robert Comis 
M.D., Group Chair. 
 
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12.2 Response Evaluation Criteria 
Response will be determined by the Principal Investigator according to the 
Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin 
and Non-Hodgkin Lymphoma: The Lugano Classification[1] and documented in the CRFs. 
The response criteria are summarized below: 
   
 
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12.3 Calculation of Creatinine Clearance Using the Cockcroft-Gault Formula 
 
Creatinine Clearance (men) = (140-Age) × Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL) × 72 
 
Creatinine Clearance (women) = 0.85 × (140-Age) × Lean Body Weight [kilograms] 
Serum Creatinine (mg/dL) × 72 
Reference: 
Gault MH, Longerich LL, Harnett JD, et al. Predicting glomerular function from adjusted 
serum creatinine (editorial). Nephron 1992;62:249. 
 
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